GLP-1 Receptor Agonists and Cardiovascular Outcomes: 3 Studies

Blonde L, Pencek R, MacConell L. Association among weight change, glycemic control, and markers of cardiovascular risk with exenatide once weekly: a pooled analysis of patients with type 2 diabetes. Cardiovasc Diabetol. 2015;14:12.

Exenatide is a GLP-1 receptor agonist shown to reduce HbA1c and body weight in patients with type 2 diabetes. Researchers pooled data from eight studies of exenatide once-weekly and grouped patients into quartiles by weight loss. Analyses were conducted to see if there was a correlation between weight loss, glycemic control, and several cardiovascular outcomes.

The median changes in body weight were: quartile 1: –6.0 kg; quartile 2: –3.0 kg; quartile 3: –1.0 kg; quartile 4: +1.0 kg. Although patients in each quartile had reductions in HbA1c and fasting plasma glucose (FPG), the greatest reductions were in the patients with the greatest weight loss (quartile 1 vs. 4: change in HbA1c –1.6% vs. 1.2%, change in FPG –41 mg/dL vs. –25 mg/dL).

The greatest reductions were in the patients with the greatest weight loss (quartile 1 vs. 4: change in HbA1c –1.6% vs. 1.2%, change in FPG –41 mg/dL vs. –25 mg/dL). Patients in quartiles 1 to 3 had reductions from baseline in systolic blood pressure, LDL cholesterol, total cholesterol, and triglycerides.

Blonde et al wrote: “Improvements in CV risk markers (excluding DBP) and liver enzymes from baseline were observed with exenatide once weekly in the majority of body weight loss quartiles and with the greatest improvement in the quartile with the greatest reduction of body weight…The results of the analysis also support the role of exenatide once weekly as an effective and well-tolerated treatment option for patients with T2DM, the majority of whom are overweight or obese…Whether the observed improvements in CV risk markers with exenatide once weekly translate to improvements in CV-related end points or outcomes is not presently known.”

Paul SK, Klein K, Madds D, Best JH. The association of the treatment with glucagon-like peptide-1 receptor agonist exenatide or insulin with cardiovascular outcomes in patients with type 2 diabetes: a retrospective observational study. Cardiovasc Diabetol. 2015:14:10.Full text here.

Researchers conducted a retrospective study of ambulatory care data from patients assigned exenatide twice-daily (EBID) or insulin from June 2005 to May 2009, with patient follow-up until December 2012. Analyses were conducted to evaluate the risk for macrovascular events among three groups: EBID plus oral antidiabetes drugs (OADs; n=2,804), insulin plus OADs (insulin group; n=28,551). Patients who changed between EBID and/or insulin plus OADs (EBID+insulin; n=7,870)

Patients assigned EBID or EBID+insulin had lower rates of heart failure, myocardial infarction, and stroke compared with the insulin group. Heart failure: 4.38 and 6.13 vs. 17.87 per 1,000 person years. Myocardial infarction: 1.06 and 1.15 vs. 2.54 per 1,000 person years. Stroke: 2.35 and 1.84 vs. 6.12 per 1,000 person years. These reduced event rates among patients assigned EBID or EBID+insulin translated into significantly reduced risk for heart failure, myocardial infarction, and stroke compared with the insulin group (P

“This comparative longitudinal study demonstrated for the first time (to the best of our knowledge) that patients with T2DM who are treated with EBID, in addition to OADs, have lower rates and comparative risks The authors wrote: of HF, MI, and stroke than those treated with conventional combination treatment of insulin with OADs...Our population-based study provided evidence for the potential CV benefits of treatment with the GLP-1R agonist exenatide, while used in combination with conventional antidiabetic therapies ...While the confirmatory results from clinical trials are awaited, our epidemiological study provides much needed guiding information to the clinicians who are trying to balance the optimum glycaemic control along with management of CV risks in patients with T2DM.”Full text here.

Seshasai SRK, Bennett RL, Petrie JR, et al. Cardiovascular safety of the GLP-1 receptor agonist taspoglutide in people with type 2 diabetes: An individual participant data meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2015;doi:10.1111/dom.1244.[Epub ahead of print]

Taspoglutide is a once-weekly GLP-1 receptor agonist. Phase III trials of taspoglutide were halted in 2010 due to serious hypersensitivity reactions and gastrointestinal side effects. Prior to the cessation of phase III trials, a prespecified plan was developed to evaluate the short-term cardiovascular safety of taspoglutide. Researchers conducted a meta-analysis using individual participant data from nine randomized controlled trials assessing the safety and efficacy of taspoglutide in 7,056 patients with type 2 diabetes.The primary outcomes of the meta-analysis was a composite of cardiovascular disease death, acute myocardial infarction, stroke and hospitalization for unstable angina.

No significant difference in cardiovascular death, acute myocardial infarction, or stroke were noted between patients assigned taspoglutide or placebo.The pooled odds ratio for the composite endpoint among patients assigned taspoglutide was 0.94 (95% CI, 0.57-1.66). No excess risk for all-cause death was seen in patients assigned taspoglutide (OR=0.89; 95% CI, 0.38-2.07).No significant difference in systolic or diastolic blood pressure was seen in patients assigned taspoglutide and comparator treatments.

The authors wrote: “Although the T-Emerge programme was discontinued in view of gastrointestinal adverse effects and hypersensitivity reactions to taspoglutide, the current meta-analysis is nevertheless important in advancing our knowledge regarding the cardiovascular safety of GLP-1 receptor agonists, especially long-acting, once-weekly preparations that are likely to improve both glycaemic control and treatment compliance…Several meta-analyses of short-term RCTs have now suggested the overall safety and efficacy of once-daily GLP-1 receptor agonists. Pending the completion of several long-term cardiovascular outcome trials using other agents in the class, this pooled analysis of worldwide data on taspoglutide adds further to this literature.”