SGLT2 Inhibitors and Cardiorenal Outcomes

Our top area to watch for 2019 is the advent of sodium glucose cotransporter 2 (SGLT2) inhibitors, oral anti-hyperglycemic agents that have been recently approved for the treatment of type 2 diabetes mellitus (T2DM).

Aside from their glucose-lowering effect, SGLT2 inhibitors have also been shown to reduce blood pressure, body weight, and albuminuria. These multiple beneficial metabolic effects have contributed, at least in part, to reductions in cardiovascular and renal outcomes observed in large cardiovascular outcome trials. As a result, the American Diabetes Association’s 2019 Standards of Medical Care in Diabetes (1) now recommends SGLT2 inhibitors as second-line therapy after metformin in patients with T2DM and atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease (CKD).

These agents promote glycosuria by selectively inhibiting SGLT2 transporters, which are expressed in the proximal tubule and are responsible for more than 90% of filtered glucose reabsorption. In addition to this, SGLT2 inhibitors also augment urinary sodium excretion, which contributes to plasma volume contraction and alterations in intrarenal hemodynamics (discussed below).

SGLT2 inhibitors currently approved by the US Food and Drug administration include empagliflozin (Jardiance), canagliflozin (Invokana), dapagliflozin (Farxiga), and ertugliflozin (Steglatro). Combination formulations are also available: empagliflozin/metformin (Synjardy), canagliflozin/metformin (Invokamet), dapagliflozin/metformin (Xigduo XR), and ertugloflozin/metformin (Segluromet).

Several large randomized controlled trials have recently been published, demonstrating the cardiovascular and renal benefits of these new agents.

The first of these was the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Event Outcome Trial in Type 2 Diabetes Mellitus Patients) (2), reported in 2015 (Figure 1). EMPA-REG OUTCOME was a randomized double-blind placebo-controlled trial that included 7020 participants with T2DM and established cardiovascular disease. This trial demonstrated that empagliflozin reduced the risk of major adverse cardiovascular events in addition to standard of care, driven by a 38% relative risk reduction in cardiovascular death. Empagliflozin also reduced the risk of heart failure by 35% and the composite renal outcome of doubling of serum creatinine, ESKD, or renal death by 46%.

Figure 1.

The EMPA-REG OUTCOME trial

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The CANVAS (Canagliflozin Cardiovascular Assessment Study) Program (4) integrated data from two parallel randomized trials involving 10,142 participants with T2DM and high cardiovascular risk (Figure 2). The CANVAS program demonstrated that canagliflozin also reduced the risk of major adverse cardiovascular events, heart failure, and adverse renal outcomes but increased the risk of amputations, mainly at the toe/metatarsal level.

Figure 2.

The CANVAS clinical trial program

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In November 2018, The DECLARE-TIMI 58 trial was published. This trial enrolled 17,160 participants with T2DM, two-thirds of whom did not have prior cardiovascular disease (i.e., a majority primary prevention cohort). While dapagliflozin did not reduce the risk of major adverse cardiovascular events, it did reduce the risk of hospitalization for heart failure and the renal composite outcome (40% decrease in eGFR, ESKD, or renal death), without any major safety concerns.

A characteristic feature of SGLT2 inhibitors is that their glycemic efficacy is dependent on glomerular filtration, and thus their effect on HbA1c diminishes with declining kidney function. In contrast, effects on blood pressure and albuminuria appear to be preserved in people with reduced kidney function, and secondary analyses of the EMPA-REG OUTCOME trial (4) and the CANVAS Program (5) suggest that the cardiovascular and renal benefits are similar regardless of baseline kidney function down to eGFR 30 mL/min per 1.73 m2 (Figure 3).

Figure 3.

Cardiovascular and renal outcomes with canagliflozin

A frequently cited explanation for the renoprotective effect of SGLT2 inhibitors is that they reduce intraglomerular pressure, which is critical in the pathogenesis of diabetic kidney disease. These agents increase distal sodium delivery to the macula densa, which activates tubuloglomerular feedback to promote afferent arteriolar vasoconstriction, and thus reduce intraglomerular pressure. This is reflected in an acute “dip” in eGFR, similar to that seen with inhibition of the renin-angiotensin-aldosterone system (RAAS). Importantly, approximately 80% of participants in these SGLT2 inhibitor trials were also receiving RAAS inhibition, which suggests that the renoprotective effects of these two classes of medications are additive, without any additional risk of acute kidney injury. However, participants with eGFR <30 mL/min per 1.73 m2 were excluded from these trials, so the effects in this population are still unknown.

In July 2018, the CREDENCE (Canagliflozin and Renal Endpoint in Diabetes with Established Nephropathy Clinical Evaluation) trial was prematurely terminated because prespecified efficacy criteria had been achieved at a scheduled interim analysis (6). CREDENCE is a randomized double-blind placebo-controlled trial, which enrolled 4401 participants with stage 2 or 3 CKD and macroalbuminuria. Approximately 60% of these participants had an eGFR <60 mL/min per 1.73 m2 at enrollment, and all were required to be on a maximally tolerated dose of ACE inhibitor or ARB for at least 4 weeks prior to randomization. The results of this study will be presented on April 15, 2019, as a late-breaking clinical trial session at the World Congress of Nephrology in Melbourne, Australia.

Other dedicated CKD outcome trials that are forthcoming include EMPA-KIDNEY (7) and DAPA-CKD (8). Given the putative mechanism for renoprotection, both trials are enrolling participants with and without T2DM, and will thus provide important data on the effects of SGLT2 inhibition for cardiorenal protection in both populations.

February 2019 (Vol. 11, Number 2)