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Journal Watch 28/06/2023

Welcome to our weekly round-up of the latest bariatric and obesity-related papers published in the medical literature. As ever, we have looked far and wide to give you an overview of papers including several papers from The Lancet reporting on the latest data from studies assessing the effectiveness of Retatrutide (a GIP, GLP-1 and glucagon receptor agonist), once-daily oral semaglutide 25mg and 50mg, Tirzepatide and oral orforglipron. In addition, we feature a paper looking at the incidence of adverse mental health outcomes after sleeve gastrectomy compared with gastric bypass, and more (please note, log-in maybe required to access the full paper).

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

US researchers have reported that in people with type 2 diabetes, retatrutide (a single peptide with agonist activity at the glucose-dependent insulinotropic polypeptide (GIP), GLP-1, and glucagon receptors) 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.

In this randomised, double-blind, double-dummy, placebo-controlled and active comparator-controlled, parallel-group, phase 2 trial, 281 participants were recruited from 42 research and health-care centres in the USA. They were randomly assigned (2:2:2:1:1:1:1:2) to receive once-weekly injections of placebo, 1.5mg dulaglutide or retatrutide maintenance doses of 0.5 mg, 4mg (starting dose 2mg), 4mg (no escalation), 8mg (starting dose 2mg), 8mg (starting dose 4mg) or 12mg (starting dose 2mg). The primary endpoint was change in HbA1c from baseline to 24 weeks and secondary endpoints included change in HbA1c and bodyweight at 36 weeks.

In total, 237 (84%) participants completed the study and 222 (79%) completed study treatment. HbA1c reductions with retatrutide were significantly greater (p<0.0001) than placebo in all but the 0.5mg group and greater than 1.5mg dulaglutide in the 8mg slow escalation group (p=0·0019) and 12mg escalation group (p=0.0002).

Bodyweight decreased dose dependently with retatrutide at 36 weeks by 3.19% for the 0.5 mg group, 7.92% for the 4mg escalation group, 10.37%for the 4mg group, 16.81% for the 8mg slow escalation group, 16.34% (1.65) for the 8mg fast escalation group and 16.94% for the 12mg escalation group, versus 3% with placebo and 2.02% with 1.5mg dulaglutide.

Mild-to-moderate gastrointestinal adverse events, including nausea, diarrhoea, vomiting, and constipation, were reported in 67 (35%) of 190 participants in the retatrutide groups. There were no reports of severe hypoglycaemia and no deaths during the study.

The study was sponsored by Eli Lilly.

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Efficacy and safety of once-daily oral semaglutide 25 mg and 50 mg compared with 14 mg in adults with type 2 diabetes (PIONEER PLUS): a multicentre, randomised, phase 3b trial

An international team of researchers have found oral semaglutide 25mg and 50mg were superior to 14mg in reducing HbA1c and bodyweight in adults with inadequately controlled type 2 diabetes.

This global, multicentre, randomised, double-blind, phase 3b trial, carried out at 177 sites in 14 countries, enrolled 1,606 (n=936 [58·3%] male; n=670 [41·7%] female; mean [SD] age 58·2 [10·8] years) adults who received oral semaglutide 14mg (n=536), 25mg (n=535) or 50mg (n=535). At baseline, mean (SD) HbA1c was 9% and mean bodyweight was 96.4kg.

Mean changes in HbA1c at week 52 were −1.5 percentage points with oral semaglutide 14mg, −1.8 percentage points with 25mg and −2 percentage points with 50mg (p<0·0001). Adverse events were reported by 404 (76%) participants in the oral semaglutide 14mg group, 422 (79%) in the 25mg group and 428 (80%) in the 50mg group.

Gastrointestinal disorders, which were mostly mild to moderate, occurred more frequently with oral semaglutide 25mg and 50mg than with 14mg.

The study was funded by Novo Nordisk.

To access this paper, please click here

Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial

An international team of researchers have reported once-weekly tirzepatide 10mg and 15mg provided substantial and clinically meaningful reduction in bodyweight, with a safety profile that was similar to other incretin-based therapies for weight management.

SURMOUNT-2 is a phase 3, double-blind, randomised, placebo-controlled trial was conducted in seven countries. The study enrolled 938 adults who were randomly assigned and received at least one dose of tirzepatide 10mg (n=312), tirzepatide 15mg (n=311) or placebo (n=315). Baseline mean bodyweight was 100.7kg, BMI 36.1kg/m2 and HbA1c 8.02%.

Mean change in bodyweight at week 72 with tirzepatide 10mg and 15mg was –12.8% and –14.7% (, respectively, and –3·2% with placebo, resulting in estimated treatment differences versus placebo of –9.6% percentage points with tirzepatide 10mg and –11.6% percentage points with tirzepatide 15mg (all p<0·0001).

The most frequent adverse events with tirzepatide were gastrointestinal-related, including nausea, diarrhoea, and vomiting and were mostly mild to moderate in severity, with few events leading to treatment discontinuation (<5%). Serious adverse events were reported by 68 (7%) participants overall and two deaths occurred in the tirzepatide 10 mg group (not considered to be related to the study treatment by the investigator).

The study was funded by Eli Lilly.

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Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study

In this phase 2 trial the novel, the oral, non-peptide GLP-1 receptor agonist orforglipron at doses of 12mg or greater showed significant reductions in HbA1c and bodyweight, compared with placebo or dulaglutide.

In this 26-week, phase 2, double-blind, randomised, multicentre study, 383 participants were enrolled and randomly assigned (5:5:5:5:5:3:3:3:3) to placebo, dulaglutide 1.5mg once per week or orforglipron 3mg, 12mg, 24mg, 36mg (group 1), 36mg (group 2), 45mg (group 1) or 45mg (group 2) once per day.

At week 26, mean change in HbA1c with orforglipron was up to –2.10% versus –0.43% with placebo and –1.10% with dulaglutide. HbA1c reduction was statistically superior with orforglipron versus placebo and change in mean bodyweight at week 26 was up to –10.1 kg with orforglipron versus –2.2kg for placebo and –3.9kg for dulaglutide. The incidence of treatment-emergent adverse events ranged from 61.8% to 88.9% in orforglipron-treated participants, compared with 61.8% with placebo and 56% with dulaglutide. The majority were gastrointestinal events (44.1% to 70.4% with orforglipron, 18.2% with placebo, and 34% with dulaglutide) of mild to moderate severity.

They concluded that ‘orforglipron might provide an alternative to injectable GLP-1 receptor agonists and oral semaglutide, with the prospect of less burdensome administration to achieve treatment goals in people with type 2 diabetes’.

The study was funded by Eli Lilly and Company.

To access this paper, please click here

Incidence of adverse mental health outcomes after sleeve gastrectomy compared with gastric bypass and restrictive bariatric procedures: a retrospective cohort study

Researchers from Australia have found variable associations between bariatric surgeries and hospitalisation with psychiatric diagnoses might indicate distinct vulnerabilities among patient cohorts or that differing anatomical and/or functional changes may contribute to effects on mental health.

The study examined rates of suicide and hospitalization with psychiatric diagnoses after sleeve gastrectomy compared with gastric bypass and restrictive procedures (gastric banding/gastroplasty). In total, 121,203 patients were included, with median follow-up of 4.5 years per patient.

They reported 77 suicides, with no evidence of difference in rates by surgery type (rates [95% CI] per 100,000 person years: 9.6 restrictive, 10.8 sleeve gastrectomy, 20.4 gastric bypass; p=0.18). Rates of admission with self-harm declined after restrictive and sleeve procedures however, admission with anxiety disorders, any psychiatric diagnosis, and as a psychiatric inpatient increased after sleeve gastrectomy and gastric bypass, but not restrictive procedures. Admissions with substance-use disorder increased after all surgery types.

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