It’s early days, but semaglutide and friends have a competitor drug class on the horizon.
It never rains but it pours.
Without looking for this information, the Back Page learned the other day that 260 million Americans are predicted to be overweight or obese by 2050, that over half are already eligible for GLP-1 receptor agonist treatment and that the world prevalence of diabetes has quadrupled in 30 years.
Whether or not you blame fast internet for the obesity epidemic, semaglutide, tirzepatide et al. have come along just in time – as we keep reporting, with their effects on everything from diabetes to CVD to hidradenitis suppurativa to alcohol use disorder to knee osteoarthritis, it’s hard not to see them as bona fide miracle drugs.
OK, there are a few downsides and rarities.
But it’s the less dramatic and more common GI side effects that seem more likely to drive the drugs’ startlingly high discontinuation rate (that, and the cost, which is higher in the US).
Given you have to take them in perpetuity, what if you could get the benefits without the nausea, cramps, vomiting, diarrhoea and/or constipation?
A team at the University of Copenhagen, in a paper published in Nature, has not only sought to address tolerability, but also tackled the other side of the weight-loss equation besides calories ingested: energy expended.
It’s only an animal study so far, but their results are very impressive.
Using a diabetes genetic database they identified a receptor – neurokinin 2 receptor (NK2R), also known as tachykinin receptor 2 – strongly associated with Hba1C levels but not previously linked to glucose homeostasis or cardiometabolic health.
They found that increased NK2R expression in the nucleus accumbens of the brain was associated with decreased HbA1c levels, with or without adjustment for BMI.
Obese mice treated with an NK2R agonist called EB1002 both reduced their food intake and increased their energy expenditure.
The mice’s respiratory exchange ratio decreased, implying the burning of fats for energy.
Their blood sugar stabilised “independent of changes in insulin secretion or food intake reduction”, meaning improved insulin sensitivity.
The team then looked at the effects on hunger-associated hormones and found leptin and glucagon were significantly decreased and peptide YY was significantly increased following a week of daily injections.
A single injection of EB1002 resulted in 10-15% weight loss over seven days.
Looking at body composition after a week of daily injections, they found the weight loss was all in fat, with lean mass spared.
The mice seemed to tolerate the compound well, “without any overt signs of discomfort or changes in physical activity”, and only “transient loose stools” at the highest doses.
The team also, using an earlier version of the compound, induced weight loss without side effects in macaque monkeys while reducing their fasting glucose, plasma triglycerides, LDL cholesterol and insulin: C-peptide ratio (an indicator of fatty liver), and improved their insulin sensitivity.
There’s a lot more in this paper but you get the picture, and so far – translation to humans permitting – it’s quite rosy.
The authors modestly conclude that, given the success of existing drugs, an NK2R agonist would most likely find its place in a combination therapy.
“The recent advances in biopharmaceutical therapies for T2D and obesity have set incredibly high innovation bars,” they write.
“However, we believe that features of NK2R agonism such as energy expenditure with no signals of increased cardiovascular risk, lean mass sparing, lack of nausea and, crucially, insulin sensitisation could complement the current drug repertoire, particularly in the context of individuals living with both obesity and T2D.”
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