In the last 10 years, the study of medications for type 2 diabetes (T2D) has rapidly expanded its investigational footprint to evaluate cardiovascular (CV) effects, a shift driven largely by regulatory guidance that requires at least a demonstration of CV safety. Clinical investigators are also concerned with the effect diabetes medications have on atherosclerotic vascular outcomes as well as HF.
Working with Covance’s Dr. Jonathan Plehn in the webinar The Diabetic Heart: A Focus On Heart Failure, I recently provided a high-level overview of the clinical outcomes data examining the effect of antihyperglycemic therapies on heart failure (HF).
Only a handful of trials1 have analyzed more versus less-intensive glycemic control with regards to the effects on HF. In the ACCORD trial, there was a trend for increased risk with more intense glucose control (OR 1.23, 95% CI 0.97-1.57). In contrast, the UKPDS, ADVANCE and VADT trials suggested a favorable effect, although these results were not clinically relevant nor statistically significant. Meta-analysis of the totality of these data suggests there is essentially no effect, either positive or negative, on HF events with glycometabolic modulation using the older therapies available for T2D. Below, I review specific therapies in more detail.
Metformin: generally safe
Metformin appears to be quite safe in patients with HF, and possibly even beneficial. For example, epidemiologic observational data in a Medicare population discharged from hospital on metformin with a primary diagnosis of HF were associated with a 14% lower relative risk over one year compared with patients prescribed non-insulin sensitizers2. As a result, in the US, its boxed warning about a greater risk of lactic acidosis was removed under the direction of the FDA in 20062.
Thiazolidinediones: increased risk for HF
In contrast, the thiazolidinediones are statistically associated with increased risk for HF primarily based on post-marketing surveillance data but also on data from randomized trials with active comparators or placebo-controls3. For rosiglitazone, the parameter estimate is about 130 percent increased risk for HF events, whereas for pioglitazone it’s a more modest 30% increased risk. Both medications clearly increase the risk for HF, which is most likely attributable to renal sodium reclamation. There has been no clear signal for direct cardiac toxicity. Therefore, both rosiglitazone and pioglitazone continue to be contraindicated in HF patients.
Dipeptidyl Peptidase-4 (DPP-4) Inhibitors: results vary
Three large-scale, randomized CV outcomes trials evaluating DPP-4 inhibitors versus placebos showed a neutral effect on CV outcomes. In the SAVOR trial of saxagliptin4, which included over 16,000 patients with cardiovascular disease or cardiovascular risk factors, a 27% increased relative risk for incident HF with saxagliptin was observed. In the EXAMINE trial of alogliptin5 that included patients who had experienced acute coronary syndromes, there was a 19% increased risk for HF which was not statistically significant. However, and more importantly, in patients who entered EXAMINE without prior HF, there was a statistically significant 76% relative increased likelihood for incident HF with alogliptin. In contrast, the TECOS trial with sitagliptin failed to show increased HF risk with the study drug6. The FDA has concluded that saxagliptin and alogliptin may increase the risk for HF and their respective product labels include this warning. In contrast, both sitagliptin and linagliptin, the other DPP-4 inhibitor sold in the U.S., do not feature this product label warning. Instead their label suggests cautious use and monitoring of patients prescribed with these drugs who have risk factors for HF.
Glucagon-like Peptide (GLP)-1 Receptor Agonists
In the ELIXA trial, the once-daily injectable GLP-1 receptor agonist, lixisenatide, had no effect on HF risk when compared with placebo7. However, in the LEADER trial, with once-daily injectable liraglutide versus placebo, there was a significant 13% relative risk reduction for CV death, myocardial infarction and stroke (basic major adverse cardiac event [MACE] criteria) and no statistical differences in HF risk. Based on these data, the FDA has allowed a product-labeled indication for liraglutide for the prevention of CV death, myocardial infarction and stroke for patient with T2D who have atherosclerotic vascular disease or associated risk factors. However, in a dedicated trial of 300 patients with HF with reduced ejection fraction (HFrEF), patients assigned to liraglutide tended to have a greater likelihood of HF hospitalization readmissions than standard-of-care plus placebo-assigned patients. This result barely missed being statistically significant (possibly due to the relatively small number of patients included in the study) and at this time caution should be exercised with regard to the use of GLP-1 receptor agonists in patients with advanced HFrEF.
Finally, the SUSTAIN-6 trial involved another promising drug, semaglutide, a once-weekly injectable, GLP-1 receptor agonist8. In this study, semaglutide affected a 26% relative risk reduction of MACE events. There was no statistical difference for HF hospitalizations with a point estimate towards 11% increased risk based on only 90 HF events captured.
Sodium-glucose Co-transporter 2 (SGLT2) Inhibitors: new hope in diabetic HF
In the landmark EMPA-REG OUTCOME trial of over 7,000 patients with atherosclerotic vascular disease randomly assigned to one of two different doses of the SGLT2 inhibitor, empagliflozin, or a placebo, empagliflozin at both doses had a statistically significant, 14% reduction in MACE events as well as a 38% reduction in CV and 32% reduction in all-cause mortality9. This is the best available evidence for CV risk reduction for a glycometabolic medication. Particularly remarkable was an unexpected beneficial effect on HF (not a pre-specified primary endpoint) – a statistically significant 35 % reduction in HF hospitalizations. This has generated considerable interest in the industry in the potential value of this drug class in both patients with and without diabetes who have HF.
More recently, the combined analysis of the CANVAS and CANVAS-R (renal) sister trials in which patients with high CV risk were randomized to canagliflozin or placebo, active drug assignment was associated with remarkably similar reductions in MACE events (14%) and HF hospitalizations-an exploratory endpoint (33% relative risk reduction) to EMPA-REG OUTCOME10. However, unlike EMPA-REG OUTCOME, in the canagliflozin trials there were no statistical improvements in all-cause mortality or CV death. Notably, the approximately doubling of risk for amputations detected in patients on active treatment has led to a boxed warning for this adverse event on top of prior warnings for acute renal injury and increased bone fractures. These associated side effects have not been observed with empagliflozin.
The question of whether or not the beneficial CV event rates observed with empagliflozin and canagliflozin are an SGLT2 inhibitor class effect is unresolved and data from ongoing CV outcomes trials of other SGLT2 inhibitors are pending. For now, empagliflozin is the drug of choice in this class and should be considered in patients with T2D at high CV risk in order to prevent or delay the onset of HF and prolong life. The ADA has endorsed empagliflozin for patients with longstanding diabetes with atherosclerotic vascular disease to prevent CV death, and the FDA has accepted a product label modification with empagliflozin also indicated for reduction of CV death.
Harmful effects of insulin?
When looking at insulin’s effect on HF risk, there are decades of epidemiologic evidence demonstrating independent associations between insulin use and HF risk. However, a randomized trial that evaluated insulin glargine versus usual care in a patient population primarily with T2D showed a trend toward 11% relative risk reduction with insulin glargine. While not statistically significant, this is reassuring with regards to the safety of glargine vis-à-vis HF incidence.
Anti-hyperglycemic therapies and strategies may influence the risk for HF. Some may increase the risk, such as hyper-intensification of glucose control, thiazolidinediones, saxagliptin and alogliptin. Those considered neutral or safe are glargine insulin, sitagliptin, lixisenatide, liraglutide and semaglutide. Finally, the apparent deleterious effects on HF risk of selected therapies such as saxagliptin and alogliptin appear to be independent of glycemic effects. Empagliflozin and canagliflozin reduce the risk for HF, and metformin also appears to reduce the mortality risk. Ongoing trials prospectively testing the effect of other SGLT2 inhibitors on HF events will determine whether the EMPA-REG and CANVAS results are repeatable and whether the apparent salutary benefits are a drug class effect.
Dr. Darren K. McGuire, MD, MHSc is Professor of Medicine at UT Southwestern Medical Center in Dallas, Texas in the Division of Cardiology, where he holds the Dallas Heart Ball Chair for Research on Heart Disease in Women and is a Distinguished Teaching Professor. Dr. McGuire is the Lead Physician of the Parkland Hospital and Health System Cardiology clinics. Dr. McGuire’s expertise is in large scale clinical trial design and execution, and drug registration/regulation, with a focus in the area of diabetes and cardiovascular disease. He presently has leadership roles for numerous international cardiovascular clinical outcomes trials, including T2DM, obesity, and lipid trials. Dr. McGuire is a previous member of the FDA Cardiovascular and Renal Drugs Advisory Committee and remains an FDA ad hoc consultant. He is Deputy Editor of Circulation and Senior Editor of Diabetes and Vascular Disease Research. Dr. McGuire has authored/co-authored over 240 peer-reviewed manuscripts, reviews, editorials and book chapters.
- Skyler, J. et al. “Intensive Glycemic Control and the Prevention of Cardiovascular Events: Implications of the ACCORD, ADVANCE, and VA Diabetes Trials: A Position Statement of the American Diabetes Association and a Scientific Statement of the American College of Cardiology Foundation and the American Heart Association.” Diabetes Care 2009: 187–192.
- Masoudi, FA., et al. “Thiazolidinediones, metformin, and outcomes in older patients with diabetes and heart failure: an observational study.” Circulation 2005; 111(5): 583-90.
- Lago, RM., et al. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet 2007; 9593: 1129-36.
- Scirica, BM., et al. Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus. N Engl J Med 2013; 369: 1317–1326.
- White, WB., et al. Alogliptin after Acute Coronary Syndrome in Patients with Type 2 Diabetes. N Engl J Med 2013; 369: 1327–1335.
- Green, JB., et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2015; 373:232–242.
- Pfeffer, MA., et al. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. N Engl J Med 2015; 373: 2247-2257.
- Marso, SP. et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2016; 375:1834-1844.
- Zinman, B., et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 2015; 373:2117-2128.
- Neal, B., et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med 2017; DOI: 10.1056/NEJMoa1611925