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PPAR Agonists Raise Heart Failure Risk for Pre-diabetic and T2DM Patients

In the meta-analysis of 14 randomized trials, DPP-4 inhibitors were also found to increase cardiovascular risk slightly while the effect of insulin glargine was neutral….

Data was reviewed from 14 randomized controlled trials of 95,502 patients with or at risk for type 2 diabetes taking new or more intensive glucose-lowering medications or strategies and cardiovascular outcomes; the primary endpoint was incidence of heart failure. Across all trials, 4% of patients developed a heart failure event and almost 10% suffered a major adverse cardiovascular event. Overall, glucose-lowering medications or strategies increased the risk for heart failure by around 14% compared to standard of care or placebo.

The heart failure risk was greatest in patients taking peroxisome proliferator-activated receptor agonists (PPARs), intermediate with dipeptidyl peptidase-4 (DPP-4) inhibitors, and neutral with insulin glargine. Target-based intensive glycemic control strategies and intensive weight loss were not associated with an increased risk.

Lead investigator Dr. Jacob Udell, of the Peter Munk Cardiac Centre at the University Health Network (UHN) and the Women’s College Hospital (WCH), both in Toronto, Canada, explains that the “increased risk was directly associated with the type of diabetes therapy that was chosen, with some drugs more likely to cause heart failure than others, compared with placebo or standard care.”

Senior author Dr. Michael Farkouh, chair of the Peter Munk Centre of Excellence in Multinational Clinical Trials, adds: “While some drugs showed an increased risk, other strategies tested, such as intensive weight loss to control blood sugar, showed a trend towards a lower risk for heart failure.”

Overall, the results show that for every kilo of weight gain due to sugar-lowering diabetes treatment, there was an associated 7% higher risk of heart failure directly linked to that treatment.

The authors note that the relative increase in the risk of heart failure outweighed a 5% fall in heart attacks. They also calculated that for around every 200 patients treated, there was one extra hospital admission for heart failure after an average follow-up of 4 years.

  • Practice Pearls:
  • Some glucose-lowering medications may increase the risk of heart failure in patients with or at risk for type 2 diabetes, with variations seen among different drug classes.
  • The heart failure risk was greatest in patients taking peroxisome proliferator-activated receptor agonists (PPARs), intermediate with dipeptidyl peptidase-4 (DPP-4) inhibitors, and neutral with insulin glargine.
  • Those with type 2 diabetes are at greater risk of heart failure no matter what drug they may be using.

Glucose-lowering drugs or strategies and cardiovascular outcomes in patients with or at risk for type 2 diabetes: a meta-analysis of randomised controlled trials, Jacob A Udell, et al., Lancet Diabetes Endocrinol., doi:10.1016/S2213-8587(15)00044-3, published online 16 March 2015, abstract. Presented at the 64th Annual Scientific Session of the American College of Cardiology in San Diego, CA.