European Association for the Study of Diabetes 2018

The 54th European Association for the Study of Diabetes Annual Meeting 2018 convened in Berlin, Germany, from October 1 to 5. Concluding the meeting was the presentation of the American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) Consensus Report for the Management of Hyperglycemia in Type 2 Diabetes.1 The report draws on 479 papers published over the past 4 years, offering recommendations on providing patient-centered diabetes care and choosing diabetes medications. This new guidance report provides detailed algorithms for choosing therapy based on a patient's primary area of concern. Specific roadmaps exist for choosing treatment based on atherosclerotic cardiovascular disease (ASCVD) or chronic kidney disease (CKD) status, hypoglycemia minimization, weight loss concern, and cost issues. The statement explicitly recommends prescribing a sodium–glucose cotransporter 2 (SGLT2) inhibitor or glucagon-like peptide-1 (GLP-1) receptor agonist for patients with ASCVD. If a patient is not meeting HbA1c goals, consideration should be given to adding an SGLT2 inhibitor or GLP-1 receptor agonist with proven cardiovascular (CV) benefit; if a patient is at target HbA1c, consideration should be given to switching to or adding one of these. The algorithm recommends either an SGLT2 inhibitor or GLP-1 receptor agonist with proven CV benefit for those with predominant ASCVD, but prefers an SGLT2 inhibitor over a GLP-1 receptor agonist if heart failure or CKD predominates (SGLT2 inhibitors should only be used if effective glomerular filtration rate [eGFR] is adequate). If HbA1c remains above target after this addition, or if the patient cannot tolerate the therapy, adding the other class should be considered. Subsequently, any class with CV safety can be considered.

In addition, results from the Effect of Albiglutide, When Added to Standard Blood Glucose Lowering Therapies, on Major Cardiovascular Events in Subjects With Type 2 Diabetes Mellitus (HARMONY-Outcomes) trial2 were presented. GlaxoSmithKline's (Brentford, UK) now-discontinued GLP-1 agonist Tanzeum (albiglutide) conveyed a significant 22% relative risk reduction on three-point major adverse cardiovascular events (MACE; non-fatal myocardial infarction [MI], non-fatal stroke, or CV death; hazard ratio [HR] 0.78, 95% confidence interval [CI] 0.68-0.90; P = 0.0006 for superiority). The HARMONY-Outcomes trial enrolled a fully secondary prevention population and followed 9463 patients for a median of 1.6 years. Notably, the reduction in MACE appears to have been driven by a significant 25% reduction in non-fatal MI (HR 0.75, 95% CI 0.61-0.90), although this must be considered “nominal” given the hierarchical statistical testing plan. On the secondary composite endpoint of CV death or hospitalization for heart failure, results favored albiglutide but did not reach statistical significance (HR 0.85, 95% CI 0.70-1.04). In terms of safety, serious adverse events were balanced between treatment and placebo (20% vs 22%, respectively), and no individual serious adverse event occurred in more than 2% of patients.

In a Phase 2b readout, Dr Juan Frias (National Research Institute, Los Angeles, California) revealed glycemic and weight loss results for Eli Lilly's (Indianapolis, Indiana) LY3298176 (LY), a once-weekly gastric inhibitory polypeptide (GIP)/GLP-1 dual agonist.3 In a 26-week dose-ranging study (n = 316), four doses of LY (1, 5, 10, and 15 mg) were examined in comparison to both dulaglutide 1.5 mg and placebo. On weight loss, 22% of those on LY 10 mg and 25% of those on LY 15 mg achieved at least 15% weight loss, which was significant compared with both placebo and dulaglutide. In addition, 6% of those on LY 5 mg achieved this weight loss, but this result was not statistically significant. Moreover, 18% of those on LY 10 mg and 30% of those on LY 15 mg achieved an HbA1c <5.7%, both significant against placebo and dulaglutide. For comparison, 2% of the placebo group, 2% of the dulaglutide group, and 4% of the LY 5 mg group achieved this result. However, tolerability issues represent a significant concern, because 25% of those on LY 15 mg discontinued treatment because of adverse events. Specifically, 66% of patients in the LY 15 mg group, along with 51% in the LY 10 mg group, experienced gastrointestinal (GI) side effects such as nausea, vomiting, and diarrhea, compared with 43% on dulaglutide and 10% on placebo.

Finally, results from the Phase 3 Empagliflozin as Adjunctive to Insulin Therapy in Patients with T1DM (EASE) program4 for Eli Lilly and Boehringer Ingelheim's (Ingelheim am Rhein, Germany) Jardiance (empagliflozin) in type 1 diabetes (T1D) were presented, comprised of EASE-2 (n = 730) and EASE-3 (n = 977). Results demonstrated significant HbA1c, time-in-range, and weight loss benefits with three doses of empagliflozin (2.5, 10, and 25 mg) compared with placebo. The results also indicated a consistent dose-response relationship, in line with other Phase 3 studies of SGLT inhibitors in T1D.7, 8 In EASE-3, the 2.5 mg dose of empagliflozin did not increase risk of diabetic ketoacidosis (DKA) compared with placebo: over 26 weeks, there were two certain DKA events among 241 participants randomized to 2.5 mg empagliflozin (1.2% incidence), compared with three certain events in the placebo group (0.8% incidence).

US Food and Drug Administration Advisory Committee Meeting on CV Outcomes Trials

From October 24 to 25, the US Food and Drug Administration (FDA) convened an Advisory Committee to review and discuss its 2008 guidance on the assessment of CV risk for new type 2 diabetes (T2D) drugs. Following 2 days of presentations and discussions on CV outcome trial design and utility, the committee (consisting of 19 endocrinologists, cardiologists, statisticians, and patient and consumer representatives) cast an extremely close vote of 10–9 (yes–no) on the sole voting question: should an unacceptable increase in CV risk be excluded for all new drugs to improve glycemic control in patients with T2D, regardless of the presence or absence of a signal for CV risk in the development program? The FDA's timeline of action concerning this vote remains unclear.

Cardiometabolic Health Congress 2018

The Cardiometabolic Health Congress 2018 took place from October 24 to 27 in Boston, Massachusetts. Dr John Buse (University of North Carolina, Chapel Hill, North Carolina) noted that approximately 4% of patients with T1D in the US (>50 000 individuals) are currently using SGLT2 inhibitors off-label. Still, Dr Buse explained that DKA risk remains a significant issue, citing an approximate 6% absolute risk increase (questionable cases) and an approximate 2% to 3% increase (adjudicated cases) across previous studies of SGLT inhibitors in T1D. Moreover, Dr Buse emphasized that patient selection is crucial. Along those lines, Dr Irl Hirsch (University of Washington, Seattle, Washington) pointed out that patients most likely to experience DKA are those using insulin pumps, due to set occlusions, and, less-intuitively, women.