American Diabetes Association 78th Scientific Sessions

The 78th Scientific Sessions of the American Diabetes Association (ADA) took place in Orlando (FL, USA), 22–26 June 2018. There, Novo Nordisk (Bagsvaerd, Denmark) presented full data from the Efficacy and Safety of Oral Semaglutide Versus Placebo In Subjects With Type 2 Diabetes Mellitus Treated With Diet and Exercise Only (PIONEER 1) trial. Oral glucagon-like peptide-1 receptor agonist (GLP-1) semaglutide significantly lowered HbA1c and body weight without any increased risk of hypoglycemia at 26 weeks. In an on-treatment analysis, HbA1c fell by 0.8% in the 3-mg treatment group, 1.3% in the 7-mg group, and 1.5% in the 14-mg group, compared with a 0.1% drop in the placebo group (P < 0.001 for all comparisons). Oral semaglutide also gave weight loss of approximately 1.8, 2.7, and 4.1 kg with the 3-, 7-, and 14-mg doses, respectively; however, mean weight loss was approximately 1.4 kg in the placebo group, leading to estimated treatment differences of approximately 0.5 kg (not significant), 1.4 kg (P < 0.05), and 2.7 kg (P < 0.001), in the 3-, 7-, and 14-mg dose groups, respectively. The composite outcome of HbA1c <7.0% without weight gain or hypoglycemia was achieved by 73% of participants on high-dose semaglutide compared with 27% of those on placebo (P < 0.001), and the composite of at least 1% HbA1c decline with at least 3% body weight loss was seen in 54% and 11% of participants, respectively (P < 0.001).

In addition, Dr Athena Philis-Tsimikas (Scripps Clinic, San Diego, CA, USA) presented data from a Clinical Trial Comparing Glycaemic Control and Safety of Insulin Degludec/Liraglutide (IDegLira) Versus Insulin Glargine (IGlar) as add-on Therapy to SGLT2i in Subjects With Type 2 Diabetes Mellitus (DUAL IX).1 In this study, mean HbA1c fell 1.9% from a baseline of 8.2% to 6.3% with IDegLira and 1.7% from 8.4% to 6.7% with insulin glargine (P < 0.0001 for comparison). Moreover, insulin degludec/liraglutide was associated with a 58% lower risk of severe or confirmed symptomatic hypoglycemia versus insulin glargine (0.37 vs 0.90 events/patient-years; 38 vs 95 total events; P = 0.0035), and average total daily insulin dose was lower with insulin degludec/liraglutide (36 units/day) than with insulin glargine (54 units/day; P < 0.0001 for comparison). Finally, the proportion of participants achieving HbA1c <7.0% without hypoglycemia or weight gain was 42% in the insulin degludec/liraglutide group, compared with 17% in the insulin glargine group (odds ratio [OR] 3.36; 95% confidence interval [CI] 2.09–5.41).

Johnson & Johnson (New Brunswick, NJ, USA) also presented an observational study of four claims databases (OBSERVE-4D).2 In OBSERVE-4D, the sodium–glucose cotransporter 2 (SGLT2) inhibitor canagliflozin was found to be not associated with an increased risk of below-knee amputations compared with non-SGLT2 inhibitor diabetes therapies (excluding metformin; intent-to-treat hazard ratio [HR] 1.01 [95% CI 0.93–1.10; P = 0.71]; on-treatment HR 0.75 [95% CI 0.40–1.41; P = 0.25]). Moreover, the study confirmed the heart failure benefits of the SGLT2 inhibitor class, because on-treatment analysis identified a 61% risk reduction in hospitalization for heart failure with canagliflozin compared with non-SGLT2 therapies (HR 0.39; 95% CI 0.26–0.60; P = 0.01), and no difference on this heart failure endpoint with canagliflozin compared with other SGLT2 inhibitors (HR 0.90; 95% CI 0.71–1.13; P = 0.22). However, the mean duration of follow-up was only 6 months, and only approximately 25% of the sample had established cardiovascular disease (CVD).

Finally, Dr Chantal Mathieu (University of Leuven, Leuven, Belgium) shared the first results from the Dapagliflozin Evaluation in Patients With Inadequately Controlled Type 1 Diabetes (DEPICT 2) trial.3 After 24 weeks, patients randomized to 5 mg dapagliflozin as an adjunct therapy to insulin (n = 271) saw a placebo-adjusted HbA1c decline of 0.37%, whereas those randomized to 10 mg dapagliflozin (n = 270) saw a placebo-adjusted HbA1c decline of 0.42% (both P < 0.0001). Total daily insulin dose fell 11% for both doses relative to placebo (P < 0.0001), and placebo-adjusted total body weight loss was 3% with 5 mg dapagliflozin and 4% with 10 mg dapagliflozin (P < 0.0001 for both). The composite endpoint of ≥0.5% HbA1c reduction without severe hypoglycemia was achieved by 40% of the lower-dose 5-mg group and by 42% of the higher-dose 10-mg group, compared with only 20% of the placebo group. However, diabetic ketoacidosis (DKA) occurred in seven and six people from the 5- and 10-mg dapagliflozin arms, respectively, which corresponds to event rates of 2% and 3%. There were no instances of DKA reported in the placebo arm of the study.

Updates on oral semaglutide

In May and June 2018, Novo Nordisk reported topline results for PIONEER 2 (http://hugin.info/2013/R/2195846/850845.pdf, accessed 8 August 2018), PIONEER 3 (http://hugin.info/2013/R/2201779/853971.pdf, accessed 8 August 2018), PIONEER 4, and PIONEER 7 (https://www.novonordisk.com/media/news-details.2200408.html, accessed 8 August 2018). PIONEER 2 compared oral semaglutide head-to-head with Eli Lilly and Boehringer Ingelheim's (Ingelheim am Rhein, Germany) SGLT2 inhibitor Jardiance (empagliflozin). After 26 weeks, patients with type 2 diabetes mellitus (n = 816) experienced superior HbA1c reductions of 1.4% with 14 mg oral semaglutide, compared with a 0.9% reduction with 25 mg empagliflozin; there was no significant difference in weight loss between the two treatment arms (no P-value disclosed). However, in a secondary on-treatment analysis, investigators did find a significant weight loss benefit to oral semaglutide (4.7 kg) versus empagliflozin (3.8 kg) at 52 weeks of treatment. In that on-treatment analysis, HbA1c at 26 and 52 weeks had declined by a mean 1.4% and 1.3%, respectively, in the oral semaglutide group, compared with 0.9% and 0.8%, respectively, in the SGLT2 group.

PIONEER 3 compared oral semaglutide to Merck's (Kenilworth, NJ, USA) dipeptidyl peptidase (DPP)-4 inhibitor Januvia (sitagliptin). The study (n = 1864) evaluated 3-, 7-, and 14-mg once-daily doses of oral semaglutide, and the two higher doses offered significantly more HbA1c lowering and weight loss than 100 mg sitagliptin. In the on-treatment analysis, 14 mg oral semaglutide was associated with a mean 1.4% HbA1c decline after 26 weeks and 1.1% after 78 weeks, compared with reductions of 0.8% and 0.4% at 26 and 78 weeks, respectively, with sitagliptin. Weight loss at 26 and 78 weeks was 3.3 and 3.5 kg, respectively, with 14 mg oral semaglutide, compared with 0.7 and 1.1 kg with sitagliptin. Nausea was more common with oral semaglutide than sitagliptin. Between 7% and 15% of participants randomized to oral semaglutide experienced nausea over the course of 78 weeks, compared with 7% of patients on sitagliptin.

Results from PIONEER 4 and PIONEER 7 were announced simultaneously. PIONEER 4 (n = 711) was a 52-week head-to-head trial of 14 mg oral semaglutide versus injectable the GLP-1 agonist Victoza (liraglutide). In the on-treatment analysis, oral semaglutide gave a non-inferior 1.3% HbA1c reduction at 26 weeks, compared with 1.1% with liraglutide; at Week 52, HbA1c had fallen 1.2% and 0.9% in the semaglutide and liraglutide groups, respectively. Moreover, oral semaglutide gave a superior 4.7 and 5.0 kg weight loss at 26 and 52 weeks, respectively, compared with 3.2 and 3.1 kg with Victoza. PIONEER 7 (n = 504) was a 52-week study comparing dose-adjusted oral semaglutide with Januvia (sitagliptin). In the on-treatment analysis, oral semaglutide gave a superior average 1.4% drop in HbA1c, compared with 0.7% with sitagliptin at Week 52; body weight reductions at 52 weeks were also superior with semaglutide than sitagliptin (2.9 vs 0.8 kg, respectively).