As the added health benefits of weight-loss drugs are paraded in more and more research papers, and pharmaceutical groups up the ante in the race to get the drugs on the market, some US experts have questioned the absolute benefits of the medicines, notes MedicalBrief.
In the latest research touting the benefits of weight-loss drugs, a retrospective cohort study in Cleveland, USA, involving more than 1.65m US participants found that people with type 2 diabetes who used GLP-1RAs had a lower risk of 10 of 13 types of so-called obesity-associated cancers than those who used insulin (see study below).
This comes as Eli Lilly announced this week that its recent trial results showed its drug Zepbound reduces the risk of hospitalisation, death and other outcomes for obese adults with a common type of heart failure. The drug (tirzepatide) reduced the risk of a composite of heart failure urgent visit or hospitalisation, oral diuretic intensification or cardiovascular death, by 38% compared with a placebo, the company said.
However, a group of US experts have now put the final results of last year’s SELECT trial into context – findings where investigators touted a 20% reduced risk of a major cardiovascular event with semaglutide (Wegovy) compared with placebo, a figure that sounds impressive on the face of it.
In a Medpage Today series called Ozempic: Weighing the Risks and Benefits, the experts say since release of the results, it has been argued that the absolute benefit, a 1.5 percentage-point difference between the two groups of patients who were overweight and had pre-existing cardiovascular disease, is much smaller.
Indeed, 6.5% of people taking the glucagon-like peptide-1 (GLP-1) receptor agonist had a major cardiovascular event, as did 8% of those on placebo.
While that’s a significant difference, it’s a small one, several experts said.
“That sounds very impressive, 20%, but it’s misleading,” said Diana Zuckerman, PhD, president of the National Centre for Health Research in Washington.
“I mean, it’s still good. But as an individual person making a decision about how much money they’re willing to spend for this drug, and all the side effects, whether it’s nausea or vomiting or diarrhoea … it just may not be worth it to them.”
David Phizackerley, BSc, MRPharmS, deputy editor of The BMJ’s Drug & Therapeutics Bulletin, penned an editorial on the absolute cardiovascular benefits in the SELECT trial, noting that the 1.5% absolute risk reduction means that 67 people would need to take the drug for 34 months – the length of the study – to prevent just one primary endpoint event (heart attack, stroke, or cardiovascular death). The other 66 people would not see any cardiovascular benefit at all.
“If it were over a year, you’d have to treat three times as many people to have one person benefit,” Phizackerley added.
On top of that, he pointed out that only one of the three components of the composite endpoint was significant.
There was a significant benefit for non-fatal myocardial infarction (HR 0.72, 95% CI 0.61-0.85), but “even that was quite small” at a 1% absolute risk reduction (2.7% for semaglutide vs 3.7% for placebo), he said.
“You do the maths on that, and it’s a number needed to treat of 100, so you’d have to treat 100 people to prevent one event,” Phizackerley told MedPage Today.
“Say you’re sitting with a patient who wants a realistic explanation of what this drug might do for them. If I said, ‘We have a room of 100 people, and if I give it to all 100, one of you will walk out with a benefit. The other 99 won’t’. That’s redressing the balance.”
The other two parts of the composite endpoint were death from cardiovascular causes (2.5% vs 3%) and non-fatal stroke (1.7% vs 1.9%), neither of which was significant (HR 0.85, 95% CI 0.71-1.01, P=0.07; and HR 0.93, 95% CI 0.74-1.15).
Michael Lincoff, MD, of the Cleveland Clinic, the lead author on the SELECT study, disagreed with Phizackerley’s and Zuckerman’s interpretations of the trial results, arguing that a 20% relative risk reduction is “a big deal in cardiovascular medicine”.
“We consider a successful trial a 15% reduction, some are 20% or 25%,” Lincoff said. “That’s a significant reduction in terms of being clinically relevant.”
As for the non-significant components of the composite endpoint, Lincoff said triallists “never expect components to be significant unless we do a trial powered for that”.
“We powered the trial for the composite endpoint.”
The fact that there was no effect on non-fatal stroke was interesting, Lincoff said, because “other trials of GLP-1s in patients with (type 2) diabetes actually showed very big effects on stroke”, including the SUSTAIN-6 trial of semaglutide in type 2 diabetes (HR 0.61, 95% CI 0.38-0.99, P=0.04).
“Whether or not that’s real, or just a play of chance in these patients, we don’t know," he said about the SELECT findings, adding that there was a “strong trend” in the reduction in cardiovascular death and in overall mortality, “so all things were moving in approximately the same direction”.
While a cardiovascular outcomes study for tirzepatide is ongoing, a pre-specified cardiovascular meta-analysis of seven randomised controlled trials from the SURPASS programme focused on patients with type 2 diabetes found a lower risk of a primary composite cardiovascular endpoint (cardiovascular death, myocardial infarction, stroke, and hospitalised unstable angina), but it wasn’t significant.
Despite questions about the true benefit of GLP-1 agonists in cardiovascular disease, Medicare will now pay for semaglutide in adults with cardiovascular disease and either obesity or overweight (the federal insurer is still not allowed to cover weight loss drugs for shedding kilos).
At a cost of more than $1 000 per month, however, some question whether the potential cardiovascular benefit is worth it – not just because of the small absolute risk reduction in the SELECT trial, but also because patients don’t stay on the drug, for both tolerance and cost reasons, Zuckerman said.
Zuckerman said other research has shown that about 44% of people stopped taking semaglutide within six months, and 60% had dropped it by the end of a year. While that study is a retrospective claims analysis, it may better reflect real-world use than a clinical trial, she said.
“Talking about these (drugs) as a way to make people healthier, therefore, Medicare and Medicaid should pay for it, is very misleading, because the vast majority of people don’t take it long enough to benefit,” Zuckerman said. “If you’ve got millions of people trying it for a few months, that’s an enormous amount of money with zero benefit.”
“We know that the natural evolution of this is that more drugs will come on the market and prices will change,” Lincoff added. “But that doesn’t change the fact that we have to grapple with it now.”
Indeed, rates of overweight and obesity are “exploding around the world, despite 20 or 30 years or more of people trying to address the root causes”, Lincoff said. “The traditional approaches of diet, exercise, counselling, whatever we’ve been doing, aren’t working.
“I think we all worry about medicalising a large proportion of the world’s population. But the reality is that overweight and obesity are associated with increased risk – not just cardiovascular risk, but a variety of other metabolic and orthopaedic (conditions) and cancer. … No one would suggest (semaglutide) takes the place of public health efforts to help control the explosion. But as it stands now, we don’t have other good therapies.”
Meanwhile, participants in the US study, none of whom had been diagnosed with cancer at baseline, were followed up for 15 years. Compared with using insulin, taking GLP-1RAs was tied to significant reductions in the risk of developing gallbladder, pancreatic, liver, ovarian, colorectal, oesophageal, endometrial, and kidney cancers and meningioma and multiple myeloma, the researchers reported in JAMA Network Open.
There was no significant reduction in cancer risk among participants who used GLP-1RAs compared with those who used metformin, another medication used to treat type 2 diabetes.
Instead, GLP-1RAs were associated with an increased risk of kidney cancer compared with metformin, found the team, which was led by Case Western Reserve University School of Medicine.
Study details
Glucagon-Like Peptide 1 Receptor Agonists and 13 Obesity-Associated Cancers in Patients With Type 2 Diabetes
Lindsey Wang, Rong Xu, David Kaelber, et al.
Published in JAMA Network on 5 July 2024
Key Points
Question
Is there clinical evidence supporting the potential benefits of glucagon-like peptide receptor agonists (GLP-1RAs) for the prevention of 13 obesity-associated cancers (OACs)?
Findings
This cohort study of more than 1.6m patients with type 2 diabetes (T2D) who had no prior diagnosis of 13 OACs found that patients with T2D treated with GLP-1RAs vs insulin had a significant risk reduction in 10 of 13 OACs, including oesophageal, colorectal, endometrial, gallbladder, kidney, liver, ovarian, and pancreatic cancer as well as meningioma and multiple myeloma. No decrease in cancer risk was associated with GLP-1RAs compared with metformin.
Meaning
This study provides clinical data suggesting that GLP-1RAs may reduce the risk of specific OACs compared with insulins.
Abstract
Importance
Thirteen human malignant neoplasms have been identified as obesity-associated cancers (OACs), ie, the presence of excess body fat is associated with increased risk of developing cancer and worse prognosis in patients with these specific tumours. The glucagon-like peptide receptor agonist (GLP-1RA) class of pharmaceuticals are effective agents for the treatment of type 2 diabetes (T2D) and for achieving weight loss, but the association of GLP-1RAs with the incident risk of 13 OACs is unclear.
Objective
To compare the incident risk of each of the 13 OACs in patients with T2D who were prescribed GLP-1RAs vs insulins or metformin.
Design, Setting, and Participants
This retrospective cohort study was based on a nationwide multicentre database of electronic health records (EHRs) of 113 million US patients. The study population included 1 651 452 patients with T2D who had no prior diagnosis of OACs and were prescribed GLP-1RAs, insulins, or metformin during March 2005 to November 2018. Data analysis was conducted on April 26, 2024.
Exposures
Prescription of GLP-1RAs, insulins, or metformin.
Main Outcomes and Measures
Incident (first-time) diagnosis of each of the 13 OACs occurring during a 15-year follow-up after the exposure was examined using Cox proportional hazard and Kaplan-Meier survival analyses with censoring applied. Hazard ratios (HRs), cumulative incidences, and 95% CIs were calculated. All models were adjusted for confounders at baseline by propensity-score matching baseline covariates.
Results
In the study population of 1 651 452 patients with T2D (mean [SD] age, 59.8 [15.1] years; 827 873 [50.1%] male and 775 687 [47.0%] female participants; 5780 [0.4%] American Indian or Alaska Native, 65 893 [4.0%] Asian, 281 242 [17.0%] black, 13 707 [0.8%] Native Hawaiian or Other Pacific Islander, and 1 000 780 [60.6%] white participants), GLP-1RAs compared with insulin were associated with a significant risk reduction in 10 of 13 OACs, including in gallbladder cancer (HR, 0.35; 95% CI, 0.15-0.83), meningioma (HR, 0.37; 95% CI, 0.18-0.74), pancreatic cancer (HR, 0.41; 95% CI, 0.33-0.50), hepatocellular carcinoma (HR, 0.47; 95% CI, 0.36-0.61), ovarian cancer (HR, 0.52; 95% CI, 0.03-0.74), colorectal cancer (HR, 0.54; 95% CI, 0.46-0.64), multiple myeloma (HR, 0.59; 95% CI, 0.44-0.77), oesophageal cancer (HR, 0.60; 95% CI, 0.42-0.86), endometrial cancer (HR, 0.74; 95% CI, 0.60-0.91), and kidney cancer (HR, 0.76; 95% CI, 0.64-0.91). Although not statistically significant, the HR for stomach cancer was less than 1 among patients who took GLP-1RAs compared with those who took insulin (HR, 0.73; 95% CI, 0.51-1.03). GLP-1RAs were not associated with a reduced risk of postmenopausal breast cancer or thyroid cancer. Of those cancers that showed a decreased risk among patients taking GLP-1RAs compared with those taking insulin, HRs for patients taking GLP-1RAs vs those taking metformin for colorectal and gallbladder cancer were less than 1, but the risk reduction was not statistically significant. Compared with metformin, GLP-1RAs were not associated with a decreased risk of any cancers, but were associated with an increased risk of kidney cancer (HR, 1.54; 95% CI, 1.27-1.87).
Conclusions and Relevance
In this study, GLP-1RAs were associated with lower risks of specific types of OACs compared with insulins or metformin in patients with T2D. These findings provide preliminary evidence of the potential benefit of GLP-1RAs for cancer prevention in high-risk populations and support further preclinical and clinical studies for the prevention of certain OACs.
NEJM article – Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (Open access)
Reuters – Lilly says weight loss drug cuts heart failure risk by 38% in trial
Medpage Today article – How Good Is Wegovy’s Heart Benefit (Open access)
See more from MedicalBrief archives:
The mystery behind new obesity drugs
Global race heats up for weight-loss drug pill
Weight loss drug trial suggests significant heart benefit
Tirzepatide effective for obstructive sleep apnoea – US study