Tirzepatide in obesity, From Base to Peak: CME notes

Revision notes from this CME, written from the speaker's own slides. The talk ran in three parts, from the disease model through the SURMOUNT trials to safety and dosing. The slides were sponsored material, and the trial data and prescribing points are reproduced here as they were presented.

Part 1

Obesity as a Disease and Dual Incretin Action

Dr Khizer Hussain Junaidy, MD (Pharmacology), Diabetologist & Bariatric Physician

The deck frames obesity as a chronic relapsing disease and explains how tirzepatide acts on both GIP and GLP-1 receptors.

Obesity is a chronic, progressive, relapsing and multifactorial disease. Psychosocial, genetic, environmental and physiological factors all contribute. It also acts as a gateway to other noncommunicable diseases.
Major bodies now classify obesity as a chronic disease. These include the European Association for the Study of Obesity, the American Association of Clinical Endocrinology, the Obesity Medicine Association, Obesity Canada and the European Commission.
Weight reduction improves or prevents many obesity-related complications. Benefits are described across dyslipidaemia, hypertension, cardiovascular risk, type 2 diabetes prevention and remission, osteoarthritis, sleep apnoea, GERD, MAFLD, MASH and PCOS, with benefit growing as percentage weight loss rises.
HbA1c, triglycerides and blood pressure continue to fall even beyond 15% weight loss. So greater weight reduction keeps adding metabolic benefit.
Tirzepatide is a single molecule that binds both human GIP and GLP-1 receptors. Its GIP receptor activity is similar to native GIP, while its GLP-1 receptor activity is lower than native GLP-1.
Proposed metabolic roles include increased insulin sensitivity, lipid-buffering capacity, blood flow and storage capacity in adipose tissue, reduced proinflammatory immune-cell infiltration, reduced food intake and decreased nausea centrally, and glucose-dependent effects on insulin and glucagon in the pancreas.
No dose adjustment is required in renal impairment, including end-stage renal disease, or in hepatic impairment.

In clinicExplain to patients that obesity is a chronic disease, and that sustained weight reduction is expected to improve blood pressure, lipids and glycaemia together.

Part 2

SURMOUNT Efficacy Data

Dr Khizer Hussain Junaidy, MD (Pharmacology), Diabetologist & Bariatric Physician

SURMOUNT-1 to SURMOUNT-5 tested tirzepatide in obesity or overweight, showing large weight, waist and cardiometabolic gains, and superiority over semaglutide in SURMOUNT-5.

The programme covers SURMOUNT-1 (vs placebo, N=2539), SURMOUNT-2 (obesity or overweight with type 2 diabetes, N=938), SURMOUNT-3 (after an intensive lifestyle programme, N=806), SURMOUNT-4 (maintenance of weight reduction, N=783) and SURMOUNT-5 (vs semaglutide, N=750). Treatment was 72 weeks, except 88 weeks in SURMOUNT-4. Trials cannot be compared with each other because of differing design and criteria.
SURMOUNT-1 studied adults with BMI 30 kg/m2 or more, or BMI 27 kg/m2 or more with at least one obesity-related complication, excluding diabetes. All arms, including placebo, received a reduced-calorie diet with a 500 kcal per day deficit and at least 150 minutes of physical activity per week.
In SURMOUNT-1, tirzepatide 15 mg gave a mean body weight reduction of 22.5% at 72 weeks (mean baseline weight 104.8 kg). More than 6 in 10 participants on tirzepatide reached 20% or more weight reduction, and about 4 in 10 on 15 mg reached 25% or more.
Weight reduction of any degree occurred in 96.6%, 96.7% and 97.7% of participants on tirzepatide 5 mg, 10 mg and 15 mg, compared with 66.9% on placebo.
In SURMOUNT-1, waist circumference fell by 19.9 cm on 15 mg at 72 weeks. Cardiometabolic improvements across doses were systolic blood pressure 7.0-8.2 mm Hg lower, diastolic 4.6-5.5 mm Hg lower, triglycerides 24.3-31.4% lower, LDL cholesterol 5.3-8.6% lower and HDL cholesterol 7.0-8.6% higher.
A DEXA substudy showed total fat mass fell 33.9% and visceral fat mass 40.1% with pooled tirzepatide, against 8.2% and 7.3% with placebo. Total lean mass fell 10.9% versus 2.6%.
SURMOUNT-5 was an open-label phase 3b trial. Tirzepatide at maximum tolerated dose (10 mg or 15 mg) gave 21.6% weight reduction at 72 weeks versus 15.4% with semaglutide at maximum tolerated dose (1.7 mg or 2.4 mg). Weight reduction of 25% or more was reached by 36.2% versus 19.4%, and waist circumference fell 20.0 cm versus 14.7 cm. Open-label design is a limitation and there was no placebo arm.

In clinicSet expectations using trial figures, but remind patients that all SURMOUNT results were achieved alongside a reduced-calorie diet and increased physical activity.

Part 3

Safety, Dosing and Practical Counselling

Dr Khizer Hussain Junaidy, MD (Pharmacology), Diabetologist & Bariatric Physician

Adverse effects were mainly gastrointestinal and transient during escalation, and the deck sets out a stepwise weekly titration from 2.5 mg to a 15 mg maximum.

In SURMOUNT-1, the commonest adverse reactions were gastrointestinal, mostly mild to moderate, and mainly during dose escalation, falling over time. Rates across 5 mg, 10 mg and 15 mg were nausea 24.6-33.3%, diarrhoea 18.7-23.0%, constipation 11.7-17.1%, dyspepsia 8.9-11.3% and vomiting 8.3-12.2%, against placebo rates of 9.5%, 7.3%, 5.8%, 4.2% and 1.7%.
Other SURMOUNT-1 reactions included decreased appetite, abdominal pain, hair loss (about 5% versus 0.9% placebo), dizziness, eructation and injection site reactions. Discontinuation for adverse reactions was 4.3-7.1% versus 2.6% on placebo, and for gastrointestinal reactions 1.3-2.9% versus 0.3%.
In SURMOUNT-5 the safety profile was similar to earlier SURMOUNT trials. Nausea was 43.6% with tirzepatide versus 44.4% with semaglutide, vomiting 15.0% versus 21.3%, and injection site reactions 8.6% versus 0.3%. Discontinuation for adverse reactions was 6.1% versus 8.0%. These were not study endpoints, so no inference should be drawn.
Counsel patients on simple measures for gastrointestinal effects: split three daily meals into four or more smaller meals, avoid fatty foods, try bland foods and stop eating when full. Multidisciplinary care may help with side effect control and proper nutrition.
Loss of fluids and dehydration from side effects may reduce kidney function when starting treatment. Advise patients to drink plenty of fluids to avoid dehydration.
Dosing is once weekly subcutaneous. Start at 2.5 mg for 4 weeks, then increase to 5 mg. If needed for individual treatment goals, increase by 2.5 mg after at least 4 weeks at the current dose, up to a maximum of 15 mg weekly. Recommended maintenance doses are 5 mg, 10 mg and 15 mg.
The summary slide states that, added to a reduced-calorie diet and increased physical activity, patients could achieve significant and sustained weight reduction and better cardiometabolic parameters, with average reductions up to 22.9% in SURMOUNT-1 and up to 26.0% (27.6 kg) at week 88 in SURMOUNT-4. Cardiometabolic improvements were weight loss dependent and not adjusted for multiplicity.

In clinicWarn patients before starting that nausea, diarrhoea and vomiting are commonest during dose escalation, usually settle, and are managed with smaller bland meals and good hydration.