Retatrutide: what it is and what studies found

The detailed research

Retatrutide's published human data come from phase 1 and phase 2 randomized trials ^[1][2][24]. Substudies and meta-analyses add more detail ^[27][28][29]. How Ellum weighs these designs is set out in How Ellum decides status, grades and what we publish.

In the paper that described the molecule, retatrutide lowered body weight in obese mice. It also improved blood sugar control in those mice ^[3]. The same paper reported a phase 1 study in people ^[3]. There, safety and tolerability looked similar to other incretin drugs ^[3]. A 12-week phase 1b trial then enrolled 72 adults with type 2 diabetes ^[2]. It compared retatrutide with placebo and with dulaglutide, an active comparator ^[2]. At week 12, HbA1c fell by 1.2 to 1.6 points more than placebo in the three highest groups ^[2]. Weight loss appeared to grow with dose ^[2].

The phase 2 obesity trial was double-blind, randomized and placebo-controlled ^[1]. It enrolled 338 adults with a BMI of 30 or more ^[1]. Adults with a BMI of 27 to under 30 could join if they had a weight-related condition ^[1]. Of those enrolled, 51.8% were men ^[1]. The main endpoint was weight change at 24 weeks ^[1]. Mean change ranged from -7.2% in the lowest group to -17.5% in the highest ^[1]. The placebo group changed by -1.6% ^[1]. At 48 weeks, the range was -8.7% to -24.2%, against -2.1% with placebo ^[1]. In the highest group, 100% lost at least 5% of body weight, 93% lost at least 10%, and 83% lost at least 15% ^[1]. On placebo, the shares were 27%, 9% and 2% ^[1].

The phase 2 type 2 diabetes trial enrolled 281 adults at 42 US centres ^[24]. They were randomly assigned to retatrutide, placebo or dulaglutide ^[24]. Participants and investigators did not know who got which. At 24 weeks, HbA1c fell by up to 2.02 points with retatrutide ^[24]. It fell by 0.01 with placebo and 1.41 with dulaglutide ^[24]. At 36 weeks, body weight fell by up to 16.94% with retatrutide ^[24]. It fell by 3.00% with placebo and 2.02% with dulaglutide ^[24]. Of the 281 adults, 237 completed the study ^[24].

A liver-fat substudy of the obesity trial enrolled 98 adults ^[27]. All had fatty liver disease and at least 10% liver fat ^[27]. At 24 weeks, liver fat fell, in relative terms, by 42.9% in the lowest group and 82.4% in the highest ^[27]. With placebo, it rose by 0.3% ^[27]. In the highest group, 86% reached normal liver fat, against none on placebo ^[27]. A body-composition substudy of the diabetes trial enrolled 189 adults ^[28]. Of these, 103 had DXA scans, a type of X-ray body scan, at the start and at week 36 ^[28]. Total fat mass fell by 15.2% to 26.1% in the three higher groups ^[28]. It fell by 4.5% with placebo ^[28]. The authors found the share of weight lost as lean mass similar to other obesity treatments ^[28].

A meta-analysis pooled 3 randomized trials with 878 patients ^[29]. It found a mean weight difference of -14.33% versus placebo ^[29]. Its authors called for larger, longer trials ^[29]. A systematic review of 26 placebo-controlled trials reported weight loss of up to 22.1% more than placebo with retatrutide at 48 weeks ^[30]. That review found no head-to-head trials. Differences between trials prevented a pooled analysis ^[30]. A network meta-analysis of 27 trials found the largest weight and waist changes with retatrutide's two highest groups and tirzepatide's highest group ^[31]. Effects were smaller in people with type 2 diabetes ^[31]. A model-based analysis covered 55 trials and 12 GLP-1-type drugs, retatrutide included ^[32]. It estimated how weight change builds over time ^[32]. A meta-analysis of 25 trials in fatty liver disease found that GLP-1-based drugs cut liver fat by 5.21% overall ^[33]. The clearest effect was with retatrutide ^[33].

In obese mice with triple-negative breast cancer tumors, one lab study reported smaller tumors with retatrutide ^[34]. Chemotherapy also worked better in those mice. This is animal work and says nothing about people ^[34].

TRIUMPH is a phase 3 program of four randomized, double-blind trials ^[4]. It includes over 5,800 participants ^[4]. It covers weight, sleep apnea and knee osteoarthritis, plus one trial in people with heart disease ^[4]. Another trial covers heart and kidney outcomes over about 5 years, with a listed enrollment of 10,000 ^[5]. One covers liver outcomes, with tirzepatide and placebo arms and 4,500 listed ^[6]. Others compare retatrutide with semaglutide in type 2 diabetes, 1,250 listed ^[9], and with tirzepatide in obesity, 800 listed ^[11]. Others cover chronic low back pain, 586 listed ^[14], and keeping weight off, 643 listed ^[12]. These trials are listed as active or recruiting, so they are plans, not findings ^{[5][6][9][11][12][14]}.

Several trials are listed as completed ^{[7][8][10][16][19]}. One is a weight trial with knee osteoarthritis and sleep apnea subsets, 2,335 listed ^[7]. Another is a trial in obesity with heart disease, 1,946 listed ^[8]. Another is a type 2 diabetes trial with a sleep apnea subset, 1,152 listed ^[10]. Two more are a knee osteoarthritis trial, 445 listed ^[16], and a phase 2 kidney trial, 146 listed ^[19]. Their results do not appear in the published papers Ellum cites ^{[7][8][10][16][19]}.

Ellum's Peptide Access Index lists retatrutide alongside other compounds. About Ellum describes who publishes these summaries.

More on Retatrutide side effects in animal and lab studies

Retatrutide's side-effect findings come from trials in adults and from reviews of those trials ^[1][2][30]. In a phase 1 study in people, safety and tolerability looked similar to other incretin drugs ^[3].

In the 12-week phase 1b trial, 72 adults with type 2 diabetes took part ^[2]. Adverse events were reported by 63% on retatrutide, 60% on dulaglutide and 54% on placebo ^[2]. Most were gastrointestinal ^[2]. Of the 72 adults, 29 left the study early ^[2].

In the phase 2 diabetes trial, 35% of retatrutide participants had mild-to-moderate gut events ^[24]. The rate ranged from 13% in the lowest group to 50% in one higher group ^[24]. It was 13% on placebo and 35% on dulaglutide ^[24]. In the phase 2 obesity trial, gut events were tied to dose and mostly mild to moderate ^[1]. Heart rate rose with dose and declined after 24 weeks ^[1]. In the body-composition substudy, serious adverse events occurred in 2 of 32, 0 of 31, 3 of 33 and 1 of 30 participants across the retatrutide groups ^[28]. They occurred in 2 of 29 on placebo and 0 of 34 on dulaglutide ^[28]. No deaths were reported ^[28].

A meta-analysis of 3 randomized trials found no significant difference in adverse events versus placebo ^[29]. Its relative risk was 1.11 ^[29]. A review of 26 trials of GLP-1-type drugs included retatrutide ^[30]. Gut events hit 47% to 84% of drug groups and 13% to 63% of placebo groups ^[30]. Stopping for adverse events was rare, and so were serious events ^[30]. A network meta-analysis found that none of the drugs studied raised serious or low-blood-sugar events ^[31]. Retatrutide was among those drugs ^[31]. A model-based analysis found nausea more common than with placebo across GLP-1-type drugs ^[32]. A fatty liver meta-analysis included retatrutide trials ^[33]. It saw no drug-related liver adverse effects ^[33].

A review of 62 trials of GLP-1-type drugs included retatrutide ^[40]. Pancreatitis risk was a little higher overall, with a risk ratio of 1.44 ^[40]. The rise was not significant when split by background medicine ^[40]. That analysis found no overall link with pancreatic cancer ^[40]. Reviews of this drug class report loss of lean mass ^[41][42]. One review put it at about 10% of lean mass ^[41]. Another said over 25% of weight lost is fat-free mass ^[42]. Long-term safety data are still needed ^[36].

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