Practical Ways to Achieve Targets in Diabetes Care
Abstract
Peter J. Rentzepis, Martin J. Kurian, Ann M. Carracher, 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 Closer Look, a periodical that brings together news and insights in these areas. Each month, the Journal of Diabetes includes this News feature, in which Rentzepis, Kurian, Carracher, and Close review the latest developments relevant to researchers and clinicians.
Practical Ways to Achieve Targets in Diabetes Care (ATDC) 2018 took place in Keystone, Colorado, from 12 to 15 July 2018. There, Dr Ralph DeFronzo (University of Texas Health Science Center, San Antonio, Texas) highlighted the efficacy of a triple therapy consisting of a glucagon-like peptide-1 receptor agonist (GLP-1), metformin, and a low-dose thiazolidinedione (TZD), such as pioglitazone. He referenced 6-year results from the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT) study, presented at the 78th Scientific Sessions of the American Diabetes Association (ADA) in June 20181: triple combination of exenatide/metformin/pioglitazone gave a mean HbA1c of 5.8% at 6 years, compared with 6.7% in the group receiving only metformin, sulfonylureas, and insulin glargine.
However, Dr DeFronzo shared that if he designed this trial today, he would instead test triple therapy of a GLP-1, pioglitazone, and a sodium–glucose cotransporter 2 (SGLT2) inhibitor, the last of which was not available when EDICT was designed.
In addition, Dr Irl Hirsch (University of Washington Medicine, Seattle, Washington) outlined the need for a study examining closed loop technology versus standard therapy in patients with type 1 diabetes mellitus (T1DM) in order to demonstrate a relationship between glucose variability and long-term outcomes. Commenting on glucose variability, Dr Hirsch argued that frequent hypoglycemia and hyperglycemia are negative outcomes in and of themselves; however, there are also molecular and cellular principles that led him to believe the variability between frequent hypoglycemia and hyperglycemia could be even more detrimental than the effects of sustained hypoglycemia (arrhythmia, inflammation) or sustained hyperglycemia (microvascular complications) alone. Dr Hirsch cited evidence from an Australian study2 examining 1604 adolescents stratified across four time periods, before and after the availability of rapid-acting insulin analogs. Retinopathy fell over time even though HbA1c levels remained steady, leading Dr Hirsch to suspect a reduction in glucose variability is responsible for the reduction in complications and driving his interest in a long-term outcomes study of glucose variability.
World Congress on Prevention of Diabetes and its Complications
The World Congress on Prevention of Diabetes and its Complications (WCPD) 2018 took place in Edinburgh, Scotland, from 16 to 18 July 2018. There, Dr Ann Albright (Centers for Disease Control and Prevention, Atlanta, Georgia) discussed the US National Diabetes Prevention Program (NDPP) and underscored the need for better use of technology in order to scale-up prevention programs. Dr Albright emphasized that the use of technology can both scale the impact of healthcare providers and help reach people who cannot or will not travel to a Diabetes Prevention Program (DPP) site. She pointed to Omada Health (San Francisco, California) as a successful digital company to materialize from the NDPP; Omada currently stands as the largest DPP in the US, serving over 150 000 people with prediabetes. Commenting on insurance coverage, Dr Albright expressed strong support for the decision by Medicare to cover DPPs but explained her frustration that Medicare does not cover “virtual” DPPs outside a few special scenarios. Finally, Dr Albright shared that over 100 insurers and employers cover the NDPP as a benefit and more than 3.4 million public employees and dependents in 18 US states have NDPP lifestyle change programs as a covered benefit.
| Company updates | |
|---|---|
| June 18, 2018: | JDRF (New York City, New York) and Gubra (Hørsholm, Denmark) announced a 1-year partnership to develop a new glucose-responsive insulin (GRI). JDRF's financial investment is undisclosed, and Gubra will also be contributing funds to the next stage of development, which is focused on refining the preclinical candidate's glucose sensitivity range to enable in vivo proof-of-concept clamp studies in model organisms. Gubra expects its GRI to reach the clinical stage in 2–3 years and anticipates finding a partner for clinical development. The company is currently targeting once-daily dosing. |
| June 21, 2018: | Novo Nordisk (Bagsværd, Denmark) announced a new research partnership with Kallyope (New York City, New York) to discover, license, and develop novel peptide therapies for diabetes and obesity. According to the terms of agreement, Kallyope will receive an undisclosed upfront payment plus research support from Novo Nordisk. The two companies will collaborate to conduct in vitro and in vivo proof-of-concept studies, and Novo Nordisk has the option to license up to six products from this partnership. After optioning a candidate, Novo Nordisk will be solely responsible for all development, manufacturing, and commercialization, whereas Kallyope will receive a licensing fee and possible research, development, and sales milestones as well as royalties (all undisclosed). |
| July 1, 2018: | AstraZeneca (Cambridge, UK) announced that the Committee for Medicinal Products for Human Use (CHMP) has recommended GLP-1 agonist autoinjector device Bydureon BCise (exenatide once weekly) for European Medicines Agency (EMA) approval. This product was accepted for active EMA review in October 2017, and a final EMA decision is expected in 2018. The US Food and Drug Administration (FDA) approved Bydureon BCise in October 2017, and the product was launched to US pharmacies in the first quarter of 2018. The main trial of Bydureon BCise, Efficacy and Safety of Exenatide Once Weekly Suspension in Subjects With Type 2 Diabetes (DURATION-NEO-1; n = 375),3 showed that once-weekly exenatide administered via autoinjector gave a 1.4% drop in HbA1c compared with a 1.0% drop with twice-daily exenatide (Byetta) after 28 weeks. A second trial, Comparison Study of the Glycemic Effects, Safety, and Tolerability of Exenatide Once Weekly Suspension to Sitagliptin and Placebo in Subjects With Type 2 Diabetes Mellitus (DURATION-NEO-2; n = 365),4 compared once-weekly exenatide via autoinjector to once-daily sitagliptin tablets with similar results. |
| July 16, 2018: | Johnson & Johnson (New Brunswick, New Jersey) announced that the Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE) renal outcomes trial for the SGLT2 inhibitor canagliflozin (Invokana) was stopped early, approximately 1 year ahead of scheduled completion. An Independent Data Monitoring Committee conducted a prespecified interim analysis and reported that Invokana had already shown efficacy on the primary composite endpoint (end-stage renal disease, doubling of serum creatinine, or renal or cardiovascular death). The CREDENCE trial enrolled patients with type 2 diabetes mellitus (T2DM) and an estimated glomerular filtration rate (eGFR) between 30 and 90 mL/min per 1.73 m2. |
| July 16, 2018: | The FDA delayed its decision on a cardiovascular indication for Johnson & Johnson's Invokana (canagliflozin) by 3 months. The company filed a Supplemental New Drug Application (sNDA) for the SGLT2 inhibitor based on positive results from the CANagliflozin cardioVascular Assessment Study (CANVAS).5 The FDA requested additional analyses from the company, and a regulatory decision is now expected by the end of October 2018. |
| July 18, 2018: | Researchers from the University of Alabama at Birmingham reported that once-daily oral verapamil, a calcium channel blocker, promoted endogenous β-cell function while reducing insulin requirements and hypoglycemia in adults with recent-onset T1DM (n = 32).6 This Phase 2 trial randomized patients with recent-onset T1DM (<3 months since diagnosis) to verapamil or placebo for 12 months; treatment was added onto participants’ background insulin therapy. Verapamil was associated with greater C-peptide area under the curve at both 3 and 12 months (P = 0.0270 and P = 0.0186 vs placebo, respectively). At 12 months, total daily insulin dose needed to maintain glucose control was also significantly lower in the verapamil compared with placebo group; from a similar baseline, total daily insulin dose grew 27% with verapamil compared with 70% with placebo (P = 0.0312). Furthermore, hypoglycemia risk was significantly lowered with verapamil compared with placebo (0.5 vs 2.7 events per month, respectively; P = 0.0387). Verapamil was well tolerated and adverse events were more or less balanced across arms, with the exception of constipation, a known side-effect of verapamil. |
| July 19, 2018: | Eli Lilly (Indianapolis, Indiana) announced that AWARD-7 (A Study Comparing Dulaglutide With Insulin Glargine on Glycemic Control in Participants With Type 2 Diabetes and Moderate or Severe Chronic Kidney Disease)7 data have been added to the US product label for the GLP-1 agonist Trulicity (dulaglutide). This year-long trial (n = 576) was presented as a late-breaking abstract at ADA 2017, demonstrating dulaglutide's benefits over basal insulin in patients with T2DM and chronic kidney disease (CKD). Dulaglutide offered similar HbA1c reductions to basal insulin glargine when both were given alongside mealtime insulin lispro, but weight loss was significantly greater in the dulaglutide group and hypoglycemia risk was significantly reduced. |
| July 19, 2018: | Eli Lilly and Boehringer Ingelheim (Ingelheim am Rhein, Germany) announced that the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin (Tradjenta) met its primary endpoint in the CARMELINA (Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mellitus) trial, demonstrating non-inferiority to placebo on three-point major cardiovascular events (non-fatal myocardial infarction [MI], non-fatal stroke, cardiovascular [CV] death). Participants in this cardiovascular outcomes trial (CVOT; n = 6979) were adults with T2DM facing high CV risk, defined as micro- or macroalbuminuria, prior CV event, or impaired renal function. Eli Lilly and Boehringer Ingelheim also have a second ongoing CVOT for Tradjenta, against an active comparator of sulfonylurea glimepiride, expected to complete in March 2019. |
| July 25, 2018: | Eli Lilly submitted nasal glucagon to both the FDA and EMA. This marks the first regulatory submission of a next-generation glucagon candidate. Regulatory decisions are anticipated in mid-2019. |
| August 1, 2018: | Sanofi (Paris, France) announced the Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure (SOLOIST-WHF; n = 4000) trial to investigate sotagliflozin in patients with T2DM and worsening heart failure. The study is expected to complete in January 2021. Accompanying SOLOIST-WHF is a smaller Phase 2 pharmacodynamics and safety study of sotagliflozin (n = 81) in patients hospitalized with worsening heart failure, set to complete in November 2019. The SOLOIST-WHF trial will enroll patients with T2DM who also have prior heart failure and who recently experienced worsening heart failure. Sanofi and partner Lexicon (The Woodlands, Texas) expect to file sotagliflozin for a heart failure indication, pending positive results, in 2021. |
| August 2, 2018: | “Insulin Pen Products,” including GLP-1 agonist/basal insulin combination pens, were added to the FDA's first quarter of 2018 watch list. The FDA is evaluating the need for regulatory action due to product use error, specifically the failure to remove the inner needle cover). |
| August 3, 2018: | Johnson & Johnson announced a positive opinion from CHMP on a label update for the SGLT2 inhibitor Invokana (canagliflozin), including changes to the indication statement. This decision also applies to Vokanamet, the fixed-dose combination of canagliflozin with metformin. In the third quarter of 2017, the company submitted both an sNDA to the FDA and a Type II Variation application to the EMA, requesting a CV indication based on results from the CANVAS program.5 According to Johnson & Johnson, Invokana's new label would include information from the CANVAS program, reflecting a reduction in major adverse CV events (CV mortality, non-fatal MI, and non-fatal stroke) among patients with T2DM and baseline CV disease or high CV risk. |
| August 8, 2018: | Novo Nordisk announced that it will conduct a single, superiority-powered CVOT for Phase 3 oral semaglutide, as well as a bridging study between oral and injectable semaglutide (Ozempic), in order to support a CV indication for both formulations. The post-market SOUL CVOT for Ozempic (injectable semaglutide) has been canceled. Instead of SOUL, the company will focus first and foremost on demonstrating cardioprotection with oral semaglutide in a trial to begin in early 2019. In an alternative scenario, PIONEER 6 (A Trial Investigating the Cardiovascular Safety of Oral Semaglutide in Subjects With Type 2 Diabetes), which is expected to read out at the end of 2018, could demonstrate CV superiority with oral semaglutide versus placebo, although PIONEER 6 was designed to show non-inferiority. In this case, the combination of PIONEER 6 and SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes)8 data would likely support a CV indication for both oral and injectable semaglutide, as per Novo Nordisk. |
| August 13, 2018: | Xeris Pharmaceuticals (Chicago, Illinois) submitted a New Drug Application (NDA) for its Glucagon Rescue Pen to the FDA. Under a standard 10- to 12-month review period, a decision on the NDA can be expected in mid-2019. |
