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Manu V. Venkat, Rajiv R. Narayan, 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, Narayan, 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).

Barbara Davis Center Keystone Conference, Keystone, Colorado, 2013

  1. Top of page
  2. Barbara Davis Center Keystone Conference, Keystone, Colorado, 2013
  3. American Association of Diabetes Educators 40th Annual Meeting, Philadelphia, Pennsylvania, 2013
  4. References

“Practical Ways to Achieve Targets in Diabetes Care,” held in Keystone, Colorado, brought together luminaries from the diabetes community just a couple weeks after the massive American Diabetes Association's 73rd Scientific Sessions. As such, many of the conversations at Keystone were an extension and deeper dive into discussions that began at ADA.

Prominent among the discussion of diabetes technology was the role of self-monitoring of blood glucose (SMBG) in type 2 diabetes. In this area, Dr. Linong Ji (Peking University People's Hospital, Beijing, China) discussed the two-phase, single-arm, prospective COMPASS trial, which examined the role of SMBG in Chinese type 2 diabetes patients. A questionnaire completed during the study's first phase indicated that 65% of patients reported irregular blood glucose measurements. Worse still, 40% of patients reported not owning a blood glucose meter at home, instead relying on hospital measurements. In the second phase of the study, 818 patients with A1cs greater than 8% began using the Accu-Chek Integra blood glucose meter. By the end of 3 months, mean A1c dropped from a baseline of 8.5% to 7.0% (among those patients whose duration of insulin use was less than 8 months, a 2.8% drop in A1c was observed from a mean baseline of 10.3%). The improvements in in A1c were sustained at the 6-month follow-up, and Dr. Ji commented that a further follow-up is planned. We were very excited to see a study that quantifies the benefits of blood glucose testing in type 2 diabetes, especially given that SMBG has not historically been emphasized in many parts of China.

We were rather surprised at this conference by the number of panelists and speakers who touted the use of sulfonylureas (SFUs), given their link to higher mortality and hypoglycemia risk.[1] Among them, Dr. Robert Rizza (Mayo Clinic, Rochester, MN) claimed he used them “all the time,” and was unworried by the data linking their use to decreased beta cell function. Dr. Satish Garg (Barbara Davis Center, Aurora, CO) noted that SFUs play “a very important role” among his patients, to the point where uses them more than DPP-4 inhibitors. Of course, we would like to learn more about which SFUs are being used, as data indicates that newer drugs from the class might have slightly better safety profiles.[2]

In another talk, Dr. Linong Ji ruminated on the troubling realities of diabetes care in Asia. Diabetes prevalence in the adult Chinese population has skyrocketed to 10% in the past decade, and up to 60% of cases remain undiagnosed. In his discussion of the China Cardiometabolic Registries' observational, cross-sectional, multi-center study, he chose to underscore the finding that the majority of Chinese type 2 diabetes patients have co-morbidities such as hypertension and dyslipidemia. As such, he said, controlling cardiovascular risk factors is one of the biggest challenges for healthcare providers in China. Moreover, Dr. Ji told the audience that incretins do not yet have a presence in Chinese diabetes care – instead most patients are on either oral agents (metformin, sulfonylureas, and alpha-glucosidase inhibitors in descending order of use) or insulin. Overall, he emphasized the need for establishing a greater capacity for dealing with chronic conditions like diabetes, as the current Chinese healthcare system is targeted towards the treatment of more acute conditions.

American Association of Diabetes Educators 40th Annual Meeting, Philadelphia, Pennsylvania, 2013

  1. Top of page
  2. Barbara Davis Center Keystone Conference, Keystone, Colorado, 2013
  3. American Association of Diabetes Educators 40th Annual Meeting, Philadelphia, Pennsylvania, 2013
  4. References

Healthcare providers, chief among them diabetes educators, convened upon the Pennsylvania Convention Center in early August to discuss mobile health, diabetes drugs, treatment paradigms, and diabetes technology. The focus here was less on the presentation of new data, and more on the translation of current research into a more manageable form for patients.

On the type 2 diabetes drug front, we noticed some cautious optimism for the new SGLT-2 inhibitor class and more broad reassurance about incretins' pancreatic safety. Dr. Evan Sisson (VCU School of Pharmacy, Richmond, VA) was one of multiple speakers to recommend the combination of basal insulin with sulfonylureas to cover prandial glucose spikes. Although his overall message was valuable in that he offered many creative examples and solutions for individualizing treatment, the presentation was fairly cost-focused, whereas we felt aspects of the conversation like efficacy and adherence were somewhat overlooked.

Behavior-change was a major point of discussion for many speakers and sessions at AADE, with one of the keynote speakers, Dr. Fogg (Stanford University, Palo Alto, CA) describing models, theories, and tips developed and tested at his laboratory. Among his many nuggets of wisdom were that small patient successes can build confidence over time, new habits can begin as small behaviors performed directly after established habits, and environments can be modified to shape pro-health behaviors.

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. Top of page
  2. Barbara Davis Center Keystone Conference, Keystone, Colorado, 2013
  3. American Association of Diabetes Educators 40th Annual Meeting, Philadelphia, Pennsylvania, 2013
  4. References
Company Updates
July 26: GlaxoSmithKline CEO Andrew Witty led the company's 2Q13 financial update. Looming large throughout the call was the Chinese Government's investigation of allegedly inappropriate business practices on the part of high-level GSK management in the country. Management noted that the suspected culprits were operating outside the company's usual checks and controls. They emphasized that the investigation is at a very early stage, and that GSK management is cooperating fully with the relevant authorities. An indictment could threaten sales in one of the fastest growing markets for diabetes pharmaceuticals.
July 26:Healthrageous, Boehringer Ingelheim, and United BioSource launched the SMART Digital Study for type 2 diabetes. The study will use a web and smartphone-delivered program that includes a wireless glucose meter that transmits data to clinical monitors, A1c home test kits, a personalized action plan, and Bayer's A1c Now kits. Interestingly, participants will be recruited from “nearly a dozen large US employers for the study.”
July 30:The EMA's CHMP issued a statement upon the conclusion of its review of incretins. In the CHMP's view, current data do not adequately support an association between incretin-based therapies and pancreatic adverse events (pancreatitis and pancreatic cancer). The investigation was initiated in response to early data such as the results of Dr. Peter Butler's pancreatic morphology study, which found a higher rate of pancreatitis and pancreatic duct metaplasia in samples from type 2 diabetes patients on incretin therapies. The CHMP stated that a number of methodological limitations and potential sources of bias undermined the study's findings, suggesting that the study does not change the existing evidence base for incretins’ pancreatic safety. The report also emphasized ongoing monitoring of diabetes patients on incretins and alluded to the EMA's SAFEGUARD Consortium, which will provide 240 million patient-years of exposure for glucose-lowering agents.
July 31:Takeda announced that the EMA's CHMP granted a positive opinion for its DPP-4 inhibitor Vipidia (alogliptin), along with the fixed-dose combinations (FDCs) Vipdomet (alogliptin/metformin) and Incresync (alogliptin/pioglitazone). The candidates are indicated for the treatment of type 2 diabetes in patients who are uncontrolled on existing therapies. The EMA has 67 days after the release of a CHMP opinion to file its final decision, placing the deadline for Takeda's candidates in early October (matching Takeda's previous guidance of a decision during FY2013). The positive opinion came after a thorough review of the drugs’ clinical trial program, which included the phase 3 ENDURE program and interim data from EXAMINE, alogliptin's CVOT. In Takeda's F4Q12 update, supplementary materials suggested alogliptin would also launch in China and Brazil, though no timeline was specified.
July 31:Lilly and BI announced the initiation of CARMELINA, a cardiovascular and renal outcomes study for their DPP-4 inhibitor candidate Tradjenta (linagliptin). The study has a primary outcome of time to first major adverse cardiovascular event, including myocardial infarction, non-fatal stroke, hospitalization for unstable angina, or death attributable to cardiovascular factors. Lilly and BI plan to enroll approximately 8300 patients and complete the trial in early 2018. Another cardiovascular outcomes trial for linagliptin, CAROLINA (ongoing), will compare the cardiovascular outcomes profile of linagliptin to that of the sulfonylurea glimepiride.
August 4:J&J was fined 530 000 yuan ($86 000) after a Shanghai court ruled that the company's minimum resale prices violated anti-monopoly laws. Sanofi and Eli Lilly also received visits from Chinese regulators: Sanofi remarked that the Shenyang Administration for Industry and Commerce visited a regional office for an unknown purpose, and Lilly commented they were visited by Shenyang authorities “earlier this year.” This news closely follows Chinese police accusing GlaxoSmithKline of bribing officials and doctors to boost sales and raise the price of its medication.
August 6:Aimedics announced its decision to voluntarily recall its HypoMon sleep-time hypoglycemic monitor from the UK and Australia. They wrote in a very short post, “recent field trials had revealed that the HypoMon alarm was not performing as well as had been expected.” The company's website notes that in clinical studies, the HypoMon identified approximately 80% of night-time hypoglycemia events.
August 13:The Lancet published data from a phase 3 study of BI/Lilly's linagliptin (Tradjenta) in elderly people (>70 years old) with type 2 diabetes. Despite the fact that the >65 year-old age group is the group most vulnerable to diabetes and its complications, clinical trials often exclude this population from studies of anti-diabetic agents. In this trial, 241 people with type 2 diabetes receiving metformin, SFU, basal insulin, or a combination of these drugs at baseline were randomized 2:1 to linagliptin or placebo. The mean baseline age was 75 years and mean baseline A1c was 7.8% (fairly low). After 24 weeks, the mean placebo-adjusted A1c reduction was 0.64%. No serious adverse events were seen related to linagliptin. Hypoglycemia was the most common adverse event in both the linagliptin and placebo groups, but there was no statistically significant difference between the groups (24% in the linagliptin group and 17% in the placebo group; P = 0.2083).
August 14:MannKind released topline data for the two phase 3 trials of its ultra-rapid-acting inhaled insulin Afrezza – one study enrolled type 1 diabetes patients, while the other enrolled type 2 patients. Notably, both the type 1 and type 2 studies met their primary endpoints. For the type 2 diabetes study, the primary endpoint was change in A1c over 24 weeks in the Afrezza group vs. oral therapy alone plus a placebo inhalation powder – use of Afrezza led to a 0.8% decline in A1c vs. 0.4% in those on oral therapy alone (P < 0.0001; no baseline A1c provided). In type 1 patients, the primary endpoint was change in A1c vs. insulin aspart over 24 weeks – A1c declined by 0.2% in the Afrezza group vs. a decline of 0.4% in the insulin aspart group (no P-value or baseline provided). Though Afrezza was non-inferior to aspart, MannKind's compound still had significant benefits regarding hypoglycemia, weight change, and fasting blood glucose in type 1 diabetes. An amendment to Afrezza's NDA will be submitted to the FDA in late 2013, according to MannKind. Previously, management has expected a 6-month Agency review, meaning approval would come around March or April of 2014.
September 2:At the 2013 Congress of the European Society of Cardiology, we received the results of the DPP-4 inhibitor cardiovascular outcomes trials SAVOR-TIMI 53 (BMS/AZ's Onglyza [saxagliptin]) and EXAMINE (Takeda's Nesina [alogliptin]). Both trials reinforced DPP-4 inhibitor cardiovascular safety, demonstrating the drugs’ non-inferiority with regards to a composite MACE endpoint compared to placebo with hazard ratios very close to 1.00 or exactly 1.00, suggesting no increased cardiovascular risk or benefit. One reason that the data from these trials was so eagerly anticipated was because of the trials’ sizes: SAVOR studied over 16 000 patients while EXAMINE studied over 5000. Notably, there was a statistically significantly increased risk of hospitalization for heart failure in SAVOR, but this risk did not translate to an increase in MACE or cardiovascular mortality. Neither SAVOR nor EXAMINE indicated a significantly increased risk of pancreatitis or pancreatic cancer, which endocrinologists should find hugely reassuring. Other adverse events of interest that have affected other diabetes drug classes (e.g., fractures, other cancers) were also balanced between treatment and placebo groups.
September 2:Astellas and MSD KK announced that they entered into a co-promotion agreement in Japan for Astellas’ SGLT-2 inhibitor ipragliflozin. As a reminder, Astellas filed ipragliflozin in Japan in March and is awaiting a regulatory decision. Merck's decision to partner on ipragliflozin in Japan is an interesting development as the field works to anticipate what impact SGLT-2 inhibitors will have on other anti-diabetic drug classes. In Merck's 1Q13 call, management warned that they were starting to see lower year-over-year (YOY) growth in Japan due to the Januvia franchise's high market penetration (more than 50% of the DPP-4 inhibitor market, with DPP-4 inhibitors being prescribed more often than metformin). Indeed, in 2Q13, Japan was the only region in which Januvia franchise sales did not grow (this was also partly due to foreign exchange).
September 4:Elcelyx Therapeutics announced that its once-daily NewMet, a delayed-release formulation of metformin, met its primary endpoint in a phase 2b dose-finding study. NewMet was associated with a statistically significant reduction in fasting plasma glucose at 4 weeks of treatment compared to placebo. The company plans to disclose full results from the trial in late October. NewMet seems to achieve efficacy on par with that of generic metformin, but with 65% lower plasma exposure levels – this means that the drug may be appropriate for the millions of patients that cannot currently take metformin due to renal impairment of gastrointestinal sensitivity.
September 12:Sanofi announced the withdrawal of the US FDA new drug application (NDA) for its GLP-1 agonist candidate Lyxumia (lixisenatide), which it developed in conjunction with Zealand Pharma. The rationale for the decision was an unwillingness to disclose interim data from ELIXA, the drug's cardiovascular outcomes trial – early disclosure would have the potential to bias the study's final results. Sanofi likely did not wish to take an undue risk with the approval of lixisenatide, given the greater future potential of a lixisenatide/Lantus (insulin glargine) combination therapy. The company will likely re-submit the NDA after the completion of ELIXA in 2015.
September 17:Novo Nordisk recently announced that its long-acting basal insulin Tresiba (insulin degludec) will be launched in India towards the end of 2013. As of 2012, there were an estimated 63 million diabetes patients in India, making it Tresiba's largest market as of yet. As background, Tresiba is indicated for the treatment of both type 1 and type 2 diabetes and allows for flexible dosing intervals. It will be made available in India through the FlexTouch pen, which can deliver adjustable doses of up to 80 units per injection. During its 2Q13 financial update, Novo Nordisk highlighted its effort to bring Tresiba to market in China, another burgeoning Asian economy with a large and growing population of diabetes patients. Tresiba has already launched in various EU countries, Japan, Mexico, and Switzerland.
September 17:Chinese insulin maker Gan & Lee Pharmaceuticals allegedly spent around CNY 800 million (∼$130 million) on bribes in China over the past 5 years. An anonymous sales representative initially shared the news with the 21st Century Business Herald, a Guangzhou-based publication. The individual claimed that the bribery campaign, which escalated in 2012, was intended to boost product sales in preparation for the company's planned initial public offering. The company has stated that it is looking into the allegations.