Danish Study Suggests Cardioprotective Effects of GLP-1 Agonist and Insulin

December 17, 2014

Evidence to date is conflicting on the potential role of antihyperglycemic drugs, old and new, in cardioprotection. Results reported here add to the pool and fuel ongoing study.

The glucagon-like peptide-1 analogue liraglutide and insulin could both protect against acute myocardial infarction (AMI) in patients with type 2 diabetes (T2DM), according to a study conducted in Denmark and published in June 2014 in the Journal of Diabetes & Metabolism.

“Our registry study shows a significant association between liraglutide use and reduced risk of AMI in type 2 diabetes. The findings were dose- and duration-dependent, underlining the association,” commented first author Jakob Starup-Linde, an MD and PhD student in the Department of Endocrinology and Internal Medicine at Aarhus University Hospital in Denmark.

“Insulin was neutral in unadjusted analyses for HbA1c and other biochemistry variables, but protective against AMI when adjusted for these variables. Other antidiabetics had neutral effects,”  Starup-Linde added.

Past studies have suggested that native GLP-1 and GLP-1 analogues could potentially reduce excess cardiovascular morbidity and mortality in patients with diabetes, according to background information in the article. These benefits could be linked to improved glycemic control, and perhaps independent effects of the drugs themselves. Evidence is conflicting, however, with some studies suggesting cardiovascular benefits with metformin and neutral outcomes for dipeptidyl peptidase-4 (DPP-4) inhibitors. Little is known about which antihyperglycemic, if any, could provide better cardioprotection.

The study used a nested case-control design. Cases were those patients who had had an AMI after receiving a diagnosis of diabetes. Controls were patients who had never had an AMI after receiving a diagnosis of T2DM. Researchers used the Danish National Hospital Discharge Register to extract patient information dating from 1977 to 2011. ICD-9 codes were used to identify date of T2DM diagnosis, date of AMI, and comorbidities. Using ATC codes, they also identified data on medication use and biochemical parameters for a subset of patients from a registry in the central region of Jutland, Denmark.

The registries did not include lifestyle information (physical activity, smoking, alcohol, diet, and weight), so these variables were excluded from the analysis.

The analysis included 10,727 patients with a mean age of 63 years. AMI subsequent to receiving a diagnosis of T2DM was seen in 3% of cases. More than 50% of both cases and controls used biguanides and insulin, 37% of cases and 38% of controls used β-cell stimulants, and 3.8% of cases and 15.3% of controls used liraglutide.

Preliminary analyses suggested that only liraglutide decreased the risk of AMI (OR= 0.386, 95% CI 0.218-0.682).  Insulin, β-cell stimulants, glitazones, the GLP-1 analogue exenatide, and DPP-4 inhibitors did not significantly affect risk for AMI.  Risk of having an AMI was linked to having already had an AMI before T2DM diagnosis (OR=36.004, 95% CI 24.441-53.038), increasing age (OR 1.027, 95% CI 1.016-1.039), increasing duration of diabetes (1.060, 95% CI 1.043-1.077), being male (OR 1.310, 95% CI 1.025-1.676), having heart failure (OR 2.083, 95% CI 1.459-2.973), and peripheral arterial disease (OR 1.506, 95% CI 1.032-2.198). 

Further analyses of a subgroup from central Jutland (n=1072), adjusted for LDL, HDL, total cholesterol, triglycerides, HbA1c, and creatinine, and suggested that insulin was significantly associated with lowered risk of AMI (OR 0.235, 95% CI 0.073-0.757). Among patients in this group who received liraglutide (n=180), none were included in this subanalysis since none had an AMI, which “supports a beneficial effect of liraglutide,” the authors mentioned.

Liraglutide was also linked to significantly decreased HbA1c (mean 0.47%, p<.0001), LDL (mean 0.14, p=0.0004), total cholesterol (0.23 mmol/l, p<.0001), and triglycerides (mean 0.26 mmol/l, p=.023).

Possible mechanisms by which liraglutide could protect against AMI include increased myocardial blood flow and improved myocardial glucose metabolism, according to Starup-Linde. Another explanation could be tighter glucose control when treating with liraglutide or insulin, he added. Improved weight, lipids, and blood pressure could also play roles.

“Due to the [observational] nature of the study, caution should be made when interpreting the results as causality cannot be determined,” Starup-Linde pointed out. “The results of large outcome trials on GLP-1 agonists are expected in the coming years. Further results are needed to determine whether liraglutide should be the preferred second-line antidiabetic drug.”


This study was supported by an unrestricted grant from Novo Nordisk A/S.


Starup-Linde J, Scheel-Thomsen J, Gejl M, et al. Liraglutide and insulin are associated with a decreased risk of acute myocardial infarction in type 2 diabetes mellitus patients.  J Diabetes Metab. 2014;5:389. Doi: 10.4172/2155-6156.1000389