Practice Update: Diabetes

CARDIOVASCULAR COMPLICATIONS 18

Differential Effects of Dapagliflozin on Cardiovascular Risk Factors at Varying Degrees of Renal Function Clinical Journal of the American Society of Nephrology: CJASN

Take-home message • Dapagliflozin, a glucose-lowering drug, selectively inhibits SGLT2 and has been shown to decrease HbA1c, body weight, BP and urinary albumin-to-creatinine ratio. Previous studies suggest that HbA1c-lowering effects of dapagliflozin are attenu- ated with impaired renal function. The authors in this study investigated other cardiovascular risk factors at different eGFR levels. Data from 11 phase III clinical trials were pooled to assess the effect of 10 mg dapag- liflozin vs placebo over 24 weeks in patients with type 2 diabetes with different baseline eGFR. Effects of dapagliflozin on body weight, BP, and urinary albumin-to-creatinine ratio were similar and were not influ- enced by baseline eGFR. Adverse events occurred more frequently in the lowest eGFR subgroup in both dapagliflozin and placebo-treated patients. • The effect of dapagliflozin may be partly mediated via non-glucosuric dependent mechanisms. I n this paper, Petrykiv et al report that the SGLT2 inhibitor dapagliflozin causes similar reductions in body weight, blood pressure (BP), and albumin excretion, and an increase in hematocrit regardless of the degree of chronic kidney disease (CKD), based on eGFR levels of 45-60, 61-89, and >90 mL/min/1.73 m 2 , despite reductions in the efficacy of dapagliflozin in improving hemoglobin A1c as the GFR decreased. 1 These data were obtained from a pooled analysis of 11 phase III clinical trials. Similar results have been found in a prospective, placebo-controlled trial of patients with CKD with empagliflozin and with canagliflozin from a pooled analysis of 4 clinical trials of patients with CKD. 2,3 COMMENT By Mark E Molitch MD

Abstract BACKGROUND AND OBJECTIVE Sodium glucose cotransporter 2 inhibition with dapagliflozin decreases hemoglobin A1c (HbA1c), body weight, BP, and albuminu- ria (urinary albumin-to-creatinine ratio). Dapagliflozin also modestly increases hematocrit, likely related to osmotic diuresis/natriuresis. Prior studies sug- gest that the HbA1c-lowering effects of dapagliflozin attenuate at lower eGFR. However, effects on other cardiovascu- lar risk factors at different eGFR levels are incompletely understood.

albumin-to-creatinine ratio were larger in the low- est eGFR subgroup (P value interaction <0.001). Adverse events occurred more frequently in the lowest eGFR subgroup; this was true for both dapagliflozin- and placebo-treated patients. CONCLUSIONS The HbA1c-lowering effects of dapagliflozin decrease as renal function declines. However, dapagliflozin consistently decreases body weight, BP, and urinary albu- min-to-creatinine ratio regardless of eGFR. These effects in conjunction with the finding of similar effects on hematocrit, a proxy for vol- ume contraction, suggest that the effects of dapagliflozin are partly mediated via nongluco- suric-dependent mechanisms. Differential effects of dapagliflozin on cardi- ovascular risk factors at varying degrees of renal function. Clin J Am Soc Nephrol 2017 May 08;12(5)751-759, S Petrykiv, CD Sjöström, PJ Greasley, et al. long-term outcomes were very significantly improved, likely substantially due to these nonglycemic factors. 6,7 The results of the cardiovascular outcomes study for canagliflozin (CANVAS) will be presented at the American Diabetes Association annual meeting in San Diego in June 2017, and a similar study for dapagliflozin is still ongoing. So, what is the clinician to do with these drugs as the GFR falls? Clearly, these drugs are less effective from a glycemic control perspective when the eGFR is <60 mL/ min/1.73 m 2 . Dapagliflozin is not approved for use when the eGFR falls below this point, but empagliflozin and canagliflozin can be used down to an eGFR <45 mL/ min/1.73 m 2 , albeit the dose of canagliflozin www.practiceupdate.com/c/53788

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This pooled analysis of 11 phase 3 clinical tri- als assessed changes in HbA1c, body weight, BP, hematocrit, and urinary albumin-to-creati- nine ratio with placebo (n=2178) or dapagliflozin 10 mg (n=2226) over 24 weeks in patients with type 2 diabetes according to baseline eGFR (eGFR≥45 to <60 ml/min per 1.73 m(2), eGFR≥60 to <90 ml/min per 1.73 m(2), and eGFR≥90 ml/ min per 1.73 m(2)). RESULTS Compared with placebo, reductions in HbA1c with dapagliflozin were 0.6%, 0.5%, and 0.3%, respectively, for each consecu- tive lower eGFR subgroup (P value interaction <0.001). Effects of dapagliflozin on hematocrit, body weight, and BP were similar regardless of baseline eGFR, suggesting that effects poten- tially related to volume and natriuresis are eGFR independent. Moreover, among individuals with baseline urinary albumin-to-creatinine ratio ≥30 mg/g, placebo-adjusted reductions in urinary Prospective, randomized trials of patients with CKD treated with canagliflozin and dapagliflozin are ongoing. If these results do not parallel the changes in glucose levels, what is causing them? We diabetologists tend to forget the first letter of SGLT2; the “S” stands for sodium. In addition to glucose, these drugs also block sodium reabsorption in the proximal tubule. This results in a greater delivery of sodium to the macula densa, which increases tubuloglomerular feedback, resulting in reduced intraglomerular pressure. 4,5 The increased urinary sodium loss and volume contraction also lead to the BP and weight reduction. 4 In the EMPA- REG study, both cardiovascular and renal

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