SGLT-2 Inhibitors and GLP-1 Analogues: Why Cardiologists Should be Prescribing These Drugs
The old way of treating diabetes was, well, to treat the diabetes. But today we are lucky enough to have several drugs that not only treat diabetes, but can also help with common comorbidities, including cardiovascular and renal disease, as well as obesity. I’m talking about the SGLT-2 inhibitors and GLP-1 agonists.
Let’s start with the SGLT-2 inhibitors. A growing number of studies now find they favorably modulate renal endpoints, even in those with heart failure. Specifically, data from the CREDENCE trial with canagliflozin and the DAPA-CKD study with dapagliflozin suggest a powerful effect of this class of drugs in modulating renal and cardiac outcomes.
In the CREDENCE trial, 4,401 patients with type 2 diabetes and CKD were randomized to canagliflozin or placebo. The trial was stopped early after a planned interim analysis at a median follow-up of 2.62 years. The relative risk of the primary outcome (a composite of end-stage kidney disease, a doubling of the serum creatinine level, or death from renal or cardiovascular causes) was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1.000 patient-years, respectively. There was also a significantly lower relative risk of end-stage kidney disease in the canagliflozin group, as well as a lower risk of cardiovascular death, myocardial infarction, stroke, and hospitalization for heart failure.1
The DAPA-CKD study randomly assigned 4,304 patients with CKD with or without diabetes to dapagliflozin (10 mg once daily) or placebo. This trial, too, was halted early because of efficacy. Over a median of 2.4 years the primary outcome event (a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes) occurred in 9.2% in the dapagliflozin group and 14.5% in the placebo group. The benefits were statistically significantly regardless of diabetes status.2
The implications are particularly intriguing when looking at a meta-analysis of DAPA-HF and EMPEROR-Reduced. The latter study found that the SGLT-2 inhibitor empagliflozin had a 24% lower risk of the combined primary endpoint of death, hospitalization for heart failure, or an emergent/urgent heart failure visit requiring intravenous treatment.3
It also showed that the use of an SGLT-2 inhibitor reduced the risk of major kidney outcomes by 38%. Importantly, the benefit occurred across a range of CKD.
Overall, I believe that the natriuretic, cardioprotective, and nephroprotective effects of these agents are compelling reasons to initiate these medications in patients with CKD, many of whom have either incipient or manifest heart failure. However, the presence of CKD is not an indication to begin these agents.
Now let’s turn to the potential of the GLP-1 agonists. Studies find significant effectiveness for weight loss and reducing cardiovascular events.4,5 However, we still need to determine the most appropriate patients for use as a first-line therapy. Interestingly, studies demonstrate some heterogeneity in effects of these agents in reducing myocardial infarction and stroke. Although studies with some agents seem to reduce CV mortality, this is not consistent. While this may reflect baseline differences in trials, the question is if some of exendin-4 based regimens may be less effective than human GLP-1 analogs.4,5 Further, the presence or absence of prior cardiovascular disease seems to be a factor in some trials but not others.
What are your thoughts on the use of SGLT-2 agents in patients with CKD? Is there a GFR threshold at which you begin using? Do you think that the presence of CKD is a powerful arbitrator of benefits? Which patients would you start on a GLP-1 RA and which on an SGLT-2 inhibitor? Please leave a comment below.
1 Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019;380(24):2295-2306.
2 Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020;383(15):1436-1446.
3 Packer M, Anker SD, Butler J, et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020;383(15):1413-1424.
4 Husain M, Birkenfeld AL, Donsmark M, et al. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2019 Aug 29;381(9):841-851.
5 Honigberg MC, Chang LS, McGuire DK, et al. Use of Glucagon-Like Peptide-1 Receptor Agonists in Patients With Type 2 Diabetes and Cardiovascular Disease: A Review. JAMA Cardiol. 2020. Online ahead of print.
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