Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

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Marso SP, et al. "Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes". The New England Journal of Medicine. 2016. 375(18):1834-1844.
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Clinical Question

In patients with type 2 DM at high CV risk, is semaglutide non-inferior to placebo in terms of CV safety?

Bottom Line

In patients with type 2 DM at high CV risk, semaglutide is non-inferior to placebo in terms of CV safety.

Major Points

In patients with T2DM with increased risk of CV events, the EMPA-REG OUTCOME and LEADER showed that empagliflozin and liraglutide was associated with improved CV outcomes, respectively. Semaglutide is a glucagon-like peptide 1 (GLP-1) analogue in development with a half-life of approximately 7 days. The objective of the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6) is to assess the CV safety of semaglutide as compared to placebo in patients with T2DM.

The randomized, double-blind, placebo-controlled, noninferiority trial randomized 3297 patients to receive semaglutide (once-weekly, 0.5 mg or 1.0 mg) or placebo for 104 weeks. The primary outcome was the composite of CV mortality, nonfatal MI, or nonfatal stroke. The outcome was observed in 6.6% and 8.9% of the semaglutide and placebo groups, respectively (hazard ratio 0.74; 95%CI 0.58-0.95; P<0.001 for noninferiority). As compared to placebo, semaglutide was associated with more frequent gastrointestinal events. The trial also noted that the semaglutide group had a higher incidence of diabetic retinonpathy as compared to placebo (3 vs. 1.8%, hazard ratio 1.76; 95% CI 1.11-2.78; P=0.02). It was concluded that the noninferiority of semaglutide was confirmed.

Guidelines

As of February 2017, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, double-blind, parallel-group, placebo-controlled trial
  • N=3,297
    • semaglutide 0.5 mg (n=826)
    • semaglutide 1 mg (n=822)
    • placebo 0.5 mg (n=824)
    • placebo 1 mg (n=825)
  • Setting: 230 sites in 20 countries
  • Enrollment: February to Deecember 2013
  • Median follow-up: 2.1 years
  • Analysis: non-inferiority
  • Primary outcome: CV mortality, nonfatal MI, or nonfatal stroke.

Population

Inclusion Criteria

  • Type 2 DM
    • Either if patients have not been treated with anti-hyperglycemic drug, or treated with ≤2 anti-hyperglycemic drug with or without insulin (basal or premixed)
  • Hemoglobin A1c ≥7%
  • Age ≥50 years with ≥1 criteria below:
    • Established CV disease (previous CV, cerebrovascular, or peripheral vascular disease)
    • heart failure (NYHA class II or III)
    • CKD ≥stage 3
  • Age ≥60 years with ≥1 criteria below:
    • persistent microalbuminuria or proteinuria
    • LVH (on ECG or imaging)
    • LV systolic or diastolic dysfunction (on imaging)
    • ankle/brachial pressure index<0.9

Exclusion Criteria

  • received a dipeptidyl-peptidase (DPP) 4 inhibitor ≤30 days or a GLP-1–receptor agonist or insulin (except basal or premixed) ≤90 days before screening
  • acute coronary or cerebrovascular event ≤90 days before randomization
  • planned coronary, carotid, or peripheral artery revascularization
  • long-term dialysis
  • Type 1 DM
  • chronic pancreatitis or idiopathic acute pancreatitis
  • end-stage liver disease
  • solid organ transplant (previous or planned)
  • malignancy diagnosed in the previous 5 years
  • personal history of multiple endocrine neoplasia type 2 (MEN2), familial or non-familial medullary thyroid carcinoma
  • family history of MEN2 or familial medullary thyroid carcinoma
  • screening calcitonin ≥50 ng/L
  • NYHA class IV heart failure
  • acute worsening of glycemic control ≤90 days prior to screening
  • hypersensitivity (known or suspected) to semaglutide
  • pregnant, breast-feeding, or not on adequate contraception

Baseline Characteristics

From the semaglutide 1 mg group (n=822)

  • Demographics: age 64.7±7.1 years; males 63%; white race 84.1%
  • Body weight 92.9±21.1 kg; BMI 32.9±6.18 kg/m2
  • Duration of diabetes: 14.1±8.2 years; HbA1c: 8.7±1.5%
  • Treatment for diabetes:
    • biguanides 72.3%; sulfonylurea 42.5%; thiazolidinedione 2.6%; alpha-glucosidase inhibitors 0.9%; meglitinides 2.8%; SGLT-2 inhibitors 0.1%
    • insulin 58%
  • PMH: IHD 60.2%; MI 32.1%; heart failure 21.9%; ischemic stroke 10.8%; hemorrhagic stroke 2.9%; hypertension 93.8%; non-smoker: 44.3%
  • BP: systolic 135.8±17 mm Hg; diastolic 76.9±10.2 mm Hg
  • Cholesterol: LDL-C 83.3±41.2 mg/dL; HDL-C 43.4±26.9 mg/dL
  • Renal function: normal 29.9%; eGFR<15 ml/min/1.73m2 0.5%

Interventions

  • Randomized to receive semaglutide, subcutaneous, 0.5 mg or 1 mg, or matched placebo
  • The trial consists of 104 weeks of treatment and a 5-week follow-up

Outcomes

Comparisons are semaglutide vs. placebo

Primary Outcomes

CV mortality, nonfatal MI, or nonfatal stroke
6.6% vs. 8.9% (HR 0.74; 95% CI 0.58-0.95; P<0.001 for noninferiority and P=0.02 for superiority)

Secondary Outcomes

CV mortality, nonfatal MI, nonfatal stroke, coronary or peripheral revascularization, hospitalization for heart failure or unstable angina
12.1% vs. 16% (HR 0.74; 95% CI 0.62-0.89; P=0.002)
All-cause mortality, nonfatal MI, or nonfatal stroke
7.4% vs. 9.6% (HR 0.77; 95% CI 0.61-0.97; P=0.03)
All-cause mortality
3.8% vs. 3.6% (HR 1.05; 95% CI 0.74-1.50; P=0.79)
CV mortality
2.7% vs. 2.8% (HR 0.98; 95% CI 0.65-1.48; P=0.92)
Nonfatal MI
2.9% vs. 3.9% (HR 0.74; 95% CI 0.51-1.08; P=0.12)
Nonfatal stroke
1.6% vs. 2.7% (HR 0.61; 95% CI 0.38-0.99; P=0.04)
Hospitalization for heart failure or unstable angina
1.3% vs. 1.6% (HR 0.82; 95% CI 0.47-1.44; P=0.49)
Revascularization
5% vs. 7.6% (HR 0.65; 95% CI 0.50-0.86; P=0.003)
Hospitalization for heart failure
3.6% vs. 3.3% (HR 1.11; 95% CI 0.77-1.61; P=0.57)
Retinopathy complications
3% vs. 1.8% (HR 1.76; 95% CI 1.11-2.78; P=0.02)
New or worsening nephropathy
3.8% vs. 6.1% (HR 0.64; 95% CI 0.46-0.88; P=0.005)

Other analysis

HbA1C difference post-treatment
semaglutide 0.5 mg vs. placebo: −1.1% vs. 0.4% (0.7% point lower than placebo; P<0.001)
semaglutide 1 mg vs. placebo: −1.4% vs. 0.4% (1% point lower than placebo; P<0.001)
Body weight difference post-treatment
semaglutide 0.5 mg vs. placebo: −3.6 kg vs. −0.7 kg (2.9 kg lower than placebo; P<0.001)
semaglutide 1 mg vs. placebo: −4.9 kg vs. −0.5 kg (4.3 kg lower than placebo; P<0.001)
Systolic BP difference post-treatment
semaglutide 0.5 mg vs. placebo: 3.4 mm Hg vs. 2.2 mm Hg (1.3 mm Hg lower than placebo; P=0.1)
semaglutide 1 mg vs. placebo: 5.4 mm Hg vs. 2.8 mm Hg (2.6 mm Hg lower than placebo; P<0.001)
Pulse rate difference post-treatment
semaglutide 0.5 mg vs. placebo: 2.1 bpm vs. 0.1 bpm (2 bpm higher than placebo; P<0.001)
semaglutide 1 mg vs. placebo: 2.4 bpm vs. -0.1 bpm (2.5 bpm higher than placebo; P<0.001)

Subgroup Analysis

No significant interactions for age, gender, race, ethnicity BMI, HbA1C, duration of diabetes, heart failure severity, history of vascular disease, insulin treatment or renal function

Adverse Events

  • all events:
    semaglutide 0.5 mg vs. placebo: 89.6% vs. 90.8% (P-value not provided)
    semaglutide 1 mg vs. placebo: 89.1% vs.89.2% (P-value not provided)
  • serious adverse events:
    semaglutide 0.5 mg vs. placebo: 35% vs. 39.9% (P-value not provided)
    semaglutide 1 mg vs. placebo: 33.6% vs.36.1% (P-value not provided)
  • severe adverse events
    semaglutide 0.5 mg vs. placebo: 24.2% vs. 26.2% (P-value not provided)
    semaglutide 1 mg vs. placebo: 25.2% vs. 23.5% (P-value not provided)
  • gastrointestinal adverse events (nausea, vomiting, diarrhea)
    semaglutide 0.5 mg vs. placebo: 50.7% vs. 35.7% (P-value not provided)
    semaglutide 1 mg vs. placebo: 52.3% vs. 35.2% (P-value not provided)
  • nausea leading to treatment discontinuation
    semaglutide 0.5 mg vs. placebo: 2.2% vs. 0.2% (P-value not provided)
    semaglutide 1 mg vs. placebo: 4.6% vs. 0.2% (P-value not provided)
  • diarrhea leading to treatment discontinuation
    semaglutide 0.5 mg vs. placebo: 1.8% vs. 0.6% (P-value not provided)
    semaglutide 1 mg vs. placebo: 2.3% vs. 0.2% (P-value not provided)
  • acute pancreatitis
    semaglutide 0.5 mg vs. placebo: 0.7 vs. 0.4% (P-value not provided)
    semaglutide 1 mg vs. placebo: 0.4% vs. 1.1% (P-value not provided)
  • gallbladder disorder
    semaglutide 0.5 mg vs. placebo: 3.9% vs. 4.6% (P-value not provided)
    semaglutide 1 mg vs. placebo: 3.2% vs. 2.8% (P-value not provided)
  • neoplasm (benign and malignant)
    semaglutide 0.5 mg vs. placebo: 8% vs. 8.5% (P-value not provided)
    semaglutide 1 mg vs. placebo: 10.8% vs. 8.4% (P-value not provided)
  • pancreatic malignancy
    semaglutide 0.5 mg vs. placebo: 0% vs. 0.2% (P-value not provided)
    semaglutide 1 mg vs. placebo: 0.1% vs. 0.2% (P-value not provided)
  • hypoglycemia
    semaglutide 0.5 mg vs. placebo: 23.1% vs. 21.5% (P-value not provided)
    semaglutide 1 mg vs. placebo: 21.7% vs. 21% (P-value not provided)

Criticisms

Funding

  • Novo Nordisk

Further Reading