Incretins research update
medwireNews: One of the first original research sessions of EASD 2017 included updates from the TECOS, SUSTAIN 6, and DURATION-7 and -8 trials.
The first presentation, from Samuel Engel (Merck & Co, Inc, Rahway, New Jersey, USA) on behalf of the TECOS investigators, looked in more detail at the ability of sitagliptin to delay the progression of patients with type 2 diabetes to insulin therapy. Overall, sitagliptin treatment was associated with a 30% reduction in the risk for progressing to insulin treatment, but Engel revealed that this varied according to patients’ background antidiabetes therapy.
In all, 77% of the total 11,263 patients were taking metformin, 22% a sulfonylurea, and 94% were taking both. Patients were progressively older and with longer diabetes duration across these subgroups, and were more likely to start insulin therapy during follow-up, at 4.7%, 11.0%, and 17.2%, respectively. Patients taking metformin with or without a sulfonylurea were significantly less likely to progress to insulin therapy if they were taking sitagliptin, with respective risk reductions of 33% and 36%, but there was no effect among patients taking a sulfonylurea alone.
Next, Katherine Tuttle (Providence Health Care, Spokane, Washington, USA) recapped the AWARD7 primary findings, originally presented at ADA in June this year. The study found dulaglutide to be non-inferior to insulin glargine (both given in combination with bolus insulin) for glycemic control in patients with moderate to severe chronic kidney disease, with both treatments delivering around a 1.2% reduction in glycated hemoglobin (HbA1c) levels.
However, patients taking dulaglutide had a significantly greater reduction in bodyweight than those taking insulin glargine, as well as less hypoglycemia and better renal outcomes. Specifically, patients taking the 1.5 and 0.75 mg dulaglutide doses had respective 27.7% and 26.7% reductions in albuminuria during 26 weeks of treatment, compared with a 16.4% reduction in the insulin glargine group. Likewise, the estimated glomerular filtration rate deteriorated by a corresponding 0.8% and 3.3% versus 7.7%.
The latest DURATION-7 analysis, presented by Juan Frias (National Research Institute, Los Angeles, California, USA), lends support to the primary findings by showing superior efficacy of exenatide over basal insulin across the spectrum of individual patient responses.
Among the 461 patients, there was a 19.5 percentage point between-group difference favoring exenatide in those who achieved glycemic control without gaining weight or experiencing major hypoglycemia. And 80.9% of patients who took exenatide achieved at least some reduction in HbA1c, compared with 59.7% of the insulin group, and 62.3% versus 39.8% achieved at least some reduction in bodyweight. Only 7.4% of patients taking exenatide had increases in both HbA1c and bodyweight, compared with 23.3% of those assigned to receive insulin.
Bodyweight was also a focus of a SUSTAIN 6 analysis presented by Agostino Consoli (University of Chieti, Italy). Analysis of this secondary outcome showed that, among the 3297 patients, those taking semaglutide at doses of 0.5 and 1.0 mg lost a respective 3.6 and 4.9 kg by week 104 of the trial, whereas the matched placebo groups lost 0.5–0.7 kg.
Semaglutide was also superior to placebo for reduction in waist circumference and the proportion of patients who lost at least 5% or 10% of their starting bodyweight.
Consoli noted that this effect occurred irrespective of patients’ baseline body mass index (BMI) category; even those below 25 kg/m2 lost an average of 2.3 kg with semaglutide treatment, versus a 0.7–1.0 kg increase with placebo. Overall weight loss with semaglutide was greater in the higher BMI categories, however.
The one presentation that did not involve a large clinical trial came from Natasha Bergmann (University of Copenhagen, Denmark), who reported on an attempt to reproduce a known effect of incretins in animals in human volunteers.
In mice, she explained, dual therapy targeting both the glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors has an additive effect on food intake and weight loss.
However, Bergmann’s team found, in line with previous research, that this was not the case in humans – in this case 18 overweight and obese men, aged a median of 38 years, with a BMI of 33 kg/m2 but normal glucose metabolism.
The men were given infusions of GIP, GLP-1, both, or neither over 270 minutes on separate study days in a randomized order. The infusions, particularly those containing GLP-1, influenced the men’s levels of insulin, C-peptide, and glucagon over time, and GLP-1 infusion was associated with reduced food intake, but there was no sign of an additive effect with GIP on any of these measures or on resting energy expenditure.
And lastly in this session, the DURATION-8 investigators presented their 52-week findings, as reported here.
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