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Skin autofluorescence predicts 4-year CVD risk in diabetes
LISBON – Skin autofluorescence predicts new-onset type 2 diabetes and cardiovascular disease, according to data from a large prospective study reported at the annual meeting of the European Association for the Study of Diabetes.
Robert van Waateringe, MD, of University Medical Centre Groningen, the Netherlands, presented findings from an analysis of 80,253 individuals participating in the Dutch LifeLines population cohort study showing that skin autofluorescence, a noninvasive biomarker of advanced glycation end products accumulation, was associated with a higher risk of type 2 diabetes (odds ratio, 1.27 per arbitrary unit; 95% confidence interval, 1.06-1.52; P less than .01) after adjustment for common type 2 diabetes risk factors but not after further adjustment for impaired fasting glucose and hemoglobin A1c.
“Skin autofluorescence actually measures the accumulation of advanced glycation end products in the skin, which are also known as AGEs,” Dr. Waateringe explained during an oral presentation.
“AGEs are formed by the nonenzymatic glycation of proteins, lipids, and nucleic acids, which is also known as the Maillard reaction.” There are also exogenous sources, he said, such as heat-processed foods, including fries, steaks, and cookies; AGEs are also found in tobacco smoke.
“The formation and accumulation of AGEs is increased in people with diabetes as a result of hyperglycemia; they are also increased in people with impaired renal function due to their impaired excretion. AGEs cannot only form cross links in the skin but also in the vascular wall, leading to structural and functional tissue impairment,” he added.
It is possible to measure AGEs noninvasively in the skin based on their fluorescent properties, and Dr. Waateringe and his associates used a point-of-care device that has been available for clinical use since 2006 (AGE Reader, Diagnoptics Technologies B.V.). The device has a one-off cost of just under $6,000 (€5,000) and has been “extensively validated” for use by diabetologists and family physicians, with results in a mere 12 seconds, according to the manufacturer. To use the reader, a subject places his or her forearm on top of the unit and allows three separate recordings to be made, which are then averaged. Results are shown according to age, as the accumulation of AGEs increases with advancing age, and can indicate if someone is not at CV risk, is at limited CV risk, is at increased CV risk, or is at definite CV risk.
“We have recently shown that skin autofluorescence is associated with several clinical lifestyle factors in nondiabetic individuals,” Dr. Waateringe said. These factors included older age, being male, having a high BMI and/or high blood glucose levels, the presence of the metabolic syndrome, current smoking, and coffee consumption.
In the current study, Dr. Waateringe and associates included people without a prior history of type 2 diabetes or CVD who underwent baseline investigations between 2007 and 2013 and had a skin autofluorescence measurement available. The development of incident type 2 diabetes was determined between 2014 and 2016 by self-report or by a fasting blood glucose measurement of 6.9 mmol/L or greater or an HbA1c level of 6.5% of more. Self-reports of CVD were obtained, including myocardial infarction, cerebrovascular event, heart failure, or chronic cardiac insufficiency.
As might be expected, the patients who developed incident diabetes (n = 995) versus those who did not (79,252) at 4 years’ follow-up were older (54 years vs. 44 years, P less than .0001), had a larger waist circumference (102 cm vs. 90 cm, P less than .0001), and had a higher fasting glucose (5.9 mmol/L vs. 4.9 mmol/L; P less than .001). They also had higher skin autofluorescence (2.19 vs. 1.91AU, P less than .0001).
Similarly, patients who developed incident CVD (n = 879) versus those who did not (9,368) were older and had a larger waist, higher blood pressure, lower high-density lipoprotein cholesterol, and higher skin autofluorescence.
Skin autofluorescence levels were even higher in people with both new-onset type 2 diabetes and incident CVD than in those with either disease alone, Dr. Waateringe reported.
“Skin autofluorescence predicts type 2 diabetes and cardiovascular disease; however, impaired fasting glucose remained the strongest predictor for type 2 diabetes, and current smoking status was most strongly associated with cardiovascular disease,” he said.
Dr. Waateringe and his coinvestigators noted that skin autofluorescence may be particularly useful in screening for incident type 2 diabetes and CVD in low-risk populations and are looking at using it in combinations with existing risk scores, such as the Finnish Diabetes Risk Score (FINDRISC) and the Systematic Coronary Risk Evaluation (SCORE).
Data so far suggest that combining skin autofluorescence with FINDRISC improves diabetes detection and may prove useful for population screening in which further blood glucose of HbA1c testing could be used to confirm.
Although the present study included people from White European or Caucasian backgrounds, recent studies suggest that this method of detecting AGEs works in people with darker skin tones, although there is a lower reflection and this might influence the readings. Might people getting tanned on holiday also have skewed results? queried one delegate. Dr. Waateringe replied that tans or sunburns were not expected to affect the results.
There is an individual variability in skin autofluorescence of about 6% over the course of the day, Dr. Waateringe acknowledged in response to a question on the technique’s reproducibility.
Dr. van Waateringe reported he had no disclosures. One coinvestigator is founder and shareholder of Diagnoptics Technology, which developed the point-of-care device used in the study.
LISBON – Skin autofluorescence predicts new-onset type 2 diabetes and cardiovascular disease, according to data from a large prospective study reported at the annual meeting of the European Association for the Study of Diabetes.
Robert van Waateringe, MD, of University Medical Centre Groningen, the Netherlands, presented findings from an analysis of 80,253 individuals participating in the Dutch LifeLines population cohort study showing that skin autofluorescence, a noninvasive biomarker of advanced glycation end products accumulation, was associated with a higher risk of type 2 diabetes (odds ratio, 1.27 per arbitrary unit; 95% confidence interval, 1.06-1.52; P less than .01) after adjustment for common type 2 diabetes risk factors but not after further adjustment for impaired fasting glucose and hemoglobin A1c.
“Skin autofluorescence actually measures the accumulation of advanced glycation end products in the skin, which are also known as AGEs,” Dr. Waateringe explained during an oral presentation.
“AGEs are formed by the nonenzymatic glycation of proteins, lipids, and nucleic acids, which is also known as the Maillard reaction.” There are also exogenous sources, he said, such as heat-processed foods, including fries, steaks, and cookies; AGEs are also found in tobacco smoke.
“The formation and accumulation of AGEs is increased in people with diabetes as a result of hyperglycemia; they are also increased in people with impaired renal function due to their impaired excretion. AGEs cannot only form cross links in the skin but also in the vascular wall, leading to structural and functional tissue impairment,” he added.
It is possible to measure AGEs noninvasively in the skin based on their fluorescent properties, and Dr. Waateringe and his associates used a point-of-care device that has been available for clinical use since 2006 (AGE Reader, Diagnoptics Technologies B.V.). The device has a one-off cost of just under $6,000 (€5,000) and has been “extensively validated” for use by diabetologists and family physicians, with results in a mere 12 seconds, according to the manufacturer. To use the reader, a subject places his or her forearm on top of the unit and allows three separate recordings to be made, which are then averaged. Results are shown according to age, as the accumulation of AGEs increases with advancing age, and can indicate if someone is not at CV risk, is at limited CV risk, is at increased CV risk, or is at definite CV risk.
“We have recently shown that skin autofluorescence is associated with several clinical lifestyle factors in nondiabetic individuals,” Dr. Waateringe said. These factors included older age, being male, having a high BMI and/or high blood glucose levels, the presence of the metabolic syndrome, current smoking, and coffee consumption.
In the current study, Dr. Waateringe and associates included people without a prior history of type 2 diabetes or CVD who underwent baseline investigations between 2007 and 2013 and had a skin autofluorescence measurement available. The development of incident type 2 diabetes was determined between 2014 and 2016 by self-report or by a fasting blood glucose measurement of 6.9 mmol/L or greater or an HbA1c level of 6.5% of more. Self-reports of CVD were obtained, including myocardial infarction, cerebrovascular event, heart failure, or chronic cardiac insufficiency.
As might be expected, the patients who developed incident diabetes (n = 995) versus those who did not (79,252) at 4 years’ follow-up were older (54 years vs. 44 years, P less than .0001), had a larger waist circumference (102 cm vs. 90 cm, P less than .0001), and had a higher fasting glucose (5.9 mmol/L vs. 4.9 mmol/L; P less than .001). They also had higher skin autofluorescence (2.19 vs. 1.91AU, P less than .0001).
Similarly, patients who developed incident CVD (n = 879) versus those who did not (9,368) were older and had a larger waist, higher blood pressure, lower high-density lipoprotein cholesterol, and higher skin autofluorescence.
Skin autofluorescence levels were even higher in people with both new-onset type 2 diabetes and incident CVD than in those with either disease alone, Dr. Waateringe reported.
“Skin autofluorescence predicts type 2 diabetes and cardiovascular disease; however, impaired fasting glucose remained the strongest predictor for type 2 diabetes, and current smoking status was most strongly associated with cardiovascular disease,” he said.
Dr. Waateringe and his coinvestigators noted that skin autofluorescence may be particularly useful in screening for incident type 2 diabetes and CVD in low-risk populations and are looking at using it in combinations with existing risk scores, such as the Finnish Diabetes Risk Score (FINDRISC) and the Systematic Coronary Risk Evaluation (SCORE).
Data so far suggest that combining skin autofluorescence with FINDRISC improves diabetes detection and may prove useful for population screening in which further blood glucose of HbA1c testing could be used to confirm.
Although the present study included people from White European or Caucasian backgrounds, recent studies suggest that this method of detecting AGEs works in people with darker skin tones, although there is a lower reflection and this might influence the readings. Might people getting tanned on holiday also have skewed results? queried one delegate. Dr. Waateringe replied that tans or sunburns were not expected to affect the results.
There is an individual variability in skin autofluorescence of about 6% over the course of the day, Dr. Waateringe acknowledged in response to a question on the technique’s reproducibility.
Dr. van Waateringe reported he had no disclosures. One coinvestigator is founder and shareholder of Diagnoptics Technology, which developed the point-of-care device used in the study.
LISBON – Skin autofluorescence predicts new-onset type 2 diabetes and cardiovascular disease, according to data from a large prospective study reported at the annual meeting of the European Association for the Study of Diabetes.
Robert van Waateringe, MD, of University Medical Centre Groningen, the Netherlands, presented findings from an analysis of 80,253 individuals participating in the Dutch LifeLines population cohort study showing that skin autofluorescence, a noninvasive biomarker of advanced glycation end products accumulation, was associated with a higher risk of type 2 diabetes (odds ratio, 1.27 per arbitrary unit; 95% confidence interval, 1.06-1.52; P less than .01) after adjustment for common type 2 diabetes risk factors but not after further adjustment for impaired fasting glucose and hemoglobin A1c.
“Skin autofluorescence actually measures the accumulation of advanced glycation end products in the skin, which are also known as AGEs,” Dr. Waateringe explained during an oral presentation.
“AGEs are formed by the nonenzymatic glycation of proteins, lipids, and nucleic acids, which is also known as the Maillard reaction.” There are also exogenous sources, he said, such as heat-processed foods, including fries, steaks, and cookies; AGEs are also found in tobacco smoke.
“The formation and accumulation of AGEs is increased in people with diabetes as a result of hyperglycemia; they are also increased in people with impaired renal function due to their impaired excretion. AGEs cannot only form cross links in the skin but also in the vascular wall, leading to structural and functional tissue impairment,” he added.
It is possible to measure AGEs noninvasively in the skin based on their fluorescent properties, and Dr. Waateringe and his associates used a point-of-care device that has been available for clinical use since 2006 (AGE Reader, Diagnoptics Technologies B.V.). The device has a one-off cost of just under $6,000 (€5,000) and has been “extensively validated” for use by diabetologists and family physicians, with results in a mere 12 seconds, according to the manufacturer. To use the reader, a subject places his or her forearm on top of the unit and allows three separate recordings to be made, which are then averaged. Results are shown according to age, as the accumulation of AGEs increases with advancing age, and can indicate if someone is not at CV risk, is at limited CV risk, is at increased CV risk, or is at definite CV risk.
“We have recently shown that skin autofluorescence is associated with several clinical lifestyle factors in nondiabetic individuals,” Dr. Waateringe said. These factors included older age, being male, having a high BMI and/or high blood glucose levels, the presence of the metabolic syndrome, current smoking, and coffee consumption.
In the current study, Dr. Waateringe and associates included people without a prior history of type 2 diabetes or CVD who underwent baseline investigations between 2007 and 2013 and had a skin autofluorescence measurement available. The development of incident type 2 diabetes was determined between 2014 and 2016 by self-report or by a fasting blood glucose measurement of 6.9 mmol/L or greater or an HbA1c level of 6.5% of more. Self-reports of CVD were obtained, including myocardial infarction, cerebrovascular event, heart failure, or chronic cardiac insufficiency.
As might be expected, the patients who developed incident diabetes (n = 995) versus those who did not (79,252) at 4 years’ follow-up were older (54 years vs. 44 years, P less than .0001), had a larger waist circumference (102 cm vs. 90 cm, P less than .0001), and had a higher fasting glucose (5.9 mmol/L vs. 4.9 mmol/L; P less than .001). They also had higher skin autofluorescence (2.19 vs. 1.91AU, P less than .0001).
Similarly, patients who developed incident CVD (n = 879) versus those who did not (9,368) were older and had a larger waist, higher blood pressure, lower high-density lipoprotein cholesterol, and higher skin autofluorescence.
Skin autofluorescence levels were even higher in people with both new-onset type 2 diabetes and incident CVD than in those with either disease alone, Dr. Waateringe reported.
“Skin autofluorescence predicts type 2 diabetes and cardiovascular disease; however, impaired fasting glucose remained the strongest predictor for type 2 diabetes, and current smoking status was most strongly associated with cardiovascular disease,” he said.
Dr. Waateringe and his coinvestigators noted that skin autofluorescence may be particularly useful in screening for incident type 2 diabetes and CVD in low-risk populations and are looking at using it in combinations with existing risk scores, such as the Finnish Diabetes Risk Score (FINDRISC) and the Systematic Coronary Risk Evaluation (SCORE).
Data so far suggest that combining skin autofluorescence with FINDRISC improves diabetes detection and may prove useful for population screening in which further blood glucose of HbA1c testing could be used to confirm.
Although the present study included people from White European or Caucasian backgrounds, recent studies suggest that this method of detecting AGEs works in people with darker skin tones, although there is a lower reflection and this might influence the readings. Might people getting tanned on holiday also have skewed results? queried one delegate. Dr. Waateringe replied that tans or sunburns were not expected to affect the results.
There is an individual variability in skin autofluorescence of about 6% over the course of the day, Dr. Waateringe acknowledged in response to a question on the technique’s reproducibility.
Dr. van Waateringe reported he had no disclosures. One coinvestigator is founder and shareholder of Diagnoptics Technology, which developed the point-of-care device used in the study.
AT EASD 2017
Key clinical point: Skin autofluorescence may be a useful biomarker for population screening of type 2 diabetes.
Major finding: Skin autofluorescence was higher in individuals with incident type 2 diabetes (2.19 vs. 1.91 arbitrary units [AU], P less than .0001) and CVD (2.23 vs. 1.91 AU, P less than .0001) than in those without at 4 years’ follow-up.
Data source: A large observational, prospective, population-cohort study involving approximately 80,000 individuals without previously diagnosed diabetes.
Disclosures: The speaker reported having no disclosures. A coinvestigator is founder and shareholder of Diagnostics Technology, which developed the point-of-care device used in the study.
Delayed-release metformin proves promising for diabetic renal disease
LISBON – in a 16-week, dose-ranging, phase 2 trial performed in patients with type 2 diabetes mellitus and chronic kidney disease (CKD).
There was also a reduced incidence of gastrointestinal side effects with metformin DR versus immediate-release (IR) metformin (less than 16% at all doses tested vs. 28%), particularly with regard to nausea (1%-3% vs. 10%).
“Based on concerns about the potential for lactic acidosis, primarily in patients with fairly severe renal impairment, metformin use is contraindicated in patients with stage IV chronic kidney disease,” Dr. Frias observed. Furthermore its use is restricted in patients with stage IIIB CKD, with European guidelines recommending lower starting (500 mg) and maximum (1,000 mg) daily doses, and U.S. guidelines recommending continuing treatment with caution in those already on metformin and not initiating metformin in new patients with this stage of kidney disease.
Treating patients with type 2 diabetes mellitus (T2DM) and later stages of CKD is challenging, as there are issues with almost all of the available alternatives to metformin, he noted. For instance, insulin use and sulfonylureas carry the risk of hypoglycemia, which is higher in patients with stage IIIB/IV renal disease than without. The dipeptidyl peptidase-4 inhibitors are “modestly able to reduce A1c, but generally do much better in combination with metformin, which is often contraindicated in these patients,” Dr. Frias said. Sodium glucose cotransporter 2 inhibitors are “generally not effective” in this patient group, he said.
Metformin DR is being specifically developed to manage patients with T2DM patients and stage IIIB/IV CKD, Dr. Frias said. Its enteric coating helps it bypass the stomach and upper intestine and so ensures that the majority of metformin absorption occurs in the lower bowel to reduce systemic exposure while retaining its positive effects on glycemic mechanisms such as the secretion of glucagon-like peptide 1.
In the current phase 2 study, 571 patients with T2DM and stage I/II CKD were recruited. Patients with stage IIIB/IV were not included because of the restrictions on the use of metformin.
Patients were randomized to receive placebo or metformin DR (600 mg, 900 mg, 1,200 mg, and 1,500 mg twice daily) in a double-blind comparison, with a single-blind reference arm of metformin IR, (1,000 mg once daily for the first week then 1,000 mg twice daily) also included as part of the study design.
The change in hemoglobin A1c (HbA1c) from baseline levels to week 16 of treatment, the primary endpoint, was significantly (P less than .05) greater with metformin DR) than with placebo (–0.49%, –0.62%, and –0.06%, respectively). Changes in fasting plasma glucose (FPG) from week 4 to week 16 were also higher with metformin DR than with placebo, with the 1,200 metformin DR dose achieving a 25.1 mg/dL drop in FPG, “almost 80% of the fasting glucose–lowering capacity of the immediate release formulation.”
While the changes in HbA1c (-1.10%) and FPG (-32.6 m/dL) were greatest with metformin IR, the lower systemic exposure needs to be considered, Dr. Frias said. The plasma exposure with metformin DR was less than 37% that of metformin IR.
“If we normalize for systemic exposure, so for any given unit, if you will, of systemic exposure, you actually had [a 1.5-fold] improved hemoglobin A1c with the delayed-release formulation, and a twofold increase in the fasting glucose,” Dr. Frias reported. “So from a practical point of view, if you needed to reach those ‘safe’ plasma concentrations with an immediate-release formulation, you would have to lower [the dose of] that formulation, probably to a dose that would not be efficacious for a patient.”
As for safety, any adverse event (AE) occurred in 41.7% of placebo-treated patients, in 47.9% of metformin IR–treated patients, and in 55.3%, 48.4%, 39.6%, and 43.8%, of those taking metformin DR at the respective doses of 600 mg, 900 mg, 1,200 mg, and 1, 500 mg.
Serious AEs were recorded in 4.2% of placebo-treated patients, 1.1% of metformin IR-treated patients, and in 1.1%, 0%, 4.2%, and 1.0% those taking increasing doses of metformin DR.
There were fewer AEs related to study medication (12.8%, 13.7%, 14.6%, and 9.4%) and subsequently resulting in discontinuation (3.2%, 2.1%, 7.3%, 2.1%) with metformin DR than with metformin IR (25.5%, 8.5%). Of placebo-treated patients, 6.3% developed a treatment-related AE, and 6.3% discontinued the study as a result.
“The improved risk/benefit profile that’s seen [in this study] would lead you to think that this would be a formulation that would be effective, particularly in patients with CKD IIIB or IV,” Dr. Frias concluded, noting that further studies would need to look into this possibility further.
The study was funded by Elcelyx Therapeutics. Dr. Frias disclosed receiving research support from Abbvie, Eli Lilly, IONIS, Janssen, Johnson & Johnson, Merck, Mylan, Novartis, Pfizer, and vTv therapeutics. He has also received research support from and participated in scientific advisory boards for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Novo Nordisk, and Theracos. A coauthor is an employee of Elcelyx Therapeutics and disclosed being a shareholder of the company.
LISBON – in a 16-week, dose-ranging, phase 2 trial performed in patients with type 2 diabetes mellitus and chronic kidney disease (CKD).
There was also a reduced incidence of gastrointestinal side effects with metformin DR versus immediate-release (IR) metformin (less than 16% at all doses tested vs. 28%), particularly with regard to nausea (1%-3% vs. 10%).
“Based on concerns about the potential for lactic acidosis, primarily in patients with fairly severe renal impairment, metformin use is contraindicated in patients with stage IV chronic kidney disease,” Dr. Frias observed. Furthermore its use is restricted in patients with stage IIIB CKD, with European guidelines recommending lower starting (500 mg) and maximum (1,000 mg) daily doses, and U.S. guidelines recommending continuing treatment with caution in those already on metformin and not initiating metformin in new patients with this stage of kidney disease.
Treating patients with type 2 diabetes mellitus (T2DM) and later stages of CKD is challenging, as there are issues with almost all of the available alternatives to metformin, he noted. For instance, insulin use and sulfonylureas carry the risk of hypoglycemia, which is higher in patients with stage IIIB/IV renal disease than without. The dipeptidyl peptidase-4 inhibitors are “modestly able to reduce A1c, but generally do much better in combination with metformin, which is often contraindicated in these patients,” Dr. Frias said. Sodium glucose cotransporter 2 inhibitors are “generally not effective” in this patient group, he said.
Metformin DR is being specifically developed to manage patients with T2DM patients and stage IIIB/IV CKD, Dr. Frias said. Its enteric coating helps it bypass the stomach and upper intestine and so ensures that the majority of metformin absorption occurs in the lower bowel to reduce systemic exposure while retaining its positive effects on glycemic mechanisms such as the secretion of glucagon-like peptide 1.
In the current phase 2 study, 571 patients with T2DM and stage I/II CKD were recruited. Patients with stage IIIB/IV were not included because of the restrictions on the use of metformin.
Patients were randomized to receive placebo or metformin DR (600 mg, 900 mg, 1,200 mg, and 1,500 mg twice daily) in a double-blind comparison, with a single-blind reference arm of metformin IR, (1,000 mg once daily for the first week then 1,000 mg twice daily) also included as part of the study design.
The change in hemoglobin A1c (HbA1c) from baseline levels to week 16 of treatment, the primary endpoint, was significantly (P less than .05) greater with metformin DR) than with placebo (–0.49%, –0.62%, and –0.06%, respectively). Changes in fasting plasma glucose (FPG) from week 4 to week 16 were also higher with metformin DR than with placebo, with the 1,200 metformin DR dose achieving a 25.1 mg/dL drop in FPG, “almost 80% of the fasting glucose–lowering capacity of the immediate release formulation.”
While the changes in HbA1c (-1.10%) and FPG (-32.6 m/dL) were greatest with metformin IR, the lower systemic exposure needs to be considered, Dr. Frias said. The plasma exposure with metformin DR was less than 37% that of metformin IR.
“If we normalize for systemic exposure, so for any given unit, if you will, of systemic exposure, you actually had [a 1.5-fold] improved hemoglobin A1c with the delayed-release formulation, and a twofold increase in the fasting glucose,” Dr. Frias reported. “So from a practical point of view, if you needed to reach those ‘safe’ plasma concentrations with an immediate-release formulation, you would have to lower [the dose of] that formulation, probably to a dose that would not be efficacious for a patient.”
As for safety, any adverse event (AE) occurred in 41.7% of placebo-treated patients, in 47.9% of metformin IR–treated patients, and in 55.3%, 48.4%, 39.6%, and 43.8%, of those taking metformin DR at the respective doses of 600 mg, 900 mg, 1,200 mg, and 1, 500 mg.
Serious AEs were recorded in 4.2% of placebo-treated patients, 1.1% of metformin IR-treated patients, and in 1.1%, 0%, 4.2%, and 1.0% those taking increasing doses of metformin DR.
There were fewer AEs related to study medication (12.8%, 13.7%, 14.6%, and 9.4%) and subsequently resulting in discontinuation (3.2%, 2.1%, 7.3%, 2.1%) with metformin DR than with metformin IR (25.5%, 8.5%). Of placebo-treated patients, 6.3% developed a treatment-related AE, and 6.3% discontinued the study as a result.
“The improved risk/benefit profile that’s seen [in this study] would lead you to think that this would be a formulation that would be effective, particularly in patients with CKD IIIB or IV,” Dr. Frias concluded, noting that further studies would need to look into this possibility further.
The study was funded by Elcelyx Therapeutics. Dr. Frias disclosed receiving research support from Abbvie, Eli Lilly, IONIS, Janssen, Johnson & Johnson, Merck, Mylan, Novartis, Pfizer, and vTv therapeutics. He has also received research support from and participated in scientific advisory boards for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Novo Nordisk, and Theracos. A coauthor is an employee of Elcelyx Therapeutics and disclosed being a shareholder of the company.
LISBON – in a 16-week, dose-ranging, phase 2 trial performed in patients with type 2 diabetes mellitus and chronic kidney disease (CKD).
There was also a reduced incidence of gastrointestinal side effects with metformin DR versus immediate-release (IR) metformin (less than 16% at all doses tested vs. 28%), particularly with regard to nausea (1%-3% vs. 10%).
“Based on concerns about the potential for lactic acidosis, primarily in patients with fairly severe renal impairment, metformin use is contraindicated in patients with stage IV chronic kidney disease,” Dr. Frias observed. Furthermore its use is restricted in patients with stage IIIB CKD, with European guidelines recommending lower starting (500 mg) and maximum (1,000 mg) daily doses, and U.S. guidelines recommending continuing treatment with caution in those already on metformin and not initiating metformin in new patients with this stage of kidney disease.
Treating patients with type 2 diabetes mellitus (T2DM) and later stages of CKD is challenging, as there are issues with almost all of the available alternatives to metformin, he noted. For instance, insulin use and sulfonylureas carry the risk of hypoglycemia, which is higher in patients with stage IIIB/IV renal disease than without. The dipeptidyl peptidase-4 inhibitors are “modestly able to reduce A1c, but generally do much better in combination with metformin, which is often contraindicated in these patients,” Dr. Frias said. Sodium glucose cotransporter 2 inhibitors are “generally not effective” in this patient group, he said.
Metformin DR is being specifically developed to manage patients with T2DM patients and stage IIIB/IV CKD, Dr. Frias said. Its enteric coating helps it bypass the stomach and upper intestine and so ensures that the majority of metformin absorption occurs in the lower bowel to reduce systemic exposure while retaining its positive effects on glycemic mechanisms such as the secretion of glucagon-like peptide 1.
In the current phase 2 study, 571 patients with T2DM and stage I/II CKD were recruited. Patients with stage IIIB/IV were not included because of the restrictions on the use of metformin.
Patients were randomized to receive placebo or metformin DR (600 mg, 900 mg, 1,200 mg, and 1,500 mg twice daily) in a double-blind comparison, with a single-blind reference arm of metformin IR, (1,000 mg once daily for the first week then 1,000 mg twice daily) also included as part of the study design.
The change in hemoglobin A1c (HbA1c) from baseline levels to week 16 of treatment, the primary endpoint, was significantly (P less than .05) greater with metformin DR) than with placebo (–0.49%, –0.62%, and –0.06%, respectively). Changes in fasting plasma glucose (FPG) from week 4 to week 16 were also higher with metformin DR than with placebo, with the 1,200 metformin DR dose achieving a 25.1 mg/dL drop in FPG, “almost 80% of the fasting glucose–lowering capacity of the immediate release formulation.”
While the changes in HbA1c (-1.10%) and FPG (-32.6 m/dL) were greatest with metformin IR, the lower systemic exposure needs to be considered, Dr. Frias said. The plasma exposure with metformin DR was less than 37% that of metformin IR.
“If we normalize for systemic exposure, so for any given unit, if you will, of systemic exposure, you actually had [a 1.5-fold] improved hemoglobin A1c with the delayed-release formulation, and a twofold increase in the fasting glucose,” Dr. Frias reported. “So from a practical point of view, if you needed to reach those ‘safe’ plasma concentrations with an immediate-release formulation, you would have to lower [the dose of] that formulation, probably to a dose that would not be efficacious for a patient.”
As for safety, any adverse event (AE) occurred in 41.7% of placebo-treated patients, in 47.9% of metformin IR–treated patients, and in 55.3%, 48.4%, 39.6%, and 43.8%, of those taking metformin DR at the respective doses of 600 mg, 900 mg, 1,200 mg, and 1, 500 mg.
Serious AEs were recorded in 4.2% of placebo-treated patients, 1.1% of metformin IR-treated patients, and in 1.1%, 0%, 4.2%, and 1.0% those taking increasing doses of metformin DR.
There were fewer AEs related to study medication (12.8%, 13.7%, 14.6%, and 9.4%) and subsequently resulting in discontinuation (3.2%, 2.1%, 7.3%, 2.1%) with metformin DR than with metformin IR (25.5%, 8.5%). Of placebo-treated patients, 6.3% developed a treatment-related AE, and 6.3% discontinued the study as a result.
“The improved risk/benefit profile that’s seen [in this study] would lead you to think that this would be a formulation that would be effective, particularly in patients with CKD IIIB or IV,” Dr. Frias concluded, noting that further studies would need to look into this possibility further.
The study was funded by Elcelyx Therapeutics. Dr. Frias disclosed receiving research support from Abbvie, Eli Lilly, IONIS, Janssen, Johnson & Johnson, Merck, Mylan, Novartis, Pfizer, and vTv therapeutics. He has also received research support from and participated in scientific advisory boards for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Novo Nordisk, and Theracos. A coauthor is an employee of Elcelyx Therapeutics and disclosed being a shareholder of the company.
AT EASD 2017
Key clinical point: A delayed-release formulation of metformin appears have a risk/benefit profile that would enable use in patients with type 2 diabetes and chronic kidney disease.
Major finding: Change in HbA1c at week 16 (primary endpoint) was –0.49%, –0.62%, and –0.06%, for metformin DR 1,200 mg, 1,500 mg, and placebo, respectively, P less than .05).
Data source: A 16-week, dose-ranging phase 2 trial involving 571 patients with T2DM and CKD.
Disclosures: The study was funded by Elcelyx Therapeutics. Dr. Frias disclosed receiving research support from Abbvie, Eli Lilly, IONIS, Janssen, Johnson & Johnson, Merck, Mylan, Novartis, Pfizer, and vTv therapeutics. He has also received research support from and participated in scientific advisory boards for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Novo Nordisk, and Theracos. A coauthor is an employee of Elcelyx Therapeutics and disclosed being a shareholder of the company.
Empagliflozin’s effects independent of CVD risk factors
LISBON – The mortality reductions that can be achieved with the sodium–glucose cotransporter 2 inhibitor empagliflozin versus placebo in people with type 2 diabetes remained after investigators controlled for traditional cardiovascular (CV) risk factors over time, analyses from the EMPA-REG OUTCOME trial showed.
The 38% reduction in CV deaths and 32% reduction in all-cause mortality that were observed in the main trial (N Engl J Med. 2015;373:2117-28) were “largely unchanged when adjusted for control of blood pressure, LDL cholesterol, and glycated hemoglobin (HbA1c) during the study,” David Fitchett, MD, reported at the annual meeting of the European Association for the Study of Diabetes.
“EMPA-REG OUTCOME was the first diabetes outcome trial to show a reduction in the primary cardiovascular endpoint,” Dr. Fitchett, a cardiologist on the staff of St. Michael’s Hospital, University of Toronto, said. “It was designed as a safety study, but the statistical analysis allowed for an efficacy analysis once safety had been proven.”
EMPA-REG OUTCOME was an international, multicenter, phase 3, randomized, double-blind, placebo-controlled trial set up to look at the effects of a once-daily dose of empagliflozin (Jardiance) versus placebo on CV events in 7,020 adults with type 2 diabetes with established CV disease. Empagliflozin (10 mg or 25 mg) or placebo was given in addition to the standard of care, with the design stipulating that glucose-lowering treatment should be unchanged for the first 3 months.
The trial continued until an adjudicated primary outcome event, defined as a composite of CV death, nonfatal myocardial infarction, or nonfatal stroke, had occurred in at least 691 patients. This three-point major cardiovascular outcome (MACE) occurred in 10.5% of patients treated with empagliflozin and in 12.5% of those who had been given placebo, with a 14% reduction overall (HR, 0.86; 95% CI, 0.74–0.99; P = .04). Almost all of this benefit was due to the reduction in CV deaths, Dr. Fitchett noted, which in turn drove the reduction in all-cause mortality.
The question, then, was how did empagliflozin have this apparent cardiovascular effect? Seeking an answer, the core EMPA-REG OUTCOME investigators looked to see if it could be explained by changes in blood pressure, LDL cholesterol, or HbA1c level, as small reductions had been seen in the main trial. Cox proportional analyses were performed to see how controlling for each of these might affect the results. In these analyses, control of blood pressure was defined as achieving a systolic value of less than 140 mm Hg and a diastolic value of less than 90 mm Hg; control of LDL cholesterol as a value of less than 100 mg/dL, and control of HbA1c level as a value below 7.5%.
Comparing baseline values to the last recorded values, the proportions of patients who achieved control of HbA1c with empagliflozin were a respective 26.7% and 46.7% versus 25.5% and 34% for placebo. LDL cholesterol was controlled in 70.6% and 68.7%, respectively, with empagliflozin and in 72.9% and 70% with placebo. The proportions of patients who achieved control of HbA1c, LDL cholesterol, and blood pressure were 12.6% and 21.8% for empagliflozin and 11.7% and 16.7% for placebo.*
The latest findings “suggest that the mortality reductions in the EMPA-REG OUTCOME trial were not driven by control of these standard cardiovascular risk factors during the trial,” Dr. Fitchett concluded.
In a separate poster presentation at the meeting, EMPA-REG OUTCOME investigators reported that empagliflozin also reduced heart failure outcomes, regardless of blood pressure, LDL cholesterol, or HbA1c control. Hazard ratios for hospitalization for heart failure with or without CV death were 0.64-0.67 (95% CIs, 0.49–0.87). Other subanalyses from the study showed that neither baseline HbA1c nor change in HbA1c predicted the reduction in CV deaths with empagliflozin and that background glucose-lowering treatment – metformin or sulfonylurea use – did not change the results.
The Boehringer Ingelheim and Lilly Diabetes Alliance funded the study. Dr. Fitchett disclosed receiving honoraria from Sanofi, Merck, Amgen, AstraZeneca, Eli Lilly, and Boehringer Ingelheim.
*This article was updated Sept. 28, 2017.
LISBON – The mortality reductions that can be achieved with the sodium–glucose cotransporter 2 inhibitor empagliflozin versus placebo in people with type 2 diabetes remained after investigators controlled for traditional cardiovascular (CV) risk factors over time, analyses from the EMPA-REG OUTCOME trial showed.
The 38% reduction in CV deaths and 32% reduction in all-cause mortality that were observed in the main trial (N Engl J Med. 2015;373:2117-28) were “largely unchanged when adjusted for control of blood pressure, LDL cholesterol, and glycated hemoglobin (HbA1c) during the study,” David Fitchett, MD, reported at the annual meeting of the European Association for the Study of Diabetes.
“EMPA-REG OUTCOME was the first diabetes outcome trial to show a reduction in the primary cardiovascular endpoint,” Dr. Fitchett, a cardiologist on the staff of St. Michael’s Hospital, University of Toronto, said. “It was designed as a safety study, but the statistical analysis allowed for an efficacy analysis once safety had been proven.”
EMPA-REG OUTCOME was an international, multicenter, phase 3, randomized, double-blind, placebo-controlled trial set up to look at the effects of a once-daily dose of empagliflozin (Jardiance) versus placebo on CV events in 7,020 adults with type 2 diabetes with established CV disease. Empagliflozin (10 mg or 25 mg) or placebo was given in addition to the standard of care, with the design stipulating that glucose-lowering treatment should be unchanged for the first 3 months.
The trial continued until an adjudicated primary outcome event, defined as a composite of CV death, nonfatal myocardial infarction, or nonfatal stroke, had occurred in at least 691 patients. This three-point major cardiovascular outcome (MACE) occurred in 10.5% of patients treated with empagliflozin and in 12.5% of those who had been given placebo, with a 14% reduction overall (HR, 0.86; 95% CI, 0.74–0.99; P = .04). Almost all of this benefit was due to the reduction in CV deaths, Dr. Fitchett noted, which in turn drove the reduction in all-cause mortality.
The question, then, was how did empagliflozin have this apparent cardiovascular effect? Seeking an answer, the core EMPA-REG OUTCOME investigators looked to see if it could be explained by changes in blood pressure, LDL cholesterol, or HbA1c level, as small reductions had been seen in the main trial. Cox proportional analyses were performed to see how controlling for each of these might affect the results. In these analyses, control of blood pressure was defined as achieving a systolic value of less than 140 mm Hg and a diastolic value of less than 90 mm Hg; control of LDL cholesterol as a value of less than 100 mg/dL, and control of HbA1c level as a value below 7.5%.
Comparing baseline values to the last recorded values, the proportions of patients who achieved control of HbA1c with empagliflozin were a respective 26.7% and 46.7% versus 25.5% and 34% for placebo. LDL cholesterol was controlled in 70.6% and 68.7%, respectively, with empagliflozin and in 72.9% and 70% with placebo. The proportions of patients who achieved control of HbA1c, LDL cholesterol, and blood pressure were 12.6% and 21.8% for empagliflozin and 11.7% and 16.7% for placebo.*
The latest findings “suggest that the mortality reductions in the EMPA-REG OUTCOME trial were not driven by control of these standard cardiovascular risk factors during the trial,” Dr. Fitchett concluded.
In a separate poster presentation at the meeting, EMPA-REG OUTCOME investigators reported that empagliflozin also reduced heart failure outcomes, regardless of blood pressure, LDL cholesterol, or HbA1c control. Hazard ratios for hospitalization for heart failure with or without CV death were 0.64-0.67 (95% CIs, 0.49–0.87). Other subanalyses from the study showed that neither baseline HbA1c nor change in HbA1c predicted the reduction in CV deaths with empagliflozin and that background glucose-lowering treatment – metformin or sulfonylurea use – did not change the results.
The Boehringer Ingelheim and Lilly Diabetes Alliance funded the study. Dr. Fitchett disclosed receiving honoraria from Sanofi, Merck, Amgen, AstraZeneca, Eli Lilly, and Boehringer Ingelheim.
*This article was updated Sept. 28, 2017.
LISBON – The mortality reductions that can be achieved with the sodium–glucose cotransporter 2 inhibitor empagliflozin versus placebo in people with type 2 diabetes remained after investigators controlled for traditional cardiovascular (CV) risk factors over time, analyses from the EMPA-REG OUTCOME trial showed.
The 38% reduction in CV deaths and 32% reduction in all-cause mortality that were observed in the main trial (N Engl J Med. 2015;373:2117-28) were “largely unchanged when adjusted for control of blood pressure, LDL cholesterol, and glycated hemoglobin (HbA1c) during the study,” David Fitchett, MD, reported at the annual meeting of the European Association for the Study of Diabetes.
“EMPA-REG OUTCOME was the first diabetes outcome trial to show a reduction in the primary cardiovascular endpoint,” Dr. Fitchett, a cardiologist on the staff of St. Michael’s Hospital, University of Toronto, said. “It was designed as a safety study, but the statistical analysis allowed for an efficacy analysis once safety had been proven.”
EMPA-REG OUTCOME was an international, multicenter, phase 3, randomized, double-blind, placebo-controlled trial set up to look at the effects of a once-daily dose of empagliflozin (Jardiance) versus placebo on CV events in 7,020 adults with type 2 diabetes with established CV disease. Empagliflozin (10 mg or 25 mg) or placebo was given in addition to the standard of care, with the design stipulating that glucose-lowering treatment should be unchanged for the first 3 months.
The trial continued until an adjudicated primary outcome event, defined as a composite of CV death, nonfatal myocardial infarction, or nonfatal stroke, had occurred in at least 691 patients. This three-point major cardiovascular outcome (MACE) occurred in 10.5% of patients treated with empagliflozin and in 12.5% of those who had been given placebo, with a 14% reduction overall (HR, 0.86; 95% CI, 0.74–0.99; P = .04). Almost all of this benefit was due to the reduction in CV deaths, Dr. Fitchett noted, which in turn drove the reduction in all-cause mortality.
The question, then, was how did empagliflozin have this apparent cardiovascular effect? Seeking an answer, the core EMPA-REG OUTCOME investigators looked to see if it could be explained by changes in blood pressure, LDL cholesterol, or HbA1c level, as small reductions had been seen in the main trial. Cox proportional analyses were performed to see how controlling for each of these might affect the results. In these analyses, control of blood pressure was defined as achieving a systolic value of less than 140 mm Hg and a diastolic value of less than 90 mm Hg; control of LDL cholesterol as a value of less than 100 mg/dL, and control of HbA1c level as a value below 7.5%.
Comparing baseline values to the last recorded values, the proportions of patients who achieved control of HbA1c with empagliflozin were a respective 26.7% and 46.7% versus 25.5% and 34% for placebo. LDL cholesterol was controlled in 70.6% and 68.7%, respectively, with empagliflozin and in 72.9% and 70% with placebo. The proportions of patients who achieved control of HbA1c, LDL cholesterol, and blood pressure were 12.6% and 21.8% for empagliflozin and 11.7% and 16.7% for placebo.*
The latest findings “suggest that the mortality reductions in the EMPA-REG OUTCOME trial were not driven by control of these standard cardiovascular risk factors during the trial,” Dr. Fitchett concluded.
In a separate poster presentation at the meeting, EMPA-REG OUTCOME investigators reported that empagliflozin also reduced heart failure outcomes, regardless of blood pressure, LDL cholesterol, or HbA1c control. Hazard ratios for hospitalization for heart failure with or without CV death were 0.64-0.67 (95% CIs, 0.49–0.87). Other subanalyses from the study showed that neither baseline HbA1c nor change in HbA1c predicted the reduction in CV deaths with empagliflozin and that background glucose-lowering treatment – metformin or sulfonylurea use – did not change the results.
The Boehringer Ingelheim and Lilly Diabetes Alliance funded the study. Dr. Fitchett disclosed receiving honoraria from Sanofi, Merck, Amgen, AstraZeneca, Eli Lilly, and Boehringer Ingelheim.
*This article was updated Sept. 28, 2017.
AT EASD 2017
Key clinical point:
Major finding: The 38% reduction in CV deaths and 32% reduction in all-cause mortality were largely unchanged after adjustment for blood pressure, LDL cholesterol, and HbA1c at baseline and during the study.
Data source: Secondary analyses of EMPA-REG OUTCOME, a phase 3, randomized controlled trial of 7,020 people with type 2 diabetes at high risk for cardiovascular events who were receiving standard care.
Disclosures: The Boehringer Ingelheim and Lilly Diabetes Alliance funded the study. Dr. Fitchett disclosed receiving honoraria from Sanofi, Merck, Amgen, AstraZeneca, Eli Lilly, and Boehringer Ingelheim.
CONCEPTT: Continuous glucose monitoring during pregnancy benefits baby
LISBON – , according to the investigators of a prospective, multicenter, randomized, controlled study who found that it improved a number of neonatal outcomes.
In the open-label Continuous Glucose Monitoring in Pregnant Women with Type 1 Diabetes(CONCEPTT) study, infants born to mothers who had used continuous glucose monitoring (CGM) versus those who had not had a 49% lower chance of being large for gestational age (53% vs. 69%, odds ratio [OR] 0.51, P = .0210) and were 52% less likely to need neonatal intensive care lasting for longer than 24 hours (27% vs. 43%, OR 0.48, P = .0157).
Neonates born to mothers who used CGM during their pregnancy were also less likely to experience hypoglycemia (15% vs. 28%, OR 0.45, P = .0250) and were able to leave the hospital with their mother 1 day earlier (P = .0091) than those born to mothers who did not use CGM.However, these were secondary outcomes of the study, which first looked at how CGM affected the glycemic profile of the mother.“To the best of our knowledge, this is the first trial to demonstrate a benefit of CGM on health outcomes beyond glucose control,” Helen Murphy, MD, one of the CONCEPTT trial’s two principal investigators, said at the annual meeting of the European Association for the Study of Diabetes.
“We would suggest, on the back of these data, that CGM should be offered to all pregnant women with type 1 diabetes using intensive insulin therapy during the first trimester,” Dr. Murphy said, adding that results of the study were simultaneously published online in the Lancet (2017 Sept. 15. doi. 10.1016/S0140-6736(17)32400-5).
“The CONCEPTT study will change the future for pregnant women with diabetes,” commented Elisabeth Mathiesen, MD, who was the EASD’s invited discussant for the study, and who congratulated the investigators for “a well performed study” and being “brave,” as “performing a RCT [randomized controlled trial] in pregnancy is not easy”.
Satish Garg, MD, and Sarit Polsky, MD, of the Barbara Davis Center for Diabetes at the University of Colorado, Denver, agreed in an editorial (Lancet 2017; Sept. 12. doi: 10.1016/S0140-6736(17)32449-2) accompanying the published article that the study findings were clinically important.
“We believe that the CONCEPTT results support CGM use during pregnancy for all women with type 1 diabetes,” they wrote, adding that the mother’s “time in [glycated hemoglobin, HbA1C] range might become an important measure in pregnancies with type 1 diabetes.”
Dr. Garg and Dr. Polsky also suggested that endocrine and obstetric medical societies take note and perhaps revise accordingly their guidelines on the use of CGM during pregnancy in diabetic women.
CONCEPTT involved 325 women with type 1 diabetes; 215 were pregnant at the time of enrollment, and 110 were planning on becoming pregnant in the near future.
Co-principal investigator Denice Feig, MD, of Sinai Health System in Toronto, explained that women were eligible for inclusion in the trial if they had type 1 diabetes for at least 1 year, were aged between 18 and 40 years, and had been using daily insulin delivered by either an insulin pump or multiple daily injections (MDI). At enrollment, the participants’ insulin regimen had to been stable for at least 4 weeks before randomization to CGM with capillary glucose monitoring or capillary glucose monitoring alone and their glycemic control had to be suboptimal.
Two groups of women were studied: a “pre-pregnancy group” of women who were planning on pregnancy and wanted to optimize their glycemic control before conception, and a “pregnancy group” of women in their first trimester (less than 14 weeks’ gestation) who were due to have a live, singleton birth as confirmed by ultrasound.
The primary outcome of the trial was the change in HbA1C from baseline to 34 weeks, with pre-specified secondary outcomes of various CGM measures, neoneonatal outcomes, and patient-reported outcomes.
Pregnant women using CGM had lower HbA1C levels during the trial than women who did not have CGM monitoring, although the difference was small (–0.19%, P = .0207).
The use of CGM was associated with more time spent in target HbA1C range (68% of women using CMG vs. 61% of those not using CGM, P = .0034), with less time being hyperglycemic (27% vs. 37%, P = .0279) and comparable rates of hypoglycemia (17 vs. 21 episodes) and time spent being hypoglycemic (2% vs. 4%, P = .10).“The CGM effects were very comparable among insulin pump and MDI users and across 31 international sites,” Dr. Murphy summarized, although she noted that there was no consistent benefit of using CGM seen in women who were planning a pregnancy. Dr. Feig noted that the strengths of the study were the large sample size and that CGM was used continuously from the first trimester until delivery. Women using both pumps and MDI were included at multiple centers and countries, and HbA1C was centrally assessed, with detailed CGM measures used in an exclusively type 1 diabetes population.“Of note, one needed to treat only six women with CGM to prevent one episode of large for gestational age,” Dr. Feig reported. “One needed to treat only eight women to prevent one neonatal hypoglycemia, and six women to prevent one NICU [neonatal intensive care unit] admission over 24 hours.”
There were some limitations, of course, including: around 20% of women had missing data on their HbA1C level; women using CGM also made more unscheduled visits to their health care providers although there are no data on the frequency of self-monitoring of blood glucose or frequency of insulin bolus dosing; and the study was open label.
In her independent précis of the trial, Dr. Mathiesen, professor of endocrinology and chief physician managing pregnant women with diabetes at the Rigshospitalet University Hospital in Copenhagen, noted that there were some other downsides to using CGM in the study.
The CONCEPTT study was funded by the Juvenile Diabetes Research Foundation, the Canadian Clinical Trial Network, the National Institute for Health Research, the Center for Mother, Infant, and Child Research, and the Jaeb Center for Health Research. Medtronic also supported the study by providing the CGM sensors and systems at a reduced cost. Dr. Feig declared she had no competing interests. Dr. Murphy disclosed sitting on an advisory board for Medtronic and receiving personal fees from Novo Nordisk and Roche, unrelated to the current study. Dr. Mathiesen was the invited EASD independent commentator for the trial and did not give any disclosures. Dr. Garg has received advisory board consulting fees and research grants from Medtronic and several other pharmaceutical companies specializing in diabetes care. Dr. Polsky has received research funding from DexCom for diabetes device use in patients with diabetes paid directly to the University of Denver.
LISBON – , according to the investigators of a prospective, multicenter, randomized, controlled study who found that it improved a number of neonatal outcomes.
In the open-label Continuous Glucose Monitoring in Pregnant Women with Type 1 Diabetes(CONCEPTT) study, infants born to mothers who had used continuous glucose monitoring (CGM) versus those who had not had a 49% lower chance of being large for gestational age (53% vs. 69%, odds ratio [OR] 0.51, P = .0210) and were 52% less likely to need neonatal intensive care lasting for longer than 24 hours (27% vs. 43%, OR 0.48, P = .0157).
Neonates born to mothers who used CGM during their pregnancy were also less likely to experience hypoglycemia (15% vs. 28%, OR 0.45, P = .0250) and were able to leave the hospital with their mother 1 day earlier (P = .0091) than those born to mothers who did not use CGM.However, these were secondary outcomes of the study, which first looked at how CGM affected the glycemic profile of the mother.“To the best of our knowledge, this is the first trial to demonstrate a benefit of CGM on health outcomes beyond glucose control,” Helen Murphy, MD, one of the CONCEPTT trial’s two principal investigators, said at the annual meeting of the European Association for the Study of Diabetes.
“We would suggest, on the back of these data, that CGM should be offered to all pregnant women with type 1 diabetes using intensive insulin therapy during the first trimester,” Dr. Murphy said, adding that results of the study were simultaneously published online in the Lancet (2017 Sept. 15. doi. 10.1016/S0140-6736(17)32400-5).
“The CONCEPTT study will change the future for pregnant women with diabetes,” commented Elisabeth Mathiesen, MD, who was the EASD’s invited discussant for the study, and who congratulated the investigators for “a well performed study” and being “brave,” as “performing a RCT [randomized controlled trial] in pregnancy is not easy”.
Satish Garg, MD, and Sarit Polsky, MD, of the Barbara Davis Center for Diabetes at the University of Colorado, Denver, agreed in an editorial (Lancet 2017; Sept. 12. doi: 10.1016/S0140-6736(17)32449-2) accompanying the published article that the study findings were clinically important.
“We believe that the CONCEPTT results support CGM use during pregnancy for all women with type 1 diabetes,” they wrote, adding that the mother’s “time in [glycated hemoglobin, HbA1C] range might become an important measure in pregnancies with type 1 diabetes.”
Dr. Garg and Dr. Polsky also suggested that endocrine and obstetric medical societies take note and perhaps revise accordingly their guidelines on the use of CGM during pregnancy in diabetic women.
CONCEPTT involved 325 women with type 1 diabetes; 215 were pregnant at the time of enrollment, and 110 were planning on becoming pregnant in the near future.
Co-principal investigator Denice Feig, MD, of Sinai Health System in Toronto, explained that women were eligible for inclusion in the trial if they had type 1 diabetes for at least 1 year, were aged between 18 and 40 years, and had been using daily insulin delivered by either an insulin pump or multiple daily injections (MDI). At enrollment, the participants’ insulin regimen had to been stable for at least 4 weeks before randomization to CGM with capillary glucose monitoring or capillary glucose monitoring alone and their glycemic control had to be suboptimal.
Two groups of women were studied: a “pre-pregnancy group” of women who were planning on pregnancy and wanted to optimize their glycemic control before conception, and a “pregnancy group” of women in their first trimester (less than 14 weeks’ gestation) who were due to have a live, singleton birth as confirmed by ultrasound.
The primary outcome of the trial was the change in HbA1C from baseline to 34 weeks, with pre-specified secondary outcomes of various CGM measures, neoneonatal outcomes, and patient-reported outcomes.
Pregnant women using CGM had lower HbA1C levels during the trial than women who did not have CGM monitoring, although the difference was small (–0.19%, P = .0207).
The use of CGM was associated with more time spent in target HbA1C range (68% of women using CMG vs. 61% of those not using CGM, P = .0034), with less time being hyperglycemic (27% vs. 37%, P = .0279) and comparable rates of hypoglycemia (17 vs. 21 episodes) and time spent being hypoglycemic (2% vs. 4%, P = .10).“The CGM effects were very comparable among insulin pump and MDI users and across 31 international sites,” Dr. Murphy summarized, although she noted that there was no consistent benefit of using CGM seen in women who were planning a pregnancy. Dr. Feig noted that the strengths of the study were the large sample size and that CGM was used continuously from the first trimester until delivery. Women using both pumps and MDI were included at multiple centers and countries, and HbA1C was centrally assessed, with detailed CGM measures used in an exclusively type 1 diabetes population.“Of note, one needed to treat only six women with CGM to prevent one episode of large for gestational age,” Dr. Feig reported. “One needed to treat only eight women to prevent one neonatal hypoglycemia, and six women to prevent one NICU [neonatal intensive care unit] admission over 24 hours.”
There were some limitations, of course, including: around 20% of women had missing data on their HbA1C level; women using CGM also made more unscheduled visits to their health care providers although there are no data on the frequency of self-monitoring of blood glucose or frequency of insulin bolus dosing; and the study was open label.
In her independent précis of the trial, Dr. Mathiesen, professor of endocrinology and chief physician managing pregnant women with diabetes at the Rigshospitalet University Hospital in Copenhagen, noted that there were some other downsides to using CGM in the study.
The CONCEPTT study was funded by the Juvenile Diabetes Research Foundation, the Canadian Clinical Trial Network, the National Institute for Health Research, the Center for Mother, Infant, and Child Research, and the Jaeb Center for Health Research. Medtronic also supported the study by providing the CGM sensors and systems at a reduced cost. Dr. Feig declared she had no competing interests. Dr. Murphy disclosed sitting on an advisory board for Medtronic and receiving personal fees from Novo Nordisk and Roche, unrelated to the current study. Dr. Mathiesen was the invited EASD independent commentator for the trial and did not give any disclosures. Dr. Garg has received advisory board consulting fees and research grants from Medtronic and several other pharmaceutical companies specializing in diabetes care. Dr. Polsky has received research funding from DexCom for diabetes device use in patients with diabetes paid directly to the University of Denver.
LISBON – , according to the investigators of a prospective, multicenter, randomized, controlled study who found that it improved a number of neonatal outcomes.
In the open-label Continuous Glucose Monitoring in Pregnant Women with Type 1 Diabetes(CONCEPTT) study, infants born to mothers who had used continuous glucose monitoring (CGM) versus those who had not had a 49% lower chance of being large for gestational age (53% vs. 69%, odds ratio [OR] 0.51, P = .0210) and were 52% less likely to need neonatal intensive care lasting for longer than 24 hours (27% vs. 43%, OR 0.48, P = .0157).
Neonates born to mothers who used CGM during their pregnancy were also less likely to experience hypoglycemia (15% vs. 28%, OR 0.45, P = .0250) and were able to leave the hospital with their mother 1 day earlier (P = .0091) than those born to mothers who did not use CGM.However, these were secondary outcomes of the study, which first looked at how CGM affected the glycemic profile of the mother.“To the best of our knowledge, this is the first trial to demonstrate a benefit of CGM on health outcomes beyond glucose control,” Helen Murphy, MD, one of the CONCEPTT trial’s two principal investigators, said at the annual meeting of the European Association for the Study of Diabetes.
“We would suggest, on the back of these data, that CGM should be offered to all pregnant women with type 1 diabetes using intensive insulin therapy during the first trimester,” Dr. Murphy said, adding that results of the study were simultaneously published online in the Lancet (2017 Sept. 15. doi. 10.1016/S0140-6736(17)32400-5).
“The CONCEPTT study will change the future for pregnant women with diabetes,” commented Elisabeth Mathiesen, MD, who was the EASD’s invited discussant for the study, and who congratulated the investigators for “a well performed study” and being “brave,” as “performing a RCT [randomized controlled trial] in pregnancy is not easy”.
Satish Garg, MD, and Sarit Polsky, MD, of the Barbara Davis Center for Diabetes at the University of Colorado, Denver, agreed in an editorial (Lancet 2017; Sept. 12. doi: 10.1016/S0140-6736(17)32449-2) accompanying the published article that the study findings were clinically important.
“We believe that the CONCEPTT results support CGM use during pregnancy for all women with type 1 diabetes,” they wrote, adding that the mother’s “time in [glycated hemoglobin, HbA1C] range might become an important measure in pregnancies with type 1 diabetes.”
Dr. Garg and Dr. Polsky also suggested that endocrine and obstetric medical societies take note and perhaps revise accordingly their guidelines on the use of CGM during pregnancy in diabetic women.
CONCEPTT involved 325 women with type 1 diabetes; 215 were pregnant at the time of enrollment, and 110 were planning on becoming pregnant in the near future.
Co-principal investigator Denice Feig, MD, of Sinai Health System in Toronto, explained that women were eligible for inclusion in the trial if they had type 1 diabetes for at least 1 year, were aged between 18 and 40 years, and had been using daily insulin delivered by either an insulin pump or multiple daily injections (MDI). At enrollment, the participants’ insulin regimen had to been stable for at least 4 weeks before randomization to CGM with capillary glucose monitoring or capillary glucose monitoring alone and their glycemic control had to be suboptimal.
Two groups of women were studied: a “pre-pregnancy group” of women who were planning on pregnancy and wanted to optimize their glycemic control before conception, and a “pregnancy group” of women in their first trimester (less than 14 weeks’ gestation) who were due to have a live, singleton birth as confirmed by ultrasound.
The primary outcome of the trial was the change in HbA1C from baseline to 34 weeks, with pre-specified secondary outcomes of various CGM measures, neoneonatal outcomes, and patient-reported outcomes.
Pregnant women using CGM had lower HbA1C levels during the trial than women who did not have CGM monitoring, although the difference was small (–0.19%, P = .0207).
The use of CGM was associated with more time spent in target HbA1C range (68% of women using CMG vs. 61% of those not using CGM, P = .0034), with less time being hyperglycemic (27% vs. 37%, P = .0279) and comparable rates of hypoglycemia (17 vs. 21 episodes) and time spent being hypoglycemic (2% vs. 4%, P = .10).“The CGM effects were very comparable among insulin pump and MDI users and across 31 international sites,” Dr. Murphy summarized, although she noted that there was no consistent benefit of using CGM seen in women who were planning a pregnancy. Dr. Feig noted that the strengths of the study were the large sample size and that CGM was used continuously from the first trimester until delivery. Women using both pumps and MDI were included at multiple centers and countries, and HbA1C was centrally assessed, with detailed CGM measures used in an exclusively type 1 diabetes population.“Of note, one needed to treat only six women with CGM to prevent one episode of large for gestational age,” Dr. Feig reported. “One needed to treat only eight women to prevent one neonatal hypoglycemia, and six women to prevent one NICU [neonatal intensive care unit] admission over 24 hours.”
There were some limitations, of course, including: around 20% of women had missing data on their HbA1C level; women using CGM also made more unscheduled visits to their health care providers although there are no data on the frequency of self-monitoring of blood glucose or frequency of insulin bolus dosing; and the study was open label.
In her independent précis of the trial, Dr. Mathiesen, professor of endocrinology and chief physician managing pregnant women with diabetes at the Rigshospitalet University Hospital in Copenhagen, noted that there were some other downsides to using CGM in the study.
The CONCEPTT study was funded by the Juvenile Diabetes Research Foundation, the Canadian Clinical Trial Network, the National Institute for Health Research, the Center for Mother, Infant, and Child Research, and the Jaeb Center for Health Research. Medtronic also supported the study by providing the CGM sensors and systems at a reduced cost. Dr. Feig declared she had no competing interests. Dr. Murphy disclosed sitting on an advisory board for Medtronic and receiving personal fees from Novo Nordisk and Roche, unrelated to the current study. Dr. Mathiesen was the invited EASD independent commentator for the trial and did not give any disclosures. Dr. Garg has received advisory board consulting fees and research grants from Medtronic and several other pharmaceutical companies specializing in diabetes care. Dr. Polsky has received research funding from DexCom for diabetes device use in patients with diabetes paid directly to the University of Denver.
AT EASD 2017
Key clinical point: Continuous glucose monitoring should be offered to women with type 1 diabetes on intensive insulin therapy during their pregnancy.
Major finding: Neonatal outcomes were significantly better if women used CGM while they were pregnant than if they did not. Some maternal outcomes were also improved.
Data source: CONCEPTT: a prospective, multicenter, open-label, randomized controlled trial of 325 women with type 1 diabetes: 215 were pregnant; 110 were planning a pregnancy.
Disclosures: The study was funded by the Juvenile Diabetes Research Foundation, the Canadian Clinical Trial Network, the National Institute for Health Research, the Center for Mother, Infant, and Child Research, and the Jaeb Center for Health Research. Medtronic also supported the study by providing the CGM sensors and systems at a reduced cost. One of the study presenters disclosed sitting on an advisory board for Medtronic.
Alirocumab’s ODYSSEY continues: Efficacy unaffected by insulin, beats fenofibrate
LISBON – , plus it may have an edge over using older, add-on lipid-lowering therapies such as fibrates.
The findings were presented at the annual meeting of the European Association for the Study of Diabetes.
In one study involving 76 insulin-treated patients with T1DM, treatment with alirocumab (Praluent, Sanofi/Regeneron Pharmaceuticals) reduced low-density lipoprotein cholesterol levels by a mean of 47.8% versus placebo from baseline to week 24 (P less than .0001), the primary endpoint of the study.
Furthermore, in a separate study involving 413 patients with T2DM with mixed hyperlipidemia, alirocumab decreased levels of non–high-density lipoprotein cholesterol (non-HDL-C) by 33.3% compared with fenofibrate (P less than .0001).
These new results from the ODYSSEY DM-INSULIN and ODYSSEY DM-DYSLIPIDEMIA trials, respectively, add to those already presented this year at the annual scientific sessions of the American Diabetes Association.
“We have studied two groups of high- to very-high cardiovascular risk patients with diabetes mellitus: those on insulin and those with mixed dyslipidemia in whom previously only secondary data were available,” said Stefano Del Prato, MD, who presented the lipid study. “These are dedicated studies in these specific populations,” he added.
In these high-risk diabetic populations, Dr. Del Prato, professor of endocrinology and metabolism and chief of the section of diabetes, University of Pisa, Italy, observed “alirocumab was superior in lipid-lowering efficacy compared to standard care, with no specific safety issues.”
Efficacy unaffected by co-administration with insulin use
Helen Colhoun, MD, AXA chair of medical informatics and life course epidemiology at the University of Edinburgh, presented the updated findings of the ODYSSEY DM-INSULIN study, which recruited 517 patients, the majority (n = 441) of whom had T2DM.
In the study, alirocumab, a monoclonal antibody that targets proprotein convertase subtilisin–kexin type 9 (PCSK9), was compared with placebo in patients with established atherosclerotic cardiovascular disease or other cardiovascular risk factors, and in whom LDL-C was 70 mg/dL (1.8 mmol/L) or higher.
The percentage change in LDL-C from baseline to week 24 was similarly reduced in T1DM and T2DM, Dr. Colhoun observed, and commensurate with data seen across the ODYSSEY phase III trials program. Of note, the majority of type 2 (80%) and type 1 (63%) patients did not need the dose of alirocumab to be increased and remained on the starting dose of 75 mg every 2 weeks.
The results of the ODYSSEY DM-INSULIN trial, which were published online, Sept. 14, 2017, to coincide with their presentation at the meeting, also showed that the percentage change in LDL-C over time is “well sustained” and that 70% and 76% of patients with T1DM and T2DM, respectively, can achieve an LDL-C target of less than 70 mg/dL (1.8 mmol/L) and 79% and 71% can hit a non-HDL-C target of less than 100 mg/dL (2.6 mmol/L).
Other lipid parameters – including apolipoprotein (Apo) B, total cholesterol, Lp(a), and triglycerides – were also reduced to a greater extent in patients treated with alirocumab versus those given placebo. Dr. Colhoun drew attention to the reduction in Lp(a), which dropped by 23% in patients with T1DM and by 19% in patients with T2DM, as it is an important risk factor for peripheral vascular disease, and it is not affected by statin therapy.
“What this trial has told us is that coadministering alirocumab with insulin does not adversely affect its efficacy,” said Dr. Colhoun. “There’s absolutely no evidence of alirocumab altering HbA1c or fasting plasma glucose,” she added. There was also no affect on how patients were treated, either with insulin therapy or antihyperglycemic drugs.
Overall safety findings were “reassuring” and anti-drug antibodies were rare (2.1%) and did not affect the lipid-lowering effects of alirocumab.
Alirocumab beats fenofibrate as add-on lipid-lowering therapy
Presenting the ODYSSEY DM-DYSLIPIDEMIA data, which involved patients with T2DM, Dr. Del Prato observed that alirocumab was “generally well tolerated” and did not affect HbA1c or fasting plasma glucose levels.
He presented new data from a prespecified analysis that looked at the subgroup of 72 patients who were randomized into an alirocumab (n = 48) or fenofibrate (n = 24) as usual care arm. Dr. Del Prato reminded the audience that the choice of usual treatment was decided by the study investigators prior to randomizing patients, and that other usual care treatments included in the study were ezetimibe, omega-3 fatty acids, nicotinic acid, or no lipid-lowering therapy.
As in the insulin study, the majority (63.6%) of patients treated with alirocumab remained on the starting dose of 75 mg every 2 weeks and did not need up-titration.
Changes in the percentage of non-HDL-C from baseline over time were greater in the alirocumab group than in the usual care group, both in the overall population and in the fenofibrate subanalysis.
Higher percentages of patients treated with alirocumab achieved non-HDL-C compared with those given usual care (66.9% vs. 17.7% in overall population, 65.2% vs. 10.1% in fenofibrate sub-analysis) and LDL-C (70.8% vs. 16.3% and 71.9% vs. 17.5%, respectively) goals at week 24.
Alirocumab also significantly reduced levels of Apo B, total cholesterol, and Lp(a) versus the overall usual care group and also versus the fenofibrate usual care group, Dr. Del Prato said.
Taking the two studies together, he concluded: “These data support alirocumab as a treatment option in people with diabetes mellitus and hypercholesterolemia despite maximally tolerated statins,” Dr. Del Prato said.
Will the lipid-benefits translate into improved cardiovascular outcomes?
The question now is whether the lipid-lowering effects of alirocumab in patients with diabetes will translate into improved cardiovascular outcomes in patients with diabetes.
The results of the ODYSSEY OUTCOMES trial, which is evaluating cardiovascular outcomes during treatment with alirocumab after an acute coronary syndrome, are expected next year. While the trial is not being conducted specifically in patients with diabetes, it is expected that there will be subpopulations of T1DM and T2DM patients included.
Cardiovascular outcomes data on the PCSK9 inhibitor, evolocumab (Repatha, Amgen) in the FOURIER trial were published in March (N Engl J Med 2017;376:1713-22) and provide some evidence that a reduction in major cardiovascular events may be possible with these agents.
Providing independent comment on the study, Angelo Avogaro, MD, of the University of Padova, Italy, said that the additional LDL-C lowering effect of alirocumab on top of statins could theoretically halve the projected 10-year risk of cardiovascular disease using data from the two ODYSSEY studies and the UKPDS Risk Engine. Using a baseline 10-year cardiovascular risk of around 26%-28%, this could be reduced to 11%-13%, he suggested.
Of note, Dr. Avogaro said, was that, at baseline, not all patients were on high intensity statins, the majority received moderate doses, with a good number of patients taking none or who were intolerant to statins included. “This, I like,” he observed.
A reassuring point was that there was no signal of having a detrimental effect on neurocognitive dysfunction, Dr. Avogaro observed, which concurs with recent data published on evolocumab (N Engl J Med 2017; 377:633-43).
Nevertheless, longer-follow-up is needed to examine adverse effects, “especially in those insulin-treated patients experiencing severe hypoglycemic reactions.”
The ODYSSEY DM studies were funded by Sanofi and Regeneron Pharmaceuticals.
Dr. Colhoun has received research grants from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Pfizer, Regeneron Pharmaceuticals, Roche Pharmaceuticals, and Sanofi. She has also been a consultant for Eli Lilly, Regeneron Pharmaceuticals, and Sanofi.
Dr. Del Prato has received research funding from AstraZeneca, Boehringer Ingelheim, Novartis, Merck Sharpe & Dohme, and Novo Nordisk. He is a consultant for or has received honoraria from the preceding companies, as well as from Eli Lilly, GlaxoSmithKline, Janssen Pharmaceuticals, Laboratoires Servier, Sanofi-Aventis, and Takeda Pharmaceuticals.
LISBON – , plus it may have an edge over using older, add-on lipid-lowering therapies such as fibrates.
The findings were presented at the annual meeting of the European Association for the Study of Diabetes.
In one study involving 76 insulin-treated patients with T1DM, treatment with alirocumab (Praluent, Sanofi/Regeneron Pharmaceuticals) reduced low-density lipoprotein cholesterol levels by a mean of 47.8% versus placebo from baseline to week 24 (P less than .0001), the primary endpoint of the study.
Furthermore, in a separate study involving 413 patients with T2DM with mixed hyperlipidemia, alirocumab decreased levels of non–high-density lipoprotein cholesterol (non-HDL-C) by 33.3% compared with fenofibrate (P less than .0001).
These new results from the ODYSSEY DM-INSULIN and ODYSSEY DM-DYSLIPIDEMIA trials, respectively, add to those already presented this year at the annual scientific sessions of the American Diabetes Association.
“We have studied two groups of high- to very-high cardiovascular risk patients with diabetes mellitus: those on insulin and those with mixed dyslipidemia in whom previously only secondary data were available,” said Stefano Del Prato, MD, who presented the lipid study. “These are dedicated studies in these specific populations,” he added.
In these high-risk diabetic populations, Dr. Del Prato, professor of endocrinology and metabolism and chief of the section of diabetes, University of Pisa, Italy, observed “alirocumab was superior in lipid-lowering efficacy compared to standard care, with no specific safety issues.”
Efficacy unaffected by co-administration with insulin use
Helen Colhoun, MD, AXA chair of medical informatics and life course epidemiology at the University of Edinburgh, presented the updated findings of the ODYSSEY DM-INSULIN study, which recruited 517 patients, the majority (n = 441) of whom had T2DM.
In the study, alirocumab, a monoclonal antibody that targets proprotein convertase subtilisin–kexin type 9 (PCSK9), was compared with placebo in patients with established atherosclerotic cardiovascular disease or other cardiovascular risk factors, and in whom LDL-C was 70 mg/dL (1.8 mmol/L) or higher.
The percentage change in LDL-C from baseline to week 24 was similarly reduced in T1DM and T2DM, Dr. Colhoun observed, and commensurate with data seen across the ODYSSEY phase III trials program. Of note, the majority of type 2 (80%) and type 1 (63%) patients did not need the dose of alirocumab to be increased and remained on the starting dose of 75 mg every 2 weeks.
The results of the ODYSSEY DM-INSULIN trial, which were published online, Sept. 14, 2017, to coincide with their presentation at the meeting, also showed that the percentage change in LDL-C over time is “well sustained” and that 70% and 76% of patients with T1DM and T2DM, respectively, can achieve an LDL-C target of less than 70 mg/dL (1.8 mmol/L) and 79% and 71% can hit a non-HDL-C target of less than 100 mg/dL (2.6 mmol/L).
Other lipid parameters – including apolipoprotein (Apo) B, total cholesterol, Lp(a), and triglycerides – were also reduced to a greater extent in patients treated with alirocumab versus those given placebo. Dr. Colhoun drew attention to the reduction in Lp(a), which dropped by 23% in patients with T1DM and by 19% in patients with T2DM, as it is an important risk factor for peripheral vascular disease, and it is not affected by statin therapy.
“What this trial has told us is that coadministering alirocumab with insulin does not adversely affect its efficacy,” said Dr. Colhoun. “There’s absolutely no evidence of alirocumab altering HbA1c or fasting plasma glucose,” she added. There was also no affect on how patients were treated, either with insulin therapy or antihyperglycemic drugs.
Overall safety findings were “reassuring” and anti-drug antibodies were rare (2.1%) and did not affect the lipid-lowering effects of alirocumab.
Alirocumab beats fenofibrate as add-on lipid-lowering therapy
Presenting the ODYSSEY DM-DYSLIPIDEMIA data, which involved patients with T2DM, Dr. Del Prato observed that alirocumab was “generally well tolerated” and did not affect HbA1c or fasting plasma glucose levels.
He presented new data from a prespecified analysis that looked at the subgroup of 72 patients who were randomized into an alirocumab (n = 48) or fenofibrate (n = 24) as usual care arm. Dr. Del Prato reminded the audience that the choice of usual treatment was decided by the study investigators prior to randomizing patients, and that other usual care treatments included in the study were ezetimibe, omega-3 fatty acids, nicotinic acid, or no lipid-lowering therapy.
As in the insulin study, the majority (63.6%) of patients treated with alirocumab remained on the starting dose of 75 mg every 2 weeks and did not need up-titration.
Changes in the percentage of non-HDL-C from baseline over time were greater in the alirocumab group than in the usual care group, both in the overall population and in the fenofibrate subanalysis.
Higher percentages of patients treated with alirocumab achieved non-HDL-C compared with those given usual care (66.9% vs. 17.7% in overall population, 65.2% vs. 10.1% in fenofibrate sub-analysis) and LDL-C (70.8% vs. 16.3% and 71.9% vs. 17.5%, respectively) goals at week 24.
Alirocumab also significantly reduced levels of Apo B, total cholesterol, and Lp(a) versus the overall usual care group and also versus the fenofibrate usual care group, Dr. Del Prato said.
Taking the two studies together, he concluded: “These data support alirocumab as a treatment option in people with diabetes mellitus and hypercholesterolemia despite maximally tolerated statins,” Dr. Del Prato said.
Will the lipid-benefits translate into improved cardiovascular outcomes?
The question now is whether the lipid-lowering effects of alirocumab in patients with diabetes will translate into improved cardiovascular outcomes in patients with diabetes.
The results of the ODYSSEY OUTCOMES trial, which is evaluating cardiovascular outcomes during treatment with alirocumab after an acute coronary syndrome, are expected next year. While the trial is not being conducted specifically in patients with diabetes, it is expected that there will be subpopulations of T1DM and T2DM patients included.
Cardiovascular outcomes data on the PCSK9 inhibitor, evolocumab (Repatha, Amgen) in the FOURIER trial were published in March (N Engl J Med 2017;376:1713-22) and provide some evidence that a reduction in major cardiovascular events may be possible with these agents.
Providing independent comment on the study, Angelo Avogaro, MD, of the University of Padova, Italy, said that the additional LDL-C lowering effect of alirocumab on top of statins could theoretically halve the projected 10-year risk of cardiovascular disease using data from the two ODYSSEY studies and the UKPDS Risk Engine. Using a baseline 10-year cardiovascular risk of around 26%-28%, this could be reduced to 11%-13%, he suggested.
Of note, Dr. Avogaro said, was that, at baseline, not all patients were on high intensity statins, the majority received moderate doses, with a good number of patients taking none or who were intolerant to statins included. “This, I like,” he observed.
A reassuring point was that there was no signal of having a detrimental effect on neurocognitive dysfunction, Dr. Avogaro observed, which concurs with recent data published on evolocumab (N Engl J Med 2017; 377:633-43).
Nevertheless, longer-follow-up is needed to examine adverse effects, “especially in those insulin-treated patients experiencing severe hypoglycemic reactions.”
The ODYSSEY DM studies were funded by Sanofi and Regeneron Pharmaceuticals.
Dr. Colhoun has received research grants from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Pfizer, Regeneron Pharmaceuticals, Roche Pharmaceuticals, and Sanofi. She has also been a consultant for Eli Lilly, Regeneron Pharmaceuticals, and Sanofi.
Dr. Del Prato has received research funding from AstraZeneca, Boehringer Ingelheim, Novartis, Merck Sharpe & Dohme, and Novo Nordisk. He is a consultant for or has received honoraria from the preceding companies, as well as from Eli Lilly, GlaxoSmithKline, Janssen Pharmaceuticals, Laboratoires Servier, Sanofi-Aventis, and Takeda Pharmaceuticals.
LISBON – , plus it may have an edge over using older, add-on lipid-lowering therapies such as fibrates.
The findings were presented at the annual meeting of the European Association for the Study of Diabetes.
In one study involving 76 insulin-treated patients with T1DM, treatment with alirocumab (Praluent, Sanofi/Regeneron Pharmaceuticals) reduced low-density lipoprotein cholesterol levels by a mean of 47.8% versus placebo from baseline to week 24 (P less than .0001), the primary endpoint of the study.
Furthermore, in a separate study involving 413 patients with T2DM with mixed hyperlipidemia, alirocumab decreased levels of non–high-density lipoprotein cholesterol (non-HDL-C) by 33.3% compared with fenofibrate (P less than .0001).
These new results from the ODYSSEY DM-INSULIN and ODYSSEY DM-DYSLIPIDEMIA trials, respectively, add to those already presented this year at the annual scientific sessions of the American Diabetes Association.
“We have studied two groups of high- to very-high cardiovascular risk patients with diabetes mellitus: those on insulin and those with mixed dyslipidemia in whom previously only secondary data were available,” said Stefano Del Prato, MD, who presented the lipid study. “These are dedicated studies in these specific populations,” he added.
In these high-risk diabetic populations, Dr. Del Prato, professor of endocrinology and metabolism and chief of the section of diabetes, University of Pisa, Italy, observed “alirocumab was superior in lipid-lowering efficacy compared to standard care, with no specific safety issues.”
Efficacy unaffected by co-administration with insulin use
Helen Colhoun, MD, AXA chair of medical informatics and life course epidemiology at the University of Edinburgh, presented the updated findings of the ODYSSEY DM-INSULIN study, which recruited 517 patients, the majority (n = 441) of whom had T2DM.
In the study, alirocumab, a monoclonal antibody that targets proprotein convertase subtilisin–kexin type 9 (PCSK9), was compared with placebo in patients with established atherosclerotic cardiovascular disease or other cardiovascular risk factors, and in whom LDL-C was 70 mg/dL (1.8 mmol/L) or higher.
The percentage change in LDL-C from baseline to week 24 was similarly reduced in T1DM and T2DM, Dr. Colhoun observed, and commensurate with data seen across the ODYSSEY phase III trials program. Of note, the majority of type 2 (80%) and type 1 (63%) patients did not need the dose of alirocumab to be increased and remained on the starting dose of 75 mg every 2 weeks.
The results of the ODYSSEY DM-INSULIN trial, which were published online, Sept. 14, 2017, to coincide with their presentation at the meeting, also showed that the percentage change in LDL-C over time is “well sustained” and that 70% and 76% of patients with T1DM and T2DM, respectively, can achieve an LDL-C target of less than 70 mg/dL (1.8 mmol/L) and 79% and 71% can hit a non-HDL-C target of less than 100 mg/dL (2.6 mmol/L).
Other lipid parameters – including apolipoprotein (Apo) B, total cholesterol, Lp(a), and triglycerides – were also reduced to a greater extent in patients treated with alirocumab versus those given placebo. Dr. Colhoun drew attention to the reduction in Lp(a), which dropped by 23% in patients with T1DM and by 19% in patients with T2DM, as it is an important risk factor for peripheral vascular disease, and it is not affected by statin therapy.
“What this trial has told us is that coadministering alirocumab with insulin does not adversely affect its efficacy,” said Dr. Colhoun. “There’s absolutely no evidence of alirocumab altering HbA1c or fasting plasma glucose,” she added. There was also no affect on how patients were treated, either with insulin therapy or antihyperglycemic drugs.
Overall safety findings were “reassuring” and anti-drug antibodies were rare (2.1%) and did not affect the lipid-lowering effects of alirocumab.
Alirocumab beats fenofibrate as add-on lipid-lowering therapy
Presenting the ODYSSEY DM-DYSLIPIDEMIA data, which involved patients with T2DM, Dr. Del Prato observed that alirocumab was “generally well tolerated” and did not affect HbA1c or fasting plasma glucose levels.
He presented new data from a prespecified analysis that looked at the subgroup of 72 patients who were randomized into an alirocumab (n = 48) or fenofibrate (n = 24) as usual care arm. Dr. Del Prato reminded the audience that the choice of usual treatment was decided by the study investigators prior to randomizing patients, and that other usual care treatments included in the study were ezetimibe, omega-3 fatty acids, nicotinic acid, or no lipid-lowering therapy.
As in the insulin study, the majority (63.6%) of patients treated with alirocumab remained on the starting dose of 75 mg every 2 weeks and did not need up-titration.
Changes in the percentage of non-HDL-C from baseline over time were greater in the alirocumab group than in the usual care group, both in the overall population and in the fenofibrate subanalysis.
Higher percentages of patients treated with alirocumab achieved non-HDL-C compared with those given usual care (66.9% vs. 17.7% in overall population, 65.2% vs. 10.1% in fenofibrate sub-analysis) and LDL-C (70.8% vs. 16.3% and 71.9% vs. 17.5%, respectively) goals at week 24.
Alirocumab also significantly reduced levels of Apo B, total cholesterol, and Lp(a) versus the overall usual care group and also versus the fenofibrate usual care group, Dr. Del Prato said.
Taking the two studies together, he concluded: “These data support alirocumab as a treatment option in people with diabetes mellitus and hypercholesterolemia despite maximally tolerated statins,” Dr. Del Prato said.
Will the lipid-benefits translate into improved cardiovascular outcomes?
The question now is whether the lipid-lowering effects of alirocumab in patients with diabetes will translate into improved cardiovascular outcomes in patients with diabetes.
The results of the ODYSSEY OUTCOMES trial, which is evaluating cardiovascular outcomes during treatment with alirocumab after an acute coronary syndrome, are expected next year. While the trial is not being conducted specifically in patients with diabetes, it is expected that there will be subpopulations of T1DM and T2DM patients included.
Cardiovascular outcomes data on the PCSK9 inhibitor, evolocumab (Repatha, Amgen) in the FOURIER trial were published in March (N Engl J Med 2017;376:1713-22) and provide some evidence that a reduction in major cardiovascular events may be possible with these agents.
Providing independent comment on the study, Angelo Avogaro, MD, of the University of Padova, Italy, said that the additional LDL-C lowering effect of alirocumab on top of statins could theoretically halve the projected 10-year risk of cardiovascular disease using data from the two ODYSSEY studies and the UKPDS Risk Engine. Using a baseline 10-year cardiovascular risk of around 26%-28%, this could be reduced to 11%-13%, he suggested.
Of note, Dr. Avogaro said, was that, at baseline, not all patients were on high intensity statins, the majority received moderate doses, with a good number of patients taking none or who were intolerant to statins included. “This, I like,” he observed.
A reassuring point was that there was no signal of having a detrimental effect on neurocognitive dysfunction, Dr. Avogaro observed, which concurs with recent data published on evolocumab (N Engl J Med 2017; 377:633-43).
Nevertheless, longer-follow-up is needed to examine adverse effects, “especially in those insulin-treated patients experiencing severe hypoglycemic reactions.”
The ODYSSEY DM studies were funded by Sanofi and Regeneron Pharmaceuticals.
Dr. Colhoun has received research grants from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Pfizer, Regeneron Pharmaceuticals, Roche Pharmaceuticals, and Sanofi. She has also been a consultant for Eli Lilly, Regeneron Pharmaceuticals, and Sanofi.
Dr. Del Prato has received research funding from AstraZeneca, Boehringer Ingelheim, Novartis, Merck Sharpe & Dohme, and Novo Nordisk. He is a consultant for or has received honoraria from the preceding companies, as well as from Eli Lilly, GlaxoSmithKline, Janssen Pharmaceuticals, Laboratoires Servier, Sanofi-Aventis, and Takeda Pharmaceuticals.
AT EASD 2017
Key clinical point: Alicrocumab significantly reduced lipids in patients with type 1 and type 2 diabetes who remain at high cardiovascular risk despite statin therapy.
Major findings: From baseline to week 24, greater mean differences in low-density lipoprotein cholesterol were seen with alirocumab versus placebo in both T1DM (47.8%) and T2DM (49%) insulin-treated patients. In a separate trial, a 33% mean difference was seen between alirocumab and fenofibrate in the reduction of non–high density lipoprotein cholesterol.
Data source: Two randomized, controlled trials of alirocumab: ODYSSEY DM-INSULIN involving 441 T2DM and 76 T1DM insulin-treated patients and ODYSSEY DM-DYSLIPIDEMIA in 413 T2DM patients with mixed dyslipidemia.
Disclosures: Sanofi and Regeneron Pharmaceuticals funded the studies. All speakers except for the independent commentator disclosed receiving advisory fees, research grants, or both, from Sanofi/Regeneron Pharmaceuticals in addition to other companies involved in the manufacture and sale of drugs to treat diabetes.
No increased overall cardiovascular risk seen with exenatide use
“We did not observe any specific safety issues during our trial; there was no adverse signal with respect to heart failure, despite the higher mean heart rate in the exenatide group than in the placebo group, and events of acute pancreatitis and pancreatic cancer were rare, with similar rates in the two groups,” according to researchers led by Rury R. Holman, F.Med.Sci. Their study was published online Sept. 14 in the New England Journal of Medicine, and was presented at the annual meeting of the European Association for the Study of Diabetes.
For the trial, which was funded by Amylin Pharmaceuticals and known as the Exenatide Study of Cardiovascular Event Lowering (EXSCEL), the researchers randomly assigned 14,752 patients with type 2 diabetes at 687 sites in 35 countries to receive subcutaneous injections of extended-released exenatide at a dose of 2 mg, or matching placebo once per week, from June 18, 2010, through Sept. 16, 2015. The patients were followed for a median of 3.2 years and the main outcome of interest was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or stroke.
In the meantime, the intention-to-treat analysis revealed that exenatide was noninferior to placebo with respect to safety (P less than .001) but was not superior to placebo with respect to safety (P = .06). The researchers observed no significant differences between the two groups in the rates of death from cardiovascular causes, fatal or nonfatal MI, or stroke, hospitalization for heart failure or for acute coronary syndrome, or in the incidence of cute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events.
“The pragmatic design of the trial included integration with usual care and wide-ranging eligibility criteria,” the researchers wrote. “For example, patients with any degree of cardiovascular risk who were at least 18 years of age (with no upper age limit) were eligible. To further augment the potential generalizability of any findings, we evaluated the cardiovascular effect of once-weekly extended-release exenatide in the usual-care setting by maintaining the focus of management of diabetes and cardiovascular risk with the usual-care provider.”
The researchers acknowledged certain limitations of the study, including the rate of premature discontinuation of the trial regimen, “which was driven by patient decision. We speculate that probable factors for discontinuation were the complexity of the first-generation injection device that was used and the fact that our trial had no run-in period.”
The trial was conducted jointly by the Duke Clinical Research Institute and the University of Oxford Diabetes Trial Unit, in collaboration with Amylin Pharmaceuticals. Dr. Holman and his coauthors reported having numerous financial ties to the pharmaceutical industry.
PRIMARY SOURCE: N Engl J Med 2017 Sept. 14. doi: 10.1056/NEJMoa1612917
“We did not observe any specific safety issues during our trial; there was no adverse signal with respect to heart failure, despite the higher mean heart rate in the exenatide group than in the placebo group, and events of acute pancreatitis and pancreatic cancer were rare, with similar rates in the two groups,” according to researchers led by Rury R. Holman, F.Med.Sci. Their study was published online Sept. 14 in the New England Journal of Medicine, and was presented at the annual meeting of the European Association for the Study of Diabetes.
For the trial, which was funded by Amylin Pharmaceuticals and known as the Exenatide Study of Cardiovascular Event Lowering (EXSCEL), the researchers randomly assigned 14,752 patients with type 2 diabetes at 687 sites in 35 countries to receive subcutaneous injections of extended-released exenatide at a dose of 2 mg, or matching placebo once per week, from June 18, 2010, through Sept. 16, 2015. The patients were followed for a median of 3.2 years and the main outcome of interest was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or stroke.
In the meantime, the intention-to-treat analysis revealed that exenatide was noninferior to placebo with respect to safety (P less than .001) but was not superior to placebo with respect to safety (P = .06). The researchers observed no significant differences between the two groups in the rates of death from cardiovascular causes, fatal or nonfatal MI, or stroke, hospitalization for heart failure or for acute coronary syndrome, or in the incidence of cute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events.
“The pragmatic design of the trial included integration with usual care and wide-ranging eligibility criteria,” the researchers wrote. “For example, patients with any degree of cardiovascular risk who were at least 18 years of age (with no upper age limit) were eligible. To further augment the potential generalizability of any findings, we evaluated the cardiovascular effect of once-weekly extended-release exenatide in the usual-care setting by maintaining the focus of management of diabetes and cardiovascular risk with the usual-care provider.”
The researchers acknowledged certain limitations of the study, including the rate of premature discontinuation of the trial regimen, “which was driven by patient decision. We speculate that probable factors for discontinuation were the complexity of the first-generation injection device that was used and the fact that our trial had no run-in period.”
The trial was conducted jointly by the Duke Clinical Research Institute and the University of Oxford Diabetes Trial Unit, in collaboration with Amylin Pharmaceuticals. Dr. Holman and his coauthors reported having numerous financial ties to the pharmaceutical industry.
PRIMARY SOURCE: N Engl J Med 2017 Sept. 14. doi: 10.1056/NEJMoa1612917
“We did not observe any specific safety issues during our trial; there was no adverse signal with respect to heart failure, despite the higher mean heart rate in the exenatide group than in the placebo group, and events of acute pancreatitis and pancreatic cancer were rare, with similar rates in the two groups,” according to researchers led by Rury R. Holman, F.Med.Sci. Their study was published online Sept. 14 in the New England Journal of Medicine, and was presented at the annual meeting of the European Association for the Study of Diabetes.
For the trial, which was funded by Amylin Pharmaceuticals and known as the Exenatide Study of Cardiovascular Event Lowering (EXSCEL), the researchers randomly assigned 14,752 patients with type 2 diabetes at 687 sites in 35 countries to receive subcutaneous injections of extended-released exenatide at a dose of 2 mg, or matching placebo once per week, from June 18, 2010, through Sept. 16, 2015. The patients were followed for a median of 3.2 years and the main outcome of interest was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or stroke.
In the meantime, the intention-to-treat analysis revealed that exenatide was noninferior to placebo with respect to safety (P less than .001) but was not superior to placebo with respect to safety (P = .06). The researchers observed no significant differences between the two groups in the rates of death from cardiovascular causes, fatal or nonfatal MI, or stroke, hospitalization for heart failure or for acute coronary syndrome, or in the incidence of cute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events.
“The pragmatic design of the trial included integration with usual care and wide-ranging eligibility criteria,” the researchers wrote. “For example, patients with any degree of cardiovascular risk who were at least 18 years of age (with no upper age limit) were eligible. To further augment the potential generalizability of any findings, we evaluated the cardiovascular effect of once-weekly extended-release exenatide in the usual-care setting by maintaining the focus of management of diabetes and cardiovascular risk with the usual-care provider.”
The researchers acknowledged certain limitations of the study, including the rate of premature discontinuation of the trial regimen, “which was driven by patient decision. We speculate that probable factors for discontinuation were the complexity of the first-generation injection device that was used and the fact that our trial had no run-in period.”
The trial was conducted jointly by the Duke Clinical Research Institute and the University of Oxford Diabetes Trial Unit, in collaboration with Amylin Pharmaceuticals. Dr. Holman and his coauthors reported having numerous financial ties to the pharmaceutical industry.
PRIMARY SOURCE: N Engl J Med 2017 Sept. 14. doi: 10.1056/NEJMoa1612917
FROM EASD 2017
Key clinical point: Exenatide was noninferior to placebo with respect to cardiovascular safety but was not superior with respect to efficacy.
Major finding: Among patients with type 2 diabetes with and without previous cardiovascular disease, once-weekly administration of exenatide does not appear to cause an increase in their overall cardiovascular risk.
Study details: A randomized, placebo-controlled trial of 14,752 diabetic patients with or without previous cardiovascular disease.
Disclosures: The trial was conducted jointly by the Duke Clinical Research Institute and the University of Oxford Diabetes Trial Unit, in collaboration with Amylin Pharmaceuticals. Dr. Holman and his coauthors reported having numerous financial ties to the pharmaceutical industry.
Source: Rury R. Holman, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2017 Sept 14. doi: 10.1056/NEJMoa1612917.
AWARD-7: Dulaglutide benefits patients with diabetic renal disease
LISBON – Patients with type 2 diabetes mellitus who also have moderate-to-severe chronic kidney disease (CKD) may be as effectively treated with the glucagonlike peptide–1 receptor agonist dulaglutide (Trulicity) as insulin glargine, the results of an international study showed.
Although comparable effects on glycemic control were seen, patients who received dulaglutide rather than insulin glargine in conjunction with prandial insulin lispro (Humalog) exhibited greater weight loss, had fewer episodes of hypoglycemia, and experienced beneficial effects on two important renal parameters.
The adverse event profile of dulaglutide was typical of that seen with GLP-1 receptor antagonism, noted Dr. Tuttle, who is the executive director of Providence Medical Research Center, Providence Sacred Heart Medical Center in Spokane, Washington, and clinical professor of medicine in the nephrology division at the University of Washington in Seattle.
In Europe, the use of dulaglutide in patients with severely reduced kidney function is not currently recommended, and monitoring is required in the United States in those with gastrointestinal side effects.
AWARD-7 was a randomized, open-label parallel-arm study comparing once-weekly dulaglutide (0.75 mg or 1.5 mg) with insulin glargine plus prandial insulin lispro in 576 subjects who had T2DM and stage 3-4 chronic kidney disease. The aim of the trial was to show noninferiority of the dulaglutide regimen to the insulin glargine regimen.
The trial was open label because the dose of insulin glargine had to be regulated, Dr. Tuttle explained, but the dose of dulaglutide given was blinded. The dose of insulin glargine was targeted to fasting plasma glucose to achieve a value between 5.6 mmol/L and 8.3 mmol/L. The dose of insulin lispro was also adjusted to target preprandial plasma glucose between 6.7 mmol/L and 10.0 mmol/L.
Patients were included if they had a glycated hemoglobin (HbA1c) level of at least 7.5% but less than or equal to 10.5% (at least 57 but less than or equal to 91 mmol/mol) and an eGFR less than 60 but greater than or equal to 15 mL/min per 1.73 m2 at screening.
Approximately 45% of dulaglutide- and 52% of glargine-treated subjects were women; the average age of participants was 65 years, with an average duration of diabetes of around 18 years. The mean HbA1c level at study entry was 8.6% (70.5 mmol/mol), with around half of participants having a HbA1c above 8.5% (69.4 mmol/mol) at entry.
The majority of patients included had an eGFR of less than 45 mL/min per 1.73 m2, and about 30% of patients had stage 4 CKD (eGFR at least 15 but less than 30 mL/min per 1.73 m2), about 45% had macroalbuminuria, and a third or more had microalbuminuria.
The primary endpoint was change in HbA1c from baseline to week 26, and this was comparable for both dulaglutide (at around –1.1% to –1.2%) and insulin glargine (around –1.1%). The effects were maintained at 52 weeks, Dr. Tuttle said, adding that similar percentages (approximately 70% or more) of patients in the groups achieved a target HbA1c of less than 8.0 (64 mmol/mol) at 26 and at 52 weeks. Similar results were seen when the more conventional target of less than 7% (less than 52 mmol/mol) was used, with around 30% of patients achieving this target at 26 and at 52 weeks.
As for weight change, the insulin-treated patients gained about 1 kg in weight over the full course of the study while a dose-dependent decrease in weight of about 2-3 kg was seen with dulaglutide treatment.
“Rates of hypoglycemia were consistently lower in the dulaglutide groups [than in the glargine group],” Dr. Tuttle said, noting “the lowest rates of hypoglycemia were actually seen with the highest dose of dulaglutide.”
The rate of total hypoglycemia (less than or equal to 3.9 mmol/mol) in the 1.5-mg and 0.75-mg dulaglutide groups was 50% and 59.8% of patients, respectively, versus almost 75% of the glargine-treated patients. Rates for documented symptomatic (40.5%, 48.1%, 63.4%), nocturnal (20.5%, 23.8%, 47.9%), and severe (0%, 2.6%, 6.7%) hypoglycemia followed a similar pattern.
“Albuminuria was reduced in all study groups, but there were greater reductions in the patients receiving dulaglutide at 26 weeks,” Dr. Tuttle said. The mean change in UACR from baseline to week 26 was –27.7 for the 1.5-mg dose of dulaglutide, –26.7 for the 0.75-mg dose, and –16.4 for insulin glargine.
The expected rate of eGFR decline at week 26 was also lower with dulaglutide 1.5 mg and 0.75 mg than with glargine, at a respective –0.8%, –3.3%, and –7.7% or –0.1, –0.4, and –1.9 mL/min per 1.73 m2.
“In patients at this stage of CKD, we expect about a 4- to 5-mL per minute loss, so they are right on target or as expected in the insulin group, but this was essentially extinguished in the dulaglutide groups, where there was no significant loss in eGFR during the 26-week time period,” said Dr. Tuttle.
The only difference in side effect profiles between the dulaglutide groups and the glargine group was a higher rate of gastrointestinal side effects. Nausea was seen in 19.8%, 14.2%, and 4.6% of patients given the dulaglutide 1.5 mg, dulaglutide 0.75 mg, and glargine, respectively, with vomiting reported by 13.5%, 8.4%, and 4.6%.
Eli Lilly funded the study. Dr. Tuttle disclosed acting as a consultant on therapies for diabetic kidney disease for Eli Lilly, Boehringer Ingelheim, Gilead, and AstraZeneca.
This article was updated September 28, 2017.
LISBON – Patients with type 2 diabetes mellitus who also have moderate-to-severe chronic kidney disease (CKD) may be as effectively treated with the glucagonlike peptide–1 receptor agonist dulaglutide (Trulicity) as insulin glargine, the results of an international study showed.
Although comparable effects on glycemic control were seen, patients who received dulaglutide rather than insulin glargine in conjunction with prandial insulin lispro (Humalog) exhibited greater weight loss, had fewer episodes of hypoglycemia, and experienced beneficial effects on two important renal parameters.
The adverse event profile of dulaglutide was typical of that seen with GLP-1 receptor antagonism, noted Dr. Tuttle, who is the executive director of Providence Medical Research Center, Providence Sacred Heart Medical Center in Spokane, Washington, and clinical professor of medicine in the nephrology division at the University of Washington in Seattle.
In Europe, the use of dulaglutide in patients with severely reduced kidney function is not currently recommended, and monitoring is required in the United States in those with gastrointestinal side effects.
AWARD-7 was a randomized, open-label parallel-arm study comparing once-weekly dulaglutide (0.75 mg or 1.5 mg) with insulin glargine plus prandial insulin lispro in 576 subjects who had T2DM and stage 3-4 chronic kidney disease. The aim of the trial was to show noninferiority of the dulaglutide regimen to the insulin glargine regimen.
The trial was open label because the dose of insulin glargine had to be regulated, Dr. Tuttle explained, but the dose of dulaglutide given was blinded. The dose of insulin glargine was targeted to fasting plasma glucose to achieve a value between 5.6 mmol/L and 8.3 mmol/L. The dose of insulin lispro was also adjusted to target preprandial plasma glucose between 6.7 mmol/L and 10.0 mmol/L.
Patients were included if they had a glycated hemoglobin (HbA1c) level of at least 7.5% but less than or equal to 10.5% (at least 57 but less than or equal to 91 mmol/mol) and an eGFR less than 60 but greater than or equal to 15 mL/min per 1.73 m2 at screening.
Approximately 45% of dulaglutide- and 52% of glargine-treated subjects were women; the average age of participants was 65 years, with an average duration of diabetes of around 18 years. The mean HbA1c level at study entry was 8.6% (70.5 mmol/mol), with around half of participants having a HbA1c above 8.5% (69.4 mmol/mol) at entry.
The majority of patients included had an eGFR of less than 45 mL/min per 1.73 m2, and about 30% of patients had stage 4 CKD (eGFR at least 15 but less than 30 mL/min per 1.73 m2), about 45% had macroalbuminuria, and a third or more had microalbuminuria.
The primary endpoint was change in HbA1c from baseline to week 26, and this was comparable for both dulaglutide (at around –1.1% to –1.2%) and insulin glargine (around –1.1%). The effects were maintained at 52 weeks, Dr. Tuttle said, adding that similar percentages (approximately 70% or more) of patients in the groups achieved a target HbA1c of less than 8.0 (64 mmol/mol) at 26 and at 52 weeks. Similar results were seen when the more conventional target of less than 7% (less than 52 mmol/mol) was used, with around 30% of patients achieving this target at 26 and at 52 weeks.
As for weight change, the insulin-treated patients gained about 1 kg in weight over the full course of the study while a dose-dependent decrease in weight of about 2-3 kg was seen with dulaglutide treatment.
“Rates of hypoglycemia were consistently lower in the dulaglutide groups [than in the glargine group],” Dr. Tuttle said, noting “the lowest rates of hypoglycemia were actually seen with the highest dose of dulaglutide.”
The rate of total hypoglycemia (less than or equal to 3.9 mmol/mol) in the 1.5-mg and 0.75-mg dulaglutide groups was 50% and 59.8% of patients, respectively, versus almost 75% of the glargine-treated patients. Rates for documented symptomatic (40.5%, 48.1%, 63.4%), nocturnal (20.5%, 23.8%, 47.9%), and severe (0%, 2.6%, 6.7%) hypoglycemia followed a similar pattern.
“Albuminuria was reduced in all study groups, but there were greater reductions in the patients receiving dulaglutide at 26 weeks,” Dr. Tuttle said. The mean change in UACR from baseline to week 26 was –27.7 for the 1.5-mg dose of dulaglutide, –26.7 for the 0.75-mg dose, and –16.4 for insulin glargine.
The expected rate of eGFR decline at week 26 was also lower with dulaglutide 1.5 mg and 0.75 mg than with glargine, at a respective –0.8%, –3.3%, and –7.7% or –0.1, –0.4, and –1.9 mL/min per 1.73 m2.
“In patients at this stage of CKD, we expect about a 4- to 5-mL per minute loss, so they are right on target or as expected in the insulin group, but this was essentially extinguished in the dulaglutide groups, where there was no significant loss in eGFR during the 26-week time period,” said Dr. Tuttle.
The only difference in side effect profiles between the dulaglutide groups and the glargine group was a higher rate of gastrointestinal side effects. Nausea was seen in 19.8%, 14.2%, and 4.6% of patients given the dulaglutide 1.5 mg, dulaglutide 0.75 mg, and glargine, respectively, with vomiting reported by 13.5%, 8.4%, and 4.6%.
Eli Lilly funded the study. Dr. Tuttle disclosed acting as a consultant on therapies for diabetic kidney disease for Eli Lilly, Boehringer Ingelheim, Gilead, and AstraZeneca.
This article was updated September 28, 2017.
LISBON – Patients with type 2 diabetes mellitus who also have moderate-to-severe chronic kidney disease (CKD) may be as effectively treated with the glucagonlike peptide–1 receptor agonist dulaglutide (Trulicity) as insulin glargine, the results of an international study showed.
Although comparable effects on glycemic control were seen, patients who received dulaglutide rather than insulin glargine in conjunction with prandial insulin lispro (Humalog) exhibited greater weight loss, had fewer episodes of hypoglycemia, and experienced beneficial effects on two important renal parameters.
The adverse event profile of dulaglutide was typical of that seen with GLP-1 receptor antagonism, noted Dr. Tuttle, who is the executive director of Providence Medical Research Center, Providence Sacred Heart Medical Center in Spokane, Washington, and clinical professor of medicine in the nephrology division at the University of Washington in Seattle.
In Europe, the use of dulaglutide in patients with severely reduced kidney function is not currently recommended, and monitoring is required in the United States in those with gastrointestinal side effects.
AWARD-7 was a randomized, open-label parallel-arm study comparing once-weekly dulaglutide (0.75 mg or 1.5 mg) with insulin glargine plus prandial insulin lispro in 576 subjects who had T2DM and stage 3-4 chronic kidney disease. The aim of the trial was to show noninferiority of the dulaglutide regimen to the insulin glargine regimen.
The trial was open label because the dose of insulin glargine had to be regulated, Dr. Tuttle explained, but the dose of dulaglutide given was blinded. The dose of insulin glargine was targeted to fasting plasma glucose to achieve a value between 5.6 mmol/L and 8.3 mmol/L. The dose of insulin lispro was also adjusted to target preprandial plasma glucose between 6.7 mmol/L and 10.0 mmol/L.
Patients were included if they had a glycated hemoglobin (HbA1c) level of at least 7.5% but less than or equal to 10.5% (at least 57 but less than or equal to 91 mmol/mol) and an eGFR less than 60 but greater than or equal to 15 mL/min per 1.73 m2 at screening.
Approximately 45% of dulaglutide- and 52% of glargine-treated subjects were women; the average age of participants was 65 years, with an average duration of diabetes of around 18 years. The mean HbA1c level at study entry was 8.6% (70.5 mmol/mol), with around half of participants having a HbA1c above 8.5% (69.4 mmol/mol) at entry.
The majority of patients included had an eGFR of less than 45 mL/min per 1.73 m2, and about 30% of patients had stage 4 CKD (eGFR at least 15 but less than 30 mL/min per 1.73 m2), about 45% had macroalbuminuria, and a third or more had microalbuminuria.
The primary endpoint was change in HbA1c from baseline to week 26, and this was comparable for both dulaglutide (at around –1.1% to –1.2%) and insulin glargine (around –1.1%). The effects were maintained at 52 weeks, Dr. Tuttle said, adding that similar percentages (approximately 70% or more) of patients in the groups achieved a target HbA1c of less than 8.0 (64 mmol/mol) at 26 and at 52 weeks. Similar results were seen when the more conventional target of less than 7% (less than 52 mmol/mol) was used, with around 30% of patients achieving this target at 26 and at 52 weeks.
As for weight change, the insulin-treated patients gained about 1 kg in weight over the full course of the study while a dose-dependent decrease in weight of about 2-3 kg was seen with dulaglutide treatment.
“Rates of hypoglycemia were consistently lower in the dulaglutide groups [than in the glargine group],” Dr. Tuttle said, noting “the lowest rates of hypoglycemia were actually seen with the highest dose of dulaglutide.”
The rate of total hypoglycemia (less than or equal to 3.9 mmol/mol) in the 1.5-mg and 0.75-mg dulaglutide groups was 50% and 59.8% of patients, respectively, versus almost 75% of the glargine-treated patients. Rates for documented symptomatic (40.5%, 48.1%, 63.4%), nocturnal (20.5%, 23.8%, 47.9%), and severe (0%, 2.6%, 6.7%) hypoglycemia followed a similar pattern.
“Albuminuria was reduced in all study groups, but there were greater reductions in the patients receiving dulaglutide at 26 weeks,” Dr. Tuttle said. The mean change in UACR from baseline to week 26 was –27.7 for the 1.5-mg dose of dulaglutide, –26.7 for the 0.75-mg dose, and –16.4 for insulin glargine.
The expected rate of eGFR decline at week 26 was also lower with dulaglutide 1.5 mg and 0.75 mg than with glargine, at a respective –0.8%, –3.3%, and –7.7% or –0.1, –0.4, and –1.9 mL/min per 1.73 m2.
“In patients at this stage of CKD, we expect about a 4- to 5-mL per minute loss, so they are right on target or as expected in the insulin group, but this was essentially extinguished in the dulaglutide groups, where there was no significant loss in eGFR during the 26-week time period,” said Dr. Tuttle.
The only difference in side effect profiles between the dulaglutide groups and the glargine group was a higher rate of gastrointestinal side effects. Nausea was seen in 19.8%, 14.2%, and 4.6% of patients given the dulaglutide 1.5 mg, dulaglutide 0.75 mg, and glargine, respectively, with vomiting reported by 13.5%, 8.4%, and 4.6%.
Eli Lilly funded the study. Dr. Tuttle disclosed acting as a consultant on therapies for diabetic kidney disease for Eli Lilly, Boehringer Ingelheim, Gilead, and AstraZeneca.
This article was updated September 28, 2017.
AT EASD 2017
Key clinical point: Dulaglutide had more beneficial effects on renal parameters than insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease.
Major finding: The primary endpoint of change in HbA1c level from baseline to week 26 was comparable for both dulaglutide and insulin glargine.
Data source: A randomized, open-label parallel-arm study comparing once-weekly dulaglutide (0.75 or 1.5 mg) or insulin glargine plus prandial insulin lispro in 576 subjects with type 2 diabetes mellitus and stage 3–4 CKD.
Disclosures: Eli Lilly funded the study. The presenting author has been a consultant on therapies for diabetic kidney disease for Eli Lilly, Boehringer Ingelheim, Gilead, and AstraZeneca.