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July 12, 2024
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Combined SGLT2 and GLP-1 therapy lowers risk for CVD, kidney disease in type 2 diabetes

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Key takeaways:

  • SGLT2 inhibitors cut the risk for adverse CV outcomes and CKD for adults with type 2 diabetes using a GLP-1.
  • Combined SGLT2 and GLP-1 therapy may provide additional benefits than either medication alone.
Perspective from Ralph A. DeFronzo, MD

Combined SGLT2 inhibitor and GLP-1 receptor agonist therapy could provide additional cardiovascular and renal benefits for adults with type 2 diabetes, according to data from a meta-analysis published in The Lancet Diabetes & Endocrinology.

“These data represent the largest and most comprehensive evaluation of the effects of SGLT2 inhibitors on clinical outcomes with and without GLP-1 receptor agonists,” Brendon Neuen, MBBS, MSc, PhD, associate professor, nephrologist and director of kidney trials at Royal North Shore Hospital and senior research fellow at The George Institute for Global Health in Sydney, told Healio. “The results of our study provide strong support for the use of both medicines in combination to reduce CV and kidney disease in people with type 2 diabetes.”

Brendon Neuen, MBBS, MSc, PhD

Neuen and colleagues conducted a meta-analysis of 12 trials that were part of SMART-C, a collection of trials that assess the effects of SGLT2 inhibitors on a primary clinical outcome for adults. The meta-analysis only included trials exclusively enrolling people with diabetes. Researchers assessed two CV endpoints: major adverse CV events, which were a composite of nonfatal myocardial infarction, nonfatal stroke or CV death; and hospitalization for heart failure (HF) or CV death. Two kidney outcomes were assessed: a composite outcome for chronic kidney disease progression of a 40% or greater decline in estimated glomerular filtration rate, chronic dialysis, kidney transplantation or death from kidney failure; and the annual total and chronic rate of change in eGFR. Risk reduction was assessed for both adults using a GLP-1 receptor agonist and those not using a GLP-1 at baseline.

There were 73,238 adults with diabetes included in the meta-analysis, of which 4.2% were using a GLP-1 receptor agonist at baseline.

Risk reductions for CVD, CKD

Major adverse CV events occurred in 9.8% of adults. Participants using an SGLT2 inhibitor had a lower risk for a major adverse CV event than those not using an SGLT2 inhibitor (HR = 0.89; 95% CI, 0.85-0.94). The reduced risk was similar for adults using a GLP-1 at baseline (HR = 0.81; 95% CI, 0.63-1.03) and those not using a GLP-1 (HR = 0.9; 95% CI, 0.86-0.94).

Hospitalization for HF and CV death occurred in 8.5% of participants. Use of an SGLT2 inhibitor lowered the risk for HF hospitalization or CV death compared with adults receiving placebo (HR = 0.77; 95% CI, 0.74-0.81). SGLT2 inhibitors had a similar effect on risk reduction for hospitalization for HF and CV death for those using a GLP-1 (HR = 0.76; 95% CI, 0.57-1.01) and those not using a GLP-1 (HR = 0.78; 95% CI, 0.74-0.82).

Adults using an SGLT2 inhibitor had a lower risk for CKD progression compared with those receiving placebo (HR = 0.67; 95% CI, 0.62-0.72). The risk was similar for adults using an SGLT2 plus a GLP-1 at baseline (HR = 0.65; 95% CI, 0.46-0.94) and those using only an SGLT2 inhibitor (HR = 0.67; 95% CI, 0.62-0.72). SGLT2 use was also associated with a slower annual rate of decline in eGFR, regardless of GLP-1 use at baseline.

“The cardiovascular and kidney protective effects of SGLT2 inhibitors and GLP-1 receptor agonists are likely to be explained through distinct mechanistic pathways,” the researchers wrote. “Both classes of agents reduce cardiometabolic risk factors such as HbA1c, body weight, blood pressure and albuminuria, although the effects of GLP-1 receptor agonists on glycemia and body weight are substantially greater than those of SGLT2 inhibitors. However, these effects are unlikely to fully explain the magnitude of benefit observed on the clinical outcomes for either class.”

Adults using an SGLT2 inhibitor had a lower risk for all-cause mortality than those not using an SGLT2 (HR = 0.89; 95% CI, 0.84-0.93). The risk reduction with SGLT2 use similar for adults using a GLP-1 at baseline (HR = 0.82; 95% CI, 0.6-1.13) and those not using a GLP-1 (HR = 0.89; 95% CI, 0.84-0.94).

Rates of serious adverse events in the meta-analysis were lower with adults using an SGLT 2 compared with placebo. Safety outcomes were similar among adults using a GLP-1 at baseline and those not using a GLP-1.

Combined therapy ‘highly beneficial’

Neuens said the findings revealed the potential benefits of combined therapy with SGLT2 inhibitors and GLP-1 receptor agonists.

“The results are strengthened by the types of patients included in the analysis — those with type 2 diabetes at high CV risk, those with established HF, and those with kidney disease,” Neuen said. “Our findings should engender confidence that the combined use of both medicines is likely to be highly beneficial in broad types of patients with type 2 diabetes.”

Neuen said wider use of both classes of medications could help reduce the burden of CVD and kidney disease and present economic and health system benefits. He said future research should assess the economic impact of combined SGLT2 and GLP-1 therapy in different settings.

For more information:

Brendon Neuen, MBBS, MSc, PhD, can be reached at bneuen@georgeinstitute.org.au.