Tirzepatide induces weight loss in overweight/obese patients with T2D

Treatment with once-weekly tirzepatide, a GIP* and GLP-1** receptor agonist, led to a substantial weight reduction among overweight or obese adults with type 2 diabetes (T2D), according to the phase III SURMOUNT-2 trial presented at ADA 2023.

“About 90 percent of patients with T2D have overweight or obesity. Patients with obesity and T2D have two diseases, and both should be treated effectively,” said principal investigator Professor Timothy Garvey from the University of Alabama at Birmingham, Alabama, US.

The SURMOUNT-2 trial enrolled 938 adults (mean age 54.2 years, 50.7 percent female) with T2D, who were obese or overweight (mean BMI 36.1 kg/m²), to assess the efficacy and safety of tirzepatide for chronic weight management. Participants were randomized to receive tirzepatide 10 mg (n=312) or 15 mg (n=311) once weekly or placebo (n=315) in addition to lifestyle intervention for 72 weeks. Tirzepatide was started at a dose of 2.5 mg once weekly, followed by 2.5 mg increments every 4 weeks until the randomized dose was reached (ie, 10 or 15 mg at 12 or 20 weeks, respectively). [Lancet 2023;doi:10.1016/S0140-6736(23)01200-X]

Change in body weight

In the treatment-regimen estimand*** analysis, patients who received tirzepatide achieved mean weight reductions of 12.8 percent (10 mg) and 14.7 percent (15 mg) at week 72, whereas those who received placebo only had a 3.2-percent weight reduction.

More tirzepatide-treated patients achieved a body weight-reduction threshold of ≥5 percent than those on placebo at week 72 (79.2 percent [10 mg] and 82.8 percent [15 mg] vs 32.5 percent; p<0.001).

Similarly, a higher proportion of patients treated with tirzepatide experienced a ≥20 percent weight reduction compared with placebo (21.5 percent [10 mg] and 30.8 percent [15 mg] vs 1.0 percent; p<0.001).

Glycaemia-related outcomes

At week 72, mean HbA_1c levels were reduced by 2.07 percent and 2.08 percent with tirzepatide 10 and 15 mg, respectively. With placebo, the corresponding rate was only 0.51 percent.

Almost half of tirzepatide recipients achieved normoglycaemia (HbA_1c of <5.7 percent) compared with those on placebo (46.0 percent [10 mg] and 48.6 percent [15 mg] vs 3.9 percent; p<0.001). “This occurred with no severe hypoglycaemia and very low rates of level 2 hypoglycaemia,” Garvey noted.

“I never thought we would see normalization of HbA_1c in diabetics with this degree of weight loss,” he added.

Cardiometabolic risk factors

Tirzepatide recipients had greater reductions in waist circumference (-10.8 [10 mg] and -13.1 [15 mg] vs -3.4 cm; p<0.001) and BMI (-4.7 [10 mg] and -5.4 [15 mg] vs -1.2 kg/m²; p<0.001) than placebo recipients at week 72.

Tirzepatide treatment also led to greater improvements in other cardiometabolic risk factors, including systolic blood pressure and fasting triglycerides, HDL cholesterol, and non-HDL cholesterol, compared with placebo, the researchers noted. [Lancet 2023;doi:10.1016/S0140-6736(23)01200-X]

“Overall, tirzepatide met all primary and key secondary endpoints [in the treatment-regimen estimand analysis]”, said Garvey.

Safety profile

The overall rates of treatment-emergent adverse events (TEAEs) were similar between the tirzepatide and placebo arms.

The most frequent TEAEs reported with both doses of tirzepatide were nausea, diarrhoea, and vomiting. All were considered mild or moderate in severity and decreased over time, said Dr Naveed Sattar from the University of Glasgow, UK, who presented the safety data.

Importantly, no cases of severe hyperglycaemia were reported, he added.

“The tolerability and safety profile of tirzepatide in people living with obesity/overweight and T2D was consistent with that observed in the SURPASS studies and of other incretin-based therapies for obesity,” said Sattar.

“Overall, both tirzepatide 10 and 15 mg demonstrated superior and clinically meaningful body weight reduction vs placebo in participants with obesity/overweight and T2D,” Sattar concluded.

“Moreover, treatment with both doses of tirzepatide translated to clinically meaningful improvements in [glycaemic control] and cardiometabolic risk factors,” he added.