TBD Meeting (4154-18)

BERLIN – An investigational oral formulation of the glucagonlike peptide–1 receptor agonist (GLP-1 RA) semaglutide reduced glycated hemoglobin (HbA_1c) to a greater extent than did placebo at all doses tested in patients with type 2 diabetes mellitus (T2DM) in the phase 3a PIONEER 1 trial.

The estimated mean change in HbA_1c from baseline to week 26 – the primary endpoint – using an on-treatment analysis was –0.8% with a once-daily dose of 3 mg, –1.3% with a once-daily dose of 7 mg, and –1.5% with a once-daily dose of 14 mg. The corresponding value for placebo was –0.1%, with all comparisons statistically significant (P less than .001).

The on-treatment analysis evaluated treatment effects for all randomized patients (n = 703) and assumed that all subjects remained on-treatment and excluded the effect of any rescue medication. Results for an intention-to-treat (ITT) analysis provided similar results, however, with estimated mean changes in HbA_1c of –0.9%, –1.2%, and –1.4% for the three respective semaglutide doses and –0.3% for placebo.

“There was a very nice dose-dependent decrease in HbA_1c, which was superior to placebo for all doses of semaglutide” said study investigator Martin Haluzík, MD, at the annual meeting of the European Association for the Study of Diabetes.

“I think it’s quite important to stress the magnitude of the decrease of HbA_1c, because with the highest dose it was –1.5% from a baseline of 8%, which I believe is something that hasn’t ever really been seen with any other oral antidiabetic medication,” added Dr. Haluzík, professor of internal medicine at the 1st Faculty of Medicine at Charles University and deputy head of the Institute for Clinical and Experimental Medicine, both in Prague.

Currently, GLP-1 RAs are available only in a subcutaneous formulation, Dr. Haluzík reminded his audience, adding that oral semaglutide was the first GLP-1 RA to be developed in a tablet formulation and was in the late stages of clinical development.

PIONEER 1 is the first of 10 phase 3a trials with oral semaglutide to be reported. “Additional studies, across the full spectrum of diabetes care, in special populations, comparing it with active comparators with varied trial duration, have been completed or will be completed in 2018,” said coinvestigator for the study Vanita Aroda, MD, during a separate presentation at a dedicated symposium on the PIONEER program.

Dr. Aroda, the director of the diabetes research program at Brigham and Women’s Hospital in Boston, observed that oral semaglutide was being evaluated from early care as monotherapy in the PIONEER 1 study. The other trials, such as PIONEER 2, PIONEER 3, PIONEER 4, and PIONEER 7 were looking at oral semaglutide in combination with oral antidiabetic agents versus various active comparators; PIONEER 5 and PIONEER 6 were in special populations; and PIONEER 8 was looking at its use on top of basal insulin. Two further trials are also part of the study program.

“I think this is the first time that we actually have completed data of an entire program, including cardiovascular data, all within the same year,” Dr. Aroda said. “All of the studies are in the process of data analysis or data reporting.”

PIONEER 1 was a multicenter, randomized, double-blind, placebo-controlled trial examining efficacy and safety of semaglutide versus placebo in 703 adults with drug-naive T2DM who were being treated with diet and exercise only.

Three doses of oral semaglutide – 3 mg, 7 mg, and 14 mg – were assessed and compared with placebo. There was a fixed 4-week dose escalation period, with all patients starting treatment with 3 mg of semaglutide and then increasing to 7 mg by week 4 and 14 mg by week 8. This was to try to reduce the risk of gastrointestinal side effects, which are known to occur with GLP-1 RAs.

Secondary outcome measures were change in body weight, fasting plasma glucose, HbA_1c below a target of 7% (53 mmol/mol), which were all measured from baseline to week 26; adverse events, including severe and blood glucose–confirmed symptomatic hypoglycemic episodes, were assessed out to week 31.

The average age of patients in the trial was around 55 years, around half were female, and the starting HbA_1c was approximately 8%.The mean body weight ranged from 86.9 kg to 89 kg in the different treatment groups, with a similar body mass index of about 32 kg/m².

Clinically meaningful weight loss, compared with placebo, was only achieved with the highest dose of oral semaglutide, with a –4.1 kg reduction versus –1.5 kg for placebo from baseline to week 26 (P less than .001, on-treatment analysis). Reductions in body weight for the 3-mg and 7-mg oral semaglutide doses were a respective –1.7 kg and –2.5 kg. ITT results were again similar, with weight losses of –1.5, –2.3, and –3.7 kg for the 3-, 7-, and 14-mg doses of oral semaglutide, respectively, and –1.4 kg for placebo.

More patients treated with oral semaglutide 3, 7, or 14 mg versus placebo achieved an HbA_1c of below 7% (59.1%, 71.9%, and 80.3%, respectively, vs. 33.8%) or a body weight loss of 5% or more (21.3%, 28.7%, and 44.3% vs. 15.7%).

Furthermore, more patients treated with oral semaglutide achieved an HbA_1c of or below 7% without hypoglycemic episodes or body weight gain than did those given placebo. There were also more patients who achieved an HbA_1c reduction of at least 1% and a weight loss of 3% or higher.

“Oral semaglutide demonstrated a safety and tolerability profile consistent with that of [injectable] GLP-1 RAs,” Dr. Haluzík reported. Adverse events were seen in 57.7%, 53.1%, and 56.6%of patients treated with 3, 7, and 14 mg of oral semaglutide and 55.6% of those treated with placebo.

The most common adverse events seen with oral semaglutide affected the gastrointestinal tract, with nausea affecting 8%, 5.1%, and 16% of 3, 7, and 14 mg–treated patients versus 5.6% of placebo-treated patients. Vomiting affected a respective 2.9%, 4.6%, 6.9%, and 2.1%, and diarrhea a respective 8.6%, 5.1%, 5.1%, and 2.2%.

Severe or blood glucose–confirmed, symptomatic hypoglycemia was reported in 2.9%, 1.1%, and 0.6%of those treated with 3, 7, 14 mg of oral semaglutide and 0.6% of placebo-treated patients.

PIONEER 1 represents a “step change in GLP-1 receptor agonist therapy”, said Cliff Bailey, MD, who discussed the trial aa the EASD’s independent commentator during a symposium on the PIONEER program. These data are “leading to a new delivery route for GLP-1 receptor agonists, from injection to oral,” and “this can be done with good metabolic efficacy, with substantial reductions in A_1c and body weight, and with a safety profile that’s comparable to the subcutaneous injection.”

Dr. Bailey, who is professor of clinical science at Aston University in Birmingham, England, noted, however, the oral dosing of semaglutide “requires patient commitment because it needs to be taken before breakfast time, and it may also, to some extent, affect the timing of some of the other medications.”

The study was sponsored by Novo Nordisk. Dr. Haluzík disclosed acting as a consultant to AstraZeneca, Eli Lilly, Johnson & Johnson, Mundipharma, Novatin, Novo Nordisk, and Sanofi Aventis. Dr. Aroda was an investigator in the PIONEER 1 study and disclosed acting as a consultant to Novo Nordisk; she also disclosed relationships with multiple other pharmaceutical companies, including AstraZeneca, BMS, Calbra, Eisai, Elcelyx Therapeutics, Janssen, and Sanofi Aventis. Dr. Bailey acknowledged attending advisory boards, undertaking ad hoc consultancy work, and receiving research and travel support from several pharmaceutical companies that included Novo Nordisk.

SOURCES: Haluzík M et al. EASD 2018, Abstract 38; Aroda V. EASD 2018, Session S18 - PIONEER Trial; Bailey C. EASD 2018, Session S18 - PIONEER Trial.

BERLIN – An investigational oral formulation of the glucagonlike peptide–1 receptor agonist (GLP-1 RA) semaglutide reduced glycated hemoglobin (HbA_1c) to a greater extent than did placebo at all doses tested in patients with type 2 diabetes mellitus (T2DM) in the phase 3a PIONEER 1 trial.

The estimated mean change in HbA_1c from baseline to week 26 – the primary endpoint – using an on-treatment analysis was –0.8% with a once-daily dose of 3 mg, –1.3% with a once-daily dose of 7 mg, and –1.5% with a once-daily dose of 14 mg. The corresponding value for placebo was –0.1%, with all comparisons statistically significant (P less than .001).

The on-treatment analysis evaluated treatment effects for all randomized patients (n = 703) and assumed that all subjects remained on-treatment and excluded the effect of any rescue medication. Results for an intention-to-treat (ITT) analysis provided similar results, however, with estimated mean changes in HbA_1c of –0.9%, –1.2%, and –1.4% for the three respective semaglutide doses and –0.3% for placebo.

“There was a very nice dose-dependent decrease in HbA_1c, which was superior to placebo for all doses of semaglutide” said study investigator Martin Haluzík, MD, at the annual meeting of the European Association for the Study of Diabetes.

“I think it’s quite important to stress the magnitude of the decrease of HbA_1c, because with the highest dose it was –1.5% from a baseline of 8%, which I believe is something that hasn’t ever really been seen with any other oral antidiabetic medication,” added Dr. Haluzík, professor of internal medicine at the 1st Faculty of Medicine at Charles University and deputy head of the Institute for Clinical and Experimental Medicine, both in Prague.

Currently, GLP-1 RAs are available only in a subcutaneous formulation, Dr. Haluzík reminded his audience, adding that oral semaglutide was the first GLP-1 RA to be developed in a tablet formulation and was in the late stages of clinical development.

PIONEER 1 is the first of 10 phase 3a trials with oral semaglutide to be reported. “Additional studies, across the full spectrum of diabetes care, in special populations, comparing it with active comparators with varied trial duration, have been completed or will be completed in 2018,” said coinvestigator for the study Vanita Aroda, MD, during a separate presentation at a dedicated symposium on the PIONEER program.

Dr. Aroda, the director of the diabetes research program at Brigham and Women’s Hospital in Boston, observed that oral semaglutide was being evaluated from early care as monotherapy in the PIONEER 1 study. The other trials, such as PIONEER 2, PIONEER 3, PIONEER 4, and PIONEER 7 were looking at oral semaglutide in combination with oral antidiabetic agents versus various active comparators; PIONEER 5 and PIONEER 6 were in special populations; and PIONEER 8 was looking at its use on top of basal insulin. Two further trials are also part of the study program.

“I think this is the first time that we actually have completed data of an entire program, including cardiovascular data, all within the same year,” Dr. Aroda said. “All of the studies are in the process of data analysis or data reporting.”

PIONEER 1 was a multicenter, randomized, double-blind, placebo-controlled trial examining efficacy and safety of semaglutide versus placebo in 703 adults with drug-naive T2DM who were being treated with diet and exercise only.

Three doses of oral semaglutide – 3 mg, 7 mg, and 14 mg – were assessed and compared with placebo. There was a fixed 4-week dose escalation period, with all patients starting treatment with 3 mg of semaglutide and then increasing to 7 mg by week 4 and 14 mg by week 8. This was to try to reduce the risk of gastrointestinal side effects, which are known to occur with GLP-1 RAs.

Secondary outcome measures were change in body weight, fasting plasma glucose, HbA_1c below a target of 7% (53 mmol/mol), which were all measured from baseline to week 26; adverse events, including severe and blood glucose–confirmed symptomatic hypoglycemic episodes, were assessed out to week 31.

The average age of patients in the trial was around 55 years, around half were female, and the starting HbA_1c was approximately 8%.The mean body weight ranged from 86.9 kg to 89 kg in the different treatment groups, with a similar body mass index of about 32 kg/m².

Clinically meaningful weight loss, compared with placebo, was only achieved with the highest dose of oral semaglutide, with a –4.1 kg reduction versus –1.5 kg for placebo from baseline to week 26 (P less than .001, on-treatment analysis). Reductions in body weight for the 3-mg and 7-mg oral semaglutide doses were a respective –1.7 kg and –2.5 kg. ITT results were again similar, with weight losses of –1.5, –2.3, and –3.7 kg for the 3-, 7-, and 14-mg doses of oral semaglutide, respectively, and –1.4 kg for placebo.

More patients treated with oral semaglutide 3, 7, or 14 mg versus placebo achieved an HbA_1c of below 7% (59.1%, 71.9%, and 80.3%, respectively, vs. 33.8%) or a body weight loss of 5% or more (21.3%, 28.7%, and 44.3% vs. 15.7%).

Furthermore, more patients treated with oral semaglutide achieved an HbA_1c of or below 7% without hypoglycemic episodes or body weight gain than did those given placebo. There were also more patients who achieved an HbA_1c reduction of at least 1% and a weight loss of 3% or higher.

“Oral semaglutide demonstrated a safety and tolerability profile consistent with that of [injectable] GLP-1 RAs,” Dr. Haluzík reported. Adverse events were seen in 57.7%, 53.1%, and 56.6%of patients treated with 3, 7, and 14 mg of oral semaglutide and 55.6% of those treated with placebo.

The most common adverse events seen with oral semaglutide affected the gastrointestinal tract, with nausea affecting 8%, 5.1%, and 16% of 3, 7, and 14 mg–treated patients versus 5.6% of placebo-treated patients. Vomiting affected a respective 2.9%, 4.6%, 6.9%, and 2.1%, and diarrhea a respective 8.6%, 5.1%, 5.1%, and 2.2%.

Severe or blood glucose–confirmed, symptomatic hypoglycemia was reported in 2.9%, 1.1%, and 0.6%of those treated with 3, 7, 14 mg of oral semaglutide and 0.6% of placebo-treated patients.

PIONEER 1 represents a “step change in GLP-1 receptor agonist therapy”, said Cliff Bailey, MD, who discussed the trial aa the EASD’s independent commentator during a symposium on the PIONEER program. These data are “leading to a new delivery route for GLP-1 receptor agonists, from injection to oral,” and “this can be done with good metabolic efficacy, with substantial reductions in A_1c and body weight, and with a safety profile that’s comparable to the subcutaneous injection.”

Dr. Bailey, who is professor of clinical science at Aston University in Birmingham, England, noted, however, the oral dosing of semaglutide “requires patient commitment because it needs to be taken before breakfast time, and it may also, to some extent, affect the timing of some of the other medications.”

The study was sponsored by Novo Nordisk. Dr. Haluzík disclosed acting as a consultant to AstraZeneca, Eli Lilly, Johnson & Johnson, Mundipharma, Novatin, Novo Nordisk, and Sanofi Aventis. Dr. Aroda was an investigator in the PIONEER 1 study and disclosed acting as a consultant to Novo Nordisk; she also disclosed relationships with multiple other pharmaceutical companies, including AstraZeneca, BMS, Calbra, Eisai, Elcelyx Therapeutics, Janssen, and Sanofi Aventis. Dr. Bailey acknowledged attending advisory boards, undertaking ad hoc consultancy work, and receiving research and travel support from several pharmaceutical companies that included Novo Nordisk.

SOURCES: Haluzík M et al. EASD 2018, Abstract 38; Aroda V. EASD 2018, Session S18 - PIONEER Trial; Bailey C. EASD 2018, Session S18 - PIONEER Trial.

BERLIN – An investigational oral formulation of the glucagonlike peptide–1 receptor agonist (GLP-1 RA) semaglutide reduced glycated hemoglobin (HbA_1c) to a greater extent than did placebo at all doses tested in patients with type 2 diabetes mellitus (T2DM) in the phase 3a PIONEER 1 trial.

The estimated mean change in HbA_1c from baseline to week 26 – the primary endpoint – using an on-treatment analysis was –0.8% with a once-daily dose of 3 mg, –1.3% with a once-daily dose of 7 mg, and –1.5% with a once-daily dose of 14 mg. The corresponding value for placebo was –0.1%, with all comparisons statistically significant (P less than .001).

The on-treatment analysis evaluated treatment effects for all randomized patients (n = 703) and assumed that all subjects remained on-treatment and excluded the effect of any rescue medication. Results for an intention-to-treat (ITT) analysis provided similar results, however, with estimated mean changes in HbA_1c of –0.9%, –1.2%, and –1.4% for the three respective semaglutide doses and –0.3% for placebo.

“There was a very nice dose-dependent decrease in HbA_1c, which was superior to placebo for all doses of semaglutide” said study investigator Martin Haluzík, MD, at the annual meeting of the European Association for the Study of Diabetes.

“I think it’s quite important to stress the magnitude of the decrease of HbA_1c, because with the highest dose it was –1.5% from a baseline of 8%, which I believe is something that hasn’t ever really been seen with any other oral antidiabetic medication,” added Dr. Haluzík, professor of internal medicine at the 1st Faculty of Medicine at Charles University and deputy head of the Institute for Clinical and Experimental Medicine, both in Prague.

Currently, GLP-1 RAs are available only in a subcutaneous formulation, Dr. Haluzík reminded his audience, adding that oral semaglutide was the first GLP-1 RA to be developed in a tablet formulation and was in the late stages of clinical development.

PIONEER 1 is the first of 10 phase 3a trials with oral semaglutide to be reported. “Additional studies, across the full spectrum of diabetes care, in special populations, comparing it with active comparators with varied trial duration, have been completed or will be completed in 2018,” said coinvestigator for the study Vanita Aroda, MD, during a separate presentation at a dedicated symposium on the PIONEER program.

Dr. Aroda, the director of the diabetes research program at Brigham and Women’s Hospital in Boston, observed that oral semaglutide was being evaluated from early care as monotherapy in the PIONEER 1 study. The other trials, such as PIONEER 2, PIONEER 3, PIONEER 4, and PIONEER 7 were looking at oral semaglutide in combination with oral antidiabetic agents versus various active comparators; PIONEER 5 and PIONEER 6 were in special populations; and PIONEER 8 was looking at its use on top of basal insulin. Two further trials are also part of the study program.

“I think this is the first time that we actually have completed data of an entire program, including cardiovascular data, all within the same year,” Dr. Aroda said. “All of the studies are in the process of data analysis or data reporting.”

PIONEER 1 was a multicenter, randomized, double-blind, placebo-controlled trial examining efficacy and safety of semaglutide versus placebo in 703 adults with drug-naive T2DM who were being treated with diet and exercise only.

Three doses of oral semaglutide – 3 mg, 7 mg, and 14 mg – were assessed and compared with placebo. There was a fixed 4-week dose escalation period, with all patients starting treatment with 3 mg of semaglutide and then increasing to 7 mg by week 4 and 14 mg by week 8. This was to try to reduce the risk of gastrointestinal side effects, which are known to occur with GLP-1 RAs.

Secondary outcome measures were change in body weight, fasting plasma glucose, HbA_1c below a target of 7% (53 mmol/mol), which were all measured from baseline to week 26; adverse events, including severe and blood glucose–confirmed symptomatic hypoglycemic episodes, were assessed out to week 31.

The average age of patients in the trial was around 55 years, around half were female, and the starting HbA_1c was approximately 8%.The mean body weight ranged from 86.9 kg to 89 kg in the different treatment groups, with a similar body mass index of about 32 kg/m².

Clinically meaningful weight loss, compared with placebo, was only achieved with the highest dose of oral semaglutide, with a –4.1 kg reduction versus –1.5 kg for placebo from baseline to week 26 (P less than .001, on-treatment analysis). Reductions in body weight for the 3-mg and 7-mg oral semaglutide doses were a respective –1.7 kg and –2.5 kg. ITT results were again similar, with weight losses of –1.5, –2.3, and –3.7 kg for the 3-, 7-, and 14-mg doses of oral semaglutide, respectively, and –1.4 kg for placebo.

More patients treated with oral semaglutide 3, 7, or 14 mg versus placebo achieved an HbA_1c of below 7% (59.1%, 71.9%, and 80.3%, respectively, vs. 33.8%) or a body weight loss of 5% or more (21.3%, 28.7%, and 44.3% vs. 15.7%).

Furthermore, more patients treated with oral semaglutide achieved an HbA_1c of or below 7% without hypoglycemic episodes or body weight gain than did those given placebo. There were also more patients who achieved an HbA_1c reduction of at least 1% and a weight loss of 3% or higher.

“Oral semaglutide demonstrated a safety and tolerability profile consistent with that of [injectable] GLP-1 RAs,” Dr. Haluzík reported. Adverse events were seen in 57.7%, 53.1%, and 56.6%of patients treated with 3, 7, and 14 mg of oral semaglutide and 55.6% of those treated with placebo.

The most common adverse events seen with oral semaglutide affected the gastrointestinal tract, with nausea affecting 8%, 5.1%, and 16% of 3, 7, and 14 mg–treated patients versus 5.6% of placebo-treated patients. Vomiting affected a respective 2.9%, 4.6%, 6.9%, and 2.1%, and diarrhea a respective 8.6%, 5.1%, 5.1%, and 2.2%.

Severe or blood glucose–confirmed, symptomatic hypoglycemia was reported in 2.9%, 1.1%, and 0.6%of those treated with 3, 7, 14 mg of oral semaglutide and 0.6% of placebo-treated patients.

PIONEER 1 represents a “step change in GLP-1 receptor agonist therapy”, said Cliff Bailey, MD, who discussed the trial aa the EASD’s independent commentator during a symposium on the PIONEER program. These data are “leading to a new delivery route for GLP-1 receptor agonists, from injection to oral,” and “this can be done with good metabolic efficacy, with substantial reductions in A_1c and body weight, and with a safety profile that’s comparable to the subcutaneous injection.”

Dr. Bailey, who is professor of clinical science at Aston University in Birmingham, England, noted, however, the oral dosing of semaglutide “requires patient commitment because it needs to be taken before breakfast time, and it may also, to some extent, affect the timing of some of the other medications.”

The study was sponsored by Novo Nordisk. Dr. Haluzík disclosed acting as a consultant to AstraZeneca, Eli Lilly, Johnson & Johnson, Mundipharma, Novatin, Novo Nordisk, and Sanofi Aventis. Dr. Aroda was an investigator in the PIONEER 1 study and disclosed acting as a consultant to Novo Nordisk; she also disclosed relationships with multiple other pharmaceutical companies, including AstraZeneca, BMS, Calbra, Eisai, Elcelyx Therapeutics, Janssen, and Sanofi Aventis. Dr. Bailey acknowledged attending advisory boards, undertaking ad hoc consultancy work, and receiving research and travel support from several pharmaceutical companies that included Novo Nordisk.

SOURCES: Haluzík M et al. EASD 2018, Abstract 38; Aroda V. EASD 2018, Session S18 - PIONEER Trial; Bailey C. EASD 2018, Session S18 - PIONEER Trial.

BERLIN – Diuretics may need to be used cautiously in patients with type 2 diabetes mellitus who are at risk of lower limb amputation, suggest observational study findings presented at the annual meeting of the European Association for the Study of Diabetes.

Sara Freeman/MDedge News

A significant and independent increase in the risk of lower limb events, predominantly lower-extremity amputations was seen among patients with type 2 diabetes mellitus (T2DM) who were treated with diuretics versus those who were not. The adjusted hazard ratios in a propensity-matched cohort was 1.60 (95% confidence interval, 1.06-2.42; P = .027) for lower limb events, 2.13 (95% CI, 1.17-3.87; P = .013) for lower limb amputations, and 1.12 (95% CI, 0.70-1.79; P = .6443) for lower limb revascularizations.

“We know diabetes is a leading cause of nontraumatic lower limb amputations in the world,” and thus a very important public health issue, said study investigator Ronan Roussel, MD, PhD, of Hôpital Bichat, Assistance Publique Hôpitaux de Paris. “Many contributing factors are identified, susceptibility to infection, impaired wound healing, peripheral neuropathy; but the most important is the presence of peripheral arterial disease.”

The risk of diabetic amputations is of specific interest because of the recent findings from CANVAS, where treatment with canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, was linked to an almost doubled rate of amputations versus placebo (HR, 1.97; 95% CI, 1.41-2.75) in patients with T2DM.

Conflicting results have been seen in observational studies with other SGLT2 inhibitors, however, and it’s not clear if the risk of amputations is just seen with canagliflozin or if it may be a class effect. The underlying mechanism is unknown, but one theory is that hypovolemia may be involved. If this is the case, Dr. Roussel explained, then diuretics would have a similar safety profile as SGLT2 inhibitors in terms of increasing the risk of amputations.

The aim of the present study was to look at the association between lower limb events and diuretic usage in patients with T2DM. Data on 1,459 subjects with T2DM treated with diuretics and data on lower limb events and amputations were obtained from the single-center SURDIAGENE study. Of these, 670 were and 789 were not taking diuretics.

Baseline differences between diuretic and nondiuretic users were seen, such as diuretic users being older (67 vs. 63 years), having longer diabetes duration (16 vs. 13 years), and being more likely to have cardiovascular disease (32.5% vs. 23.4%). A propensity-score approach was used to even out these differences, leaving a population of 1,074 subjects in the final matched cohort.

Over a median follow-up of 7.2 years, 12.7% of diuretic and 7.2% of nondiuretic users experienced lower limb events (P = .001). In multivariate and sensitivity analyses, lower limb amputations remained significantly higher in patients who had been treated with a diuretic than in those who had not.

These are “hypothesis-generating” data, Dr. Roussel pointed out and “we don’t want to be overconclusive, of course.” However, they may explain the risk signal seen with SGLT2 inhibitors in the CANVAS study. Further studies are needed to explore the role of drug-induced hypovolemia in the association between the use of diuretics and lower limb events.

Sara Freeman/MDedge News

EASD delegate Prashanth Vas, MBBS, MRCP, PhD, noted during the discussion that the use of diuretics was ubiquitous. “Nearly everyone uses diuretics,” he said. The potential risk of lower limb amputation and treatment with SGLT2 inhibitors had “been vexing us for some time since the data from CANVAS came out.”

Dr. Vas, who is a consultant diabetologist and diabetic foot specialist at King’s College Hospital NHS Foundation in London, went on to ask why only canagliflozin was found to be associated with amputations and not the other SGLT2 drugs.

Dr. Roussel responded that data were still needed on the other drugs in this class and that they needed to be treated with caution. The literature is not so clear, he admitted.

“It’s important that you noted it’s a single-center study,” Dr. Vas countered. “It’s very important to have multicenter data. An amputation is a decision made by someone. An amputation in one center may not be an amputation in another center.”

The SURDIAGENE study was supported by grants from the French Ministry of Health, the Association Française des Diabétiques, and the Groupement pour l’Etude des Maladies Métaboliques et Systémiques. Dr. Roussel reported relationships with Janssen, Merck, Sanofi-Aventis, AstraZeneca, and Boehringer Ingelheim. Dr. Vas was not involved in the study or analysis.

imnews@mdedge.com

SOURCE: Roussel R et al. EASD 2018, Abstract 12.

BERLIN – Diuretics may need to be used cautiously in patients with type 2 diabetes mellitus who are at risk of lower limb amputation, suggest observational study findings presented at the annual meeting of the European Association for the Study of Diabetes.

Sara Freeman/MDedge News

A significant and independent increase in the risk of lower limb events, predominantly lower-extremity amputations was seen among patients with type 2 diabetes mellitus (T2DM) who were treated with diuretics versus those who were not. The adjusted hazard ratios in a propensity-matched cohort was 1.60 (95% confidence interval, 1.06-2.42; P = .027) for lower limb events, 2.13 (95% CI, 1.17-3.87; P = .013) for lower limb amputations, and 1.12 (95% CI, 0.70-1.79; P = .6443) for lower limb revascularizations.

“We know diabetes is a leading cause of nontraumatic lower limb amputations in the world,” and thus a very important public health issue, said study investigator Ronan Roussel, MD, PhD, of Hôpital Bichat, Assistance Publique Hôpitaux de Paris. “Many contributing factors are identified, susceptibility to infection, impaired wound healing, peripheral neuropathy; but the most important is the presence of peripheral arterial disease.”

The risk of diabetic amputations is of specific interest because of the recent findings from CANVAS, where treatment with canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, was linked to an almost doubled rate of amputations versus placebo (HR, 1.97; 95% CI, 1.41-2.75) in patients with T2DM.

Conflicting results have been seen in observational studies with other SGLT2 inhibitors, however, and it’s not clear if the risk of amputations is just seen with canagliflozin or if it may be a class effect. The underlying mechanism is unknown, but one theory is that hypovolemia may be involved. If this is the case, Dr. Roussel explained, then diuretics would have a similar safety profile as SGLT2 inhibitors in terms of increasing the risk of amputations.

The aim of the present study was to look at the association between lower limb events and diuretic usage in patients with T2DM. Data on 1,459 subjects with T2DM treated with diuretics and data on lower limb events and amputations were obtained from the single-center SURDIAGENE study. Of these, 670 were and 789 were not taking diuretics.

Baseline differences between diuretic and nondiuretic users were seen, such as diuretic users being older (67 vs. 63 years), having longer diabetes duration (16 vs. 13 years), and being more likely to have cardiovascular disease (32.5% vs. 23.4%). A propensity-score approach was used to even out these differences, leaving a population of 1,074 subjects in the final matched cohort.

Over a median follow-up of 7.2 years, 12.7% of diuretic and 7.2% of nondiuretic users experienced lower limb events (P = .001). In multivariate and sensitivity analyses, lower limb amputations remained significantly higher in patients who had been treated with a diuretic than in those who had not.

These are “hypothesis-generating” data, Dr. Roussel pointed out and “we don’t want to be overconclusive, of course.” However, they may explain the risk signal seen with SGLT2 inhibitors in the CANVAS study. Further studies are needed to explore the role of drug-induced hypovolemia in the association between the use of diuretics and lower limb events.

Sara Freeman/MDedge News

EASD delegate Prashanth Vas, MBBS, MRCP, PhD, noted during the discussion that the use of diuretics was ubiquitous. “Nearly everyone uses diuretics,” he said. The potential risk of lower limb amputation and treatment with SGLT2 inhibitors had “been vexing us for some time since the data from CANVAS came out.”

Dr. Vas, who is a consultant diabetologist and diabetic foot specialist at King’s College Hospital NHS Foundation in London, went on to ask why only canagliflozin was found to be associated with amputations and not the other SGLT2 drugs.

Dr. Roussel responded that data were still needed on the other drugs in this class and that they needed to be treated with caution. The literature is not so clear, he admitted.

“It’s important that you noted it’s a single-center study,” Dr. Vas countered. “It’s very important to have multicenter data. An amputation is a decision made by someone. An amputation in one center may not be an amputation in another center.”

The SURDIAGENE study was supported by grants from the French Ministry of Health, the Association Française des Diabétiques, and the Groupement pour l’Etude des Maladies Métaboliques et Systémiques. Dr. Roussel reported relationships with Janssen, Merck, Sanofi-Aventis, AstraZeneca, and Boehringer Ingelheim. Dr. Vas was not involved in the study or analysis.

imnews@mdedge.com

SOURCE: Roussel R et al. EASD 2018, Abstract 12.

BERLIN – Diuretics may need to be used cautiously in patients with type 2 diabetes mellitus who are at risk of lower limb amputation, suggest observational study findings presented at the annual meeting of the European Association for the Study of Diabetes.

Sara Freeman/MDedge News

A significant and independent increase in the risk of lower limb events, predominantly lower-extremity amputations was seen among patients with type 2 diabetes mellitus (T2DM) who were treated with diuretics versus those who were not. The adjusted hazard ratios in a propensity-matched cohort was 1.60 (95% confidence interval, 1.06-2.42; P = .027) for lower limb events, 2.13 (95% CI, 1.17-3.87; P = .013) for lower limb amputations, and 1.12 (95% CI, 0.70-1.79; P = .6443) for lower limb revascularizations.

“We know diabetes is a leading cause of nontraumatic lower limb amputations in the world,” and thus a very important public health issue, said study investigator Ronan Roussel, MD, PhD, of Hôpital Bichat, Assistance Publique Hôpitaux de Paris. “Many contributing factors are identified, susceptibility to infection, impaired wound healing, peripheral neuropathy; but the most important is the presence of peripheral arterial disease.”

The risk of diabetic amputations is of specific interest because of the recent findings from CANVAS, where treatment with canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, was linked to an almost doubled rate of amputations versus placebo (HR, 1.97; 95% CI, 1.41-2.75) in patients with T2DM.

Conflicting results have been seen in observational studies with other SGLT2 inhibitors, however, and it’s not clear if the risk of amputations is just seen with canagliflozin or if it may be a class effect. The underlying mechanism is unknown, but one theory is that hypovolemia may be involved. If this is the case, Dr. Roussel explained, then diuretics would have a similar safety profile as SGLT2 inhibitors in terms of increasing the risk of amputations.

The aim of the present study was to look at the association between lower limb events and diuretic usage in patients with T2DM. Data on 1,459 subjects with T2DM treated with diuretics and data on lower limb events and amputations were obtained from the single-center SURDIAGENE study. Of these, 670 were and 789 were not taking diuretics.

Baseline differences between diuretic and nondiuretic users were seen, such as diuretic users being older (67 vs. 63 years), having longer diabetes duration (16 vs. 13 years), and being more likely to have cardiovascular disease (32.5% vs. 23.4%). A propensity-score approach was used to even out these differences, leaving a population of 1,074 subjects in the final matched cohort.

Over a median follow-up of 7.2 years, 12.7% of diuretic and 7.2% of nondiuretic users experienced lower limb events (P = .001). In multivariate and sensitivity analyses, lower limb amputations remained significantly higher in patients who had been treated with a diuretic than in those who had not.

These are “hypothesis-generating” data, Dr. Roussel pointed out and “we don’t want to be overconclusive, of course.” However, they may explain the risk signal seen with SGLT2 inhibitors in the CANVAS study. Further studies are needed to explore the role of drug-induced hypovolemia in the association between the use of diuretics and lower limb events.

Sara Freeman/MDedge News

EASD delegate Prashanth Vas, MBBS, MRCP, PhD, noted during the discussion that the use of diuretics was ubiquitous. “Nearly everyone uses diuretics,” he said. The potential risk of lower limb amputation and treatment with SGLT2 inhibitors had “been vexing us for some time since the data from CANVAS came out.”

Dr. Vas, who is a consultant diabetologist and diabetic foot specialist at King’s College Hospital NHS Foundation in London, went on to ask why only canagliflozin was found to be associated with amputations and not the other SGLT2 drugs.

Dr. Roussel responded that data were still needed on the other drugs in this class and that they needed to be treated with caution. The literature is not so clear, he admitted.

“It’s important that you noted it’s a single-center study,” Dr. Vas countered. “It’s very important to have multicenter data. An amputation is a decision made by someone. An amputation in one center may not be an amputation in another center.”

The SURDIAGENE study was supported by grants from the French Ministry of Health, the Association Française des Diabétiques, and the Groupement pour l’Etude des Maladies Métaboliques et Systémiques. Dr. Roussel reported relationships with Janssen, Merck, Sanofi-Aventis, AstraZeneca, and Boehringer Ingelheim. Dr. Vas was not involved in the study or analysis.

imnews@mdedge.com

SOURCE: Roussel R et al. EASD 2018, Abstract 12.

BERLIN – A significant reduction in severe hypoglycemia was seen within the first year of using continuous glucose monitoring in a registry study of more than 3,000 children with type 1 diabetes mellitus.

Prior to continuous glucose monitoring (CGM) use, 3.9% of 3,171 individuals, aged a median of 12 years, had hypoglycemia events requiring external help. After 6 months of using CGM, however, the rate of severe hypoglycemia had fallen to 1.2% (P = .10), which remained at 1.2% at 12 months (P = .002). The event rate (events per 100 patient-years) was 10.6 at baseline, 7.8 at 6 months, and 6.1 at 12 months.

Fewer hypoglycemia events leading to coma or convulsion were seen with CGM over time, with 1.3%, 0.6%, and 0.7% of patients reporting at least one event at baseline, 6 months (P = .08), and 12 months (P = .15), respectively. Corresponding event rates were 2.5, 1.6, and 1.7 per 100 patient-years.

“The use of continuous glucose monitoring systems has increased considerably in the past years in individuals with type 1 diabetes,” noted Julia Hermann, a PhD student at Ulm University (Germany), at the annual meeting of the European Association for the Study of Diabetes. “In Germany, for example, CGM use rose considerably when reimbursement by health insurance for CGM started in the summer of 2016.”

Ms. Hermann noted that there were studies showing improved metabolic control with CGM but that clinical studies were often limited by the population of patients studied, restricting treatment to selected patients who may have been adhering better to the use of CGM because they were in a trial.

The aim of the present study was to assess metabolic control and acute complications associated with CGM use in children during its first year of use in a real-world population. Anonymized patient records from the prospective German-Austrian-Luxembourg diabetes patient follow-up (DPV) registry were used.

The DPV database is a standardized, computed-based registry of more than 500,000 adult and pediatric patients with all types of diabetes. It was established in 1995 and receives data from 471 diabetes clinics in Germany, Austria, Luxembourg, and Switzerland.

For the current analysis patients had to be aged under 18 years, have had type 1 diabetes mellitus for at least 1 year, have data available for the months prior to starting CGM, and have at least 1 year of follow-up. For inclusion there also had to be documented use of CMG for at least half of the observation time.

The reduction of severe hypoglycemia observed was not accompanied by any deterioration in metabolic control, Ms. Hermann reported. The median baseline glycosylated hemoglobin (HbA1c) was 7.6% (59 mmol/mol) and this did not noticeably change at either the 6- or 12-month follow-up time point. Furthermore, the percentage of patients achieving a target HbA1c of less than 7.5% was 52% at baseline, 55% at 6 months, and 52% at 12 months.

The rate of diabetic ketoacidosis (DKA), defined as a pH of less than 7.3, also did not change significantly from baseline to the two follow-up points, with event rates of 1.5, 1.4, and 1.1, and the percentage of patients with at least one event being 0.8%, 0.5%, and 0.4%.

“We analyzed an overall well-controlled group of pediatric individuals with type 1 diabetes,” Ms. Hermann said. “We observed a significant reduction of severe hypoglycemia. We observed no improvements in HbA1c, but the overall HbA1c remained stable. We observed no statistically significant change in DKA.”

Future research will try to address some of the limitations that the current data may have, such as looking at a longer follow-up period and other endpoints such as hospitalization, Dr. Hermann suggested. Subgroup analyses are also planned.

“Large databases like the DPV registry ... provide a contemporary picture of diabetes treatment and how the use of diabetes technology has changed over the years and also how diabetes outcomes have improved over the years,” Ms. Hermann said. “It has yet to be seen how most recent changes and advances in diabetes technology will affect these long-term trends.”

The work was partially funded by the German Center for Diabetes Research, the German Diabetes Society, Abbott, and Sanofi. Dr. Hermann reported no personal conflicts of interest.
 

SOURCE: Hermann J et al. EASD 2018, Abstract 149.

BERLIN – A significant reduction in severe hypoglycemia was seen within the first year of using continuous glucose monitoring in a registry study of more than 3,000 children with type 1 diabetes mellitus.

Prior to continuous glucose monitoring (CGM) use, 3.9% of 3,171 individuals, aged a median of 12 years, had hypoglycemia events requiring external help. After 6 months of using CGM, however, the rate of severe hypoglycemia had fallen to 1.2% (P = .10), which remained at 1.2% at 12 months (P = .002). The event rate (events per 100 patient-years) was 10.6 at baseline, 7.8 at 6 months, and 6.1 at 12 months.

Fewer hypoglycemia events leading to coma or convulsion were seen with CGM over time, with 1.3%, 0.6%, and 0.7% of patients reporting at least one event at baseline, 6 months (P = .08), and 12 months (P = .15), respectively. Corresponding event rates were 2.5, 1.6, and 1.7 per 100 patient-years.

“The use of continuous glucose monitoring systems has increased considerably in the past years in individuals with type 1 diabetes,” noted Julia Hermann, a PhD student at Ulm University (Germany), at the annual meeting of the European Association for the Study of Diabetes. “In Germany, for example, CGM use rose considerably when reimbursement by health insurance for CGM started in the summer of 2016.”

Ms. Hermann noted that there were studies showing improved metabolic control with CGM but that clinical studies were often limited by the population of patients studied, restricting treatment to selected patients who may have been adhering better to the use of CGM because they were in a trial.

The aim of the present study was to assess metabolic control and acute complications associated with CGM use in children during its first year of use in a real-world population. Anonymized patient records from the prospective German-Austrian-Luxembourg diabetes patient follow-up (DPV) registry were used.

The DPV database is a standardized, computed-based registry of more than 500,000 adult and pediatric patients with all types of diabetes. It was established in 1995 and receives data from 471 diabetes clinics in Germany, Austria, Luxembourg, and Switzerland.

For the current analysis patients had to be aged under 18 years, have had type 1 diabetes mellitus for at least 1 year, have data available for the months prior to starting CGM, and have at least 1 year of follow-up. For inclusion there also had to be documented use of CMG for at least half of the observation time.

The reduction of severe hypoglycemia observed was not accompanied by any deterioration in metabolic control, Ms. Hermann reported. The median baseline glycosylated hemoglobin (HbA1c) was 7.6% (59 mmol/mol) and this did not noticeably change at either the 6- or 12-month follow-up time point. Furthermore, the percentage of patients achieving a target HbA1c of less than 7.5% was 52% at baseline, 55% at 6 months, and 52% at 12 months.

The rate of diabetic ketoacidosis (DKA), defined as a pH of less than 7.3, also did not change significantly from baseline to the two follow-up points, with event rates of 1.5, 1.4, and 1.1, and the percentage of patients with at least one event being 0.8%, 0.5%, and 0.4%.

“We analyzed an overall well-controlled group of pediatric individuals with type 1 diabetes,” Ms. Hermann said. “We observed a significant reduction of severe hypoglycemia. We observed no improvements in HbA1c, but the overall HbA1c remained stable. We observed no statistically significant change in DKA.”

Future research will try to address some of the limitations that the current data may have, such as looking at a longer follow-up period and other endpoints such as hospitalization, Dr. Hermann suggested. Subgroup analyses are also planned.

“Large databases like the DPV registry ... provide a contemporary picture of diabetes treatment and how the use of diabetes technology has changed over the years and also how diabetes outcomes have improved over the years,” Ms. Hermann said. “It has yet to be seen how most recent changes and advances in diabetes technology will affect these long-term trends.”

The work was partially funded by the German Center for Diabetes Research, the German Diabetes Society, Abbott, and Sanofi. Dr. Hermann reported no personal conflicts of interest.
 

SOURCE: Hermann J et al. EASD 2018, Abstract 149.

BERLIN – A significant reduction in severe hypoglycemia was seen within the first year of using continuous glucose monitoring in a registry study of more than 3,000 children with type 1 diabetes mellitus.

Prior to continuous glucose monitoring (CGM) use, 3.9% of 3,171 individuals, aged a median of 12 years, had hypoglycemia events requiring external help. After 6 months of using CGM, however, the rate of severe hypoglycemia had fallen to 1.2% (P = .10), which remained at 1.2% at 12 months (P = .002). The event rate (events per 100 patient-years) was 10.6 at baseline, 7.8 at 6 months, and 6.1 at 12 months.

Fewer hypoglycemia events leading to coma or convulsion were seen with CGM over time, with 1.3%, 0.6%, and 0.7% of patients reporting at least one event at baseline, 6 months (P = .08), and 12 months (P = .15), respectively. Corresponding event rates were 2.5, 1.6, and 1.7 per 100 patient-years.

“The use of continuous glucose monitoring systems has increased considerably in the past years in individuals with type 1 diabetes,” noted Julia Hermann, a PhD student at Ulm University (Germany), at the annual meeting of the European Association for the Study of Diabetes. “In Germany, for example, CGM use rose considerably when reimbursement by health insurance for CGM started in the summer of 2016.”

Ms. Hermann noted that there were studies showing improved metabolic control with CGM but that clinical studies were often limited by the population of patients studied, restricting treatment to selected patients who may have been adhering better to the use of CGM because they were in a trial.

The aim of the present study was to assess metabolic control and acute complications associated with CGM use in children during its first year of use in a real-world population. Anonymized patient records from the prospective German-Austrian-Luxembourg diabetes patient follow-up (DPV) registry were used.

The DPV database is a standardized, computed-based registry of more than 500,000 adult and pediatric patients with all types of diabetes. It was established in 1995 and receives data from 471 diabetes clinics in Germany, Austria, Luxembourg, and Switzerland.

For the current analysis patients had to be aged under 18 years, have had type 1 diabetes mellitus for at least 1 year, have data available for the months prior to starting CGM, and have at least 1 year of follow-up. For inclusion there also had to be documented use of CMG for at least half of the observation time.

The reduction of severe hypoglycemia observed was not accompanied by any deterioration in metabolic control, Ms. Hermann reported. The median baseline glycosylated hemoglobin (HbA1c) was 7.6% (59 mmol/mol) and this did not noticeably change at either the 6- or 12-month follow-up time point. Furthermore, the percentage of patients achieving a target HbA1c of less than 7.5% was 52% at baseline, 55% at 6 months, and 52% at 12 months.

The rate of diabetic ketoacidosis (DKA), defined as a pH of less than 7.3, also did not change significantly from baseline to the two follow-up points, with event rates of 1.5, 1.4, and 1.1, and the percentage of patients with at least one event being 0.8%, 0.5%, and 0.4%.

“We analyzed an overall well-controlled group of pediatric individuals with type 1 diabetes,” Ms. Hermann said. “We observed a significant reduction of severe hypoglycemia. We observed no improvements in HbA1c, but the overall HbA1c remained stable. We observed no statistically significant change in DKA.”

Future research will try to address some of the limitations that the current data may have, such as looking at a longer follow-up period and other endpoints such as hospitalization, Dr. Hermann suggested. Subgroup analyses are also planned.

“Large databases like the DPV registry ... provide a contemporary picture of diabetes treatment and how the use of diabetes technology has changed over the years and also how diabetes outcomes have improved over the years,” Ms. Hermann said. “It has yet to be seen how most recent changes and advances in diabetes technology will affect these long-term trends.”

The work was partially funded by the German Center for Diabetes Research, the German Diabetes Society, Abbott, and Sanofi. Dr. Hermann reported no personal conflicts of interest.
 

SOURCE: Hermann J et al. EASD 2018, Abstract 149.

BERLIN – A dry-powder nasal formulation of glucagon was as good as intramuscular delivery for the reversal of severe hypoglycemia in patients with type 1 diabetes mellitus (T1DM) in a randomized controlled trial.

Sara Freeman/MDedge News

A 100% treatment success rate (n = 66) was seen for both nasal glucagon and intramuscular glucagon, defined as an increase in plasma glucose to 70 mg/dL (3.9 mmol/L or greater) or more or an increase of 20 mg/L (1.1 mmol/L) or more from the glucose nadir within 30 minutes of administration.

Furthermore, slightly more than 97% of patients achieved treatment success within 15 minutes in both treatment groups, with mean times of 11.4 minutes for the nasal formulation and 9.8 minutes for intramuscular administration.

Similar glucose responses were observed within 40 minutes of glucagon administration, study investigator Leona Plum-Mörschel, MD, PhD, reported at the annual meeting of the European Association for the Study of Diabetes. Dr. Plum-Mörschel is the CEO of the clinical research organization Profil Mainz (Germany), which helped Eli Lilly conduct the trial.

“We are all aware and fully agree that severe hypoglycemia is a serious and potentially life-threatening complication of diabetes treatment with insulin and the sulfonylureas,” said Dr. Plum-Mörschel. At least one in three patients with diabetes reports one hypoglycemic episode per year, she added. While this is quite prevalent in patients with T1DM, it’s not uncommon for those with type 2 diabetes mellitus (T2DM) to experience hypoglycemic episodes.

“Outside of a hospital or emergency room setting, injectable glucagon is currently the only option to treat severe hypoglycemia,” Dr. Plum-Mörschel reminded delegates. “Thankfully, the available injectable glucagon emergency kits are highly effective for the treatment of hypoglycemic events,” she added.

However, for untrained caregivers they can be “really challenging to use,” according to Dr. Plum-Mörschel. This is because the available kits involve multiple steps, including reconstitution, before being ready to inject. A severe hypoglycemic event is stressful enough without them worrying about getting things right, she suggested.

This is where a nasal formulation would be advantageous, and it is something that’s been touted to be on the horizon for a few years. Studies have previously shown that nasal glucagon is comparable to intramuscular glucagon in both adult and pediatric populations. Turning the formulation used in those studies into a commercial product however, has meant more clinical testing before being licensed by the regulatory authorities.

The nasal formulation consists of a dry power containing 3 mg glucagon that is provided in a single-use, compact, and thus, portable, device. It’s been designed to be stored at room temperature and is ready to use immediately. Pressing the plunger on the device releases the fine powder that does not require inhalation to work, which means it can be given easily to an unconscious patient with severe hypoglycemia.

“The aim of the present study was to compare the efficacy and safety of commercially manufactured nasal glucagon with intramuscular glucagon for the treatment of insulin-induced hypoglycemia in adults with type 1 diabetes,” Dr. Plum-Mörschel said.

It was a randomized, single-dose, crossover study involving 70 adult patients with T1DM with hypoglycemia artificially induced by an intravenous insulin infusion during the two dosing visits. Five minutes after stopping insulin, nasal glucagon (3 mg) or intramuscular (1 mg) was given, with multiple plasma glucose measurements taken for up to 90 minutes.

The mean age of participants was 41.7 years old, 61% were male, the mean duration of diabetes was 19.8 years, with a baseline glycated hemoglobin (HbA_1c) of 7.3%.

As for safety, Dr. Plum-Mörschel noted that nasal glucagon had a safety profile that was acceptable for emergency treatment. There was no difference between the nasal or intramuscular glucagon treatment groups in the percentages of patients experiencing treatment-emergent adverse events (at least 5% frequency): nausea was seen in 22% and 29%, vomiting in 10% and 12%, and headache in 12% and 7%, respectively.

Asking patients who had been treated with nasal glucagon about specific symptoms related to nasal administration showed around 63% had watery eyes, 49% nasal itching, 39% nasal congestion, 37% a runny nose, 24% sneezing, 20% itchy eyes, and 12.9% itchy throat. “All of these events were transient, generally mild or moderate in nature, and none were serious. Indeed, there were no deaths in the study and no other serious AEs [adverse events] occurred.”

Dr. Plum-Mörschel concluded: “These results support nasal glucagon as a viable alternative to intramuscular glucagon for the treatment of severe hypoglycemia.

“I personally would expect that, due to its simplicity of use, nasal glucagon will create a greater community who can render quick aid in a rescue situation.”

The study was funded by Eli Lilly. Dr. Plum-Mörschel is an employee of Profil Mainz and has received travel grants and speaker honoraria from Eli Lilly and Novo Nordisk.
 

SOURCE: Suico J et al. EASD 2018, Abstract 150.

BERLIN – A dry-powder nasal formulation of glucagon was as good as intramuscular delivery for the reversal of severe hypoglycemia in patients with type 1 diabetes mellitus (T1DM) in a randomized controlled trial.

Sara Freeman/MDedge News

A 100% treatment success rate (n = 66) was seen for both nasal glucagon and intramuscular glucagon, defined as an increase in plasma glucose to 70 mg/dL (3.9 mmol/L or greater) or more or an increase of 20 mg/L (1.1 mmol/L) or more from the glucose nadir within 30 minutes of administration.

Furthermore, slightly more than 97% of patients achieved treatment success within 15 minutes in both treatment groups, with mean times of 11.4 minutes for the nasal formulation and 9.8 minutes for intramuscular administration.

Similar glucose responses were observed within 40 minutes of glucagon administration, study investigator Leona Plum-Mörschel, MD, PhD, reported at the annual meeting of the European Association for the Study of Diabetes. Dr. Plum-Mörschel is the CEO of the clinical research organization Profil Mainz (Germany), which helped Eli Lilly conduct the trial.

“We are all aware and fully agree that severe hypoglycemia is a serious and potentially life-threatening complication of diabetes treatment with insulin and the sulfonylureas,” said Dr. Plum-Mörschel. At least one in three patients with diabetes reports one hypoglycemic episode per year, she added. While this is quite prevalent in patients with T1DM, it’s not uncommon for those with type 2 diabetes mellitus (T2DM) to experience hypoglycemic episodes.

“Outside of a hospital or emergency room setting, injectable glucagon is currently the only option to treat severe hypoglycemia,” Dr. Plum-Mörschel reminded delegates. “Thankfully, the available injectable glucagon emergency kits are highly effective for the treatment of hypoglycemic events,” she added.

However, for untrained caregivers they can be “really challenging to use,” according to Dr. Plum-Mörschel. This is because the available kits involve multiple steps, including reconstitution, before being ready to inject. A severe hypoglycemic event is stressful enough without them worrying about getting things right, she suggested.

This is where a nasal formulation would be advantageous, and it is something that’s been touted to be on the horizon for a few years. Studies have previously shown that nasal glucagon is comparable to intramuscular glucagon in both adult and pediatric populations. Turning the formulation used in those studies into a commercial product however, has meant more clinical testing before being licensed by the regulatory authorities.

The nasal formulation consists of a dry power containing 3 mg glucagon that is provided in a single-use, compact, and thus, portable, device. It’s been designed to be stored at room temperature and is ready to use immediately. Pressing the plunger on the device releases the fine powder that does not require inhalation to work, which means it can be given easily to an unconscious patient with severe hypoglycemia.

“The aim of the present study was to compare the efficacy and safety of commercially manufactured nasal glucagon with intramuscular glucagon for the treatment of insulin-induced hypoglycemia in adults with type 1 diabetes,” Dr. Plum-Mörschel said.

It was a randomized, single-dose, crossover study involving 70 adult patients with T1DM with hypoglycemia artificially induced by an intravenous insulin infusion during the two dosing visits. Five minutes after stopping insulin, nasal glucagon (3 mg) or intramuscular (1 mg) was given, with multiple plasma glucose measurements taken for up to 90 minutes.

The mean age of participants was 41.7 years old, 61% were male, the mean duration of diabetes was 19.8 years, with a baseline glycated hemoglobin (HbA_1c) of 7.3%.

As for safety, Dr. Plum-Mörschel noted that nasal glucagon had a safety profile that was acceptable for emergency treatment. There was no difference between the nasal or intramuscular glucagon treatment groups in the percentages of patients experiencing treatment-emergent adverse events (at least 5% frequency): nausea was seen in 22% and 29%, vomiting in 10% and 12%, and headache in 12% and 7%, respectively.

Asking patients who had been treated with nasal glucagon about specific symptoms related to nasal administration showed around 63% had watery eyes, 49% nasal itching, 39% nasal congestion, 37% a runny nose, 24% sneezing, 20% itchy eyes, and 12.9% itchy throat. “All of these events were transient, generally mild or moderate in nature, and none were serious. Indeed, there were no deaths in the study and no other serious AEs [adverse events] occurred.”

Dr. Plum-Mörschel concluded: “These results support nasal glucagon as a viable alternative to intramuscular glucagon for the treatment of severe hypoglycemia.

“I personally would expect that, due to its simplicity of use, nasal glucagon will create a greater community who can render quick aid in a rescue situation.”

The study was funded by Eli Lilly. Dr. Plum-Mörschel is an employee of Profil Mainz and has received travel grants and speaker honoraria from Eli Lilly and Novo Nordisk.
 

SOURCE: Suico J et al. EASD 2018, Abstract 150.

BERLIN – A dry-powder nasal formulation of glucagon was as good as intramuscular delivery for the reversal of severe hypoglycemia in patients with type 1 diabetes mellitus (T1DM) in a randomized controlled trial.

Sara Freeman/MDedge News

A 100% treatment success rate (n = 66) was seen for both nasal glucagon and intramuscular glucagon, defined as an increase in plasma glucose to 70 mg/dL (3.9 mmol/L or greater) or more or an increase of 20 mg/L (1.1 mmol/L) or more from the glucose nadir within 30 minutes of administration.

Furthermore, slightly more than 97% of patients achieved treatment success within 15 minutes in both treatment groups, with mean times of 11.4 minutes for the nasal formulation and 9.8 minutes for intramuscular administration.

Similar glucose responses were observed within 40 minutes of glucagon administration, study investigator Leona Plum-Mörschel, MD, PhD, reported at the annual meeting of the European Association for the Study of Diabetes. Dr. Plum-Mörschel is the CEO of the clinical research organization Profil Mainz (Germany), which helped Eli Lilly conduct the trial.

“We are all aware and fully agree that severe hypoglycemia is a serious and potentially life-threatening complication of diabetes treatment with insulin and the sulfonylureas,” said Dr. Plum-Mörschel. At least one in three patients with diabetes reports one hypoglycemic episode per year, she added. While this is quite prevalent in patients with T1DM, it’s not uncommon for those with type 2 diabetes mellitus (T2DM) to experience hypoglycemic episodes.

“Outside of a hospital or emergency room setting, injectable glucagon is currently the only option to treat severe hypoglycemia,” Dr. Plum-Mörschel reminded delegates. “Thankfully, the available injectable glucagon emergency kits are highly effective for the treatment of hypoglycemic events,” she added.

However, for untrained caregivers they can be “really challenging to use,” according to Dr. Plum-Mörschel. This is because the available kits involve multiple steps, including reconstitution, before being ready to inject. A severe hypoglycemic event is stressful enough without them worrying about getting things right, she suggested.

This is where a nasal formulation would be advantageous, and it is something that’s been touted to be on the horizon for a few years. Studies have previously shown that nasal glucagon is comparable to intramuscular glucagon in both adult and pediatric populations. Turning the formulation used in those studies into a commercial product however, has meant more clinical testing before being licensed by the regulatory authorities.

The nasal formulation consists of a dry power containing 3 mg glucagon that is provided in a single-use, compact, and thus, portable, device. It’s been designed to be stored at room temperature and is ready to use immediately. Pressing the plunger on the device releases the fine powder that does not require inhalation to work, which means it can be given easily to an unconscious patient with severe hypoglycemia.

“The aim of the present study was to compare the efficacy and safety of commercially manufactured nasal glucagon with intramuscular glucagon for the treatment of insulin-induced hypoglycemia in adults with type 1 diabetes,” Dr. Plum-Mörschel said.

It was a randomized, single-dose, crossover study involving 70 adult patients with T1DM with hypoglycemia artificially induced by an intravenous insulin infusion during the two dosing visits. Five minutes after stopping insulin, nasal glucagon (3 mg) or intramuscular (1 mg) was given, with multiple plasma glucose measurements taken for up to 90 minutes.

The mean age of participants was 41.7 years old, 61% were male, the mean duration of diabetes was 19.8 years, with a baseline glycated hemoglobin (HbA_1c) of 7.3%.

As for safety, Dr. Plum-Mörschel noted that nasal glucagon had a safety profile that was acceptable for emergency treatment. There was no difference between the nasal or intramuscular glucagon treatment groups in the percentages of patients experiencing treatment-emergent adverse events (at least 5% frequency): nausea was seen in 22% and 29%, vomiting in 10% and 12%, and headache in 12% and 7%, respectively.

Asking patients who had been treated with nasal glucagon about specific symptoms related to nasal administration showed around 63% had watery eyes, 49% nasal itching, 39% nasal congestion, 37% a runny nose, 24% sneezing, 20% itchy eyes, and 12.9% itchy throat. “All of these events were transient, generally mild or moderate in nature, and none were serious. Indeed, there were no deaths in the study and no other serious AEs [adverse events] occurred.”

Dr. Plum-Mörschel concluded: “These results support nasal glucagon as a viable alternative to intramuscular glucagon for the treatment of severe hypoglycemia.

“I personally would expect that, due to its simplicity of use, nasal glucagon will create a greater community who can render quick aid in a rescue situation.”

The study was funded by Eli Lilly. Dr. Plum-Mörschel is an employee of Profil Mainz and has received travel grants and speaker honoraria from Eli Lilly and Novo Nordisk.
 

SOURCE: Suico J et al. EASD 2018, Abstract 150.

BERLIN – Adults, adolescents, and children with type 1 diabetes mellitus (T1DM) achieved better glycemic control and spent less time in a hypoglycemic state with an investigational closed-loop basal insulin delivery system than with a sensor-augmented insulin pump.

Sara Freeman/MDedge News

The primary trial endpoint of the proportion of time spent in a target glucose range of 3.9-10 mmol/L at 12 weeks was achieved by 65% of closed-loop users versus 54% of sensor-augmented insulin-pump users (P less than .0001).

In addition, fewer patients had periods of blood glucose less than 3.9 mmol/L at 12 weeks, potentially reducing their risk for hypoglycemic episodes (2.6% vs. 3.9%, P = .0130). The percentages of patients with blood glucose concentrations higher than the target range were also significantly reduced with the closed-loop system.

Glycated hemoglobin (HbA_1c) improved in both groups, from a baseline of 8% to 7.4% at 12 weeks in the closed-loop users and from 7.8% to 7.7% in the sensor-augmented insulin-pump users (mean difference –0.036%, P less than .0001). Mean glucose levels also significantly improved, with a mean between-group difference of –0.45 mmol/L (P less than .0001).

“Most of the improvements are overnight,” with a striking difference between the control and closed-loop groups of time in range, said senior study investigator Roman Hovorka, PhD, during a press briefing at the annual meeting of the European Association for the Study of Diabetes.

“Usually what people need to do is titrate insulin based on blood sugar tests, but in our system those tests are done by a monitoring system and the insulin is titrated by a computer algorithm,” study investigator Martin Tauschmann, MD, explained in an interview after the press briefing.

The prototype system consists of a modified insulin pump (Medtronic 640G) and a continuous glucose sensor (Enlite 3) that are linked by the proprietary “Cambridge control” algorithm via an Android phone. The latter calculates the optimum insulin dose, which is then relayed to the insulin pump every 10 minutes to determine how many insulin units are needed.

“The algorithm is based on mathematical modeling that is trying to predict what the glucose levels will be in the future and trying to work out the optimum insulin dose to bring the predicted glucose levels down,” noted Dr. Tauschmann, who is a pediatrician at Cambridge University (England).

It’s not a fully closed-loop system, he added, it’s a hybrid, so users still need to calculate their carbohydrate intake around mealtimes and input that into the algorithm and use bolus insulin.

“A problem with using currently available insulin formulations is that you are always behind, because we are delivering insulin in the subcutaneous tissue and it just takes some time for the insulin to be absorbed, and, in the meantime, the blood sugar levels go up,” Dr. Tauschmann observed. Studies with fully closed–loop systems, so far, have shown glucose peaking after meals. Perhaps when faster-acting insulins are tested in this setting it could work, he suggested, but perhaps simplifying how the users announce their meals is a future development for the hybrid systems.

Closed-loop insulin delivery is not a new concept. There is already one system available in the United States produced by Medtronic (670G), which was approved by the Food and Drug Administration in September 2016. However, there are no systems available in Europe and there are limited trial data on their use in an outpatient setting.

The aim of the current study, which was an open-label, multicenter, multinational, parallel-group, randomized, controlled trial, was to compare closed-loop basal insulin delivery and sensor augmented insulin pump therapy in helping a mixed adult and pediatric population of patients T1DM achieve good glucose control.

In all, 86 adults, adolescents, and children (age 6 years or older) were randomized: 46 to the closed-loop system and 40 to the control arm of sensor-augmented insulin pump therapy. The mean age of participants was 22 years in the closed-loop group and 21 years in the sensor group, with a respective 24% and 30% aged 6-12 years, 24% and 20% aged 13-21 years, 39% and 35% aged 22-40 years, and 13% and 15% aged 41 years or older. The mean duration of diabetes was 13 and 10 years, in each group, respectively.

The study data “provide more evidence that closed-loop insulin delivery, compared with standard pump and sensor, really improves HbA_1c, time spent in range, and mean glucose, and it also reduces hypoglycemia,” Dr. Tauschmann said.

Sara Freeman/MDedge News

“We didn’t have any real safety issues,” noted Dr. Hovorka, who is professor and director of research in the department of pediatrics at the University of Cambridge. There was one episode of diabetic ketoacidosis caused by infusion set failure in the closed-loop group; 16 other adverse events were noted (13 in the closed-loop group, three in the control group) that were not related to treatment.

“We have a number of studies in the pipeline,” Dr. Hovorka said. “Two exciting studies are in development. In one we are recruiting 70 subjects with newly diagnosed type 1 diabetes mellitus who will be treated with a closed-loop system. There is also a study in children aged between 1 and 7 years that is projected to start next year.”

Work is also underway to create a platform that will work with all insulin pumps and create a commercial product.

The study was funded by the Juvenile Diabetes Research Foundation with additional support from the National Institute for Health Research (England) and the Wellcome Trust. Dr. Tauschmann reported receiving speaker honoraria from Medtronic and Novo Nordisk. Dr. Hovorka reported receiving speaker honoraria from Eli Lilly and Novo Nordisk, serving on an advisory panel for Eli Lilly, receiving license fees from B. Braun Medical and Medtronic, and having patents and patent applications.

SOURCES: Tauschmann M et al. EASD 2018, Oral Presentation 19.

BERLIN – Adults, adolescents, and children with type 1 diabetes mellitus (T1DM) achieved better glycemic control and spent less time in a hypoglycemic state with an investigational closed-loop basal insulin delivery system than with a sensor-augmented insulin pump.

Sara Freeman/MDedge News

The primary trial endpoint of the proportion of time spent in a target glucose range of 3.9-10 mmol/L at 12 weeks was achieved by 65% of closed-loop users versus 54% of sensor-augmented insulin-pump users (P less than .0001).

In addition, fewer patients had periods of blood glucose less than 3.9 mmol/L at 12 weeks, potentially reducing their risk for hypoglycemic episodes (2.6% vs. 3.9%, P = .0130). The percentages of patients with blood glucose concentrations higher than the target range were also significantly reduced with the closed-loop system.

Glycated hemoglobin (HbA_1c) improved in both groups, from a baseline of 8% to 7.4% at 12 weeks in the closed-loop users and from 7.8% to 7.7% in the sensor-augmented insulin-pump users (mean difference –0.036%, P less than .0001). Mean glucose levels also significantly improved, with a mean between-group difference of –0.45 mmol/L (P less than .0001).

“Most of the improvements are overnight,” with a striking difference between the control and closed-loop groups of time in range, said senior study investigator Roman Hovorka, PhD, during a press briefing at the annual meeting of the European Association for the Study of Diabetes.

“Usually what people need to do is titrate insulin based on blood sugar tests, but in our system those tests are done by a monitoring system and the insulin is titrated by a computer algorithm,” study investigator Martin Tauschmann, MD, explained in an interview after the press briefing.

The prototype system consists of a modified insulin pump (Medtronic 640G) and a continuous glucose sensor (Enlite 3) that are linked by the proprietary “Cambridge control” algorithm via an Android phone. The latter calculates the optimum insulin dose, which is then relayed to the insulin pump every 10 minutes to determine how many insulin units are needed.

“The algorithm is based on mathematical modeling that is trying to predict what the glucose levels will be in the future and trying to work out the optimum insulin dose to bring the predicted glucose levels down,” noted Dr. Tauschmann, who is a pediatrician at Cambridge University (England).

It’s not a fully closed-loop system, he added, it’s a hybrid, so users still need to calculate their carbohydrate intake around mealtimes and input that into the algorithm and use bolus insulin.

“A problem with using currently available insulin formulations is that you are always behind, because we are delivering insulin in the subcutaneous tissue and it just takes some time for the insulin to be absorbed, and, in the meantime, the blood sugar levels go up,” Dr. Tauschmann observed. Studies with fully closed–loop systems, so far, have shown glucose peaking after meals. Perhaps when faster-acting insulins are tested in this setting it could work, he suggested, but perhaps simplifying how the users announce their meals is a future development for the hybrid systems.

Closed-loop insulin delivery is not a new concept. There is already one system available in the United States produced by Medtronic (670G), which was approved by the Food and Drug Administration in September 2016. However, there are no systems available in Europe and there are limited trial data on their use in an outpatient setting.

The aim of the current study, which was an open-label, multicenter, multinational, parallel-group, randomized, controlled trial, was to compare closed-loop basal insulin delivery and sensor augmented insulin pump therapy in helping a mixed adult and pediatric population of patients T1DM achieve good glucose control.

In all, 86 adults, adolescents, and children (age 6 years or older) were randomized: 46 to the closed-loop system and 40 to the control arm of sensor-augmented insulin pump therapy. The mean age of participants was 22 years in the closed-loop group and 21 years in the sensor group, with a respective 24% and 30% aged 6-12 years, 24% and 20% aged 13-21 years, 39% and 35% aged 22-40 years, and 13% and 15% aged 41 years or older. The mean duration of diabetes was 13 and 10 years, in each group, respectively.

The study data “provide more evidence that closed-loop insulin delivery, compared with standard pump and sensor, really improves HbA_1c, time spent in range, and mean glucose, and it also reduces hypoglycemia,” Dr. Tauschmann said.

Sara Freeman/MDedge News

“We didn’t have any real safety issues,” noted Dr. Hovorka, who is professor and director of research in the department of pediatrics at the University of Cambridge. There was one episode of diabetic ketoacidosis caused by infusion set failure in the closed-loop group; 16 other adverse events were noted (13 in the closed-loop group, three in the control group) that were not related to treatment.

“We have a number of studies in the pipeline,” Dr. Hovorka said. “Two exciting studies are in development. In one we are recruiting 70 subjects with newly diagnosed type 1 diabetes mellitus who will be treated with a closed-loop system. There is also a study in children aged between 1 and 7 years that is projected to start next year.”

Work is also underway to create a platform that will work with all insulin pumps and create a commercial product.

The study was funded by the Juvenile Diabetes Research Foundation with additional support from the National Institute for Health Research (England) and the Wellcome Trust. Dr. Tauschmann reported receiving speaker honoraria from Medtronic and Novo Nordisk. Dr. Hovorka reported receiving speaker honoraria from Eli Lilly and Novo Nordisk, serving on an advisory panel for Eli Lilly, receiving license fees from B. Braun Medical and Medtronic, and having patents and patent applications.

SOURCES: Tauschmann M et al. EASD 2018, Oral Presentation 19.

BERLIN – Adults, adolescents, and children with type 1 diabetes mellitus (T1DM) achieved better glycemic control and spent less time in a hypoglycemic state with an investigational closed-loop basal insulin delivery system than with a sensor-augmented insulin pump.

Sara Freeman/MDedge News

The primary trial endpoint of the proportion of time spent in a target glucose range of 3.9-10 mmol/L at 12 weeks was achieved by 65% of closed-loop users versus 54% of sensor-augmented insulin-pump users (P less than .0001).

In addition, fewer patients had periods of blood glucose less than 3.9 mmol/L at 12 weeks, potentially reducing their risk for hypoglycemic episodes (2.6% vs. 3.9%, P = .0130). The percentages of patients with blood glucose concentrations higher than the target range were also significantly reduced with the closed-loop system.

Glycated hemoglobin (HbA_1c) improved in both groups, from a baseline of 8% to 7.4% at 12 weeks in the closed-loop users and from 7.8% to 7.7% in the sensor-augmented insulin-pump users (mean difference –0.036%, P less than .0001). Mean glucose levels also significantly improved, with a mean between-group difference of –0.45 mmol/L (P less than .0001).

“Most of the improvements are overnight,” with a striking difference between the control and closed-loop groups of time in range, said senior study investigator Roman Hovorka, PhD, during a press briefing at the annual meeting of the European Association for the Study of Diabetes.

“Usually what people need to do is titrate insulin based on blood sugar tests, but in our system those tests are done by a monitoring system and the insulin is titrated by a computer algorithm,” study investigator Martin Tauschmann, MD, explained in an interview after the press briefing.

The prototype system consists of a modified insulin pump (Medtronic 640G) and a continuous glucose sensor (Enlite 3) that are linked by the proprietary “Cambridge control” algorithm via an Android phone. The latter calculates the optimum insulin dose, which is then relayed to the insulin pump every 10 minutes to determine how many insulin units are needed.

“The algorithm is based on mathematical modeling that is trying to predict what the glucose levels will be in the future and trying to work out the optimum insulin dose to bring the predicted glucose levels down,” noted Dr. Tauschmann, who is a pediatrician at Cambridge University (England).

It’s not a fully closed-loop system, he added, it’s a hybrid, so users still need to calculate their carbohydrate intake around mealtimes and input that into the algorithm and use bolus insulin.

“A problem with using currently available insulin formulations is that you are always behind, because we are delivering insulin in the subcutaneous tissue and it just takes some time for the insulin to be absorbed, and, in the meantime, the blood sugar levels go up,” Dr. Tauschmann observed. Studies with fully closed–loop systems, so far, have shown glucose peaking after meals. Perhaps when faster-acting insulins are tested in this setting it could work, he suggested, but perhaps simplifying how the users announce their meals is a future development for the hybrid systems.

Closed-loop insulin delivery is not a new concept. There is already one system available in the United States produced by Medtronic (670G), which was approved by the Food and Drug Administration in September 2016. However, there are no systems available in Europe and there are limited trial data on their use in an outpatient setting.

The aim of the current study, which was an open-label, multicenter, multinational, parallel-group, randomized, controlled trial, was to compare closed-loop basal insulin delivery and sensor augmented insulin pump therapy in helping a mixed adult and pediatric population of patients T1DM achieve good glucose control.

In all, 86 adults, adolescents, and children (age 6 years or older) were randomized: 46 to the closed-loop system and 40 to the control arm of sensor-augmented insulin pump therapy. The mean age of participants was 22 years in the closed-loop group and 21 years in the sensor group, with a respective 24% and 30% aged 6-12 years, 24% and 20% aged 13-21 years, 39% and 35% aged 22-40 years, and 13% and 15% aged 41 years or older. The mean duration of diabetes was 13 and 10 years, in each group, respectively.

The study data “provide more evidence that closed-loop insulin delivery, compared with standard pump and sensor, really improves HbA_1c, time spent in range, and mean glucose, and it also reduces hypoglycemia,” Dr. Tauschmann said.

Sara Freeman/MDedge News

“We didn’t have any real safety issues,” noted Dr. Hovorka, who is professor and director of research in the department of pediatrics at the University of Cambridge. There was one episode of diabetic ketoacidosis caused by infusion set failure in the closed-loop group; 16 other adverse events were noted (13 in the closed-loop group, three in the control group) that were not related to treatment.

“We have a number of studies in the pipeline,” Dr. Hovorka said. “Two exciting studies are in development. In one we are recruiting 70 subjects with newly diagnosed type 1 diabetes mellitus who will be treated with a closed-loop system. There is also a study in children aged between 1 and 7 years that is projected to start next year.”

Work is also underway to create a platform that will work with all insulin pumps and create a commercial product.

The study was funded by the Juvenile Diabetes Research Foundation with additional support from the National Institute for Health Research (England) and the Wellcome Trust. Dr. Tauschmann reported receiving speaker honoraria from Medtronic and Novo Nordisk. Dr. Hovorka reported receiving speaker honoraria from Eli Lilly and Novo Nordisk, serving on an advisory panel for Eli Lilly, receiving license fees from B. Braun Medical and Medtronic, and having patents and patent applications.

SOURCES: Tauschmann M et al. EASD 2018, Oral Presentation 19.

BERLIN – Smart insoles that warn diabetic individuals of high plantar pressures could be a simple solution to help them avoid recurrent foot ulcers, according to the results of a randomized trial.

Study participants with a history of diabetic foot ulcers wore the plantar pressure–sensing insoles (SurroSense Rx) and received feedback via sensor linked to a smart watch worn and were 71% less likely to experience a recurrent foot ulceration than were those who wore the insoles but did not get the pressure feedback (incidence rate ratio, 0.29; 95% confidence interval, 0.09-0.93; P = .037). The device has been cleared by the Food and Drug Administration.

Overall, there were few ulcers that occurred in the study, with 10 ulcers from 8,638 person-days from six patients reported in the control group and four ulcers from 11,835 person-days from four patients in the intervention group.

“Diabetic foot ulcers are a major global health and economic burden, but, in theory at least, they are ultimately preventable,” said study investigator Neil Reeves, PhD,, who presented the findings at the annual meeting of the European Association for the Study of Diabetes.

Data suggest that recurrence rates for ulceration are as high as 65% at 6 years, he said, with up to a quarter of ulcers progressing to the point where some form of amputation is needed.

“In the laboratory, we can measure plantar pressures, and these are considered as a relatively accurate proxy for diabetic foot ulcer risk. So we can discriminate between those with diabetic neuropathy, and those without, and also those with a previous history of ulceration,” Dr. Reeves said.

Dr. Reeves, who is professor of musculoskeletal biomechanics at Manchester (England) Metropolitan University, observed that the rationale behind the development of the smart insoles was to move plantar pressure measurement out of the laboratory and into the real world.

The smart insoles incorporate eight discreet pressure sensors that are connected to pod worn on the front of the participant’s own shoe and that wirelessly relay pressure information to a smartwatch. Both the control and the intervention groups received the same device, Dr. Reeves pointed out, but the difference was that the only the intervention group got any pressure feedback from the sensors to the smartwatch.

“When high pressure was experienced in the intervention group on any of these sensors, the patient was alerted both by an auditory alarm and also by being able to see this on the smartwatch,” Dr. Reeves explained.

“The patient would be alerted as to where the pressure was high on the foot and that would be a trigger to offload this high pressure.” Patients would then be instructed via the smartwatch to try to offload the pressure by either walking around for 2 minutes, actively taking the weight off the foot, or removing the shoe to check for any foreign bodies.

In all, there were 58 study participants – 32 randomized to the intervention group and 26 to the control group – who had a history of diabetic foot ulcers and peripheral neuropathy but who were able to walk independently for at least 30 steps. The mean age of patients in the intervention group was 59 years, 88% were male, 72% had type 2 diabetes mellitus, with the mean duration of diabetes was 22 years. Corresponding data in the control group were 67 years, 89% male, 85% had type 2 diabetes, and 21 years’ diabetes duration.

Patients were reviewed monthly over a period of 18 months or until plantar ulceration occurred. Information on diabetic foot ulcers was collected and standardized using a previously developed mobile app (Diabetes Sci Technol. 2018;12[1]:169-73) and then confirmed via blinded assessment by two experts.

Dr. Reeves noted that there was no significant difference in the time to ulceration between the groups, with 77.5% and 68.4% of the intervention and control group remaining ulcer free at 18 months (P = .30). When the data were adjusted for compliance, there was an 86% reduction in the risk of reulceration in the intervention versus the control group (IRR, 0.14; 95% CI, 0.03-0.63; P = .011). This analysis took into account only those study participants who had 4.5 hours or more of daily wear of the smart insoles (n = 40). On average, the insoles were worn for 6.1 hours in the control group and by 6.9 hours in the intervention group.

“We suggest that the mechanism for this beneficial effect in the present study is likely pressure offloading, which has been afforded by providing patients in the intervention group with this plantar-pressure feedback,” said Dr. Reeves.

“That’s feedback that they’ve lost naturally many years ago due to diabetic peripheral neuropathy,” he added. “So, in that respect, we would suggest that patients have really been empowered here to take control of their foot health in a way that they haven’t been able to since the onset of significant diabetic peripheral neuropathy.”

Diabetes UK provided the primary funding for the study (years 1-3), with Orpyx Medical Technologies, Canada, providing funding during the study extension (year 4). Dr. Reeves did not have any disclosures.
 

BERLIN – Smart insoles that warn diabetic individuals of high plantar pressures could be a simple solution to help them avoid recurrent foot ulcers, according to the results of a randomized trial.

Study participants with a history of diabetic foot ulcers wore the plantar pressure–sensing insoles (SurroSense Rx) and received feedback via sensor linked to a smart watch worn and were 71% less likely to experience a recurrent foot ulceration than were those who wore the insoles but did not get the pressure feedback (incidence rate ratio, 0.29; 95% confidence interval, 0.09-0.93; P = .037). The device has been cleared by the Food and Drug Administration.

Overall, there were few ulcers that occurred in the study, with 10 ulcers from 8,638 person-days from six patients reported in the control group and four ulcers from 11,835 person-days from four patients in the intervention group.

“Diabetic foot ulcers are a major global health and economic burden, but, in theory at least, they are ultimately preventable,” said study investigator Neil Reeves, PhD,, who presented the findings at the annual meeting of the European Association for the Study of Diabetes.

Data suggest that recurrence rates for ulceration are as high as 65% at 6 years, he said, with up to a quarter of ulcers progressing to the point where some form of amputation is needed.

“In the laboratory, we can measure plantar pressures, and these are considered as a relatively accurate proxy for diabetic foot ulcer risk. So we can discriminate between those with diabetic neuropathy, and those without, and also those with a previous history of ulceration,” Dr. Reeves said.

Dr. Reeves, who is professor of musculoskeletal biomechanics at Manchester (England) Metropolitan University, observed that the rationale behind the development of the smart insoles was to move plantar pressure measurement out of the laboratory and into the real world.

The smart insoles incorporate eight discreet pressure sensors that are connected to pod worn on the front of the participant’s own shoe and that wirelessly relay pressure information to a smartwatch. Both the control and the intervention groups received the same device, Dr. Reeves pointed out, but the difference was that the only the intervention group got any pressure feedback from the sensors to the smartwatch.

“When high pressure was experienced in the intervention group on any of these sensors, the patient was alerted both by an auditory alarm and also by being able to see this on the smartwatch,” Dr. Reeves explained.

“The patient would be alerted as to where the pressure was high on the foot and that would be a trigger to offload this high pressure.” Patients would then be instructed via the smartwatch to try to offload the pressure by either walking around for 2 minutes, actively taking the weight off the foot, or removing the shoe to check for any foreign bodies.

In all, there were 58 study participants – 32 randomized to the intervention group and 26 to the control group – who had a history of diabetic foot ulcers and peripheral neuropathy but who were able to walk independently for at least 30 steps. The mean age of patients in the intervention group was 59 years, 88% were male, 72% had type 2 diabetes mellitus, with the mean duration of diabetes was 22 years. Corresponding data in the control group were 67 years, 89% male, 85% had type 2 diabetes, and 21 years’ diabetes duration.

Patients were reviewed monthly over a period of 18 months or until plantar ulceration occurred. Information on diabetic foot ulcers was collected and standardized using a previously developed mobile app (Diabetes Sci Technol. 2018;12[1]:169-73) and then confirmed via blinded assessment by two experts.

Dr. Reeves noted that there was no significant difference in the time to ulceration between the groups, with 77.5% and 68.4% of the intervention and control group remaining ulcer free at 18 months (P = .30). When the data were adjusted for compliance, there was an 86% reduction in the risk of reulceration in the intervention versus the control group (IRR, 0.14; 95% CI, 0.03-0.63; P = .011). This analysis took into account only those study participants who had 4.5 hours or more of daily wear of the smart insoles (n = 40). On average, the insoles were worn for 6.1 hours in the control group and by 6.9 hours in the intervention group.

“We suggest that the mechanism for this beneficial effect in the present study is likely pressure offloading, which has been afforded by providing patients in the intervention group with this plantar-pressure feedback,” said Dr. Reeves.

“That’s feedback that they’ve lost naturally many years ago due to diabetic peripheral neuropathy,” he added. “So, in that respect, we would suggest that patients have really been empowered here to take control of their foot health in a way that they haven’t been able to since the onset of significant diabetic peripheral neuropathy.”

Diabetes UK provided the primary funding for the study (years 1-3), with Orpyx Medical Technologies, Canada, providing funding during the study extension (year 4). Dr. Reeves did not have any disclosures.
 

BERLIN – Smart insoles that warn diabetic individuals of high plantar pressures could be a simple solution to help them avoid recurrent foot ulcers, according to the results of a randomized trial.

Study participants with a history of diabetic foot ulcers wore the plantar pressure–sensing insoles (SurroSense Rx) and received feedback via sensor linked to a smart watch worn and were 71% less likely to experience a recurrent foot ulceration than were those who wore the insoles but did not get the pressure feedback (incidence rate ratio, 0.29; 95% confidence interval, 0.09-0.93; P = .037). The device has been cleared by the Food and Drug Administration.

Overall, there were few ulcers that occurred in the study, with 10 ulcers from 8,638 person-days from six patients reported in the control group and four ulcers from 11,835 person-days from four patients in the intervention group.

“Diabetic foot ulcers are a major global health and economic burden, but, in theory at least, they are ultimately preventable,” said study investigator Neil Reeves, PhD,, who presented the findings at the annual meeting of the European Association for the Study of Diabetes.

Data suggest that recurrence rates for ulceration are as high as 65% at 6 years, he said, with up to a quarter of ulcers progressing to the point where some form of amputation is needed.

“In the laboratory, we can measure plantar pressures, and these are considered as a relatively accurate proxy for diabetic foot ulcer risk. So we can discriminate between those with diabetic neuropathy, and those without, and also those with a previous history of ulceration,” Dr. Reeves said.

Dr. Reeves, who is professor of musculoskeletal biomechanics at Manchester (England) Metropolitan University, observed that the rationale behind the development of the smart insoles was to move plantar pressure measurement out of the laboratory and into the real world.

The smart insoles incorporate eight discreet pressure sensors that are connected to pod worn on the front of the participant’s own shoe and that wirelessly relay pressure information to a smartwatch. Both the control and the intervention groups received the same device, Dr. Reeves pointed out, but the difference was that the only the intervention group got any pressure feedback from the sensors to the smartwatch.

“When high pressure was experienced in the intervention group on any of these sensors, the patient was alerted both by an auditory alarm and also by being able to see this on the smartwatch,” Dr. Reeves explained.

“The patient would be alerted as to where the pressure was high on the foot and that would be a trigger to offload this high pressure.” Patients would then be instructed via the smartwatch to try to offload the pressure by either walking around for 2 minutes, actively taking the weight off the foot, or removing the shoe to check for any foreign bodies.

In all, there were 58 study participants – 32 randomized to the intervention group and 26 to the control group – who had a history of diabetic foot ulcers and peripheral neuropathy but who were able to walk independently for at least 30 steps. The mean age of patients in the intervention group was 59 years, 88% were male, 72% had type 2 diabetes mellitus, with the mean duration of diabetes was 22 years. Corresponding data in the control group were 67 years, 89% male, 85% had type 2 diabetes, and 21 years’ diabetes duration.

Patients were reviewed monthly over a period of 18 months or until plantar ulceration occurred. Information on diabetic foot ulcers was collected and standardized using a previously developed mobile app (Diabetes Sci Technol. 2018;12[1]:169-73) and then confirmed via blinded assessment by two experts.

Dr. Reeves noted that there was no significant difference in the time to ulceration between the groups, with 77.5% and 68.4% of the intervention and control group remaining ulcer free at 18 months (P = .30). When the data were adjusted for compliance, there was an 86% reduction in the risk of reulceration in the intervention versus the control group (IRR, 0.14; 95% CI, 0.03-0.63; P = .011). This analysis took into account only those study participants who had 4.5 hours or more of daily wear of the smart insoles (n = 40). On average, the insoles were worn for 6.1 hours in the control group and by 6.9 hours in the intervention group.

“We suggest that the mechanism for this beneficial effect in the present study is likely pressure offloading, which has been afforded by providing patients in the intervention group with this plantar-pressure feedback,” said Dr. Reeves.

“That’s feedback that they’ve lost naturally many years ago due to diabetic peripheral neuropathy,” he added. “So, in that respect, we would suggest that patients have really been empowered here to take control of their foot health in a way that they haven’t been able to since the onset of significant diabetic peripheral neuropathy.”

Diabetes UK provided the primary funding for the study (years 1-3), with Orpyx Medical Technologies, Canada, providing funding during the study extension (year 4). Dr. Reeves did not have any disclosures.
 

BERLIN – Diabetic foot ulcers that were designated as difficult to treat were 58% more likely to heal when they were treated with LeucoPatch than using the best standard care alone in a randomized, controlled study.

With the LeucoPatch – which contained study participants’ own cells (platelets, fibrin, and leukocytes) – 34.1% of ulcers healed within 20 weeks versus 21.6% of ulcers that were treated using the best standard care (unadjusted odds ratio, 1.58; 95% confidence interval, 1.06-2.25; P = .02). Healing was defined as complete epithelialization maintained for 4 weeks, as confirmed by an observer blinded to the treatment group.

SOURCES: Game F et al. EASD 2018, Abstract 9.

BERLIN – Diabetic foot ulcers that were designated as difficult to treat were 58% more likely to heal when they were treated with LeucoPatch than using the best standard care alone in a randomized, controlled study.

With the LeucoPatch – which contained study participants’ own cells (platelets, fibrin, and leukocytes) – 34.1% of ulcers healed within 20 weeks versus 21.6% of ulcers that were treated using the best standard care (unadjusted odds ratio, 1.58; 95% confidence interval, 1.06-2.25; P = .02). Healing was defined as complete epithelialization maintained for 4 weeks, as confirmed by an observer blinded to the treatment group.

SOURCES: Game F et al. EASD 2018, Abstract 9.

BERLIN – Diabetic foot ulcers that were designated as difficult to treat were 58% more likely to heal when they were treated with LeucoPatch than using the best standard care alone in a randomized, controlled study.

With the LeucoPatch – which contained study participants’ own cells (platelets, fibrin, and leukocytes) – 34.1% of ulcers healed within 20 weeks versus 21.6% of ulcers that were treated using the best standard care (unadjusted odds ratio, 1.58; 95% confidence interval, 1.06-2.25; P = .02). Healing was defined as complete epithelialization maintained for 4 weeks, as confirmed by an observer blinded to the treatment group.

SOURCES: Game F et al. EASD 2018, Abstract 9.

BERLIN – Lower rates of incident type 2 diabetes mellitus (T2DM) and improved glycemic control were two of the metabolic effects seen with the appetite-suppressant drug lorcaserin versus placebo on top of existing lifestyle management measures in a large-scale trial of more than 12,000 overweight or obese individuals with established cardiovascular disease or T2DM and other cardiovascular risk factors.

Sara Freeman/MDEdge News

In the CAMELLIA-TIMI 61 trial, treatment with a twice-daily, 10-mg dose of lorcaserin for a median of 3.3 years was associated with a significant 19% reduction in the risk of incident T2DM in participants with prediabetes, compared with placebo (8.5% vs. 10.3%; hazard ratio, 0.81; 95% confidence interval, 0.66-0.99; P = .038). The reduction in the risk of incident T2DM was even greater (23%) in people without diabetes at baseline (6.7% lorcaserin vs. 8.4% placebo; HR, 0.77; 95% CI, 0.63-0.94; P = .012).

Furthermore, in patients with T2DM who had a mean baseline glycated hemoglobin (HbA_1c) of 7%, an absolute 0.33% reduction was seen at 1 year between the lorcaserin and placebo groups, with more modest but still significant between-group reductions (–0.09% and –0.08%) in individuals with prediabetes or normoglycemia (all P less than .0001). When baseline HbA_1c levels were higher in patients with T2DM (8%), greater net reductions (0.52%) versus placebo were seen (P less than .0001).

These were some of the metabolic findings, published online in the Lancet to coincide with their presentation at the annual meeting of the European Association for the Study of Diabetes, that add to those already released from the CAMELLIA-TIMI 61 trial on cardiovascular safety, lead author and TIMI (Thrombolysis in Myocardial Infarction) group investigator Erin A. Bohula May, MD, observed during a press conference.

The cardiovascular safety data were presented at the 2018 annual congress of the European Society for Cardiology in August and published in the New England Journal of Medicine. These showed no increase with lorcaserin versus placebo in the risk of achieving a major cardiovascular endpoint (MACE) of cardiovascular death, MI, or stroke (HR, 0.99; 95% CI, 0.85-1.14; P less than .001 for noninferiority). There was also no difference between groups in the cumulative incidence of MACE+, which included heart failure, hospitalization for unstable angina, and the need for coronary revascularization (HR, 0.97; 95% CI, 0.87-1.07; P = .55 for superiority).

“We know that weight loss can improve cardiovascular and glycemic risk factors, but it’s difficult to achieve and maintain, and weight-loss agents are guideline-recommended adjuncts to lifestyle modification,” said Dr. Bohula May, who is a cardiovascular medicine and critical care specialist at Brigham and Women’s Hospital in Boston.

“However, prior to this study no agent had convincingly demonstrated cardiovascular safety in a rigorous clinical outcomes study,” she said, noting that several agents, such as the now-withdrawn rimonabant (Acomplia/Zimulti) and sibutramine (Meridia), had been shown to precipitate cardiovascular or psychiatric events, which led the Food and Drug Administration to mandate that all weight-loss drugs be assessed for cardiovascular safety. Lorcaserin (Belviq) is a centrally acting 5-HT_2C agonist that works by decreasing appetite and was approved by the FDA in 2012 but is not currently available in Europe.

Long-term data on the effects of weight-loss agents on glycemic parameters were limited, hence the remit of the CAMELLIA-TIMI 61 trial was to assess both the cardiovascular and metabolic safety of lorcaserin. The drug was used on a background of lifestyle modification in 6,000 obese or overweight individuals at high risk of cardiovascular events. A further 6,000 individuals received placebo.

Sara Freeman/MDEdge News

“Lorcaserin induced and maintained weight loss across the glycemic categories,” said coauthor and TIMI group investigator Benjamin Scirica, MD, also of Brigham and Women’s Hospital, who presented the metabolic data during a scientific session at the EASD meeting. Specifically, there was a net weight loss beyond that seen with placebo of 2.6 kg, 2.8 kg, and 3.3 kg in individuals with T2DM, prediabetes, and normoglycemia, respectively.

“Roughly 40% of patients with lorcaserin achieved a 5% weight loss, and about 14%-18% achieved a 10% weight loss across the glycemic categories,” Dr. Scirica reported. The corresponding values for the placebo-treated patients were 17%-18% and 4%-7%.

Naveed Sattar, MD, the independent commentator for the trial, noted the weight-loss reduction seen “was modest in the context of this trial, but I think the important point was that it was sustained. Sustained weight loss is difficult, and it was sustained on top of lifestyle and on top of the other drugs, and that is important.”

EASD/Susanne Wysocki

However, Dr. Sattar, who is professor and honorary consultant in cardiovascular and medical sciences at the University of Glasgow (Scotland), also observed that “as night follows day, glycemic improvements follow weight loss.” So, did the glycemic parameters improve purely because of the weight loss? While there is some preclinical evidence that lorcaserin may have an effect outside of its weight-lowering effects, Dr. Sattar felt this was unlikely to be clinically significant in itself.

“Obesity is probably the biggest challenge we have in the medical profession. We’ve got excellent cholesterol-lowering, blood pressure–lowering, and diabetes drugs. Yet obesity and complications are rising worldwide” and “safe weight-loss drugs remain sparse,” Dr. Sattar said.

He suggested that lorcaserin may well have an adjunctive place in the current treatment paradigm, but that place is probably “down the line” after other measures with greater weight-reducing effects or proven cardiovascular benefits were used. Not only are lifestyle modification approaches improving, Dr. Sattar said, but there are also over-the-counter options such as orlistat (Xenical), metformin, sodium-glucose cotransporter 2 inhibitors, glucagonlike peptide receptor–1 agonists, and bariatric surgery that are likely to be used first.

“This is a fantastically well done trial, we needed it,” Dr. Sattar said. However, because there was modest weight loss and no real cardiovascular benefit (but also no cardiovascular safety concern) he called the results “a bust” saying that “we have to take them at face value for what they are.”

Dr. Sattar noted that his “gut feeling at the moment is that the clinical role for lorcaserin is probably, at best, a down-the-line adjunct in those who are still obese for additional weight reduction on top of other drugs and lifestyle modifications, particularly in those who are ‘super responders.’ ” This is so long as the safety signals remain strong and there are quality of life benefits, he added.

The study was designed by the TIMI Study Group in conjunction with the executive committee and the trial sponsor, Eisai. Dr. Bohula May and Dr. Scirica reported receiving grants from Eisai, during the conduct of the study. Dr. Sattar reported grant support from Boehringer Ingelheim, and being part of an advisory board or speaker’s bureau for Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen Pharmaceuticals, Novo Nordisk, and Sanofi.

SOURCES: Bohula May EA et al. Lancet. 2018 Oct 4. doi: 10.1016/S0140-6736(18)32328-6; Bohula May EA et al. N Engl J Med. 2018; 379:1107-17; Sattar N. EASD 2018, Session S33.

BERLIN – Lower rates of incident type 2 diabetes mellitus (T2DM) and improved glycemic control were two of the metabolic effects seen with the appetite-suppressant drug lorcaserin versus placebo on top of existing lifestyle management measures in a large-scale trial of more than 12,000 overweight or obese individuals with established cardiovascular disease or T2DM and other cardiovascular risk factors.

Sara Freeman/MDEdge News

In the CAMELLIA-TIMI 61 trial, treatment with a twice-daily, 10-mg dose of lorcaserin for a median of 3.3 years was associated with a significant 19% reduction in the risk of incident T2DM in participants with prediabetes, compared with placebo (8.5% vs. 10.3%; hazard ratio, 0.81; 95% confidence interval, 0.66-0.99; P = .038). The reduction in the risk of incident T2DM was even greater (23%) in people without diabetes at baseline (6.7% lorcaserin vs. 8.4% placebo; HR, 0.77; 95% CI, 0.63-0.94; P = .012).

Furthermore, in patients with T2DM who had a mean baseline glycated hemoglobin (HbA_1c) of 7%, an absolute 0.33% reduction was seen at 1 year between the lorcaserin and placebo groups, with more modest but still significant between-group reductions (–0.09% and –0.08%) in individuals with prediabetes or normoglycemia (all P less than .0001). When baseline HbA_1c levels were higher in patients with T2DM (8%), greater net reductions (0.52%) versus placebo were seen (P less than .0001).

These were some of the metabolic findings, published online in the Lancet to coincide with their presentation at the annual meeting of the European Association for the Study of Diabetes, that add to those already released from the CAMELLIA-TIMI 61 trial on cardiovascular safety, lead author and TIMI (Thrombolysis in Myocardial Infarction) group investigator Erin A. Bohula May, MD, observed during a press conference.

The cardiovascular safety data were presented at the 2018 annual congress of the European Society for Cardiology in August and published in the New England Journal of Medicine. These showed no increase with lorcaserin versus placebo in the risk of achieving a major cardiovascular endpoint (MACE) of cardiovascular death, MI, or stroke (HR, 0.99; 95% CI, 0.85-1.14; P less than .001 for noninferiority). There was also no difference between groups in the cumulative incidence of MACE+, which included heart failure, hospitalization for unstable angina, and the need for coronary revascularization (HR, 0.97; 95% CI, 0.87-1.07; P = .55 for superiority).

“We know that weight loss can improve cardiovascular and glycemic risk factors, but it’s difficult to achieve and maintain, and weight-loss agents are guideline-recommended adjuncts to lifestyle modification,” said Dr. Bohula May, who is a cardiovascular medicine and critical care specialist at Brigham and Women’s Hospital in Boston.

“However, prior to this study no agent had convincingly demonstrated cardiovascular safety in a rigorous clinical outcomes study,” she said, noting that several agents, such as the now-withdrawn rimonabant (Acomplia/Zimulti) and sibutramine (Meridia), had been shown to precipitate cardiovascular or psychiatric events, which led the Food and Drug Administration to mandate that all weight-loss drugs be assessed for cardiovascular safety. Lorcaserin (Belviq) is a centrally acting 5-HT_2C agonist that works by decreasing appetite and was approved by the FDA in 2012 but is not currently available in Europe.

Long-term data on the effects of weight-loss agents on glycemic parameters were limited, hence the remit of the CAMELLIA-TIMI 61 trial was to assess both the cardiovascular and metabolic safety of lorcaserin. The drug was used on a background of lifestyle modification in 6,000 obese or overweight individuals at high risk of cardiovascular events. A further 6,000 individuals received placebo.

Sara Freeman/MDEdge News

“Lorcaserin induced and maintained weight loss across the glycemic categories,” said coauthor and TIMI group investigator Benjamin Scirica, MD, also of Brigham and Women’s Hospital, who presented the metabolic data during a scientific session at the EASD meeting. Specifically, there was a net weight loss beyond that seen with placebo of 2.6 kg, 2.8 kg, and 3.3 kg in individuals with T2DM, prediabetes, and normoglycemia, respectively.

“Roughly 40% of patients with lorcaserin achieved a 5% weight loss, and about 14%-18% achieved a 10% weight loss across the glycemic categories,” Dr. Scirica reported. The corresponding values for the placebo-treated patients were 17%-18% and 4%-7%.

Naveed Sattar, MD, the independent commentator for the trial, noted the weight-loss reduction seen “was modest in the context of this trial, but I think the important point was that it was sustained. Sustained weight loss is difficult, and it was sustained on top of lifestyle and on top of the other drugs, and that is important.”

EASD/Susanne Wysocki

However, Dr. Sattar, who is professor and honorary consultant in cardiovascular and medical sciences at the University of Glasgow (Scotland), also observed that “as night follows day, glycemic improvements follow weight loss.” So, did the glycemic parameters improve purely because of the weight loss? While there is some preclinical evidence that lorcaserin may have an effect outside of its weight-lowering effects, Dr. Sattar felt this was unlikely to be clinically significant in itself.

“Obesity is probably the biggest challenge we have in the medical profession. We’ve got excellent cholesterol-lowering, blood pressure–lowering, and diabetes drugs. Yet obesity and complications are rising worldwide” and “safe weight-loss drugs remain sparse,” Dr. Sattar said.

He suggested that lorcaserin may well have an adjunctive place in the current treatment paradigm, but that place is probably “down the line” after other measures with greater weight-reducing effects or proven cardiovascular benefits were used. Not only are lifestyle modification approaches improving, Dr. Sattar said, but there are also over-the-counter options such as orlistat (Xenical), metformin, sodium-glucose cotransporter 2 inhibitors, glucagonlike peptide receptor–1 agonists, and bariatric surgery that are likely to be used first.

“This is a fantastically well done trial, we needed it,” Dr. Sattar said. However, because there was modest weight loss and no real cardiovascular benefit (but also no cardiovascular safety concern) he called the results “a bust” saying that “we have to take them at face value for what they are.”

Dr. Sattar noted that his “gut feeling at the moment is that the clinical role for lorcaserin is probably, at best, a down-the-line adjunct in those who are still obese for additional weight reduction on top of other drugs and lifestyle modifications, particularly in those who are ‘super responders.’ ” This is so long as the safety signals remain strong and there are quality of life benefits, he added.

The study was designed by the TIMI Study Group in conjunction with the executive committee and the trial sponsor, Eisai. Dr. Bohula May and Dr. Scirica reported receiving grants from Eisai, during the conduct of the study. Dr. Sattar reported grant support from Boehringer Ingelheim, and being part of an advisory board or speaker’s bureau for Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen Pharmaceuticals, Novo Nordisk, and Sanofi.

SOURCES: Bohula May EA et al. Lancet. 2018 Oct 4. doi: 10.1016/S0140-6736(18)32328-6; Bohula May EA et al. N Engl J Med. 2018; 379:1107-17; Sattar N. EASD 2018, Session S33.

BERLIN – Lower rates of incident type 2 diabetes mellitus (T2DM) and improved glycemic control were two of the metabolic effects seen with the appetite-suppressant drug lorcaserin versus placebo on top of existing lifestyle management measures in a large-scale trial of more than 12,000 overweight or obese individuals with established cardiovascular disease or T2DM and other cardiovascular risk factors.

Sara Freeman/MDEdge News

In the CAMELLIA-TIMI 61 trial, treatment with a twice-daily, 10-mg dose of lorcaserin for a median of 3.3 years was associated with a significant 19% reduction in the risk of incident T2DM in participants with prediabetes, compared with placebo (8.5% vs. 10.3%; hazard ratio, 0.81; 95% confidence interval, 0.66-0.99; P = .038). The reduction in the risk of incident T2DM was even greater (23%) in people without diabetes at baseline (6.7% lorcaserin vs. 8.4% placebo; HR, 0.77; 95% CI, 0.63-0.94; P = .012).

Furthermore, in patients with T2DM who had a mean baseline glycated hemoglobin (HbA_1c) of 7%, an absolute 0.33% reduction was seen at 1 year between the lorcaserin and placebo groups, with more modest but still significant between-group reductions (–0.09% and –0.08%) in individuals with prediabetes or normoglycemia (all P less than .0001). When baseline HbA_1c levels were higher in patients with T2DM (8%), greater net reductions (0.52%) versus placebo were seen (P less than .0001).

These were some of the metabolic findings, published online in the Lancet to coincide with their presentation at the annual meeting of the European Association for the Study of Diabetes, that add to those already released from the CAMELLIA-TIMI 61 trial on cardiovascular safety, lead author and TIMI (Thrombolysis in Myocardial Infarction) group investigator Erin A. Bohula May, MD, observed during a press conference.

The cardiovascular safety data were presented at the 2018 annual congress of the European Society for Cardiology in August and published in the New England Journal of Medicine. These showed no increase with lorcaserin versus placebo in the risk of achieving a major cardiovascular endpoint (MACE) of cardiovascular death, MI, or stroke (HR, 0.99; 95% CI, 0.85-1.14; P less than .001 for noninferiority). There was also no difference between groups in the cumulative incidence of MACE+, which included heart failure, hospitalization for unstable angina, and the need for coronary revascularization (HR, 0.97; 95% CI, 0.87-1.07; P = .55 for superiority).

“We know that weight loss can improve cardiovascular and glycemic risk factors, but it’s difficult to achieve and maintain, and weight-loss agents are guideline-recommended adjuncts to lifestyle modification,” said Dr. Bohula May, who is a cardiovascular medicine and critical care specialist at Brigham and Women’s Hospital in Boston.

“However, prior to this study no agent had convincingly demonstrated cardiovascular safety in a rigorous clinical outcomes study,” she said, noting that several agents, such as the now-withdrawn rimonabant (Acomplia/Zimulti) and sibutramine (Meridia), had been shown to precipitate cardiovascular or psychiatric events, which led the Food and Drug Administration to mandate that all weight-loss drugs be assessed for cardiovascular safety. Lorcaserin (Belviq) is a centrally acting 5-HT_2C agonist that works by decreasing appetite and was approved by the FDA in 2012 but is not currently available in Europe.

Long-term data on the effects of weight-loss agents on glycemic parameters were limited, hence the remit of the CAMELLIA-TIMI 61 trial was to assess both the cardiovascular and metabolic safety of lorcaserin. The drug was used on a background of lifestyle modification in 6,000 obese or overweight individuals at high risk of cardiovascular events. A further 6,000 individuals received placebo.

Sara Freeman/MDEdge News

“Lorcaserin induced and maintained weight loss across the glycemic categories,” said coauthor and TIMI group investigator Benjamin Scirica, MD, also of Brigham and Women’s Hospital, who presented the metabolic data during a scientific session at the EASD meeting. Specifically, there was a net weight loss beyond that seen with placebo of 2.6 kg, 2.8 kg, and 3.3 kg in individuals with T2DM, prediabetes, and normoglycemia, respectively.

“Roughly 40% of patients with lorcaserin achieved a 5% weight loss, and about 14%-18% achieved a 10% weight loss across the glycemic categories,” Dr. Scirica reported. The corresponding values for the placebo-treated patients were 17%-18% and 4%-7%.

Naveed Sattar, MD, the independent commentator for the trial, noted the weight-loss reduction seen “was modest in the context of this trial, but I think the important point was that it was sustained. Sustained weight loss is difficult, and it was sustained on top of lifestyle and on top of the other drugs, and that is important.”

EASD/Susanne Wysocki

However, Dr. Sattar, who is professor and honorary consultant in cardiovascular and medical sciences at the University of Glasgow (Scotland), also observed that “as night follows day, glycemic improvements follow weight loss.” So, did the glycemic parameters improve purely because of the weight loss? While there is some preclinical evidence that lorcaserin may have an effect outside of its weight-lowering effects, Dr. Sattar felt this was unlikely to be clinically significant in itself.

“Obesity is probably the biggest challenge we have in the medical profession. We’ve got excellent cholesterol-lowering, blood pressure–lowering, and diabetes drugs. Yet obesity and complications are rising worldwide” and “safe weight-loss drugs remain sparse,” Dr. Sattar said.

He suggested that lorcaserin may well have an adjunctive place in the current treatment paradigm, but that place is probably “down the line” after other measures with greater weight-reducing effects or proven cardiovascular benefits were used. Not only are lifestyle modification approaches improving, Dr. Sattar said, but there are also over-the-counter options such as orlistat (Xenical), metformin, sodium-glucose cotransporter 2 inhibitors, glucagonlike peptide receptor–1 agonists, and bariatric surgery that are likely to be used first.

“This is a fantastically well done trial, we needed it,” Dr. Sattar said. However, because there was modest weight loss and no real cardiovascular benefit (but also no cardiovascular safety concern) he called the results “a bust” saying that “we have to take them at face value for what they are.”

Dr. Sattar noted that his “gut feeling at the moment is that the clinical role for lorcaserin is probably, at best, a down-the-line adjunct in those who are still obese for additional weight reduction on top of other drugs and lifestyle modifications, particularly in those who are ‘super responders.’ ” This is so long as the safety signals remain strong and there are quality of life benefits, he added.

The study was designed by the TIMI Study Group in conjunction with the executive committee and the trial sponsor, Eisai. Dr. Bohula May and Dr. Scirica reported receiving grants from Eisai, during the conduct of the study. Dr. Sattar reported grant support from Boehringer Ingelheim, and being part of an advisory board or speaker’s bureau for Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen Pharmaceuticals, Novo Nordisk, and Sanofi.

SOURCES: Bohula May EA et al. Lancet. 2018 Oct 4. doi: 10.1016/S0140-6736(18)32328-6; Bohula May EA et al. N Engl J Med. 2018; 379:1107-17; Sattar N. EASD 2018, Session S33.

BERLIN – Providing patient-centered care is at the heart of managing hyperglycemia in people with type 2 diabetes and is emphasized in a consensus report issued jointly by the American Diabetes Association and the European Association for the Study of Diabetes. 

Sara Freeman/MDedge News

The 2018 ADA/EASD Consensus Report also addresses clinical inertia and notes that medication adherence and persistence should be facilitated. All patients should be offered ongoing self-management education and support, Melanie J. Davies, MD, one of the two cochairs of the report-writing committee, said during a press conference at the annual meeting of the European Association for the Study of Diabetes.

The report also addresses preferred choices for glucose-lowering medications, largely based on recent findings of large-scale cardiovascular outcomes trials. There also is specific guidance on how to manage hyperglycemia in patients with atherosclerotic cardiovascular disease, chronic kidney disease, and heart failure.

“The consensus report focuses on not what an individual’s glycemic target should be or how to individualize goals but really addresses how each patient can achieve their individualized glycemic target,” Dr. Davies said.

Dr. Davies, who is professor of diabetes medicine at the University of Leicester (England) and an honorary consultant diabetologist at the University Hospitals of Leicester NHS Trust also said that the report looked at taking patient factors and preferences into account but also considered “the ever-increasing complexity around the availability of glucose-lowering agents.”

Sara Freeman/MDedge News

Practical guide to managing patients

The consensus report, which was simultaneously published in the official journals of the ADA (Diabetes Care 2018 Sep; dci180033) and the EASD (Diabetologia. 2018 Sep. doi: 10.1007/s00125-018-4729-5) to coincide with its presentation at the EASD meeting, is much more visual and aims to be more of a practical aid than was the previous position statement from 2015 (Diabetologia. 2015 Mar;58:429-42; Diabetes Care 2015 Jan;38[1]:140-9), on which it was based, Dr. Davies said.

The patient has been placed firmly at the center of the decision cycle, she observed, which starts with assessment of patient characteristics and consideration of their lifestyle, comorbidities, and clinical parameters. Specific factors that may affect the choice of treatment, such as the individualized glycosylated hemoglobin (HbA_1c) target or side effect profiles of medications, are included, as is working together with the patient to make, continually monitor, and reevaluate a shared decision plan.

In terms of lifestyle, one of the consensus recommendations is that “an individualized program of medical nutritional therapy should be offered to all patients,” with the more specific recommendation that those who are overweight or obese be advised of the health benefits of weight loss and be encouraged to participate in dietary modifications that may include food substitution. Increasing activity is also highly recommended based on long-established evidence that this can help reduce HbA_1c level. Recommendations for when to consider bariatric surgery for weight management also are included.
 

Clarity on treating comorbidities

Previously discussed in June at the ADA’s annual meeting, the consensus report has undergone fine-tuning and multiple revisions. The report was based on a comprehensive and systematic review of the diabetes literature available from 2014 through February 2018. Overall, more than 6,000 randomized trials, reviews, and meta-analyses were considered and distilled down to a list of around 500 papers that were then thoroughly reviewed by an expert panel.

Sara Freeman/MDedge News

“I guarantee, there’s never been a paper that’s been more peer reviewed,” said John Buse, MD, PhD, the other cochair of the report’s writing committee. A total of 35 named individuals reviewed and provided more than 800 detailed comments among them, which were considered and reflected in the final version.

Dr. Buse is the Verne S. Caviness Distinguished Professor, chief of the division of endocrinology, and director of the diabetes center at the University of North Carolina at Chapel Hill.

“There’s much more clarity now,” added Dr. Davies, referring to the changes made to how patients with comorbidities are managed. If somebody does have atherosclerotic cardiovascular disease or chronic kidney disease, there is now clear direction on which glucose-lowering therapy should be considered first, and what to do if the HbA_1c remains above target.

For example, in patients who have established atherosclerotic cardiovascular disease, the recommendation is, after metformin, to choose either a glucagonlike peptide–1 (GLP-1) receptor agonist or a sodium-glucose cotransporter 2 (SGLT2) inhibitor with proven cardiovascular benefit.

If heart failure or chronic kidney disease coexist, then an SGLT2 inhibitor shown to reduce their progression should be favored, or if contraindicated or not preferred, a GLP-1 receptor agonist with proven cardiovascular benefit should be given.

The main action, pros and cons of interventions, and the various medications are shown in tables to clearly guide clinicians in the decision-making process, Dr. Buse said.
 

First-line management

The first line recommended glucose-lowering therapy for hyperglycemia in type 2 diabetes remains metformin, together with comprehensive lifestyle advice, Dr. Buse observed.

“A huge controversy in the [diabetes] community asks, ‘Is metformin the first-line therapy because it’s cheap and was the first oral agent studied and has a long history?’ or is it something that really is based on medical evidence?” Dr. Buse acknowledged. Although combinations of glucose-lowering drugs have been proposed upfront, “the evidence for that is largely from small studies, in limited numbers of sites, such that, for now, we generally recommend starting on a single-agent medication if lifestyle management is not enough to control glucose.”

If there is a need to intensify treatment as the patient’s HbA_1c remains above their individualized target, then other drugs may be added to step up the treatment. The consensus report then looks at which drugs might be best to add, based on the need to avoid hypoglycemia, promote weight loss, and/or if cost or availability is a major issue.

If patients need the greater glucose-lowering effects of an injectable medication, a GLP-1 receptor agonist – not insulin – is recommended, Dr. Buse observed. However, for patients with extreme and symptomatic hyperglycemia, insulin is then recommended.

There also is guidance on when to consider oral therapies in conjunction with injectable therapies, with the consensus recommendation stating: Patients who are unable to maintain glycemic targets on basal insulin in combination with oral medication can have treatment intensified with GLP-1 receptor agonists, SGLT2 inhibitors, or prandial insulin.

The ADA perspective

Sara Freeman/MDedge News

William T. Cefalu, MD, chief scientific, medical and mission officer of the ADA observed that the “ADA fully endorses the ADA/EASD Consensus Report” and had already added a statement on the recommendations into its Standards of Medical Care in Diabetes – 2018 as part of the organization’s Living Standards Update. This was a change made last year to allow real-time updates of practice recommendations based on new and evolving evidence released in between the annual process of updating the Society’s Standards.

“Much, if not all, of these recommendations from this paper will be incorporated into our Standards,” said Dr. Cefalu. “We applaud the authors of the consensus paper; we think this was an outstanding group, and we really feel that this is a paradigm change in diabetes management,” he added. “Instead of relying on the [HbA_1c] number in an algorithm, this puts the patient at the center; patient-related factors, patient preferences, adherence, compliance, and more importantly, the underlying disease state … this really is a comprehensive approach to management.”

The stratification of patients by cardiovascular disease, kidney disease, or heart failure is a particularly noteworthy, as is the advice on which agent to choose if weight management is an issue. Finally, there are the considerations of costs of therapy, and what to do if there is the risk of hypoglycemia. “The consensus recommendations and approach to glycemic management in adults with type 2 diabetes presented within the report reflects the current view of the ADA,” Dr. Cefalu confirmed.
 

The EASD perspective

Sara Freeman/MDedge News

“The EASD was again delighted to go into cooperation with our colleagues and friends at the ADA because is it is so important to bring out a consensus on where we need to go in this forest of glucose-lowering therapies,” said Chantal Mathieu, MD, PhD, vice-president of the EASD.

“The fact that this consensus paper puts the patient front and center, and makes that an integral part of glucose-lowering therapy, and also that lifestyle is being accentuated again, together with education in every patient is crucial,” Dr. Mathieu, who is professor of medicine at the Katholieke Universiteit Leuven (Belgium), and a coauthor of the report, added.

“At EASD, we also believe that it is very important to bring this consensus paper to life,” she added, which is part of her role as the chair of postgraduate education at the EASD. Two of the EASD’s main remits is to ensure that the results of research and education are brought to the diabetes community at large, she said.

In every figure in the paper there is a highlight to say, “please avoid clinical inertia, reassess and modify treatment if necessary, at least every 3-6 months,” Dr. Mathieu noted during the EASD congress.

Sara Freeman/MDedge News

David Matthews, MD, professor of diabetic medicine at the University of Oxford (England) and president-elect of the EASD, commented on the 2018 ADA/EASD Consensus Report after its presentation at the EASD meeting. “The reality is that you’ve got to think extremely hard with your patients about what the balances between risks and benefits are,” Dr. Matthews said. “We encourage you to do this, what you have here is a wonderful handbook to guide you in your decision making.”

Dr. Davies reported receiving personal fees and/or grants from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Gilead, Intarcia Therapeutics/Servier, Janssen, Merck Sharp & Dohme, Mitsubishi Tanabi, Novo Nordisk, Sanofi, and Takeda.

Dr. Buse disclosed acting as a consultant to and/or receiving research support from Adocia, AstraZeneca, Eli Lilly, GI Dynamics, Intarcia Therapeutics, MannKind, NovaTarg, Neurimmune, Novo Nordisk, Senseonics, and vTv Therapeutics with fees paid to the University of North Carolina. He holds stock options in Mellitus Health, PhaseBio and Stability Health.

Dr. Mathieu disclosed relationships with (advisory boards, speakers bureaus, and/or research support) from Abbott, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Hanmi Pharmaceuticals, Intrexon, Janssen Pharmaceuticals, MannKind, Medtronic, MSD, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, Sanofi, and UCB.

Dr. Cefalu had no disclosures and Dr. Matthews had no relevant conflicts of interest other than becoming the EASD president-elect during the meeting.

BERLIN – Providing patient-centered care is at the heart of managing hyperglycemia in people with type 2 diabetes and is emphasized in a consensus report issued jointly by the American Diabetes Association and the European Association for the Study of Diabetes. 

Sara Freeman/MDedge News

The 2018 ADA/EASD Consensus Report also addresses clinical inertia and notes that medication adherence and persistence should be facilitated. All patients should be offered ongoing self-management education and support, Melanie J. Davies, MD, one of the two cochairs of the report-writing committee, said during a press conference at the annual meeting of the European Association for the Study of Diabetes.

The report also addresses preferred choices for glucose-lowering medications, largely based on recent findings of large-scale cardiovascular outcomes trials. There also is specific guidance on how to manage hyperglycemia in patients with atherosclerotic cardiovascular disease, chronic kidney disease, and heart failure.

“The consensus report focuses on not what an individual’s glycemic target should be or how to individualize goals but really addresses how each patient can achieve their individualized glycemic target,” Dr. Davies said.

Dr. Davies, who is professor of diabetes medicine at the University of Leicester (England) and an honorary consultant diabetologist at the University Hospitals of Leicester NHS Trust also said that the report looked at taking patient factors and preferences into account but also considered “the ever-increasing complexity around the availability of glucose-lowering agents.”

Sara Freeman/MDedge News

Practical guide to managing patients

The consensus report, which was simultaneously published in the official journals of the ADA (Diabetes Care 2018 Sep; dci180033) and the EASD (Diabetologia. 2018 Sep. doi: 10.1007/s00125-018-4729-5) to coincide with its presentation at the EASD meeting, is much more visual and aims to be more of a practical aid than was the previous position statement from 2015 (Diabetologia. 2015 Mar;58:429-42; Diabetes Care 2015 Jan;38[1]:140-9), on which it was based, Dr. Davies said.

The patient has been placed firmly at the center of the decision cycle, she observed, which starts with assessment of patient characteristics and consideration of their lifestyle, comorbidities, and clinical parameters. Specific factors that may affect the choice of treatment, such as the individualized glycosylated hemoglobin (HbA_1c) target or side effect profiles of medications, are included, as is working together with the patient to make, continually monitor, and reevaluate a shared decision plan.

In terms of lifestyle, one of the consensus recommendations is that “an individualized program of medical nutritional therapy should be offered to all patients,” with the more specific recommendation that those who are overweight or obese be advised of the health benefits of weight loss and be encouraged to participate in dietary modifications that may include food substitution. Increasing activity is also highly recommended based on long-established evidence that this can help reduce HbA_1c level. Recommendations for when to consider bariatric surgery for weight management also are included.
 

Clarity on treating comorbidities

Previously discussed in June at the ADA’s annual meeting, the consensus report has undergone fine-tuning and multiple revisions. The report was based on a comprehensive and systematic review of the diabetes literature available from 2014 through February 2018. Overall, more than 6,000 randomized trials, reviews, and meta-analyses were considered and distilled down to a list of around 500 papers that were then thoroughly reviewed by an expert panel.

Sara Freeman/MDedge News

“I guarantee, there’s never been a paper that’s been more peer reviewed,” said John Buse, MD, PhD, the other cochair of the report’s writing committee. A total of 35 named individuals reviewed and provided more than 800 detailed comments among them, which were considered and reflected in the final version.

Dr. Buse is the Verne S. Caviness Distinguished Professor, chief of the division of endocrinology, and director of the diabetes center at the University of North Carolina at Chapel Hill.

“There’s much more clarity now,” added Dr. Davies, referring to the changes made to how patients with comorbidities are managed. If somebody does have atherosclerotic cardiovascular disease or chronic kidney disease, there is now clear direction on which glucose-lowering therapy should be considered first, and what to do if the HbA_1c remains above target.

For example, in patients who have established atherosclerotic cardiovascular disease, the recommendation is, after metformin, to choose either a glucagonlike peptide–1 (GLP-1) receptor agonist or a sodium-glucose cotransporter 2 (SGLT2) inhibitor with proven cardiovascular benefit.

If heart failure or chronic kidney disease coexist, then an SGLT2 inhibitor shown to reduce their progression should be favored, or if contraindicated or not preferred, a GLP-1 receptor agonist with proven cardiovascular benefit should be given.

The main action, pros and cons of interventions, and the various medications are shown in tables to clearly guide clinicians in the decision-making process, Dr. Buse said.
 

First-line management

The first line recommended glucose-lowering therapy for hyperglycemia in type 2 diabetes remains metformin, together with comprehensive lifestyle advice, Dr. Buse observed.

“A huge controversy in the [diabetes] community asks, ‘Is metformin the first-line therapy because it’s cheap and was the first oral agent studied and has a long history?’ or is it something that really is based on medical evidence?” Dr. Buse acknowledged. Although combinations of glucose-lowering drugs have been proposed upfront, “the evidence for that is largely from small studies, in limited numbers of sites, such that, for now, we generally recommend starting on a single-agent medication if lifestyle management is not enough to control glucose.”

If there is a need to intensify treatment as the patient’s HbA_1c remains above their individualized target, then other drugs may be added to step up the treatment. The consensus report then looks at which drugs might be best to add, based on the need to avoid hypoglycemia, promote weight loss, and/or if cost or availability is a major issue.

If patients need the greater glucose-lowering effects of an injectable medication, a GLP-1 receptor agonist – not insulin – is recommended, Dr. Buse observed. However, for patients with extreme and symptomatic hyperglycemia, insulin is then recommended.

There also is guidance on when to consider oral therapies in conjunction with injectable therapies, with the consensus recommendation stating: Patients who are unable to maintain glycemic targets on basal insulin in combination with oral medication can have treatment intensified with GLP-1 receptor agonists, SGLT2 inhibitors, or prandial insulin.

The ADA perspective

Sara Freeman/MDedge News

William T. Cefalu, MD, chief scientific, medical and mission officer of the ADA observed that the “ADA fully endorses the ADA/EASD Consensus Report” and had already added a statement on the recommendations into its Standards of Medical Care in Diabetes – 2018 as part of the organization’s Living Standards Update. This was a change made last year to allow real-time updates of practice recommendations based on new and evolving evidence released in between the annual process of updating the Society’s Standards.

“Much, if not all, of these recommendations from this paper will be incorporated into our Standards,” said Dr. Cefalu. “We applaud the authors of the consensus paper; we think this was an outstanding group, and we really feel that this is a paradigm change in diabetes management,” he added. “Instead of relying on the [HbA_1c] number in an algorithm, this puts the patient at the center; patient-related factors, patient preferences, adherence, compliance, and more importantly, the underlying disease state … this really is a comprehensive approach to management.”

The stratification of patients by cardiovascular disease, kidney disease, or heart failure is a particularly noteworthy, as is the advice on which agent to choose if weight management is an issue. Finally, there are the considerations of costs of therapy, and what to do if there is the risk of hypoglycemia. “The consensus recommendations and approach to glycemic management in adults with type 2 diabetes presented within the report reflects the current view of the ADA,” Dr. Cefalu confirmed.
 

The EASD perspective

Sara Freeman/MDedge News

“The EASD was again delighted to go into cooperation with our colleagues and friends at the ADA because is it is so important to bring out a consensus on where we need to go in this forest of glucose-lowering therapies,” said Chantal Mathieu, MD, PhD, vice-president of the EASD.

“The fact that this consensus paper puts the patient front and center, and makes that an integral part of glucose-lowering therapy, and also that lifestyle is being accentuated again, together with education in every patient is crucial,” Dr. Mathieu, who is professor of medicine at the Katholieke Universiteit Leuven (Belgium), and a coauthor of the report, added.

“At EASD, we also believe that it is very important to bring this consensus paper to life,” she added, which is part of her role as the chair of postgraduate education at the EASD. Two of the EASD’s main remits is to ensure that the results of research and education are brought to the diabetes community at large, she said.

In every figure in the paper there is a highlight to say, “please avoid clinical inertia, reassess and modify treatment if necessary, at least every 3-6 months,” Dr. Mathieu noted during the EASD congress.

Sara Freeman/MDedge News

David Matthews, MD, professor of diabetic medicine at the University of Oxford (England) and president-elect of the EASD, commented on the 2018 ADA/EASD Consensus Report after its presentation at the EASD meeting. “The reality is that you’ve got to think extremely hard with your patients about what the balances between risks and benefits are,” Dr. Matthews said. “We encourage you to do this, what you have here is a wonderful handbook to guide you in your decision making.”

Dr. Davies reported receiving personal fees and/or grants from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Gilead, Intarcia Therapeutics/Servier, Janssen, Merck Sharp & Dohme, Mitsubishi Tanabi, Novo Nordisk, Sanofi, and Takeda.

Dr. Buse disclosed acting as a consultant to and/or receiving research support from Adocia, AstraZeneca, Eli Lilly, GI Dynamics, Intarcia Therapeutics, MannKind, NovaTarg, Neurimmune, Novo Nordisk, Senseonics, and vTv Therapeutics with fees paid to the University of North Carolina. He holds stock options in Mellitus Health, PhaseBio and Stability Health.

Dr. Mathieu disclosed relationships with (advisory boards, speakers bureaus, and/or research support) from Abbott, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Hanmi Pharmaceuticals, Intrexon, Janssen Pharmaceuticals, MannKind, Medtronic, MSD, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, Sanofi, and UCB.

Dr. Cefalu had no disclosures and Dr. Matthews had no relevant conflicts of interest other than becoming the EASD president-elect during the meeting.

BERLIN – Providing patient-centered care is at the heart of managing hyperglycemia in people with type 2 diabetes and is emphasized in a consensus report issued jointly by the American Diabetes Association and the European Association for the Study of Diabetes. 

Sara Freeman/MDedge News

The 2018 ADA/EASD Consensus Report also addresses clinical inertia and notes that medication adherence and persistence should be facilitated. All patients should be offered ongoing self-management education and support, Melanie J. Davies, MD, one of the two cochairs of the report-writing committee, said during a press conference at the annual meeting of the European Association for the Study of Diabetes.

The report also addresses preferred choices for glucose-lowering medications, largely based on recent findings of large-scale cardiovascular outcomes trials. There also is specific guidance on how to manage hyperglycemia in patients with atherosclerotic cardiovascular disease, chronic kidney disease, and heart failure.

“The consensus report focuses on not what an individual’s glycemic target should be or how to individualize goals but really addresses how each patient can achieve their individualized glycemic target,” Dr. Davies said.

Dr. Davies, who is professor of diabetes medicine at the University of Leicester (England) and an honorary consultant diabetologist at the University Hospitals of Leicester NHS Trust also said that the report looked at taking patient factors and preferences into account but also considered “the ever-increasing complexity around the availability of glucose-lowering agents.”

Sara Freeman/MDedge News

Practical guide to managing patients

The consensus report, which was simultaneously published in the official journals of the ADA (Diabetes Care 2018 Sep; dci180033) and the EASD (Diabetologia. 2018 Sep. doi: 10.1007/s00125-018-4729-5) to coincide with its presentation at the EASD meeting, is much more visual and aims to be more of a practical aid than was the previous position statement from 2015 (Diabetologia. 2015 Mar;58:429-42; Diabetes Care 2015 Jan;38[1]:140-9), on which it was based, Dr. Davies said.

The patient has been placed firmly at the center of the decision cycle, she observed, which starts with assessment of patient characteristics and consideration of their lifestyle, comorbidities, and clinical parameters. Specific factors that may affect the choice of treatment, such as the individualized glycosylated hemoglobin (HbA_1c) target or side effect profiles of medications, are included, as is working together with the patient to make, continually monitor, and reevaluate a shared decision plan.

In terms of lifestyle, one of the consensus recommendations is that “an individualized program of medical nutritional therapy should be offered to all patients,” with the more specific recommendation that those who are overweight or obese be advised of the health benefits of weight loss and be encouraged to participate in dietary modifications that may include food substitution. Increasing activity is also highly recommended based on long-established evidence that this can help reduce HbA_1c level. Recommendations for when to consider bariatric surgery for weight management also are included.
 

Clarity on treating comorbidities

Previously discussed in June at the ADA’s annual meeting, the consensus report has undergone fine-tuning and multiple revisions. The report was based on a comprehensive and systematic review of the diabetes literature available from 2014 through February 2018. Overall, more than 6,000 randomized trials, reviews, and meta-analyses were considered and distilled down to a list of around 500 papers that were then thoroughly reviewed by an expert panel.

Sara Freeman/MDedge News

“I guarantee, there’s never been a paper that’s been more peer reviewed,” said John Buse, MD, PhD, the other cochair of the report’s writing committee. A total of 35 named individuals reviewed and provided more than 800 detailed comments among them, which were considered and reflected in the final version.

Dr. Buse is the Verne S. Caviness Distinguished Professor, chief of the division of endocrinology, and director of the diabetes center at the University of North Carolina at Chapel Hill.

“There’s much more clarity now,” added Dr. Davies, referring to the changes made to how patients with comorbidities are managed. If somebody does have atherosclerotic cardiovascular disease or chronic kidney disease, there is now clear direction on which glucose-lowering therapy should be considered first, and what to do if the HbA_1c remains above target.

For example, in patients who have established atherosclerotic cardiovascular disease, the recommendation is, after metformin, to choose either a glucagonlike peptide–1 (GLP-1) receptor agonist or a sodium-glucose cotransporter 2 (SGLT2) inhibitor with proven cardiovascular benefit.

If heart failure or chronic kidney disease coexist, then an SGLT2 inhibitor shown to reduce their progression should be favored, or if contraindicated or not preferred, a GLP-1 receptor agonist with proven cardiovascular benefit should be given.

The main action, pros and cons of interventions, and the various medications are shown in tables to clearly guide clinicians in the decision-making process, Dr. Buse said.
 

First-line management

The first line recommended glucose-lowering therapy for hyperglycemia in type 2 diabetes remains metformin, together with comprehensive lifestyle advice, Dr. Buse observed.

“A huge controversy in the [diabetes] community asks, ‘Is metformin the first-line therapy because it’s cheap and was the first oral agent studied and has a long history?’ or is it something that really is based on medical evidence?” Dr. Buse acknowledged. Although combinations of glucose-lowering drugs have been proposed upfront, “the evidence for that is largely from small studies, in limited numbers of sites, such that, for now, we generally recommend starting on a single-agent medication if lifestyle management is not enough to control glucose.”

If there is a need to intensify treatment as the patient’s HbA_1c remains above their individualized target, then other drugs may be added to step up the treatment. The consensus report then looks at which drugs might be best to add, based on the need to avoid hypoglycemia, promote weight loss, and/or if cost or availability is a major issue.

If patients need the greater glucose-lowering effects of an injectable medication, a GLP-1 receptor agonist – not insulin – is recommended, Dr. Buse observed. However, for patients with extreme and symptomatic hyperglycemia, insulin is then recommended.

There also is guidance on when to consider oral therapies in conjunction with injectable therapies, with the consensus recommendation stating: Patients who are unable to maintain glycemic targets on basal insulin in combination with oral medication can have treatment intensified with GLP-1 receptor agonists, SGLT2 inhibitors, or prandial insulin.

The ADA perspective

Sara Freeman/MDedge News

William T. Cefalu, MD, chief scientific, medical and mission officer of the ADA observed that the “ADA fully endorses the ADA/EASD Consensus Report” and had already added a statement on the recommendations into its Standards of Medical Care in Diabetes – 2018 as part of the organization’s Living Standards Update. This was a change made last year to allow real-time updates of practice recommendations based on new and evolving evidence released in between the annual process of updating the Society’s Standards.

“Much, if not all, of these recommendations from this paper will be incorporated into our Standards,” said Dr. Cefalu. “We applaud the authors of the consensus paper; we think this was an outstanding group, and we really feel that this is a paradigm change in diabetes management,” he added. “Instead of relying on the [HbA_1c] number in an algorithm, this puts the patient at the center; patient-related factors, patient preferences, adherence, compliance, and more importantly, the underlying disease state … this really is a comprehensive approach to management.”

The stratification of patients by cardiovascular disease, kidney disease, or heart failure is a particularly noteworthy, as is the advice on which agent to choose if weight management is an issue. Finally, there are the considerations of costs of therapy, and what to do if there is the risk of hypoglycemia. “The consensus recommendations and approach to glycemic management in adults with type 2 diabetes presented within the report reflects the current view of the ADA,” Dr. Cefalu confirmed.
 

The EASD perspective

Sara Freeman/MDedge News

“The EASD was again delighted to go into cooperation with our colleagues and friends at the ADA because is it is so important to bring out a consensus on where we need to go in this forest of glucose-lowering therapies,” said Chantal Mathieu, MD, PhD, vice-president of the EASD.

“The fact that this consensus paper puts the patient front and center, and makes that an integral part of glucose-lowering therapy, and also that lifestyle is being accentuated again, together with education in every patient is crucial,” Dr. Mathieu, who is professor of medicine at the Katholieke Universiteit Leuven (Belgium), and a coauthor of the report, added.

“At EASD, we also believe that it is very important to bring this consensus paper to life,” she added, which is part of her role as the chair of postgraduate education at the EASD. Two of the EASD’s main remits is to ensure that the results of research and education are brought to the diabetes community at large, she said.

In every figure in the paper there is a highlight to say, “please avoid clinical inertia, reassess and modify treatment if necessary, at least every 3-6 months,” Dr. Mathieu noted during the EASD congress.

Sara Freeman/MDedge News

David Matthews, MD, professor of diabetic medicine at the University of Oxford (England) and president-elect of the EASD, commented on the 2018 ADA/EASD Consensus Report after its presentation at the EASD meeting. “The reality is that you’ve got to think extremely hard with your patients about what the balances between risks and benefits are,” Dr. Matthews said. “We encourage you to do this, what you have here is a wonderful handbook to guide you in your decision making.”

Dr. Davies reported receiving personal fees and/or grants from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Gilead, Intarcia Therapeutics/Servier, Janssen, Merck Sharp & Dohme, Mitsubishi Tanabi, Novo Nordisk, Sanofi, and Takeda.

Dr. Buse disclosed acting as a consultant to and/or receiving research support from Adocia, AstraZeneca, Eli Lilly, GI Dynamics, Intarcia Therapeutics, MannKind, NovaTarg, Neurimmune, Novo Nordisk, Senseonics, and vTv Therapeutics with fees paid to the University of North Carolina. He holds stock options in Mellitus Health, PhaseBio and Stability Health.

Dr. Mathieu disclosed relationships with (advisory boards, speakers bureaus, and/or research support) from Abbott, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Hanmi Pharmaceuticals, Intrexon, Janssen Pharmaceuticals, MannKind, Medtronic, MSD, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, Sanofi, and UCB.

Dr. Cefalu had no disclosures and Dr. Matthews had no relevant conflicts of interest other than becoming the EASD president-elect during the meeting.

BERLIN – Patients with type 2 diabetes mellitus (T2DM) achieved “impressive” drops in glycated hemoglobin, or HbA_1c, of up to 2.4% and in body weight of up to 11.3 kg with the investigational drug LY3298176 in a phase 2b trial.

Sara Freeman/MDedge News

The primary endpoint was the change in HbA_1c at 26 weeks, which showed significant reductions from baseline of 1.6%, 2%, and 2.4% for the 5-mg, 10-mg, and 15-mg doses, respectively, of the drug tested. By comparison, a drop of just 1.1% was seen for dulaglutide, and 0.1% for placebo.

The higher doses of LY3298176, which is a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and the glucagonlike peptide–1 (GLP-1) receptor, used in the trial helped up to 90% of patients achieve an HbA_1c of 7% or less, 82% of patients to achieve an HbA1c of 6.5% or less, and up to 30% of patients to achieve an HbA1c of less than 5.7%, a range which is considered normal for people without diabetes.

As for weight loss, the 5-mg, 10-mg, and 15-mg doses of LY3298176 helped patients achieve significant –4.8-kg, –8.7-kg, and –11.3-kg changes from baseline, respectively. These were greater than those seen with dulaglutide (–2.7 kg) and placebo (–0.4 kg).

More than one third of patients treated with the novel drug achieved at least a 10% or more change in their starting body weight, with a quarter of patients on the 15-mg dose achieving a 15% or more change in bodyweight.

“These are very, very impressive data both from an A_1c-lowering perspective and also from a weight reduction perspective,” said the study’s principal investigator Juan Frias, MD, at a press briefing held at the annual meeting of the European Association for the Study of Diabetes (EASD).

GLP-1 receptor agonist therapy is a recommended treatment for T2DM because it addresses many of the important pathophysiologic problems, from blood glucose control and weight loss to reducing cardiovascular risk, Dr. Frias observed.

He added that the first GLP-1 receptor agonists became available in the United States in 2005. Their use in T2DM has recently been further endorsed in a consensus report (Diabetes Care. 2018 Sep. doi: rg/10.2337/dci18-0033; Diabetologia. 2018. doi: 10.1007/s00125-018-4729-5) issued jointly by the American Diabetes Association and the EASD.

“Despite the potency of these agents, many of our patients are not achieving adequate glycemic or weight control, so we could always use new agents that are more potent as long as they’re safe for the patient,” said Dr. Frias, who is a clinical endocrinologist and the chief executive officer at the National Research Institute in Los Angeles

LY3298176 is a novel unimolecular, multifunctional peptide that is being developed by Eli Lilly as a dual GIP/GLP-1 receptor agonist for the treatment of T2DM. It consists of 39 amino acids linked to a C20 fatty–diacid moiety and has a mean half-life of around 5 days, which means it can be dosed weekly, Dr. Frias observed.

The effect of targeting both GIP and the GLP-1 receptor simultaneously is possibly both additive and complementary, Dr. Frias suggested. Additive effects may include a decrease in food intake and an increase in insulin secretion, with opposing effects on glucagon secretion, with the additional effects of increased glucose uptake with GIP and delayed gastric emptying with GLP-1 receptor agonism.

Sara Freeman/MDedge News

“When you think back on what the history, biology, and discovery of these compounds was, it isn’t at all obvious you’d pair these two [to make] a so-called ‘twincreatin’ – there is so much overlap,” said Matthias Tschöp, MD, who was invited to discuss the findings after the presentation at the EASD meeting.

Dr. Tschöp, who is the head of the division of neuroendocrinology at the Institute for Diabetes and Obesity at Helmholtz Zentrum München in Neuherberg , Germany, noted that it’s an interesting combination, but it’s not the only approach being tested – there are other twincretin combinations. GIP on its own doesn’t seem to do much, but it must be the combination that is important, it was suggested during discussion.

A total of 318 patients with T2DM and a starting HbA_1c of 7%-10.5% were studied and randomized equally to one of six weekly treatment groups: LY3298176 at doses of either 1 mg, 5 mg, 10 mg, or 15 mg, given subcutaneously; 1.5 mg of dulaglutide; or a placebo injection.

The two highest doses of LY3298176 were titrated rather quickly, Dr. Frias said, and this is important when it comes to the side effect profile. In a subsequent study, the dose titration schedule was amended to prolong the titration period to try to avoid some of the side effects seen, according to Dr. Frias.

Adverse events predominantly affected the gastrointestinal system, with any grade nausea, vomiting, and diarrhea seen in a respective 20%-40%, 7%-26%, and 24%-32% of patients taking the 5-mg, 10-mg, and 15-mg doses. Corresponding rates in dulaglutide-treated patients were, approximately, 30%, 9%, and 17%.

“The safety profile of the dual agonist is really similar to that which you see with selective GLP-1 receptor agonists,” Dr. Frias observed. “The most common adverse events were seen at the higher doses and pertained to GI tolerability, but the majority of these events were mild to moderate and dissipated with time and [could] be reduced significantly by appropriate titration.”

Dr. Frias said: “This novel dual GIP/GLP-1 receptor agonist certainly has the potential to be become a very promising treatment option for patients with type 2 diabetes.”

He added: “In my experience as an investigator, as a clinician, I’ve never really seen this magnitude of A_1c reduction in this percentage of patients and also with this level of weight loss as well, certainly greater than with a selective GLP-1 receptor agonist.”

Further long-term studies are needed, and the phase 3 program in T2DM will be called SURPASS, according to a press statement issued by Eli Lilly. The phase 3 studies are expected to begin “no later than early 2019,” the statement said, and be completed in late 2021. The drug company also noted that it is “evaluating next steps in the study of GIP/GLP-1 RA for obesity and other conditions.”

SOURCE: Frias JP et al. EASD 2018, Session S31; Frias JP et al. Lancet. 2018 Oct 4. doi: 10.1016/S0140-6736(18)32260-8.

BERLIN – Patients with type 2 diabetes mellitus (T2DM) achieved “impressive” drops in glycated hemoglobin, or HbA_1c, of up to 2.4% and in body weight of up to 11.3 kg with the investigational drug LY3298176 in a phase 2b trial.

Sara Freeman/MDedge News

The primary endpoint was the change in HbA_1c at 26 weeks, which showed significant reductions from baseline of 1.6%, 2%, and 2.4% for the 5-mg, 10-mg, and 15-mg doses, respectively, of the drug tested. By comparison, a drop of just 1.1% was seen for dulaglutide, and 0.1% for placebo.

The higher doses of LY3298176, which is a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and the glucagonlike peptide–1 (GLP-1) receptor, used in the trial helped up to 90% of patients achieve an HbA_1c of 7% or less, 82% of patients to achieve an HbA1c of 6.5% or less, and up to 30% of patients to achieve an HbA1c of less than 5.7%, a range which is considered normal for people without diabetes.

As for weight loss, the 5-mg, 10-mg, and 15-mg doses of LY3298176 helped patients achieve significant –4.8-kg, –8.7-kg, and –11.3-kg changes from baseline, respectively. These were greater than those seen with dulaglutide (–2.7 kg) and placebo (–0.4 kg).

More than one third of patients treated with the novel drug achieved at least a 10% or more change in their starting body weight, with a quarter of patients on the 15-mg dose achieving a 15% or more change in bodyweight.

“These are very, very impressive data both from an A_1c-lowering perspective and also from a weight reduction perspective,” said the study’s principal investigator Juan Frias, MD, at a press briefing held at the annual meeting of the European Association for the Study of Diabetes (EASD).

GLP-1 receptor agonist therapy is a recommended treatment for T2DM because it addresses many of the important pathophysiologic problems, from blood glucose control and weight loss to reducing cardiovascular risk, Dr. Frias observed.

He added that the first GLP-1 receptor agonists became available in the United States in 2005. Their use in T2DM has recently been further endorsed in a consensus report (Diabetes Care. 2018 Sep. doi: rg/10.2337/dci18-0033; Diabetologia. 2018. doi: 10.1007/s00125-018-4729-5) issued jointly by the American Diabetes Association and the EASD.

“Despite the potency of these agents, many of our patients are not achieving adequate glycemic or weight control, so we could always use new agents that are more potent as long as they’re safe for the patient,” said Dr. Frias, who is a clinical endocrinologist and the chief executive officer at the National Research Institute in Los Angeles

LY3298176 is a novel unimolecular, multifunctional peptide that is being developed by Eli Lilly as a dual GIP/GLP-1 receptor agonist for the treatment of T2DM. It consists of 39 amino acids linked to a C20 fatty–diacid moiety and has a mean half-life of around 5 days, which means it can be dosed weekly, Dr. Frias observed.

The effect of targeting both GIP and the GLP-1 receptor simultaneously is possibly both additive and complementary, Dr. Frias suggested. Additive effects may include a decrease in food intake and an increase in insulin secretion, with opposing effects on glucagon secretion, with the additional effects of increased glucose uptake with GIP and delayed gastric emptying with GLP-1 receptor agonism.

Sara Freeman/MDedge News

“When you think back on what the history, biology, and discovery of these compounds was, it isn’t at all obvious you’d pair these two [to make] a so-called ‘twincreatin’ – there is so much overlap,” said Matthias Tschöp, MD, who was invited to discuss the findings after the presentation at the EASD meeting.

Dr. Tschöp, who is the head of the division of neuroendocrinology at the Institute for Diabetes and Obesity at Helmholtz Zentrum München in Neuherberg , Germany, noted that it’s an interesting combination, but it’s not the only approach being tested – there are other twincretin combinations. GIP on its own doesn’t seem to do much, but it must be the combination that is important, it was suggested during discussion.

A total of 318 patients with T2DM and a starting HbA_1c of 7%-10.5% were studied and randomized equally to one of six weekly treatment groups: LY3298176 at doses of either 1 mg, 5 mg, 10 mg, or 15 mg, given subcutaneously; 1.5 mg of dulaglutide; or a placebo injection.

The two highest doses of LY3298176 were titrated rather quickly, Dr. Frias said, and this is important when it comes to the side effect profile. In a subsequent study, the dose titration schedule was amended to prolong the titration period to try to avoid some of the side effects seen, according to Dr. Frias.

Adverse events predominantly affected the gastrointestinal system, with any grade nausea, vomiting, and diarrhea seen in a respective 20%-40%, 7%-26%, and 24%-32% of patients taking the 5-mg, 10-mg, and 15-mg doses. Corresponding rates in dulaglutide-treated patients were, approximately, 30%, 9%, and 17%.

“The safety profile of the dual agonist is really similar to that which you see with selective GLP-1 receptor agonists,” Dr. Frias observed. “The most common adverse events were seen at the higher doses and pertained to GI tolerability, but the majority of these events were mild to moderate and dissipated with time and [could] be reduced significantly by appropriate titration.”

Dr. Frias said: “This novel dual GIP/GLP-1 receptor agonist certainly has the potential to be become a very promising treatment option for patients with type 2 diabetes.”

He added: “In my experience as an investigator, as a clinician, I’ve never really seen this magnitude of A_1c reduction in this percentage of patients and also with this level of weight loss as well, certainly greater than with a selective GLP-1 receptor agonist.”

Further long-term studies are needed, and the phase 3 program in T2DM will be called SURPASS, according to a press statement issued by Eli Lilly. The phase 3 studies are expected to begin “no later than early 2019,” the statement said, and be completed in late 2021. The drug company also noted that it is “evaluating next steps in the study of GIP/GLP-1 RA for obesity and other conditions.”

SOURCE: Frias JP et al. EASD 2018, Session S31; Frias JP et al. Lancet. 2018 Oct 4. doi: 10.1016/S0140-6736(18)32260-8.

BERLIN – Patients with type 2 diabetes mellitus (T2DM) achieved “impressive” drops in glycated hemoglobin, or HbA_1c, of up to 2.4% and in body weight of up to 11.3 kg with the investigational drug LY3298176 in a phase 2b trial.

Sara Freeman/MDedge News

The primary endpoint was the change in HbA_1c at 26 weeks, which showed significant reductions from baseline of 1.6%, 2%, and 2.4% for the 5-mg, 10-mg, and 15-mg doses, respectively, of the drug tested. By comparison, a drop of just 1.1% was seen for dulaglutide, and 0.1% for placebo.

The higher doses of LY3298176, which is a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and the glucagonlike peptide–1 (GLP-1) receptor, used in the trial helped up to 90% of patients achieve an HbA_1c of 7% or less, 82% of patients to achieve an HbA1c of 6.5% or less, and up to 30% of patients to achieve an HbA1c of less than 5.7%, a range which is considered normal for people without diabetes.

As for weight loss, the 5-mg, 10-mg, and 15-mg doses of LY3298176 helped patients achieve significant –4.8-kg, –8.7-kg, and –11.3-kg changes from baseline, respectively. These were greater than those seen with dulaglutide (–2.7 kg) and placebo (–0.4 kg).

More than one third of patients treated with the novel drug achieved at least a 10% or more change in their starting body weight, with a quarter of patients on the 15-mg dose achieving a 15% or more change in bodyweight.

“These are very, very impressive data both from an A_1c-lowering perspective and also from a weight reduction perspective,” said the study’s principal investigator Juan Frias, MD, at a press briefing held at the annual meeting of the European Association for the Study of Diabetes (EASD).

GLP-1 receptor agonist therapy is a recommended treatment for T2DM because it addresses many of the important pathophysiologic problems, from blood glucose control and weight loss to reducing cardiovascular risk, Dr. Frias observed.

He added that the first GLP-1 receptor agonists became available in the United States in 2005. Their use in T2DM has recently been further endorsed in a consensus report (Diabetes Care. 2018 Sep. doi: rg/10.2337/dci18-0033; Diabetologia. 2018. doi: 10.1007/s00125-018-4729-5) issued jointly by the American Diabetes Association and the EASD.

“Despite the potency of these agents, many of our patients are not achieving adequate glycemic or weight control, so we could always use new agents that are more potent as long as they’re safe for the patient,” said Dr. Frias, who is a clinical endocrinologist and the chief executive officer at the National Research Institute in Los Angeles

LY3298176 is a novel unimolecular, multifunctional peptide that is being developed by Eli Lilly as a dual GIP/GLP-1 receptor agonist for the treatment of T2DM. It consists of 39 amino acids linked to a C20 fatty–diacid moiety and has a mean half-life of around 5 days, which means it can be dosed weekly, Dr. Frias observed.

The effect of targeting both GIP and the GLP-1 receptor simultaneously is possibly both additive and complementary, Dr. Frias suggested. Additive effects may include a decrease in food intake and an increase in insulin secretion, with opposing effects on glucagon secretion, with the additional effects of increased glucose uptake with GIP and delayed gastric emptying with GLP-1 receptor agonism.

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“When you think back on what the history, biology, and discovery of these compounds was, it isn’t at all obvious you’d pair these two [to make] a so-called ‘twincreatin’ – there is so much overlap,” said Matthias Tschöp, MD, who was invited to discuss the findings after the presentation at the EASD meeting.

Dr. Tschöp, who is the head of the division of neuroendocrinology at the Institute for Diabetes and Obesity at Helmholtz Zentrum München in Neuherberg , Germany, noted that it’s an interesting combination, but it’s not the only approach being tested – there are other twincretin combinations. GIP on its own doesn’t seem to do much, but it must be the combination that is important, it was suggested during discussion.

A total of 318 patients with T2DM and a starting HbA_1c of 7%-10.5% were studied and randomized equally to one of six weekly treatment groups: LY3298176 at doses of either 1 mg, 5 mg, 10 mg, or 15 mg, given subcutaneously; 1.5 mg of dulaglutide; or a placebo injection.

The two highest doses of LY3298176 were titrated rather quickly, Dr. Frias said, and this is important when it comes to the side effect profile. In a subsequent study, the dose titration schedule was amended to prolong the titration period to try to avoid some of the side effects seen, according to Dr. Frias.

Adverse events predominantly affected the gastrointestinal system, with any grade nausea, vomiting, and diarrhea seen in a respective 20%-40%, 7%-26%, and 24%-32% of patients taking the 5-mg, 10-mg, and 15-mg doses. Corresponding rates in dulaglutide-treated patients were, approximately, 30%, 9%, and 17%.

“The safety profile of the dual agonist is really similar to that which you see with selective GLP-1 receptor agonists,” Dr. Frias observed. “The most common adverse events were seen at the higher doses and pertained to GI tolerability, but the majority of these events were mild to moderate and dissipated with time and [could] be reduced significantly by appropriate titration.”

Dr. Frias said: “This novel dual GIP/GLP-1 receptor agonist certainly has the potential to be become a very promising treatment option for patients with type 2 diabetes.”

He added: “In my experience as an investigator, as a clinician, I’ve never really seen this magnitude of A_1c reduction in this percentage of patients and also with this level of weight loss as well, certainly greater than with a selective GLP-1 receptor agonist.”

Further long-term studies are needed, and the phase 3 program in T2DM will be called SURPASS, according to a press statement issued by Eli Lilly. The phase 3 studies are expected to begin “no later than early 2019,” the statement said, and be completed in late 2021. The drug company also noted that it is “evaluating next steps in the study of GIP/GLP-1 RA for obesity and other conditions.”

SOURCE: Frias JP et al. EASD 2018, Session S31; Frias JP et al. Lancet. 2018 Oct 4. doi: 10.1016/S0140-6736(18)32260-8.