Pooled Analysis Confirms CV Benefits of DPP-4 Inhibition

August 2013, Vol 6 ADA 2013 Highlights
Mary Mosley

Chicago, IL—Diabetes is known to confer approximately a 2-fold increased risk for vascular disease, independent of other cardiovascular (CV) risk factors. The topic was discussed in a session at the 2013 American Diabetes Association (ADA) annual meeting. The presence of diabetes is equivalent in risk to a history of coronary heart disease.

Key characteristics of the CV biopathology in patients with type 2 diabetes include:

  • Younger age
  • Asymptomatic disease or atypical symptoms
  • More advanced disease at the time of diagnosis
  • High mortality rate (70%-75% of all deaths in diabetes result from CV disease).

New Evidence for CV Benefits of DPP-4 Inhibition
The ability of glucose-lowering drugs to reduce CV risk in type 2 diabetes continues to be debated. Mechanistic studies have indicated that dipeptidyl peptidase (DPP)-4 inhibitors may have nonglycemic CV benefits, including lowering of blood pressure and triglycerides; improving endothelial and left-ventricular function; and the reduction of myocardial infarct size, inflammation and oxidative stress, and atherosclerotic plaque volume.

In one recent study, CV events and all-cause mortality were reduced with a DPP-4 inhibitor compared with an active comparator in an independent meta-analysis of 70 trials with nearly 42,000 patients and a mean 44-week follow-up (Monami M, et al. Diabetes Obes Metab. 2013;15:112-120).

The reduction in myocardial infarction (MI) with the DPP-4 inhibitor was greater than would be predicted based on traditional risk factors, suggesting a role for other mechanisms, stated the investigators. The Mantel-Haenszel odds ratio was 0.71 for major adverse coronary events.

The CV safety of the DPP-4 inhibitor linagliptin was evaluated by comparing the incidence of CV events and mortality in type 2 diabetes with other glucose-lowering drugs. At the ADA meeting, Odd Erik Johansen, MD, PhD, Senior Clinical Program Leader, Boehringer Ingelheim, Norway.

“There is a well-established association between cardiovascular events and Type 2 diabetes,” said Dr Johansen. “In fact, CV events rank as the major cause of death in patients with diabetes, accounting for more than 50% of all diabetes fatalities. It is therefore important to identify treatments that do not increase the risk of CV events even further.”

Dr Johansen presented the updated pooled analysis of 9569 patients in 19 multicenter, double-blind, parallel-group studies in which patients were randomized to linagliptin (N = 5847) or to a comparator (N = 3612). The comparator was placebo (N = 2675), glimepiride (N = 775), or voglibose (N = 162). The length of the trials ranged from 12 weeks to 2 years.

CV Events Reduced by 22% with Linagliptin
A 22% reduction in the primary end point of combined CV death, MI, stroke, and hospitalization for unstable angina was seen with linagliptin versus the combined comparator (hazard ratio [HR], 0.78; 95% confidence interval, 0.55-1.12). The incidence rate of the primary end point was 13.4 per 1000 patient-years in the linagliptin group and 18.9 in the comparator group.

The secondary CV end point of CV death, stroke, or MI was reduced by 26% with linagliptin, and all adjudicated CV events by 18% with linagliptin versus the combined comparators for both end points. The incidence rates per 1000 patient-years were 9.3 and 14.0 for the secondary CV end point, and 21.5 and 29.1 for all adjudicated CV events for the linagliptin and comparator groups, respectively. A blinded independent expert committee prospectively adjudicated the CV events.

The HRs for the tertiary CV end points were 1.04 for CV death, 0.86 for nonfatal MI, 0.34 for nonfatal stroke, 0.09 for transient ischemic stroke, and 1.08 for hospitalization for unstable angina.

The mean age of the patients was 59 years, 45% were women, and approximately 60% were white. Approximately 55% of the population had diabetes for >5 years, and the mean hemoglobin A1c was 8.1%. Nearly 11% of the patients receiving linagliptin and 12% of the patients receiving a comparator had moderate-to-severe renal insufficiency. Approximately 73% of the linagliptin group and 76% of the comparator group received CV drugs for primary and secondary prevention.

In a representative cohort of patients with type 2 diabetes and a diverse background of CV risk (from low to high) and concomitant treatment (treatment naïve to insulin), linagliptin was not associated with an increased risk of CV events, said Dr Johansen.

CARMELINA, a CV and renal outcomes study, and CAROLINA, a CV outcomes study, will more fully investigate the CV safety of linagliptin.

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Last modified: October 7, 2013
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