Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Caitlin Higgins, Mercer University College of Pharmacy

Victoza ® (liraglutide) is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes (T2DM). Liraglutide is injected subcutaneously once daily, independently of meals. The package insert states liraglutide should be initiated at 0.6 mg per day for one week, then increased to 1.2 to 1.8 mg. [1]

A review article of three large clinical trials addressed the cardiovascular (CV) outcomes when more intensive glycemic control is implemented in T2DM patients. All three trials studied middle-aged or older (mean age 60–68 years) participants with established T2DM (mean duration 8–11 years) and either known CV disease or multiple major CV disease risk factors. [2]

A meta-analysis of the three clinical trials suggests glucose lowering may have a modest but statistically significant reduction in major CV disease outcomes, primarily nonfatal myocardial infarction, but no significant effect on mortality. [3]

According to Current Atherosclerosis Reports, treatment advances in diabetes and improved glycemic control have been shown to improve microvascular outcomes. Studies have shown metformin and empagliflozin to affect macrovascular outcomes. The article states CV risk cannot be mitigated with glucose lowering alone as prevention of CV disease in patients with diabetes is primarily achieved with the use of medications that address other risk factors such as anti-hypertensives or statins. [4]

In a clinical study published by Atherosclerosis, metformin and liraglutide were shown to be cardioprotective by protecting human endothelial cells against high glucose-induced oxidative stress. [5]

A 2012 meta-analysis of 25 randomized controlled trials has shown statistically significant reductions in systolic blood pressure, diastolic blood pressure, and total cholesterol with GLP-1 agonists versus placebo. [6]

Title: Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes [7]
Design Multicenter (410 sites in 32 countries), double blind, placebo-controlled trial; N = 9340
Objective Assess the effect of treatment with liraglutide compared with placebo on the incidence of CV events in adults with T2DM that are at high risk for CV events
Study Groups Liraglutide plus standard of care (SOC) versus placebo plus SOC
Methods Patients with T2DM who were at high risk for CV disease participated in a two-week placebo run-in period, then were randomly assigned, in a 1:1 ratio, to receive liraglutide or placebo. The minimum planned follow-up was 42 months, with a maximum of 60 months of receiving the assigned regimen and an additional 30 days of follow-up afterward.
Duration Median duration of 3.8 years (ranges from 3.5 to 5 years)
Primary Outcome Measure First occurrence of death from CV causes, nonfatal myocardial infarction, or nonfatal stroke
Baseline Characteristics Baseline Characteristic Liraglutide

(N = 4,668)

Placebo

(N = 4,672)

Male sex, n (%) 3011 (64.5) 2992 (64.0)
Age, years 64.2 +/- 7.2 64.4 +/- 7.2
Diabetes duration, years 12.8 +/- 8.0 12.9 +/- 8.1
Glycated hemoglobin, % 8.7 +/- 1.6 8.7 +/- 1.5
Body mass index (BMI), kg/m2 32.5 +/- 6.3 32.5 +/- 6.3
Body weight, kg 91.9 +/- 21.2 91.6 +/- 20.8
Systolic blood pressure, mmHg 135.9 +/- 17.8 135.9 +/- 17.7
Diastolic blood pressure, mmHg 77.2 +/- 10.3 77.0 +/- 10.1
Heart failure, n (%) 835 (17.9) 832 (178)
Established CV disease (age >50, prior myocardial infarction, stroke, transient ischemic attack, revascularization, stenosis) 3831 (82.1) 3767 (80.6)
CVD risk factors (age >60, microalbuminuria, proteinuria, hypertension and left ventricular hypertrophy, left ventricular dysfunction, ankle-brachial index <0.9) 837 (17.9) 905 (19.4)
Results Endpoint Superiority

P-value

Liraglutide, n (%)

 

Placebo, n (%)

 

Primary Outcome 0.01 608 (13) 694 (14.9)
Death from any cause 0.02 381 (8.2) 447 (9.6)
Death from CV causes 0.007 219 (4.7) 278 (6.0)
Death from non-CV causes

 

0.66 162 (3.5) 169 (3.6)
Nonfatal myocardial infarction 0.11 281 (6.0) 317 (6.8)
Nonfatal stroke 0.30 159 (3.4) 177 (3.8)
Microvascular event including retinopathy and nephropathy 0.02 355 (7.6) 416 (8.9)
Adverse Events Liraglutide,

n (%)

Placebo,

n (%)

Common Adverse Events

Hypoglycemia 2039 (43.7) 2130 (45.6)
Pancreatitis or neoplasm 495 (10.6) 455 (9.7)

Serious Adverse Events

Diabetic foot ulcer 181 (3.9) 198 (4.2)
Cholelithiasis 145 (3.1) 90 (1.9)
Severe hypoglycemia 114 (2.4) 153 (3.3)
Hypothyroidism 44 (0.9) 33 (0.7)
Allergic reaction 59 (1.3) 44 (0.9)
Injection-site reaction 32 (0.7) 12 (0.3)

Percentage that Discontinued due to Adverse Events

Gastrointestinal events: nausea, vomiting, diarrhea, increased lipase level, decreased appetite, and abdominal pain and discomfort 182 (3.9) 41 (0.9)
Study Author Conclusions In the time-to-event analysis, the rate of the first occurrence of death from CV causes, nonfatal myocardial infarction, or nonfatal stroke among patients with T2DM was lower with liraglutide than with placebo.

Previous studies in a similar population of patients have shown intensive glycemic control to significantly reduce microvascular events (nephropathy and retinopathy) and major adverse CV disease events (myocardial infarction, stroke, and CV disease death).

In patients who were taking standard therapy in the current study, those in the liraglutide group were less likely to experience the primary outcome, death from CV causes, death from any cause, and microvascular events than those in the placebo group.

Current diabetes guidelines place metformin as a first line therapy as it can lower glycated hemoglobin (A1C) values by 1% to 1.5% and may cause weight loss. Other oral anti-diabetic (OAD) medications are used in combination with metformin as dual or triple therapy. However, in the LEAD trials, liraglutide in particular has reduced A1C values by 1.5% in individuals with T2DM, when used as monotherapy or in combination with one or more selected OAD drugs. [8, 9]

Thus, the previous studies align with the current study results in that GLP-1 agonists, such as liraglutide, should be considered as a preferred second-line therapy in T2DM patients who are at a high risk for CV disease.

References:

  1. Liraglutide [package insert]. Plainsboro, NJ: Novo Nordisk, Inc; 2015.
  2. Fox CS, Golden SH, Anderson C, et al. Update on Prevention of Cardiovascular Disease in Adults With Type 2 Diabetes Mellitus in Light of Recent Evidence: A Scientific Statement From the American Heart Association and the American Diabetes Association. Diabetes Care. 2015;38(9):1777-803.
  3. Boussageon R, Bejan-Angoulvant T, Saadatian-Elahi M, et al. Effect of intensive glu- cose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials. BMJ 2011;343:d4169
  4. Sarraju A, Kim SH, Knowles JW. Cardiometabolic Effects of Glucagon-Like Peptide-1 Agonists. Curr Atheroscler Rep. 2016;18(2):7.
  5. Batchuluun B, Inoguchi T, Sonoda N, et al. Metformin and liraglutide ameliorate high glucose-induced oxidative stress via inhibition of PKC-NAD(P)H oxidase pathway in human aortic endothelial cells. Atherosclerosis. 2014;232(1):156-64.
  6. Vilsboll T, Christensen M, Junker AE, Knop FK, Gluud LL. Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials. BMJ. 2012;344:d7771.
  7. Marso SP, Daniels GH, Brown-frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016; doi: 10.1056/NEJMoa1603827.
  8. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Diabetes Care 2012;35:1364-79.
  9. Garber AJ. Long-acting glucagon-like peptide 1 receptor agonists: a review of their efficacy and tolerability. Diabetes Care. 2011;34 Suppl 2:S279-84.
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