Peptidtermészetű molekuláról van szó, az agonista hatást döntően a GIP-receptorokon és kevésbé a GLP-1- és a glukagonreceptorokon fejti ki. Hetente egyszer subcutan adandó. Az ADA 2023. évi kongresszusán a retatrutiddal kapcsolatban két vizsgálat eredményét ismertették, az egyiket elhízásban, a másikat T2DM-betegek körében végezték. Az eredmények neves szaklapok hasábjain rögtön elérhetőkké váltak. A két vizsgálat nyomán a fejlesztő cég (Eli Lilly) a retatrutid fázis-3 vizsgálatsorozatának megkezdése mellett döntött (TRIUMPH vizsgálatok). Az eredmények lényegét magyar nyelven foglaljuk össze, az angol nyelvű abstractot teljes terjedelemben adjuk közre.
Jastreboff AM, Kaplan LM, Frías JP, Wu Q, Du Y, Gurbuz S, Coskun T, Haupt A, Milicevic Z, Hartman ML; Retatrutide phase 2 obesity trial investigators: Triple-hormone-receptor agonist retatrutide for obesity - a phase 2 trial. N Engl J Med 2023; 389(6): 514-526.
Az elhízással kapcsolatos kettős vak, randomizált, placebokontrollos, fázis-2 vizsgálatot olyan felnőtt egyének körében végezték, akiknek BMI értéke 30-50 kg/m2 volt, vagy 27-<30 kg/m2, de legalább egy, testsúlyfelesleggel összefüggő szövődmény jelenléte igazolható volt (diabetes kivételével). A betegek (n = 338) az aktív ágon a retatrutid különböző dózisait kapták (heti egyszer subcutan 1 mg, 4 mg, 8 mg, 12 mg), az összehasonlító ágon placebo szerepelt, a tanulmány 48 hetes volt. Végpontként a testsúly százalékos változását értékelték a 24. és 48. hétnél. A 24. hétnél a testsúly kiindulási helyzethez viszonyított százalékos változása a retatrutidot kapók körében az alábbi volt (sorrendben: 1 mg, 4 mg, 8 mg, 12 mg): -7,2%, -12,9%, -17,3%, -17,5%; a placebo ágon -1,6%. A 48. hétnél a testsúly kiindulási helyzethez viszonyított százalékos változása a retatrutidot kapók körében az alábbiak szerint alakult (sorrendben: 1 mg, 4 mg, 8 mg, 12 mg): -8,7%, -17,1%, -22,8%, -24,2%; a placebo ágon -2,1%. A 48. hétnél a testsúly kiindulási helyzethez viszonyított 5%-os, 10%-os és ≥15%-os csökkenését az alábbiak szerint figyelték meg: retatrutid 4 mg: 92%, 75%, 60%; 8 mg: 100%, 91%, 75%; 12 mg: 100%, 93%, 83%; placebo ágon: 27%, 8%, 2%. A retatrutid mellékhatásaként gasztrointesztinális tüneteket regisztráltak, amelyeknek előfordulása a dózissal összefüggött, enyhe-mérsékelt fokú volt, és ritkábban alakult ki akkor, ha a kezdő dózis alacsonyabb volt.
Abstract
Background: Retatrutide (LY3437943) is an agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and glucagon receptors. Its dose-response relationships with respect to side effects, safety, and efficacy for the treatment of obesity are not known.
Methods: We conducted a phase 2, double-blind, randomized, placebo-controlled trial involving adults who had a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of 30 or higher or who had a BMI of 27 to less than 30 plus at least one weight-related condition. Participants were randomly assigned in a 2:1:1:1:1:2:2 ratio to receive subcutaneous retatrutide (1 mg, 4 mg [initial dose, 2 mg], 4 mg [initial dose, 4 mg], 8 mg [initial dose, 2 mg], 8 mg [initial dose, 4 mg], or 12 mg [initial dose, 2 mg]) or placebo once weekly for 48 weeks. The primary end point was the percentage change in body weight from baseline to 24 weeks. Secondary end points included the percentage change in body weight from baseline to 48 weeks and a weight reduction of 5% or more, 10% or more, or 15% or more. Safety was also assessed.
Results: We enrolled 338 adults, 51.8% of whom were men. The least-squares mean percentage change in body weight at 24 weeks in the retatrutide groups was -7.2% in the 1-mg group, -12.9% in the combined 4-mg group, -17.3% in the combined 8-mg group, and -17.5% in the 12-mg group, as compared with -1.6% in the placebo group. At 48 weeks, the least-squares mean percentage change in the retatrutide groups was -8.7% in the 1-mg group, -17.1% in the combined 4-mg group, -22.8% in the combined 8-mg group, and -24.2% in the 12-mg group, as compared with -2.1% in the placebo group. At 48 weeks, a weight reduction of 5% or more, 10% or more, and 15% or more had occurred in 92%, 75%, and 60%, respectively, of the participants who received 4 mg of retatrutide; 100%, 91%, and 75% of those who received 8 mg; 100%, 93%, and 83% of those who received 12 mg; and 27%, 9%, and 2% of those who received placebo. The most common adverse events in the retatrutide groups were gastrointestinal; these events were dose-related, were mostly mild to moderate in severity, and were partially mitigated with a lower starting dose (2 mg vs. 4 mg). Dose-dependent increases in heart rate peaked at 24 weeks and declined thereafter.
Conclusions: In adults with obesity, retatrutide treatment for 48 weeks resulted in substantial reductions in body weight.
https://www.nejm.org/doi/10.1056/NEJMoa2301972
Rosenstock J, Frias J, Jastreboff AM, Du Y, Lou J, Gurbuz S, Thomas MK, Hartman ML, Haupt A, Milicevic Z, Coskun T: 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. Lancet 2023; 402(10401): 529-544.
A T2DM-betegek körében végzett kettős vak, randomizált, fázis-2 vizsgálatban az összehasonlító ágon placebo mellett aktív készítmény (dulaglutid) is szerepelt. A vizsgálatot olyan felnőtt (életkor 18-75 év) T2DM-betegek körében végezték az Egyesült Államokban, akiknek HbA1c-értéke 7,0-10,5%, BMI értéke 20-50 kg/m2 volt és életmódterápia mellett metformint (napi ≥1000 mg) kaptak. A betegek (n = 281) az aktív ágon a retatrutid különböző dózisait kapták (heti egyszer subcutan 0,5 mg, 4 mg, 8 mg, 12 mg), az összehasonlító ágon placebo vagy dulaglutid (heti 1x1,5 mg subcutan) szerepelt, a tanulmány 36 hetes volt. Elsődleges végpontként a HbA1c változását értékelték a 24. hétnél, másodlagos végpontként a 36. hétnél értékelték a HBA1c és a testsúly változását. Kiindulási helyzetben a betegek életkora 56,2 év, a diabetestartam 8,1 év, a HbA1c 8,3%, a BMI 35,0 kg/m2, a testsúly 98,2 kg volt. A vizsgálatnak összesen 8 ága volt, mert a retatrutid 4 mg és 8 mg-os csoportban a terápiás eszkaláció üteme szerint külön is értékelték az adatokat. A terjedelmes dolgozat minden eredményét nem lehet áttekinteni, csak a legfontosabbak említésére van lehetőség. A HbA1c-érték a vizsgálat 24. heténél a retatrutid 12 mg ágon -2,02%-kal, a 36. héten -2,16%-kal csökkent. A HbA1c <7,0% értéket a retatrutid 12 mg ágon a betegek 80%-a elérte (placebo: 22%, dulaglutid: 60%). A HbA1c <5,7%-ot (normoglykaemiát) elérők aránya a retatrutid 12 mg ágon 27% volt (placebo 3%, dulaglutid 3%). A testsúly az összes retatrutid ágat tekintve a 36. hétnél 16,94%-kal csökkent (placebo: 3%, dulaglutid 2,0%). Retatrutid mellett előnyösen csökkent a vérnyomás, a triglicerid és a non-HDL-koleszterin értéke. A mellékhatások gasztrointesztinális jellegűek voltak, az előfordulás a dózissal összefüggött. Súlyos hypoglykaemia, haláleset nem fordult elő.
Abstract
Background: According to current consensus guidelines for type 2 diabetes management, bodyweight management is as important as attaining glycaemic targets. Retatrutide, a single peptide with agonist activity at the glucose-dependent insulinotropic polypeptide (GIP), GLP-1, and glucagon receptors, showed clinically meaningful glucose-lowering and bodyweight-lowering efficacy in a phase 1 study. We aimed to examine the efficacy and safety of retatrutide in people with type 2 diabetes across a range of doses.
Methods: In this randomised, double-blind, double-dummy, placebo-controlled and active comparator-controlled, parallel-group, phase 2 trial, participants were recruited from 42 research and health-care centres in the USA. Adults aged 18-75 years with type 2 diabetes, glycated haemoglobin (HbA1c) of 7·0-10·5% (53·0-91·3 mmol/mol), and BMI of 25-50 kg/m2 were eligible for enrolment. Eligible participants were treated with diet and exercise alone or with a stable dose of metformin (≥1000 mg once daily) for at least 3 months before the screening visit. Participants were randomly assigned (2:2:2:1:1:1:1:2) using an interactive web-response system, with stratification for baseline HbA1c and BMI, to receive once-weekly injections of placebo, 1·5 mg dulaglutide, or retatrutide maintenance doses of 0·5 mg, 4 mg (starting dose 2 mg), 4 mg (no escalation), 8 mg (starting dose 2 mg), 8 mg (starting dose 4 mg), or 12 mg (starting dose 2 mg). Participants, study site personnel, and investigators were masked to treatment allocation until after study end. The primary endpoint was change in HbA1c from baseline to 24 weeks, and secondary endpoints included change in HbA1c and bodyweight at 36 weeks. Efficacy was analysed in all randomly assigned, except inadvertently enrolled, participants, and safety was assessed in all participants who received at least one dose of study treatment. The study is registered at ClinicalTrials.gov, NCT04867785.
Findings: Between May 13, 2021, and June 13, 2022, 281 participants (mean age 56·2 years [SD 9·7], mean duration of diabetes 8·1 years [7·0], 156 [56%] female, and 235 [84%] White) were randomly assigned and included in the safety analysis (45 in the placebo group, 46 in the 1·5 mg dulaglutide group, and 47 in the retatrutide 0·5 mg group, 23 in the 4 mg escalation group, 24 in the 4 mg group, 26 in the 8 mg slow escalation group, 24 in the 8 mg fast escalation group, and 46 in the 12 mg escalation group). 275 participants were included in the efficacy analyses (one each in the retatrutide 0·5 mg group, 4 mg escalation group, and 8 mg slow escalation group, and three in the 12 mg escalation group were inadvertently enrolled). 237 (84%) participants completed the study and 222 (79%) completed study treatment. At 24 weeks, least-squares mean changes from baseline in HbA1c with retatrutide were -0·43% (SE 0·20; -4·68 mmol/mol [2·15]) for the 0·5 mg group, -1·39% (0·14; -15·24 mmol/mol [1·56]) for the 4 mg escalation group, -1·30% (0·22; -14·20 mmol/mol [2·44]) for the 4 mg group, -1·99% (0·15; -21·78 mmol/mol [1·60]) for the 8 mg slow escalation group, -1·88% (0·21; -20·52 mmol/mol [2·34]) for the 8 mg fast escalation group, and -2·02% (0·11; -22·07 mmol/mol [1·21]) for the 12 mg escalation group, versus -0·01% (0·21; -0·12 mmol/mol [2·27]) for the placebo group and -1·41% (0·12; -15·40 mmol/mol [1·29]) for the 1·5 mg dulaglutide group. HbA1c reductions with retatrutide were significantly greater (p<0·0001) than placebo in all but the 0·5 mg group and greater than 1·5 mg dulaglutide in the 8 mg slow escalation group (p=0·0019) and 12 mg escalation group (p=0·0002). Findings were consistent at 36 weeks. Bodyweight decreased dose dependently with retatrutide at 36 weeks by 3·19% (SE 0·61) for the 0·5 mg group, 7·92% (1·28) for the 4 mg escalation group, 10·37% (1·56) for the 4 mg group, 16·81% (1·59) for the 8 mg slow escalation group, 16·34% (1·65) for the 8 mg fast escalation group, and 16·94% (1·30) for the 12 mg escalation group, versus 3·00% (0·86) with placebo and 2·02% (0·72) with 1·5 mg dulaglutide. For retatrutide doses of 4 mg and greater, decreases in weight were significantly greater than with placebo (p=0·0017 for the 4 mg escalation group and p<0·0001 for others) and 1·5 mg dulaglutide (all p<0·0001). Mild-to-moderate gastrointestinal adverse events, including nausea, diarrhoea, vomiting, and constipation, were reported in 67 (35%) of 190 participants in the retatrutide groups (from six [13%] of 47 in the 0·5 mg group to 12 [50%] of 24 in the 8 mg fast escalation group), six (13%) of 45 participants in the placebo group, and 16 (35%) of 46 participants in the 1·5 mg dulaglutide group. There were no reports of severe hypoglycaemia and no deaths during the study.
Interpretation: In people with type 2 diabetes, retatrutide showed clinically meaningful improvements in glycaemic control and robust reductions in bodyweight, with a safety profile consistent with GLP-1 receptor agonists and GIP and GLP-1 receptor agonists. These phase 2 data also informed dose selection for the phase 3 programme.
https://www.hearmenowstories.org/images/lancet-retatrutide.pdf
Prof. Dr. Jermendy György
Az MDT web-szerkesztősége nevében
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