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Short Communication | DOI: https://doi.org/10.31579/2768-0487/111
1 Endocrinology Division, Olive View-UCLA Medical Center, David-Geffen UCLA Medical School, CA, USA.
2 Department of Medicine, Olive View-UCLA Medical Center, David-Geffen UCLA Medical School, CA, USA.
*Corresponding Author: Nasser Mikhail, Endocrinology Division, Olive View-UCLA Medical Center, David-Geffen UCLA Medical School, CA, USA.
Citation: Mikhail N., Wali S., (2023), Retatrutide as a Novel Treatment for Obesity and Type 2 Diabetes, Journal of Clinical and Laboratory Research. 6(2); DOI:10.31579/2768-0487/111
Copyright: Nasser Mikhail, Endocrinology Division, Olive View-UCLA Medical Center, David-Geffen UCLA Medical School, CA, USA.
Received: 02 August 2023 | Accepted: 16 August 2023 | Published: 01 September 2023
Keywords: retatrutide; glp-1; gip; glucagon; obesity; diabetes; tirzepatide
Retatrutide is a triple hormone agonist of the receptors of glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide (GIP) and glucagon that can be administered subcutaneously once a week. Different doses and escalation schedules of retatrutide were evaluated in 2 phase 2 American trials of subjects with obesity (n=338) and type 2 diabetes (n=281). In the obesity trial of 48 week-duration, percentage change in body weight from baseline after 24 weeks and 48 weeks were the primary and secondary outcomes respectively. At 24 weeks, mean percentage decrease in weight ranged from 7.2perencetage to 17.5perencetage across retatrutide groups versus 1.6perencetage with placebo. At 48 weeks, the decrease was 8.7perencetage to 24.2perencetage versus 2.1perencetage with placebo. In the diabetes trial, the primary endpoint was change in glycated hemoglobin (HbA1c) values from baseline to week 24. This trial included an active treatment group receiving dulaglutide 1.5 mg once weekly. Secondary endpoints included change in HbA1c and body weight at 36 weeks. At 24 weeks, mean HbA1c reductions was 0.43perencetage to 2.02perencetage with retatrutide, 1.4perencetage with dulaglutide and 0.01perencetage with placebo. At 36 weeks, mean percentage weight reductions were 3.2perencetage to 16.9perencetage with retatrutide, 2.0perencetage with dulaglutide and 3.0perencetagewith placebo. While the decrease in HbA1c levels reached a plateau at 24 weeks, weight loss in the 2 studies was progressive without evidence of attenuation effect up to the end of follow-up at 36-48 weeks. The most common adverse effects of retatrutide were gastrointestinal (GI) such as nausea, diarrhea, vomiting and constipation reported by 13-50perencetage in the retatrutide groups compared with 35perencetagein the dulaglutide group, and 13perencetage in the placebo group. Discontinuation rates due to adverse effects were also higher with retatrutide being 16-17perencetage compared with 2perencetage with dulaglutide and 0-4perencetage with placebo. In summary, retatrutide is highly effective drug in causing substantial weight loss and HbA1c reduction. Yet, tolerance to this drug seems sub-optimal. Phase 3 trials are urgently needed to clarify efficacy and safety of retatrutide.
Retatrutide (LY3437943) is a novel triple agonist of the 3 receptors GLP-1, GIP, and glucagon [1]. Compared to the native hormones, retatrutide shows 2.9-fold less potency at the glucagon receptor (GCCR), 2.5-fold less potency at the GLP-1 receptor, and 8.9-fold greater potency at human GIP receptor [1]. The approximate half-life of retatrutide is approximately 6 days making it suitable for once weekly administration [2]. Pre-clinical studies and phase 1 trials showed that retatrutide was highly effective in promoting weight loss and lowering HbA1c levels [1,2]. Recently, 2 phase 2 studies designed to examine efficacy and safety of retatrutide for treatment of obesity and type 2 diabetes were published (table 1) [3,4]. The main purpose of this article is to provide an appraisal about this novel agent based on available data.
| Obesity trial [3] | Type 2 diabetes trial [4] | |
| Design | Double-blind, randomized, placebo-controlled, 7 groups, in the USA | Double-blind, double-dummy, randomized, placebo-controlled, 8 groups, in the USA |
| Study duration | 48 weeks | 36 weeks |
| Subjects | N=338, mean age 48.2 years, 48% women, 88% Whites, 35% Hispanics | N=281, mean age 56.2 years, 56% women, 84% Whites, 47% Hispanics |
| Baseline mean body weight and BMI | 107.7 kg and 37.3 kg/m2 | 98.2 kg and 35.0 kg/m2 |
| Baseline HbA1c | 5.6% | 8.3% |
| Intervention | Retatrutide 1 mg, 4 mg (starting dose 2 mg), 4 mg (starting dose 2 mg), 8 mg (starting dose 2 mg), 8 mg (starting dose 4 mg), or 12 mg (starting dose 2 mg) subcutaneously once a week vs placebo | Retatrutide 0.5 mg, 4 mg (starting dose 2mg), 4 mg (no escalation), 8 mg (starting dose 2 mg), 8 mg (starting dose 4 mg), or 12 mg (starting dose 2 mg), 1.5 mg dulaglutide, or placebo |
| Primary end point | Percentage change in weight from baseline to 24 weeks | Change in HbA1c from baseline to week 24 |
| Secondary endpoints | Percentage change in weight from baseline to 48 weeks, weight reduction of ≥5%, ≥10%, or ≥15% | Change in HbA1c and weight from baseline to week 36 |
| Effect of retatrutide on weight | At 24 weeks: -7.2% to -17.5% with retatrutide vs -1.6% with placebo. At 48 weeks: -8.7% to -24.2% with retatrutide vs -2.1% with placebo | At 36 weeks: -3.2% to -16.9% with retatrutide vs -2.0% with dulaglutide, and -3.0% with placebo |
| Effect of retatrutide on HbA1c levels | At 24 weeks: -0.1% to -0.4% vs +0.1% with placebo | At 24 weeks: -0.43% to -2.02% with retatrutide vs -1.41% with dulaglutide, and –0.01% with placebo |
| Drug discontinuation rates due to adverse effects | 7-16% with retatrutide vs 0% with placebo | 0-17% with retatrutide vs 2% with dulaglutide vs 4% with placebo |
| Supraventricular arrhythmias and cardiac conduction disorders | 4-14% with retatrutide vs 3% with placebo | 4-8% with retatrutide, 4% with dulaglutide, 2% with placebo |
Abbreviations in the table: BMI: body mass index, HbA1c: glycated hemoglobin.
Table 1: Overview of phase 2 trials of retatrutide for treatment of obesity and type 2 diabetes.
Retatrutide for treatment of obesity
Retatrutide, in different subcutaneous doses of 1, 4, 8 and 12 mg and escalation schedules, was evaluated for treatment of obesity in a phase 2, randomized, placebo-controlled, double-blind trial of 48 week-duration in the USA (table 1) [3]. Contrary to most preceding obesity trials that predominantly enrolled women, this study included 51.8% men [3]. Participants (n=338) had mean age of 48.2 years, and mean baseline weight of 107.7 kg, and body mass index (BMI) of 37.3 kg/m2 (table 1) [3]. All subjects received lifestyle intervention including regular counseling sessions [3]. At 24 weeks, mean percentage decrease in weight (primary outcome) ranged from 7.2% to 17.5% with different retatrutide doses compared with 1.6% with placebo. At 48 weeks, there was progressive decrease in weight (secondary outcome) ranging from 8.7% to 24.2% with retatrutide versus 2.1% with placebo [3]. Weight loss was dose-related between retatrutide doses of 1 to 8 mg. However, the difference in weight loss between the highest 2 doses, 8 and 12 mg, was minimal [3]. Inspection of the trajectory of weight loss with time showed that weight loss with retatrutide was evident after 4-8 weeks and progressed with no evidence of plateau to the end of follow-up at 48 weeks [3]. At 48 weeks, weight reduction of ≥15% was achieved by 75-83% of subjects who received 8-12 mg dose of retatrutide. Interestingly, women and subjects with BMI of ≥35 kg/m2 had more weight loss than men and subjects with BMI < 35>
Retatrutide for treatment of type 2 diabetes
In another phase 2 trial in the USA, retatrutide was evaluated for treatment of type 2 diabetes in comparison with subcutaneous dulaglutide (1.5 mg/weekly) and placebo (table 1) [4]. Study duration was 36 weeks. The primary outcome was change in HbA1c values from baseline to 24 weeks, whereas secondary endpoints were changes in HbA1c and weight after 36 weeks (table 1) [4]. Patients (n=281, 56% women, mean age 56 years) had type 2 diabetes of approximately 8 year-duration uncontrolled on metformin
with mean baseline HbA1c of 8.3% [4]. At 24 weeks, reductions in HbA1c levels were dose-related in the retatrutide groups ranging from 0.43 to 2.02%, versus 1.31% in the dulaglutide group and 0.01% in the placebo group [4]. HbA1c reductions were significantly greater with the 2 retatrutide highest doses (8 mg given in slow escalation and 12 mg/week) than with dulaglutide (P<0>
Effects of retatrutide on cardiovascular risk factors
Amelioration of several cardiovascular risk factors, mainly due to weight loss, was observed with retatrutide treatment [3,4]. In the obesity study, 72% of the participants who had prediabetes at baseline in the retatrutide groups reverted to normoglycemia (HbA1C < 5>
Safety of retatrutide
In the 2 phase 2 trials, 16-17% discontinued retatrutide compared with 0-4% with placebo due to adverse effects (table 1) [3,4]. In general, safety profile of retatrutide mimics that of incretin-based drugs with GI adverse effects being the most common in incidence and the most frequent cause of drug discontinuation. GI adverse effects (nausea, diarrhea, vomiting and constipation) were dose-related and occurred mainly during the early dose escalation period [3,4]. In the obesity trial, proportions of subjects reporting nausea were 14-60% with retatrutide versus 11% with placebo [3]. In the diabetes study, GI adverse effects were reported by 13-50% in the retatrutide group, 35% in the dulaglutide group, and 13% in the placebo group [4]. This relatively high rate of GI adverse effect may be attributed to the glucagon receptor agonism component of retatrutide. In fact, glucagon has been shown to slow gastric emptying and inhibit GI motility [5].
Effect of retatrutide on heart rate
Increase in heart rate, of approximately 2-6 beats per minute (bpm) compared with placebo, was observed with use of all GLP-1 receptor agonists and with the dual GLP-1/GIP receptor agonist tirzepatide [6-11]. However, this adverse effect did not result in increase in cardiovascular events in dedicated randomized trials [7,8]. With retatrutide, the increase in heart rate peaked 24 weeks after starting treatment and partially declined thereafter [3,4]. Placebo-adjusted increase in heart rate by retatrutide was 5.6 bpm in the obesity trial at 48 weeks and 7.5 bpm in the diabetes trial after 36 weeks [3]. In the latter study, corresponding increase was 5 bpm with dulaglutide. Furthermore, cardiac arrhythmias occurred in 4-14% and 2-3% in the retatrutide groups and placebo group, respectively in the 2 trials [3,4]. The increase in heart rate by teratrutide could be mediated in part by glucagon receptor agonism. Indeed, most, but not all, studies have shown that glucagon administration increases heart rate acutely in humans [12].
Advantages of retatrutide
The major advantage of teratrutide is its high efficacy for weight loss that exceeds efficacy of all available anti-obesity drugs. The dual GLP-1 and GIP agonist tirzepatide is currently considered the most effective drug to lower HbA1c levels and promote weight loss [10,11]. While no direct comparison between retatrutide and tirzepatide is available and duration of use is different (36-48 weeks with retatrutide versus 72 weeks with tirzepatide), retatrutide may be superior to tirzepatide in both parameters, particularly weight loss (table 2) [3,4,10,11].
| Retatrutide [3,4] | Tirzepatide [10,11] | |
| Maximum percentage weight loss in obese subjects without diabetes | 24.2% vs 2.1% placebo at 48 weeks. Difference 22.1% [3] | 20.9% vs 3.1% placebo at 72 weeks. Difference 17.8% [11] |
| Maximum weight loss in patients with type 2 diabetes | 16.9% vs 3.0% placebo at 36 weeks. Difference 13.9% [4] | 12.8% vs 3.2% placebo at 72 weeks. Difference 9.6% [11] |
| Maximum HbA1c reduction in patients with type 2 diabetes | 2.02% vs 0.01% placebo at 36 weeks. Difference 2.01% [4] | 2.1% vs 0.5% placebo at 72 weeks. Difference 1.6% [11] |
Abbreviations: HbA1c; glycated hemoglobin.
Table 2. Efficacy of retatrutide and tirzepatide in treatment of obesity and type 2 diabetes Furthermore, the difference.
in efficacy of weight reduction between the 2 agents may become even greater with more prolonged use of teratrutide beyond 48 weeks. This enhanced efficacy of retatrutide in promoting weight loss is most likely mediated through glucagon receptor agonism. In fact, Goscun et al [1] have shown that retatrutide caused weight loss in obese mice by increasing energy expenditure through glucagon receptor engagement. Moreover, a phase 1 study has shown that retatrutide may decrease appetite and increase sensation of fullness and satiety in patients with type 2 diabetes [2]. Decreased appetite was reported by 11-31% among retatrutide-treated subjects (vs 9% placebo) in the obesity trial and by 10% (vs 2% placebo) in the diabetes trial [3,4].
The main limitation of retatrutide is the high frequency rates of discontinuation due to adverse effects reaching 17% with the highest doses. These rates are much higher than the 7% discontinuation rate reported with the highest dose of tirzepatide (15 mg/week) versus 4% with placebo [10]. Since most GI adverse effects occurred during retatrutide dose escalation, the use of smaller starting doses and slower titration might decrease the incidence of GI adverse effects. In addition, the increase in pulse rate and arrhythmias is concerning and should be inspected thoroughly in pending trials, preferably using Holter monitoring of heart rate.
No doubt, retatrutide is a promising novel tri-agonist of receptors of the 2 incretins GLP-1 and GIP and glucagon. This drug showed high efficacy in causing weight loss not previously recorded with any anti-obesity agent. Additionally, its efficacy for treatment of type 2 diabetes is at least comparable to tirzepatide (table 2). Meanwhile, tolerance to retratrutide may be suboptimal with unacceptable high discontinuation rates due to adverse effects. Moreover, there are signals of increase incidence of cardiac arrhythmias associated with its use. Ongoing large-scale phase 3 trials should clarify efficacy and safety of retratrutide in subjects with obesity and type 2 diabetes. In addition, adequately powered and long-term (at least 3 years) studies designed to see the effects of retatrutide on cardiovascular events and mortality should be conducted.
The authors have no conflict of interest to declare.
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Journal of Clinical Cardiology and Cardiovascular Intervention The submission and review process was adequate. However I think that the publication total value should have been enlightened in early fases. Thank you for all.
