Diabetes News

The American Diabetes Association 76th Scientific Sessions (ADA 2016) took place from 10 to 14 June 2016 in New Orleans (LA, USA), drawing over 16 000 attendees hailing from over 120 countries. A major highlight of the conference was the announcement of the results from the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial, a double-blind randomized placebo-controlled time- and event-driven trial in which participants (n = 9340) were treated for at least 3.5 but no more than 5 years.1 The trial was designed to accumulate at least 611 events included in the three-point major adverse cardiac events (MACE) primary endpoint (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) and, by study end, demonstrated a significant 13 % risk reduction (hazard ratio [HR] 0.87; 95 % confidence interval [CI] 0.78–0.97; P = 0.01) in the primary endpoint with Novo Nordisk's (Bagsværd, Denmark) glucagon-like peptide-1 (GLP-1) agonist Victoza (liraglutide) versus placebo, both in addition to standard care. Results for an expanded MACE composite endpoint (including coronary revascularization and hospitalization for unstable angina or heart failure) were consistent with the primary results, demonstrating a significant 12 % risk reduction with liraglutide (HR 0.87; 95 % CI 0.81–0.96; P = 0.005). The risk reduction was derived from all three components of MACE, but the largest contribution appeared to come from the significant 22 % risk reduction for cardiovascular death (HR 0.78; 95 % CI 0.66–0.93; P = 0.007); all-cause mortality was also reduced by 15 % (HR 0.85; 95 % CI 0.74–0.97; P = 0.02). The point estimates for non-fatal myocardial infarction and non-fatal stroke trended in the right direction, but the results did not reach statistical significance. The HR for non-fatal myocardial infarction was 0.88 (95 % CI 0.75–1.03; P = 0.11) and the hazard ratio for non-fatal stroke was 0.89 (95 % CI 0.72–1.11; P = 0.30). There was also a significant 16 % risk reduction (HR 0.84; 95 % CI 0.73–0.97; P = 0.02) for the composite microvascular endpoint driven by a 22 % risk reduction for adverse renal events (HR 0.78; 95 % CI 0.67–0.92; P = 0.003). The results for hospitalization for heart failure were neutral, but trended in the right direction (HR 0.87; 95 % CI 0.73–1.05; P = 0.14). In addition, hypoglycemia was significantly reduced with liraglutide, likely due to greater use of insulin and sulfonylureas in the placebo group. Dr Christoph Wanner (University Hospital of Würzburg, Würzburg, Germany) shared full renal data from the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME),2 demonstrating a 39 % risk reduction for new-onset or worsening kidney disease for Lilly (Indianapolis, IN, USA) and Boehringer Ingelheim's (Ingelheim, Germany) sodium–glucose cotransporter 2 (SGLT2) inhibitor Jardiance (empagliflozin). Further, the empagliflozin-treated group experienced a 55 % reduction in the initiation of renal replacement therapy (such as dialysis), a 44 % reduction in doubling of creatinine, and a 38 % reduction in progression to macroalbuminuria. Dr Bo Ahrén (Lund University, Lund, Sweden) presented full results from the Efficacy and Safety of Semaglutide Once-weekly Versus Sitagliptin Once-daily as add-on to Metformin and/or TZD in Subjects With Type 2 Diabetes (SUSTAIN 2) trial. In this double-blinded double-dummy active-controlled parallel-group trial (n = 1231), the once-weekly GLP-1 agonist semaglutide at doses of 0.5 and 1.0 mg produced 0.77 % and 1.06 % greater reductions in HbA1c, respectively, than Merck's Januvia (sitagliptin 100 mg) after 56 weeks of treatment (P < 0.0001 for both). In total, semaglutide at doses of 0.5 and 1.0 mg produced reductions in HbA1c of 1.3 % and 1.6 %, respectively, compared to the 0.5 % reduction in HbA1c see with sitagliptin (baseline HbA1c = 8.1 %; P < 0.0001). Participants treated with semaglutide 0.5 and 1.0 mg experienced a 17.4 and 26.74 mg/dL reduction in fasting plasma glucose (FPG), respectively, compared with participants treated with sitagliptin (baseline FPG 169.4 mg/dL; P < 0.0001). Overall, participants on semaglutide 0.5 and 1.0 mg experienced FPG reductions of 37.4 and 46.7 mg/dL, respectively, compared with a 20.8 mg/dL reduction in FPG with sitagliptin. End-of-trial seven-point self-monitoring of blood glucose (SMBG) profiles were lower at every point for participants treated with semaglutide compared with sitagliptin and with baseline. At 56 weeks, 78 % and 69 % of participants in the semaglutide 1.0 and 0.5 mg groups, respectively, achieved an end-of-trial HbA1c of <7.0 %, compared with 36 % of the sitagliptin-treated group. In addition, at 56 weeks, 66 % and 53 % of the semaglutide 1.0 and 0.5 mg groups, respectively, achieved a target HbA1c of ≤6.5 %, compared with 20 % of the sitagliptin-treated group. Dr Andrew Ahmann (Oregon Health & Science University, Portland, OR, USA) presented full results from the Efficacy and Safety of Semaglutide Once-weekly Versus Exenatide ER 2.0 mg Once-weekly as add-on to 1–2 Oral Antidiabetic Drugs (OADs) in Subjects With Type 2 Diabetes (SUSTAIN 3) trial. In the open-label active-controlled parallel-group SUSTAIN 3 trial (n = 813), participants treated with semaglutide 1.0 mg experienced a 0.62 % greater reduction in HbA1c (P < 0.0001) compared with participants treated with exenatide extended release (ER) 2.0 mg (AstraZeneca's once-weekly Bydureon). Overall, those in the semaglutide-treated group experienced a mean 1.5 % reduction in HbA1c, compared with a 0.9 % reduction in the exenatide-treated group (baseline HbA1c 8.3 %; P < 0.0001). Dr Ahmann emphasized that the HbA1c curves for the semaglutide and exenatide groups diverged early on and stayed significantly different throughout the trial. That said, many of those attending the meeting found the results to be curious inasmuch as the 0.9 % reduction in HbA1c in the exenatide-treated group from a baseline HbA1c of 8.3 % was less than that observed in most clinical trials. By way of comparison, a recent meta-analysis found exenatide to have 1.09 % greater HbA1c-lowering effect than placebo, and equivalent HbA1c-lowering effects to liraglutide and dulaglutide.3 End-of-trial seven-point SMBG profiles were lower at every point for participants treated with semaglutide compared with both exenatide and to baseline, although the difference appeared to be less marked than the separation between the semaglutide and sitagliptin SMBG profiles (as expected, given the generally accepted greater glucose-lowering efficacy of GLP-1 agonists compared with dipeptidyl peptidase [DPP]-4 inhibitors); it would have been more helpful, from our view, to have continuous glucose monitoring (CGM) data than SMBG data. At 56 weeks, 67 % of participants in the semaglutide group achieved an end-of-trial HbA1c of <7.0 %, compared with 40 % of the exenatide-treated group. Similarly, at 56 weeks, 47 % of the semaglutide group achieved a target HbA1c of ≤6.5 %, compared with 22 % of the exenatide-treated group. Dr Julio Rosenstock (Dallas Diabetes and Endocrine Center, Dallas, TX, USA) presented results from the Phase 3 study to evaluate cardiovascular outcomes in patients with type 2 diabetes (T2D) treated with ITCA 650 (FREEDOM-2), demonstrating significantly greater HbA1c reductions (1.5 % vs 0.8 %; P < 0.001) and weight loss (4 vs 1.3 kg; P < 0.001) with Intarcia's (Boston, MA, USA) implantable GLP-1 agonist ITCA 650 compared with Merck's (Whitehouse Station, NJ, USA) DPP-4 inhibitor Januvia (sitagliptin). The double-blind trial randomized 535 patients with T2D on metformin to receive either ITCA 650 + oral placebo or Januvia + implantable placebo for 52 weeks. Patients received the initiation dose of ITCA 650 for 13 weeks and switched to the maintenance dose for the remaining 39 weeks. The HbA1c difference between the groups was already significant at 6 weeks and stabilized at Week 26; final reductions in HbA1c were 1.5 % with ITCA 650 and 0.8 % with Januvia (P < 0.001) with baseline HbA1c 8.6 %–8.7 %. ITCA 650 also produced significantly greater reductions in FPG than Januvia (47 vs 28 mg/dL; P < 0.001). Weight loss followed a similar pattern as the reductions in HbA1c, with a fairly early separation that stabilized at around Week 26 and remained stable throughout the trial. The final weight reduction was 4 kg (~8.8 lb) with ITCA 650 compared with 1.3 kg (~2.9 lb) with Januvia (baseline body mass index 33 kg/m2; P < 0.001). In addition, ITCA 650 was superior in terms of the percentage of patients achieving the composite endpoint of HbA1c reduction >0.5 % and weight loss ≥2 kg (61 % vs 28 %; P < 0.001) and the percentage achieving HbA1c targets of <7 % (61 % vs 42 %) and <6.5 % (44 % vs 21 %). As expected, there were more gastrointestinal events in the ITCA 650 group, although the discontinuation rates due to these events were low (4.5 % for nausea and 2.3 % for vomiting). Importantly, the rate of procedure-related adverse events was quite low (<1 %) in both groups. Dr Rosenstock also emphasized that nausea rates peaked when the initial dose was started and when the dose was escalated, but rates were quite low throughout the rest of the trial. May 9: GI Dynamics (Lexington, MA, USA; and Sydney, NSW, Australia) released new 1-year interim data from the REVISE Diabesity study, demonstrating that EndoBarrier plus liraglutide achieved significantly greater reductions in HbA1c and weight compared with either EndoBarrier or liraglutide alone. The 2-year multicenter trial randomized people with T2D and obesity to either EndoBarrier + liraglutide 1.2 mg (n = 24), EndoBarrier only (n = 24), or liraglutide 1.8 mg only (n = 22). At 12 months, the EndoBarrier + liraglutide group achieved an HbA1c reduction of 2.1 % (baseline HbA1c 9.6 %). Meanwhile, the EndoBarrier and liraglutide monotherapy groups achieved HbA1c reductions of 1.2 % and 1.3 %, respectively (baseline HbA1c 9.3 % and 9.7 %, respectively). The combination group achieved weight loss of 11.3 % (baseline weight 113 kg) at 12 months, whereas the EndoBarrier and liraglutide monotherapy groups achieved weight loss of 10.8 % (baseline weight 116 kg) and 3.5 % (baseline weight 114 kg), respectively. Six participants (25 %) in the combination group experienced a reduction in diabetes medications, even given the significant HbA1c difference. The combination was well tolerated and all serious device-related adverse events in the EndoBarrier-treated participants were resolved after device removal. May 18: Zealand Pharma (Copenhagen, Denmark) announced that its Phase 2 trial for the single-dose stable glucagon analog ZP4207 is fully enrolled. The trial (n = 56) is evaluating the pharmacokinetic and pharmacodynamic profiles of several single doses of ZP4207 (0.1, 0.3, 0.6, and 1.0 mg) versus native glucagon in patients with type 1 diabetes (T1D) after induced hypoglycemia. Results from the Phase 2 trial are expected in the third quarter of 2016. May 18: Oramed (Jerusalem, Israel) released positive topline results from a Phase 2b trial of its oral insulin candidate ORMD-0801. The double-blind 28-day study (n = 180 patients with T2D) met its primary endpoint by demonstrating a statistically significant 6.47 % reduction in pooled night-time glucose (P = 0.0268) as measured by CGM, compared with placebo. ORMD-0801 demonstrated no drug-related serious adverse events. Oramed plans to present and publish the full results at a later date. May 24: Janssen (Beerse, Belgium) announced that the US Food and Drug Administration (FDA) has expanded the indication for its SGLT-2 inhibitor/metformin fixed-dose combination Invokamet (canagliflozin/metformin), allowing use as a first-line treatment in T2D. May 24: Lilly (Indianapolis, IN, USA) highlighted a new Phase 1 soluble glucagon candidate in its pipeline during a research and development update. The company pointed out the potential utility of this candidate in bihormonal closed loop systems, and noted that it is a soluble, short-acting, solution-stable product with a pharmacokinetic and pharmacodynamic profile similar to native glucagon. Lilly's latest pipeline also shows a new addition of a preclinical long-acting glucagon. May 27: AstraZeneca (London, UK) announced that its DPP-4 inhibitor/SGLT-2 inhibitor fixed-dose combination of saxagliptin and dapagliflozin has received a positive opinion from the European Medicine Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP). The European Commission will now review the opinion and issue a final decision in the next few months; the decision will apply to all 28 European Union member countries, in addition to Iceland, Norway, and Liechtenstein. May 31: Lilly (Indianapolis, IN, USA) announced FDA approval of its Boehringer Ingelheim-partnered (Ingelheim, Germany) DPP-4 inhibitor/ER metformin fixed-dose combination (FDC) Jentadueto XR (linagliptin/metformin XR). The combination contains either 2.5 or 5 mg linagliptin and 1000 mg metformin and is dosed as a once-daily pill, down from two daily pills with the previously approved Jentadueto (linagliptin/metformin). June 8: Adocia (Lyon, France) announced the development of BioChaperone Glucagon, a stable glucagon formulation that could have potential in a ready-to-use rescue device for severe hypoglycemia and as part of a bihormonal artificial pancreas system. The company has generated “promising” preclinical results for the product and plans to begin clinical trials in the first half of 2017. Adocia also announced that it plans to discontinue its two non-diabetes programs in order to focus more resources on diabetes. June 14: The FDA released a Drug Safety Communication strengthening the existing warnings for Janssen's (Beerse, Belgium) SGLT-2 inhibitor Invokana (canagliflozin) and AstraZeneca's (London, UK) SGLT-2 inhibitor Farxiga (dapagliflozin) about the risk of acute kidney injury. The announcement advises patients to seek immediate medical attention if they experience symptoms of acute kidney injury. It advises providers to consider potential predisposing factors for acute kidney injury and assess kidney function prior to starting treatment with either drug, monitor periodically thereafter, and promptly discontinue treatment if symptoms appear. This warning was based on a search of the FDA Adverse Event Reporting System, showing 101 confirmable cases of acute kidney injury with the two drugs between March 2013 and October 2015. June 20: Poxel (Lyon, France) announced positive topline results from the first stage of its Phase 1 trial for the AMP-activated protein kinase (AMPK) activator PXL770. The study (n = 64 healthy males) demonstrated a favorable safety and tolerability profile and dose-dependent increases in plasma exposure (Cmax and area under the curve) with six single ascending doses of the candidate. The second part of the study is on track to evaluate safety, tolerability, pharmacokinetics, and target engagement of multiple ascending doses of PXL770. Earlier preclinical results4 suggested that PXL770 has the potential to improve glucose tolerance, lipids, and liver weight in patients with T2D. Ongoing clinical trials will determine whether this profile is confirmed. June 30: OPKO Health (Miami, FL, USA) announced its acquisition of Transition Therapeutics (Toronto, Canada), which has in its pipeline the GLP-1/glucagon dual agonist TT401, the only product in its class to show positive Phase 2 results so far. In May, Transition Therapeutics shared that it was preparing a development plan for the clinical advancement of TT401 and was looking for a well-suited partner for Phase 3 development activities and commercial preparations. These announcements came after Lilly declined to advance the dual agonist to a Phase 3 trial.

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