American Diabetes Association (ADA) 73rd Scientific Sessions

June 21-25, 2013; Chicago, IL

Linagliptin Demonstrates Good Cardiovascular Safety Profile

Dipeptidyl-peptidase-IV (DPP-4) inhibitors have become an important oral second-line therapy when patients do not reach their glycemic targets with metformin monotherapy or as a first-line therapy when metformin is not tolerated or contraindicated. Because these agents are still relatively new, there have been concerns over their potential cardiovascular risk. During an oral abstract session at the ADA meeting, Odd Erik Johansen, MD, PhD, senior clinical program leader, Boehringer Ingelheim, provided new favorable safety data regarding the DPP-4 inhibitor linagliptin. He noted that patients taking this agent were not at higher risk of having cardiovascular events compared with patients who took other drugs. These findings were the result of an analysis of 19 multicenter, randomized, double-blind, parallel group studies funded by Boehringer Ingelheim.

In 2011, the US Food and Drug Administration approved linagliptin as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The recommended dose of linagliptin is 5 mg taken orally once daily with or without food. Because linagliptin is eliminated via a hepatobiliary route, compared with other DPP-4 inhibitors that have a renal route, dose adjustment is not needed for patients with chronic kidney disease. In addition, Johansen noted that studies have shown the DPP-4 class of antidiabetic drugs to have nonglycemic cardiovascular benefits, including reducing blood pressure and triglyceride levels.

Johnson, an employee of Boehringer Ingelheim, led the analysis of the 19 trials, which randomly assigned patients to receive linagliptin (n=5847) or a comparison drug (n=3612) for at least 12 weeks and up to 2 years. The groups were well balanced; approximately 55% of patients were men, the mean patient age was 58 years, and the mean body mass index was 29 kg/m². Both groups were diverse in terms of low to high risk of having cardiovascular complications and being treatment-naïve or taking concomitant medications. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, and hospitalization for unstable angina pectoris. The incidence rate of the primary end point was 13.4 per 1000 person-years in the linagliptin group and 18.9 per 1000 person-years in the comparison drug group (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.55-1.12). The combined rate of cardiovascular death, stroke, or myocardial infarction was also lower in the linagliptin group compared with the comparison drug group (HR, 0.74; 95% CI, 0.49-1.13).

Cardiovascular deaths were found in 0.2% of patients in each group. Nonfatal myocardial infarction was found in 0.4% of patients in the linagliptin group and 0.6% of patients in the comparison drug group, while the rates of nonfatal stroke were 0.2% and 0.5%, respectively.

Johansen noted that independent of other risk factors, patients with type 2 diabetes have at least twice as much risk of experiencing a wide range of vascular diseases, including myocardial infarction. He mentioned that patients with type 2 diabetes and those with a history of coronary artery disease are in the same risk category of having cardiovascular disease. He added that more patients with type 2 diabetes are having cardiovascular problems, and they are occurring earlier in life and are more advanced at the time of diagnosis; thus, independent of the medication prescribed, clinicians need to keep these risks in mind.       

Johansen stated that Boehringer Ingelheim continues to evaluate the cardiovascular safety of linagliptin and is conducting two additional trials: the CARMELINA (Cardiovascular Safety with Linagliptin in Patients with Type 2 Diabetes Mellitus: A Pre-Specified, Prospective, and Adjudicated Meta-Analysis of a Phase 3 Program) study, which is a cardiovascular and renal outcomes trial that includes 8300 patients; and the CAROLINA (Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients with Type 2 Diabetes) study, which is a cardiovascular outcomes study enrolling 6103 patients and comparing linagliptin with the sulfonylurea glimepiride.—Christina Loguidice

This study was funded by Boehringer Ingelheim.

Pooled Data Analysis Shows Similar Safety and Efficacy of Canagliflozin Across Age Groups

In March 2013, the FDA approved canagliflozin for use with diet and exercise in patients with type 2 diabetes. Canagliflozin is an oral medication and the first FDA-approved drug in a new class of agents known as sodium-glucose co-transporter 2 (SGLT2) inhibitors. By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose, thereby increasing urinary glucose excretion. Previous studies have shown that older adults (≥65 years) on canagliflozin have a higher incidence of adverse reactions (eg, hypotension, postural dizziness, orthostatic hypotension, syncope, dehydration) than their younger counterparts as a result of the reduced intravascular volume caused by this agent, particularly with the 300-mg daily dose. But a late-breaking poster session at the ADA meeting demonstrated similar efficacy and safety of canagliflozin across age groups with regard to glycemic control, changes in body weight, and general tolerance.

The study outlined during the session was led by Bruce Bode, MD, diabetes specialist, Atlanta Diabetes Associates in Atlanta, GA, and was a pooled data analysis of four randomized, placebo-controlled trials that lasted 26 weeks and included a total of 2313 patients who received placebo or canagliflozin as monotherapy, as an add-on to metformin, as an add-on to metformin plus a sulfonylurea, and as an add-on to metformin plus pioglitazone. The canagliflozin doses were 100 mg or 300 mg taken once daily. In the analysis of these trials, patients were stratified by age (ie, <65 years and ≥65 years).             

At baseline, the groups were well balanced and all patients had a hemoglobin A_1c (HbA_1c) level between 7.0% and 10.5%. Of the patients <65 years of age, approximately 50% were men, 70% were white, mean age was 53 years, and the mean duration of type 2 diabetes was 6.5 years. Of the patients ≥65 years of age, approximately 50% were men, 85% were white, mean age was 70 years, and mean duration of type 2 diabetes was 10 years.

After 26 weeks, 85.9% of patients <65 years of age and 85.4% of patients ≥65 years of age completed the treatment regimen they were randomly assigned to. Of those <65 years of age, the mean reduction in HbA_1c from baseline was 1.08% in the 300-mg canagliflozin group, 0.89% in the 100-mg canagliflozin group, and 0.15% in the placebo group. For patients ≥65 years of age, the mean reduction in HbA_1c from baseline was 0.88% in the 300-mg canagliflozin group, 0.69% in the 100-mg canagliflozin group, and 0.05% in the placebo group.       

In addition, for patients <65 years of age, the mean reduction in fasting plasma glucose (FPG) from baseline was 36.0 mg/dL in the 300-mg canagliflozin group and 27.0 mg/dL in the 100-mg canagliflozin group. The FPG increased by a mean of 4.4 mg/dL in the placebo group. For patients ≥65 years of age, the mean reduction in FPG from baseline was 33.1 mg/dL in the 300-mg canagliflozin group and 20.4 mg/dL in the 100-mg canagliflozin group. The FPG increased by a mean of 1.6 mg/dL in the placebo group.

Furthermore, for patients <65 years of age, the mean reduction in body weight from baseline was 3.4 kg in the 300-mg canagliflozin group, 2.8 kg in the 100-mg canagliflozin group, and 0.6 kg in the placebo group. For patients ≥65 years of age, the mean reduction in body weight from baseline was 3.8 kg in the 300-mg canagliflozin group, 2.9 kg in the 100-mg canagliflozin group, and 0.6 kg in the placebo group.

The authors noted that patients in each age category tolerated both doses of canagliflozin, although there were higher rates of genital mycotic infections and osmotic diuresis-related adverse events among patients taking canagliflozin compared with those receiving placebo.—Tim Casey

This study was funded by Janssen Research & Development, LLC.

Phentermine and Topiramate Improves Weight Loss and Glycemic Control in Overweight Persons

In July 2012, the FDA approved phentermine and topiramate extended-release to be used in combination with a reduced-calorie diet and exercise for chronic weight management. The oral medication is intended for obese adults (body weight index [BMI] ≥30 kg/m²) or overweight adults (BMI ≥27 kg/m²) with at least one weight-related condition, such as hypertension, type 2 diabetes, or dyslipidemia. Because the risk of type 2 diabetes increases with BMI, the ADA recommends that overweight or obese adults with prediabetes or type 2 diabetes lose weight to improve their glycemic control. During a poster session at the ADA meeting, researchers reported the results of a randomized, double-blind phase 3 trial that showed that phentermine and topiramate extended-release pills could help meet this objective.

In this study, the authors randomly assigned 2487 overweight and obese adults with at least two weight-related comorbidities to receive placebo, 7.5-mg phentermine/46-mg topiramate, or 15-mg phentermine/92-mg topiramate once daily. Patients had a BMI between 27 kg/m² and 45 kg/m². The mean age of patients was 52.1 years, 67% were women, and 87% were white. In all BMI categories, patients in the phentermine and topiramate extended-release groups had a significant weight reduction compared with the placebo group (P<.0001 in all comparisons). For patients with a BMI <30 kg/m², mean weight loss at week 56 was 0.9% in the placebo group, 9.9% in the 7.5-mg phentermine/46-mg topiramate group, and 8.8% in the 15-mg phentermine/92-mg topiramate group. For patients with a BMI between 30 kg/m² to 35 kg/m², mean weight loss at week 56 was 2.3% in the placebo group, 7.7% in the 7.5-mg phentermine/46-mg topiramate group, and 10.4% in the 15-mg phentermine/92-mg topiramate group. For patients with a BMI from 35 kg/m² to 40 kg/m², mean weight loss at week 56 was 2.3% in the placebo group, 8.8% in the 7.5-mg phentermine/46-mg topiramate group, and 10.2% in the 15-mg phentermine/92-mg topiramate group. For patients with BMI ≥40 kg/m², mean weight loss at week 56 was 2.7% in the placebo group, 8.4% in the 7.5-mg phentermine/46-mg topiramate group, and 11.6% in the 15-mg phentermine/92-mg topiramate group.

The analysis also included 1698 patients with dysglycemia, which the authors defined as a baseline fasting plasma glucose ≥100 mg/dL or blood glucose ≥100 mg/dL in the 2 hours following an oral glucose tolerance test. The obese or overweight adults with dysglycemia who received phentermine and topiramate extended-release pills had a mean weight loss of 7.7% to 11.6% after 56 weeks of treatment. The weight loss was consistent across all BMI categories and was associated with improvements in glycemic control.

The most common treatment-related adverse events for patients taking phentermine and topiramate extended-release pills were paresthesia, dry mouth, constipation, dizziness, insomnia, dysgeusia, and nausea. In addition, 8% of patients in the placebo group, 11% of patients in the 7.5-mg phentermine/46-mg topiramate group, and 19% of patients in the 15-mg phentermine/92-mg topiramate group had a treatment-related adverse event that led to discontinuation. Fewer than 1% of patients in the phentermine and topiramate extended-release groups had hypoglycemia, but none of the events were considered severe, according to the researchers.—Tim Casey

The study was funded by VIVUS Inc.