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DURATION-8: Exenatide/dapagliflozin efficacy holds up at 1 year
SAN DIEGO – A year of treatment with once-weekly exenatide and once-daily dapagliflozin significantly outperformed either therapy alone for patients whose type 2 diabetes was uncontrolled on metformin, investigators reported at the annual scientific sessions of the American Diabetes Association.
At week 52, hemoglobin A1c, fasting and 2-hour postprandial glucose levels, body weight, and systolic blood pressure improved significantly more in the exenatide/dapagliflozin arm than in the dapagliflozin/placebo arm in the multicenter randomized, double-blind, phase III DURATION-8 trial, Cristian Guja, MD, said in a late-breaking poster. Exenatide/dapagliflozin also topped dapagliflozin/placebo on glycemic outcomes but not on measures of body weight or blood pressure.
Exenatide (Byetta, AstraZeneca) is a glucagon-like peptide–1 (GLP-1) receptor agonist, while dapagliflozin (Farxiga, AstraZeneca) is a sodium-glucose cotransporter–2 (SGLT-2) inhibitor. For the study, Dr. Guja and coinvestigators randomly assigned patients with type 2 diabetes and HbA1c levels of 8%-12% despite metformin therapy to receive one of three regimens: exenatide once weekly (2-mg subcutaneous injection) plus dapagliflozin (10-mg oral tablet), exenatide with daily placebo tablets, or dapagliflozin with weekly injected placebo. Between weeks 8 and 28, patients received rescue therapy with basal insulin according to progressively stricter fasting plasma glucose criteria that culminated at 200 mg/dL. From weeks 36 to 52, patients received rescue therapy if their HbA1c level exceeded 8%.
A total of 695 patients were randomized to one of the three study arms, and 564 (81%) patients completed 1 year of treatment. Improvements at 1 year resembled those at week 28. Between baseline and week 52, HbA1c levels fell by an average of 1.75% in the exenatide/dapagliflozin arm, 0.37% more than with exenatide/placebo (P less than .01) and 0.52% more than with dapagliflozin/placebo (P less than .01). Combination therapy also cut mean fasting plasma glucose levels by 63 mg/dL, which was 18 mg/dL more than with exenatide/placebo (P less than .001) and 23 mg/dL more than with dapagliflozin/placebo (P less than .001). Two-hour postprandial glucose levels dropped by 82 mg/dL with dual therapy, 18.4 mg/dL more than with exenatide/placebo (P less than .01), and 23 mg/dL more than with dapagliflozin/placebo (P less than .001). Recipients of dual therapy also lost an average of 3.3 kg over a period of 1 year and cut their systolic blood pressure by a mean of 4.5 mm, reductions that significantly exceeded those with exenatide/placebo but not with dapagliflozin/placebo.
Proportionally fewer patients needed rescue therapy in the dual-treatment arm (27%), compared with the exenatide/placebo arm (32%) or the dapagliflozin/placebo arm (38%). Most patients needed rescue therapy because their HbA1c levels exceeded 8%, not because their fasting glucose level exceeded 200 mg/dL, Dr. Guja said.
Combination therapy was “well tolerated, with no unexpected adverse events,” Dr. Guja reported. At 52 weeks, the groups had similar rates of serious adverse events, gastrointestinal adverse events, and adverse events leading to treatment discontinuation. In each arm, about 4% of patients stopped treatment because of adverse events. Dual therapy was associated with slightly higher rates of injection-site nodules (9%) and headaches (6%), compared with exenatide or dapagliflozin alone. There were no cases of severe hypoglycemia or acute renal failure. Glomerular filtration rates dropped by an average of 2 mL/ min per 1.73 m2 after 1 year of exenatide/dapagliflozin, by 1.2 mL/min per 1.73 m2 with exenatide/placebo, and by 0.8 mL/min per 1.73 m2 with dapagliflozin/placebo.
Baseline characteristics were similar between groups in DURATION-8. Glycated hemoglobin levels averaged 9.3% in each arm, fasting plasma glucose averaged 195-198 mg/dL, body mass index averaged 32-33 kg/m2, and systolic blood pressure averaged 130 mm Hg.
AstraZeneca markets Byetta and Farxiga and sponsored the trial. Dr. Guja reported having been on a speakers bureau for AstraZeneca, and she disclosed ties to several other pharmaceutical companies.
SAN DIEGO – A year of treatment with once-weekly exenatide and once-daily dapagliflozin significantly outperformed either therapy alone for patients whose type 2 diabetes was uncontrolled on metformin, investigators reported at the annual scientific sessions of the American Diabetes Association.
At week 52, hemoglobin A1c, fasting and 2-hour postprandial glucose levels, body weight, and systolic blood pressure improved significantly more in the exenatide/dapagliflozin arm than in the dapagliflozin/placebo arm in the multicenter randomized, double-blind, phase III DURATION-8 trial, Cristian Guja, MD, said in a late-breaking poster. Exenatide/dapagliflozin also topped dapagliflozin/placebo on glycemic outcomes but not on measures of body weight or blood pressure.
Exenatide (Byetta, AstraZeneca) is a glucagon-like peptide–1 (GLP-1) receptor agonist, while dapagliflozin (Farxiga, AstraZeneca) is a sodium-glucose cotransporter–2 (SGLT-2) inhibitor. For the study, Dr. Guja and coinvestigators randomly assigned patients with type 2 diabetes and HbA1c levels of 8%-12% despite metformin therapy to receive one of three regimens: exenatide once weekly (2-mg subcutaneous injection) plus dapagliflozin (10-mg oral tablet), exenatide with daily placebo tablets, or dapagliflozin with weekly injected placebo. Between weeks 8 and 28, patients received rescue therapy with basal insulin according to progressively stricter fasting plasma glucose criteria that culminated at 200 mg/dL. From weeks 36 to 52, patients received rescue therapy if their HbA1c level exceeded 8%.
A total of 695 patients were randomized to one of the three study arms, and 564 (81%) patients completed 1 year of treatment. Improvements at 1 year resembled those at week 28. Between baseline and week 52, HbA1c levels fell by an average of 1.75% in the exenatide/dapagliflozin arm, 0.37% more than with exenatide/placebo (P less than .01) and 0.52% more than with dapagliflozin/placebo (P less than .01). Combination therapy also cut mean fasting plasma glucose levels by 63 mg/dL, which was 18 mg/dL more than with exenatide/placebo (P less than .001) and 23 mg/dL more than with dapagliflozin/placebo (P less than .001). Two-hour postprandial glucose levels dropped by 82 mg/dL with dual therapy, 18.4 mg/dL more than with exenatide/placebo (P less than .01), and 23 mg/dL more than with dapagliflozin/placebo (P less than .001). Recipients of dual therapy also lost an average of 3.3 kg over a period of 1 year and cut their systolic blood pressure by a mean of 4.5 mm, reductions that significantly exceeded those with exenatide/placebo but not with dapagliflozin/placebo.
Proportionally fewer patients needed rescue therapy in the dual-treatment arm (27%), compared with the exenatide/placebo arm (32%) or the dapagliflozin/placebo arm (38%). Most patients needed rescue therapy because their HbA1c levels exceeded 8%, not because their fasting glucose level exceeded 200 mg/dL, Dr. Guja said.
Combination therapy was “well tolerated, with no unexpected adverse events,” Dr. Guja reported. At 52 weeks, the groups had similar rates of serious adverse events, gastrointestinal adverse events, and adverse events leading to treatment discontinuation. In each arm, about 4% of patients stopped treatment because of adverse events. Dual therapy was associated with slightly higher rates of injection-site nodules (9%) and headaches (6%), compared with exenatide or dapagliflozin alone. There were no cases of severe hypoglycemia or acute renal failure. Glomerular filtration rates dropped by an average of 2 mL/ min per 1.73 m2 after 1 year of exenatide/dapagliflozin, by 1.2 mL/min per 1.73 m2 with exenatide/placebo, and by 0.8 mL/min per 1.73 m2 with dapagliflozin/placebo.
Baseline characteristics were similar between groups in DURATION-8. Glycated hemoglobin levels averaged 9.3% in each arm, fasting plasma glucose averaged 195-198 mg/dL, body mass index averaged 32-33 kg/m2, and systolic blood pressure averaged 130 mm Hg.
AstraZeneca markets Byetta and Farxiga and sponsored the trial. Dr. Guja reported having been on a speakers bureau for AstraZeneca, and she disclosed ties to several other pharmaceutical companies.
SAN DIEGO – A year of treatment with once-weekly exenatide and once-daily dapagliflozin significantly outperformed either therapy alone for patients whose type 2 diabetes was uncontrolled on metformin, investigators reported at the annual scientific sessions of the American Diabetes Association.
At week 52, hemoglobin A1c, fasting and 2-hour postprandial glucose levels, body weight, and systolic blood pressure improved significantly more in the exenatide/dapagliflozin arm than in the dapagliflozin/placebo arm in the multicenter randomized, double-blind, phase III DURATION-8 trial, Cristian Guja, MD, said in a late-breaking poster. Exenatide/dapagliflozin also topped dapagliflozin/placebo on glycemic outcomes but not on measures of body weight or blood pressure.
Exenatide (Byetta, AstraZeneca) is a glucagon-like peptide–1 (GLP-1) receptor agonist, while dapagliflozin (Farxiga, AstraZeneca) is a sodium-glucose cotransporter–2 (SGLT-2) inhibitor. For the study, Dr. Guja and coinvestigators randomly assigned patients with type 2 diabetes and HbA1c levels of 8%-12% despite metformin therapy to receive one of three regimens: exenatide once weekly (2-mg subcutaneous injection) plus dapagliflozin (10-mg oral tablet), exenatide with daily placebo tablets, or dapagliflozin with weekly injected placebo. Between weeks 8 and 28, patients received rescue therapy with basal insulin according to progressively stricter fasting plasma glucose criteria that culminated at 200 mg/dL. From weeks 36 to 52, patients received rescue therapy if their HbA1c level exceeded 8%.
A total of 695 patients were randomized to one of the three study arms, and 564 (81%) patients completed 1 year of treatment. Improvements at 1 year resembled those at week 28. Between baseline and week 52, HbA1c levels fell by an average of 1.75% in the exenatide/dapagliflozin arm, 0.37% more than with exenatide/placebo (P less than .01) and 0.52% more than with dapagliflozin/placebo (P less than .01). Combination therapy also cut mean fasting plasma glucose levels by 63 mg/dL, which was 18 mg/dL more than with exenatide/placebo (P less than .001) and 23 mg/dL more than with dapagliflozin/placebo (P less than .001). Two-hour postprandial glucose levels dropped by 82 mg/dL with dual therapy, 18.4 mg/dL more than with exenatide/placebo (P less than .01), and 23 mg/dL more than with dapagliflozin/placebo (P less than .001). Recipients of dual therapy also lost an average of 3.3 kg over a period of 1 year and cut their systolic blood pressure by a mean of 4.5 mm, reductions that significantly exceeded those with exenatide/placebo but not with dapagliflozin/placebo.
Proportionally fewer patients needed rescue therapy in the dual-treatment arm (27%), compared with the exenatide/placebo arm (32%) or the dapagliflozin/placebo arm (38%). Most patients needed rescue therapy because their HbA1c levels exceeded 8%, not because their fasting glucose level exceeded 200 mg/dL, Dr. Guja said.
Combination therapy was “well tolerated, with no unexpected adverse events,” Dr. Guja reported. At 52 weeks, the groups had similar rates of serious adverse events, gastrointestinal adverse events, and adverse events leading to treatment discontinuation. In each arm, about 4% of patients stopped treatment because of adverse events. Dual therapy was associated with slightly higher rates of injection-site nodules (9%) and headaches (6%), compared with exenatide or dapagliflozin alone. There were no cases of severe hypoglycemia or acute renal failure. Glomerular filtration rates dropped by an average of 2 mL/ min per 1.73 m2 after 1 year of exenatide/dapagliflozin, by 1.2 mL/min per 1.73 m2 with exenatide/placebo, and by 0.8 mL/min per 1.73 m2 with dapagliflozin/placebo.
Baseline characteristics were similar between groups in DURATION-8. Glycated hemoglobin levels averaged 9.3% in each arm, fasting plasma glucose averaged 195-198 mg/dL, body mass index averaged 32-33 kg/m2, and systolic blood pressure averaged 130 mm Hg.
AstraZeneca markets Byetta and Farxiga and sponsored the trial. Dr. Guja reported having been on a speakers bureau for AstraZeneca, and she disclosed ties to several other pharmaceutical companies.
AT THE ADA ANNUAL SCIENTIFIC SESSIONS
Key clinical point: Exenatide/dapagliflozin therapy was more effective than either drug alone in type 2 diabetes that was uncontrolled with metformin.
Major finding: At week 52, dual therapy significantly outperformed exenatide alone in terms of hemoglobin A1c, fasting and 2-hour postprandial glucose, body weight, and systolic blood pressure. Dual therapy also significantly topped dapagliflozin alone on glycemic measures.
Data source: DURATION-8, a double-blind, randomized, active-controlled phase III trial of 695 patients with type 2 diabetes.
Disclosures: AstraZeneca markets Byetta and Farxiga and sponsored the trial. Dr. Guja reported having been on a speakers bureau for AstraZeneca and disclosed ties to several other pharmaceutical companies.
ODYSSEY: Alirocumab improves lipids but not glycemic targets in 2DM
SAN DIEGO – The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab helped correct dyslipidemia but did not improve glucose control in patients with type 2 diabetes mellitus, investigators reported at the annual scientific sessions of the American Diabetes Association.
In the international, double-blind ODYSSEY DM-Insulin trial, 24 weeks of alirocumab (Praluent, Sanofi and Regeneron) therapy cut low-density lipoprotein (LDL) cholesterol levels by an average of 49% more than placebo (P less than .0001), said Lawrence A. Leiter, MD, professor of medicine and nutritional sciences at the University of Toronto. Alirocumab also significantly reduced non–high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) levels. However, hemoglobin A1c, fasting plasma glucose, total insulin dose, and number of antihyperglycemic drugs remained nearly identical between the trial arms throughout follow-up.
About 94% of patients in each arm completed the trial. Most were in their mid-60s, white, obese, and already on a moderate or high-intensity statin, with baseline fasting plasma glucose levels of about 150 mg per dL and HbA1c levels of 7.5%. The most common treatment-associated adverse events were myalgia (4%) and arthralgia (3%). Rates of local and systemic allergic drug reactions, neurologic or neurocognitive events, and elevated transaminases were low and similar between groups, according to Dr. Leiter, who is also director of the lipid clinic at the Li Ka Shing Knowledge Institute at St. Michael’s Hospital.
Robert R. Henry, MD, who is professor of medicine at the University of California, San Diego, discussed the ODYSSEY DM-Dyslipidemia trial which compared alirocumab with usual care in patients with type 2 diabetes whose mixed dyslipidemia was inadequately controlled with maximum tolerable statin therapy. In all, 413 patients received open-label alirocumab (75 mg–150 mg) or placebo plus optional ezetimibe, fenofibrate, omega-3 fatty acids, or nicotinic acid every 2 weeks for 24 weeks. At the end of treatment, non-HDL cholesterol dropped about 33% more with alirocumab than usual care (P less than .0001). Alirocumab also produced significant declines in LDL cholesterol, apolipoprotein B, total cholesterol, and lipoprotein(a), and a 6% increase in HDL cholesterol as compared with usual care. Once again, alirocumab induced no changes in HbA1c or fasting plasma glucose levels. The most common treatment-related adverse events were urinary tract infections, diarrhea, and nasopharyngitis.
Sanofi US and Regeneron Pharmaceuticals make alirocumab and funded the trials. Dr. Leiter disclosed research grants and consulting relationships with Regeneron, Sanofi, Eli Lilly and Company, and several other pharmaceutical companies. Dr. Henry disclosed consulting and advisory relationships with Sanofi and many other pharmaceutical companies.
SAN DIEGO – The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab helped correct dyslipidemia but did not improve glucose control in patients with type 2 diabetes mellitus, investigators reported at the annual scientific sessions of the American Diabetes Association.
In the international, double-blind ODYSSEY DM-Insulin trial, 24 weeks of alirocumab (Praluent, Sanofi and Regeneron) therapy cut low-density lipoprotein (LDL) cholesterol levels by an average of 49% more than placebo (P less than .0001), said Lawrence A. Leiter, MD, professor of medicine and nutritional sciences at the University of Toronto. Alirocumab also significantly reduced non–high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) levels. However, hemoglobin A1c, fasting plasma glucose, total insulin dose, and number of antihyperglycemic drugs remained nearly identical between the trial arms throughout follow-up.
About 94% of patients in each arm completed the trial. Most were in their mid-60s, white, obese, and already on a moderate or high-intensity statin, with baseline fasting plasma glucose levels of about 150 mg per dL and HbA1c levels of 7.5%. The most common treatment-associated adverse events were myalgia (4%) and arthralgia (3%). Rates of local and systemic allergic drug reactions, neurologic or neurocognitive events, and elevated transaminases were low and similar between groups, according to Dr. Leiter, who is also director of the lipid clinic at the Li Ka Shing Knowledge Institute at St. Michael’s Hospital.
Robert R. Henry, MD, who is professor of medicine at the University of California, San Diego, discussed the ODYSSEY DM-Dyslipidemia trial which compared alirocumab with usual care in patients with type 2 diabetes whose mixed dyslipidemia was inadequately controlled with maximum tolerable statin therapy. In all, 413 patients received open-label alirocumab (75 mg–150 mg) or placebo plus optional ezetimibe, fenofibrate, omega-3 fatty acids, or nicotinic acid every 2 weeks for 24 weeks. At the end of treatment, non-HDL cholesterol dropped about 33% more with alirocumab than usual care (P less than .0001). Alirocumab also produced significant declines in LDL cholesterol, apolipoprotein B, total cholesterol, and lipoprotein(a), and a 6% increase in HDL cholesterol as compared with usual care. Once again, alirocumab induced no changes in HbA1c or fasting plasma glucose levels. The most common treatment-related adverse events were urinary tract infections, diarrhea, and nasopharyngitis.
Sanofi US and Regeneron Pharmaceuticals make alirocumab and funded the trials. Dr. Leiter disclosed research grants and consulting relationships with Regeneron, Sanofi, Eli Lilly and Company, and several other pharmaceutical companies. Dr. Henry disclosed consulting and advisory relationships with Sanofi and many other pharmaceutical companies.
SAN DIEGO – The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab helped correct dyslipidemia but did not improve glucose control in patients with type 2 diabetes mellitus, investigators reported at the annual scientific sessions of the American Diabetes Association.
In the international, double-blind ODYSSEY DM-Insulin trial, 24 weeks of alirocumab (Praluent, Sanofi and Regeneron) therapy cut low-density lipoprotein (LDL) cholesterol levels by an average of 49% more than placebo (P less than .0001), said Lawrence A. Leiter, MD, professor of medicine and nutritional sciences at the University of Toronto. Alirocumab also significantly reduced non–high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) levels. However, hemoglobin A1c, fasting plasma glucose, total insulin dose, and number of antihyperglycemic drugs remained nearly identical between the trial arms throughout follow-up.
About 94% of patients in each arm completed the trial. Most were in their mid-60s, white, obese, and already on a moderate or high-intensity statin, with baseline fasting plasma glucose levels of about 150 mg per dL and HbA1c levels of 7.5%. The most common treatment-associated adverse events were myalgia (4%) and arthralgia (3%). Rates of local and systemic allergic drug reactions, neurologic or neurocognitive events, and elevated transaminases were low and similar between groups, according to Dr. Leiter, who is also director of the lipid clinic at the Li Ka Shing Knowledge Institute at St. Michael’s Hospital.
Robert R. Henry, MD, who is professor of medicine at the University of California, San Diego, discussed the ODYSSEY DM-Dyslipidemia trial which compared alirocumab with usual care in patients with type 2 diabetes whose mixed dyslipidemia was inadequately controlled with maximum tolerable statin therapy. In all, 413 patients received open-label alirocumab (75 mg–150 mg) or placebo plus optional ezetimibe, fenofibrate, omega-3 fatty acids, or nicotinic acid every 2 weeks for 24 weeks. At the end of treatment, non-HDL cholesterol dropped about 33% more with alirocumab than usual care (P less than .0001). Alirocumab also produced significant declines in LDL cholesterol, apolipoprotein B, total cholesterol, and lipoprotein(a), and a 6% increase in HDL cholesterol as compared with usual care. Once again, alirocumab induced no changes in HbA1c or fasting plasma glucose levels. The most common treatment-related adverse events were urinary tract infections, diarrhea, and nasopharyngitis.
Sanofi US and Regeneron Pharmaceuticals make alirocumab and funded the trials. Dr. Leiter disclosed research grants and consulting relationships with Regeneron, Sanofi, Eli Lilly and Company, and several other pharmaceutical companies. Dr. Henry disclosed consulting and advisory relationships with Sanofi and many other pharmaceutical companies.
AT THE ADA ANNUAL SCIENTIFIC SESSIONS
Key clinical point:
Major finding: After 24 weeks of treatment, average low-density lipoprotein levels fell by about 43%-49% (P less than .0001, compared with placebo, in each trial).
Data source: ODYSSEY DM-Insulin included 441 patients on insulin for type 2 diabetes who had elevated LDL levels and other cardiovascular risk factors. ODYSSEY DM-Dyslipidemia included 413 patients with type 2 diabetes and mixed dyslipidemia despite maximally tolerated statins.
Disclosures: Sanofi and Regeneron Pharmaceuticals funded the trial. Dr. Leiter disclosed research grants and consulting relationships with Regeneron, Sanofi, Eli Lilly, and several other pharmaceutical companies.
IDegLira equals basal-bolus insulin in HbA1c, lowers hypoglycemia risk
SAN DIEGO – When basal insulin alone does not achieve glucose targets in type 2 diabetes, a single fixed-dose injection of insulin degludec and liraglutide (IDegLira) is as effective as multiple insulin injections and has a significantly lower risk of hypoglycemia, according to a randomized, multicenter, open-label, industry-sponsored trial.
After 26 weeks of treatment, average hemoglobin A1c levels dropped similarly with once-daily IDegLira (1.48%) as with basal insulin glargine U100 plus mealtime injections of short-acting insulin aspart (1.46%; P less than .0001 for noninferiority), reported Liana K. Billings, MD, at the annual scientific sessions of the American Diabetes Association.
Patients also needed significantly less insulin and lost significantly more weight on IDegLira, compared with the basal-bolus regimen. “This is some of the most robust, most impressive data I’ve seen in years,” Julio Rosenstock, MD, director of the Dallas Diabetes and Endocrine Center in Texas, commented from the audience. Dr. Rosenstock was not involved in the trial and has studied other combination regimens for type 2 diabetes.
The advent of new insulins and adjunct therapies gives clinicians many potential algorithms for treating type 2 diabetes patients. The ADA recommends that health care professionals consider dual or triple therapy if patients do not meet glycemic targets with lifestyle changes and metformin alone. However, weight gain, hypoglycemia, and complex treatment regimens can make it difficult to intensify treatment in the real world, Dr. Billings said.
Insulin degludec is an ultra–long-acting basal insulin analogue, while liraglutide is a GLP-1 receptor agonist. The open-label, phase III DUAL VII study compared once-daily IDegLira injection (Xultophy, Novo Nordisk) with once-daily basal insulin glargine (Lantus, Sanofi) U100 plus bolus insulin aspart (NovoLog, Novo Nordisk) at mealtimes in 506 adults with type 2 diabetes. All patients were on metformin and glargine (typically 34 U) at baseline. Most were in their late 50s and obese, with an average 13-year duration of type 2 diabetes and HbA1c levels of 8.2% despite treatment. The IDegLira group started at 16 U and titrated by 2 U twice weekly to reach a fasting glucose target of 72-90 mg/dL. Basal-bolus patients maintained their baseline glargine dose and added 4 U mealtime bolus insulin aspart, titrating to target by 1 U twice weekly. The primary endpoint was change in HbA1c levels after 26 weeks. More than 98% of patients completed the trial. Approximately two-thirds of patients in both arms achieved an HbA1c level below 7%, but IDegLira recipients were significantly more likely to do so without gaining weight or experiencing hypoglycemia during the last 12 weeks of treatment (odds ratio, 10.39; 95% CI, 5.76-18.75). The IDegLira arm received significantly less daily insulin than the basal-bolus arm (40 U versus 84 U; P less than .0001), and IDegLira patients lost an average of 0.93 kg, while the comparison group gained 2.64 kg. Rates of serious adverse events were low and similar between arms. The cumulative rate of nausea was higher with IDegLira (11.1%) than with basal-bolus therapy (1.6%), Dr. Billings said. There were no deaths or unexpected adverse events.
Novo Nordisk makes Xultophy and funded the trial. Dr. Billings reported having served on advisory panels and speaker bureaus for Novo Nordisk.
SAN DIEGO – When basal insulin alone does not achieve glucose targets in type 2 diabetes, a single fixed-dose injection of insulin degludec and liraglutide (IDegLira) is as effective as multiple insulin injections and has a significantly lower risk of hypoglycemia, according to a randomized, multicenter, open-label, industry-sponsored trial.
After 26 weeks of treatment, average hemoglobin A1c levels dropped similarly with once-daily IDegLira (1.48%) as with basal insulin glargine U100 plus mealtime injections of short-acting insulin aspart (1.46%; P less than .0001 for noninferiority), reported Liana K. Billings, MD, at the annual scientific sessions of the American Diabetes Association.
Patients also needed significantly less insulin and lost significantly more weight on IDegLira, compared with the basal-bolus regimen. “This is some of the most robust, most impressive data I’ve seen in years,” Julio Rosenstock, MD, director of the Dallas Diabetes and Endocrine Center in Texas, commented from the audience. Dr. Rosenstock was not involved in the trial and has studied other combination regimens for type 2 diabetes.
The advent of new insulins and adjunct therapies gives clinicians many potential algorithms for treating type 2 diabetes patients. The ADA recommends that health care professionals consider dual or triple therapy if patients do not meet glycemic targets with lifestyle changes and metformin alone. However, weight gain, hypoglycemia, and complex treatment regimens can make it difficult to intensify treatment in the real world, Dr. Billings said.
Insulin degludec is an ultra–long-acting basal insulin analogue, while liraglutide is a GLP-1 receptor agonist. The open-label, phase III DUAL VII study compared once-daily IDegLira injection (Xultophy, Novo Nordisk) with once-daily basal insulin glargine (Lantus, Sanofi) U100 plus bolus insulin aspart (NovoLog, Novo Nordisk) at mealtimes in 506 adults with type 2 diabetes. All patients were on metformin and glargine (typically 34 U) at baseline. Most were in their late 50s and obese, with an average 13-year duration of type 2 diabetes and HbA1c levels of 8.2% despite treatment. The IDegLira group started at 16 U and titrated by 2 U twice weekly to reach a fasting glucose target of 72-90 mg/dL. Basal-bolus patients maintained their baseline glargine dose and added 4 U mealtime bolus insulin aspart, titrating to target by 1 U twice weekly. The primary endpoint was change in HbA1c levels after 26 weeks. More than 98% of patients completed the trial. Approximately two-thirds of patients in both arms achieved an HbA1c level below 7%, but IDegLira recipients were significantly more likely to do so without gaining weight or experiencing hypoglycemia during the last 12 weeks of treatment (odds ratio, 10.39; 95% CI, 5.76-18.75). The IDegLira arm received significantly less daily insulin than the basal-bolus arm (40 U versus 84 U; P less than .0001), and IDegLira patients lost an average of 0.93 kg, while the comparison group gained 2.64 kg. Rates of serious adverse events were low and similar between arms. The cumulative rate of nausea was higher with IDegLira (11.1%) than with basal-bolus therapy (1.6%), Dr. Billings said. There were no deaths or unexpected adverse events.
Novo Nordisk makes Xultophy and funded the trial. Dr. Billings reported having served on advisory panels and speaker bureaus for Novo Nordisk.
SAN DIEGO – When basal insulin alone does not achieve glucose targets in type 2 diabetes, a single fixed-dose injection of insulin degludec and liraglutide (IDegLira) is as effective as multiple insulin injections and has a significantly lower risk of hypoglycemia, according to a randomized, multicenter, open-label, industry-sponsored trial.
After 26 weeks of treatment, average hemoglobin A1c levels dropped similarly with once-daily IDegLira (1.48%) as with basal insulin glargine U100 plus mealtime injections of short-acting insulin aspart (1.46%; P less than .0001 for noninferiority), reported Liana K. Billings, MD, at the annual scientific sessions of the American Diabetes Association.
Patients also needed significantly less insulin and lost significantly more weight on IDegLira, compared with the basal-bolus regimen. “This is some of the most robust, most impressive data I’ve seen in years,” Julio Rosenstock, MD, director of the Dallas Diabetes and Endocrine Center in Texas, commented from the audience. Dr. Rosenstock was not involved in the trial and has studied other combination regimens for type 2 diabetes.
The advent of new insulins and adjunct therapies gives clinicians many potential algorithms for treating type 2 diabetes patients. The ADA recommends that health care professionals consider dual or triple therapy if patients do not meet glycemic targets with lifestyle changes and metformin alone. However, weight gain, hypoglycemia, and complex treatment regimens can make it difficult to intensify treatment in the real world, Dr. Billings said.
Insulin degludec is an ultra–long-acting basal insulin analogue, while liraglutide is a GLP-1 receptor agonist. The open-label, phase III DUAL VII study compared once-daily IDegLira injection (Xultophy, Novo Nordisk) with once-daily basal insulin glargine (Lantus, Sanofi) U100 plus bolus insulin aspart (NovoLog, Novo Nordisk) at mealtimes in 506 adults with type 2 diabetes. All patients were on metformin and glargine (typically 34 U) at baseline. Most were in their late 50s and obese, with an average 13-year duration of type 2 diabetes and HbA1c levels of 8.2% despite treatment. The IDegLira group started at 16 U and titrated by 2 U twice weekly to reach a fasting glucose target of 72-90 mg/dL. Basal-bolus patients maintained their baseline glargine dose and added 4 U mealtime bolus insulin aspart, titrating to target by 1 U twice weekly. The primary endpoint was change in HbA1c levels after 26 weeks. More than 98% of patients completed the trial. Approximately two-thirds of patients in both arms achieved an HbA1c level below 7%, but IDegLira recipients were significantly more likely to do so without gaining weight or experiencing hypoglycemia during the last 12 weeks of treatment (odds ratio, 10.39; 95% CI, 5.76-18.75). The IDegLira arm received significantly less daily insulin than the basal-bolus arm (40 U versus 84 U; P less than .0001), and IDegLira patients lost an average of 0.93 kg, while the comparison group gained 2.64 kg. Rates of serious adverse events were low and similar between arms. The cumulative rate of nausea was higher with IDegLira (11.1%) than with basal-bolus therapy (1.6%), Dr. Billings said. There were no deaths or unexpected adverse events.
Novo Nordisk makes Xultophy and funded the trial. Dr. Billings reported having served on advisory panels and speaker bureaus for Novo Nordisk.
AT THE ADA ANNUAL SCIENTIFIC SESSIONS
Key clinical point: A single daily injection of fixed-dose insulin degludec and liraglutide (IDegLira) improved hemoglobin A1c levels as much as basal-bolus insulin therapy while producing significantly less hypoglycemia.
Major finding: HbA1c levels dropped similarly with IDegLira (1.48%) or basal insulin glargine U100 plus mealtime injections of short-acting insulin aspart (1.46%; P less than .0001 for noninferiority).
Data source: DUAL VII, a multicenter, randomized, open-label, phase III trial of 506 adults with type 2 diabetes who did not reach glucose targets on basal insulin glargine and metformin.
Disclosures: Novo Nordisk makes Xultophy and funded the trial. Dr. Billings reported having served on advisory panels and speaker bureaus for Novo Nordisk.
Consistent weight benefits seen in empagliflozin use
SAN DIEGO – In a follow-up to the blockbuster trial results linking the type 2 diabetes drug empagliflozin (Jardiance) to a dramatically lower risk of cardiac death, researchers report that the drug improved weight-related measures in multiple groups.
Two daily doses of empagliflozin, 10 mg and 25 mg, “had consistent and robust effects on lowering weight, waist circumference, and other markers of body fat across most patients regardless of their age, sex, or degree of abdominal obesity,” study lead author Ian J. Neeland, MD, of the department of medicine at UT Southwestern Medical Center, Dallas, said in an interview. “Our next step is to determine if these effects may contribute to the improvement in cardiovascular risk seen with the drug.”
“In the EMPA-REG OUTCOME study, empagliflozin treatment significantly reduced the risk of cardiovascular death by 38%,” Dr. Neeland said. “We also observed that patients treated with empagliflozin had improvements in markers of body fatness such as weight, waist circumference, and estimated total body fat. Since we know that obesity is a major risk factor for cardiovascular disease, we were interested in finding out if the improvements in weight and other markers of body fatness may have contributed to the observed cardiovascular benefits of empagliflozin in the study. One part of this was to examine whether the drug had consistent effects on body fat according to other important cardiovascular risk factors.”
The researchers analyzed changes in body weight, waist circumference, index of central obesity, and estimated total body fat from baseline to week 164 in a study that randomly assigned participants with type 2 diabetes and cardiovascular disease to placebo or 10 mg or 25 mg of empagliflozin. The number of patients in the groups were 2,333, 2,345 and 2,342, respectively, and their mean baseline weight was around 86.0 kg.
In general, researchers found that across groups, weight measures improved more in drug-treated patients than those treated with placebo. The higher dose (25 mg) often had a greater effect; the two available doses of the drug are 10 mg and 20 mg.
For example, the placebo-adjusted mean reduction in weight was –1.70 kg in men (95% confidence interval, –2.14 to –1.27) in the 10-mg group and 2.18 kg (95% CI, –2.61 to –1.75) in the 25-mg group. For women, the reduction was –1.32 kg (95% CI, –2.02 to –0.62) in the 10-mg group and –1.44 kg (95% CI, –2.15 to –0.73) in the 25-mg group.
“Patients lost on average 1.5-2 kg of weight – about 4 pounds – with empagliflozin, compared with placebo,” Dr. Neeland said. “Although quality of life and other metrics of better health were not systematically collected, we do know that people who lose weight and waist circumference tend to feel better, have fewer health problems, and live longer, compared with people who remain obese.”
Dr. Neeland said researchers still need to understand whether the improvements in obesity markers contribute to the drug’s positive cardiac effects.
Study funding was not reported. The original EMPA-REG OUTCOME trial was funded by Boehringer Ingelheim and Eli Lilly. Dr. Neeland disclosed consultant/speakers bureau support from Boehringer Ingelheim. He is a scientific advisory board member for Advanced MR Analytics AB.
SAN DIEGO – In a follow-up to the blockbuster trial results linking the type 2 diabetes drug empagliflozin (Jardiance) to a dramatically lower risk of cardiac death, researchers report that the drug improved weight-related measures in multiple groups.
Two daily doses of empagliflozin, 10 mg and 25 mg, “had consistent and robust effects on lowering weight, waist circumference, and other markers of body fat across most patients regardless of their age, sex, or degree of abdominal obesity,” study lead author Ian J. Neeland, MD, of the department of medicine at UT Southwestern Medical Center, Dallas, said in an interview. “Our next step is to determine if these effects may contribute to the improvement in cardiovascular risk seen with the drug.”
“In the EMPA-REG OUTCOME study, empagliflozin treatment significantly reduced the risk of cardiovascular death by 38%,” Dr. Neeland said. “We also observed that patients treated with empagliflozin had improvements in markers of body fatness such as weight, waist circumference, and estimated total body fat. Since we know that obesity is a major risk factor for cardiovascular disease, we were interested in finding out if the improvements in weight and other markers of body fatness may have contributed to the observed cardiovascular benefits of empagliflozin in the study. One part of this was to examine whether the drug had consistent effects on body fat according to other important cardiovascular risk factors.”
The researchers analyzed changes in body weight, waist circumference, index of central obesity, and estimated total body fat from baseline to week 164 in a study that randomly assigned participants with type 2 diabetes and cardiovascular disease to placebo or 10 mg or 25 mg of empagliflozin. The number of patients in the groups were 2,333, 2,345 and 2,342, respectively, and their mean baseline weight was around 86.0 kg.
In general, researchers found that across groups, weight measures improved more in drug-treated patients than those treated with placebo. The higher dose (25 mg) often had a greater effect; the two available doses of the drug are 10 mg and 20 mg.
For example, the placebo-adjusted mean reduction in weight was –1.70 kg in men (95% confidence interval, –2.14 to –1.27) in the 10-mg group and 2.18 kg (95% CI, –2.61 to –1.75) in the 25-mg group. For women, the reduction was –1.32 kg (95% CI, –2.02 to –0.62) in the 10-mg group and –1.44 kg (95% CI, –2.15 to –0.73) in the 25-mg group.
“Patients lost on average 1.5-2 kg of weight – about 4 pounds – with empagliflozin, compared with placebo,” Dr. Neeland said. “Although quality of life and other metrics of better health were not systematically collected, we do know that people who lose weight and waist circumference tend to feel better, have fewer health problems, and live longer, compared with people who remain obese.”
Dr. Neeland said researchers still need to understand whether the improvements in obesity markers contribute to the drug’s positive cardiac effects.
Study funding was not reported. The original EMPA-REG OUTCOME trial was funded by Boehringer Ingelheim and Eli Lilly. Dr. Neeland disclosed consultant/speakers bureau support from Boehringer Ingelheim. He is a scientific advisory board member for Advanced MR Analytics AB.
SAN DIEGO – In a follow-up to the blockbuster trial results linking the type 2 diabetes drug empagliflozin (Jardiance) to a dramatically lower risk of cardiac death, researchers report that the drug improved weight-related measures in multiple groups.
Two daily doses of empagliflozin, 10 mg and 25 mg, “had consistent and robust effects on lowering weight, waist circumference, and other markers of body fat across most patients regardless of their age, sex, or degree of abdominal obesity,” study lead author Ian J. Neeland, MD, of the department of medicine at UT Southwestern Medical Center, Dallas, said in an interview. “Our next step is to determine if these effects may contribute to the improvement in cardiovascular risk seen with the drug.”
“In the EMPA-REG OUTCOME study, empagliflozin treatment significantly reduced the risk of cardiovascular death by 38%,” Dr. Neeland said. “We also observed that patients treated with empagliflozin had improvements in markers of body fatness such as weight, waist circumference, and estimated total body fat. Since we know that obesity is a major risk factor for cardiovascular disease, we were interested in finding out if the improvements in weight and other markers of body fatness may have contributed to the observed cardiovascular benefits of empagliflozin in the study. One part of this was to examine whether the drug had consistent effects on body fat according to other important cardiovascular risk factors.”
The researchers analyzed changes in body weight, waist circumference, index of central obesity, and estimated total body fat from baseline to week 164 in a study that randomly assigned participants with type 2 diabetes and cardiovascular disease to placebo or 10 mg or 25 mg of empagliflozin. The number of patients in the groups were 2,333, 2,345 and 2,342, respectively, and their mean baseline weight was around 86.0 kg.
In general, researchers found that across groups, weight measures improved more in drug-treated patients than those treated with placebo. The higher dose (25 mg) often had a greater effect; the two available doses of the drug are 10 mg and 20 mg.
For example, the placebo-adjusted mean reduction in weight was –1.70 kg in men (95% confidence interval, –2.14 to –1.27) in the 10-mg group and 2.18 kg (95% CI, –2.61 to –1.75) in the 25-mg group. For women, the reduction was –1.32 kg (95% CI, –2.02 to –0.62) in the 10-mg group and –1.44 kg (95% CI, –2.15 to –0.73) in the 25-mg group.
“Patients lost on average 1.5-2 kg of weight – about 4 pounds – with empagliflozin, compared with placebo,” Dr. Neeland said. “Although quality of life and other metrics of better health were not systematically collected, we do know that people who lose weight and waist circumference tend to feel better, have fewer health problems, and live longer, compared with people who remain obese.”
Dr. Neeland said researchers still need to understand whether the improvements in obesity markers contribute to the drug’s positive cardiac effects.
Study funding was not reported. The original EMPA-REG OUTCOME trial was funded by Boehringer Ingelheim and Eli Lilly. Dr. Neeland disclosed consultant/speakers bureau support from Boehringer Ingelheim. He is a scientific advisory board member for Advanced MR Analytics AB.
AT THE ADA ANNUAL SCIENTIFIC SESSIONS
Key clinical point:
Major finding: Placebo-adjusted mean reduction in weight was –1.70 kg in men for daily 10-mg dose group and –2.18 kg in daily 25-mg group. For women, the losses were –1.32 kg in the 10-mg group and –1.44 kg in the 25-mg group.
Data source: Secondary analysis of 164-week randomized, double-blind, placebo-controlled study of patients with type 2 diabetes and cardiovascular disease assigned to placebo or 10-mg or 25-mg doses of empagliflozin.
Disclosures: Study funding was not reported. The original EMPA-REG OUTCOME trial was funded by Boehringer Ingelheim and Eli Lilly.
CANVAS: Canagliflozin cuts cardiovascular events, doubles risk of amputations
SAN DIEGO –
After an average of 188 weeks of follow-up, the combined rate of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke was 26.9 events per 1,000 person-years of canagliflozin treatment and 31.5 events per 1,000 person-years of placebo treatment (hazard ratio, 0.86; 95% confidence interval, 0.75-0.97; P less than .001 for noninferiority; P = .02 for superiority) in the Canagliflozin Cardiovascular Assessment Study (CANVAS) and its sister trial, CANVAS-R, investigators reported at the annual scientific sessions of the American Diabetes Association. The report was published simultaneously in the New England Journal of Medicine (N Engl J Med. 2017 Jun 12. doi: 10.1056/NEJMoa1611925).
But unexpectedly, canagliflozin also doubled the risk of amputations, said Dr. Neal, who is with the University of New South Wales and the George Institute for Global Health in Sydney. Treating 1,000 patients for 5 years would lead to 15 excess amputations, including 10 amputations of the toes or forefoot and five amputations at the ankle or above, he said.
The reason for this heightened risk is unknown. Other sodium-glucose co-transporter 2 (SGLT-2) development programs did not comprehensively monitor amputations, so it is unclear whether this is a class effect, Dr. Neal said. For now, the Food and Drug Administration is requiring a boxed warning for canagliflozin, while its European Union product label recommends carefully monitoring patients, emphasizing foot care and hydration, and considering stopping treatment if patients develop lower-extremity ulcers, infection, osteomyelitis, or gangrene.
Canagliflozin might also increase the risk of fractures, Dr. Bruce and his coinvestigators noted. Hazard ratios for overall and low-trauma fractures reached statistical significance in CANVAS, but not in CANVAS-R. As in other trials of SGLT-2 inhibitors, canagliflozin significantly increased the risk of female and male genital mycotic infections (respective HR, 4.27 and 3.76) and was associated with osmotic diuresis (HR, 2.80), and volume depletion (HR, 1.44). However, canagliflozin was not associated with malignancies, hepatic injury, pancreatitis, diabetic ketoacidosis, photosensitivity, hypersensitivity reactions, hypoglycemia, venous thrombotic events, or urinary tract infections.
Canagliflozin (Invokana, Janssen) inhibits SGLT-2, which is responsible for about 90% of renal glucose reabsorption. The FDA approved the medication in 2013 based on interim results from the CANVAS trial, which included 4,330 adults with type 2 diabetes and a history of symptomatic atherosclerotic cardiovascular disease or multiple cardiovascular risk factors. Patients were usually in their 60s, male, and hypertensive. Two-thirds had atherosclerotic cardiovascular disease and about 14% had heart failure. Background medications included metformin, insulin, sulfonylurea, DPP-4 inhibitors, GLP-1 receptor agonists, and cardioprotective agents. Patients were randomly assigned to receive canagliflozin 300 mg or 100 mg or placebo.
Investigators designed the CANVAS-R trial to further evaluate canagliflozin in another 5,813 patients with type 2 diabetes. The SGLT-2 inhibitor met its primary MACE endpoint in the overall pooled analysis and in numerous demographic and clinical subgroups, Dr. Neal said. Canagliflozin also significantly cut the risk of hospitalization for heart failure (HR, 0.67), and met a “hard” composite endpoint of renal death, end-stage renal disease, or a 40% reduction in estimated glomerular filtration rate (HR, 0.60).
Compared with placebo, treatment induced regression of albuminuria and reduced loss of renal function, said coinvestigator Dick de Zeeuw, MD, PhD, of the University of Groningen (the Netherlands). “These data suggest a potential renoprotective effect of canagliflozin treatment in patients with type 2 diabetes at high cardiovascular risk, on top of treatment with angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers,” he said.
However, patients were twice as likely to undergo amputations on canagliflozin, compared with those on placebo (HR, 1.97; 95% CI, 1.41-2.75). Risks were similar for amputation of the toe or forefoot, at the ankle, below the knee, and above the knee, Dr. Neal said. Predictors of amputation also were similar in all arms of the trials, and included peripheral vascular disease, male sex, neuropathy, and hemoglobin A1c above 8%. Amputation was not associated with non-loop diuretic therapy, smoking, hypertension, or age.
Janssen Research and Development makes canagliflozin and sponsored the trials. Dr. Neal and Dr. Zeeuw disclosed consultancy, travel support, or grants from Janssen paid to their institutions, and ties to several other pharmaceutical companies.
SAN DIEGO –
After an average of 188 weeks of follow-up, the combined rate of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke was 26.9 events per 1,000 person-years of canagliflozin treatment and 31.5 events per 1,000 person-years of placebo treatment (hazard ratio, 0.86; 95% confidence interval, 0.75-0.97; P less than .001 for noninferiority; P = .02 for superiority) in the Canagliflozin Cardiovascular Assessment Study (CANVAS) and its sister trial, CANVAS-R, investigators reported at the annual scientific sessions of the American Diabetes Association. The report was published simultaneously in the New England Journal of Medicine (N Engl J Med. 2017 Jun 12. doi: 10.1056/NEJMoa1611925).
But unexpectedly, canagliflozin also doubled the risk of amputations, said Dr. Neal, who is with the University of New South Wales and the George Institute for Global Health in Sydney. Treating 1,000 patients for 5 years would lead to 15 excess amputations, including 10 amputations of the toes or forefoot and five amputations at the ankle or above, he said.
The reason for this heightened risk is unknown. Other sodium-glucose co-transporter 2 (SGLT-2) development programs did not comprehensively monitor amputations, so it is unclear whether this is a class effect, Dr. Neal said. For now, the Food and Drug Administration is requiring a boxed warning for canagliflozin, while its European Union product label recommends carefully monitoring patients, emphasizing foot care and hydration, and considering stopping treatment if patients develop lower-extremity ulcers, infection, osteomyelitis, or gangrene.
Canagliflozin might also increase the risk of fractures, Dr. Bruce and his coinvestigators noted. Hazard ratios for overall and low-trauma fractures reached statistical significance in CANVAS, but not in CANVAS-R. As in other trials of SGLT-2 inhibitors, canagliflozin significantly increased the risk of female and male genital mycotic infections (respective HR, 4.27 and 3.76) and was associated with osmotic diuresis (HR, 2.80), and volume depletion (HR, 1.44). However, canagliflozin was not associated with malignancies, hepatic injury, pancreatitis, diabetic ketoacidosis, photosensitivity, hypersensitivity reactions, hypoglycemia, venous thrombotic events, or urinary tract infections.
Canagliflozin (Invokana, Janssen) inhibits SGLT-2, which is responsible for about 90% of renal glucose reabsorption. The FDA approved the medication in 2013 based on interim results from the CANVAS trial, which included 4,330 adults with type 2 diabetes and a history of symptomatic atherosclerotic cardiovascular disease or multiple cardiovascular risk factors. Patients were usually in their 60s, male, and hypertensive. Two-thirds had atherosclerotic cardiovascular disease and about 14% had heart failure. Background medications included metformin, insulin, sulfonylurea, DPP-4 inhibitors, GLP-1 receptor agonists, and cardioprotective agents. Patients were randomly assigned to receive canagliflozin 300 mg or 100 mg or placebo.
Investigators designed the CANVAS-R trial to further evaluate canagliflozin in another 5,813 patients with type 2 diabetes. The SGLT-2 inhibitor met its primary MACE endpoint in the overall pooled analysis and in numerous demographic and clinical subgroups, Dr. Neal said. Canagliflozin also significantly cut the risk of hospitalization for heart failure (HR, 0.67), and met a “hard” composite endpoint of renal death, end-stage renal disease, or a 40% reduction in estimated glomerular filtration rate (HR, 0.60).
Compared with placebo, treatment induced regression of albuminuria and reduced loss of renal function, said coinvestigator Dick de Zeeuw, MD, PhD, of the University of Groningen (the Netherlands). “These data suggest a potential renoprotective effect of canagliflozin treatment in patients with type 2 diabetes at high cardiovascular risk, on top of treatment with angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers,” he said.
However, patients were twice as likely to undergo amputations on canagliflozin, compared with those on placebo (HR, 1.97; 95% CI, 1.41-2.75). Risks were similar for amputation of the toe or forefoot, at the ankle, below the knee, and above the knee, Dr. Neal said. Predictors of amputation also were similar in all arms of the trials, and included peripheral vascular disease, male sex, neuropathy, and hemoglobin A1c above 8%. Amputation was not associated with non-loop diuretic therapy, smoking, hypertension, or age.
Janssen Research and Development makes canagliflozin and sponsored the trials. Dr. Neal and Dr. Zeeuw disclosed consultancy, travel support, or grants from Janssen paid to their institutions, and ties to several other pharmaceutical companies.
SAN DIEGO –
After an average of 188 weeks of follow-up, the combined rate of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke was 26.9 events per 1,000 person-years of canagliflozin treatment and 31.5 events per 1,000 person-years of placebo treatment (hazard ratio, 0.86; 95% confidence interval, 0.75-0.97; P less than .001 for noninferiority; P = .02 for superiority) in the Canagliflozin Cardiovascular Assessment Study (CANVAS) and its sister trial, CANVAS-R, investigators reported at the annual scientific sessions of the American Diabetes Association. The report was published simultaneously in the New England Journal of Medicine (N Engl J Med. 2017 Jun 12. doi: 10.1056/NEJMoa1611925).
But unexpectedly, canagliflozin also doubled the risk of amputations, said Dr. Neal, who is with the University of New South Wales and the George Institute for Global Health in Sydney. Treating 1,000 patients for 5 years would lead to 15 excess amputations, including 10 amputations of the toes or forefoot and five amputations at the ankle or above, he said.
The reason for this heightened risk is unknown. Other sodium-glucose co-transporter 2 (SGLT-2) development programs did not comprehensively monitor amputations, so it is unclear whether this is a class effect, Dr. Neal said. For now, the Food and Drug Administration is requiring a boxed warning for canagliflozin, while its European Union product label recommends carefully monitoring patients, emphasizing foot care and hydration, and considering stopping treatment if patients develop lower-extremity ulcers, infection, osteomyelitis, or gangrene.
Canagliflozin might also increase the risk of fractures, Dr. Bruce and his coinvestigators noted. Hazard ratios for overall and low-trauma fractures reached statistical significance in CANVAS, but not in CANVAS-R. As in other trials of SGLT-2 inhibitors, canagliflozin significantly increased the risk of female and male genital mycotic infections (respective HR, 4.27 and 3.76) and was associated with osmotic diuresis (HR, 2.80), and volume depletion (HR, 1.44). However, canagliflozin was not associated with malignancies, hepatic injury, pancreatitis, diabetic ketoacidosis, photosensitivity, hypersensitivity reactions, hypoglycemia, venous thrombotic events, or urinary tract infections.
Canagliflozin (Invokana, Janssen) inhibits SGLT-2, which is responsible for about 90% of renal glucose reabsorption. The FDA approved the medication in 2013 based on interim results from the CANVAS trial, which included 4,330 adults with type 2 diabetes and a history of symptomatic atherosclerotic cardiovascular disease or multiple cardiovascular risk factors. Patients were usually in their 60s, male, and hypertensive. Two-thirds had atherosclerotic cardiovascular disease and about 14% had heart failure. Background medications included metformin, insulin, sulfonylurea, DPP-4 inhibitors, GLP-1 receptor agonists, and cardioprotective agents. Patients were randomly assigned to receive canagliflozin 300 mg or 100 mg or placebo.
Investigators designed the CANVAS-R trial to further evaluate canagliflozin in another 5,813 patients with type 2 diabetes. The SGLT-2 inhibitor met its primary MACE endpoint in the overall pooled analysis and in numerous demographic and clinical subgroups, Dr. Neal said. Canagliflozin also significantly cut the risk of hospitalization for heart failure (HR, 0.67), and met a “hard” composite endpoint of renal death, end-stage renal disease, or a 40% reduction in estimated glomerular filtration rate (HR, 0.60).
Compared with placebo, treatment induced regression of albuminuria and reduced loss of renal function, said coinvestigator Dick de Zeeuw, MD, PhD, of the University of Groningen (the Netherlands). “These data suggest a potential renoprotective effect of canagliflozin treatment in patients with type 2 diabetes at high cardiovascular risk, on top of treatment with angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers,” he said.
However, patients were twice as likely to undergo amputations on canagliflozin, compared with those on placebo (HR, 1.97; 95% CI, 1.41-2.75). Risks were similar for amputation of the toe or forefoot, at the ankle, below the knee, and above the knee, Dr. Neal said. Predictors of amputation also were similar in all arms of the trials, and included peripheral vascular disease, male sex, neuropathy, and hemoglobin A1c above 8%. Amputation was not associated with non-loop diuretic therapy, smoking, hypertension, or age.
Janssen Research and Development makes canagliflozin and sponsored the trials. Dr. Neal and Dr. Zeeuw disclosed consultancy, travel support, or grants from Janssen paid to their institutions, and ties to several other pharmaceutical companies.
AT THE ADA ANNUAL SCIENTIFIC SESSIONS
Key clinical point: Canagliflozin significantly reduced the risk of cardiovascular and renal events but doubled the risk of amputation, compared with placebo, in patients with type 2 diabetes.
Major finding: The hazard ratio for cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke was 0.86 in favor of canagliflozin (P = .02 for superiority). Patients on treatment were twice as likely to undergo amputations, compared to those on placebo (HR, 1.97).
Data source: Two international, randomized, double-blind trials of more than 10,000 adults with type 2 diabetes at high risk of cardiovascular disease.
Disclosures: Janssen Research and Development makes canagliflozin and sponsored the trials. Dr. Neal and Dr. Zeeuw disclosed consultancy, travel support, or grants from Janssen paid to their institutions and ties to several other pharmaceutical companies.
DEVOTE: Degludec and glargine had similar risk with less severe hypoglycemia
SAN DIEGO – For patients with type 2 diabetes at high risk of cardiovascular disease, the ultra–long-acting, once-daily basal insulin degludec produced a similar risk of major adverse cardiovascular events as glargine with a significantly lower risk of severe hypoglycemia, new data show.
Nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death occurred in 325 (8.5%) patients on degludec and 356 (9.3%) patients on glargine (hazard ratio, 0.91; 95% confidence interval, 0.78 to 1.06; P = .21) in DEVOTE (the Trial Comparing Cardiovascular Safety of Insulin Degludec versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events). Rates of severe hypoglycemia were 4.9% and 6.6%, respectively (P less than .001), investigators reported at the annual scientific sessions of the American Diabetes Association and simultaneously in the New England Journal of Medicine (2017 Jun 12. doi: 10.1056/NEJMoa1615692).
Insulin degludec injection (Tresiba®, Novo Nordisk) is a basal insulin analog, the long, soluble hexamer chains of which are metabolized only at the ends, yielding at least a 42-hour duration of action, Todd Hobbs, MD, chief medical officer of Novo Nordisk, Princeton, N.J., explained in an interview. In contrast, glargine has about a 12-hour half-life. Previous trials of degludec did not adjudicate cardiovascular endpoints, which the U.S. Food and Drug Administration only recently began requiring for insulins, Dr. Hobbs said. In response to an FDA request, the phase III, international, randomized, double-blind DEVOTE trial compared the cardiovascular safety of daily basal insulin degludec (100 U per mL) with that of glargine U100 in more than 7,600 adults with type 2 diabetes.
Fully 98% of patients completed the 2-year trial. The overall risk of major adverse cardiac events resembled that of each individual component, including cardiovascular death (HR, 0.96; 95% CI, 0.76-1.21; P = .71), nonfatal myocardial infarction (HR, 0.85; 95% CI, 0.68-1.06; P = .15), and nonfatal stroke (HR, 0.90; 95% CI, 0.65-1.23; P =. 50). Degludec remained noninferior to glargine when researchers added unstable angina to the primary endpoint and accounted for patient location, treatment duration, length of follow-up, and age, sex, body mass index, and renal function.
Both insulins produced similar HbA1c levels of about 7.5%, but degludec cut fasting plasma glucose by about 5 mg per mL more, compared with glargine (P less than .001), the investigators reported. Furthermore, the odds ratio for severe hypoglycemia significantly favored degludec (HR, 0.73; 95% CI, 0.60-0.89; P less than .001). In other words, 40 patients would need to receive degludec rather than glargine to prevent one event of severe hypoglycemia. Previous studies have shown similar results, Dr. Buse said. In a pooled analysis of all five trials of type 2 diabetes in the degludec clinical development program, degludec was associated with a significantly lower risk of hypoglycemia, particularly nocturnal episodes, than was glargine (Diabetes Obes Metab. 2013;15:175-84).
Findings were similar in the double-blind SWITCH 2 trial (Diabetologia. 2016;59[Suppl 1]:1-581).
DEVOTE identified no safety issues for degludec, compared with glargine. Each arm had similar rates of serious or severe adverse events, leading to treatment discontinuation, and neoplasms. Nonetheless, DEVOTE had several limitations, said Elizabeth R. Seaquist, MD, of the University of Minnesota, Minneapolis, who was not involved in the study. “Investigators could modify the titration protocol based on clinical judgment, and it isn’t clear whether this modification was applied equally in both arms,” she said at ADA. “Another weakness is that there were no data collected about moderate symptomatic hypoglycemia, the most common type of hypoglycemia that patients experience.” DEVOTE also did not examine how often blood glucose dropped below 54 mg per dL, the point at which patients often do not know they are hypoglycemic. Investigators also should examine whether degludec cuts health care costs or improves sleep or quality of life, whether its glycemic benefits extends to patients who are insulin-naive or have severe kidney disease, and how it compares with glargine U300, she added.
Insulin degludec received FDA approval in September 2015, based on interim results of DEVOTE. Novo Nordisk makes insulin degludec and sponsored the trial. Dr. Buse disclosed consulting fees from Novo Nordisk and ties to many other pharmaceutical companies. Dr. Seaquist disclosed ties to Novo Nordisk, Eli Lilly, Locemia, and Lucera. Dr. Hobbs is chief medical officer for Novo Nordisk.
SAN DIEGO – For patients with type 2 diabetes at high risk of cardiovascular disease, the ultra–long-acting, once-daily basal insulin degludec produced a similar risk of major adverse cardiovascular events as glargine with a significantly lower risk of severe hypoglycemia, new data show.
Nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death occurred in 325 (8.5%) patients on degludec and 356 (9.3%) patients on glargine (hazard ratio, 0.91; 95% confidence interval, 0.78 to 1.06; P = .21) in DEVOTE (the Trial Comparing Cardiovascular Safety of Insulin Degludec versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events). Rates of severe hypoglycemia were 4.9% and 6.6%, respectively (P less than .001), investigators reported at the annual scientific sessions of the American Diabetes Association and simultaneously in the New England Journal of Medicine (2017 Jun 12. doi: 10.1056/NEJMoa1615692).
Insulin degludec injection (Tresiba®, Novo Nordisk) is a basal insulin analog, the long, soluble hexamer chains of which are metabolized only at the ends, yielding at least a 42-hour duration of action, Todd Hobbs, MD, chief medical officer of Novo Nordisk, Princeton, N.J., explained in an interview. In contrast, glargine has about a 12-hour half-life. Previous trials of degludec did not adjudicate cardiovascular endpoints, which the U.S. Food and Drug Administration only recently began requiring for insulins, Dr. Hobbs said. In response to an FDA request, the phase III, international, randomized, double-blind DEVOTE trial compared the cardiovascular safety of daily basal insulin degludec (100 U per mL) with that of glargine U100 in more than 7,600 adults with type 2 diabetes.
Fully 98% of patients completed the 2-year trial. The overall risk of major adverse cardiac events resembled that of each individual component, including cardiovascular death (HR, 0.96; 95% CI, 0.76-1.21; P = .71), nonfatal myocardial infarction (HR, 0.85; 95% CI, 0.68-1.06; P = .15), and nonfatal stroke (HR, 0.90; 95% CI, 0.65-1.23; P =. 50). Degludec remained noninferior to glargine when researchers added unstable angina to the primary endpoint and accounted for patient location, treatment duration, length of follow-up, and age, sex, body mass index, and renal function.
Both insulins produced similar HbA1c levels of about 7.5%, but degludec cut fasting plasma glucose by about 5 mg per mL more, compared with glargine (P less than .001), the investigators reported. Furthermore, the odds ratio for severe hypoglycemia significantly favored degludec (HR, 0.73; 95% CI, 0.60-0.89; P less than .001). In other words, 40 patients would need to receive degludec rather than glargine to prevent one event of severe hypoglycemia. Previous studies have shown similar results, Dr. Buse said. In a pooled analysis of all five trials of type 2 diabetes in the degludec clinical development program, degludec was associated with a significantly lower risk of hypoglycemia, particularly nocturnal episodes, than was glargine (Diabetes Obes Metab. 2013;15:175-84).
Findings were similar in the double-blind SWITCH 2 trial (Diabetologia. 2016;59[Suppl 1]:1-581).
DEVOTE identified no safety issues for degludec, compared with glargine. Each arm had similar rates of serious or severe adverse events, leading to treatment discontinuation, and neoplasms. Nonetheless, DEVOTE had several limitations, said Elizabeth R. Seaquist, MD, of the University of Minnesota, Minneapolis, who was not involved in the study. “Investigators could modify the titration protocol based on clinical judgment, and it isn’t clear whether this modification was applied equally in both arms,” she said at ADA. “Another weakness is that there were no data collected about moderate symptomatic hypoglycemia, the most common type of hypoglycemia that patients experience.” DEVOTE also did not examine how often blood glucose dropped below 54 mg per dL, the point at which patients often do not know they are hypoglycemic. Investigators also should examine whether degludec cuts health care costs or improves sleep or quality of life, whether its glycemic benefits extends to patients who are insulin-naive or have severe kidney disease, and how it compares with glargine U300, she added.
Insulin degludec received FDA approval in September 2015, based on interim results of DEVOTE. Novo Nordisk makes insulin degludec and sponsored the trial. Dr. Buse disclosed consulting fees from Novo Nordisk and ties to many other pharmaceutical companies. Dr. Seaquist disclosed ties to Novo Nordisk, Eli Lilly, Locemia, and Lucera. Dr. Hobbs is chief medical officer for Novo Nordisk.
SAN DIEGO – For patients with type 2 diabetes at high risk of cardiovascular disease, the ultra–long-acting, once-daily basal insulin degludec produced a similar risk of major adverse cardiovascular events as glargine with a significantly lower risk of severe hypoglycemia, new data show.
Nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death occurred in 325 (8.5%) patients on degludec and 356 (9.3%) patients on glargine (hazard ratio, 0.91; 95% confidence interval, 0.78 to 1.06; P = .21) in DEVOTE (the Trial Comparing Cardiovascular Safety of Insulin Degludec versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events). Rates of severe hypoglycemia were 4.9% and 6.6%, respectively (P less than .001), investigators reported at the annual scientific sessions of the American Diabetes Association and simultaneously in the New England Journal of Medicine (2017 Jun 12. doi: 10.1056/NEJMoa1615692).
Insulin degludec injection (Tresiba®, Novo Nordisk) is a basal insulin analog, the long, soluble hexamer chains of which are metabolized only at the ends, yielding at least a 42-hour duration of action, Todd Hobbs, MD, chief medical officer of Novo Nordisk, Princeton, N.J., explained in an interview. In contrast, glargine has about a 12-hour half-life. Previous trials of degludec did not adjudicate cardiovascular endpoints, which the U.S. Food and Drug Administration only recently began requiring for insulins, Dr. Hobbs said. In response to an FDA request, the phase III, international, randomized, double-blind DEVOTE trial compared the cardiovascular safety of daily basal insulin degludec (100 U per mL) with that of glargine U100 in more than 7,600 adults with type 2 diabetes.
Fully 98% of patients completed the 2-year trial. The overall risk of major adverse cardiac events resembled that of each individual component, including cardiovascular death (HR, 0.96; 95% CI, 0.76-1.21; P = .71), nonfatal myocardial infarction (HR, 0.85; 95% CI, 0.68-1.06; P = .15), and nonfatal stroke (HR, 0.90; 95% CI, 0.65-1.23; P =. 50). Degludec remained noninferior to glargine when researchers added unstable angina to the primary endpoint and accounted for patient location, treatment duration, length of follow-up, and age, sex, body mass index, and renal function.
Both insulins produced similar HbA1c levels of about 7.5%, but degludec cut fasting plasma glucose by about 5 mg per mL more, compared with glargine (P less than .001), the investigators reported. Furthermore, the odds ratio for severe hypoglycemia significantly favored degludec (HR, 0.73; 95% CI, 0.60-0.89; P less than .001). In other words, 40 patients would need to receive degludec rather than glargine to prevent one event of severe hypoglycemia. Previous studies have shown similar results, Dr. Buse said. In a pooled analysis of all five trials of type 2 diabetes in the degludec clinical development program, degludec was associated with a significantly lower risk of hypoglycemia, particularly nocturnal episodes, than was glargine (Diabetes Obes Metab. 2013;15:175-84).
Findings were similar in the double-blind SWITCH 2 trial (Diabetologia. 2016;59[Suppl 1]:1-581).
DEVOTE identified no safety issues for degludec, compared with glargine. Each arm had similar rates of serious or severe adverse events, leading to treatment discontinuation, and neoplasms. Nonetheless, DEVOTE had several limitations, said Elizabeth R. Seaquist, MD, of the University of Minnesota, Minneapolis, who was not involved in the study. “Investigators could modify the titration protocol based on clinical judgment, and it isn’t clear whether this modification was applied equally in both arms,” she said at ADA. “Another weakness is that there were no data collected about moderate symptomatic hypoglycemia, the most common type of hypoglycemia that patients experience.” DEVOTE also did not examine how often blood glucose dropped below 54 mg per dL, the point at which patients often do not know they are hypoglycemic. Investigators also should examine whether degludec cuts health care costs or improves sleep or quality of life, whether its glycemic benefits extends to patients who are insulin-naive or have severe kidney disease, and how it compares with glargine U300, she added.
Insulin degludec received FDA approval in September 2015, based on interim results of DEVOTE. Novo Nordisk makes insulin degludec and sponsored the trial. Dr. Buse disclosed consulting fees from Novo Nordisk and ties to many other pharmaceutical companies. Dr. Seaquist disclosed ties to Novo Nordisk, Eli Lilly, Locemia, and Lucera. Dr. Hobbs is chief medical officer for Novo Nordisk.
AT THE ADA ANNUAL SCIENTIFIC SESSIONS
Key clinical point: The ultra–long-acting basal insulin degludec was noninferior to glargine in terms of cardiovascular risk and was superior in terms of severe hypoglycemia.
Major finding: Nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death occurred in 325 (8.5%) patients on degludec and 356 (9.3%) patients on glargine (HR, 0.91; 95% CI, 0.78-1.06; P = .21). Rates of severe hypoglycemia were 4.9% and 6.6%, respectively (P less than .001).
Data source: A randomized, double-blind, multicenter trial of 7,637 adults with type 2 diabetes at high risk of cardiovascular disease.
Disclosures: Novo Nordisk makes insulin degludec and sponsored the trial. Dr. Buse disclosed consulting fees from Novo Nordisk and ties to many other pharmaceutical companies. Dr. Seaquist disclosed ties to Novo Nordisk, Eli Lilly, Locemia, and Lucera. Dr. Hobbs is chief medical officer for Novo Nordisk.
Providers buck lipid recommendations in high-risk diabetes
SAN DIEGO – In the 3 months before their atherosclerotic cardiovascular event, 40% of high-risk patients with diabetes received no prescription for lipid-lowering therapy, researchers reported at the annual scientific sessions of the American Diabetes Association.
Underprescribing of high-intensity statins was also “particularly apparent for patients with diabetes mellitus alone, although rates improved somewhat over follow-up,” Sarah S. Cohen, PhD, of EpidStat Institute in Ann Arbor, Mich., said in a late-breaking poster. The findings highlight the need to educate providers and patients on the importance of addressing cardiovascular risk factors and disease in the diabetes setting, she wrote with her associates from the Mayo Clinic and Amgen.
Hypertension and dyslipidemia are classic companions of type 2 diabetes and “clear risk factors” for atherosclerotic cardiovascular disease (ASCVD), according to 2017 care guidelines from the American Diabetes Association.
“Diabetes itself confers independent risk,” the guidelines add. To characterize real-world use of lipid-lowering therapies in patients with diabetes, ASCVD, or both conditions, Dr. Cohen and her associates analyzed electronic medical records from more than 7,400 adults in Minnesota with new-onset type 2 diabetes mellitus or ASCVD, or incident ASCVD and existing diabetes between 2005 and 2012. During this period, about 4,500 patients were diagnosed with diabetes and another 570 patients with an existing diagnosis of diabetes were diagnosed with ASCVD based on incident myocardial infarction, unstable angina, stroke, or revascularization. An additional 2,300 patients had ASCVD alone.
Patients with existing diabetes and incident ASCVD tended to be in their 70s, two-thirds had used tobacco, 31% were overweight, and 54% were obese, the investigators found. Nonetheless, 40% of patients received no lipid-lowering therapy in the 3 months before the ASCVD event and 90% received no high-intensity statins. Three months after the event, 75% of patients were on lipid-lowering therapy and 64% were on moderate- or high-intensity statins. Patients with incident diabetes alone tended to be in their late 50s, about 60% had used tobacco, and two-thirds were obese. Only 34%, however, were prescribed moderate or high-intensity statins within 3 months after their diabetes diagnosis, and this proportion rose to just 46% at 2 years.
Diabetes is known to boost the risk of cardiovascular disease, but incident diabetes seldom triggered a prescription for lipid-lowering therapy in this cohort, the researchers concluded. Incident ASCVD was much more likely to elicit a prescription, but comorbid diabetes did not further improve the chances of receiving guideline-recommended therapy.
The ADA recommends screening for and treating modifiable CVD risk factors even in the prediabetes setting. For patients with clinical diabetes, providers should evaluate history of dyslipidemia, obtain a fasting lipid profile, and recommend lifestyle changes to address glycemic, blood pressure, and lipid goals, ADA guidelines state. In addition, comorbid diabetes and ASCVD merit high-intensity statin therapy, and diabetic patients with additional risk factors for CVD merit consideration of moderate- or high-intensity statin therapy, according to the recommendations.
The researchers lacked data on prescription fill rates, so they might have overestimated the proportion of patients taking lipid-lowering therapies, they noted. They also had no data on reasons for not prescribing lipid-lowering therapies.
Amgen and the National Institute on Aging provided funding. Dr. Cohen disclosed research funding from Amgen, which makes evolocumab, a lipid-lowering drug. She had no other conflicts of interest.
SAN DIEGO – In the 3 months before their atherosclerotic cardiovascular event, 40% of high-risk patients with diabetes received no prescription for lipid-lowering therapy, researchers reported at the annual scientific sessions of the American Diabetes Association.
Underprescribing of high-intensity statins was also “particularly apparent for patients with diabetes mellitus alone, although rates improved somewhat over follow-up,” Sarah S. Cohen, PhD, of EpidStat Institute in Ann Arbor, Mich., said in a late-breaking poster. The findings highlight the need to educate providers and patients on the importance of addressing cardiovascular risk factors and disease in the diabetes setting, she wrote with her associates from the Mayo Clinic and Amgen.
Hypertension and dyslipidemia are classic companions of type 2 diabetes and “clear risk factors” for atherosclerotic cardiovascular disease (ASCVD), according to 2017 care guidelines from the American Diabetes Association.
“Diabetes itself confers independent risk,” the guidelines add. To characterize real-world use of lipid-lowering therapies in patients with diabetes, ASCVD, or both conditions, Dr. Cohen and her associates analyzed electronic medical records from more than 7,400 adults in Minnesota with new-onset type 2 diabetes mellitus or ASCVD, or incident ASCVD and existing diabetes between 2005 and 2012. During this period, about 4,500 patients were diagnosed with diabetes and another 570 patients with an existing diagnosis of diabetes were diagnosed with ASCVD based on incident myocardial infarction, unstable angina, stroke, or revascularization. An additional 2,300 patients had ASCVD alone.
Patients with existing diabetes and incident ASCVD tended to be in their 70s, two-thirds had used tobacco, 31% were overweight, and 54% were obese, the investigators found. Nonetheless, 40% of patients received no lipid-lowering therapy in the 3 months before the ASCVD event and 90% received no high-intensity statins. Three months after the event, 75% of patients were on lipid-lowering therapy and 64% were on moderate- or high-intensity statins. Patients with incident diabetes alone tended to be in their late 50s, about 60% had used tobacco, and two-thirds were obese. Only 34%, however, were prescribed moderate or high-intensity statins within 3 months after their diabetes diagnosis, and this proportion rose to just 46% at 2 years.
Diabetes is known to boost the risk of cardiovascular disease, but incident diabetes seldom triggered a prescription for lipid-lowering therapy in this cohort, the researchers concluded. Incident ASCVD was much more likely to elicit a prescription, but comorbid diabetes did not further improve the chances of receiving guideline-recommended therapy.
The ADA recommends screening for and treating modifiable CVD risk factors even in the prediabetes setting. For patients with clinical diabetes, providers should evaluate history of dyslipidemia, obtain a fasting lipid profile, and recommend lifestyle changes to address glycemic, blood pressure, and lipid goals, ADA guidelines state. In addition, comorbid diabetes and ASCVD merit high-intensity statin therapy, and diabetic patients with additional risk factors for CVD merit consideration of moderate- or high-intensity statin therapy, according to the recommendations.
The researchers lacked data on prescription fill rates, so they might have overestimated the proportion of patients taking lipid-lowering therapies, they noted. They also had no data on reasons for not prescribing lipid-lowering therapies.
Amgen and the National Institute on Aging provided funding. Dr. Cohen disclosed research funding from Amgen, which makes evolocumab, a lipid-lowering drug. She had no other conflicts of interest.
SAN DIEGO – In the 3 months before their atherosclerotic cardiovascular event, 40% of high-risk patients with diabetes received no prescription for lipid-lowering therapy, researchers reported at the annual scientific sessions of the American Diabetes Association.
Underprescribing of high-intensity statins was also “particularly apparent for patients with diabetes mellitus alone, although rates improved somewhat over follow-up,” Sarah S. Cohen, PhD, of EpidStat Institute in Ann Arbor, Mich., said in a late-breaking poster. The findings highlight the need to educate providers and patients on the importance of addressing cardiovascular risk factors and disease in the diabetes setting, she wrote with her associates from the Mayo Clinic and Amgen.
Hypertension and dyslipidemia are classic companions of type 2 diabetes and “clear risk factors” for atherosclerotic cardiovascular disease (ASCVD), according to 2017 care guidelines from the American Diabetes Association.
“Diabetes itself confers independent risk,” the guidelines add. To characterize real-world use of lipid-lowering therapies in patients with diabetes, ASCVD, or both conditions, Dr. Cohen and her associates analyzed electronic medical records from more than 7,400 adults in Minnesota with new-onset type 2 diabetes mellitus or ASCVD, or incident ASCVD and existing diabetes between 2005 and 2012. During this period, about 4,500 patients were diagnosed with diabetes and another 570 patients with an existing diagnosis of diabetes were diagnosed with ASCVD based on incident myocardial infarction, unstable angina, stroke, or revascularization. An additional 2,300 patients had ASCVD alone.
Patients with existing diabetes and incident ASCVD tended to be in their 70s, two-thirds had used tobacco, 31% were overweight, and 54% were obese, the investigators found. Nonetheless, 40% of patients received no lipid-lowering therapy in the 3 months before the ASCVD event and 90% received no high-intensity statins. Three months after the event, 75% of patients were on lipid-lowering therapy and 64% were on moderate- or high-intensity statins. Patients with incident diabetes alone tended to be in their late 50s, about 60% had used tobacco, and two-thirds were obese. Only 34%, however, were prescribed moderate or high-intensity statins within 3 months after their diabetes diagnosis, and this proportion rose to just 46% at 2 years.
Diabetes is known to boost the risk of cardiovascular disease, but incident diabetes seldom triggered a prescription for lipid-lowering therapy in this cohort, the researchers concluded. Incident ASCVD was much more likely to elicit a prescription, but comorbid diabetes did not further improve the chances of receiving guideline-recommended therapy.
The ADA recommends screening for and treating modifiable CVD risk factors even in the prediabetes setting. For patients with clinical diabetes, providers should evaluate history of dyslipidemia, obtain a fasting lipid profile, and recommend lifestyle changes to address glycemic, blood pressure, and lipid goals, ADA guidelines state. In addition, comorbid diabetes and ASCVD merit high-intensity statin therapy, and diabetic patients with additional risk factors for CVD merit consideration of moderate- or high-intensity statin therapy, according to the recommendations.
The researchers lacked data on prescription fill rates, so they might have overestimated the proportion of patients taking lipid-lowering therapies, they noted. They also had no data on reasons for not prescribing lipid-lowering therapies.
Amgen and the National Institute on Aging provided funding. Dr. Cohen disclosed research funding from Amgen, which makes evolocumab, a lipid-lowering drug. She had no other conflicts of interest.
AT THE ADA ANNUAL SCIENTIFIC SESSIONS
Key clinical point: Underprescribing of lipid-lowering therapies persists despite guidelines on their importance in patients with diabetes.
Major finding: About 40% of high-risk patients with diabetes were not prescribed lipid-lowering therapy in the 3 months before an atherosclerotic cardiovascular event.
Data source: Analyses of electronic medical records from 7,414 patients diagnosed with diabetes, atherosclerotic cardiovascular disease, or both between 2005 and 2012.
Disclosures: Amgen and the National Institute on Aging provided funding. Dr. Cohen disclosed research funding from Amgen, which makes evolocumab, a lipid-lowering drug. She had no other conflicts of interest.
REMOVAL: Metformin may reduce cardiac risk in type 1 diabetes but doesn’t improve glucose control
SAN DIEGO – Findings from the landmark 3-year REMOVAL trial find that metformin could hold potential as a tool to reduce cardiovascular disease (CVD) risk in patients with type 1 diabetes. But – in a challenge to current British and American guidelines – findings from the study suggest that the drug doesn’t meaningfully improve glycemic control.
“The CVD benefit is suggestive, but it’s by no means conclusive,” Naveed Sattar, MD, PhD, of the University of Glasgow said in a presentation at the scientific meetings of the American Diabetic Association. As for glycemic control, “you should not prescribe metformin if you want a clinical change in hemoglobin A1c,” he said.
The findings don’t examine CVD outcomes, and researchers bemoaned their inability to launch such a project because of limitations in funding. Still, the study, funded by the Juvenile Diabetes Research Foundation, is the largest to examine metformin in type 1 diabetes.
The Food and Drug Administration has not approved metformin for type 1 diabetes. However, the American Diabetes Association’s 2017 Standard of Care guidelines note that “adding metformin to insulin therapy may reduce insulin requirements and improve metabolic control in overweight/obese patients with poorly controlled type 1 diabetes” (Diabetes Care. 2017 Jan;40[Suppl 1]).
“Metformin has known efficacy for reducing HbA1c, and, at the time we did this, it was one of few diabetes drugs with indications of an effect on cardiovascular disease risk,” study coauthor Helen M. Colhoun, MD, of the University of Edinburgh said during the discussion following the presentation.
The REMOVAL (cardiovascular and metabolic effects of metformin in patients with type 1 diabetes) trial took place from 2011 to 2014. Involved researchers at 23 hospital diabetes clinics around the world randomly assigned 428 patients to metformin (n = 219) and placebo (n = 209) arms.
The patients were all 40 years or older, with a mean age of 55 years. All patients had been diagnosed with type 1 diabetes at least five years prior to the study and met at least 3 of 10 criteria for high risk of cardiovascular disease. Men accounted for 59% of the patients, about 98% were white, and about 79% were obese or overweight. Patients had high levels of use of statins (73%), blood pressure medications (73%), and antiplatelet drugs (39%).
Participants took oral metformin 1,000 mg twice daily or placebo. The results were reported at the ADA meeting and simultaneously online on June 11, 2017 in Lancet Diabetes Endocrinology (2017 Jun 11. doi: 10.1016/S2213-8587[17]30194-8).
In regard to CVD indicators, the researchers did not find significant reduction in the progression of average common carotid artery intima-media thickness (cIMT) (–0.005 mm per year; 95% confidence interval, –0.012-0.002; P = .1664) in metformin, vs. placebo.
There was, however, a significant reduction in maximal cIMT (–0.013 mm per year; 95% CI, –0.024 to –0.003; P = .0093). The study describes this as a surrogate measure for atherosclerosis progression, although it’s a tertiary rather than primary outcome.
Researchers saw a slight decline in HbA1c in the metformin group (–0.13%; 95% CI, –0.22 to –0.037; P = .0060), but researchers say this occurred early and was not sustained.
In the metformin group, compared with placebo, researchers also found reductions in body weight (–1.17 kg; 95% CI,–1.66 to –0.69; p less than .0001) and LDL cholesterol (–0.13 mmol/L; 95% CI, –0.24 to –0.03; P = .0117) on average.
Researchers didn’t find a significant average reduction in insulin use in the metformin group, compared with placebo (–0.005 units per kg; 95% CI, –0.022-0.012, P = .545), although they did notice “a small but sustained reduction in patients allocated to metformin (estimated in post-hoc analyses as –0.023 units per kg; 95% CI, –0.045 to –0.0005; P = .045).”
Rates of gastrointestinal problems were higher in the metformin group, and 27% of these patients discontinued treatment, compared with 12% of placebo patients (P = .0002). Five of the metformin patients died (as did two of the placebo patients), but researchers didn’t link the deaths to medication.
The findings were clearly disappointing. “We’re certainly not claiming that this is a positive trial,” said study coauthor Dr. Colhoun.
A member of the audience at the AAD meeting asked another coauthor, Irene Hramiak, MD, of the University of Western Ontario, London, whether she would prescribe metformin to a patient with type 1 diabetes and a high risk of CVD. “Probably not,” she said, but she added that it may have value in adolescents with weight issues. In those cases, she said, there may be a benefit to improving weight control and lowering insulin doses.
In light of the study findings, the authors recommend revising guidelines that suggest the use of metformin in type 1 diabetes: “We identified a transient improvement in glycemia that reverted to baseline with insulin dose reduction and identified no suggestion of greater benefit in overweight or obese patients.”
The study adds, “Rather than a role in glycemic control, our findings suggest that long-term use of metformin in type 1 diabetes might reduce the long-term risk of cardiovascular disease via small but sustained reductions in bodyweight and LDL cholesterol.”
The Juvenile Diabetes Research Foundation funded the study. Merck Germany KGaA provided medication and shipping for free. Itamar Medical donated equipment and services. Dr. Sataar reported consulting fees and/or research support from Amgen, Boehringer Ingelheim, Eli Lilly, Janssen, and Novo Nordisk. Dr. Colhoun and Dr. Hramiak reported multiple disclosures, including advisory panel, research support, and speaker’s bureau and stock/shareholder relationships.
This article was updated June 19, 2017.
SAN DIEGO – Findings from the landmark 3-year REMOVAL trial find that metformin could hold potential as a tool to reduce cardiovascular disease (CVD) risk in patients with type 1 diabetes. But – in a challenge to current British and American guidelines – findings from the study suggest that the drug doesn’t meaningfully improve glycemic control.
“The CVD benefit is suggestive, but it’s by no means conclusive,” Naveed Sattar, MD, PhD, of the University of Glasgow said in a presentation at the scientific meetings of the American Diabetic Association. As for glycemic control, “you should not prescribe metformin if you want a clinical change in hemoglobin A1c,” he said.
The findings don’t examine CVD outcomes, and researchers bemoaned their inability to launch such a project because of limitations in funding. Still, the study, funded by the Juvenile Diabetes Research Foundation, is the largest to examine metformin in type 1 diabetes.
The Food and Drug Administration has not approved metformin for type 1 diabetes. However, the American Diabetes Association’s 2017 Standard of Care guidelines note that “adding metformin to insulin therapy may reduce insulin requirements and improve metabolic control in overweight/obese patients with poorly controlled type 1 diabetes” (Diabetes Care. 2017 Jan;40[Suppl 1]).
“Metformin has known efficacy for reducing HbA1c, and, at the time we did this, it was one of few diabetes drugs with indications of an effect on cardiovascular disease risk,” study coauthor Helen M. Colhoun, MD, of the University of Edinburgh said during the discussion following the presentation.
The REMOVAL (cardiovascular and metabolic effects of metformin in patients with type 1 diabetes) trial took place from 2011 to 2014. Involved researchers at 23 hospital diabetes clinics around the world randomly assigned 428 patients to metformin (n = 219) and placebo (n = 209) arms.
The patients were all 40 years or older, with a mean age of 55 years. All patients had been diagnosed with type 1 diabetes at least five years prior to the study and met at least 3 of 10 criteria for high risk of cardiovascular disease. Men accounted for 59% of the patients, about 98% were white, and about 79% were obese or overweight. Patients had high levels of use of statins (73%), blood pressure medications (73%), and antiplatelet drugs (39%).
Participants took oral metformin 1,000 mg twice daily or placebo. The results were reported at the ADA meeting and simultaneously online on June 11, 2017 in Lancet Diabetes Endocrinology (2017 Jun 11. doi: 10.1016/S2213-8587[17]30194-8).
In regard to CVD indicators, the researchers did not find significant reduction in the progression of average common carotid artery intima-media thickness (cIMT) (–0.005 mm per year; 95% confidence interval, –0.012-0.002; P = .1664) in metformin, vs. placebo.
There was, however, a significant reduction in maximal cIMT (–0.013 mm per year; 95% CI, –0.024 to –0.003; P = .0093). The study describes this as a surrogate measure for atherosclerosis progression, although it’s a tertiary rather than primary outcome.
Researchers saw a slight decline in HbA1c in the metformin group (–0.13%; 95% CI, –0.22 to –0.037; P = .0060), but researchers say this occurred early and was not sustained.
In the metformin group, compared with placebo, researchers also found reductions in body weight (–1.17 kg; 95% CI,–1.66 to –0.69; p less than .0001) and LDL cholesterol (–0.13 mmol/L; 95% CI, –0.24 to –0.03; P = .0117) on average.
Researchers didn’t find a significant average reduction in insulin use in the metformin group, compared with placebo (–0.005 units per kg; 95% CI, –0.022-0.012, P = .545), although they did notice “a small but sustained reduction in patients allocated to metformin (estimated in post-hoc analyses as –0.023 units per kg; 95% CI, –0.045 to –0.0005; P = .045).”
Rates of gastrointestinal problems were higher in the metformin group, and 27% of these patients discontinued treatment, compared with 12% of placebo patients (P = .0002). Five of the metformin patients died (as did two of the placebo patients), but researchers didn’t link the deaths to medication.
The findings were clearly disappointing. “We’re certainly not claiming that this is a positive trial,” said study coauthor Dr. Colhoun.
A member of the audience at the AAD meeting asked another coauthor, Irene Hramiak, MD, of the University of Western Ontario, London, whether she would prescribe metformin to a patient with type 1 diabetes and a high risk of CVD. “Probably not,” she said, but she added that it may have value in adolescents with weight issues. In those cases, she said, there may be a benefit to improving weight control and lowering insulin doses.
In light of the study findings, the authors recommend revising guidelines that suggest the use of metformin in type 1 diabetes: “We identified a transient improvement in glycemia that reverted to baseline with insulin dose reduction and identified no suggestion of greater benefit in overweight or obese patients.”
The study adds, “Rather than a role in glycemic control, our findings suggest that long-term use of metformin in type 1 diabetes might reduce the long-term risk of cardiovascular disease via small but sustained reductions in bodyweight and LDL cholesterol.”
The Juvenile Diabetes Research Foundation funded the study. Merck Germany KGaA provided medication and shipping for free. Itamar Medical donated equipment and services. Dr. Sataar reported consulting fees and/or research support from Amgen, Boehringer Ingelheim, Eli Lilly, Janssen, and Novo Nordisk. Dr. Colhoun and Dr. Hramiak reported multiple disclosures, including advisory panel, research support, and speaker’s bureau and stock/shareholder relationships.
This article was updated June 19, 2017.
SAN DIEGO – Findings from the landmark 3-year REMOVAL trial find that metformin could hold potential as a tool to reduce cardiovascular disease (CVD) risk in patients with type 1 diabetes. But – in a challenge to current British and American guidelines – findings from the study suggest that the drug doesn’t meaningfully improve glycemic control.
“The CVD benefit is suggestive, but it’s by no means conclusive,” Naveed Sattar, MD, PhD, of the University of Glasgow said in a presentation at the scientific meetings of the American Diabetic Association. As for glycemic control, “you should not prescribe metformin if you want a clinical change in hemoglobin A1c,” he said.
The findings don’t examine CVD outcomes, and researchers bemoaned their inability to launch such a project because of limitations in funding. Still, the study, funded by the Juvenile Diabetes Research Foundation, is the largest to examine metformin in type 1 diabetes.
The Food and Drug Administration has not approved metformin for type 1 diabetes. However, the American Diabetes Association’s 2017 Standard of Care guidelines note that “adding metformin to insulin therapy may reduce insulin requirements and improve metabolic control in overweight/obese patients with poorly controlled type 1 diabetes” (Diabetes Care. 2017 Jan;40[Suppl 1]).
“Metformin has known efficacy for reducing HbA1c, and, at the time we did this, it was one of few diabetes drugs with indications of an effect on cardiovascular disease risk,” study coauthor Helen M. Colhoun, MD, of the University of Edinburgh said during the discussion following the presentation.
The REMOVAL (cardiovascular and metabolic effects of metformin in patients with type 1 diabetes) trial took place from 2011 to 2014. Involved researchers at 23 hospital diabetes clinics around the world randomly assigned 428 patients to metformin (n = 219) and placebo (n = 209) arms.
The patients were all 40 years or older, with a mean age of 55 years. All patients had been diagnosed with type 1 diabetes at least five years prior to the study and met at least 3 of 10 criteria for high risk of cardiovascular disease. Men accounted for 59% of the patients, about 98% were white, and about 79% were obese or overweight. Patients had high levels of use of statins (73%), blood pressure medications (73%), and antiplatelet drugs (39%).
Participants took oral metformin 1,000 mg twice daily or placebo. The results were reported at the ADA meeting and simultaneously online on June 11, 2017 in Lancet Diabetes Endocrinology (2017 Jun 11. doi: 10.1016/S2213-8587[17]30194-8).
In regard to CVD indicators, the researchers did not find significant reduction in the progression of average common carotid artery intima-media thickness (cIMT) (–0.005 mm per year; 95% confidence interval, –0.012-0.002; P = .1664) in metformin, vs. placebo.
There was, however, a significant reduction in maximal cIMT (–0.013 mm per year; 95% CI, –0.024 to –0.003; P = .0093). The study describes this as a surrogate measure for atherosclerosis progression, although it’s a tertiary rather than primary outcome.
Researchers saw a slight decline in HbA1c in the metformin group (–0.13%; 95% CI, –0.22 to –0.037; P = .0060), but researchers say this occurred early and was not sustained.
In the metformin group, compared with placebo, researchers also found reductions in body weight (–1.17 kg; 95% CI,–1.66 to –0.69; p less than .0001) and LDL cholesterol (–0.13 mmol/L; 95% CI, –0.24 to –0.03; P = .0117) on average.
Researchers didn’t find a significant average reduction in insulin use in the metformin group, compared with placebo (–0.005 units per kg; 95% CI, –0.022-0.012, P = .545), although they did notice “a small but sustained reduction in patients allocated to metformin (estimated in post-hoc analyses as –0.023 units per kg; 95% CI, –0.045 to –0.0005; P = .045).”
Rates of gastrointestinal problems were higher in the metformin group, and 27% of these patients discontinued treatment, compared with 12% of placebo patients (P = .0002). Five of the metformin patients died (as did two of the placebo patients), but researchers didn’t link the deaths to medication.
The findings were clearly disappointing. “We’re certainly not claiming that this is a positive trial,” said study coauthor Dr. Colhoun.
A member of the audience at the AAD meeting asked another coauthor, Irene Hramiak, MD, of the University of Western Ontario, London, whether she would prescribe metformin to a patient with type 1 diabetes and a high risk of CVD. “Probably not,” she said, but she added that it may have value in adolescents with weight issues. In those cases, she said, there may be a benefit to improving weight control and lowering insulin doses.
In light of the study findings, the authors recommend revising guidelines that suggest the use of metformin in type 1 diabetes: “We identified a transient improvement in glycemia that reverted to baseline with insulin dose reduction and identified no suggestion of greater benefit in overweight or obese patients.”
The study adds, “Rather than a role in glycemic control, our findings suggest that long-term use of metformin in type 1 diabetes might reduce the long-term risk of cardiovascular disease via small but sustained reductions in bodyweight and LDL cholesterol.”
The Juvenile Diabetes Research Foundation funded the study. Merck Germany KGaA provided medication and shipping for free. Itamar Medical donated equipment and services. Dr. Sataar reported consulting fees and/or research support from Amgen, Boehringer Ingelheim, Eli Lilly, Janssen, and Novo Nordisk. Dr. Colhoun and Dr. Hramiak reported multiple disclosures, including advisory panel, research support, and speaker’s bureau and stock/shareholder relationships.
This article was updated June 19, 2017.
AT THE ADA ANNUAL SCIENTIFIC SESSIONS
Key clinical point: Metformin may reduce cardiac risk in adult type 1 patients, but it doesn’t improve glycemic control. Discontinuation is common.
Major finding: Maximal carotid artery intima-media thickness (cIMT), a surrogate measure for atherosclerosis progression, fell by a mean –0.013 mm per year (95% CI, –0.024 to –0.003; P = .0093), although a similar measure, mean cIMT, dropped by just –0.005 mm per year (95% CI, –0.012-0.002; P = .1664). HbA1c in the metformin group fell by –0.13% (95% CI, –0.22 to –0.037; P = .0060). Of metformin patients, 27% discontinued treatment, compared with 12% of placebo patients (P = .0002).
Data source: A 3-year double-blind, randomized, placebo-controlled trial in patients, aged 40+ years with type 1 diabetes and at least 3 of 10 cardiac risk factors, assigned to oral metformin 1,000 mg twice daily (n = 219) or placebo (209).
Disclosures: The Juvenile Diabetes Research Foundation funded the study. Merck Germany KGaA provided medication and shipping for free. Itamar Medical donated equipment and services. Dr. Sataar reported consulting fees and/or research support from Amgen, Boehringer Ingelheim, Eli Lilly, Janssen, and Novo Nordisk. Dr. Colhoun and Dr. Hramiak reported multiple disclosures, including advisory panel, research support, and speaker’s bureau and stock/shareholder relationships.
Liraglutide produced cardiometabolic benefits in patients with schizophrenia
SAN DIEGO – The glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide significantly lessened glucose tolerance, glycemic control, and other cardiometabolic risk factors in overweight or obese prediabetic patients receiving clozapine or olanzapine for schizophrenia, according to the findings of a randomized, double-blind, placebo-controlled trial.
Liraglutide was generally well tolerated and conferred cardiometabolic benefits similar to those in past studies of patients who were not on antipsychotic therapy, said Louise Vedtofte, PhD, of the University of Copenhagen. After 16 weeks of treatment, a 75-gram oral glucose tolerance test showed that 2-hour plasma glucose levels were 23% lower with liraglutide compared with placebo (P less than .001), she said at the annual scientific sessions of the American Diabetes Association.
Liraglutide patients also lost an average of 5.2 kg more body weight, cut 4.1 cm more from their waist circumference, and were significantly more likely to normalize their fasting plasma glucose and hemoglobin A1c levels compared with the placebo group (P less than .001 for each comparison), she said. The report by Dr. Vedtofte and her associates was published in JAMA Psychiatry simultaneously with the presentation at the meeting (2017 June 10. doi: 10.1001/jamapsychiatry.2017.1220).
Antipsychotics are core therapies in schizophrenia spectrum disorders but also cause increased appetite, weight gain, and cardiometabolic disturbances, noted Dr. Vedtofte. About a third of patients with schizophrenia who receive antipsychotics develop metabolic syndrome, and some 15% go on to develop diabetes. Clozapine and olanzapine cause more weight gain than do other antipsychotics, but swapping either medication for a more weight-neutral alternative can threaten the well-being of patients with schizophrenia, she emphasized. “Olanzapine and clozapine are good for the patients’ mental health, but are detrimental for their somatic health.”
As a GLP-1 receptor agonist, liraglutide inhibits appetite and food intake, and the Food and Drug Administration has approved treatment at doses of 1.8 mg for type 2 diabetes and 3 mg once daily for obesity. To explore how liraglutide affects patients on antipsychotics, Dr. Vedtofte and her associates randomly assigned 103 adults with schizophrenia spectrum disorders from two clinical sites in Denmark to receive placebo or 0.6 mg liraglutide subcutaneously once daily, up-titrated by 0.6 mg weekly to a maximum dose of 1.8 mg. At baseline, all patients were receiving stable treatment with clozapine, olanzapine, or both; had a body mass index of at least 27 kg/m2; and were prediabetic, with fasting plasma glucose levels of 110 to 125 mg/dL, HbA1c levels of 6.1%-6.4%, or 2-hour plasma glucose levels of 140 mg/dL or higher during the 75-gram oral glucose tolerance test.[[{"fid":"198022","view_mode":"medstat_image_flush_right","attributes":{"alt":"Louise Vedtofte, PhD, of the University of Copenhagen","height":"220","width":"147","class":"media-element file-medstat-image-flush-right","data-delta":"1"},"fields":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Dr. Louise Vedtofte","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"1":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Dr. Louise Vedtofte","field_file_image_credit[und][0][value]":""}},"link_text":false}]]
Fully 93% of patients completed the study. At week 16, glucose tolerance improved significantly in the liraglutide group (P less than .001) but not in the placebo group (P less than .001 for difference between groups) after the researchers controlled for age, sex, illness duration, BMI, Clinical Global Impressions Scale severity score, and antipsychotic treatment. Glucose tolerance normalized in 30 patients who received liraglutide (64%) compared with 8 in the placebo group (16%; P less than .001), Dr. Vedtofte said.
Besides its benefits to waist circumference and weight loss, liraglutide was associated with reductions in systolic blood pressure (average, 5 mm Hg; visceral fat, 0.25 kg; and low-density lipoprotein levels, 15 mg/dL). These changes occurred even though liraglutide did not significantly alter C-peptide or glucagon secretion in the multivariate analysis of glucose tolerance test results, Dr. Vedtofte said. “The rate of nausea was 62% in liraglutide patients and 32% with placebo, but nausea was transient and did not explain the weight loss in subgroup analyses,” she added.
Liraglutide did not alter clinical liver function, but treated patients experienced a small (1.3 U/L), statistically significant rise in amylase levels. Rates of other adverse events were similar between groups except that patients were more likely to experience orthostatic hypotension on liraglutide (8.2%) than on placebo (0%; P = .04). Treatment with liraglutide did not significantly increase the likelihood of serious somatic or psychiatric adverse events, but one patient died while on therapy. “This patient was a man in his 60s with longstanding schizophrenia who was admitted to the hospital with vomiting and diarrhea, and died 3 days later,” Dr. Vedtofte said. Autopsy did not reveal the cause of death, but the patients showed no change in mental status or other signs of adverse therapeutic effects, she added.
Novo Nordisk funded the study and provided liraglutide and placebo injections. Additional support came from Capital Region Psychiatry Research Group, the foundation of King Christian X of Denmark, and the Lundbeck Foundation. Dr. Vedtofte had no disclosures.
SAN DIEGO – The glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide significantly lessened glucose tolerance, glycemic control, and other cardiometabolic risk factors in overweight or obese prediabetic patients receiving clozapine or olanzapine for schizophrenia, according to the findings of a randomized, double-blind, placebo-controlled trial.
Liraglutide was generally well tolerated and conferred cardiometabolic benefits similar to those in past studies of patients who were not on antipsychotic therapy, said Louise Vedtofte, PhD, of the University of Copenhagen. After 16 weeks of treatment, a 75-gram oral glucose tolerance test showed that 2-hour plasma glucose levels were 23% lower with liraglutide compared with placebo (P less than .001), she said at the annual scientific sessions of the American Diabetes Association.
Liraglutide patients also lost an average of 5.2 kg more body weight, cut 4.1 cm more from their waist circumference, and were significantly more likely to normalize their fasting plasma glucose and hemoglobin A1c levels compared with the placebo group (P less than .001 for each comparison), she said. The report by Dr. Vedtofte and her associates was published in JAMA Psychiatry simultaneously with the presentation at the meeting (2017 June 10. doi: 10.1001/jamapsychiatry.2017.1220).
Antipsychotics are core therapies in schizophrenia spectrum disorders but also cause increased appetite, weight gain, and cardiometabolic disturbances, noted Dr. Vedtofte. About a third of patients with schizophrenia who receive antipsychotics develop metabolic syndrome, and some 15% go on to develop diabetes. Clozapine and olanzapine cause more weight gain than do other antipsychotics, but swapping either medication for a more weight-neutral alternative can threaten the well-being of patients with schizophrenia, she emphasized. “Olanzapine and clozapine are good for the patients’ mental health, but are detrimental for their somatic health.”
As a GLP-1 receptor agonist, liraglutide inhibits appetite and food intake, and the Food and Drug Administration has approved treatment at doses of 1.8 mg for type 2 diabetes and 3 mg once daily for obesity. To explore how liraglutide affects patients on antipsychotics, Dr. Vedtofte and her associates randomly assigned 103 adults with schizophrenia spectrum disorders from two clinical sites in Denmark to receive placebo or 0.6 mg liraglutide subcutaneously once daily, up-titrated by 0.6 mg weekly to a maximum dose of 1.8 mg. At baseline, all patients were receiving stable treatment with clozapine, olanzapine, or both; had a body mass index of at least 27 kg/m2; and were prediabetic, with fasting plasma glucose levels of 110 to 125 mg/dL, HbA1c levels of 6.1%-6.4%, or 2-hour plasma glucose levels of 140 mg/dL or higher during the 75-gram oral glucose tolerance test.[[{"fid":"198022","view_mode":"medstat_image_flush_right","attributes":{"alt":"Louise Vedtofte, PhD, of the University of Copenhagen","height":"220","width":"147","class":"media-element file-medstat-image-flush-right","data-delta":"1"},"fields":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Dr. Louise Vedtofte","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"1":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Dr. Louise Vedtofte","field_file_image_credit[und][0][value]":""}},"link_text":false}]]
Fully 93% of patients completed the study. At week 16, glucose tolerance improved significantly in the liraglutide group (P less than .001) but not in the placebo group (P less than .001 for difference between groups) after the researchers controlled for age, sex, illness duration, BMI, Clinical Global Impressions Scale severity score, and antipsychotic treatment. Glucose tolerance normalized in 30 patients who received liraglutide (64%) compared with 8 in the placebo group (16%; P less than .001), Dr. Vedtofte said.
Besides its benefits to waist circumference and weight loss, liraglutide was associated with reductions in systolic blood pressure (average, 5 mm Hg; visceral fat, 0.25 kg; and low-density lipoprotein levels, 15 mg/dL). These changes occurred even though liraglutide did not significantly alter C-peptide or glucagon secretion in the multivariate analysis of glucose tolerance test results, Dr. Vedtofte said. “The rate of nausea was 62% in liraglutide patients and 32% with placebo, but nausea was transient and did not explain the weight loss in subgroup analyses,” she added.
Liraglutide did not alter clinical liver function, but treated patients experienced a small (1.3 U/L), statistically significant rise in amylase levels. Rates of other adverse events were similar between groups except that patients were more likely to experience orthostatic hypotension on liraglutide (8.2%) than on placebo (0%; P = .04). Treatment with liraglutide did not significantly increase the likelihood of serious somatic or psychiatric adverse events, but one patient died while on therapy. “This patient was a man in his 60s with longstanding schizophrenia who was admitted to the hospital with vomiting and diarrhea, and died 3 days later,” Dr. Vedtofte said. Autopsy did not reveal the cause of death, but the patients showed no change in mental status or other signs of adverse therapeutic effects, she added.
Novo Nordisk funded the study and provided liraglutide and placebo injections. Additional support came from Capital Region Psychiatry Research Group, the foundation of King Christian X of Denmark, and the Lundbeck Foundation. Dr. Vedtofte had no disclosures.
SAN DIEGO – The glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide significantly lessened glucose tolerance, glycemic control, and other cardiometabolic risk factors in overweight or obese prediabetic patients receiving clozapine or olanzapine for schizophrenia, according to the findings of a randomized, double-blind, placebo-controlled trial.
Liraglutide was generally well tolerated and conferred cardiometabolic benefits similar to those in past studies of patients who were not on antipsychotic therapy, said Louise Vedtofte, PhD, of the University of Copenhagen. After 16 weeks of treatment, a 75-gram oral glucose tolerance test showed that 2-hour plasma glucose levels were 23% lower with liraglutide compared with placebo (P less than .001), she said at the annual scientific sessions of the American Diabetes Association.
Liraglutide patients also lost an average of 5.2 kg more body weight, cut 4.1 cm more from their waist circumference, and were significantly more likely to normalize their fasting plasma glucose and hemoglobin A1c levels compared with the placebo group (P less than .001 for each comparison), she said. The report by Dr. Vedtofte and her associates was published in JAMA Psychiatry simultaneously with the presentation at the meeting (2017 June 10. doi: 10.1001/jamapsychiatry.2017.1220).
Antipsychotics are core therapies in schizophrenia spectrum disorders but also cause increased appetite, weight gain, and cardiometabolic disturbances, noted Dr. Vedtofte. About a third of patients with schizophrenia who receive antipsychotics develop metabolic syndrome, and some 15% go on to develop diabetes. Clozapine and olanzapine cause more weight gain than do other antipsychotics, but swapping either medication for a more weight-neutral alternative can threaten the well-being of patients with schizophrenia, she emphasized. “Olanzapine and clozapine are good for the patients’ mental health, but are detrimental for their somatic health.”
As a GLP-1 receptor agonist, liraglutide inhibits appetite and food intake, and the Food and Drug Administration has approved treatment at doses of 1.8 mg for type 2 diabetes and 3 mg once daily for obesity. To explore how liraglutide affects patients on antipsychotics, Dr. Vedtofte and her associates randomly assigned 103 adults with schizophrenia spectrum disorders from two clinical sites in Denmark to receive placebo or 0.6 mg liraglutide subcutaneously once daily, up-titrated by 0.6 mg weekly to a maximum dose of 1.8 mg. At baseline, all patients were receiving stable treatment with clozapine, olanzapine, or both; had a body mass index of at least 27 kg/m2; and were prediabetic, with fasting plasma glucose levels of 110 to 125 mg/dL, HbA1c levels of 6.1%-6.4%, or 2-hour plasma glucose levels of 140 mg/dL or higher during the 75-gram oral glucose tolerance test.[[{"fid":"198022","view_mode":"medstat_image_flush_right","attributes":{"alt":"Louise Vedtofte, PhD, of the University of Copenhagen","height":"220","width":"147","class":"media-element file-medstat-image-flush-right","data-delta":"1"},"fields":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Dr. Louise Vedtofte","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][format]":"plain_text","field_file_image_credit[und][0][format]":"plain_text"},"type":"media","field_deltas":{"1":{"format":"medstat_image_flush_right","field_file_image_caption[und][0][value]":"Dr. Louise Vedtofte","field_file_image_credit[und][0][value]":""}},"link_text":false}]]
Fully 93% of patients completed the study. At week 16, glucose tolerance improved significantly in the liraglutide group (P less than .001) but not in the placebo group (P less than .001 for difference between groups) after the researchers controlled for age, sex, illness duration, BMI, Clinical Global Impressions Scale severity score, and antipsychotic treatment. Glucose tolerance normalized in 30 patients who received liraglutide (64%) compared with 8 in the placebo group (16%; P less than .001), Dr. Vedtofte said.
Besides its benefits to waist circumference and weight loss, liraglutide was associated with reductions in systolic blood pressure (average, 5 mm Hg; visceral fat, 0.25 kg; and low-density lipoprotein levels, 15 mg/dL). These changes occurred even though liraglutide did not significantly alter C-peptide or glucagon secretion in the multivariate analysis of glucose tolerance test results, Dr. Vedtofte said. “The rate of nausea was 62% in liraglutide patients and 32% with placebo, but nausea was transient and did not explain the weight loss in subgroup analyses,” she added.
Liraglutide did not alter clinical liver function, but treated patients experienced a small (1.3 U/L), statistically significant rise in amylase levels. Rates of other adverse events were similar between groups except that patients were more likely to experience orthostatic hypotension on liraglutide (8.2%) than on placebo (0%; P = .04). Treatment with liraglutide did not significantly increase the likelihood of serious somatic or psychiatric adverse events, but one patient died while on therapy. “This patient was a man in his 60s with longstanding schizophrenia who was admitted to the hospital with vomiting and diarrhea, and died 3 days later,” Dr. Vedtofte said. Autopsy did not reveal the cause of death, but the patients showed no change in mental status or other signs of adverse therapeutic effects, she added.
Novo Nordisk funded the study and provided liraglutide and placebo injections. Additional support came from Capital Region Psychiatry Research Group, the foundation of King Christian X of Denmark, and the Lundbeck Foundation. Dr. Vedtofte had no disclosures.
AT THE ADA ANNUAL SCIENTIFIC SESSIONS
Key clinical point:
Major finding: Glucose tolerance improved significantly from baseline in the liraglutide group (P less than .001) but not in the placebo group (P less than .001 for difference between groups) after 16 weeks.
Data source: A randomized double-blinded trial of 103 overweight or obese adults with prediabetes and schizophrenia spectrum disorders on stable antipsychotic therapy with clozapine, olanzapine, or both.
Disclosures: Novo Nordisk funded the study and provided the liraglutide and placebo injections. Capital Region Psychiatry Research Group, the foundation of King Christian X of Denmark, and the Lundbeck Foundation provided additional support. Dr. Vedtofte had no disclosures. .
Quality measures and diabetic foot care: What endos need to know
SAN DIEGO – As quality measures in health care continue to grow in importance, it behooves endocrinologists to pay more attention to the mental as well as physical well-being of patients with diabetic foot conditions before and after treatment.
“We’re on a path from volume-based practice to really showing that what we’re doing actually works, and diabetic foot is going to be caught up in there. It’s really important that we understand how [the diabetic foot] is affecting our patients physically and mentally. We’ll have to measure what we do and see it if improves,” said Dane K. Wukich, MD, professor and Dr. Charles F. Gregory distinguished chair of the department of orthopedic surgery at University of Texas Southwestern Medical Center, Dallas, in a presentation at the annual scientific sessions of the American Diabetes Association.
Foot amputations are becoming less common but remain a dreaded complication of diabetes. The Centers for Disease Control and Prevention has estimated that hospital discharges for lower-extremity amputation among people with diabetes declined dramatically – by as much as 50% or more depending on the type – from 2003 to 2009. Still, in 2009, the levels were 1.8 cases per 1,000 patients for toe amputation, 0.5 cases per 1,000 patients for foot amputation, and 0.9 and 0.4 cases per 1,000 for below- and above-knee amputation, respectively.
The commonly used 36-Item Short Form Quality of Life Survey (SF-36 QOL) may offer useful insight into quality of life in diabetic foot patients after treatment, but it is not precise enough to gauge patients’ mental health issues.
Patient-reported outcomes will become more important in diabetic foot treatments, Dr. Wukich said, “but sometimes a successful outcome in what we do does not always equate to an improvement in quality of life.”
For example, he said, it’s true that patients with diabetic foot disease fear losing their legs more than death. He led a study published earlier this year that found patients with diabetic foot conditions were 79% more likely to say amputation is their greatest fear, topping even death (odds ratio, 1.79; 96% confidence interval, 1.13-2.81; P = .01 [Foot Ankle Spec. 2017 Feb 1]).
But “saving a foot that’s not in a good position” can be devastating for a patient, even worse than amputation, he said.
Quality of life measurements will provide insight for doctors and insurers as they track the success of diabetic foot treatments. But Dr. Wukich said there’s a big mystery about one aspect of quality of life (QOL) measurements: Why don’t diabetic foot problems significantly disrupt the mental component of quality of life measures?
He coauthored a 2014 study – of 50 patients with diabetes and Charcot foot and 56 patients with diabetes only – that found a significant gap in physical QOL measures (P less than .001) but nearly identical measures in mental QOL (P less than .644) (Foot Ankle Int. 2014;35[3]195-200).
He asked: “How could somebody have a Charcot problem with a deformed foot, walking around in a boot for years and not have it affect their mental quality of life?”
One possibility is that neuropathy reduces the mental burden of pain because it hurts less, he suggested. But the answer could lie in the strategies used in calculating scores commonly used in the SF-36 QOL tool, he said. Recent unpublished research suggests that the orthogonal calculation may artificially increase mental QOL scores in these cases, he said. The oblique method may be more accurate, he said, but more study is needed.
In the big picture, he said, “assessing quality of life can help us establish the optimal methods of treatment, evaluate treatment outcomes, and identify patients at risk of mortality, admission, and depression. It’s going to guide us in the pay-for-performance arena.”
During the meeting, Dr. Wukich was presented with the American Diabetes Associations 2017 Roger Pecoraro Award, which recognizes a researcher “who has made significant scientific contributions and demonstrates an untiring commitment to improving the understanding of the detection, treatment, and prevention of diabetic foot complications.”
Dr. Wukich reported that he has no relevant financial disclosures.
SAN DIEGO – As quality measures in health care continue to grow in importance, it behooves endocrinologists to pay more attention to the mental as well as physical well-being of patients with diabetic foot conditions before and after treatment.
“We’re on a path from volume-based practice to really showing that what we’re doing actually works, and diabetic foot is going to be caught up in there. It’s really important that we understand how [the diabetic foot] is affecting our patients physically and mentally. We’ll have to measure what we do and see it if improves,” said Dane K. Wukich, MD, professor and Dr. Charles F. Gregory distinguished chair of the department of orthopedic surgery at University of Texas Southwestern Medical Center, Dallas, in a presentation at the annual scientific sessions of the American Diabetes Association.
Foot amputations are becoming less common but remain a dreaded complication of diabetes. The Centers for Disease Control and Prevention has estimated that hospital discharges for lower-extremity amputation among people with diabetes declined dramatically – by as much as 50% or more depending on the type – from 2003 to 2009. Still, in 2009, the levels were 1.8 cases per 1,000 patients for toe amputation, 0.5 cases per 1,000 patients for foot amputation, and 0.9 and 0.4 cases per 1,000 for below- and above-knee amputation, respectively.
The commonly used 36-Item Short Form Quality of Life Survey (SF-36 QOL) may offer useful insight into quality of life in diabetic foot patients after treatment, but it is not precise enough to gauge patients’ mental health issues.
Patient-reported outcomes will become more important in diabetic foot treatments, Dr. Wukich said, “but sometimes a successful outcome in what we do does not always equate to an improvement in quality of life.”
For example, he said, it’s true that patients with diabetic foot disease fear losing their legs more than death. He led a study published earlier this year that found patients with diabetic foot conditions were 79% more likely to say amputation is their greatest fear, topping even death (odds ratio, 1.79; 96% confidence interval, 1.13-2.81; P = .01 [Foot Ankle Spec. 2017 Feb 1]).
But “saving a foot that’s not in a good position” can be devastating for a patient, even worse than amputation, he said.
Quality of life measurements will provide insight for doctors and insurers as they track the success of diabetic foot treatments. But Dr. Wukich said there’s a big mystery about one aspect of quality of life (QOL) measurements: Why don’t diabetic foot problems significantly disrupt the mental component of quality of life measures?
He coauthored a 2014 study – of 50 patients with diabetes and Charcot foot and 56 patients with diabetes only – that found a significant gap in physical QOL measures (P less than .001) but nearly identical measures in mental QOL (P less than .644) (Foot Ankle Int. 2014;35[3]195-200).
He asked: “How could somebody have a Charcot problem with a deformed foot, walking around in a boot for years and not have it affect their mental quality of life?”
One possibility is that neuropathy reduces the mental burden of pain because it hurts less, he suggested. But the answer could lie in the strategies used in calculating scores commonly used in the SF-36 QOL tool, he said. Recent unpublished research suggests that the orthogonal calculation may artificially increase mental QOL scores in these cases, he said. The oblique method may be more accurate, he said, but more study is needed.
In the big picture, he said, “assessing quality of life can help us establish the optimal methods of treatment, evaluate treatment outcomes, and identify patients at risk of mortality, admission, and depression. It’s going to guide us in the pay-for-performance arena.”
During the meeting, Dr. Wukich was presented with the American Diabetes Associations 2017 Roger Pecoraro Award, which recognizes a researcher “who has made significant scientific contributions and demonstrates an untiring commitment to improving the understanding of the detection, treatment, and prevention of diabetic foot complications.”
Dr. Wukich reported that he has no relevant financial disclosures.
SAN DIEGO – As quality measures in health care continue to grow in importance, it behooves endocrinologists to pay more attention to the mental as well as physical well-being of patients with diabetic foot conditions before and after treatment.
“We’re on a path from volume-based practice to really showing that what we’re doing actually works, and diabetic foot is going to be caught up in there. It’s really important that we understand how [the diabetic foot] is affecting our patients physically and mentally. We’ll have to measure what we do and see it if improves,” said Dane K. Wukich, MD, professor and Dr. Charles F. Gregory distinguished chair of the department of orthopedic surgery at University of Texas Southwestern Medical Center, Dallas, in a presentation at the annual scientific sessions of the American Diabetes Association.
Foot amputations are becoming less common but remain a dreaded complication of diabetes. The Centers for Disease Control and Prevention has estimated that hospital discharges for lower-extremity amputation among people with diabetes declined dramatically – by as much as 50% or more depending on the type – from 2003 to 2009. Still, in 2009, the levels were 1.8 cases per 1,000 patients for toe amputation, 0.5 cases per 1,000 patients for foot amputation, and 0.9 and 0.4 cases per 1,000 for below- and above-knee amputation, respectively.
The commonly used 36-Item Short Form Quality of Life Survey (SF-36 QOL) may offer useful insight into quality of life in diabetic foot patients after treatment, but it is not precise enough to gauge patients’ mental health issues.
Patient-reported outcomes will become more important in diabetic foot treatments, Dr. Wukich said, “but sometimes a successful outcome in what we do does not always equate to an improvement in quality of life.”
For example, he said, it’s true that patients with diabetic foot disease fear losing their legs more than death. He led a study published earlier this year that found patients with diabetic foot conditions were 79% more likely to say amputation is their greatest fear, topping even death (odds ratio, 1.79; 96% confidence interval, 1.13-2.81; P = .01 [Foot Ankle Spec. 2017 Feb 1]).
But “saving a foot that’s not in a good position” can be devastating for a patient, even worse than amputation, he said.
Quality of life measurements will provide insight for doctors and insurers as they track the success of diabetic foot treatments. But Dr. Wukich said there’s a big mystery about one aspect of quality of life (QOL) measurements: Why don’t diabetic foot problems significantly disrupt the mental component of quality of life measures?
He coauthored a 2014 study – of 50 patients with diabetes and Charcot foot and 56 patients with diabetes only – that found a significant gap in physical QOL measures (P less than .001) but nearly identical measures in mental QOL (P less than .644) (Foot Ankle Int. 2014;35[3]195-200).
He asked: “How could somebody have a Charcot problem with a deformed foot, walking around in a boot for years and not have it affect their mental quality of life?”
One possibility is that neuropathy reduces the mental burden of pain because it hurts less, he suggested. But the answer could lie in the strategies used in calculating scores commonly used in the SF-36 QOL tool, he said. Recent unpublished research suggests that the orthogonal calculation may artificially increase mental QOL scores in these cases, he said. The oblique method may be more accurate, he said, but more study is needed.
In the big picture, he said, “assessing quality of life can help us establish the optimal methods of treatment, evaluate treatment outcomes, and identify patients at risk of mortality, admission, and depression. It’s going to guide us in the pay-for-performance arena.”
During the meeting, Dr. Wukich was presented with the American Diabetes Associations 2017 Roger Pecoraro Award, which recognizes a researcher “who has made significant scientific contributions and demonstrates an untiring commitment to improving the understanding of the detection, treatment, and prevention of diabetic foot complications.”
Dr. Wukich reported that he has no relevant financial disclosures.
AT THE ADA ANNUAL SCIENTIFIC SESSIONS