Author + information
- Nikolaus Marx, MD∗ ()
- Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Aachen, Germany
- ↵∗Address for correspondence:
Dr. Nikolaus Marx, University Hospital, RWTH Aachen, Pauwelsstrasse 22 Aachen, NRW 52074, Germany.
Sodium-glucose co-transporter 2 (SGLT2) inhibitors, such as empagliflozin, canagliflozin, and dapagliflozin, are novel antidiabetic drugs that exhibit their glucose-lowering properties by increasing urinary glucose excretion. SGLT2 inhibitors are used to treat patients with type 2 diabetes, and they can be combined with any other glucose-lowering agent. Inhibition of the SGLT2 receptor in the proximal tubule of the kidney leads to an increase in glucose excretion up to 80 to 100 g/day. In addition, SGLT2 inhibitors temporarily also increase excretion of sodium (1).
In the cardiology community, SGLT2 inhibition received a lot of attention after publication of the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) in 2015 (2). In this study, empagliflozin treatment of patients with type 2 diabetes and prevalent cardiovascular (CV) disease significantly reduced the primary endpoint of CV death, myocardial infarction, and stroke, as well as CV death and total mortality compared with placebo. In addition, and unexpectedly, empagliflozin significantly reduced hospitalization for heart failure, as well as heart failure–related CV death. In the recently published Integrated CANVAS (CANagliflozin cardioVascular Assessment Study) Program, canagliflozin also reduced the primary endpoint of CV death, myocardial infarction, and stroke compared with placebo in patients with type 2 diabetes and high CV risk, and the drug showed a similar effect on heart failure hospitalization rates (3).
Many potential mechanisms have been discussed in the scientific community, but so far only limited data from clinical studies or experimental models exist to explain the somewhat unexpected outcomes in these clinical endpoint trials clearly. Potential modes of action could include early hemodynamic changes, a reduction of whole-body sodium content and/or blood pressure and weight, diuretic effects without a reflectory sympathetic activation, reduction in cardiac oxygen demand, and changes in cardiac energy metabolism (4,5). None of these mechanisms can probably solely explain the reduction in CV events in the EMPA-REG OUTCOME trial and in the Integrated CANVAS Program; unfortunately, so far, no large-scale data exist on cardiac imaging or CV biomarkers that could potentially provide more mechanistic insight. In this issue of the Journal, Januzzi et al. (6) provide intriguing data, in 666 patients with type 2 diabetes who were randomized to canagliflozin or placebo, by showing the effect of SGLT2 inhibitor treatment on various prognostic CV biomarkers (N-terminal pro–B-type natriuretic peptide [NT-proBNP], high-sensitivity troponin I [hsTnI], soluble ST2 [sST2], and galectin-3) over 2 years. Their study demonstrated that canagliflozin, compared with placebo, delayed the rise of serum NT-proBNP and hsTnI over 2 years, whereas no effect on serum sST2 was seen. In addition, with respect to galectin-3, these investigators found a modest increase from baseline with canagliflozin versus placebo, with a significant difference after 6 months and 1 year, but no difference after 2 years. These retrospective data from a large trial in patients with type 2 diabetes may help to shed some light on the mechanisms contributing to the beneficial CV effects of SGLT2 inhibitors. Because changes in biomarkers over time are thought to provide prognostic information (7), the results of the study by Januzzi et al. (6) suggest that SGLT2 inhibitors may prevent or delay the development of CV disease, particularly the development of heart failure.
What can we learn from these data with respect to the results of EMPA-REG OUTCOME and the Integrated CANVAS Program?
In EMPA-REG OUTCOME (2) hospitalization for heart failure was reduced in subjects both with and without a history of heart failure, findings suggesting that SGLT2 inhibitors may eventually prevent the development of heart failure in the high-risk population of patients with type 2 diabetes. As such, the biomarker results of Januzzi et al. (6) could fit this concept, thus confirming modulation of the “natural history” of heart failure development in diabetes. Nonetheless, the population in the trial reported Januzzi et al. (6) in this issue of the Journal is different because older patients with type 2 diabetes and a moderately increased CV risk were included (6). In contrast, in the EMPA-REG OUTCOME trial, all patients had prevalent cardiovascular disease (CVD), and in the Integrated CANVAS Program, patients were at high CV risk (around 65% with a history of CVD) (3). From other CV outcome trials (e.g., LEADER [Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results] with liraglutide) in patients with diabetes, we learned that the phenotype of patients with CVD and those at high risk without prevalent CVD may be important with respect to responsiveness to drug therapy. As such, the biomarker data shown here can only to a limited extent be extrapolated to the higher-risk populations in EMPA-REG OUTCOME and the Integrated CANVAS Program. In addition, the current study is lacking very early measurements of NT-proBNP and troponin. It would have been nice to see these data because they could have helped to explain the early separation of the curves for heart failure hospitalization in both CV outcome trials.
Taken together, Januzzi et al. (6) should be congratulated for providing large-scale biomarker data in patients with type 2 diabetes who were treated with SGLT2 inhibitors. These data may certainly pave the way for future research with a focus on the prevention of CVD and heart failure development in diabetes and, as such, stimulate further studies to explain more precisely the effects seen in the EMPA-REG OUTCOME and Integrated CANVAS Program CV outcome trials.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the author and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Marx has received support for clinical trial leadership from Boehringer Ingelheim; has served as a consultant to Boehringer Ingelheim, Sanofi, Merck Sharp & Dohme, Bristol-Myers Squibb, AstraZeneca, Eli Lilly, Novo Nordisk, and Bayer; has received grant support from Boehringer Ingelheim; and has served as a speaker for Boehringer Ingelheim Sanofi, Merck Sharp & Dohme, Bristol-Myers Squibb, AstraZeneca, Eli Lilly, Novo Nordisk, and Bayer.
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