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.
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.”
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.
Perspective
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Have we finally emerged from the dark ages? The EDICT study, employing diabetes medications (GLP-1 receptor agonist, pioglitazone, metformin) that correct the basic underlying pathophysiologic defects present in type 2 diabetes, convincingly demonstrated that combination therapy produces a greater and more durable reduction in HbA1c than the treat-to-fail approach using diabetes medications (sulfonylureas, metformin, insulin) that do not correct the basic metabolic and cellular defects (insulin resistance and beta-cell dysfunction) present in type 2 diabetes patients. Such combination therapy would, on a long-term basis, be expected to reduce microvascular complications.
A recent meta-analysis by Apperloo and colleagues provides evidence that addition of an SGLT2 inhibitor to a GLP-1 receptor agonist effectively reduces cardiovascular events and progression of chronic kidney disease in high-risk type 2 diabetes patients. In the meta-analysis, SGLT2 inhibitors significantly reduced major adverse cardiovascular events (MACE), hospitalization for heart failure (HF) plus CV death, and progression of CKD by 11%, 23% and 33%, respectively, compared to placebo. Similar benefit was observed in patients with diabetes treated with and without a GLP-1 receptor agonist.
In a large study involving 12,548 propensity matched type 2 diabetes patients from three U.S.-based insurance claims databases, addition of an SGLT2 inhibitor to background therapy with GLP-1 receptor agonist reduced the composite CV outcome by 24%, myocardial infraction by 29% and all-cause mortality by 32% (Dave CV, et al. Circulation. 2020;doi:10.1161/CIRCULATIONAHA.120.047965), consistent with the results of this study.
Based on these retrospective analyses, one could argue that all newly diagnosed, as well as established, type 2 diabetes patients should be started simultaneously, within a few weeks to months, on an SGLT2 inhibitor plus a GLP-1 receptor agonist. The present author is a strong advocate of this approach. From both the mechanistic and clinical standpoints, it is reasonable to expect that GLP-1s and SGLT2s would produce additive CV and renal protective effects. The CV benefits of the SGLT2 inhibitor on HF and CV death (primarily driven by HF) are observed with months and most likely are hemodynamically driven (simultaneous reduction in preload and afterload), while those of GLP-1s on MACE take 12 to 16 months to be seen and most likely are related to the drug’s antiatherogenic effects.
An important caveat is that the studies by Apperloo and colleagues and Dave and colleagues examined the addition of an SGLT2 to a GLP-1 receptor agonist and not the reverse. With regard to this, the recently published FLOW study (Perkovic V, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2403347) demonstrated that addition of semaglutide (Ozempic/Wegovy, Novo Nordisk) to an SGLT2 inhibitor showed no renal protective effect (HR = 1.07, 95% CI 0.69-1.67), although the number of subjects receiving an SGLT2 (16%) in this study was relatively small. There also was no benefit of semaglutide in North American patients with CKD; all of the renal protective effect of semaglutide was observed among South Asian and European patients, raising questions about ethnic-related differences in the drug’s renal protective effect. Further, while essentially all SGLT2 inhibitors have been shown to produce very similar effects on HF, progression of CKD, reduction in HbA1c and weight loss, there are major differences between the effect of different GLP-1 receptor agonists on all of these parameters.
On a more upbeat note are the results of DURATION 8 (Jabbour SA, et al. Diabetes Care. 2020;doi: 10.2337/dc19-1350), which examined the initiation of combination therapy with exenatide once-weekly (Bydureon, AstraZeneca) plus dapagliflozin (Farxiga, AstraZeneca) vs. dapagliflozin monotherapy and vs. exenatide monotherapy on HbA1c. The HbA1c decreased by 1.70%, 1.06% and 1.29% with exenatide/dapagliflozin, dapagliflozin and exenatide, respectively, clearly demonstrating an additive effect of combination therapy. Unfortunately, the sample size and follow up in DURATION 8 were too small to draw conclusions about CV outcomes.
In summary, it is time to emerge from the dark ages and to consider initiation of therapy in type 2 diabetes patients with a GLP-1 plus an SGLT2, starting with the GLP-1 receptor agonist as per Apperloo and colleagues and Dave and colleagues. It is likely that these two classes of diabetes agents will produce additive cardiorenal protective effects. Further, while SGLT2 inhibitors provide no protection against stroke, a benefit of the GLP-1 receptor agonist on this devastating outcome is well established. Additive benefits of combined GLP-1/SGLT2 therapy on other metabolic parameters, including HbA1c, weight loss and MASH, all can be expected. Let the light shine.
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