Cardiologists and SGLT2 Inhibitors
The “Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction” trial (1) randomized 4,744 patients with New York Heart Association class II, III or IV symptoms to dapagliflozin 10 mg daily or placebo. Dapagliflozin is a Sodium GLucose Transporter type 2 (SGLT2) inhibitor so it reduces renal reabsorption of both sodium and glucose. This gives these drugs both diuretic and glucose-losing properties. The combined endpoint of worsening heart failure (HF) (defined as requiring outpatient IV therapy or admission and cardiovascular [CV)] death) was reduced 26% (95% confidence limits [CI]: -15 to -35%) over a median follow-up of 18.2 months.(1) Death from any cause was also reduced 17% (CI -3 to -29%). Dapagliflozin was equally effective in reducing worsening HF and CV death in the patients with and without type 2 diabetes (T2DM). Interestingly, 93% of the subjects were already treated with a loop diuretic and 71% were already treated with a mineralocorticoid receptor antagonist. This Is important because a trial of empaglifloxin reduced CV deaths in T2DM patients without HF (2), but it was not known if an SGLT2 inhibitor would reduce death in HF patients on diuretics. Another SGLT2 inhibitor, canagliflozin, has been shown to reduce the combined endpoint of death from renal or CV disease and the development of end-stage renal disease in patients with albuminuric chronic kidney disease and GFRs >30 ml/min/1.73 m2. (3)
What’s not to love about SGLT2 inhibitors? They reduce glucose, body weight, blood pressure, HF events, renal progression, and death in selected patient groups. But many cardiologists are reluctant to treat diabetes with SGLT2 inhibitors for various reasons including the fear of stepping on the toes of referring clinicians. Larry Bird was a great basketball player because he wanted the ball. If the appropriate cardiac patients are not on these and other life saving drugs then cardiologists need to “want the ball”. Treatment with SGLT2 is simple. The starting dose for both empaglifloxin and dapagliflozin is10 mg. The starting does for canagliflozin is 100 mg (as in “you can use a higher dose-agliflozin”). You cannot produce hypoglycemia if the patient is not on insulin or a sulfonylurea because patients cannot excrete excess glucose if there is no excess glucose. The drugs are not recommended with GRFs <45, not because of drug buildup and toxicity, but because they are ineffective at reducing glucose absorption if there is too little flow to the kidney.
The only real concerns with these agents are dehydration (so diuretics in some patients may need to be decreased) and Fournier’s gangrene, which is a life-threatening infection of the perineal area. Genital infections were observed in 6.5% of patients with empaglifoxin3, but was not mentioned in the dapagliflozin study. I warn patients to be extremely meticulous with cleanliness of the perineal area, especially if they have any urinary incontinence.
There is already a push for cardiologist to get more involved in diabetes management because diabetes is a vascular disease. These studies of dapa-, empa-, and cana- gliflozin will only add to that impetus.
1. McMurray JJ, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995–2008.
2. 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. https://doi.org/10.1056/NEJMoa1504720. doi: 10.1056/NEJMoa1504720.
3. 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.
I have lectured for Boehringer Ingelheim, the company that makes empaglifloxin.
