Author + information
- Published online September 24, 2018.
- aDepartment of Medicine, Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina
- bDuke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina
- ↵∗Address for correspondence:
Dr. Adam D. DeVore, Duke Clinical Research Institute, 2400 Pratt Street, NP-8064, Durham, North Carolina 27705.
- dipeptidyl peptidase-4 inhibitor
- glucagon-like peptide-1 agonist
- heart failure
- sodium glucose co-transporter-2 inhibitor
- type 2 diabetes
The overlapping epidemics of heart failure (HF) and diabetes require the attention and best efforts of the HF community. We urgently need to change the trajectory of these major public health issues. The burden of both conditions is increasing over time. By 2030, more than 8 million people in the United States (1 in every 33 persons) will have HF, with total estimated costs of more than $53 billion per year (1). The problem with diabetes is even worse. More than 9% of the U.S. population currently has diabetes, with associated total annual costs of $327 billion (2,3). If current trends continue, an estimated 21% of the U.S. adult population will have diabetes by 2050 (4). In addition, patients affected with both HF and diabetes have worse functional class, symptoms, and outcomes, including all-cause mortality, than patients with HF without diabetes (5).
Many of us treat patients affected by both conditions, and the encouraging news is that emerging data suggest promising treatments. For example, sodium glucose co-transporter (SGLT)-2 inhibitors are associated with a lower risk of major cardiovascular events, including HF hospitalization, in cardiovascular outcome trials of patients with type 2 diabetes and established atherosclerotic complications (6). Glucagon-like peptide (GLP)-1 receptor agonists administered to similar patients also reduce the risk of major adverse cardiovascular events without increasing HF risk (6).
What cannot be lost in this conversation, however, is the importance of HF prevention. Current HF guidelines make specific recommendations for the prevention of HF in patients at increased risk for cardiovascular disease, including an optimal blood pressure target (7). In contrast, there are limited recommendations for the prevention of HF in patients with diabetes, beyond advocating for control of hyperglycemia and use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers when otherwise indicated.
In this issue of JACC: Heart Failure, Kramer et al. (8) provide an interesting comparison among GLP-1 receptor agonists, dipeptidyl peptidase (DPP)-4 inhibitors, and SGLT-2 inhibitors on the risk of HF in patients with type 2 diabetes (8). The investigators performed a systematic review and meta-analysis that included data from 9 placebo-controlled, randomized clinical trials. This well-done analysis of 33,457 patients identified several key findings. First, there was no association between reduction in hemoglobin A1C level and risk of HF hospitalization over time. Second, neither the use of GLP-1 receptor agonists nor DPP-4 inhibitors was associated with a reduction in HF hospitalization (relative risk [RR]: 0.94; 95% confidence interval [CI]: 0.84 to 1.04; and RR of 1.11; 95% CI: 0.95 to 1.3, respectively) compared with placebo. Third, the use of SGLT-2 inhibitors was associated with a notable reduction in HF hospitalization (RR: 0.56; 95% CI: 0.41 to 0.77) compared with placebo. These findings suggest that specific drug classes, rather than glycemic targets, should be the focus of HF prevention efforts.
These data for glycemic control are important to consider in the context of other studies. For example, data from the 20-year-old UKPDS (UK Prospective Diabetes Study) are worth reviewing. UKPDS was a clinical trial of patients who were diagnosed with type 2 diabetes, who were then randomized to a strategy of intensive blood glucose control or to conventional therapy. Patients with HF were excluded. Patients in the intensive blood glucose control arm received metformin, sulfonylureas, or insulin. A post hoc analysis of the main trial found that patients with lower blood glucose levels in both treatment arms had a lower risk of incident HF (9). A 1% reduction in hemoglobin A1C was associated with 16% reduction in the risk of HF (p = 0.021), although this was attenuated and was no longer significant after adjustment for treatment assignment. In contrast, there was no association with glycemic control and HF outcomes in other large trials of glycemic control including the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial, and the VADT (Veterans Affairs Diabetes Trial). How do we reconcile these differences? Importantly, the studies included here as well as the study by Kramer et al. (8) occurred during different time periods with different background therapy (including recognition of the importance of blood pressure control), different eligibility criteria, and different durations of follow-up. ACCORD, ADVANCE, and VADT included patients with longer duration of diabetes and assessed the impact of far more intensive glycemic targets than were tested in the UKPDS trial. It is possible that achievement of a reasonable degree of glycemic control early in the course of diabetes provides some protection against the development of HF over the long term. However, this advantage may be lost in patients with more established and complicated disease. In such patients, the selection of particular antihyperglycemic drug classes may be more important to reducing HF risk.
Resolving the question of whether specific drug classes or glycemic control for diabetic patients with stage A HF is important and the public health implications are profound. To our knowledge, there are no ongoing or planned trials designed to answer this issue, although these questions are ideal for a pragmatic clinical trial of strategies to prevent HF. Instead, we are likely to learn more about the role of SGLT-2 inhibitors in cardiovascular disease through observational data as these medications are adopted into practice, as well as ongoing clinical trials of SGLT-2 inhibitors as treatments for HF with reduced or preserved ejection fraction.
↵∗ Editorials published in JACC: Heart Failure reflect the views of the authors and do not necessarily represent the views of JACC: Heart Failure or the American College of Cardiology.
Dr. DeVore has received research support from Amgen, American Heart Association, National Heart, Lung, and Blood Institute, and Novartis; and has consulted for Novartis. Dr. Green has received research support from Boehringer Ingelheim, GlaxoSmithKline, Sanofi, and National Institute of Diabetes and Digestive and Kidney Diseases; and has consulted for Boehringer Ingelheim, AstraZeneca, and NovoNordisk.
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- ↵Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2017. Available at: https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf. Accessed July 26, 2018.
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