GLP-1RAs Confer Multiple Health Benefits in Patients with Type 2 Diabetes

A new meta-analysis affirms improvements in cardiovascular, kidney and overall outcomes in patients given a GLP-1RA versus SGLT2i for management of type 2 diabetes. Even in those without established cardiovascular disease, significant benefits are achieved with glucagon-like peptide-1 receptor agonists.

With Soren Lund Kristensen, MD, PhD, Priyathama Vellanki, MD, and Mikhail Kosiborod, MD

In a meta-analysis analyzing data from seven trials and involving 56,004 participants, the researchers evaluated the efficacy of glucagon-like peptide-1 receptor agonists (GLP-1RA) in patients with type 2 diabetes (T2D) in terms of cardiovascular events, overall mortality and kidney outcomes.1

The results shed light on the beneficial role that GLP-1 RAs may confer in primary prevention following analysis of patients (n=12,983) who did not have established cardiovascular disease but exhibited other risk factors; the researchers also found some benefit in these individuals, although it was not as strong.1

Data amassed on GLP-RA trials show significant positive outcomes for T2D.

Data Review Supports Cardiovascular, Renal, and Overall Mortality Benefits of GLP-1RAs

"We see a convincing and quite consistent reduction of major adverse cardiovascular events (MACE) in the active treatment arms across the GLP-1 RA trials. Additionally, this benefit extends to a reduction in all-cause mortality," said study co-author Soren Lund Kristensen, MD, PhD, a cardiology fellow at Copenhagen University Hospital in Denmark.

An important finding, he told EndocrineWeb, is that most of the trials included patients with type 2 diabetes and established cardiovascular disease. "Due to a lower number of patients and events, the results for 'primary prevention' in patients with no prior cardiovascular disease was less convincing in the sense that the benefit of GLP-1 RA may be lower in this population."

The researchers searched Medline and the Cochrane Central Register of Controlled Trials up to June 15, 2019, looking for placebo-controlled studies that reported MACE outcomes in patients taking a GLP-1R. Using a random-effects model, they estimated overall hazard ratios for MACE, component outcomes, mortality from any cause, hospital admissions for heart failure, kidney outcomes and key safety outcomes (including severe hypoglycemia, pancreatitis and pancreatic cancer).1

The drugs and key trials included in this meta-analysis are:

  • Lixisenatide (ELIXA)
  • Liraglutide (LEADER)
  • Semaglutide (SUSTAIN-6)
  • Exenatide (EXSCEL)
  • Albiglutide (HARMONY Outcomes)
  • Dulaglutide (REWIND)
  • Oral semaglutide (PIONEER 6)

Overall, this class of medications—GLP-1RAs—reduced MACE by 12% (HR .88, 95% CI, P = 0.0001) but there were no significant differences found across the subgroups examined. Death from cardiovascular causes were reduced by 12% (95% CI, P = 0.003). The hazard ration for fatal and non-fatal stroke was 0.84 (P = 0.0001) for MI, .91 (P = 0.043).1

The medication reduced all-cause mortality by 12% (p=0.001), hospital admission for heart failure by 9% (P = 0.0028). The researchers looked at a broad composite kidney outcome that included development of new-onset macroalbuminuria, decline in GFR or increase in creatinine, progression to end-state kidney disease or death from kidney causes. They found a 17% reduction (P < 0.0001), mainly due to a reduction in urinary albumin excretion.1

No increase in the risk of severe hypoglycemia, pancreatitis or pancreatic cancer was found,1 according to Dr. Kristensen.

Persuasive Support for GLP-1RAs in Primary Prevention  

"For me, the bottom line is—we see a convincing and quite consistent reduction of MACE in the active treatment arms across the GLP-1 RA trials and additionally this benefit extends to a reduction in all-cause mortality," Dr. Kristensen told EndocrineWeb.

In the paper, the researchers note that the duration of treatment effect differs substantially between the drugs studied, ''although effect duration does not reflect structural homology, with some GLP-1 Ras of each type" having a short half life and others long. The duration of drug action did not seem to modify the treatment effect, but there may be an interaction related to chemical structure, with potentially smaller effects on MACE with drugs based on exendin-4, the authors say. That question needs to be studied further, the researchers say; the ongoing AMPLITUDE-O trial may help answer that question.1

"Overall, the GLP-1RA class seems to reduce MACE," said Priyathama Vellanki, MD, assistant professor of medicine at Emory University after reviewing the paper for EndocrineWeb. "The result of this meta-analysis is consistent with the findings from the original studies, which is to be expected. There were two studies with exendin-4 based drugs (EXSCEL and ELIXA) that did not show a difference in MACE.”

“The overwhelming majority of the trials used analogs similar to GLP-1 RA rather than exendin-4 drugs, which could have influenced the improvement in MACE. Although this class of drugs was not a significant factor, the patient population in ELIXA was different in that they had had a recent coronary event. As the authors pointed out, a significant number of patients in the EXSCEL discontinued the drug," said Dr. Vellanki.

Another leading expert, Mikhail Kosiborod, MD, director of cardiometabolic research at St. Lukes MidAmerica Heart Institute and professor of medicine at the University of Missouri at Kansas City, described the review as "very useful because it essentially puts together the findings from previous trials in one neat package."

The findings highlight what he suggests should be a paradigm shift in the way experts think about treating patients with type 2 diabetes. "In the past, disease management has been about hemoglobin A1C levels and glycemic control," he told EndocrineWeb. "Now, we realize that in addition to glycemic control, the key objective, the goal of management, must be the prevention of diabetic complications."

Debate Continues: GLP-1RA or SGLT2i for T2D Complications  

Given the findings of this meta-analysis, might GLP-1Ras offer better overall outcomes for more patients with type 2 diabetes?

''This is a bit difficult to answer based on the examined trials, which were all testing GLP-1 RAs but we did find a benefit in terms of kidney function and a reduction in heart failure hospitalizations, which were previously only apparent for sodium-glucose co-transporter 2 inhibitors (SGLT2i)  ,” Dr. Kristensen told EndocrineWeb. “However, the risk reduction observed for kidney and heart failure outcomes in the current meta-analysis is not of the same magnitude as what has been found in the SGLT-2 trials. Whether the two drug classes could have additive effects remains to be seen as very few patients in the examined GLP-1RA trials were treated with SGLT-2s."

Dr. Vellanki, on the other hand, said: ''If heart failure predominates [in a patient], I would tend to use an SGLT-2i rather than a GLP-1RA," and I would also take into account compliance, tolerability and other factors. "Some patients are more likely to take an oral medication [SGLT2] versus injection although oral semaglutide is now a good option."

The decision of which antidiabetes medication to select is difficult because drawing comparisons between these two drug classes is complicated by the fact that they are not the same and their mechanisms differ. 

"In terms of deciding which drug for each patient, it's a nuanced discussion whereby the clinician must try to understand the patient’s preferences and what is most important to the patient." Any discussion must of course take into consideration individual risk factors for cardiovascular events, kidney disease, and other diabetes-related complications,” said Dr. Kosiborod.

What the meta-analysis shows, he added, is that the GLP-1 RAs have a favorable benefit-risk ratio. "This therapeutic class of agents represents an excellent treatment option for treating type 2 diabetes."

Trial Data of GLP-1RAs Reinforces Current Guidelines

"Our findings confirm the recommendations in the 2018 consensus report from the ADA and EASD recommending initiation of either GLP-1RA or SGLT-2 inhibitors in patients with type 2 diabetes and clinical cardiovascular diabetes," 2 said Dr. Kristensen.

"Approximately 70 to 80% of the patients included in this meta-analysis were already treated with metformin but you could wonder whether to go directly to GLP-1RA or SGLT-2i in patients with newly diagnosed type 2 diabetes and established cardiovascular disease," he said. Taken together, "I would say our findings strength the notion to initiate GLP-1RA treatment early on in patients with type 2 diabetes," Dr. Kristensen said.

"In fact, I already prescribe these medications based on cardiovascular risk,” Dr. Vellani said, adding: “The ADA 2019 guidelines suggest the addition of a GLP-1RA as a second agent if there is established CVD.3

Whether I will start relying on the findings from the ELIZA trial or EXSCEL study to achieve cardiovascular risk reduction is more up for consideration. However, I base my decision on affordability, ease of use, and compliance with metformin still always initiated as a first line agent." And she makes sure patients are optimized for cardiovascular risk by prescribing beta-blockers, statins, or ACE-I/ARBs, as needed.

Dr. Kristensen has no relevant disclosures. Dr. Vellanki has received consulting fees from Boehringer-Ingelheim. Dr. Kosiborod reports receiving fees from several companies, including Astra Zeneca, Janssen, Merck and GSK.

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