The Lancet study unveils exciting findings on retatrutide as a novel treatment for type 2 diabetes

By Neha MathurReviewed by Lily Ramsey, LLMJun 29 2023

In a recent article published in The Lancet, researchers performed a phase II randomized clinical trial (RCT) in the United States (US) among adults aged 18–75 years with type 2 diabetes (T2D) between May 13, 2021, and June 13, 2022.

The study aimed to evaluate the efficacy and safety of a range of doses of retatrutide, a novel single peptide with activity against three receptor agonists, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon receptor agonist that demonstrated clinically relevant glucose- and bodyweight-lowering efficacy in a phase I study. 

Study: Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. Image Credit: AhmetMisirligul/Shutterstock.com

Background

Though glucagon receptor agonists are available for short-term use in hypoglycemia patients, GIP receptor agonists are unavailable for clinical use.

Five agonists that provide GLP-1 and glucagon receptor activity are in phase I/II of clinical development, of which only cotadutide and SAR425899 have shown substantial glycaemic efficacy. However, their effects on body weight were comparable to GLP-1 receptor agonists.

Evidence shows that tirzepatide also confers better glycaemic control and bodyweight reductions than GLP-1 receptor agonists. Nonetheless, glucagon receptor agonist activity can increase energy expenditure, as assessed in several studies conducted among human subjects.

The ratio of glucagon versus GLP-1 activity is a key determinant of the efficacy and safety profile of GLP-1 and glucagon agonists. There is adequate preclinical evidence that retatrutide (LY3437943) attains that balance and improves glucose control and lipid metabolism. It also helps reduce body weight by decreasing energy intake and increasing energy expenditure. 

Few other GIP, GLP-1, and glucagon receptor agonists, e.g., HM15211 and SAR441255, have reached early clinical development. Studies have shown that even multiple rises of retatrutide are well-tolerated by people with T2D, and it improves overall cardiometabolic risk measures, irrespective of dosage.

About the study

The present study recruited adults aged 18–75 with T2D, glycated hemoglobin (HbA1c) between 53 and 91·3 mmol/mol, and body mass index (BMI) of 25–50 kg/m² from 42 research and health-care US centers. They assigned participants to four groups receiving four maintenance retatrutide doses, 0·5, 4, 8, and 12 mg.

Some participants in the 4 mg dose group initiated treatment at a 2 mg dose, which they later escalated to 4 mg. Likewise, some participants assigned to the 8 mg dose group underwent a slow (from 2 to 4 to 8 mg) or fast dose escalation (from 4 to 8 mg).

For dose escalation, the team increased the retatrutide dose every four weeks till they attained the maintenance dose. 

The study screening lasted three weeks, and its treatment and safety follow-up lasted 36- and four weeks, respectively. Further, the researchers trained all participants to use syringes and single-dose pens, facilitating injecting study drugs on-site at randomization.

Additionally, they reviewed participants’ injection techniques at weeks one, two, four, eight, and 12 and repeated training, if needed. The team assessed compliance to study drug treatment via participant diaries at study visits.

The primary and secondary endpoints were changes in HbA1c levels from baseline to 24 weeks and 36 weeks. They also assessed the percentage of participants reaching HbA1c of <7% (53 mmol/mol), change in fasting blood glucose, blood pressure (BP), lipid measures, and body weight during this time.

Additionally, the participants self-monitored prespecified exploratory efficacy endpoints, such as blood glucose level changes during this time. 

Finally, the team determined safety and tolerability endpoints, e.g., drug-related adverse events, vitals, laboratory parameters, and electrocardiograms.

Results 

There were 534 participants in screening; however, only 222 participants with a mean age were 56·2 years completed the treatment, of which 156 were females. The mean duration of diabetes in study participants was 8.1 years, and their average HbA1c, body mass index (BMI), and body weight were 8.3%, 35 kg/m², and 98·2 kg, respectively.

There were six retatrutide groups, where 47, 23, 24, 26, 24, and 46 individuals received retatrutide 0·5 mg, 4mg, 8mg slow and fast doses, and 12mg escalated doses, respectively.

For comparison, there were two other study groups with 45 and 46 individuals who received one injection of placebo and 1·5 mg dulaglutide every week. The safety and efficacy analyses encompassed 281 and 275 participants, respectively. The team excluded six, i.e., one individual from each retatrutide group.

In this trial, individuals in the retatrutide 12 mg escalation group, at week 36, showed HbA1c reductions of up to 2.16%, i.e., 23·59 mmol/mol. The effect was higher for a 4 mg dose or higher, suggesting the maximal effect required more treatment time. Moreover, the dose-dependent effect did not vary between the 8 mg and 12 mg groups.

Bodyweight reduction is a crucial component of T2D treatment. Encouragingly, in the retatrutide 12 mg escalation group, individuals showed up to ~17% bodyweight reductions at 36 weeks, a magnitude of reduction not documented till date in any other phase II\ III trials testing GLP-1 and GLP-1 receptor agonists in people with T2D.

For context, in other studies with different study designs and subject-level differences, researchers have documented weight reductions of up to ~5% with other drugs, e.g., 7·2% with 2 mg semaglutide after treatment periods of up to 68 weeks.

However, up to 63% of retatrutide-treated participants lost 15% of body weight in lesser time, which could lead to T2D remission. Perhaps, retatrutide helped people attain potentially greater body weight reduction in part by increasing energy expenditure and fatty acid oxidation.

In addition, retatrutide dose-dependently decreased systolic and diastolic BP and improved lipid measures. For instance, they reduced non-HDL cholesterol concentrations and triglycerides by up to 35%. Owing to its glucagon activity, retatrutide increased hepatic fatty acid oxidation and reduced hepatic lipogenesis.

It also increased lipolysis in adipose tissue by GIP receptor activation. In this way, it reduced liver fat and improved lipid profiles.

Furthermore, it brought about dose-dependent reductions in concentrations of gluconeogenic amino acids (AAs), e.g., alanine and arginine, and lesser reductions in concentrations of phenylalanine and histidine, two essential AAs.

Conclusions

The study results confirmed the observations from a prior 12-week phase I study. In the current phase II RCT, retatrutide showed remarkable and clinically relevant glycaemic control in a 36-week treatment period.

Besides, it improved the lipid profile and reduced blood pressure, i.e., much-improved cardiometabolic outcomes, and even its safety profile was comparable to other GLP-1, GIP, and glucagon receptor agonist classes, with reports of only transient gastrointestinal adverse events that were mild or moderate. 

They occurred more frequently with the 4 mg starting dose groups rather than the 2 mg starting dose groups. Taken together, the study findings highlighted the need for phase III trials to further test the efficacy and safety of retatrutide in obese people with or without T2D.