Journal of Diabetes <scp>NEWS</scp>

Journal of DiabetesVolume 6, Issue 2 p. 96-99 Journal of Diabetes NEWSFree Access Journal of Diabetes NEWS First published: 14 November 2013 https://doi.org/10.1111/1753-0407.12109AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Manu V. Venkat and Kelly L. Close are of Close Concerns (http://www.closeconcerns.com), a healthcare information company focused exclusively on diabetes and obesity care. Close Concerns publishes Diabetes Close Up and Closer Look, periodicals that bring together news and insights in these areas. Bimonthly, the Journal of Diabetes includes this News feature, in which Venkat and Close review the latest developments relevant to researchers and clinicians. Readers of Journal of Diabetes involved in the clinical care of patients with diabetes (including students and educators) may request a complimentary 1-year subscription to Close Concerns' monthly newsletter, Diabetes Close Up (kelly.close@closeconcerns.com). European Association for the Study of Diabetes 49th Annual Meeting, Barcelona, Spain, 2013 The European Association for the Study of Diabetes (EASD) 49th Annual Meeting brought together diabetologists from Europe and elsewhere to discuss the latest science and therapeutic options in diabetes care. Additionally, the conference featured a number of symposia discussing data presented earlier in the year. Although there were a few notable talks on diabetes technology, the conference focused more on diabetes pharmacotherapy and basic science research. The prevention of hypoglycemia has become an increasingly important goal in diabetes care; as a result, we were eager to hear the results of the HypoAna study, which investigated the hypoglycemia associated with insulin analogs versus the hypoglycemia seen with human insulins.1 The 2-year crossover trial enrolled 159 type 1 diabetes patients with recurrent severe hypoglycemia (at least two episodes in the past year) and randomized them to a basal-bolus regimen with either insulin detemir and insulin aspart or human insulin. Analog insulin treatment resulted in a 29% rate reduction (P < 0.05) in severe hypoglycemia in an intention-to-treat analysis, which rose to 34% when adjusted for HbA1c. This corresponds to an absolute rate reduction of 0.5 severe hypoglycemia episodes per patient-year. Despite the reduction in hypoglycemia, the insulin analogs also translated to a 0.13% HbA1c advantage over human insulin (P < 0.05; baseline HbA1c of 8.0%). A temporal analysis demonstrated that the insulin analogs were particularly effective at reducing nocturnal hypoglycemia. Dr Craig Currie (Cardiff University, Cardiff, UK) and his research group presented a series of retrospective database analyses on the safety of insulins and sulfonylureas. The data were drawn from the UK's Clinical Practice Research Datalink (CPRD), a dataset that includes approximately 10% (∼10 million) of all patients treated in primary care in the UK. An analysis comparing dipeptidyl peptidase (DPP)-4 inhibitors and sulfonylureas (on top of metformin background therapy) found that sulfonylureas were associated with an adjusted hazard ratio of 1.357 (P = 0.010) for all-cause mortality compared with DPP-4 inhibitors. The effect of sulfonylureas on all-cause mortality was seen again in a comparison of sulfonylurea monotherapy and metformin monotherapy: here, sulfonylureas were associated with an adjusted hazard ratio of 1.580 (P < 0.001) for all-cause mortality. All subgroup analyses in both the monotherapy and combination therapy analyses seemed to confirm the relative safety of the comparator relative to the sulfonylurea. A similar retrospective analysis of the safety of exogenous insulin found that a “high daily dose” (>1.5 U/kg per day) was associated with an adjusted hazard ratio of 2.15 for all-cause mortality compared with the “low daily dose” group (<0.5 U/kg per day). Although the sulfonylurea study results fall in line with mounting evidence that sulfonylureas (perhaps via increases in hypoglycemia) can increase mortality,2 the insulin results were somewhat unexpected. A possible explanation could be indication bias: patients who had poorer glycemic control (and were therefore more likely to experience complications and death) were likely prescribed insulin more frequently than healthier patients. A symposium on DPP-4 inhibitors and cardiovascular disease was loaded with commentary (and some new subanalyses) on the SAVOR TIMI-53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus) and EXAMINE (Examination of Cardiovascular Outcomes: Alogliptin vs. Standard of Care) cardiovascular outcomes trials for Bristol-Myers Squibb–AstraZeneca's Onglyza (saxagliptin) and Takeda's Nesina (alogliptin), respectively. The primary results of these two studies were first presented at this year's European Society of Cardiology (ESC) annual meeting.3 As background, both trials found no significant difference between the treatment and comparator arms with regard to cardiovascular disease or mortality. Dr Itamar Raz (Hadassah Medical Center, Jerusalem, Israel) presented the results of a secondary analysis of the hypoglycemia data in SAVOR. Although significantly more hypoglycemia was seen in the saxagliptin arm compared with placebo, the analysis showed that there was only a significant increase in hypoglycemia for patients also on sulfonylureas and/or those with a baseline HbA1c below 7.0%. A major discussion point during the symposium was the statistically significant 27% increase in risk for hospitalization for heart failure seen in SAVOR-TIMI 53's treatment arm (a non-significant trend towards an increase was also seen in EXAMINE). There was broad consensus at the meeting that this signal merits further investigation through secondary analyses of the data. The conference featured a few presentations on the early intensive insulin treatment paradigm. Dr JT Woo (Kyung Hee University Hospital, Seoul, South Korea) shared data from a study of 97 patients with newly diagnosed type 2 diabetes (mean baseline HbA1c of 10%) who were randomized to 12 weeks intensive insulin therapy or oral antidiabetic medications. After a 2-year follow-up, the intensive insulin therapy group had a remarkable 46% diabetes remission rate compared with an 18% rate with oral medications alone (P = 0.02). A study presented by Dr Shumin Yang (Chongqing Medical University, Chongqing, China) compared the efficacy of metformin-based oral antidiabetic therapy and insulin glargine after a short-term (10–14 day) run-in phase of intensive insulin therapy in 44 newly diagnosed drug-naïve type 2 diabetes patients with fasting plasma glucose levels above 11.1 mmol/L (200 mg/dL) or postprandial glucose excursions above 16.7 mmol/L (300 mg/dL). In the oral antidiabetic therapy group, metformin was initiated at 425 mg, b.i.d., and titrated to a maximum dose of 2500 mg/day; subsequently, gliclazide or glimepiride could be added if needed. Following intensive insulin therapy, oral antidiabetic therapy showed similar efficacy in sustained fasting and postprandial glucose control as well as HbA1c compared with insulin glargine. We noticed a growing amount of attention on the use of non-insulin pharmacotherapies in type 1 diabetes patients. A single-arm open-label 8-week proof-of-concept study presented by Dr Bruce Perkins (Toronto General Research Institute, Ontario, Canada) found that the sodium–glucose cotransporter 2 (SGLT-2) inhibitor empagliflozin led to an average HbA1c decrease of 0.4% from a baseline of 8.0%. In a symposium presentation, Dr Urd Kielgast (University of Copenhagen, Copenhagen, Denmark) stated that incretin therapies hold promise as a tool to help type 1 diabetes patients reduce daily insulin requirements, improve glycemic control, and reduce body weight. Further exploration of the use of non-insulin pharmacotherapy in type 1 diabetes would be valuable, given that type 1 diabetes patients have fewer treatment tools available compared with type 2 diabetes patients. If you are interested in receiving the full Close Concerns report on the Keystone Conference or the American Association of Diabetes Educators Annual Meeting, please email Kelly Close (kelly.close@closeconcerns.com). References 1 Kristensen PL, Pedersen-Bjergaard U, Beck-Nielsen H et al. A prospective randomized cross-over study of the effect of insulin analogues and human insulin on the frequency of severe hypoglycemia in patients with type 1 diabetes and recurrent hypoglycaemia (the HypoAna trial): Study rationale and design. BMC Endocr Disord. 2012; 12: 10. CrossrefPubMedWeb of Science®Google Scholar 2 Monami M, Genovese S, Mannucci E. Cardiovascular safety of sulfonylureas: A meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2013; 15: 938– 953. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 3 Scirica BM, Bhatt DL, Braunwald E et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013; 369: 1317– 1326. CrossrefCASPubMedWeb of Science®Google Scholar 4 Chang JS. Update on Anti-VEGF therapy in diabetic macular edema, neovascular AMD, and retinal vein occlusion. The Opthalmology Report. 2013; 5: 5– 8. Google Scholar Company Updates September 20: Johnson & Johnson announced that the European Union's (EU) Committee for Medicinal Products for Human Use (CHMP) granted a positive opinion recommending the approval of the SGLT-2 inhibitor Invokana (canagliflozin). The CHMP opinions are referred to the European Commission, which is tasked with making the final regulatory decision on the product. September 23: During a sponsored event at the European Association for the Study of Diabetes 49th Annual meeting, Abbot unveiled its new “Flash” glucose monitoring system that is designed to overcome the major limitation of both blood glucose monitoring and continuous glucose monitoring. The technology involves the use of a 14-day factory-calibrated sensor and a wireless touchscreen reader device. October 1: Lexicon Pharmaceuticals announced positive topline proof-of-concept results for its SGLT-1–SGLT-2 dual inhibitor LX4211 in patients with renal impairment. The Phase 1 study randomized 30 type 2 diabetes patients with renal impairment (Stage 3 or 4 chronic kidney disease) to either LX4211 400 mg once daily or placebo. The investigators found that LX4211 demonstrated a significant reduction in postprandial glucose over placebo and produced statistically significant elevations in glucagon-like peptide-1 (GLP-1) levels. Full results from the trial will likely be presented in 2014. October 1: Bayer–Regeneron's Eylea (intravitreal aflibercept) met its primary endpoint in the first two of its four Phase 3 trials4 for diabetic macular edema (DME). Eylea is an anti-vascular endothelial growth factor agent that is currently marketed for wet age-related macular degeneration. In the VIVID-DME (VEGF Trap-Eye in Vision Impairment Due to DME) and VISTA-DME (Study of Intravitreal Administration of VEGF Trap-Eye in Patients with DME) trials, patients treated with a 2-mg injection every month for 1 year achieved a mean improvement in best-corrected visual acuity of 10.5 and 12.5 letters, respectively. October 3: At Lilly's annual Investor Community Meeting, company management announced the submission of the once-weekly GLP-1 agonist dulaglutide to regulatory authorities in the US and EU. The company also unveiled the drug's delivery device, which is engineered to relieve patient needle injection anxiety. The device automatically extends its 29-gauge needle, delivers the drug, and retracts the needle with the push of a single button, meaning that patients never need to see or handle the needle. During the presentation, management also noted that the company (along with its Diabetes Alliance partner Boehringer Ingelheim) hopes to submit fixed-dose combinations of its SGLT-2 inhibitor candidate empagliflozin and its DPP-4 inhibitor Tradjenta (linagliptin) to regulatory authorities in 2014. If the companies follow this timeline and the combination is approved, it would likely be the first fixed-dose combination of an SGLT-2 inhibitor and a DPP-4 inhibitor available on the market. October 3: BHV Pharma announced positive Phase 2 results from a study of its SGLT-2 inhibitor candidate remogliflozin etabonate in type 2 diabetes patients with renal impairment. There were no clinically or statistically significant differences in the drug's pharmacokinetic profile (half-life or area under the curve) in patients with mild or moderate renal impairment (creatinine clearance of 50–80 and 30–49 mL/min, respectively). October 11: Novo Nordisk Chief Scientific Officer Dr Mads Thomsen indicated in an interview with the Danish newspaper Børsen that investments of up to 20 billion Danish Kroner (approximately US$3.65 billion) may be needed to develop, produce, and market a portfolio of oral insulins and GLP-1 agonists. He stated that a portfolio of tablet insulins and/or GLP-1 agonist, if successfully developed and approved, would be a “game changer” in the diabetes care arena due to the adherence issues associated with injections. October 14: Hanmi Pharmaceuticals announced the launch of a multinational Phase 2b study program for LAPS-Exendin4, the company's once-monthly GLP-1 agonist. The studies will test once-weekly and once-monthly administration of the agent in approximately 250 type 2 diabetes patients, with the goal of determining the optimal dosing for Phase 3 testing as well as investigating the compound's effect on obesity. Early clinical data indicate that the compound has a plasma half-life of over 150 h. October 15: MannKind resubmitted its New Drug Application to the US Food and Drug Administration (FDA) for its inhalable insulin candidate Afrezza. Company management stated that it still expects a 6-month FDA review, placing a regulatory decision in April 2014. October 15: Halozyme announced that Yale researchers began an artificial pancreas study testing the company's hyaluronidase to speed insulin absorption. The 20-patient trial will test hyaluronidase administration preceding insulin administration and as a coformulation with insulin. Both approaches will be compared to using insulin alone. October 16: Sanofi and Regeneron reported positive Phase 3 monotherapy results for their low-density lipoprotein–cholesterol (LDL-C)-lowering drug alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. The mean LDL-C reduction from baseline to 24 weeks was 47%, threefold higher than the 16% reduction seen with the statin alternative ezetimibe (P < 0.0001). This was the first of the 12 trials in the candidate's ODYSSEY Phase 3 clinical trial program to report data. October 17: Xeris Pharmaceuticals initiated a Phase 2 trial of the company's stabilized glucagon. The randomized double-blind three-way crossover trial (n = 24 healthy volunteers) is designed to evaluate the safety, tolerability, and comparative pharmacokinetics and pharmacodynamics of the stabilized glucagon formulation relative to Eli Lilly's currently marketed glucagon. The trial is focused on the glucagon formulation for Xeris' first product, an auto-injector pen for severe hypoglycemia (G-Pen). October 30: Pfizer announced during its third-quarter financial update that it, along with partner Merck, has advanced the SGLT-2 inhibitor candidate ertugliflozin into Phase 3 clinical testing. Pfizer management also announced that the company's PCSK9 candidate bococizumab (RN-316) was advanced into a Phase 3 testing program, which will include two full cardiovascular outcomes trials. October 31: Novo Nordisk announced the beginning of patient enrollment in the cardiovascular outcomes trial for its ultralong-acting basal insulin candidate Tresiba (insulin degludec). The trial, named DEVOTE (A Trial Comparing Cardiovascular Safety of Insulin Degludec Versus Insulin Glargine in Subjects With Type 2 Diabetes at High Risk of Cardiovascular Events), is double-blinded and will enroll 7500 type 2 diabetes patients >50 years of age who are at high risk for cardiovascular disease, and use insulin glargine as a comparator. The primary endpoint is major adverse cardiac events (MACE; a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke). It will be an event-driven trial, with an estimated primary completion date of November 2018. Novo Nordisk hopes to use interim data after 2–3 years to support a regulatory resubmission in the US. Volume6, Issue2March 2014Pages 96-99 ReferencesRelatedInformation

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