‘Twincretin’ Beats Glargine for Diabetes in Pivotal Trial
The “two incretins” tirzepatide scored another pivotal-trial win in full, posted outcomes from the multicenter SURPASS-four trial, which compared the investigational agent to insulin glargine for remedy of kind two diabetes. They look at 1,995 randomized sufferers with inadequately managed kind two diabetes and excessive cardiovascular disorder chance.
Positive outcomes for tirzepatide from SURPASS-four, the 5th and very last registration trial for the drug, in addition to withinside the additional four research, tee up the agent for a deliberate approval submission to the Food and Drug Administration via way of means of the quit of 2021.
SURPASS-four differed from the four different pivotal trials now no longer most effective in its comparator agent, however additionally via way of means of being the longest of the five and the most effective one that, via the form of means of design, enrolled solely sufferers with both set up cardiovascular disorder or excessive chance for the disease.
The new outcomes “offer preliminary help for glycemic manage [by tirzepatide] being sustained for greater than 1 12 months,” wrote Stefano Del Prato, MD, and pals of their posted document in The Lancet.
Despite the trial’s number one endpoint of alternate in hemoglobin A1c after fifty-two weeks on remedy, the have a look at persisted for some other 12 months and had a meantime on the treatment of eighty-five weeks, with 7% of enrolled sufferers final on the remedy for the most on-remedy follow-up of 104 weeks.
Potent Glycemic Control
The number one endpoint confirmed that remedy with tripeptide produced a mean incremental discount in A1c of 0.99% amongst 328 sufferers handled with a ten mg weekly subcutaneous dosage compared with the 1,000 sufferers who acquired insulin glargine (Basaglar, Lantus, Toujeo). A mean 1.14% incremental discount in A1c amongst 338 sufferers on a 15-mg dosage as soon as weekly, said Del Prato, professor, and leader of the segment of diabetes at the University of Pisa (Italy).
This met the prespecified standards for noninferiority of tripeptide to insulin glargine for a discount of A1c, the have a look at’s number one objective, and additionally met the have a look at’s prespecified definition of superiority, each statistically considerable outcomes. They have a look at further examined a weekly tripeptide dosage of five mg that become notably advanced to insulin glargine for glycemic management.
“The significance of A1c discount and the proportions of sufferers achieving glycemic goals seem like large than in comparable research wherein GLP-1 [glucagon-like peptide–1] receptor agonists had been as compared with glargine,” the investigators wrote of their document.
The A1c impact of tirzepatide visible throughout all 5 SURPASS trials “surpasses what we have got visible with different [glycemic control] drugs, with the viable exception of insulin,” stated Jan W. Eriksson, MD, Ph.D., professor of medical diabetes and metabolism at Uppsala (Sweden) University.
The outcomes additionally confirmed numerous different clinically significant advantages from tirzepatide remedy. Mixed final results of discount of A1c to much less than 7% and not using a weight advantage and no clinically considerable documented symptomatic or excessive hypoglycemia occurred in 74%-88% of sufferers withinside the three tripeptide hands compared with 13% of sufferers handled with insulin glargine.
After fifty-two weeks on remedy, frame weight fell via way of means of a mean of 8%, 11%, and 13% from baseline withinside the three tripeptide remedy hands in a dose-structured way, while weight rose via the form of means of a mean of 2% amongst folks that acquired insulin glargine. Weight discount of at the least 10% occurred in 36%-66% of sufferers handled with tripeptide, compared with 2% on remedy with insulin glargine.
SURPASS-four now no longer runs as a blinded have a look at due to variations in the management of the comparator dealers.
Safety Appears Similar to GLP-1 Receptor Agonists
The protection profile of tirzepatide in SURPASS-four, because it becomes in all the different four trials within the SURPASS series, becomes regular with formerly said protection of dealers withinside the GLP-1 receptor agonist class, stated Del Prato. It becomes a predicted locating as tirzepatide combines interest as a GLP-1 receptor agonist with interest as a glucose-structured insulinotropic polypeptide (GIP) receptor agonist in an unmarried molecule.
The maximum, not unusual place damaging outcomes had been gastrointestinal, such as diarrhea, nausea, reduced appetite, and vomiting. Most of those outcomes had been moderate or moderate, and that they occurred most customarily at some point of dose escalation of tirzepatide withinside the first 24 weeks on remedy.
The GIP receptor agonist impact of tirzepatide may also lessen nausea skilled via way of means of sufferers because of the drug’s GLP-1 receptor agonist action, Eriksson, precise discussant for the SURPASS trials, stated at some point of a consultation Sept. 30 on the annual digital assembly of the European Association for the Study of Diabetes (EASD).
Clinically significant or excessive hypoglycemia occurred in 8% of all sufferers on tripeptide, and not using an apparent dose relationship, approximately 1/2 of the price of the sufferers handled with insulin glargine. Notably, the hypoglycemia episodes amongst sufferers dealt with tripeptide clustered nearly absolutely withinside the subgroup of sufferers who additionally took a sulfonylurea agent at some point of the have a look at.
(SURPASS-four allowed enrolled sufferers to be on their heritage antidiabetes routine during the have a look at, and at baseline, 95% had been taking metformin, 54% had been on a sulfonylurea, and approximately 1 / 4 had been on a sodium-glucose cotransporter-2 inhibitor.)
“I could advocate now no longer the use of tripeptide with insulin or with a sulfonylurea,” Eriksson stated. Aside from this chance for hypoglycemia while tripeptide is used simultaneously with positive different anti-diabetes drugs, the SURPASS trials have proven “no different vital protection signals,” Eriksson added.
Cardiovascular Safety
All enrolled sufferers had both recognized coronary, cerebrovascular, or peripheral arterial disorder or had been at an excessive chance for having one or greater of those situations due to the fact they had been at the least 50 years vintage with a record of both persistent kidney disorder with depressed glomerular filtration or coronary heart failure.
During whole follow-up, the composite price of cardiovascular death, MI, stroke, or hospitalization for volatile angina become numerically much less withinside the sufferers who acquired tirzepatide, five%, than in the ones on insulin glargine, 6%, a 26% relative chance discount that did now no longer attain significance. The price of overall mortality become 3% withinside the tirzepatide institution and four% amongst the ones on glargine, a 30% relative chance discount that becomes now no longer considerable.
The cardiovascular disorder results “propose that tirzepatide is secure from a cardiovascular perspective,” Del Prato stated. At the same time, he supplied the SURPASS-four outcomes at some point in the annual digital assembly of the EASD. However, a far large cardiovascular results trial of tirzepatide, SURPASS-CVOT, with greater than 12,000 randomized sufferers and a GLP-1 receptor agonist because the comparator is now in progress, with a document at the findings predicted in 2025.
Overall, outcomes from all 5 SURPASS trials of tirzepatide have proven that the drug is “powerful and secure in human beings with kind two diabetes, presenting stringent glycemic manage and further metabolic advantages such as weight loss and a development in different cardiometabolic markers,” stated Melanie J. Davies, MD, professor of diabetes remedy on the University of Leicester, England.
Looking ahead to while tripeptide might be to be had for regular use, Eriksson located it near-time period as a part of a twin or triple routine, particularly for sufferers with kind two diabetes who’re overweight or have out of control hyperglycemia, renal impairment, excessive cardiovascular disorder chance, or excessive chance for clinically significant or unreasonable hypoglycemia. A position for tripeptide as a first-line agent is currently “greater speculative,” he added, with more excellent statistics on cardiovascular results, long-time period protection, and price effectiveness.
The present proof base for tirzepatide shows “very promising efficacy” for weight reduction and glucose reduction with “reassuring protection and tolerability” and is a “very vital addition to modern-day options,” even though the long-time period protection of persistent tripeptide remedy stays unproven, he stated.
Eriksson, known as the drug’s glycemic manage “robust and durable,” is primarily based totally on the complete SURPASS program, with a “major” weight reduction impact. He additionally recommended that while the lousy impact profile of tirzepatide seems much like the GLP-1 receptor agonists, the prevalence of damaging gastrointestinal occasions can be decreased with tripeptide.
SURPASS-four and the opposite SURPASS trials had been funded via Lilly, the corporation growing tirzepatide. Del Prato has ties with Lilly, Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Merck Sharpe and Dohme, Novartis, Novo Nordisk, and Sanofi. Davies has ties with Lilly, AstraZeneca, Boehringer Ingelheim, Janssen, Merck Sharp & Dohme, Novo Nordisk, Sanofi-Aventis, Servier, Gilead Sciences, Napp Pharmaceuticals, Mitsubishi Tanabe, and Takeda. Eriksson has ties with AstraZeneca, Ilya Pharma, Merck Sharp & Dohme, and Novo Nordisk.
https://www.medscape.com/viewarticle/961762?src=#vp_1
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