June 13-17, 2014; San Francisco, CA Day #4 Highlights - Draft

Executive Highlights

Here we are finishing up the last full day of ADA 2014 – a whirlwind of a week as always! We have 10 highlights for you tonight, plus three honorable mentions. Day #4 was heavy on the drug side (including jam-packed oral sessions on GLP-1 agonists and SGLT-2 inhibitors) with far less on diabetes technology than Days #1-3. A notable exception was that we heard at the type 1 position statement panel that type 1 patients wouldn’t any longer be expected to get to goal by testing four times per day – that testing six to ten times per day may be expected, and/or to use CGM – ultimately, the position statement isn’t about telling HCPs what to use but is about telling them what is appropriate for A1c levels and then leaving it to the team to decide what tools to use.

Top 10 Highlights

1. The ADA’s new position statement on type 1 diabetes, which according to co-author Dr. Anne Peters (USC, Los Angeles, CA) was the first ever position statement for type 1 diabetes, was presented by its co-authors at an afternoon symposium. The document sets a new lower A1c target (7.5%) for pediatric type 1 patients; otherwise, the statement is as much an acknowledgment of what the field doesn’t know about type 1 as opposed to what is known. Before this position statement, the previous ADA pediatric A1c recommendations were 8.5% for patients 5 and under, 8.0% for those 6-12, and 7.5% for those 13-18. The old, more relaxed pediatric guidelines were designed to avoid hypoglycemia, but advances in insulin analogs and glucose management tools since then have allowed patients to achieve better glycemic control with less hypoglycemia. More generally, the position statement is geared to define the particular issues of care and reimbursement that affect people with type 1 as opposed to type 2. Dr. Peters noted the scarcity of medical literature on type 1 specifically; this position statement is more geared to start a necessary conversation, with more concrete recommendations left as a goal for future position statements. See our coverage below.

• Dr. Lori Laffel (Joslin Diabetes Center, Boston, MA) proudly announced the ADA’s new Position Statement, “Type 1 Diabetes Through the Lifespan,” released today online (Chiang et al., Diabetes Care 2014) just before her presentation today. Her presentation focused on the new guidelines’ call for a universal A1c target of <7.5% in all youth under 18 years, a change from the previous call for separate targets: <8.5% (0-6 years), <8% (7-12 years), and <7.5% (13-18 years). More details below.

2. Dr. Julio Rosenstock presented results of a 24-week proof of concept study demonstrating the benefits of Sanofi’s LixiLan (GLP-1/basal insulin fixed-ratio combination) over Lantus alone. LixiLan and Lantus achieved similar and striking A1c reductions (1.8% reduction on LixiLan compared to 1.6% on Lantus from 8% baseline), while LixiLan blunted postprandial glucose excursions substantially more so than Lantus (LixiLan reduced excursions by 70 mg/dl compared to 12 mg/dl on Lantus; p<0.001). A striking 84% of patients on LixiLan achieved an A1c goal of <7%; a surprisingly high 78% of Lantus patients also achieved this goal. Extraordinarily, 72% on LixiLan reached an A1c goal of ≤6.5% compared to 65% of Lantus patients. LixiLan also had a weight advantage over Lantus and similar rates of hypoglycemia. In all the data are pretty impressive (see below for more details).

3. A morning session on SGLT-2 inhibitors featured new phase 3 data from two long-term studies on Lilly/BI’s empagliflozin – in our view the results looked good, as the agent demonstrated statistically greater A1c reduction than Merck’s Januvia (sitagliptin) for the first time as well as statistical superiority (albeit by a narrow margin) over SFU glimepiride. The first study (264-OR), presented by Dr. Michael Roden (Leibniz Center for Diabetes Research, Dusseldorf, Germany), was a 52-week extension study of the 24-week phase 3 EMPA-REG MONO trial. While empagliflozin 25 mg provided comparable A1c reductions to sitagliptin after 24 weeks, at 76 weeks it demonstrated a significantly larger reduction (-0.89% placebo-adjusted) than sitagliptin (-0.66% placebo-adjusted) from a baseline of 7.9%, in addition to meaningful weight and blood pressure benefits. The second study, EMPA-REG H2H-SU (266-OR), found that empagliflozin 25 mg yielded a statistically superior A1c reduction than glimepiride over two years (-0.66% and -0.55%, respectively, from a baseline of 7.9%). Although the magnitude of the difference was modest, the differences in other key parameters were much more pronounced. Empagliflozin was associated with a far lower incidence of hypoglycemia (2.5% vs. 24%) and had a weight advantage over glimepiride of nearly 5 kg (~10 lbs). These results are valuable for BI/Lilly and providers to have in hand, as the drug was recently approved in Europe and could receive an FDA decision later this year. See below for additional details on this data.

4. We saw full data from the AWARD-2 trial, which compared Lilly’s once-weekly GLP-1 agonist dulaglutide against Sanofi’s Lantus (insulin glargine) in patients on background metformin and sulfonylurea. After 78 weeks, from a baseline of 8.1%, dulaglutide 1.5 mg (the higher dose tested) achieved a 0.90% reduction in A1c from baseline – this reached statistical superiority over insulin glargine’s -0.59% reduction. Dulaglutide 0.75 mg (the lower dose) achieved a -0.62% A1c reduction at 78 weeks, which was non-inferior to insulin glargine. Dulaglutide 1.5 mg helped ~50% of patients achieve an A1c below 7.0%, which was significantly better than the 30-35% with insulin glargine and dulaglutide 0.75 mg. Based on eight-point SMBG, dulaglutide’s relative performance was best in the evening hours, but glargine won out in the pre-morning time point (the rest were comparable). Insulin glargine caused significantly more total hypoglycemia than dulaglutide at both doses (~ eight events/patient/year with insulin glargine versus ~ five events/patient/year with dulaglutide), and more than double the incidence of nocturnal hypoglycemia. During Q&A, questions were raised about whether the insulin glargine titration algorithm was sufficiently aggressive – the insulin glargine group ended the trial with a mean insulin dose of 31 units. Presenter Dr. Francesco Giorgino (University of Bari Aldo Mori, Bari, Italy) noted that the insulin glargine arm’s achievement of glycemic targets was comparable to what has been seen in other clinical trials, but he acknowledged that investigators may have been hesitant to up-titrate insulin aggressively given that the average patient was taking over 6 mg of glimepiride daily. More than presenting a direct efficacy comparison between dulaglutide and insulin glargine, this study does a clearer job of showing that patients and providers can intensify treatment using dulaglutide with less of an increase in hypoglycemia, especially when the patient is already on a hypoglycemia-causing agent. See below for more details.

5. And now for something completely new: Zealand Pharma presented on its preclinical GLP-1/GLP-2 dual agonist program, which we learned about only recently. Zealand scientist Dr. Rasmus Just (Zealand Pharma, Glostrup, Denmark) began by explaining the rationale of adding GLP-2 agonism to GLP-1 agonism’s well-characterized positive effects on glycemia. A growing body of research suggests that the leakage of bacterial cell wall components such as lipopolysaccharide (LPS) across the intestinal wall can cause “metabolic endotoxemia,” characterized by insulin resistance and low-grade inflammation throughout the body. The key takeaway was that GLP-2 agonism (which Zealand is currently testing independently for GI disorders), by improving integrity of the gut wall and reducing inflammation, could help improve the metabolic cascade that contributes to diabetes and its complications. ZP-GG-72, the company’s first major GLP-1/GLP-2 dual agonist candidate, showed similar glucose-lowering efficacy to liraglutide and strong GLP-2 agonist action in preclinical studies, but had a relatively short half-life. Dr. Just next announced that Zealand has developed a new lead candidate, ZP-GG-23, that also has significant GLP-1-mediated efficacy on glycemic control and significant GLP-2-mediated efficacy on increasing intestinal weight, but with a half life of nearly nine hours that will enable daily dosing. As the importance of inflammation and the gut microbiome on diabetes pathophysiology continues to be elucidated, we imagine interest in Zealand’s program could grow. We will be back with additional information in our full report.

6. Dr. Jackie Elliott (Sheffield Teaching Hospitals, Sheffield, UK) shared a dramatic oral presentation on the characteristics and mortality rate of patients requiring ambulance assistance for severe hypoglycemia from April 2009 to March 2013. Notably, 23% of the ambulance callout patients (n=87) died during the study period, double the 11% death rate in the Sheffield general diabetes population. Session moderator Dr. Stephanie Amiel opened the Q&A quite appropriately: “Your data show us why we’re all here.” See below for more details.

7. We covered several valuable diabetes technology and drug posters during day #4 of ADA:

• In poster #837, Senseonics presented 90-day data (45 days blinded + 45 days unblinded) on its implantable CGM system. Overall MARD vs. YSI was 11%, ranging from a low of 7.7% to a high of 17.7%. The poster did not divulge a lot of details, so it’s hard to know how real-world this accuracy is. Patients showed a glycemic improvement from the 45-day blinded period of sensor wear to the 45-day unblinded (i.e., real-time) sensor wear – average glucose significantly improved from 175 mg/dl (blinded) to 156 mg/dl (unblinded). More details below.
• Poster #397 presented the latest update to WellDoc’s exciting type 2 diabetes hypoglycemia prediction model, which was first unveiled at DTM 2013. The original model accurately predicted hypoglycemia risk (90% of the time) on the following day based on seven prior days of infrequent SMBG data (e.g., ~1 test per day) – this poster explored the additional benefit of adding patient medication information. In addition, the enhanced model was also constructed to predict the hour of the occurrence of hypoglycemia on the following day, a big step over the previous model’s aim to predict whether hypoglycemia would occur in the next 24 hours. Adding medication information significantly boosted the model’s specificity for accurately predicting hypoglycemia – 92% vs. 70% in the previous SMBG-only model. The plan is to eventually incorporate this prediction module into BlueStar, WellDoc’s FDA-approved mobile prescription therapy for type 2 diabetes. More details below.
• Poster #685-P from BD examined provider attitudes towards the use of smaller and shorter needles as a solution for addressing problems with insulin therapy adherence. In short, providers cited needle-phobia as the primary challenge to initiating insulin therapy, but were unaware of the smallest needle on the market. Please see our coverage below.
• Lilly presented a poster suggesting that glucagon treatment for hypoglycemia would still be moderately effective in patients with type 1 diabetes taking a glucagon receptor antagonist (1038-P) with its glucagon receptor antagonist. See below for more details.
• Islet Sciences, in conjunction with GSK, presented a poster (1103-P) on a 12-week dose-ranging phase 2 trial for its SGLT-2 inhibitor, remogliflozin etabonate (n=336). The top dose tested, 1000 mg twice-daily, achieved an impressive 1.1% placebo-adjusted A1c reduction from baseline – while it is challenging to compare across trials, this is the highest A1c reduction achieved by an SGLT-2 inhibitor in a 12-week phase 2 dose ranging trial. We’ll be back in our full report with our full analysis of the trial.

8. Dr. Wen Xu (Yat-sen University, Guangzhou, China) shared 48-week data from a randomized comparison of Byetta (AstraZeneca’s exenatide), pre-mix insulin, and Actos (Takeda’s pioglitazone) in Chinese adults with newly diagnosed type 2 diabetes. The 48-week trial enrolled 416 patients with mean baseline A1c ~8.0%, age ~50, and weight ~70 kg (154 lbs). In the trial’s primary endpoint, exenatide was shown non-inferior to pre-mix insulin and pioglitazone in 48-week A1c decline (1.8% vs. 1.74% vs. 1.47%); the difference between exenatide and pioglitazone was statistically significant. Exenatide caused weight loss (3.25 kg [7.15 lbs]), pre-mix insulin caused weight gain (1.0 kg [2.2 lbs]), and pioglitazone was weight-neutral. Exenatide also improved systolic blood pressure (4 mm Hg), diastolic blood pressure (3 mm Hg), and lipid profile. As for beta-cell function, all three treatments significantly improved acute insulin response, insulin/proinsulin ratio, and disposition index; none improved HOMA-B. The improvement in disposition index was numerically largest with exenatide (statistics not given). Rates of symptomatic hypoglycemia <70 mg/dl with exenatide, premix insulin, and pioglitazone were 9.2%, 13.0%, and 3.8%, respectively. Dr. Xu noted that six exenatide-treated patients reduced their dose due to frequent confirmed hypoglycemia; excluding these patients, the rate of hypoglycemia was 4.9%. Look for more details in the ADA full report.

9. Building off of Dr. Lori Laffel’s (Joslin Diabetes Center, Boston, MA) presentation of glycemic control results from the TEENS study, Dr. Barbara Anderson (Baylor College of Medicine, Houston, TX) discussed the trial’s quality of life findings. As background, the TEENS Study is the largest, contemporary, cross-sectional study of its kind, having enrolled 5,960 patients aged 8-25 years old from 219 centers in 20 countries (and was sponsored by Sanofi). The study found that more than 70% of youth with type 1 diabetes are not achieving glycemic targets. Looking at the quality of life measures, Dr. Anderson found that achieving one’s target A1c was significantly associated with better quality of life for all age groups. A link between quality of life, and glycemic control could be the use of self-management interventions (including pump use, frequent SMBG, carbohydrate counting, and regular exercise). Dr. Anderson highlighted that these strategies were significantly associated with a higher quality of life across most age groups, and Dr. Laffel had noted that many of these were tied to reaching one’s A1c target. Dr. Anderson cited this bi-directional relationship, in her call for HCPs to discuss and support their patients’ quality of life. See more details below.

10. TCOYD and The diaTribe Foundation hosted our 8^th annual ADA Forum where a star-studded panel of diabetes experts (Drs. Bernie Zinman, John Anderson, Anne Peters, Howard Wolpert, and Rury Holman) shared their thoughts on the most impressive and surprising presentations at ADA, the next game changers for type 2 diabetes, changing the food environment, and impacting patient behavior change. Find additional details below.

Honorable Mentions

Dr. Jose Luchsinger (Columbia University, New York, NY) presented 12- and 14-year follow-up data from the Diabetes Prevention Program Outcomes Study (DPPOS) and cognitive outcomes. He found that A1C was well correlated to a decline in cognitive performance. He declared metformin “safe” from a cognitive impact standpoint, highlighting that scores on a battery of cognitive assessments were nearly equal across treatment arms (as a reminder, the treatment arms were placebo, metformin, and lifestyle intervention). On the topic of diabetes care, cognitive function, and neurodegenerative disease, Diabetes just published a suit of articles linking diabetes and Alzheimer’s disease. While it’s not the first time articles have linked diabetes and Alzheimer’s disease, these three papers did a particularly thoughtful job of assessing the literature: De Felice and Ferreira, 2014; Kleinridders, et al. 2014; Yarchoan and Arnold, 2014. It is an exciting prospect that existing diabetes drugs could possibly be positioned to affect a huge emerging problem in the world – one that could dwarf diabetes itself. We’ll be back in our full report with full details on DDPOS outcomes. You will be able to find more details in our full report.

Dr. Sue Sha (Janssen, Raritan, NJ)presented results of a randomized, double-blind, placebo-controlled study (n=36 people with type 2 diabetes) characterizing changes in plasma volume and other measures of fluid/electrolyte imbalance on J&J’s Invokana (canagliflozin) after one week and after 12 weeks of treatment with high dose (300 mg) Invokana. As a reminder, a safety concern associated with Invokana is that its diuretic mechanism cause dangerous plasma volume depletion. This study demonstrated that Invokana decreased plasma volume by about 10% after one week of treatment, but that plasma volume returned to baseline after 12 weeks of treatment. However, some markers of plasma volume depletion did not return to baseline after 12 weeks (eGFR, BUN/Cr, and hematocrit), which may suggest that lasting effects of the initial plasma volume decrease may persist longer than the volume depletion itself (see below for full details).

The morning after the poster presentation of phase 2 data for Isis’ glucagon receptor antagonist (ISIS-GCGRRx), the company held an investor event next to the Moscone Center in San Francisco to discuss the results and share its vision the agent’s future. Management highlighted that within four-to-five weeks of ISIS-GCGRRx initiation in the 13-week trial (n=75), the average patient, no matter his/her baseline fasting glucose level, reached euglycemia. Isis thinks that part of ISIS-GCGRRx’s success lies in it striking a middle ground between DPP-4 inhibitors and GLP-1 agonists in terms of elevating GLP-1 levels: ISIS-GCGRRx increases GLP-1 levels more than DPP-4s, conferring better efficacy, but less than GLP-1 agonists, thereby avoiding the GI side effects. Given the striking A1c reduction seen with ISIS-GCGRRx, Isis was quite explicit about its intention to target people with more serious type 2 diabetes (i.e., A1c >9%; failing multiple OADs, or insulin). Isis is planning to conduct further dose refinement studies, and is seeking to partner the agent before moving it into phase 3 testing. You can find additional details below.

Detailed Discussion and Commentary

Press Conference

New American Diabetes Association Position Statement on Type 1 Diabetes

Jane Chiang, MD (Stanford Medical Center, Los Altos, CA), Sue Kirkman, MD (University of North Carolina, Chapel Hill, NC), Lori Laffel, MD (Joslin Diabetes Center, Boston, MA), Anne Peters, MD (University of Southern California, Los Angeles, CA)

At a midday press briefing, the authors of the ADA’s newly released position statement on type 1 diabetes (published in Diabetes Care) explained to the assembled journalists the thinking behind the document. The panelists emphasized two crucial points, one general and one specific. The more general takeaway is that this position statement explicitly carves out a more clearly delineated space for type 1 diabetes in the ADA’s thinking. Indeed, Dr. Jane Chiang, the ADA’s Senior Vice President for Medical and Community Affairs, noted that this position statement reflects the ADA’s effort to better recognize the distinctions between type 1 and type 2 diabetes. This acknowledgment of the unique challenges faced by the type 1 diabetes patient community was a prevailing theme of the press briefing, although the speakers were hesitant to translate this recognition to specific recommendations. As Dr. Anne Peters suggested at one point, the aim of this position statement is to start a conversation about type 1 diabetes – more concrete directives on treatments and care will be left to the writers of future statements. Later in the day, Dr. Peters expressed hope that the document will be updated in around three years. One major concrete change in the new position statement is an updated A1c target for children with type 1 diabetes. All type 1 patients aged 18 and under should now have a target A1c of 7.5%; the adult benchmark remains 7.0%.

• The revised pediatric target of 7.5% for pediatric type 1 diabetes patients is specifically designed to improve pediatric outcomes and is a recognition of the improved ability to prevent hyperglycemia with newer therapies. The ADA previously recommended that only adolescents aged 13-19 strive for a 7.5% A1c; children 6-12 years of age were given a target of 8.0%, while children 5 years and under could have acceptable A1c levels of up to 8.5%. The varying benchmarks were prompted by concerns over hypoglycemia – Dr. Lori Laffel characterized these as the concerns of a “distant era,” noting the wealth of new clinical data obtained in the past 10 years – as the old thinking held that the risk of hypoglycemia in very young patients significantly outweighed the risk of complications related to poor glucose control.
  • The ADA’s position statement brings its guidelines on this topic more in line with international standards. The International Society for Pediatric and Adolescent Diabetes released a statement in 2009 recommending the same 7.5% target for children with type 1 diabetes. The speakers noted that harmonizing the ADA’s A1c targets with those of other organizations was a major priority of the position statement.
• Although the revised pediatric targets are likely to attract the most attention, the speakers emphasized that the position statement is designed to address the entire lifespan of the disease. Dr. Sue Kirkman noted that, as adult endocrinologist, it drives her crazy that people still refer to type 1 diabetes as a pediatric disease. Not only are the vast majority of people with type 1 diabetes adults, but also between a third and a half of new cases develop after the age of 18. The lifespan of people with type 1 also continues to increase, a point Dr. Kirkman illustrated by pointing to the skyrocketing number of Joslin 50-Year Medals awarded to patients in the past few years. Crucially, the position statement actively pushes against the notion that patients should be classified as pediatric, adult, or geriatric; rather, the position statement argues that the lifespan of type 1 diabetes should be viewed more as a continuum. Dr. Chiang did note one particular challenge that also serves to demarcate pediatric and adult patients: the former are generally cared for by pediatric endocrinologists, whereas the latter are often treated by primary care providers. An intention of this position statement is to smooth this transition from one type of care to the other.
• The panel repeatedly noted that what we do know about type 1 is far outweighed by what we don’t. Dr. Chiang pointed to the American College of Cardiology/American Health Association’s newly revised guidelines on cholesterol, which effectively categorize the vast majority of people with diabetes as being at-risk for cardiovascular disease and (as a result) as good candidates for statin therapy. She said that these recommendations are based on clinical data for type 2 patients, and that it can’t really be said one way or the other whether the same recommendations should also apply to type 1 diabetes patients. Dr. Kirkman agreed that cardiovascular disease (and, indeed, all microvascular and macrovascular complications) is a source of major unanswered questions for the type 1 diabetes community. More generally, Dr. Kirkman said there is still fuzziness about how many people even have type 1, and what sort of care they receive.
• As with the ADA/EASD’s recent position statement for type 2 diabetes, the individualization of care was highlighted as a priority. The speakers emphasized that both the adult and juvenile targets could be adjusted up or down to better fit the needs of individual patients. Dr. Laffel suggest that, if a patient’s A1c is 10.0%, then his or her short-term goal should be 9.0%, with 7.0% or 7.5% held up as a “distant goal.” She further stated that her priority with this position statement and type 1 diabetes care in general is to get everyone to shift their A1cs down, if only incrementally, and then start focusing on individuals who require more significant reductions.
• The position statement draws on work that Dr. Peters and Dr. Laffel began with the Type 1 Diabetes Sourcebook. Dr. Peters indicated that the position statement is reflective of many of the broader points made by the approximately 60 authors who contributed to that earlier work.

Oral Presentations: GLP-1 Agonists

Benefits of a Fixed-Ratio Formulation of Once-Daily Insulin Glargine/Lixisenatide (LixiLan) vs. Glargine in Type 2 DM Inadequately Controlled on Metformin Monotherapy (332-OR)

Julio Rosenstock, MD (Dallas Diabetes and Endocrine Center, Dallas, TX)

Dr. Julio Rosenstock presented results of a 24-week proof of concept study demonstrating that the combination of the lixisenatide and Lantus (Sanofi’s LixiLan GLP-1 agonist/basal insulin fixed-ratio combination product) has advantages over Lantus alone. This study randomized 323 people with type 2 diabetes on background metformin (relatively early-stage type 2 diabetes), to LixiLan or Lantus. LixiLan dose was adjusted according only to Lantus basal insulin requirements. Both arms achieved similar and striking A1c reductions (1.8% reduction on LixiLan compared to 1.6% on Lantus from 8% baseline), while LixiLan blunted postprandial glucose excursions substantially more so than Lantus (LixiLan reduced excursions by 70 mg/dl compared to 12 mg/dl on Lantus; p<0.001). A striking 84% of patients on LixiLan achieved an A1c goal of <7% (although a surprisingly high 78% of Lantus patients also achieved this goal); extraordinarily, 72% on LixiLan reached an A1c goal of ≤6.5% compared to 65% of Lantus patients (again, still pretty high for Lantus, probably indicating the investigators’ skill at titrating dose). Moreover, LixiLan produced a -1.2 kg [-2.6 lb] weight change over the 24 weeks compared to a 0.4 kg weight gain [0.9 lb] on Lantus. Documented symptomatic hypoglycemia (≤70 mg/dl) was similar between the two groups at 22-23%. The study also examined several composite efficacy endpoints of interest as outlined in the table below in which LixiLan was consistently better than Lantus. Frequency of nausea and vomiting with LixiLan (7.5% and 2.5%, respectively) was less in this trial compared to what has been reported for other GLP-1 agonists, but the drug was also titrated very slowly. In all, the data are very impressive – yet another testament to the strength of the GLP-1 agonist/basal insulin combination. In the introduction to his talk, Dr. Rosenstock positioned LixiLan as a better alternative for basal insulin intensification compared to adding on prandial insulin.

Oral Presentations: SGLT-2 Inhibitors

Empagliflozin (EMPA) Monotherapy for ≥76 Weeks in Drug-Naïve Patients with Type 2 Diabetes (T2DM) (264-OR)

Michael Roden, MD (Leibniz Center for Diabetes Research, Dusseldorf, Germany)

Dr. Michael Roden presented the results of a 52-week extension study of a 24-week registrational trial (EMPA-REG MONO) comparing Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin) at both 25 mg and 10 mg doses against Merck’s Januvia (sitagliptin 100 mg) and placebo in drug-naïve type 2 diabetes patients. The extension study enrolled 68% of patients enrolled in the initial study. The 24-week data demonstrated that empagliflozin provided comparable A1c reductions to sitagliptin, but the curves diverged slightly during the extension study. At week 76, empagliflozin 25 mg led to a significantly greater placebo-adjusted drop in A1c (-0.89%) relative to sitagliptin (-0.66%) (p = 0.005). The empagliflozin 10 mg arm showed a non-significant trend towards increased efficacy, with a placebo-adjusted reduction of -0.78%. As at 24 weeks, both empagliflozin doses led to significantly greater weight loss (~2.5 kg, ~6 lbs) than sitagliptin, which was weight-neutral. There were slightly more drug-related adverse events with empagliflozin than sitagliptin, which were (unsurprisingly) driven by a ~5% increase in genital infections. The sustained efficacy over 76 weeks and superior A1c reduction over sitagliptin should provide Lilly/BI with some good talking points as it begins empagliflozin’s launch in Europe and moves towards regulatory re-filing in the US.  

• Results from the original 24-week study (EMPA-REG MONO) were published in the journal Lancet in September of last year.
  • J&J’s Invokana (canagliflozin) previously demonstrated superiority to sitagliptin in a 52-week trial in patients on metformin +/- sulfonylurea – we covered the results at ADA 2012 (read our report). AZ’s Forxiga/Farxiga (dapagliflozin) has been studied as an add-on to sitagliptin, but not versus sitagliptin in phase 3.
• Of the 899 patients treated in the initial 24-week study, 68% patients continued in the extension study. Characteristics of the patients that continued into the extension study were comparable to those of patients that did not continue. There were slightly more male patients in the study, with a median age of approximately 55 years. Notably, nearly two-thirds of the patients in the study were Asian, with 50% of that group from China, 30% from Japan, and the remaining 20% from India. It is unclear how this might impact the interpretation of the results – some very early studies have suggested that DPP-4 inhibitors have greater efficacy in East Asian populations – but Dr. Roden noted during Q&A that no interaction was found between efficacy and ethnicity (Asian vs. Caucasian). Diabetes duration was on the low side, with most patients having a disease duration of 1 – 5 years. The four arms of the study were placebo, sitagliptin 100 mg, empagliflozin 10 mg, and empagliflozin 25 mg. The placebo group seemed to lose patients to follow-up at a more rapid rate than the other study arms during both the initial study and the extension study, and at week 76 only 65 patients remained in the placebo arm (relative to 132 in each of the empagliflozin arms). Perhaps as a result, the A1c results were displayed as absolute reductions and not placebo-adjusted reductions, although we calculated placebo-adjusted values below.
• After 76 weeks from the beginning of the initial study, the empagliflozin 25 mg arm achieved a significantly greater placebo-adjusted A1c reduction (-0.89%) than the sitagliptin arm (-0.66%). The difference was statistically significant (p = 0.005); baseline A1c was ~7.9%. The empagliflozin 10 mg arm achieved a numerically greater placebo-adjusted A1c reduction than sitagliptin (-0.78% vs -0.66%), but the difference was not statistically significant (p = 0.131). For background, neither empagliflozin dose achieved a statistically greater A1c reduction than empagliflozin at 24 weeks; the difference emerged gradually during the extension study, as the sitagliptin arm’s A1c crept slowly upwards while the empagliflozin groups’ A1cs held slightly more level.
• Empagliflozin led to significantly weight loss and reductions in systolic blood pressure than sitagliptin. Both empagliflozin groups achieved weight loss of approximately 2.5 kg (~6 lbs), while sitagliptin and placebo were weight neutral (p<0.001 for both empagliflozin groups vs sitagliptin). Systolic blood pressure fell by approximately 4 mmHg in the empagliflozin groups, and here to there was no appreciable change in the placebo or sitagliptin groups (p=0.001). 
• As expected, there were more genital infections in the empagliflozin arms (6%) than the sitagliptin (1%) or placebo (2%) arms. This difference drove a difference in overall treatment-related adverse events between empagliflozin and sitagliptin. Other than this difference, there were no imbalances in safety or tolerability between empagliflozin and sitagliptin. Hypoglycemia incidence was identical between the four arms.

Questions and Answers

Q: You said that the enrollment criterion for “drug-naïve” was no diabetes drug use for 12 weeks prior to the study. Were there patients in the trial who had previously been on diabetes drugs and were taken off? If so, do you know the proportion of patients who were previously treated versus those who were truly drug naïve?

A: Subjects could have been on previous metformin treatment, as long as it was discontinued more than 12 weeks before the trial. We don’t have data on the distribution, but there was no imbalance in that proportion of previously-treated patients between the groups.

Q: You mentioned that around two-thirds of the study population was Asian. Could this have introduced any genetic discrimination?

A: Yes, a specific feature of this study is that it included a high percentage of people from Asia. Out of that group, around 50% was from China, 30% from Japan, and 20% from India. There have been subgroup analyses to compare the efficacy between Asians and Caucasians, and there was no real effect – the P-value for the interaction was higher than 0.1.

Q: Could you provide more detail on the temporality of the 4 mmHg reduction in systolic blood pressure you saw at week 76? Was the difference more dramatic at the beginning of the trial, and was subsequently attenuated?

A: If you look at the time curves, the reduction was more or less maintained throughout the study. There were no marked changes at the very end, or at points in between.

Empagliflozin (EMPA) Compared with Glimepiride (GLIM) as Add-on to Metformin (MET) for 2 Years in Patients with Type 2 Diabetes (T2DM) (266-OR)

Martin Ridderstråle, MD, PhD (Steno Diabetes Center, Gentofte, Denmark)

Dr. Martin Ridderstråle presented the results of the two-year EMPA-REG H2H-SU trial, which compared Lilly/BI’s Jardiance (empagliflozin 25 mg) to the sulfonylurea (SFU) glimepiride (1-4 mg), both in addition to metformin. At week 104, from a baseline of 7.9%, empagliflozin yielded a greater reduction in A1c (-0.66%) than glimepiride (-0.55%); the difference, although modest, was enough to achieve the statistical margins for both non-inferiority and superiority. Notably, in the glimepiride arm, the average daily dose was only 2.7 mg per day – Dr. Ridderstråle suggested during Q&A that the glimepiride dosing does impact the interpretation of the efficacy results, but that the more notable findings were in areas beyond A1c. Empagliflozin was associated with a far lower incidence of hypoglycemia (2.5%) than glimepiride (24.2%). This high rate of hypoglycemia suggests to us that pushing the dose of glimepiride further would likely have been unsafe. Empagliflozin came out ahead with regards to body weight (4.5 kg [~10 lbs] difference) and blood pressure, but slightly increased cholesterol and the incidence of genital infections. These results show that empagliflozin is strongly differentiated from SFUs when it comes to factors such as hypoglycemia and weight that are very important for patients, and that the drug might even be able to deliver better A1c-lowering efficacy in the long-term. 

• This study enrolled 1.545 type 2 diabetes patients who were on stable metformin therapy. Approximately one-third of enrolled patients were Asian, and approximately 17% had diabetes duration of over 10 years. The study randomized patients 1:1 to empagliflozin 25 mg or glimepiride, with a dose range of 1-4 mg.
• Empagliflozin led to a statistically superior reduction in A1c from baseline (-0.66%) at week 102 compared to the -0.55% reduction seen with glimepiride (p = 0.015). Dr. Ridderstråle noted that the mean maximum glimepiride dose in the glimepiride arm was 2.7 mg, with only 40% reaching the maximum dose. When asked about that fact during Q&A, Dr. Ridderstråle suggested that the efficacy should be viewed as more or less comparable, with the more meaningful differentiation coming in the form of benefits beyond A1c. The time-course of A1c reductions was in line with what we have seen in previous trials: glimepiride caused a sharp initial decline that began to creep upward, while empagliflozin led to a more gradual initial reduction that held fairly steady. The curves crossed at around week 40.
• There was markedly less hypoglycemia with empagliflozin than glimepiride. Approximately 24% of patients on glimepiride experienced a confirmed hypoglycemic adverse event, while the incidence was under 3% in the empagliflozin arm (p<0.001). The only events requiring assistance (n = 2) were in the glimepiride group. Beyond providing reassurance on empagliflozin, these results indicate that the glimepiride dose was probably titrated well, as raising the dose would likely have caused an unacceptable level of hypoglycemia.
• The empagliflozin group lost 3 kg (~7 lbs) on average, while the glimepiride group lost 1kg (~3 lbs) on average. The empagliflozin group saw a slight 3 mmHg reduction in systolic blood pressure, while the glimepiride group saw a rise of 3 mmHg (p<0.001).
• There were more drug-related adverse events in the glimepiride group, driven by the increased hypoglycemia. There were more serious adverse events, however in the empagliflozin arm, although Dr. Ridderstråle noted that there was no specific signal or pattern among individual serious adverse events that drove this imbalance. Genital infections were higher with empagliflozin (~12%) than glimepiride (~2%).
• As has been seen in other SGLT-2 inhibitor trials, empagliflozin led to slight increases in total cholesterol, LDL-C, and HDL-C.

Questions and Answers

Q: Given that the mean daily dose of glimepiride in the study was only 2.7 mg, which is a ways away from the maximum licensed dose, is the superiority result questionable?

A: I do not think that it is questionable, but I do think that you have to view the data in terms of that difference in dose. I’m inclined not to emphasize the superiority finding, as I do not think that is the important finding. A better way to look at the efficacy is that the results were more or less comparable, and then interpret the other effects in that light.

Q: Why was there an elevation in genital infections but not urinary tract infections?

A: I’m not an expert on infectious disease, but from the data I have seen, apparently bacteria in the urinary tract like glucose but do not need it, while mycotic agents absolutely love glucose.

Q: Did you measure if there was a correlation between infections, volume depletion, and baseline blood sugar levels?

A: There was no difference in the level of volume depletion or infections with respect to blood sugar levels. They are seen in all levels of glycemia.

Q: I noticed that LDL cholesterol and triglycerides went up despite a reduction in weight loss and hyperglycemia. Did you measure ApoB?

A: The lipid findings were interesting, but we haven’t evaluated those details yet. Concerning triglycerides, we actually saw a decrease at 52 weeks, then a slight increase. Regarding LDL, this slight increase appears to be consistent but small, and we don’t know if it is clinically significant. There are some hypotheses about why you see that increase in LDL. One is that there is a slight increase in hematocrit, and that if you adjust for that, you see less of an increase. Another interesting theory is that if you lose sugar through urine, you need to compensate with increased energy intake and your dietary intake and composition may change. Supporting that theory is the fact that you see increases in both LDL and HDL.

Temporal Changes in Urinary Glucose Excretion (UGE), Urine Volume (UV), and Plasma Volume (PV) in Subjects with Type 2 Diabetes Mellitus (T2DM) Treated with Canagliflozin (CANA) (263-OR)

Sue Sha, MD, PhD (Janssen Research & Development, Raritan, NJ)

Dr. Sue Sha presented results of a randomized, double-blind, placebo-controlled study (n=36 people with type 2 diabetes) characterizing changes in plasma volume and other measures of fluid/electrolyte imbalance on J&J’s Invokana (canagliflozin) after one week and after 12 weeks of treatment with high dose (300 mg) Invokana. As a reminder, a safety concern associated with Invokana is that its diuretic mechanism cause dangerous plasma volume depletion. This study demonstrated that Invokana decreased plasma volume by about 10% after one week of treatment, but that plasma volume returned to baseline after 12 weeks of treatment. However, some markers of plasma volume depletion did not return to baseline after 12 weeks (eGFR, BUN/Cr, and hematocrit), which may suggest that lasting effects of the initial plasma volume decrease may persist longer than the volume depletion itself.

• Invokana lowered A1c (-0.6% placebo-adjusted) and fasting glucose (-29 mg/dl placebo-adjusted) over 12 weeks from a baseline A1c of 7.6-7.7% and baseline FPG of ~150 mg/dl. As the drug is designed to do, Invokana increased urinary glucose excretion by ~90 g/day at 1 week, and this persisted to 12 weeks.
• The small increase in urine volume (~150 ml placebo-adjusted) observed at one week returned to baseline by week 12. Correspondingly, placebo-adjusted mean plasma volume decreased by 9.7% at week one (a 300 ml placebo-adjusted decrease), and essentially returned to baseline by week 12.
• Although the plasma volume effect attenuated at week 12, a small reduction in eGFR, small increase in BUN/Cr, and small increase in hematocrit persisted through week 12, suggesting that some small reduction in plasma volume functionally remained despite the return of plasma volume to baseline.
• Invokana lowered systolic blood pressure pretty significantly in this trial (placebo-adjusted reductions of 10 mmHg sitting and 8 mmHg standing at week one) that were maintained through week 12 (placebo-adjusted reductions or 13 mmHg sitting and 14 mmHg standing). Dr. Sha noted during Q&A that the mechanism for continued blood pressure lowering despite the attenuation of urine volume is not known. The results of this study will be published in Diabetes, Obesity, and Metabolism.

Questions and Answers

Q: You showed quite a dramatic drop in systolic blood pressure, yet diminishing of the urine volume and diuresis at week 12. Any idea how the blood pressure reduction can be sustained despite the reduction of diuresis? Do you have any sodium excretion data?

A: The mechanism is not well understood. It’s very similar to results from other diuretics such as thiazides. The patterns are very similar. There are several mechanisms hypothesized, but still not well understood.

Oral Presentations: GLP-1 Agonists

Efficacy and Safety of Once-Weekly Dulaglutide vs. Insulin Glargine in Combination with Metformin and Glimepiride in Type 2 Diabetes Patients (AWARD-2) (330-OR)

Francesco Giorgino, MD, PhD (University of Bari Aldo Moro, Bari, Italy)

Dr. Francesco Giorgino presented the results of the AWARD-2 trial, which compared Lilly’s once-weekly GLP-1 agonist dulaglutide against Sanofi’s basal insulin Lantus (insulin glargine) added on to metformin and a sulfonylurea in type 2 diabetes patients for 78 weeks. At week 78, dulaglutide 1.5 mg (the highest of the two doses tested) led to a superior reduction in A1c from baseline (-0.90%) than insulin glargine (-0.59%), while dulaglutide 0.75 mg provided a non-inferior mean A1c reduction (-0.62%) relative to insulin glargine. Dulaglutide 1.5 mg led to weight loss of 2 kg (~5 lbs) at week 78, while the insulin glargine group gained over 1 kg (~3 lbs) on average. The incidence of total hypoglycemia was ~60% higher with insulin glargine than dulaglutide, and the incidence of nocturnal hypoglycemia was more than double the incidence with dulaglutide. As expected, the incidence of nausea was higher in the dulaglutide arms (15% and 8% for dulaglutide 1.5 mg and 0.75 mg, respectively) than the insulin glargine arm (2%). These results serve as evidence that GLP-1 agonism can be a more beginner-friendly initiator injectable for patients not at goal on oral medications, especially those that cause hypoglycemia. However, the fact that investigators may have held back in up-titrating insulin due to fears about hypoglycemia might limit these findings’ use as a clinical efficacy of dulaglutide and insulin glargine alone.

Oral Presentations: Hypoglycemia – Counterregulation, Risk Factors, Economic Burden, and Unawareness

Both Patients with Type 1 and Type 2 Diabetes Who Require Ambulance Assistance for Severe Hypoglycaemia Have More Than Twice the Mortality Rate of the General Diabetes Clinic (249-OR)

Jackie Elliott, PhD (Sheffield Teaching Hospitals, Sheffield, UK)

This compelling oral presentation examined the characteristics and mortality rate of patients requiring ambulance assistance for severe hypoglycemia from April 2009 to March 2013. Using data from Sheffield’s local ambulance service, the team discovered that 558 consecutive episodes of severe hypoglycemia occurred during the four-year period in 380 individuals. Notably, 23% of the ambulance callout patients (n=87) died during the 4.4 year study period, double the 11% death rate in the Sheffield general diabetes population – said Dr. Elliott, “This is an incredibly high mortality rate.” In addition, type 2 diabetes patients (mean age: 75 years) were nearly four times more likely to die than patients with type 1 diabetes (mean age: 51 years). Disturbingly, half of the 87 patients that died did so in the 12 months post-first ambulance callout, and this affected disproportionately more type 2s (54% vs. 18% of type 1s; p=0.003). Type 2 patients were significantly more likely to be transferred to the hospital following the ambulance callout (20% vs. 11%) and were more likely to live alone (33% vs. 21%) compared to type 1 patients. Sheffield widely uses human insulin, which we imagine was a key contributor to high rates of severe hypoglycemia and hospitalization. Overall, this study underscored the very real and scary nature of severe hypoglycemia, an ever-present danger for both type 1 and type 2 diabetes – the latter is underappreciated in our view, and certainly an area where CGM could help in the elderly. Session moderator Dr. Stephanie Amiel opened the Q&A quite appropriately: “Your data show us why we’re all here.”

• Sheffield’s local ambulance service responded to 558 episodes of severe hypoglycemia in 380 individuals from April 2009 to March 2013. Of these 380 patients, 79% had one episode, 16% had two or three episodes, and 6% had four or more episodes. Dr. Elliott pointed out some patients that had 11+ ambulance callouts during the four-year period!
• Following severe hypoglycemia episodes, Sheffield has a team of nurses that call patients to figure out what happened and adjust medication accordingly. This struck us as a highly valuable, relatively low-cost way to avoid recurrent events in a highly susceptible patient population. The impact of this intervention was unclear – Dr. Stephanie Amiel suggested in Q&A that this program is worth further research.

Questions and Answers

Q: On the basis of epidemiology studies, perhaps severe hypoglycemia is a marker for the fragility of patients. What can you tell us about the co-morbidities of these patients? Any idea how they died?

A: No cause of death data was linked to this. In terms of co-morbidities. I know that patients we look after in the general diabetes clinic have considerably longer co-morbidity lists vs. 5-10 years ago. I can certainly go back and look at that in more detail.

Dr. Stephanie Amiel (King’s College, London, UK): Did you see whether there was an impact of your admirable system of having hypoglycemia followed up? The number of patients that only have one episode is quite impressive.

A: Yes, you’re right. We have the diabetes nurses phoning patients up to make sure their insulin or gliclazide was reduced or stopped. We need to collect more details around the patients that died to see if there was anything else that could be done.

Q: Do you have information about the types of therapies the type 2 diabetes patients were receiving?

A: In Sheffield, we are big users of human insulin. About a third of patients on insulin were also on a sulfonylurea.

Q: So among insulin users, was there use of rapid-acting insulin, intermediate insulin, etc.?

A: It was a whole mix.

Q: Did the ambulance crew record whether hypoglycemia treatment was given prior to their arrival?

A: No. Sometimes parents had already given glucagon. But that wasn’t part of the protocol. It was sometimes added information on the ambulance sheets.

Predispsosing Factors for Hypoglycemia: Analysis from the SAVOR-TIMI 53 Trial (252-OR)

Itamar Raz, MD (Hadassah Medical Center, Jerusalem, Israel)

Dr. Itamar Raz presented results related to hypoglycemia from the SAVOR cardiovascular outcomes trial for AZ’s DPP-4 inhibitor Onglyza (saxagliptin). As a reminder, the trial’s primary results found a small but significant increase in overall hypoglycemia in the Onglyza arm compared to the placebo arm (15.3% vs. 13.4%; p<0.001). In the subset of hypoglycemia events that required hospitalization, there was no difference in frequency between the Onglyza and placebo groups. A multivariate analysis of variables associated with hypoglycemia found insulin use (particularly short-acting insulin) to be very strongly correlated with hypoglycemia, with sulfonylurea use, hypertension, long diabetes duration, and poor renal function. Stratification by baseline medication usage showed that only patients who were on baseline sulfonylurea had an elevated risk of hypoglycemia on Onglyza compared to placebo. Stratification by baseline A1c showed that the increased risk of major hypoglycemia was confined to those with baseline A1c <7%. A greater number of patients achieved glycemic targets without hypoglycemia on saxagliptin compared to placebo, where medication intensification was more likely to include SFUs or insulin.

Oral Presentations: Important Findings and Considerations in Behavioral Medicine

Opportunities to Enhance Diabetes-Specific Quality of Life (Qol) in Youth With Type 1 Diabetes (T1D): The Global Teens Study (259-OR)

Barbara Anderson, PhD (Baylor College of Medicine, Houston, TX)

Building off of Dr. Lori Laffel’s (Joslin Diabetes Center, Boston, MA) presentation of glycemic control results from the TEENS study, Dr. Barbara Anderson discussed the trial’s quality of life findings. As background, the TEENS Study is the largest, contemporary, cross-sectional study of its kind, having enrolled 5,960 patients aged 8-25 years old from 219 centers in 20 countries (and was sponsored by Sanofi). The study found that more than 70% of youth with type 1 diabetes are not achieving glycemic targets. Looking at the quality of life measures (determined using the PedsQL Diabetes Module, which looks at diabetes symptoms, treatment barriers, treatment adherence, worry, and communication problems), Dr. Anderson found that achieving one’s target A1c was significantly associated with better quality of life for all age groups (8-12 years, 13-18 years, and 19-25 years). A link between quality of life, and glycemic control could be the use of self-management interventions (including pump use, frequent SMBG, carbohydrate counting, and regular exercise). Dr. Anderson highlighted that these strategies were significantly associated with a higher quality of life across most age groups, and Dr. Laffel had noted that many of these were tied to reaching one’s A1c target. Dr. Anderson cited this bi-directional relationship, in her call for HCPs to discuss and support their patients’ quality of life.

• The TEENs Study is the largest, contemporary, cross-sectional study assessing type 1 diabetes management and psychosocial parameters in youth aged 8-25 years old (n=5,960 patients from 219 centers in 20 countries). The study’s inclusion criteria included (i) being 8-25 years old; (ii) having been diagnosed with type 1 diabetes before one turned 18 years old; (iii) having had type 1 diabetes for at least one year; (iv) receiving care at a clinic or hospital that treats at least 100 people with type 1 diabetes; and (v) having not undergone a major change in insulin regimen (i.e., going from pump to MDI or vice versa) during the past three months.
• About half of the participants were female and, as expected, the majority were Caucasian. The average patient age was 15 years, and the average diabetes duration was about seven years. About 26-29% of participants were either overweight or obese.

• Overall, the lowest quality of life measurement was “worry” (e.g., anxiety about going low or developing complications) for young adults (19-25 years), and the highest was treatment adherence for preteens (8-12 years). Quality of life measurements in the diabetes-symptoms and treatment-barriers categories remained roughly constant across age groups. In contrast, treatment adherence and worry declined as groups got older (particularly so for worry), and communication improved with age.
  • During Q&A, Dr. Anderson identified young adults as being at particularly vulnerable patient subpopulation, given its generally low quality of life and rate of reaching A1c goal (19%). This group being at high risk was previously recognized; however, this data provides more granularity on what is impacting this age group. She explained that this group’s risk is largely derived from the many life transitions they face (e.g., leaving home for college, getting a job, moving from a pediatric endocrinologist to an adult endocrinologist, etc.). Dr. Anderson thinks that the reduction in parental support, as a young adult becomes more independent, is a particularly impactful change in the life of a young adult with type 1 diabetes. 

• Overall, reaching one’s A1c target was significantly associated with better quality of life in all age groups. More specifically, diabetes symptoms, treatment barriers, and treatment adherence were significantly tied to A1c goal attainment for all age groups. However, worry and communication problems were not significantly associated with reaching one’s A1c target for young adults (it was for preteens and teens). An outstanding question is the direction of this causal relationship (i.e., does better glycemic control cause a person to have a better quality of life, or does a better quality of life enable a person to have better glycemic control). Dr. Anderson hypothesized that it is a bi-directional relationship.

• Notably, self-management behaviors were associated with higher quality of life. These behaviors included pump use, SMBG at least three times a day, carbohydrate counting, and getting at least 30 minutes of physical activity a week. As an example, pump therapy instead of MDI was associated with better quality of life in the categories of treatment barriers, treatment adherence, worry, and communication. Notably, Dr. Laffel’s presentation indicated that these strategies were also associated with a greater odds ratio of reaching one’s A1c goal. Thus, it could be that these behaviors are a link between quality of life and glycemic control.

✔ = significant association

✖ = no association

• Dr. Anderson identified a diversity set of characteristics that were associated with a lower quality of life. Dr. Anderson noted that eating disorders, DKA, financial burden, and parental work reduction or discontinuation due to diabetes could be modified, making them potential targets for HCPs to address. Of course, factors like financial burden and parental work decisions might be beyond the influence of a HCP, but they are important issues for society at large to try and address.

✔ = significant association

✖ = no association

Symposium: Type 1 Diabetes Guidelines – Are They Enough? (Supported by a grant from The Leona M. and Harry B. Helmsley Charitable Trust)

Glucose Targets

Lori Laffel, MD, MPH (Joslin Diabetes Center, Boston, MA)

Dr. Lori Laffel announced the ADA’s new Position Statement, “Type 1 Diabetes Through the Lifespan,” released today online (Chiang et al., Diabetes Care 2014) in this afternoon session. Her presentation focused on the new guidelines’ call for a universal A1c target of <7.5% in all youth under 18 years, a change from the previous call for separate targets: <8.5% (0-6 years), <8% (7-12 years), and <7.5% (13-18 years). The general goal for adults is still <7.0%, though the statement clearly articulates individualized A1c targets for older adults who are healthy (<7.5%), complex/intermediate health status (<8%), and very complex/poor health status (<8.5%). Dr. Laffel reviewed the rationale for the new targets and associated changes, highlighting that the new pediatric A1c targets are now harmonized with other international groups like ISPAD; abolish separate targets by age (i.e., simpler!); and are much needed given the average achievement of goals in type 1 diabetes care. The remainder of her talk reviewed the rationale for targets, the current state of achieving diabetes care targets in pediatrics, and opportunities for improvement.

• The evidence for glycemic targets is based on the DCCT; however, it is both intensity of hyperglycemia exposure and duration that matters. Dr. Laffel noted that an A1c of 10% for three years vs. an A1c of 8% for eight years have the same retinopathy risk. She framed this in a positive light, noting, “there is always an opportunity to help our patients.”
  • The DCCT had certain strengths and limitations that informed A1c targets. First, the trial was restricted to ages 13-39 at entry, meaning there were no data on young children or older adults (the new position statement is trying to fill that gap). Second, the DCCT adolescent cohort was unable to achieve the same A1c outcomes as the adults (another reason why the target was set higher) – this resulted in a loss of the protective effect of metabolic memory on complication risk in this cohort. Third, hypoglycemia risk increased as A1c decreased (as noted above, another reason for higher pediatric A1c targets).
• Dr. Laffel shared three examples from the literature that provide evidence that a lower 7.5% target could improve things. First, a 1990 NEJM article (Larsen et al.) showed that patients improve over time simply by knowing their A1c and glycemic target (compared to those who don’t know their A1c). Meanwhile, Boot et al., Diabet Med 2013 asked patients and parents about their perceived A1c target, which was compared to their actual A1c value. Those who perceived that their target was lower in reality had a lower actual A1c. Last, a recent study from Maahs et al. (Diabetologia 2014) compared the clinical care between the T1D Exchange and the German/Austrian DPV registries. More children from DPV were meeting the recommended A1c goals vs. children from T1D Exchange (A1c <7.5%: 56% vs. 22%; <8.5%: 90% vs. 66%). The study concluded, “The greater frequency of suboptimal control in young patients in the T1D Exchange compared with the DPV is not fully explained by a less frequent use of insulin pumps and may relate to the higher A1c targets that are recommended for this age group in the USA.”
• Dr. Laffel noted that A1c is the average of blood glucose levels over the previous two to three months, but it is weighted towards the last four weeks. She cited estimates that ~50% of an A1c level is formed in the month before the test, 25% in the month earlier, and ~25% in the month before that. We hadn’t heard this data before and wonder what implications it has for study design and duration.
• In Q&A, Dr. Laffel addressed the two arguments against lowering A1c targets in pediatrics. First, some have argued against lower targets in pediatrics, given the risk of severe hypoglycemia and its associated negative cognitive outcomes. In reality, the most recent T1D Exchange data suggests there is no increased risk of severe hypoglycemia with a lower A1c – that’s in contrast to data from the DCCT, where improvements in A1c came with a major increased risk for severe hypoglycemia. Second, some have postulated that the pre-pubertal years potentially don’t affect long-term complications risk. Dr. Laffel noted that this is difficult to study, and it’s likely more important to establish low targets and good diabetes management habits early.

Questions and Answers

Q: Is the ADA’s guideline now that toddlers and very young children should be under 7.5%? Is there any research to show that the pre-pubertal years have some protective mechanisms even if they are at higher A1cs?

A: The consensus that went into the previous age specific guidelines was of fear of hypoglycemia in the young, and consequent fear of neurocognitive compromise. There was also the potential possibility that those years prior to puberty may not have an impact on long-term risk. It’s a very difficult area to study. It’s unclear. Many are afraid to just say clearly those years don’t matter. You establish behaviors and preferences for certain glucose levels. It’s better to establish patients feeling better, healthier, and performing better in a target range. We cannot hang our hat on the years prior to puberty not counting.

Q: I recognize that hypoglycemia may not be as much of a fear as we once thought. But should we put lower limits on A1c targets? What about the patient that comes in with a 4.7% A1c – do we think that should raise a red flag?

A: That’s the point of individualizing care – looking at the risk for severe hypoglycemia.

Q: But the message coming across is that lower is better. To a limit that’s true..

A: What would you like it to be set at?

Comment: Well, someone who comes in with a 4% A1c makes me very nervous…

Posters

Clinical Benefit in Glycemic Control Using a Long-term, Implantable, Continuous Glucose Monitoring System in a 90-Day Feasibility Study (837-P)

C Mdingi, R Rastogi, A Dehennis

In this poster, Senseonics presented 90-day data (45 days blinded + 45 days unblinded) on its implantable CGM system (fluorescence-based sensor, body-worn transmitter with Bluetooth connectivity, and a mobile smartphone app). Twelve patients took part in the three-month study, and sensor accuracy was compared to YSI at in-clinic visits every ~14 days. Overall MARD vs. YSI was a strong 11%, ranging from a low of 7.7% to a high of 17.7%. The Clarke Error Grid showed 85% of points in Zone A and 14% in Zone B (n=1,890 paired CGM-YSI points). However, the poster did not divulge the calibration scheme, in-clinic glucose ranges, or specific study design details/protocols, so it’s hard to know how real-world this accuracy is. [From the Clarke Error Grid, the vast majority of points appeared to fall in the 70-180 range.] There was also no mention of the percentage of sensors lasting 90 days or any details on explantation. Indeed, the poster was really focused on comparing the 45-day blinded period of sensor wear to the 45-day unblinded (i.e., real-time) sensor wear – average glucose significantly improved from 175 mg/dl (blinded) to 156 mg/dl (unblinded), which included a 7% reduction in hyperglycemia, a 1% reduction in hypoglycemia, and an 8% improvement in time in range (75-180 mg/dl). Overall, these feasibility results are encouraging, but we would like to see a longer, larger, and more real-world study, along with more details on the sensor’s calibration scheme.

Hypoglycemia Prediction Using SMBG Data and Patient Medication Information (397-P)

B Sudharsan, M Shomali

This poster presented the latest update to WellDoc’s exciting type 2 diabetes hypoglycemia prediction model, which was first unveiled at DTM 2013. The original model accurately predicted hypoglycemia risk (90% of the time) on the following day based on seven prior days of infrequent SMBG data (e.g., ~1 test per day) – this poster explored the additional benefit of adding patient medication information (drug dosing and class: short-acting insulin, long-acting insulin, pre-mix insulin, orals). Notably, the enhanced model was also constructed to predict the hour of the occurrence of hypoglycemia on the following day, a big step over the previous model’s aim to predict whether hypoglycemia would occur in the next 24 hours. Adding medication information significantly boosted the model’s specificity for accurately predicting hypoglycemia – 92% in the enhanced model vs. 70% in the previous SMBG-only model. The model’s sensitivity for predicting hypoglycemia remained high at 89%, comparable to the prior model’s 92% sensitivity. The study concluded that real-world SMBG frequency (~1 test per day) and medication information can provide adequate data to predict hypoglycemia in type 2 diabetes. The plan is to eventually incorporate this prediction module into BlueStar, WellDoc’s FDA-approved mobile prescription therapy for type 2 diabetes We continue to be impressed by the company’s approach, which centers on using data, algorithms, and real-time feedback to help patients better manage diabetes with minimal provider burden.

• As we understand it, the WellDoc clinical and behavioral R&D team intends to optimize the patient education and coaching around predicted hypoglycemia, and then incorporate the hypoglycemia prediction model into BlueStar. Once incorporated, BlueStar’s automated, real-time coaching will educate patients about how to best manage and avoid hypoglycemia. From a patient perspective, this system would be an incredible asset to managing diabetes, particularly in those who don’t test very often or are at high risk of severe hypoglycemia.
• The researchers used de-identified self-monitored blood glucose (SMBG) data and medication information from a randomized controlled trial (Quinn et al., 2011) to train a probabilistic model. For each data sample, 11 SMBG data points were used in the seven days prior to a hypoglycemic event (defined as SMBG <70 mg/dl). Control samples used for training contained no hypoglycemia on the eighth day. The model was constructed to predict the hour of the occurrence of hypoglycemia. In order to validate the model after training, 2,099 samples not used for training the model were presented to the model without the SMBG data from the eighth day. Sensitivity and specificity for predicting the hour of hypoglycemia or no hypoglycemia on day eight were then calculated. Further validation was performed with another distinct data set of 524 samples.
• The model is grounded in a key assumption: most type 2s are not CGM users or high frequency testers. As a result, this model was designed to work based on a very real-world testing frequency observed in type 2 patients. Indeed, we think a model based on one test per day is pretty magical from a clinical and commercial relevancy standpoint. The hypoglycemia prediction is especially relevant in type 2s, where there are more patients on hypoglycemia-causing agents than there are type 1s in total.
• We’d note that WellDoc has been pretty quiet following January’s $20 million Series A round of financing (led by Merck’s prestigious Global Health Innovation Fund) – the investment was expected to fund a dedicated sales force to regionally rollout BlueStar.

Insulin Therapy: Exploring Provider Perspectives on Needle Phobia and Nonadherence (685-P)

J Krall, K Williams, R Gabbay, L Siminerio

In a BD-supported study, 23 primary care providers and three pharmacists were interviewed to assess their familiarity with and use of smaller and shorter needles as a solution for addressing problems with insulin therapy adherence. A full 70% of the physicians (n=16) reported that needle phobia is the primary challenge to initiating insulin therapy, and a striking 87% of physicians (n=20) stated that the availability of smaller needles would be an important factor in persuading patients to start injections. However, few physicians were familiar with the smallest needle available (BD’s 32-gauge, 4 mm Nano needle) or the fact that shorter needles can be used in any patient regardless of weight. Only 39% (n=9) reported prescribing a specific needle – most physicians instead deferred to default options in prescribing systems or assumed that a pharmacist would choose the best needle. To add insult to injury, the pharmacists in the survey reported referring decisions to PCPs. The authors argue, and we agree, that provider education will need to be revisited in order to increase physician awareness of these options and ultimately improve patient adherence to insulin therapy.

Patients with T1DM Show Reduced but Clinical Significant Elevations in Glucose in Response to Glucagon Injection in the Presence of LY2409021 (1038-P)

CM Kazda, P Garhyan, Y Ding, RP Kelly, TA Hardy, C Kapitza

Lilly presented a study showing that type 1 diabetes patients (n=20 males) receiving a glucagon receptor antagonist (LY2409021 100 mg or 300 mg) were still responsive to exogenously administered glucagon. For background, glucagon receptor antagonists are under investigation as a potential treatment for type 1 or type 2 diabetes. One safety concern about the class is that it may hinder a patient’s ability to recover from hypoglycemia, and this study aimed to test whether glucagon would still be an effective treatment for hypoglycemia in the presence of a glucagon receptor antagonist. The study found that one day after a single dose of LY2409021, intramuscular administration of 1 mg of glucagon in a fasting state resulted in a blunted but clinically significant elevation in blood glucose. As would be expected, the glucose rise in the placebo group was greatest (peaking at 202 mg/dl) followed by the 100 mg group (155 mg/dl) and the 300 mg group (141 mg/dl) from a baseline of ~85 mg/dl. The study did not examine the role of endogenous glucagon response, nor did it test the response during hypoglycemia. We hope to see those studies conducted as well.

TCOYD/The diaTribe Foundation Annual Forum

Closing out the last full day of ADA, over 250 attendees gathered at the historic Westin St. Francis hotel for the 8^th annual TCOYD/The diaTribe Foundation Forum where a star-studded panel of diabetes experts shared their thoughts on the most impressive and surprising presentations at ADA, the next game changers for type 2 diabetes, changing the food environment, and impacting patient behavior change. Notably, the panelists all shared cautious optimism around the artificial pancreas and pointed to the need for continued support of basic science research. Dr. Steve Edelman and our very own Kelly Close co-moderated the panel and emphasized in their introductions the need for continued partnership between every sector in the diabetes ecosystem. Ms. Close also wisely pointed out that one of the biggest challenges in life is learning when to say no and when to say yes; in her words, “Thank you to everyone joining us in saying no to the diabetes epidemic and yes to working together and continuing to fight diabetes.” Below, we’ve included selected quotes from the panel; stay tuned for additional details and the full panel discussion in our 2014 ADA full report. Below are a few quotations from the night that we just couldn’t wait to share:

“The reality of closing the loop is much closer than it has ever been before.” – Dr. Bernie Zinman (University of Toronto, Toronto, Canada) on his impressions of ADA 2014.

“In all honesty, I think the most important thing [at this ADA] was actually what I did along with three other colleagues – the first ever position statement for people with type 1 diabetes. And I don’t think any of you appreciate how hard that was, how much I had to fight for it... This is the most important thing I've done is a long time, and I hope it's what I'll be most remembered for." – Dr. Anne Peters (University of Southern California, Los Angeles, CA) on what she was most excited about at this year’s ADA.

“I went to a lecture on the changing face of type 1 diabetes and currently we have 160,000 children with type 1 diabetes. The latest projections for the year 2050 forecast that this patient population will increase to 600,000 children. This was really surprising. I’ve talked about my concern with the endocrinology workforce before, but what about pediatric endocrinology? Will we have the workforce to take care of these 600,000 patients?” – Dr. John Anderson (The First Clinic, Nashville, TN) on what ADA presentation was most surprising to him.

“I think that the monoclonal antibody PCSK9 as a once monthly injection could be transformative. It halves lipid levels. Once monthly injections could make adherence much easier. Diabetes is about living your life normally, not about having to do 10 things every day. Hopefully this will come in the near future, get regulated, and get reimbursed.” – Dr. Rury Holman (University of Oxford, Oxford, UK) on what he would most like to see that could be transformational for the diabetes field.

"The CDC got some funding, and when you sit in the office, it's, 'This is where we are, increase everything'. But diabetes is disproportionally punished, and when we point that out, it falls on deaf ears." – Dr. John Anderson on the challenges of diabetes research and funding.

“A game changer [in type 2 diabetes] would be understanding why beta cells fail. If we tickle them with GLP-1 agonists, they will work for some time, but not forever. If we could stop beta cell decline we wouldn’t need these fancy treatments and we could keep patients healthy and living longer.” Dr. Rury Holman

“One of the biggest controversies in type 2 diabetes is bariatric surgery. While it is very controversial, we can learn during the process about why we get early diabetes remission. Is it something that is happening in the gut or with GLP-1 or incretin levels? What we learn from surgery now will help us down the road.” – Dr. John Anderson on what could transform the type 2 diabetes space.

“The philosophical answer to your question is that I have realized there is no fixed body of knowledge. The more I know, the more I realize the lack of my knowledge." – Dr. Howard Wolpert (Joslin Diabetes Center, Boston, MA) what has taken him the longest to learn in diabetes.

"There are some people after ten years that they just decide to lose 50 lbs - and then they do. There is a point in peoples’ lives when the flip switches, and they are capable of making changes. How do they do that? How do I distill that and give it to patients who want to change but just can't do it. ‘Here's a pill to fix you’ - I have no idea how to do that." – Dr. Anne Peters (University of Southern California, Los Angeles, CA) on what has been the hardest thing to learn about diabetes care.

Isis Investor Event

The morning after the poster presentation of phase 2 data for Isis’ glucagon receptor antagonist (ISIS-GCGRRx), the company held an investor event next to the Moscone Center in San Francisco to discuss the results and share its vision the agent’s future. Management highlighted that within four-to-five weeks of ISIS-GCGRRx initiation in the 13-week trial (n=75), the average patient, no matter his/her baseline fasting glucose level, reached euglycemia (as measured by FPG). Isis thinks that part of ISIS-GCGRRx’s success lies in it striking a middle ground between DPP-4 inhibitors and GLP-1 agonists in terms of elevating GLP-1 levels: ISIS-GCGRRx increased GLP-1 levels up to four-fold, which is a greater rise than that driven by DPP-4 inhibitors (1.9-2 fold), resulting in better efficacy. On the flip side, the GLP-1 bump is smaller than that conferred by a GLP-1 agonist; as a result, no participants in the ISIS-GCGRRx arm reported GI side effects. Given the striking A1c reduction seen with ISIS-GCGRRx, Isis was quite explicit about its intention to target people with more serious type 2 diabetes (i.e., A1c >9%; failing multiple OADs, or insulin). Isis is planning to conduct further dose refinement studies, and is seeking to partner the agent before moving it into phase 3 testing.

• As background, the double-blind, 13-week trial randomized type 2 patients on stable metformin therapy to placebo (n=26) or Isis’s ISIS-GCGRRx (n=23 for 100 mg dose, n=10 for 200 mg dose with load, n=16 for 200 mg dose without load).
• Management highlighted that within four-to-five weeks of ISIS-GCGRRx initiation, the average patient, no matter his/her baseline fasting glucose level, reached euglycemia (as measured by FPG). In the intent-to-treat analysis, ISIS-GCGRRx provided statistically significant A1c reductions (ranging from -1.3% to -2.0%) vs. placebo (0.16%). Indeed, a relatively high percentage (ranging from 48-75%) of patients in the ISIS-GCGR groups achieved an A1c of ≤7% (for comparison, only 13% of the control group reached this goal).
• According to Dr. Robert Henry (University of California, San Diego, CA), during the event, 20% of people with type 2 diabetes have an A1c >9% (and 12% have an A1c >10%). Additionally, he noted than 50% of people on a combination of oral agents are failing treatment, as is 30-40% of people on an OAD and either insulin or a GLP-1, and 10-20% of people on insulin and a GLP-1.

-- by Adam Brown, Hannah Deming, Jessica Dong, Katherine Sanders, Joseph Shivers, Jenny Tan, Manu Venkat, Alasdair Wilkins, and Kelly Close