The benefits aren’t necessarily mediated by weight loss.
Researchers keep finding new benefits from GLP-1 receptor agonists and their newer friends, glucose-dependent insulinotropic polypeptide (GIP) receptor agonists – not all of which are flow-on effects from weight loss or better insulin sensitivity.
Four recent studies show the breadth of effects across cardiovascular, neurological, renal and pulmonary systems.
Tirzepatide and heart failure
In a double-blinded RCT published in NEJM, funded by tirzepatide maker Eli Lilly, 731 patients with obesity and heart failure with preserved ejection fraction (at least 50%) were randomised to at least a year or more of tirzepatide or placebo.
Endpoints were death from cardiovascular causes and/or worsening heart failure or cardiomyopathy after a two-year median follow-up.
Worsening heart failure and/or cardiovascular death occurred in 36 patients (10%) in the tirzepatide group and 56 (15.3%) in the placebo group, meaning a 40% reduction in that composite endpoint.
However, the benefit was in the heart failure component. Eight patients on tirzepatide died compared with five on placebo, which was not a statistically significant difference.
Cardiomyopathy scores were around 20 points better, out of a 0-100 scale, for the tirzepatide group, compared with 13 points on placebo.
Discontinuation due to adverse events (mainly gastrointestinal) occurred in 23 tirzepatide patients and five who were on placebo.
Tirzepatide (Mounjaro), a GLP-1 receptor agonist and GIP receptor agonist, was approved by the TGA in September for weight management.
Semaglutide and Alzheimer’s
A large Ohio study in Alzheimer’s & Dementia looked for real-world data to confirm an association suggested by previous research: that semaglutide reduced Alzheimer’s incidence in people with diabetes.
The team used emulated target trials with data from electronic health records on more than a million people to compare Alzheimer’s incidence between patients on semaglutide versus seven other diabetes medications.
Compared with insulin, patients on semaglutide had a two-thirds lower risk of developing Alzheimer’s. Compared with other, older GLP-1RAs, there was a 40% lower risk.
Differences between semaglutide and other comparators (metformin, DPP4is, SGLT2is, sulfonylurea and thiazolidinedione) fell in between those two.
The effects were stronger in women but still present in men. And, importantly, the effects were about the same for patients with obesity and without.
“These findings align with prior research suggesting semaglutide may offer neuroprotective effects via pathways like neuroinflammation and mitochondrial function beyond insulin resistance improvement,” the authors write.
They add that the effects may be mediated by reducing diabetes, obesity, cardiovascular disease, smoking, alcohol use and depression, all risk factors for Alzheimer’s and all showing evidence of being mitigated with semaglutide.
GLP-1s and kidneys
A meta-analysis in Lancet Diabetes and Endocrinology from The George Institute in Sydney set out to comprehensively assess the evidence of effects of GLP-1RAs on kidney and cardiovascular outcomes.
They found 11 trials to analyse with a total of 85,000 patients.
The main outcomes were, for kidneys: kidney failure (therapy such as dialysis or persistent low glomerular filtration rate) or a halving of GFR or death from kidney failure; and for cardiovascular outcomes, cardiovascular death or non-fatal myocardial infarction or non-fatal stroke (MACE).
In people with type 2 diabetes, being on any GLP-1RA reduced the adverse kidney outcomes by 18%, MACE by 13% and all-cause mortality by 12%. The results were slightly better when people without type 2 diabetes, but with overweight/obesity and/or cardiovascular disease, were included.
Serious adverse events (such as acute pancreatitis and severe hypoglycaemia) were no more common in patients on GLP-1RAs than on placebo, but they did discontinue treatment at a 50% higher rate.
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Antidiabetics and asthma
Finally, a UK study in JAMA internal Medicine examined the effects of metformin with and without add-on GLP-1RAs on asthma exacerbations and deaths.
One in three asthma patients is obese, and half of those have type 2 diabetes, the paper says. Previous research has found a reduction of asthma attacks on metformin, independent of glycaemic control and obesity.
Using the UK Clinical Practice Research Datalink Aurum health records database, they looked at 12,700 adults who had asthma and type 2 diabetes and were new to metformin.
Metformin was associated with a 30% reduction in asthma attacks. Adding a GLP-1RA reduced asthma attacks by a further 40%, and this was the only add-on to achieve such an effect.
They adjusted for variables including age, sex, socioeconomic status, BMI, HbA1c, cardiovascular disease status and other asthma medications.
The effects were stable regardless of improvement in glycaemic control or weight loss.
In the database’s original cohort of more than two million asthma patients, the authors write, glycaemic control was often poor but type 2 diabetes was not diagnosed and treatment was delayed. This argues for repurposing metformin as an asthma treatment.
While GLP-1RAs had been associated in a previous study with a two- to three-fold reduction in asthma attacks compared with other add-on antidiabetic drugs, “metformin has considerable advantages, including global availability and affordability”.
