Congress highlights

ADA 2023 highlights: Innovations to manage obesity in type 2 diabetes

By Eleanor McDermid

Laying out the current treatment options for obesity in people with type 2 diabetes for delegates at the 2023 ADA Scientific Sessions, W Timothy Garvey (University of Alabama at Birmingham) stressed that such individuals “have two diseases and both diseases should be treated effectively”.

Although some established diabetes medications do induce weight loss at the doses used to manage hyperglycaemia, he said that if healthcare professionals believe themselves to be actively treating obesity with these medications, “we’re fooling ourselves and not doing the best we can for these patients.”

He highlighted a “therapeutic gap” between current obesity medications, which induce approximately 4–10% weight loss in people with type 2 diabetes, and gastric sleeve or metabolic surgery, which promote 20–40% weight loss.

However, a new generation of weight loss medications is promising to fill this gap, with a number of phase 2 and 3 trials reported during the conference.

SURMOUNT-2: Tirzepatide for obesity in type 2 diabetes

One of these new generation of medications is tirzepatide, a dual agonist of the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GIP)-1 receptors. It is approved for used as an antihyperglycaemia agent on the basis of the results from the SURPASS series of trials, and the previously reported SURMOUNT-1 trial demonstrated marked weight loss in people with obesity but without type 2 diabetes¹.

Professor John Buse outlines the key take-home messages from trials of single and dual GLP-1 and GIP receptor agonists presented at ADA.

Describing the trial rationale, Juan Pablo Frias (Velocity Clinical Research) reminded the audience that people with type 2 diabetes do not respond to weight loss medications as well as those without, making it essential to trial putative weight loss medications specifically in this population.

SURMOUNT-2 included 938 participants, who were an average age 54.2 years with an average type 2 diabetes duration of 8.5 years². A total of 51% were women and 76% were Caucasian. People using injectable therapies or incretin-based medications were excluded.

There was a dose-escalation period of 12 or 20 weeks depending on whether people were randomised to take 10 or 15 mg/week, respectively, of tirzepatide, and the majority of the weight loss occurred during this period.

The trial participants were treated for a total of 72 weeks, during which their weight reduced by an average of 12.8% and 14.7% with the 10 and 15 mg doses, respectively, compared with 3.2% in the placebo group.

People with type 2 diabetes lost an average of 14.7% of their bodyweight with the highest tirzepatide dose used in the SURMOUNT-2 trial

The vast majority of participants lost weight – only about 3.5% gained weight, as did 22.5% of the placebo group, despite the provision of intensive lifestyle management support.

The safety profile was as anticipated for a molecule containing a GLP-1 receptor agonist, with gastrointestinal side effects the most frequent complaint.

High-dose oral semaglutide: OASIS 1, PIONEER PLUS

Oral semaglutide is the only oral GLP-1 receptor agonist currently approved for the treatment of people with type 2 diabetes at a maximum dose of 14 mg/day. Two trials reported at the conference – OASIS 1³ and PIONEER PLUS⁴ – provided the first phase 3 data for higher doses, intended to produce greater weight loss and glycaemic control in people with obesity with or without type 2 diabetes.

OASIS 1 focused on people with obesity (or overweight and at least one related comorbidity) who did not have diabetes. A total of 667 such people were randomly assigned to receive oral semaglutide 50 mg/day for 52 weeks, after a dose escalation period of 16 weeks, or placebo in addition to a lifestyle intervention.

Most weight loss occurred during the first half of the treatment period and over the full follow-up amounted to an average 15.1% reduction from baseline in the semaglutide group versus 2.4% in those given placebo.

A total of 69%, 54% and 34% of participants in the semaglutide 50 mg group lost at least 10%, 15% and 20% of their starting bodyweight. This weight loss was paralleled by significant improvements in physical function.

PIONEER PLUS included 1606 people with type 2 diabetes (average duration about 9 years) and BMI of at least 25 kg/m². People taking DPP-4 inhibitors had to stop them at randomisation, and people taking GLP-1 receptor agonists were excluded.

After a dose escalation of 8–16 weeks and maintenance period of 52–60 weeks, the average reductions in glycated haemoglobin (HbA1c) were greater with higher semaglutide doses, at 1.5%, 1.8% and 2.0% with the 14, 25 and 50 mg doses, respectively.

Bodyweight reduction was also greater with higher doses, although the degree of weight loss was less than in people without diabetes in OASIS 1, averaging 4.4%, 6.7% and 8.0% with the three doses, respectively.

Oral semaglutide 50 mg caused weight loss averaging 8.0% and 15.1% in people with and without type 2 diabetes, respectively

In both trials, the most frequent adverse events were gastrointestinal, in common with other medications in the GLP-1 receptor agonist class.

Professor John Buse offers some practical advice to help people with type 2 diabetes get the best from GLP-1 receptor agonists.

Obesity medications in the pipeline

In addition to these key phase 3 trials, five phase 2 studies of four novel medications for obesity offered a glimpse of what might be to come. See the Table for an overview of the findings.

Table: Summary data from phase 2 trials of novel medications for obesity^5-10. GIP, glucose-dependent insulinotropic polypeptide; GLP, glucagon-like peptide.

In these relatively short studies, weight loss had not plateaued, so the researchers anticipate a larger bodyweight reduction in the forthcoming longer phase 3 trials.

In-development medications with dual and triple mechanisms of action offer the potential for weight loss close or equivalent to that achieved by surgery

Medication is of course not the only option to address obesity in people with type 2 diabetes and a panel discussion on the Sunday aimed to address how help patients in the clinic to navigate these options.

Discussing shared decision making, nutritionist Eileen Myers (Fernandina Beach, Florida, USA) described it as “the pinnacle of patient-centred care”, and several times reminded the audience that “one of the options in [true] shared decision making is to do nothing”.

Professor John Buse outlines the need for pragmatism to achieve effective shared decision making.

The session also covered metabolic surgery, including the fact that it is often considered an intervention of last resort, despite being a highly effective treatment for obesity and capable, when performed early enough, of reversing type 2 diabetes.

Panellist Laura Andromalos (Fairview University of Minnesota Medical Center) said: “I see so many patients who waited so many years, or weren’t referred when they could have been referred”, but after having surgery “so many people say, ‘I wish I would have done this years ago’.”

Two presentations given on Monday and based on the Swedish Obese Subjects study underscored the importance of this treatment option. The first presentation showed a significantly reduced all-cause mortality risk among the 2010 people who underwent bariatric surgery compared with the 2037 matched controls, and this was true irrespective of whether they had type 2 diabetes (adjusted hazard ratio [HR] = 0.77) or did not (HR = 0.82)¹¹.

People with diabetes had a numerically greater treatment benefit from surgery than those without for total cardiovascular mortality and a significantly greater benefit for myocardial infarction, with adjusted HRs of 0.37 and 0.88, respectively.

For people with diabetes, these gains from surgery equated to an additional median 2.1 years’ life expectancy, although they still had an overall higher mortality risk and shorter life expectancy than those without diabetes.

Bariatric surgery reduces mortality risk and increases life expectancy in people with type 2 diabetes

The second analysis, based on the 586 participants with type 2 diabetes at baseline, showed that those who achieved remission after surgery had a significantly lower mortality risk, with an  adjusted 41% reduced risk over a median follow-up of 26 years¹². This was associated with a median 4.1 years’ additional life expectancy over 30 years.

EASD 2023: Medications, surgery and the power of exercise

By Eleanor McDermid

Maintaining weight loss in a large clinical trial

The biggest trial on obesity management to report its primary findings at EASD 2023 was SURMOUNT-4, the results of which showed that continued treatment with tirzepatide is necessary to maintain weight loss. Tirzepatide is a dual agonist of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors.

The 783 participants had a body mass index (BMI) of at least 30 kg/m² or 27 kg/m² with at least one weight-related complication (but not type 2 diabetes). All participants took tirzepatide during a 36-week run-in, titrated up to either 10 or 15 mg/week according to tolerability; 93% of people achieved the highest dose. The average weight loss during this open-label phase was 20.9%.

At week 36, the 670 trial participants who remained in the trial were randomly assigned to continue on their established dose of tirzepatide or to switch to placebo. During this blinded phase, people in the tirzepatide group continued to lose weight, reaching 25.8% below baseline by week 88, whereas those in the placebo group regained weight, finishing the trial at an average of 9.5% below baseline.

The participants’ average starting bodyweight was 107 kg and those who took tirzepatide throughout lost an average of 28 kg over the full 88 weeks. More than half of them achieved a weight reduction of at least 25%, which presenter Louis Aronne (Weill Cornell Medicine, New York, USA) stressed is “on par with that achieved with sleeve gastrectomy”.

The change in BMI in this group was equivalent to dropping from class 2 obesity to mildly overweight, he added.

SURMOUNT-4 shows the need for continued tirzepatide to maintain weight loss, despite a lasting effect of treatment

Aronne also highlighted the surprising finding that average bodyweight did not return to baseline in the placebo group, despite participants being followed up for a whole year after stopping tirzepatide. The same was true for other measures such as waist circumference and glycated haemoglobin (HbA1c), which remained 0.2 percentage points below baseline.

Adverse events were as expected for the medication class and similar between the two groups. Most drug-related events occurred during the titration period when all participants were taking the active treatment.

John Wilding (University of Liverpool, UK) gives his view of the SURMOUNT-4 trial findings.

Weight loss, fat loss, and muscle composition

Tirzepatide was approved for use in type 2 diabetes based on results from the SURPASS trials. Further results from a magnetic resonance imaging substudy of SURPASS-3, involving 296 participants, showed that tirzepatide treatment resulted in a small but statistically significant reduction in the fat content of muscle, without adversely affecting muscle composition.

During 52 weeks of treatment, people taking tirzepatide at 5, 10 or 15 mg/week had an average reduction in muscle fat infiltration (MFI) of 0.36 percentage points from a baseline of 8.06%. By contrast, those taking insulin degludec had an average increase of 0.03 percentage points from a baseline of 7.65%.

Naveed Sattar (University of Glasgow, UK), who presented this research, observed that muscle loss is common when people lose weight and is partly because less muscle mass is required when a person weighs less. But these data also indicate that a proportion of the reduction in people taking tirzepatide is caused by a reduction in fat infiltration.

The same session included the primary results of SURPASS-6, presented by Juan Frias (Velocity Clinical Research, Los Angeles, USA) and simultaneously published in JAMA¹. This showed that addition of tirzepatide resulted in better glycaemic and weight outcomes than starting insulin lispro, a prandial insulin, in people who had high HbA1c levels despite using basal insulin.

During 52 weeks of treatment, the 716 study participants randomly assigned to take tirzepatide (5, 10 or 15 mg/week) had an average 2.1 percentage point reduction in HbA1c, from a baseline of 8.8%, and a 9.0 kg reduction in bodyweight from a baseline of 90.7 kg.

People assigned to take insulin lispro had an average 1.1 percentage point reduction in HbA1c, from a baseline of 8.8%, but a 3.2 kg increase in bodyweight from a baseline of 90.3 kg.

Adding tirzepatide to basal insulin avoids the need to start prandial insulin, equating to far fewer injections

Surgical intervention and diabetes remission Moving on to surgical treatment options, the 5-year results of the Oseberg randomised controlled trial indicate that gastric bypass offers a better chance of type 2 diabetes remission than sleeve gastrectomy does.

The 109 trial participants had a BMI of at least 35 kg/m² plus type 2 diabetes, with a median duration of 4–5 years. The diabetes remission rates (HbA1c ≤6.0% on no medications) at 1 year were 74% versus 48% in the gastric bypass and sleeve gastrectomy groups, respectively.

By year 5, this had reduced to 50% versus 26%, still significantly favouring the bypass group, revealed presenter Jostein Hauge (Vestfold Hospital Trust, Tønsberg, Norway). Three people crossed over to gastric bypass during the trial; after excluding these participants, the 5-year remission rates were 50% versus 20%.

Gastric bypass surgery was associated with better obesity-specific quality of life, mostly due to improved self-esteem. However, participants more often had symptomatic postprandial hypoglycaemia after gastric bypass than after sleeve gastrectomy, with 15 versus two patients having at least one episode.

John Wilding reflects on how the options for treating obesity have expanded over recent years, with medications now able to 'bridge the gap' between lifestyle and surgical approaches.

Delayed effects of high BMI

Results from a Danish cohort study of more than 4,000 people suggest that historical BMI may be more prognostic than BMI measured at the point of type 2 diabetes diagnosis.

Sofie Kristoffersen (Steno Diabetes Center Odense, Denmark) reported that people had a significant 2.99-fold increased risk of dying within 4–6 years after diabetes diagnosis if their BMI had been greater than 35 kg/m² at the age of 20 years rather than 18.5–25 kg/m².

Likewise, having a highest lifetime BMI in the top versus bottom category was associated with a significant 2.11-fold increased mortality risk. But BMI at the time of diagnosis was not associated with mortality risk.

Spotlight on exercise

John Wilding discusses the crucial role of exercise in weight loss, and calls for a shift in thinking about diet in the context of efficacious weight-loss medications.

Two studies presented at the meeting focused on the role of exercise in losing weight and in maintaining that weight loss.

The first, presented by Cody Durrer (Rigshospitalet, Copenhagen, Denmark), showed that regular vigorous activity during a dietary intervention maximises the amount of fat mass lost in people with type 2 diabetes. This was a secondary analysis of the DOSE-EX trial, in which participants undertaking a dietary intervention were randomly assigned to undertake exercise three (moderate volume) or six (high volume) times per week, or to do no exercise.

This secondary analysis showed that people assigned dietary intervention alone had an average weight loss of 7.1%, but approximately 22% of this was fat-free mass.

People doing moderate volume exercise lost 10.3% of their bodyweight and the proportion of fat-free mass was less, at approximately 11%. Those doing a high volume of exercise lost the most weight, at 11.7%, and the proportion of fat-free mass was “basically zero”, said Durrer.

The amount of visceral adipose tissue lost was 16%, 30% and 42% in the diet-only, moderate volume exercise and high volume exercise groups, respectively.

Durrer acknowledged that a large amount of exercise is required to prevent loss of fat-free mass, but highlighted that much of the discussion around weight loss in people with diabetes is focused on diet and medications, with exercise at risk of being disregarded.

Considering that the metabolic benefits of weight loss are probably driven by the reduction in fat mass, Durrer said that “this is maybe not the best message to be putting forward to clinicians, and particularly people living with type 2 diabetes, so I would say that unless exercise interventions are completely compromising the diet they should still be considered”.

Regular exercise can optimise the health benefits associated with weight loss

Exercise may also be critical for maintaining weight loss, potentially due to a significant increase in postprandial GLP-1 levels, suggest data from a second study presented by Signe Torekov (University of Copenhagen, Denmark).

The team previously showed that undertaking a programme of moderate-to-vigorous exercise according to current World Health Organization recommendations facilitated weight maintenance after diet-induced weight loss (about 13 kg, on average), and that people’s appetite did not increase, compared with those who remained sedentary, despite the additional physical activity².

The latest findings, in a substudy of 97 participants with BMI over 30 kg/m² but without diabetes, show that participants assigned to do regular vigorous exercise had significantly higher postprandial GLP-1 levels after 52 weeks than at baseline and relative to those who remained sedentary after finishing the diet.

This suggests that vigorous exercise helps to control appetite and therefore to maintain weight loss, concluded the presenter.

Exercise within current guideline recommendations may help to prevent weight regain

References

1. Rosenstock J, Frías JP, Rodbard HW, Tofé S, Sears E, Huh R, et al. Tirzepatide vs Insulin Lispro Added to Basal Insulin in Type 2 Diabetes: The SURPASS-6 Randomized Clinical Trial. JAMA. 2023.
2. Lundgren JR, Janus C, Jensen SBK, Juhl CR, Olsen LM, Christensen RM, et al. Healthy Weight Loss Maintenance with Exercise, Liraglutide, or Both Combined. N Engl J Med. 2021;384(18):1719-1730.