SGLT2 Inhibitors Work in Type 2 Diabetes Across Levels of CV Risk, Renal Function

Two sodium glucose co-transporter 2 (SGLT2) inhibitors have beneficial effects in patients with type 2 diabetes regardless of baseline CV risk or renal function, according to two studies presented recently at the American Diabetes Association Scientific Sessions in Orlando, FL.

A post hoc analysis of the CANVAS program showed that canagliflozin (Invokana; Janssen Pharmaceuticals) improved cardiovascular and renal outcomes in patients with and without chronic kidney disease (CKD), including those with estimated glomerular filtration rates (eGFRs) down to 30 mL/min/1.73 m², Dick de Zeeuw, MD, PhD (University of Groningen, the Netherlands), reported at the meeting.

And an analysis of the EMPA-REG OUTCOME trial demonstrated that empagliflozin (Jardiance; Boehringer Ingelheim/Eli Lilly) consistently reduced risks of MACE and cardiovascular and all-cause mortality in patients with a range of calculated cardiovascular risk levels at baseline, David Fitchett, MD (St. Michael’s Hospital, Toronto, Canada), reported.

What these studies are showing “is that, at least in the patient populations studied so far, these drugs are improving cardiovascular and renal outcomes, and they're doing it in broad patient populations defined by low, intermediate, and high risk for both cardiovascular and renal outcomes,” CANVAS investigator Kenneth Mahaffey, MD (Stanford Center for Clinical Research, CA), told TCTMD.

He added, however, that because these are subgroup analyses, further dedicated studies are needed to better define the risks and benefits of SGLT2 inhibition in specific patient groups.

Benefits of Canagliflozin Seen in CKD

The SGLT2 inhibitors have been shown to have positive effects on glycemic status, blood pressure, body weight, and proteinuria in patients with type 2 diabetes, with corresponding reductions in cardiovascular events and preservation of renal function.

Because their glycemic effects are dependent on kidney function, however, the agents are not indicated for use in patients with severe renal impairment, end-stage renal disease, or a requirement for dialysis. Specifically, canagliflozin and empagliflozin are not recommended when eGFR is below 45 mL/min/1.73 m², and dapagliflozin (Farxiga; AstraZeneca) and ertugliflozin (Steglatro; Merck Sharp & Dohme) are not recommended when eGFR is below 60 mL/min/1.73 m².

The analysis of the CANVAS trial—published simultaneously online in Circulation with Brendon Neuen, MBBS (George Institute for Global Health, Sydney, Australia), as lead author—aimed to assess canagliflozin’s effects in eGFR categories ranging from 30 to < 45 mL/min/1.73 m² up to ≥ 90 mL/min/1.73 m².

The CANVAS program randomized 10,142 patients with type 2 diabetes, a history of or high risk for CVD, and an eGFR of at least 30 mL/min/1.73 m² to one of two doses of canagliflozin or placebo. At baseline, 20.1% of patients had CKD (eGFR < 60 mL/min/1.73 m²); of those patients, 71.6% had a history of cardiovascular disease.

Canagliflozin significantly reduced glycated hemoglobin (HbA1c), systolic blood pressure, body weight, and albuminuria across levels of renal function, although the glycemic effects were diminished at lower eGFR levels.

The primary cardiovascular outcome of the trial was a composite of CV death, MI, or stroke. The reduction in that endpoint seen in the overall trial population (HR 0.86; 95% CI 0.75-0.97) did not differ across eGFR levels or by CKD status (P for heterogeneity = NS for both).

Looking at secondary outcomes, the effect of canagliflozin on CV death, MI, and hospitalization for heart failure individually did not vary by renal function. There appeared to be greater benefits in terms of reducing stroke, however, in patients with lower levels of kidney function (P for heterogeneity = 0.01).

Renal outcomes also were consistently improved by canagliflozin across eGFR levels, and safety mostly did not differ by renal function. The only exception was that the risk of hypoglycemia seemed to increase as eGFR declined, although the authors note that patients with worse kidney function were more likely to be taking insulin.

When asked whether the findings support expanding use of canagliflozin to patients with eGFRs as low as 30 mL/min/1.73 m², Mahaffey responded: “I think that obviously we always have to prescribe drugs based on the FDA labeling. . . . I think that these findings suggest that you could likely use it in patients with renal insufficiency down to 30.”

But, he added, that hypothesis is being tested in the ongoing CREDENCE trial, which is enrolling patients with established kidney disease and macroalbuminuria and treating them with canagliflozin or placebo. In their paper, the authors note that other dedicated trials of SGLT2 inhibition in CKD are being planned or ongoing, including EMPA-KIDNEY with empagliflozin and DAPA-CKD with dapagliflozin.

Empagliflozin and Baseline CV Risk

In a poster presentation, Fitchett reported an analysis of the EMPA-REG OUTCOME trial results across levels of baseline CV risk, as defined by the TIMI Risk Score for Secondary Prevention (TRS 2°P). All patients in the trial had vascular disease, but 12% were considered low risk, 40% intermediate risk, 30% high risk, and 18% highest risk.

When given on top of standard care, empagliflozin reduced risks of the following outcomes:

• MACE (primary outcome): HR 0.86; 95% CI 0.74-0.99
• CV death: HR 0.62; 95% CI 0.49-0.77
• All-cause death: HR 0.68; 95% CI 0.57-0.82
• Hospitalization for heart failure: HR 0.65; 95% CI 0.50-0.85

The main trial results published in 2015 show that the effects were similar in patients with or without a prior atherothrombotic event, and this new analysis demonstrates that the findings were also consistent across baseline CV risk strata.

“These findings suggest that treatment with empagliflozin could benefit patients with type 2 diabetes mellitus and CV disease irrespective of the CV risk factor burden,” Fitchett’s poster states.

Mahaffey explained that it’s not entirely clear how the SGLT2 inhibitors are improving cardiovascular outcomes, but noted that the drugs have diuretic effects, improve control of diabetes, lower blood pressure, and reduce body weight.

“We haven't been able to identify which of these potential mechanistic effects explain the cardiovascular outcomes, and it’s likely that cardiovascular outcomes, hard endpoints, are likely improved because of a multitude of these mechanistic signals that we're seeing,” he said.