Overview - Tirzepatide for managing overweight and obesity - Guidance

Tirzepatide 15 mg enhanced the first and second-phase insulin secretion rate by 466 % and 302 % from baseline, respectively. Tirzepatide decreased hunger and prospective food consumption starting at week 1 of the treatment and increased satiety starting at week 3. Clinical studies show that tirzepatide reduces energy intake and appetite by increasing feelings of satiety (fullness), decreasing feelings of hunger, and decreasing food cravings. Animal studies show that tirzepatide can modulate fat utilization through the GIP receptor.
12 Frequency was common in clinical trials supporting the type 2 diabetes indication and uncommon in clinical trials supporting the weight management indication. 10 Frequency was common in clinical trials supporting the type 2 diabetes indication, and uncommon in SURPASS-CVOT and clinical trials supporting the weight management indication. 9 Frequency was common in clinical trials supporting the weight management indication and SURPASS-CVOT, and uncommon in clinical trials supporting the type 2 diabetes indication.
In the 40 week trial versus semaglutide 1 mg, tirzepatide 5 mg, 10 mg and 15 mg resulted in 19 %, 24 % and 25 % reduction in serum triglycerides levels respectively compared to 12 % reduction with semaglutide 1 mg. Across SURPASS 1‑5 trials, tirzepatide 5 mg, 10 mg and 15 mg resulted in reduction in serum triglyceride of 15‑19 %, 18‑27 % and 21‑25 % respectively. An additional analysis was conducted specifically for the SURPASS-4 study that enrolled patients with established CV disease. Cardiovascular evaluation in patients with type 2 diabetes mellitus In a 40 week active-controlled open-label study, (double-blind with respect to tirzepatide dose assignment) patients were randomised to tirzepatide 5 mg, 10 mg or 15 mg once weekly or semaglutide 1 mg once weekly, all in combination with metformin.
All patients entered the lead-in period (open label) and received tirzepatide treatment for 36 weeks to achieve MTD of 10 mg or 15 mg subcutaneously once weekly. At 30 weeks, tirzepatide 5 mg and 10 mg, both pooled and individually, were superior to placebo in lowering HbA1c and reducing BMI. In the open-label period, all participants on placebo were switched to tirzepatide at a maintenance dose of 5 mg while participants randomized to tirzepatide continued their treatment at the same dose of 5 or 10 mg.
The rate of clinically significant hypoglycaemia when tirzepatide was used as monotherapy or when added to other oral antidiabetic medicinal products was 1.6 % (0.01 events/patient year). Clinically significant hypoglycaemia occurred in 16.3 % (0.18 events/patient year) of patients when tirzepatide was added to sulphonylurea and basal insulin. Of these 10 patients, 5 (0.1 %) were on a background of insulin glargine or sulphonylurea who reported 1 episode each. Hypoglycaemia in patients with type 2 diabetes mellitus in adults
In pooled placebo-controlled type 2 diabetes mellitus phase 3 studies, cholelithiasis was reported in 0.3% of tirzepatide-treated patients and 0 placebo-treated patients. More patients in the tirzepatide MTD group (4.1 %) compared to the placebo group (0 %) discontinued study treatment permanently due to the gastrointestinal event. Diarrhoea occurred in 18.4 % versus 6.3 %, and nausea in 17.0 % versus 6.5 % for tirzepatide MTD versus placebo. More patients in the tirzepatide group (2.1 %) compared to the placebo group (0.4 %) discontinued permanently due to the gastrointestinal event.
In pooled placebo-controlled type 2 diabetes mellitus phase 3 studies, treatment in adult patients with tirzepatide resulted in mean increases from baseline in pancreatic amylase of 33 % to 38 % and lipase of 31 % to 42 % across doses. The clinical significance of elevations in amylase or lipase with tirzepatide is unknown in the absence of other signs and symptoms of pancreatitis. In SURPASS-CVOT (active comparator-controlled), injection site reactions were reported in 1.5 % of tirzepatide-treated patients. No difference in arrythmia and cardiac conduction disorder treatment emergent events were observed between tirzepatide 5 mg, 10 mg, 15 mg and placebo (3.8 %, 2.1 %, 3.7 % and 3 % respectively).
Cases of anaphylactic reaction and angioedema have been rarely reported with tirzepatide during post-marketing surveillance. Hypersensitivity reactions were reported in 3.2 %, 5.0 %, 3.0 %, and 4.7 % of tirzepatide-treated patients, respectively, compared to 1.7 %, 3.8 %, 2.1 %, and 3.5 % of placebo-treated patients, respectively. The frequencies of adverse drug reactions in Table 1 reflect those observed in clinical trials in adults.
In adults, tirzepatide 15 mg reduced fasting glucagon concentration by 28 % and glucagon AUC after a mixed meal by 43 %, compared with no change for placebo. Tirzepatide reduced the fasting and postprandial glucagon concentrations in a glucose dependent manner. Reduced food intake with tirzepatide contributes to body weight loss. In adults, tirzepatide 15 mg improved whole body insulin sensitivity by 63 %, as measured by M-value, a measure of glucose tissue uptake using hyperinsulinemic euglycaemic clamp.
Up to 3 % and 2.3 % had neutralising antibodies against tirzepatide activity on the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, respectively and up to 1.2 % and 0.4 % had neutralising antibodies against native GIP and native GLP-1, respectively. In selected phase 3 clinical studies, a total of tirzepatide-treated patients were assessed for anti-drug antibodies (ADA). There was no identified clinically significant effect of anti-tirzepatide antibodies on pharmacokinetics or effectiveness of tirzepatide. No tirzepatide patients discontinued drug or study due to hair loss. In tirzepatide UK -CVOT (active comparator-controlled), cholelithiasis was reported in 2.4 % of tirzepatide-treated patients.
During the trial, treatment was permanently discontinued by 9.3 % and 13.8 % of patients randomised to tirzepatide 10 mg and 15 mg respectively compared to 14.9 % randomised to placebo. In a 72-week double blind placebo-controlled study, 938 adult patients with BMI ≥27 kg/m2 and type 2 diabetes mellitus, were randomised to tirzepatide 10 mg or 15 mg once weekly or placebo. A reduction in AHI was observed with tirzepatide irrespective of age, sex, ethnicity, baseline BMI or baseline OSA severity. All patients were treated with the maximum tolerated dose (MTD; 10 mg or 15 mg) of tirzepatide or placebo, once weekly for 52 weeks. A reduction in body weight was observed with tirzepatide irrespective of age, sex, race, ethnicity, baseline BMI, and glycemic status.
Statistically significant and clinically meaningful reductions from baseline in body weight were also demonstrated. All five phase 3 studies assessed tirzepatide 5 mg, 10 mg and 15 mg. Improvement of glycaemic control, reduction of cardiovascular morbidity and mortality, and weight loss are integral parts of the treatment of type 2 diabetes. Tirzepatide induced delay in gastric emptying diminishes over time. Tirzepatide delays gastric emptying which may slow post meal glucose absorption and can lead to a beneficial effect on postprandial glycaemia.
Animal studies show that tirzepatide distributes to and activates neurons in brain regions involved in regulation of appetite and food intake. The activity of tirzepatide on the GLP‑1 receptor is lower compared to native GLP‑1 hormone. The activity of tirzepatide on the GIP receptor is similar to native GIP hormone. A prolonged period of observation and treatment of these symptoms may be necessary, taking into account the half-life of tirzepatide (approximately 5 days). The rate was 9.1 % (0.28 events/patient year) and 4.2 % (0.07 events/patient year) for tirzepatide and placebo-treated patients, respectively, when added to metformin alone.
Changes in body composition were evaluated in a sub-study in SURMOUNT-1 using dual energy X-ray absorptiometry (DEXA). When patients did not tolerate this dose, the dose was reduced to tirzepatide 10 mg or semaglutide 1.7 mg once weekly. The weight reduction was superior and clinically meaningful compared to the placebo group, in which a substantial regain of body weight lost during the lead-in phase was observed (see Table 12 and Figure 12).
8 Frequency was common in clinical trials supporting the weight management indication and in SURPASS-CVOT, uncommon in trials supporting the type 2 diabetes indication, and very rare in the paediatric type 2 diabetes mellitus trials. 7 Frequency was common in clinical trials supporting the type 2 diabetes indication and very common in clinical trials supporting the weight management indication and in SURPASS-CVOT. Frequency was common in clinical trials supporting the type 2 diabetes indication and the weight management indication and very common in SURPASS-CVOT. 5 Frequency was common in clinical trials supporting the type 2 diabetes indication and very common in SURPASS-CVOT.
Nausea occurred in 23.6 % versus 7.7 % and diarrhoea in 24.0 % versus 10.7 % for tirzepatide versus placebo. More patients in the tirzepatide 5 mg (1.9 %), 10 mg (3.3 %) and 15 mg (4.3 %) groups compared to the placebo group (0.5 %) discontinued permanently due to the gastrointestinal event. Nausea occurred in 24.6 %, 29.0 % and 28.0 % versus 8.5 % and diarrhoea in 18.7 %, 20.8 % and 22.5 % versus 7.8 % for tirzepatide 5 mg, 10 mg and 15 mg versus placebo. Nausea occurred in 12.2 %, 15.4 % and 18.3 % versus 4.3 % and diarrhoea in 11.8 %, 13.3 % and 16.2 % versus 8.9 % for tirzepatide 5 mg, 10 mg, and 15 mg versus placebo. The risk of hypoglycaemia was increased when tirzepatide was used with a sulfonylurea. The rate of clinically significant hypoglycaemic episodes was similar across tirzepatide 10 mg and 15 mg (4.3, and 6.1 events per 100 patient years of exposure, respectively) and the placebo-treated group (9.7 events per 100 patient years of exposure).