<i>Journal of Diabetes</i> NEWS

Approximately 17 300 physicians, diabetes educators, industry professionals, and researchers attended the American Diabetes Association (ADA) Scientific Sessions, 25–29 June 2010, at the Orange County Convention Center (Orlando, FL, USA), an increase of 15% from last year. As usual, the 5-day conference was a massive affair, consisting of eight tracks, 170 exhibits, and 2441 oral and poster sessions. Attendees gathered to hear analyses from large-scale clinical trials, as well as the latest results with new therapies and technologies. Certain drugs, such as the incretin therapies and the sodium–glucose cotransporter (SGLT)-2 inhibitors, continued to be areas of focus, with progress on continuous glucose monitoring (CGM) and the artificial pancreas also highlighted (http://professional.diabetes.org/Presentations_Details.aspx?typ=1&sr=adv&cng=116&meeting=116, accessed June 2010). The discussion presented by ADA President, Medicine & Science, Richard M. Bergenstal, MD (International Diabetes Center, Park Nicollet, MN, USA), on the Sensor-Augmented Pump Therapy for A1c Reduction (STAR 3) trial was fascinating. This 1-year trial included 485 Type 1 patients, ranging in age from 7 to 70 years, who had been on multiple daily injections (MDI) but not on pump therapy within the previous 3 years. Patients were randomized to MDI therapy with Carelink (the Medtronic blood glucose, insulin dose, and carbohydrate intake web-based data analysis program; n = 241) or to sensor-augmented pump (SAP) therapy using the same database (n = 244). At baseline, the two study arms were well matched for age (mean ∼32 years), duration of diabetes (mean ∼15.3 years), weight (mean ∼72.5 kg), body mass index (BMI; mean ∼25.5 kg/m2), and A1c (mean 8.3%), with all mean values reported applying to the adult group only. Patients were introduced to SAP therapy over five sessions in 5 weeks and to MDI over two sessions. Patients on MDI were assessed with retrospective blinded CGM at 6 and 12 months. Looking at the entire patient population, A1c was lowered 0.8% in the SAP treatment arm and 0.2% for patients on MDI, for an absolute difference of 0.6% improvement in the SAP group. In patients wearing the sensor more than 80% of the time, A1c was reduced 1.2%. When data from the adult population only was considered, a reduction in A1c of 1.0% was achieved in the SAP group, compared with a reduction of 0.4% in the MDI group, giving an absolute difference of 0.6% to the advantage of SAP therapy. Pediatric patients achieved a 0.4% reduction on SAP and an increase of 0.2% on MDI, giving an absolute difference of 0.5%. In the pediatric population, 44% of those on SAP therapy achieved ADA A1c goals, whereas only 20% were able to achieve glycemic goals on MDI. Benefits were achieved within 3 months of use and sustained throughout the 1-year treatment period. The rate of severe hypoglycemia did not differ significantly between the two groups and was just below 13.5 per 100 patient years (compared with 62 per 100 patient years in the Diabetes Control and Complications Trial1). The incidence of diabetic ketoacidosis was low and did not differ between the two groups; in addition, there was no significant difference in weight change between the two groups (a gain of ∼2.4 and 1.8 kg in the SAP and MDI groups, respectively). A 6-month extension study with 396 patients was recently completed and we look forward to seeing these follow-up data in the future. Allison Cohen, MD (Joslin Diabetes Center, Boston, MA, USA), extensively reviewed the clinical data on glucagon-like peptide (GLP)-1 agonists suggesting that these drugs may have cardiovascular benefits. In particular, she showed that exenatide twice daily (b.i.d.), exenatide once weekly (q.w.), and liraglutide all improved blood pressure levels in the Diabetes Therapy Utilization: Researching Changes in A1c, Weight, and Other Factors Through Intervention with Exenatide Once Weekly (DURATION) 1–3 and Liraglutide Effect and Action in Diabetes (LEAD) 1–6 trials. Exenatide b.i.d. was shown to reduce central pulse pressure independently of weight loss and glycemia. The GLP-1 agonists had variable effects on lipids but, in general, seemed to reduce total cholesterol and fasting/postprandial triglycerides. Some, but not all, studies analyzed demonstrated that the drugs improved endothelial function. Dr Cohen also cited small human studies showing improvement in left ventricular ejection fraction after acute myocardial infarction,2 as well as in patients with congestive heart failure.3 When queried during the Question-and-Answer session, Dr Cohen concluded that the evidence is currently very promising that the GLP-1 agonists may have a beneficial effect on cardiovascular disease, in particular because they reduce blood pressure. However, she cautioned that more studies are needed to further characterize the cardiovascular effects of these drugs as well as to provide an understanding of their mechanism(s) of action. We look forward to the results of the long-term cardiovascular outcomes trials Exenatide Study of Cardiovascular Event Lowering Trial (EXSCEL) and Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER), which will examine the effects of exenatide q.w. and liraglutide, respectively. Ralph A. DeFronzo, MD (The University of Texas Health Science Center, San Antonio, TX, USA), reviewed the results of the Actos Now for Prevention of Diabetes (ACTNOW) trial, with new analyses on predictors of conversion to diabetes. The ACTNOWtrial examined the effect of pioglitazone treatment on conversion to diabetes in individuals with impaired glucose tolerance (IGT), finding a robust 70% decline in the conversion to diabetes relative to placebo over a mean of 2.8 years follow-up. New analyses indicated that β-cell function improved significantly over the course of pioglitazone treatment (as measured by ΔI0–120/ΔG0–120 × Matsuda Index; Matsuda Index values of 3.4–5.4) compared with no change in the placebo group, implying an absence of insulin resistance. (Note, the Matsuda Index was introduced by Dr Masafumi Matsuda and Professor Ralph A. DeFronzo in 1999 as an index to monitor physiological insulin sensitivity from oral glucose tolerance test data. Patients who do not have insulin resistance are said to have Matsuda Index values of 2.5–3 or higher, depending on the study used. More information can be found at http://mmatsuda.diabetes-smc.jp/MIndex.html (accessed September 2010).) Subanalysis showed that improvement in b-cell function was the strongest predictor of diabetes prevention. Dr DeFronzo suggested that IGT subjects with low b-cell function could be targeted for early pharmacologic intervention with pioglitazone to prevent the onset of diabetes. However, Dr DeFronzo noted that the beneficial effects of pioglitazone treatment were lost in the following 6-month washout period, causing rates of progression to diabetes to return to untreated levels. As such, we note that although the cumulative incidence of diabetes decreased in treated patients, patients would require lifelong treatment to sustain benefit. We must learn whether adverse events were observed during the trial to ascertain the feasibility of this intriguing approach. Alberto O. Chavez, MD (The University of Texas Health Science Center, San Antonio, TX, USA), presented early results with exenatide/pioglitazone combination therapy. In the open-label trial, 25 patients were randomized to receive 10 μg exenatide b.i.d., 45 mg pioglitazone, or a combination of both for 24 weeks. At the end of the trial, combination-treated patients demonstrated significantly greater declines in A1c (–1.5% with pioglitazone, –1.3% with exenatide, and –1.8% with the combination; from baseline 8.3%); as expected, exenatide-treated patients demonstrated the most favorable change in weight (–2.5 kg; baseline BMI 33 kg/m2), whereas combined use attenuated the weight gain seen in pioglitazone-treated patients (+2.5 kg (baseline BMI 34 kg/m2) vs. +5 kg (baseline BMI 36 kg/m2)). The disposition index, a measure of background β-cell function, with medication withheld at final analysis was 1.75-fold increased with exenatide, 1.83-fold greater with pioglitazone, and 2.5-fold greater with the combination. Although the marginal additional benefit in β-cell function appeared to disappoint the audience, the small sample size complicates interpretation and larger-scale trials will be required to determine whether the incremental benefit in the long term will justify the potentially high cost of treatment. John Wilding, DM, FRCP (University Hospital Liverpool, Liverpool, UK), presented data from a Phase 3 study of the SGLT-2 inhibitor dapagliflozin as an add-on therapy to high doses of insulin plus two or fewer oral antidiabetic drugs (OADs). The trial randomized 807 Type 2 diabetes patients inadequately controlled on at least 30 units insulin daily (plus up to two OADs) to receive placebo (n = 193) or 2.5 mg (n = 202), 5 mg (n = 211), or 10 mg (n = 194) dapagliflozin daily for 24 weeks. At baseline, patients were, on average, obese (BMI 33 kg/m2) with a relatively long duration of diabetes of 13.6 years, an A1c of 8.5%, fasting plasma glucose (FPG) of 177.6 mg/dL, and a mean insulin dose of 77 units (patients were treated with insulin for an average of 6 years). Approximately half the population was on insulin alone and approximately 40% received insulin plus metformin. Patients experienced a mean decrease in A1c of 0.30% for placebo and 0.75%, 0.82%, and 0.90% for the 2.5, 5, and 10 mg doses of dapagliflozin, respectively, after 24 weeks of treatment (from baseline A1c values of 8.5%, 8.6%, 8.6%, and 8.6%, respectively). Patients on dapagliflozin also lost weight over the 24-week period (+0.02 kg in the placebo group vs. –0.98, –0.98, and –1.67 kg in the 2.5, 5, and 10 mg dapagliflozin groups, respectively). There were no increased rates of serious adverse events in the dapagliflozin group compared with placebo; the most commonly report adverse events were nasopharyngitis, urinary tract infection (UTI), and hypertension. Events suggestive of genital infection and UTI were considerably increased across all dapagliflozin-treated arms compared with placebo (in women, approximately 4% of those receiving placebo; but in the dapagliflozin arms between 6% and 14%). Roman Hovorka, PhD (University of Cambridge, Cambridge, UK), gave a whirlwind review of his work in overnight closed loop studies in children and adults with Type 1 diabetes. According to Dr Hovorka, most severe hypoglycemia occurs at night in adults, as well as in children. He went on to review data from his Artificial Pancreas Project at Cambridge (APCAM01 and APCAM03) studies in 17 children of closed loop treatment compared with continuous subcutaneous insulin infusion after a medium-sized meal and after early evening exercise, and his closed loop studies in 24 adults after an evening meal and after an evening meal with alcohol. Children ranged in age from 5 to 17 years < ¼ while adults ranged in age between 18 and 65 years. The average BMI for children and adults was 21 and 26 kg/m2, respectively. Baseline A1c was, on average, 8.5% in the pediatric group and 7.8% in the adult group, with an average duration of diabetes of 6 years for the young patients and 20 years for the older patients. The algorithm targeted a range of 70–140 mg/dL for blood glucose. The closed loop system significantly lowered overnight average glucose (126 vs. 146 mg/dLin control), standard deviation of glucose (29 vs. 43 mg/dL in control), and time spent below 70 mg/dL (2.1% vs. 4.1% in control). We found the breakdown of time in discrete ranges of glucose values most intriguing; for glucose <50, 51–70, 71–145, and >146 mg/dL, the closed loop group spent 0.0%, 3.0%, 77.0%, and 22.0% in each range, respectively, compared with control values of 4.0%, 14.0%, 47.0%, and 35.0%, respectively. Near the conclusion of his talk, Dr Hovorka addressed regulatory concerns about the device, noting that the closed loop model in his studies improved the risk of blood glucose <35 mg/dL by over 2000-fold, the risk of being <45 mg/dLby 200-fold, and the risk of being >300 mg/dL by 200-fold. In a packed auditorium, Steven E. Nissen, MD (Cleveland Clinic, Cleveland, OH, USA), led off the debate on the US Food and Drug Administration’s (FDA) newly updated cardiovascular guidelines4 with a compact and quite negative assault on blood glucose as ‘the’ clinical marker in diabetes. The insufficiency of blood glucose as a surrogate marker for cardiovascular risk, he suggested, was demonstrated with muraglitazar (dual peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonist; discontinued in 2006), which showed strong improvements in A1c, triglycerides, and high-density lipoprotein levels, but was shown to double the risk of cardiovascular events,5,6 reinforcing the need for heightened cardiovascular outcomes requirements despite potentially positive signals in early clinical trials. Moving to the Diabetes Reduction Assessment with ramipril and rosiglitazone Medication trial (DREAM), he stated that diabetes was prevented but that there was a 1.37-fold increase in cardiovascular disease with rosiglitazone.7 He suggested that ‘glucocentricity’ led us to overlook cardiovascular disease as the leading cause of death in diabetes and led to a ‘50-year gap’ in our understanding of the cardiovascular risk of many drugs. Later, he characterized the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) trial8 as ‘a sloppy mess’ (citing its open-label and unblended design, 50% dropout, conclusions confounded by the cross-over design, and published interim analysis). He stated that the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study9 had a similar patient population at baseline yet showed a threefold increase in the risk of cardiovascular mortality (although myocardial infarction events actually decreased). Overall, Dr Nissen suggested that with multiple classes of diabetes drugs on the market, the US FDA was justified to risk innovation in order to promote cardiovascular outcomes as a critical measure of efficacy in the evaluation of diabetes drugs. Former US FDA Director of the Division of Metabolism and Endocrinology Products, David G. Orloff, MD (Medpace, Cincinnati, OH, USA), provided a cerebral argument against the ‘one-size-fits-all’ design of US FDA’s updated cardiovascular guidelines. Given the ‘protean nature’ of Type 2 diabetes, he suggested that regulatory standards should be flexible and evolve to best address the most relevant potential adverse outcomes of a drug candidate. He implied that although there were more drug classes today to fight diabetes, many have problems related to tolerability, so patients do not have as many alternatives as Dr Nissen implied, and more alternatives are needed given that patients are doing quite poorly in the US overall (44% not at their glycemic target).6,10 Overall, although Dr Orloff noted that the new requirements would increase the cost of clinical trials (potentially translating to increased medical costs for patients), he suggested his argument was more for proper resource allocation; given the agency’s ability to influence enthusiasm for certain areas of research, he cautioned that there is a point when cost and risk become prohibitive for companies and resources begin to ‘flow elsewhere’. Bernard Zinman, MD (University of Toronto, Ontario, Canada), presented results from a Phase 2 proof-of-concept study of the investigational ultra long-acting insulin analog insulin degludec. In the open-label 16-week trial, 183 patients with Type 2 diabetes were randomized to receive insulin degludec once daily (q.d.), insulin degludec three times weekly (3W; dosed Monday/Wednesday/Friday), or insulin glargine q.d., in combination with background metformin therapy. At the end of treatment, A1c decline (baseline = 8.7%) was similar across the study arms at –1.3% in the insulin degludec q.d. arm, –1.5% in the insulin degludec 3W arm, and –1.5% in the insulin glargine arm. Changes in fasting plasma glucose levels (baseline = 184 mg/dL) were also similar across treatment groups: –65 mg/dL for degludec q.d., –75 mg/dL for degludec 3W, and –61 mg/dL for glargine. Rates of hypoglycemia (based on a relatively low definition of <56 mg/dL) were lower in the insulin degludec q.d. arm (0.6 events/patient year) compared to the 3W and insulin glargine arms (2.3 and 1.1 events/patient year, respectively), although the differences did not reach statistical significance. Weight gain results were not reported, although management said all treatments were weight neutral given the short duration of the trial. Rates of adverse events were similar between treatment groups, with 47% reporting at least one adverse event in the degludec q.d. arm, 50% in the 3W arm, and 66% in the glargine arm. We will look forward to more data on this front.

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