Introduction

Obesity has an adverse impact on the health of individuals, especially in those affected with chronic conditions. Intensive lifestyle management has a pivotal role in the management of obesity. Appropriate intensive lifestyle management is associated with a 5-8% weight reduction from baseline, along with improved health in people with obesity. Nevertheless, the overall effectiveness of lifestyle intervention is limited, and patients tend to regain one-third of the lost weight in the following year of the treatment. Novel incretin-based anti-obesity medications may boost the impact of intensive lifestyle intervention. Tirzepatide is a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist that has demonstrated effective and safe weight reduction in individuals with obesity. Nevertheless, the impact of tirzepatide after successful intensive lifestyle intervention has not been studied well till date.

Aim

To evaluate the efficacy of tirzepatide at 72 weeks post-randomization in adults with obesity or overweight (but without diabetes) who achieved at least 5% baseline weight loss during a 12‑week intensive lifestyle lead‑in period.

Patient Profile

• Adults with body mass index (BMI) ≥30 or ≥27 kg/m² and at least one obesity-related complication (hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease; excluding diabetes) (n = 579).
• The study subjects who had achieved ≥5% weight reduction after a 12-week intensive lifestyle intervention were eligible for this phase of the study (579/806 patients; 71.8%).

Methods

Study Design

• An 84-week, multicenter, randomized, parallel-arm, double-blind, placebo-controlled trial.
• The study consisted of 2-week screening period; a 12-week lead-in period during which participants received intensive lifestyle intervention (Dietary intake was ~1,200 kcal/day for women and ~1,500 kcal/day for men, with ≥150 min/week of moderate‑intensity physical activity); a 72-week double-blind, placebo-controlled treatment period and a 4-week safety follow-up period.

Treatment Strategy

• After a 12-week intensive lifestyle intervention period the study subjects who achieved ≥5% weight loss, were randomized (1:1) to tirzepatide maximum tolerated dose (10 or 15 mg; n = 287) or placebo (n = 292) once weekly for 72 weeks. 
• The study subjects were also instructed to follow a balanced diet with a 500 kcal per day deficit along with the continuation of physical activity. 

Outcomes

Primary Outcomes

• Mean percent weight change from randomization to week 72.
• Percentage of participants achieving weight reduction ≥5% from randomization to week 72.

Secondary Outcomes

• Percentage of participants achieving reductions in body weight of ≥10, ≥15 and ≥20% from randomization to week 72.
• Change in BMI from randomization to 72 weeks.
• Change in waist circumference (WC) from randomization to 72 weeks.
• Percentage of participants who, at week 72, maintained ≥80% of the body weight loss achieved during the 12-week lead-in period.

Exploratory Outcomes

Additional Outcomes 

Results

• Lead‑in weight loss was accompanied by reductions in WC, systolic/diastolic blood pressure, glycosylated hemoglobin (HbA1c), fasting glucose, and insulin. Mean improvements were also observed across lipid levels, except high density lipoprotein cholesterol (HDL-C) and free fatty acids.
• Patients randomized to tirzepatide achieved further weight loss, and those receiving placebo gained weight during the period of 72 weeks, following the intensive lifestyle intervention (efficacy estimand: −21.1% vs. 3.3%) (Fig. 1). 

Fig. 1: Percentage change in weight from randomization to 72 weeks (efficacy estimand)

                    

• The efficacy estimand revealed that 94.4% of participants in the tirzepatide group had an additional body weight reduction of ≥5% from randomization, as compared to 10.7% in the placebo group [Odds ratio (OR): 130.4, 95% CI 70.0 - 242.8; P < 0.001) (Fig. 2).
• Higher percentage of participants in the tirzepatide group achieved reductions in body weight of ≥10, ≥15 and ≥20% from randomization, as compared to placebo (Fig. 2).
• Greater proportion of patients treated with tirzepatide achieved ≥25% body weight reduction from randomization, as compared to those treated with placebo (efficacy estimand: 36.3% vs. 0.3%; OR: 124.6; 95% CI 24.9, 623.2) (Fig. 2).

Fig. 2: Percentage of participants meeting the weight-reduction thresholds (efficacy estimand)

• At 72 weeks, greater proportion of patients treated with tirzepatide maintained ≥80% of body weight lost during the 12-week lead-in-period, as compared to those treated with placebo (the efficacy estimand: 98.6% vs. 37.8%; OR: 101.6; 95% CI 39.2, 263.6; P < 0.001) 
• Overall, intensive lifestyle intervention followed by 72 weeks of tirzepatide resulted in a greater total weight change, as compared to placebo (-26.6% vs. −3.8%) (Fig. 3).

Fig. 3: Total weight change in the study groups from week 0 to week 84

• The BMI reduced with tirzepatide treatment but there was an increase in BMI with placebo (efficacy estimand; -7.7 kg/m² vs. 1.2 kg/m2, Table 1)). Total change in BMI with intensive lifestyle intervention followed by 72 weeks of tirzepatide treatment vs. placebo was −10.4 kg/m² vs. –1.4 kg/m² (efficacy estimand). 
• At 72 weeks, patients treated with tirzepatide experienced reduction in WC as compared to those treated with placebo (efficacy estimand; -16.8 cm vs. 1.1 cm) (Table 1). 
• Patients treated with tirzepatide also has greater improvements in systolic and diastolic blood pressure, as compared to placebo. Patients treated with tirzepatide also had further improvements in their lipid profile, fasting glucose, fasting insulin, and HbA1c (Table 1). 
• The physical functioning domain score for SF-36v2 and the IWQOL-Lite-CT physical function composite score improved to greater extent in those treated with tirzepatide, as compared to those treated with placebo (Table 1)

Table 1: Efficacy findings from randomization to week 72 (efficacy estimand)

Outcomes	LSM		Treatment Comparison
	Tirzepatide (n=287)	Placebo (n=292)	Difference from placebo (95% CI)	P value
Overall change in weight (%)	-21.1	-3.3	-24.5% (−26.1, −22.8)	< 0.001
Change in waist circumference (cm)	-16.8	1.1	-17.9 (-19.5, -16.3)	< 0.001
Change in BMI (Kg/m2)	-7.7	1.2	-8.9 (-9.6, 8.3)	NR
Fasting lipids
% change in total cholesterol (%)	-3.0	5.2	-7.8 (-10.4, -5.1)	NR
% change in non-HDL-C	-9.8	5.6	-14.6 (-17.9, -11.2)	NR
% change in HDL-C	15.4	3.6	11.4 (8.2, 14.7)	NR
% change in LDL-C	-6.1	6.1	-11.5 (-15.3, -7.5)	NR
% change in VLDL-C	-25.6	3.0	-27.8 (-32.1, -23.2)	NR
% change in triglycerides	-25.8	3.0	-28.0 (-32.3, -23.4)	NR
% change in free fatty acids	-33.1	-15.0	-21.3 (-28.4, -13.6)	NR
Change in fasting glucose (mg/dL)	-8.8	2.4	-11.2 (-13.5, -8.8)	NR
Change in HbA1c (%)	-0.5	0.0	-0.5 (-0.5, -0.4)	NR
% change in fasting insulin	-39.1	17.3	-48.1 (-53.7, -41.7)	NR
Patient reported outcomes
Change in SF-36v2 physical functioning domain score	3.3	-0.6	3.9 (2.8, 4.9)	NR
Change in IWQOL-Lite-CT physical function composite score	13.9	1.1	12.8 (9.7, 16.0)	NR

NR: Not reported

• Furthermore, higher proportion of patients treated with tirzepatide vs. placebo reported decrease in intensity of antihypertensive (4.9% vs. 1.0%) and lipid-lowering medications (2.8% vs. 1.7%). Conversely, fewer patients treated with tirzepatide vs. placebo reported increased intensity of antihypertensive (2.4 vs. 6.5%) and lipid-lowering (0.3% vs. 2.1%). 
• Mild to moderate gastrointestinal events were the most frequent adverse events, occurring more often with tirzepatide than with placebo.

Conclusion

Nat Med. 2023 Nov;29(11):2909-2918.  doi: 10.1038/s41591-023-02597-w.