Tirzepatide Once Weekly for the Treatment of Obesity in People With Type 2 Diabetes - SURMOUNT-2

Jul 21, 2023
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC; Amit Saha, MD
Summary Reviewer:
Kim A. Eagle, MD, MACC
Trial Sponsor:
Eli Lilly and Company
Date Published:
06/26/2023
Date Updated:
07/21/2023
Original Posted Date:
07/21/2023
References

Contribution To Literature:

The SURMOUNT-2 trial showed that in adults with BMI ≥27 kg/m2 and type 2 diabetes, once-weekly tirzepatide 10 mg and 15 mg were associated with more frequent and greater weight loss at 72 weeks compared with placebo.

Description:

The goal of the trial was to compare the weight loss effect of 2 doses of tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 (GIP/GLP-1) receptor agonist, versus placebo in adults with obesity and type 2 diabetes mellitus (T2DM).

Study Design

  • Randomized
  • Placebo-controlled
  • Double-blind
  • Multicenter

Patients with a body mass index (BMI) ≥27 kg/m2 with a diagnosis of T2DM and glycated hemoglobin (HbA1c) of 7-10% on stable antihyperglycemic therapy (lifestyle modification alone or oral medications) for ≥3 months were randomized to receive tirzepatide 10 mg (n = 312), tirzepatide 15 mg (n = 311), or matching placebo (n = 315) via once-weekly subcutaneous injection. Tirzepatide was initiated at 2.5 mg and up-titrated by 2.5 mg every 4 weeks to target dose. All participants received lifestyle, nutrition, and exercise counseling.

  • Total number of enrollees: 938
  • Duration of follow-up: 72 weeks
  • Mean patient age: 54.2 years
  • Percentage female: 51%

Inclusion criteria:

  • Age ≥18 years
  • BMI ≥27 kg/m2 AND HbA1c 7-10%
  • ≥1 unsuccessful attempt to lose weight via diet alone
  • ≥3 months on a stable T2DM regimen, which may include any oral medications except dipeptidyl peptidase-4 (DDP-4) inhibitors or oral GLP-1 receptor agonists

Exclusion criteria:

  • Type 1 DM or history of diabetic ketoacidosis or hyperosmolar hyperglycemic state
  • ≥1 episode of severe hypoglycemia or hypoglycemia unawareness in past 6 months
  • Use of DDP-4, oral GLP-1 receptor agonist, or any injectable diabetes medication in past 3 months
  • Any prior surgical treatment for obesity
  • Endoscopic treatment for obesity within past 6 months
  • Estimated glomerular filtration rate <30 mL/min/1.73 m2
  • Acute myocardial infarction, stroke, unstable angina, or heart failure hospitalization in past 3 months

Other salient features/characteristics:

  • Percentage Hispanic or Latino: 60%
  • Baseline mean body weight: 100.7 kg
  • Baseline mean BMI: 36.1 kg/m2
  • Baseline mean HbA1c: 8.02%
  • Percentage on sodium-glucose cotransporter 2 inhibitor (SGLT2i): 20%
  • Percentage with hypertension: 66%
  • Percentage with dyslipidemia: 61%
  • Percentage with atherosclerotic cardiovascular disease: 10%

Principal Findings:

The coprimary outcomes at 72 weeks were determined separately for tirzepatide 10 mg and 15 mg vs. placebo:

  • Coprimary outcome 1, percent change in body weight: -12.8% and -14.7% vs. -3.2%, p < 0.0001 for both
  • Coprimary outcome 2, percentage with weight reduction ≥5%: 79% and 83% vs. 32%, p < 0.0001 for both

Secondary outcomes for tirzepatide 10 mg and 15 mg vs. placebo:

  • Percentage with weight reduction ≥15%: 40% and 48% vs. 3%, p < 0.0001 for both
  • Change in HbA1c: -2.07% and -2.08% vs. -0.51%, p < 0.0001 for both
  • Mean change in body weight: -12.9 kg and -14.8 kg vs. -3.2 kg, p < 0.0001 for both
  • Mean change in BMI: -4.9 kg/m2 and -5.7 kg/m2 vs. -1.2 kg/m2, p < 0.0001 for both
  • Follow-up HbA1c <7%: 87% and 84% vs. 36%, p < 0.0001 for both
  • Follow-up HbA1c <5.7%: 46% and 49% vs. 4%, p < 0.0001 for both

Safety outcomes for tirzepatide 10 mg and 15 mg vs. placebo:

  • Discontinuation of study drug: 4% and 7% vs. 4%
  • Nausea, vomiting, or diarrhea: 51% and 57% vs. 18%
  • Confirmed pancreatitis: 0 and 1% (n = 2) vs. <1% (n = 1)
  • Hypoglycemia <54 mg/dL: 4% and 5% vs. 1%

Secondary outcomes for pooled tirzepatide group vs. placebo:

  • Mean change in systolic blood pressure (SBP): -6.3 mm Hg vs. -1.2 mm Hg, p < 0.0001
  • Percent change in fasting triglycerides: -27.2% vs. -3.3%, p < 0.0001
  • Percent change in non–high-density lipoprotein cholesterol: -5.9% vs. -3.7%, p < 0.0001

Interpretation:

The SURMOUNT-2 trial demonstrates both more frequent clinically significant weight loss (≥5% body weight) and increased magnitude of weight loss with the use of once-weekly tirzepatide in patients with obesity and T2DM. Additionally, tirzepatide was associated with a meaningful reduction in HbA1c, with normalization to nondiabetic levels in nearly half of the tirzepatide groups. Rates of drug discontinuation were similar to placebo despite an increase in predominantly gastrointestinal side effects, which occurred primarily during dose up-titration. Although outcomes between tirzepatide 10 and 15 mg were not directly compared, there appears to have been only a small increase in effect with the higher dose.

SURMOUNT-1 first demonstrated the significant weight loss (~20%) associated with tirzepatide up to 15 mg in obese patients without diabetes. T2DM is associated with increased difficulty in weight loss, as seen by the decreased effect size of semaglutide in the STEP 2 trial compared to its predecessor. Despite this, the current data highlight the still-sizable effect of tirzepatide on weight loss in this more challenging population. The increased weight loss with tirzepatide mirrors but exceeds that observed in SURPASS-2, which compared tirzepatide and semaglutide but was not primarily a weight loss study and included participants with lower BMI. There were also encouraging improvements in associated comorbidities, including SBP and dyslipidemia. Anticipated clinical trials, such as SURPASS-CVOT and SURPASS-MMO, may provide further information into whether these effects are associated with improvement in cardiovascular outcomes in addition to weight loss.

References:

Garvey WT, Frias JP, Jastreboff AM, et al., on behalf of the SURMOUNT-2 investigators. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomized, multicenter, placebo-controlled, phase 3 trial. Lancet 2023;Jun 26:[Epub ahead of print].

Editorial Comment: Frandsen CS, Madsbad S. SURMOUNT-2: new advances for treating obese type 2 diabetes with tirzepatide. Lancet 2023;Jun 26:[Epub ahead of print].

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Hypertriglyceridemia, Lipid Metabolism

Keywords: Body Mass Index, Diabetes Mellitus, Type 2, Dipeptidyl-Peptidase IV Inhibitors, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Dyslipidemias, Glucagon-Like Peptide 1, Glycated Hemoglobin A, Hypoglycemia, Lipoproteins, Obesity, Primary Prevention, Triglycerides, Weight Loss


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