SURMOUNT-1: Tirzepatide for obesity management

29th July 2022, Dr Chee L Khoo

12 months ago, at GPVoice, we announced the arrival of drug LY3298176, which now has a name, tirzepatide, as the first in its class of “twincretins” in the management of type 2 diabetes. We briefly explored the 4 Phase 3 trials looking at the efficacy and safety of trizepatide in comparison with placebo, semaglutide, insulin degludec and insulin glargine. Everything was thumbs up and we were waiting on results from trials in patients who are obese (SURMOUNT-1), has fatty liver (SYNERGY-NASH) and a cardiovascular safety out trial (SURPASS-CVOT). SURMOUNT-1 published its results recently but the other two won’t report till 2024/2025. We shall explore the results from this exciting trial which was published this week.

Many of you would have patients who have lost weight from semaglutide and dulaglutide. They typically lost between 5-10 or more kilograms over a short period of 3-6 months. Wait till you see the results from tirzepatide.

SURMOUNT-1 is a phase 3 double-blind, randomised, controlled trial conducted in 119 sites in 9 countries seeking to evaluate the efficacy and safety of tirzepatide in adults with obesity or overweight who did not have diabetes. 2539 adults with a BMI > 30 or > 27 with at least one weight-related complication (hypertension, dyslipidaemia, obstructive sleep apnoea, or cardiovascular disease) were randomised to receive either weekly subcutaneous tirzepatide 5mg, 10mg, 15mg or placebo and lifestyle measures. Lifestyle intervention included regular lifestyle counselling sessions, delivered by a dietitian or a qualified health care professional, to help the participants adhere to  healthful, balanced meals, with a deficit of 500 calories per  day, and at least 150 minutes of physical activity  per week.

Tirzepatide was initiated at a dose of 2.5 mg once weekly (or matching placebo) and was increased by 2.5 mg every 4 weeks during the dose-escalation period to reach a maintenance dose of up to 15 mg once weekly by week 20. The coprimary end points were the percentage change in body weight from baseline to week 72 and a weight reduction of 5% or more at week 72. Key secondary end points included weight reduction of 10% or more, 15% or more, and 20% or more at week 72; the change in weight from baseline to week 20; and the change from baseline to week 72 in waist circumference, systolic blood pressure, fasting insulin and lipid levels, and the physical function score on the 36-Item Short Form Health Survey.

The participants

86.0% of participants completed the primary trial treatment period (88.4% to 89.8% across the tirzepatide groups and 77.0% in the placebo group). Treatment discontinuations due to adverse events were 4.3%, 7.1%, and 6.2% with 5 mg, 10 mg, and 15 mg of tirzepatide, respectively, and 2.6% with placebo. The mean age of the participants was 44.9 years; the mean body weight was 104.8 kg, the mean BMI was 38.0; 94.5% of the participants had a BMI of 30 or higher. Participants reported an average duration of obesity of 14.4 years; 40.6% had prediabetes at baseline, and nearly two thirds had one or more weight-related complications.

 The Results

Not unexpected, all three tirzepatide doses were superior to placebo in achieving weight loss.

Average body weight reductions:

  • 15.0% (5 mg),
  • 19.5% (10 mg),
  • 20.9% (15 mg),
  • 3.1% (placebo)

This translate into an incredible 16.1kg, 22.2kg, 23.6kg and 2.4kg weight loss in the 5mg, 10mg, 15mg and placebo groups respectively.

Percentage of participants achieving body weight reductions of ≥5%:

  • 85% (5 mg),
  • 89% (10 mg),
  • 91% (15 mg),
  • 35% (placebo)

Percentage of participants achieving body weight reductions of ≥20%:

  • 30% (5 mg),
  • 50% (10 mg),
  • 57% (15 mg), 3.1% (placebo)

Clinical outcomes

Compared with placebo, the combined tirzepatide groups had a relative reduction of 3.1%, 20.3%, 4.2% in the total cholesterol, triglycerides and LDL-C levels respectively and a 8.8% increase in HDL-C. There was a 38.9% reduction in fasting insulin levels in the tirzepatide groups compared to placebo. Similarly, there was a 6.2% and 4.0% reduction in systolic and diastolic pressures compared with placebo.

At 72 weeks, 95.3% of participants in the tirzepatide groups who had prediabetes at baseline reverted to normoglycaemia compared with 61.9% in patient in the placebo group. The mean reduction in total body fat mass was 33.9% with tirzepatide, as compared with 8.2% with placebo.

Adverse events

78.9 to 81.8% of participants treated with tirzepatide reported at least one adverse event that emerged during the treatment period, as compared with 72.0% of participants in the placebo group. The most frequently reported adverse events were gastrointestinal (nausea, diarrhea, and constipation). These adverse events occurred were transient and mild to moderate in severity and occurred primarily during the dose-escalation period.

Serious adverse events occurred in 6.3% of patients but they were similar between the tirzepatide and placebo groups. 21% of these serious adverse events were considered to be related to covid-19 infections affecting both groups equally. There were 4 cases of pancreatitis evenly distributed across the treatment groups. While cholelithiasis were reported equally between the tirzepatide and placebo groups, cholecystitis were reported more commonly in the tirzepatide groups although the incidence was low (<0.6%).

In summary, the degree of weight reduction with tirzepatide is substantial and clinically meaningful. It rivals that achieved with bariatric surgery. More than 90% of patients lost >5% of body weight and >50% lost >20% of weight with tirzepatide 15mg. weight reduction with tirzepatide was accompanied by greater improvements with respect to all measured cardiovascular and metabolic risk factors, including waist circumference, systolic and diastolic blood pressure, fasting insulin and lipid than placebo.

Participants treated with tirzepatide had a percent reduction in fat mass approximately three times greater than the reduction in lean mass, resulting in an overall improvement in body composition. These improvements may translate to reduced risk of cardiovascular disease, chronic kidney disease, non-alcoholic fatty liver disease, and type 2 diabetes, among other outcomes.

We await approval by the FDA and subsequently by our TGA of tirzepatide for the treatment of obesity. I wonder how much it will cost.

References: Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, Kiyosue A, Zhang S, Liu B, Bunck MC, Stefanski A; SURMOUNT-1 Investigators. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022 Jul 21;387(3):205-216. d