Treating Diabetes with GLP-1 Reduces Heart Disease, Fewer Foot Ulcers

With Deepak L. Bhatt, MD, MPH, and Elena Christofides, MD, FACE

Two analyses from the LEADER Trial show reduced risks of deaths and better outcomes in both heart health and diabetes-related foot ulcers and associated complications in patients with type 2 diabetes who are at increased risk for cardiovascular disease.

Liraglutide appears to reduce cardiovascular outcomes regardless of LDL levels.

GLP-1 Proves Effective in Lessening Risks of 2 Common Diabetes-Related Risks

Patients with type 2 diabetes who were at heightened risk of cardiovascular disease (CVD) and received liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1) saw a reduction in CVD events and cardiovascular death, as well as diabetes-related foot ulcerations and complications, 1,2 based on analyses of two studies from the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial.

Clinical guidelines for patients with type 2 diabetes strongly recommend aiming for target levels of lipoprotein cholesterol (LPL-C) less than or equal to 55 mg/DL for those deemed at highest risk, under 70 mg/dL for those deemed at very high risk, and under 100 mg/DL for those considered to have an increased risk.3

In this post hoc analysis of the LEADER trial,1 the researchers evaluated the efficacy of the drug on cardiovascular outcomes and mortality across the entire spectrum of the patients' baseline LDL-C level and statin use.

Bottom line: The improvements achieved in cardiovascular outcomes and mortality were consistent with those seen in other studies of patients with type 2 diabetes at high CVD risk, and the favorable results were independent of LDL-C levels and evident even at very low LDL-C at baseline and with concomitant statin use.1,2

Cardiovascular Benefits of Liraglutide Presented

"The benefits of GLP-1 agonists appear to be occurring through a pathway that is independent of cholesterol-lowering medications," said Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI, FESC, a study co-author and professor of medicine at Harvard Medical School in Boston, Massachusetts. The research was presented at the European Cardiology Society in Munich, Germany, and simultaneously published in Circulation.1

"If someone with diabetes and cardiovascular disease is on a statin and their cholesterol is well-controlled, they may still gain added benefit from a GLP1 agonist," Dr. Bhatt, who is also Executive Director of the interventional cardiovascular programs at Brigham and Women's Hospital in Boston, told EndocrineWeb.

Liraglutide demonstrated a consistent reduction in MACE across all three LDL-C treatment groups. Baseline-adjusted hazard ratios were 0.72 (95% CI, 0.49–1.06), 0.82 (95% CI, 0.65–1.04), and 0.90 (95% CI, 0.79–1.03), respectively (Pinteraction = 0.51).1

In a separate report from the LEADER investigation,2 researchers found that treatment with liraglutide in those with type 2 diabetes and at high risk of CVD events did not experience an increased risk of diabetes-related foot ulcers.2

The investigators also found that those taking liraglutide were less likely to need amputation due to diabetes-related foot diseases, but the reason for this remained unclear. The results were not sufficient to determine if this finding was due to chance,2 according to findings published in Diabetes Care.

Improvements Appear Independent of LDL Cholesterol Levels

In all, 9,137 patients were followed for LDL-C.1 Participants’ baseline measures were:

  • 926 (10.1%) had LDL-C under 50 mg/dL
  • 2021 (22%) had LDL-C 50 to 70 mg/dL
  • 6240 (67.9%) had LDL-C > 70 mg/dL

At the start of the LEADER trial, 72% of participants were taking a statin, and another 10% had a statin added during the course of the study, with 9% in the drug group and 11% in the placebo group adding the drug.

Over the course of 3.8 years of follow-up, the researchers tracked primary outcomes as a three-point major adverse cardiovascular events (MACE) composite of CVD death, nonfatal myocardial infarct, and nonfatal stroke. Secondary outcomes were also monitored, including coronary revascularization, hospitalization for unstable angina, and hospitalization for heart failure.1

“When looking at the entire group of those on liraglutide versus placebo, including those with different levels of LDL-C, those in the liraglutide group had a 13% reduction in MACE,” said Dr. Bhatt. 

Higher baseline LDL-C was associated with a greater risk of CVD mortality. The crude proportion of those experiencing any of the primary outcomes (MACE) was:

  • 11.7% in the under L50 mg/dL group
  • 13.9% in the 50-70 mg/dL group
  • 14.2% in the over 70 mg/dL group

As LDL-C increased, so did the rate of CV mortality at 4.3%, 4.6% and 5.6% of the groups, respectively, (adjusted trend test, P = 0.030).1

Liraglutide May Also Reduce Risk of Foot Ulcers, Common Risk for Diabetics

Reviewing findings from the second report, LEADER Trial investigators also looked at the same 9,340 patients to assess the impact of liraglutide versus placebo in those with type 2 diabetes and at high risk of CV events on the incidence of diabetes-related foot ulcers and their sequelae.2

During the 3.8 year follow-up, similar proportions of patients reported at least one DFU episode in the liraglutide and placebo group (2.8% versus 4.1%), but that was not statistically significant (HR, 0.92, CI 0.75, 1.13, P = 0.41.)

Those in the liraglutide group had a reduction in amputations compared to the placebo group of about 35% (HR 0.65, 95% CI 0.45, 0.95, P = 0.03). The authors concede these results could be due to chance, so more research is needed.

Assessing Strategy of Adding Liraglutide to Diabetes Treatment Plan

"The drug is effective are reducing CV events in the setting of traditional risk factor management," said Elena Christofides, MD, FACE, who is Chief Operating Officer of Endocrinology Associates in Columbus, Ohio, reviewed the findings for EndocrineWeb, as she had no involvement in the LEADER study.

With regard to the LEADER sub-analysis, she said ''This publication was needed in order to discern what liraglutide brings to the CV story for the patient with diabetes in the setting of traditional risk factor modification and therapy."

"What the analysis is telling us is, it does not matter whether you have the patient at goal or lowered to a more aggressive goal, you are still going to see benefit from the liraglutide. No matter how aggressive you want to be with your [patient's] LDL, the liraglutide is still going to have added benefit because it is working independently."

She said that most clinicians were already aware of the benefit of liraglutide and the evidence to support prescribing GLP-1s to patients with T2D who were deemed at increased risk for CVD. However, some clinicians may be limited by formulary rules or patients insurance limits.

“Likewise, results of the foot ulcer analysis was not surprising,” Dr. Christofides told EndocrineWeb. When practitioners prescribe liraglutide and include an explanation about the reduced risk of amputation (as well as the caveat that this relationship needs to be studied further), it is typically very comforting to the patient, she said.

Of course, healthcare costs remain staggering, Dr. Christofides said, “but they are driven, in the case of diabetes patients, by the complications, not by the disease itself.” These two analyses suggest that liraglutide—by reducing complications of CVD and foot ulcers—may lead to significant healthcare savings, even if clinicians are not prescribing the least expensive drug.

The potential antiatherosclerotic effects of GLP-1 agonists appear to complement the lipid-lowering effects achieved with statin therapy.1

Just because the patients’ cholesterol levels may be well controlled, and as important as that is, there might be more to do to reduce CV risk, Dr. Bhatt says. Clinicians can gain substantial guidance from the detailed research letter, Dr. Bhatt says.

Funding for the LEADER trial was provided by Novo Nordisk which manufacturers Victoza.

Dr. Bhatt has no financial conflicts with regard to this study.  Dr.Christofides was not involved in the trial; she reported consulting fees from Novo Nordisk unrelated to this work.

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