Although reducing cardiovascular (CV) risk is a goal of treatment for type 2 diabetes, glucose-lowering medications can actually increase the risk of numerous CV events even while reducing glycated hemoglobin (HbA1c) levels. For large-scale antidiabetic drug trials conducted in the past decade, the US Food and Drug Administration (FDA) has required evidence that these agents do not lead to an unacceptable increase in CV risk.1
According to research published online in Diabetes, Obesity and Metabolism in January 2018, this requirement may have since fostered a false sense of safety regarding these medications.2 “Once new antidiabetic medications were approved with this regulatory reassurance, it was easy for physicians to think that they did not need to worry whether the use of a novel drug carried with it the risk of causing a major cardiovascular complication,” the authors wrote.
“The current complacency among clinicians, however, stems from an idiosyncrasy in the design of the large-scale outcomes trials in diabetes,” they noted. The narrowly defined primary end point used in these studies does not adequately capture the range of clinically important CV events that may occur in patients taking antihyperglycemic drugs. Typically, only 3 outcomes – CV death, nonfatal myocardial infarction, and nonfatal stroke – are included in the composite measure known as major adverse cardiovascular events (MACE).
Even when a drug shows favorable MACE results, it could still increase the risk of other CV events. For example, although long-acting glucagon-like peptide-1 (GLP-1) analogues have been shown to reduce the risk of all 3 MACE outcomes, they “also appear to exert deleterious effects on the clinical course of patients with established heart failure,” as stated in the January paper.3,4 Liraglutide was shown to increase the risk of hospitalization due to heart failure and serious adverse CV events, “possibly because it exerts cardiotoxic effects by virtue of their action to increase cyclic AMP in the myocardium,” the authors wrote.5,6
Dipeptidyl peptidase-4 (DPP-4) inhibitors also increase myocardial cyclic AMP, and regulatory labels indicate that saxagliptin and alogliptin may increase the risk of new-onset heart failure in patients with type 2 diabetes.7 Other potential CV complications of antidiabetic drugs include worsening of peripheral vascular disease, fatal cardiac arrhythmias, and worsening renal function.
The current emphasis on the primary end point of trials may have “inadvertently encouraged practitioners to be sanguine about the cardiovascular consequences of antihyperglycemic drugs,” the authors concluded. “If so, the clinical community urgently needs to adopt a different conceptual framework that more accurately reflects the spectrum of disorders seen in diabetes and is more aligned with the interests of patients.”
For additional clinician insight, Endocrinology Advisor checked in with Kevin M. Pantalone, DO, staff endocrinologist and director of clinical research at the Cleveland Clinic, and Marilyn Tan, MD, endocrinologist and clinical assistant professor at Stanford University School of Medicine.
Endocrinology Advisor: What are your thoughts about the recent published research and about the topic in general?
Kevin M. Pantalone, DO: The article raises many interesting points. While the typical 3-point MACE primary outcome does fail to assess many other CV outcomes of interest, it does establish at least some idea of safety – a regulatory requirement that is not mandated for all drugs; rather, this is unique for glucose-lowering therapies. Thus, I feel that establishing some idea of safety is important, which we are doing using the current CVOT [cardiovascular outcome trial] format, and that we can simply continue to use postapproval reporting of adverse outcomes as a way of monitoring adverse risk on a continual basis.
In addition, a CV outcome of interest does not need to be included within the primary outcome in order to be evaluated. While hospitalization for heart failure was not the primary outcome of the CVOTs with the SGLT2 [sodium-glucose cotransporter-2] inhibitors empagliflozin and canagliflozin, we still observed the signal that a reduction in the number of these events was occurring. Likewise, we still observed the renal protective effects in the SGLT2 inhibitor and GLP-1 RA [receptor agonist] CVOTs, even though it was not the primary outcome of interest. Both of these observations have led to additional studies to further evaluate these findings.
Also, it would be too expensive and cumbersome to power a study for 9 or 10 individual primary outcomes.
Marilyn Tan, MD: The newer diabetes agents – DPP-4 inhibitors, SGLT2 inhibitors, and GLP-1 RAs – have essentially no risk of hypoglycemia as independent agents due to their mechanisms, which is one key difference from insulin and the older sulfonylureas. Prior studies (ACCORD, VADT) have shown increased risk of death from hypoglycemia associated with overly tight control.
In addition, while insulin and sulfonylureas can promote weight gain, the newer agents tend to be weight neutral or can even help with weight loss, particularly with certain GLP-1 RAs. Even without the CV outcome benefits shown by EMPA REG (empagliflozin) and LEADER (liraglutide), these are reasons one might choose a newer agent over a more traditional diabetes medication.3,8 However, the new medications do come at a much higher cost.
The CV outcome data do somewhat change my approach. In the past, I always told patients that if they can lower their HbA1c with lifestyle changes, this was better than medication, as seen in the DPP [Diabetes Prevention Program]. Of course, lifestyle changes are still paramount, not only for diabetes management but also for management of other comorbidities that affect CV risk, such as obesity, hypertension, hyperlipidemia, and sleep apnea. Now that there seem to be additional CV protective effects with newer medications, it calls into question whether lifestyle changes alone are truly best for reducing CV risk. Does this lower our threshold to start diabetes medications for patients?
Endocrinology Advisor: What are the top takeaways regarding this topic?
Dr Pantalone: There are certainly additional adverse CV outcomes that could be considered, but it is not practical – or possible – to power a study to assess every potential outcome of interest.
Dr Tan: It is exciting that medications for HbA1c/glucose lowering are now having additional benefits, and the mechanism seems to be independent of HbA1c lowering. What’s interesting is that the CV benefits seem not to be a class effect per se, but seem to be varied based on the actual drug. That said, it’s hard to compare trials to each other since they all have slightly different inclusion criteria, and there are so many variables in these large trials that cannot be fully accounted for.
Though the CV outcomes are exciting, it’s important to note other less-beneficial outcomes, as the author points out. While there are now FDA indications for some of the newer agents (liraglutide, empagliflozin), there are also black box warnings for the newer agents. Aside from that, people often don’t cite the adverse outcomes noted in the studies since the focus is on the primary end point of CV outcomes – for example, the increased retinal events with semaglutide, increased amputations with canagliflozin, or acute kidney injury with SGLT2 inhibitors, as the author noted.
Endocrinology Advisor: What should be the focus of future research in this area?
Dr Pantalone: I think one issue that is beyond this article and that needs to be considered is whether continuing to use the current format of comparing a drug to placebo for CV safety is still appropriate. It would seem unethical to continue to enroll patients into CVOTs and randomly assign patients to placebo when there are now drugs available that have established CV risk reduction.
Moving forward, perhaps the newer therapies should be compared to the medications that have already established CV risk reduction. This will certainly “raise the bar” for these newer therapies, but if they cannot demonstrate similar CV risk reduction in a head-to-head trial, then they should not be prescribed to patients with established CVD.
Dr Tan: We are awaiting CV outcome results for other available new agents: for example, dapagliflozin, albiglutide, and dulaglitide. In addition, though some of the studies have very encouraging short-term outcome data, we still don’t have as much data with these newer agents as we do with traditional agents such as metformin. We will need to continue gathering postmarketing outcomes.
Summary: Although many of the newer antidiabetic drugs have demonstrated favorable outcomes pertaining to the narrowly defined primary end point, they may still increase the risk of other CV outcomes. Thus, clinicians should not be falsely assured of the broad CV safety of these medications.
- Joffe HV, Parks MH, Temple R. Impact of cardiovascular outcomes on the development and approval of medications for the treatment of diabetes mellitus. Rev Endocr Metab Disord. 2010;11(1):21-30.
- Packer M. Have we really demonstrated the cardiovascular safety of anti-hyperglycaemic drugs? Rethinking the concepts of macrovascular and microvascular disease in type 2 diabetes [published online January 5, 2018]. Diabetes Obes Metab. doi:10.1111/dom.13207
- Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322.
- Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.N Engl J Med. 2016;375(19):1834-1844.
- Margulies KB, Hernandez AF, Redfield MM, et al. Effects of liraglutide on clinical stability among patients with advanced heart failure and reduced ejection fraction: a randomized clinical trial. JAMA. 2016;316(5):500-508.
- Jorsal A, Kistorp C, Holmager P, et al. Effect of liraglutide, a glucagon-like peptide-1 analogue, on left ventricular function in stable chronic heart failure patients with and without diabetes (LIVE)-a multicentre, double-blind, randomised, placebo-controlled trial. Eur J Heart Fail. 2017;19(1):69-77.
- US Food and Drug Administration. FDA Drug Safety Communication: FDA adds warnings about heart failure risk to labels of type 2 diabetes medicines containing saxagliptin and alogliptin. https://www.fda.gov/downloads/Drugs/DrugSafety/UCM493965.pdf. April 5, 2016. Accessed February 21, 2018.
- Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128.