The phase 3 SURPASS-4 trial published in 2021 established that tirzepatide lowers blood sugar and supports weight loss better than insulin glargine (a long-acting insulin) for type 2 diabetes (T2D) [1]. Now new research examining a broad range of potential predictors of sustaining blood sugar control and weight loss indicates that greater weight loss, better β-cell function, and a greater decrease in low-density lipoprotein cholesterol (LDL-C or "bad cholesterol") during the first year of tirzepatide therapy are the most robust predictors of better long-term outcomes.
The latest analysis of the SURPASS-4 trial is being presented at this year's Annual Meeting of The European Association for the Study of Diabetes (EASD), Madrid (9-13 Sept).
"For individuals with diabetes, reducing and maintaining lower blood glucose levels is important to minimise the risk of long-term complications such as nerve damage, kidney damage, and an increased risk of heart disease and eye problems," explained lead author Professor Steven E Kahn from VA Puget Sound Health Care System and the University of Washington, Seattle, USA. "But not everyone will get the same results with tirzepatide. Our findings offer insight into why some people may be more successful than others at keeping the weight off and maintaining blood glucose control over the long term."
T2D is a chronic and progressive condition in which the body does not make or use insulin normally, leading to high levels of glucose in the blood. More than 30 million Americans have T2D, but despite the availability of many medications to treat diabetes, only around half of US adults with T2D achieve target haemoglobin A1c (HbA1c; a measure of blood sugar control) of less than 7% [2].
Tirzepatide works by mimicking the GLP-1 and GIP hormones that are naturally secreted by the intestine after a meal, which prompts insulin secretion. It also reduces appetite by slowing down the time it takes the stomach to empty and interacting with areas in the brain harbouring GLP-1 receptors to signal satiety. It was approved for the treatment of T2D by the US Food and Drug Administration in May 2022.
The SURPASS-4 trial compared different doses of tirzepatide (5, 10 or 15 mg) with insulin glargine in 1,995 adults (average age 63.6 years; 38% female) with T2D who were at increased risk for cardiovascular events (average HbA1c 8.5%, weight 90.3 kg, BMI 32.6 kg/m2).
On average, participants treated with all doses of tirzepatide lowered their HbA1c more than those treated with insulin glargine, and a greater proportion achieved the HbA1c target of less than or equal to 6.5% at 52 weeks (67%, 73% and 81% with 5, 10 and 15 mg of tirzepatide, respectively). Similarly, clinically meaningful weight loss (at least 10%) was achieved by 35%, 52% and 65% of participants with 5, 10 and 15 mg tirzepatide.
In this latest analysis, researchers set out to identify clinical and biochemical predictors of reaching and sustaining HbA1c and weight loss targets at 52 weeks and beyond.
Achieving sustained blood sugar and weight control was defined as 0.2% or less increase in HbA1c and 2 kg or less weight gain after week 52.
Of 619 participants treated with tirzepatide who reached the HbA1c target of less than or equal to 6.5% at week 52, 75%, 80% and 83% (5, 10 and 15 mg) sustained their HbA1c until the end of their participation in the study (median of 85 weeks, maximum of 104 weeks).
After adjusting for tirzepatide dose, age, and sex, the analyses found that the most important factors predicting glycaemic control at week 52 were higher tirzepatide dose and, at the start of the study, shorter duration of diabetes, lower HbA1c, higher beta-cell function, use of metformin only, and normal urine-albumin creatinine-ratio (a marker of kidney damage or disease).
Factors predicting sustained glycaemic control were not using sulfonylureas (a class of medications to treat T2D), smaller decline in fasting glucose and greater weight loss during the first 52 weeks, and higher beta-cell function at week 52.
For example, individuals taking the higher (15 mg) dose of tirzepatide were 39% more likely to sustain blood sugar control than those on the lower (5 mg) dose, while women were 48% more likely than men to sustain glycaemic control. Similarly, each additional 5 kg of weight lost from the start of the study until week 52 resulted in a 25% greater likelihood of sustaining blood sugar control (see figure in abstract).
Of 437 participants treated with tirzepatide who achieved clinically significant weight loss of at least 10% by week 52, 79%, 81% and 82% (5, 10 and 15 mg) maintained their weight loss.
The main factors predicting clinically significant weight loss by week 52 were higher tirzepatide dose and being female as well as lower baseline HbA1c, estimated glomerular filtration rate (marker of kidney function), and triglycerides (lipids in the blood), and no prior cardiovascular disease.
Only a greater decrease in low-density lipoprotein cholesterol (LDL-C or "bad cholesterol") during the first 52 weeks predicted sustained weight loss. However, no clinically meaningful predictor of sustained weight loss was identified.
"These results are very encouraging and one hopes we will gain more insight from upcoming studies such as SURPASS-CVOT that includes a larger number of participants followed for longer," said Professor Kahn.
