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 October 2018, no guidelines have been published that reflect the results of this trial. Of note the Standards of Medical Care in Diabetes-2018 from ADA does recommend the use of a different GLP-1 agonist, liraglutide, in patients with type 2 diabetes and established ASCVD after the use of lifestyle modifications and metformin in some patients.

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

  • Randomization in a 1:1:1:1 ratio receiving semaglutide 0.5mg, semaglutide 1mg, or a volume matched placebo
  • Randomization was stratified according to CV or CKD status, insulin treatment, and eGFR status
  • A fixed dose titration was used starting with 0.25mg for 4 weeks that escalated to 0.5mg for 4 weeks until the maintenance dose was reached, either 0.5mg or 1mg, and no changing of the maintenance dose was permitted.
  • Patients were scheduled for quarterly site visits and investigators were encouraged to treat all patients according to local guidelines to achieve the highest glycemic control and were allowed to add or adjust non investigational antihyperglycemic therapies.
  • 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

  • The primary outcome was only significant as a composite, with only nonfatal stroke being statistically significant. However, the outcomes of cardiovascular death and nonfatal MI may not have shown significance due to an inadequately sized study population.
  • The majority of patients enrolled in the study had a baseline history of cardiovascular disease, therefore, the results may not extrapolate well in a diabetic population for primary risk reduction of a cardiovascular event.
  • Adjustments to other antihyperglycemic medications may have been differed between patients
  • Individuals in the 0.5mg group may have needed a 1mg dose of semaglutide to achieve the appropriate response
  • Statistical analysis was run mainly for noninferiority, therefore, data values other than the composite primary outcome do not prove superiority.

Funding

  • Novo Nordisk

Further Reading