The annual meeting of the European Association for the Study of Diabetes (EASD) took place this year in Barcelona, Spain. The present text offers a selection of topics relevant for the field of type 2 diabetes mellitus (T2DM) discussed during that meeting.
Credence
Diabetes is the leading cause of kidney failure. Patients suffering from kidney disease have higher morbidity and mortality. The CREDENCE trial aimed at investigating the effect of canagliflozin 100 mg PO on renal outcomes in patients with T2DM (eGFR between 30- 90 mL/min/1.73m2 and stable maximal tolerated dose of ACEi or ARB for ≥4 weeks). The primary endpoint was a composite of end-stage kidney disease, doubling of serum creatinine and renal or cardio-vascular death. A total of 4401 subjects were randomised. Subjects on canagliflozin had a 30% reduction in the occurrence of the primary endpoint (hazard ratio 0.70; 95% CI, 0.59 – 0.82). The reduction was different when grouping according to eGFR:
- 30 to < 45 mL/min/1.73 m2: HR 0.75 (0.59-0.95)
- 45 to < 60 mL/min/1.73 m2: HR 0.52 (0.38-0.72)
- 60 to < 90 mL/min/1.73 m2: HR 0.82 (0.60-1.12)
These results suggested that the benefits of SGLT2 inhibitors are greater in subjects with affected, but somehow preserved renal function. The decrease in renal function showed to be slower in the group of patients taking canagliflozin.
The safety results showed, as usual for this group of medications, increased incidence of genital infections and diabetic ketoacidosis. This confirmation of the renoprotective properties of this drug in the SGLT2 class establishes the SGLT2 inhibitors as truly renoprotective drugs.
PIONEER program
The PIONEER program was a phase 3 program designed to assess efficacy and safety of oral semaglutide. The motivation for developing an oral glucagon-like peptide-1 receptor analogue (GLP-1RA) is that it might improve acceptance and adherence for patients.
Last year the results of the PIONEER-1 [1] were presented. It showed a significant reduction in HbA1c with oral semaglutide compared to placebo. PIONNEER-2 compared semaglutide against empagliflozin, PIONEER-3 [2] against sitagliptin and PIONEER-4 [3] against injectable GLP-1RA. The PIONEER-5 trial [4] investigated oral semaglutide 14 mg in patients with renal impairment. The PIONEER-6 [5] was a cardiovascular outcome trial in which the primary endpoint consisted of a composite major adverse cardiac events (MACE) outcome including CV death, non-fatal myocardial infarction or non-fatal stroke in a sample of 3183 patients with T2DM. The trial met its primary endpoint, which was non-inferiority in the 3-point MACE outcome (hazard ratio 0.79, 95% CI, 0.57 - 1.11). However, in contrast to its subcutaneous form, oral semaglutide was not superior to placebo in the CV outcomes (SUSTAIN-6 trial, including 3297 with T2DM) [6].
The PIONEER-7 trial [7] investigated flexible doses of oral semaglutide against 100 g sitagliptin and the PIONNEER-8 investigated effectivity of oral doses of semgalutide when adding basal insulin.
The overall program showed that there are no disadvantages for oral semaglutide in terms of HbA1c and body weight reduction in comparison to injectable GLP-1RA.s The general conclusion is, therefore, that oral semaglutide is a safe and effective option for T2DM patients needing improvement of the glycemic control and not willing to inject a GLP-1RA.
SUSTAIN-8
Subcutaneous semaglutide was the protagonist of this trial [8]. Semaglutide 1 mg once weekly was compared with canagliflozin 300 mg po. The study had a duration of 52 weeks and included 788 subjects with T2DM. Subjects in the semaglutide group experienced a greater mean reduction of HbA1c (-1.5%), compared to canagliflozin (-1%). A greater proportion of subjects (66.1%) achieved an HbA1c below 7% in the semaglutide group. Another positive effect of the therapy was a greater weight reduction at week 52, which was superior with semaglutide (-5.3kg change from baseline) than in canagliflozin (-4.2 kg). This is one of the first direct comparisons of a GLP-1RA to an SGLT2 inhibitor.
CAROLINA
This trial was performed in over 6,000 patients with T2DM. Patients received either linagliption 5 mg daily or glimepiride 1-4 mg daily. The primary endpoint included CV death, non-fatal myocardial infarction and non-fatal stroke. The study did not show a difference in the occurrence of the 3 points MACE endpoint (hazard ratio 0.98, 95% CI, 0.84 - 1.14). All-cause mortality was also not different between the groups (hazard ratio 0.91, 95% CI, 0.78 - 1.06). This trial not only confirms the safety of linagliptin, but also confirms the safety of the active comparator glimepiride via an indirect comparison, because all CVOT’s on DPP-IV’s have so far confirmed the cardiovascular safety of this class.
VERIFY
This interesting study investigated the benefits of early treatment of T2DM with metformin and vildagliptin instead of with metformin monotherapy with stepwise intensification. The study included 2001 subjects diagnosed with T2DM within 2 years prior to enrolment. The primary endpoint was the time from randomisation to initial treatment failure (HbA1c ≥7.0%) at two consecutive visits. The incidence of initial treatment failure in the first period of the study was significantly lower in the combination treatment group than in the monotherapy group. (hazard ratio 0.52; 95% CI, 0.45 – 0.58). After initial treatment failure, patients randomised to stepwise intensification with vildagliptin. Time to secondary failure, which was treated with basal insulin, was delayed by about a year. Over the full study duration, HbA1c was consistently lower in the combination group. The results suggest that starting therapy of metformin together with a DPP-4 inhibitor might bring benefits for the patients in terms of glycemic control compared to metformin monotherapy. Moreover, no additional safety concerns were observed, meaning that this option can be considered by the clinicians in the daily praxis.