Tirzepatide Dosing Protocol: Dual Agonist Research

Among 41 222 adults meeting the study criteria (semaglutide, 32 029; tirzepatide, 9193), 18 386 remained after propensity score matching. The mean (SD) age was 52.0 (12.9) years, 12 970 were female (70.5%), 14 182 were white (77.1%), 2171 Black (11.8%), 354 Asian (1.9%), 1679 were of other or unknown race, and 9563 (52.0%) had T2D.

Limitations: No placebo control reported.

The 160 participants (pooled tirzepatide doses n&#x2009;=&#x2009;124, placebo n&#x2009;=&#x2009;36) with baseline and end of study DXA data were 73% female and had a mean weight of 102.5&#x2009;kg and body mass index of 38.0&#x2009;kg/m2. The change in body weight, fat mass and lean mass from baseline to Week 72 was -21.3%, -33.9% and -10.9% with tirzepatide and -5.3%, -8.2% and -2.6% with placebo, respectively (p&#x2009;<&#x2009;0.001 for all comparisons).

Limitations: Standard limitations apply. Check original paper for full discussion.

A total of 751 participants underwent randomization. The least-squares mean percent change in weight at week 72 was -20.2% (95% confidence interval [CI], -21.4 to -19.1) with tirzepatide and -13.7% (95% CI, -14.9 to -12.6) with semaglutide (P<0.001).

Limitations: No placebo control reported.

In the clinical trial, tirzepatide appeared to have no impact on metabolic adaptation but led to increased fat oxidation and reductions in appetite and calorie intake during an ad libitum test meal (vs. This is the first study to provide insights into the mechanisms of action of tirzepatide on weight loss with respect to calorie intake, energy expenditure, and macronutrient utilization.

Limitations: Standard limitations apply. Check original paper for full discussion.

Between May 10, 2021, and June 24, 2023, 413 participants were screened, and 267 were randomly assigned. Due to exclusion of one study site, the mITT population was 225 participants (133 [59%] men and 92 [41%] women, mean age 50&#xb7;8 [SD 10&#xb7;7] years), with 73 in the tirzepatide 10 mg group, 77 in the tirzepatide 15 mg group, and 75 in the placebo group, of whom 192 (85%) completed both study and treatment.

Limitations: Standard limitations apply. Check original paper for full discussion.

Benchmarking of the 2 trial emulations demonstrated high agreement on all prespecified metrics. In analyses using expanded eligibility criteria, 58&#x202f;333 patients were included in the semaglutide vs sitagliptin cohort, 11&#x202f;257 for tirzepatide vs sitagliptin, and 28&#x202f;100 for tirzepatide vs semaglutide.

Limitations: Standard limitations apply. Check original paper for full discussion.

Whether cardiovascular benefits will be found with dual GLP-1/GIP receptor agonists remains uncertain, and the contribution of GIP receptor activation to cardiovascular risk has not been established. Several ongoing large-scale cardiovascular outcome trials for tirzepatide will provide a clearer understanding of where tirzepatide should be positioned in the treatment of established atherosclerotic cardiovascular disease or in people at high risk, in relation to current standard-of-care cardioprotective agents and approaches.

Limitations: Review article — no new primary data.

A total of 282 adults were randomly assigned to tirzepatide (n&#x2009;= 139) or dulaglutide (n&#x2009;= 143). Change from baseline in HbA1c at week 40 was -1.44% (SE, 0.07) with tirzepatide, 15 mg or MTD, and -0.67% (SE, 0.08) with dulaglutide, 4.5 mg or MTD (estimated treatment difference, -0.77% [95% CI, -0.98% to -0.56%; P&#x2009;<&#x2009;0.001]).

Limitations: No placebo control reported.

Tirzepatide also results in clinically important improvements in multiple obesity-related complications including sleep apnea, metabolic-dysfunction associated steatohepatitis, heart failure with preserved ejection fraction and diabetes prevention. Ongoing trials will provide further data on tirzepatide's long-term safety, efficacy (including cardiovascular outcomes) and potential cost-effectiveness for managing overweight/obesity and/or T2D.

Limitations: No placebo control reported. Review article — no new primary data.

The most common adverse events were usually short-lived gastrointestinal-related events, which were generally mild to moderate in nature, including nausea, diarrhoea, decreased appetite and vomiting. Tirzepatide is a valuable addition to the treatment options for people with inadequately controlled T2DM.

Limitations: No placebo control reported. Review article — no new primary data.

Of the 6 articles included in the review, one investigated the use of tirzepatide and showed a statistically significant reduction in area under the plasma drug concentration-time curve, maximum concentration, and time to maximum plasma concentration when tirzepatide was concomitantly administered with an oral hormonal contraceptive. The remaining 5 studies involving GLP-1 RAs did not show a statistically or clinically significant difference of impact of the agents on oral hormonal contraceptives.

Limitations: No placebo control reported. Review article — no new primary data.

Body weight, BMI, WC, FM, FBG, LDL-C, TC, TG and HOMA-IR were significantly decreased in Ex+P, Ex+T5 and Ex+T2.5 groups compared to Placebo, T5 and T2.5 groups. WHR significantly decreased in Ex+P, Ex+T5 and Ex+T2.5 groups compared to Placebo group.

Limitations: Standard limitations apply. Check original paper for full discussion.

A total of 12 randomized controlled trials were included, with a total of 11,758 patients. Meta analysis results showed that compared with the glucagon like peptide-1 receptor agonist (GLP-1 RAs), placebo and insulin groups, tirzepatide could significantly reduce the BMI (body mass index) of patients [MD&#x2009;=&#x2009;-1.71, 95% CI (-2.46, -0.95), p&#x2009;&#x2009;0.05).

Limitations: Review article — no new primary data.

There were 14&#x202f;834 patients treated with tirzepatide (mean [SD] age, 55.4 [11.8] years; 8444 [56.9%] female) and 125&#x202f;474 treated with GLP-1 RA (mean [SD] age, 58.1 [13.3] years; 67&#x202f;474 [53.8%] female). After a median (IQR) follow-up of 10.5 (5.2-15.7) months, 95 patients (0.6%) in the tirzepatide group and 166 (1.1%) in the GLP-1 RA group died.

Limitations: No placebo control reported.

Tirzepatide treatment demonstrated significant reductions in body weight compared with placebo and semaglutide, resulting in greater fat mass reduction. Tirzepatide and semaglutide significantly reduced appetite versus placebo.

Limitations: Standard limitations apply. Check original paper for full discussion.

Evidence from five SURPASS clinical trials has demonstrated that tirzepatide has potent glucose lowering and weight loss with adverse effects comparable to GLP-1 receptor agonists. This paper gives an overview of tirzepatide and SURPASS clinical trials.

Limitations: No placebo control reported.

Among 1428 randomized participants (824 [57.7%] women; mean [SD] age, 58.8 [9.7] years; mean [SD] HbA1c, 8.8% [1.0%]), 1304 (91.3%) completed the trial. At week 52, estimated mean change from baseline in HbA1c with tirzepatide (pooled cohort) was -2.1% vs -1.1% with insulin lispro, resulting in mean HbA1c levels of 6.7% vs 7.7% (estimated treatment difference, -0.98% [95% CI, -1.17% to -0.79%]; P&#x2009;<&#x2009;.001); results met noninferiority criteria and statistical superiority was achieved.

Limitations: No placebo control reported.

In people without diabetes, tirzepatide 5 to 15 mg once weekly for the treatment for obesity (SURMOUNT-1) resulted in substantial reductions in body weight (16.5% to 22.4%) over 72 weeks. Overall, the SURPASS program and SURMOUNT-1 study suggest that tirzepatide is marking a new era in T2DM and/or obesity management through dual agonism of gut hormones.

Limitations: Animal study only — human translation uncertain. Review article — no new primary data.

Moreover, tirzepatide also decreased eGFR slopes in participants with eGFR >60&#xa0;mL/min/1.73 m2 or with normoalbuminuria. We now review the potential kidney health implications of tirzepatide, addressing its structure and function, relationship to current GLP1 receptor agonists, impact of recent results for the treatment and prevention of kidney disease, and expectations for the future.

Limitations: No placebo control reported. Review article — no new primary data.

Ten trials (6836 participants) were included. Gastrointestinal (GI) AEs were the most commonly reported AEs and were dose dependent 39% (95% CI, 35%-43%), 46% (95% CI, 42%-49%), and 49% (95% CI, 38%-60%) for the 5, 10, and 15&#x2005;mg dose, respectively.

Limitations: No placebo control reported. Review article — no new primary data.

RCTs included in this study revealed that among 5800 patients, 78.22% (95%.

Limitations: Review article — no new primary data.

A total of nine trials with 9871 participants (6828 in the tirzepatide group and 3043 in the control group) that met the pre-specified criteria were included. When compared to all control groups consisting of basal insulin (glargine or degludec), selective GLP1-RA (dulaglutide or semaglutide once weekly), and placebo, an increased risk of pancreatitis was not found to be significantly associated with tirzepatide (RR 1.46, [95% CI] 0.59 to 3.61; I2&#xa0;=&#xa0;0.0%, p = 0.436).

Limitations: Review article — no new primary data.

The tirzepatide cardiovascular outcomes trial (SURPASS-CVOT) is in progress and is expected to be completed in the fall of 2024. Tirzepatide represents an attractive new option and first-in-class agent for the treatment of T2D in people unable to achieve their glycaemic or weight management goals.

Limitations: Review article — no new primary data.

Among 475 randomized participants (211 [44%] women; mean [SD] age, 60.6 [9.9] years; mean [SD] HbA1c, 8.31% [0.85%]), 451 (94.9%) completed the trial. Treatment was prematurely discontinued by 10% of participants in the 5-mg tirzepatide group, 12% in the 10-mg tirzepatide group, 18% in the 15-mg tirzepatide group, and 3% in the placebo group.

Limitations: Standard limitations apply. Check original paper for full discussion.

Moreover, it remains to be shown that GIPR agonism can improve insulin secretion in type 2 diabetic patients who have been noted in previous studies to be unresponsive to GIP. Certainly, the apparent advantage of tirzepatide, a dual incretin agonist, over GLP-1RA will spark renewed interest in the therapeutic potential of GIP in type 2 diabetes, obesity and related co-morbidities.

Limitations: No placebo control reported. Review article — no new primary data.

Seven trials (6609 participants) were included. A dose-dependent superiority in lowering HbA1c was evident with all three tirzepatide doses vs all comparators, with mean differences ranging from -17.71&#xa0;mmol/mol (-1.62%) to -22.35&#xa0;mmol/mol (-2.06%) vs placebo, -3.22&#xa0;mmol/mol (-0.29%) to -10.06&#xa0;mmol/mol (-0.92%) vs GLP-1 RAs, and -7.66&#xa0;mmol/mol (-0.70%) to -12.02&#xa0;mmol/mol (-1.09%) vs basal insulin regimens.

Limitations: Review article — no new primary data.

From April 1, 2019, to Nov 15, 2019, 502 participants were assessed for eligibility to participate in this substudy, 296 (59%) of whom were included in the enrolled MRI population and randomly assigned to treatment (tirzepatide 5 mg, n=71; tirzepatide 10 mg, n=79; tirzepatide 15 mg, n=72; and insulin degludec, n=74). Baseline demographics and clinical characteristics were similar across all treatment groups.

Limitations: No placebo control reported.

Tirzepatide is in phase III development for heart failure, obesity and cardiovascular disorders in T2DM, and in phase II development for non-alcoholic steatohepatitis. This article summarizes the milestones in the development of tirzepatide leading to this first approval for T2DM.

Limitations: No placebo control reported. Review article — no new primary data.

Between May 7, 2019, and March 31, 2021, 821 participants were assessed for study eligibility and 636 were randomly assigned to receive at least one dose of tirzepatide 5 mg (n=159), 10 mg (n=158), or 15 mg (n=160), or dulaglutide 0&#xb7;75 mg (n=159). 615 (97%) participants completed the study and 21 (3%) discontinued.

Limitations: No placebo control reported.

Between June 28, 2019, and April 8, 2021, we screened 184 individuals and enrolled 117 participants, all of whom were included in the safety population (45 in the tirzepatide 15 mg group, 44 in the semaglutide 1 mg group, and 28 in the placebo group). Because of discontinuations and exclusions due to missing or unevaluable data, 39 patients in each treatment group and 24 patients in the placebo group comprised the pharmacodynamic analysis set.

Limitations: Standard limitations apply. Check original paper for full discussion.

Tirzepatide Once Weekly for the Treatment of Obesity. (The New England journal of medicine, 2022)

Limitations: No placebo control reported.

From June 3, 2019, to Oct 28, 2020, of 705 individuals assessed for eligibility, 478 (mean baseline HbA1c 7&#xb7;9% [63 mmol/mol], age 54&#xb7;1 years [SD 11&#xb7;9], 231 [48%] women, diabetes duration 4&#xb7;7 years, and body-mass index 31&#xb7;9 kg/m2) were randomly assigned to tirzepatide 5 mg (n=121 [25%]), tirzepatide 10 mg (n=121 [25%]), tirzepatide 15 mg (n=121 [25%]), or placebo (n=115 [24%]). 66 (14%) participants discontinued the study drug and 50 (10%) discontinued the study prematurely.

Limitations: Standard limitations apply. Check original paper for full discussion.

Experiments in primary islets reveal &#x3b2;-arrestin1 limits the insulin response to GLP-1, but not GIP or tirzepatide, suggesting that the biased agonism of tirzepatide enhances insulin secretion. Imbalance toward GIP receptor, combined with distinct signaling properties at the GLP-1 receptor, together may account for the promising efficacy of this investigational agent.

Limitations: Animal study only — human translation uncertain.

This information is based on available published literature. It should not take the place of medical care and advice from your healthcare provider.

Limitations: Animal study only — human translation uncertain. Review article — no new primary data.

Homeostatic model assessment (HOMA) 2-B significantly increased with dulaglutide and tirzepatide 5, 10, and 15 mg compared with placebo (P &#x2264; .02). Proinsulin/insulin and proinsulin/C-peptide ratios significantly decreased with tirzepatide 10 and 15 mg compared with placebo and dulaglutide (P &#x2264; .007).

Limitations: Standard limitations apply. Check original paper for full discussion.

Between April 1 and Nov 15, 2019, we assessed 1947 participants for eligibility, 1444 of whom were randomly assigned to treatment. The modified intention-to-treat population was 1437 participants from the tirzepatide 5 mg (n=358), tirzepatide 10 mg (n=360), tirzepatide 15 mg (n=359), and insulin degludec (n=360) groups.

Limitations: No placebo control reported.