Tirzepatide, a novel dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist, significantly improves glycaemic control and bodyweight in patients with type 2 diabetes.
The phase 3 SURPASS-1 RCT, presented at ADA 2021 as the ADA Presidents’ Select Abstract and published in The Lancet, compared once weekly tirzepatide with placebo in 478 patients with diabetes inadequately controlled by diet and exercise alone.
Patients had a mean age of 54 years, mean BMI of 32, and a diabetes duration of 5 years. Almost half of patients had previously used oral antihyperglycaemic medications but all were naive to any injectable diabetes therapy.
Dr Julio Rosenstock, director of the Dallas Diabetes Research Centre and Professor of Medicine at the University of Texas, told ADA 2021 the HbA1c reductions with therapy were very robust.
Mean HbA1c reduced from 7.95% at baseline to between 5.88 and 6.08% after 40 weeks of tirzepatide while HbA1c remained at 7.99% with placebo.
The proportion of patients achieving glycaemic targets of HbA1c <7.0% at 40 weeks were 87% with 5 mg, 92% with 10 mg and 88% with 15 mg tirzepatide compared to 20% of controls.
The proportion of patients achieving the lower target of HBA1c ≤6.5% were 82%, 81%, 86% and 10% respectively.
Dr Rosenstock said an impressive 52% of patients on the highest dose of tirzepatide and about a third of patients on the lower doses achieved HbA1c <5.7% or “near normalisation”.
Bodyweight loss from baseline was 7-9.5 kg with increasing doses of tirzepatide compared to 0.7kg with placebo. About 70% of patients on tirzepatuide met the weight loss target of ≥5%, 40-47% of patients met the ≥10% weight loss target, and 27% on the highest dose achieved ≥15% weight loss.
Treatment related adverse events including nausea (12-18%), diarrhea (12-14%), decreased appetite (4-8%), constipation (5-6.6%) and vomiting (2.5-5.8%) were in keeping with the known side effects of GLP-1 receptor agonists.
Dr Rosestock said GI side effects subsided over the 40 weeks of treatment.
There was a low rate of hypoglycaemia (5-8%) and no severe hypoglycemia reported. Importantly, treatment discontinuation due to adverse events was a low 3-6% depending on the tirzepatide dose.
“In my judgment, I think that this type of medication has the potential to be initial therapy as monotherapy, in people who are obese or overweight with early diabetes to normalise the blood glucose but also achieve significant weight loss,” he concluded.
Commenting on the promise of the new agent, Professor Jonathan Shaw told the limbic that tirzepatide does look like a significant step forward.
“The starting point for this would be that a drug for lowering blood glucose will typically lower HbA1c by about 1 percentage point and weight loss drugs 5 or 6 kg. They’re getting over 2 percentage point reductions in HbA1c and 10 kg in weight loss.”
“There is some debate about whether this is just a very effective GLP-1 agonist or whether it is the combination that is achieving the benefits, because the GLP-1 agonist part of the drug has not been developed as a separate drug. They haven’t bolted an old drug on top of a new drug, they’ve taken two new molecules.”
Professor Shaw, from the Baker Heart and Diabetes Institute, noted that SURPASS-2 published in the NEJM, compared tirzepatide with semaglutide – one of the most potent of the GLP-1 agonists.
It found tirzepatide, at all doses, was noninferior and superior to semaglutide with respect to the mean change in HbA1c over 40 weeks.
“With high dose semaglutide or tirzepatide we’re getting into an arena of drugs which for many people would get close to normalising blood sugar.”
He said when approved, the most likely situation was that tirzepatide would be available for people who are already on treatment, almost certainly metformin.
“There are substantial appropriate financial reasons for being cautious about having to use tirzepatide in the first line. That’s almost everybody with diabetes… and these are expensive drugs while metformin is dirt cheap. It takes an awful lot to put something ahead of metformin.”
He said people would be keen to see the cardiovascular outcome trials for the new agent, given that other GLP-I agonists already have shown CV benefits.
Disclosures: SURPASS 1 and 2 were funded by Eli Lilly. Dr Rosenstock has received research support and advisory board consulting honorarium from Eli Lilly among other pharmaceutical companies.