Bites of Southern Food with Jazz: A Report from the 69th Scientific Sessions of the American Diabetes Association

INTRODUCTION

New Orleans, or Nawlins as the locals like to pronounce it, was the site of this year’s ADA meeting. A very liberal city overloaded with good but over-abundant food, easy-to-get drinks (so many hurricanes offered along Bourbon Street), and many of the lifestyle factors that carry an important and significant cardiovascular risk and, over the time, a risk for acquiring type 2 diabetes. However, New Orleans also offers the opportunity to walk around and explore neighborhoods such as the French Quarter, and walking has definite benefits both for preventing type 2 diabetes and for helping control the metabolic profiles of patients with the disease. Just as an example, a study discussed during the meeting this year revealed improvements in cardiac function and metabolic profile with moderate physical training (combined with a low glycemic and insulinemic diet) despite reducing use of antidiabetic therapy by 70% [Von Bibra, H. et al., Abst 372-OR], while further lifestyle interventions, these in China and Japan, were able to more than halve the incidence of severe retinopathy for up to 14 years, although without a major impact on nephro- or neuropathy [Gong, Q. et al., Abst 97-OR] and prevent progression to metabolic syndrome in patients with pre-metabolic syndrome [Yamashiro, T. et al., Abst 1056-P]. Furthermore, a major Diabetes Prevention Program (DPP) lifestyle curriculum proved feasible for recruiting and retaining participants at high risk for diabetes and/or cardiovascular disease, offering opportunities for risk-modifying, life-saving lifestyle intervention through diabetes educators [Amundson, H.A. et al., Abst 43-OR]. With specific guidelines available for the management of hypertension and dyslipidemia in type 2 diabetes [Shah, N.D. et al., Abst 42-OR], these approaches should markedly improve life expectancy, quality of life and health status of patients with or at risk for diabetes and prediabetes, and in fact, according to the ICAN program, lifestyle interventions fully return on the investment or even offer gains [Wolf, A.M. et al., Abst 169-OR]. Moreover, lifestyle interventions were shown effective for preventing type 2 diabetes, as per results of the PREDIAS program in the obesity-prone country of Germany [Kulzer, B. et al., Abst 1856-P]. Furthermore, available epidemiological data suggest improvements in risk control, at least in the U.S., where patients developing type 2 diabetes now have a better prognosis than in the past [Hoerger, T.J. et al., Abst 41-OR]. However, increasing therapeutic concerns have resulted in greater use of polypharmacy, especially in the elderly, and this practice has been related with an increased risk for hypoglycemia, cognitive dysfunction and poor nutritional status [Segal, A.R. et al., Abst 562-P].

These observations open hope for better prevention of diabetes and control of risk in established diabetes. However, according to a novel meta-analysis of randomized controlled trials presented as a poster during the meeting, there is a strong positive association between hemoglobin A1c levels and macrovascular complications in diabetes, which are the cause of 75% of all casualties, calling for intensive glycemic control with pharmacological intervention [Chen, H. et al., Abst 704-P]. Indeed, insulin, antidiabetic drugs and additional medications are still a requirement for the vast majority of patients, and new treatments based on known or novel therapeutic targets are evolving into ever more powerful evidence-based therapies to fight off the serious consequences of diabetes. The role of these medications is summarized in the following report, which is aimed at accompanying the abstracts of individual presentations at the meeting available through the meeting abstract section of this website (www.diabetes.org/pro) and further detailed information available in other information platforms such as Timely Topics in Medicine (TTMed.com), DailyDrugNews.com and other providers.

DIET, LIFESTYLE AND DIABETES

Although not a pharmacological therapy, diet is an important part of all management programs for diabetes, with impact not only on the control of the disease but also in the risk of acquiring it in the population at risk. Indeed, part of the risk of developing diabetes is diet itself. Some new information regarding this issue was discussed this year in New Orleans, including the IRAS study, which revealed a relationship between whole or refined grain intake and C-reactive protein levels, but not between refined grain intake and fibrinogen or plasminogen activator inhibitor-1 levels, whereas in the case of total fiber from whole grain, increased intake was related with reductions of all three contributors to atherosclerosis and type 2 diabetic cardiovascular disease [Masters, R.C. et al., Abst 284-OR; Masters, R.C. et al., Abst 959-P]. Another interesting observation is that lower potassium levels are associated with insulin resistance markers and increased risk for developing diabetes [Chatterjee, R. et al., Abst282-OR].

However, diet is not the only factor, and in addition to lifestyle interventions already mentioned in the introduction, a number of additional studies and observations demonstrated the benefits of intensive lifestyle education and management for improving the life of patients with type 2 diabetes. In that sense, the AHEAD study demonstrated that through lifestyle intervention it is possible to reduce C-reactive protein and chronic subclinical inflammation in obese individuals [Belalcazar, L.M. et al., Abst 694-P].

INSULIN AND INSULIN ANALOGS

Insulin therapy

Relatively little major news was reported on the use of natural insulins in the treatment of diabetes. Results were presented from a comparative trial demonstrating better control of oxidative stress and preservation of endothelial function with prandial recombinant human insulin compared to regular insulin or insulin lispro [Forst, T. et al., Abst 1304-P], a study that demonstrated high patient acceptability and gains in quality of life upon initiation of intensive insulin therapy early in the course of type 2 diabetes, with secondary benefits in preserving ?-cell function [Opsteen, C. et al., Abst 1855-P], a further trial in which comparable glycemic control was attained by intensive insulin therapy compared to oral treatment with metformin, pioglitazone or glipizide [Joya, J. et al., Abst 654-P], and the RABBIT study, in which basal/bolus insulin arose as the preferred option for in-hospital management of diabetic patients undergoing surgical procedures [Smiley, D. et al., Abst 571-P], although other studies reported efficacy for management of hyperglycemia in hospitalized patients treated with continuous 3% subcutaneous insulin infusion [Brea, E. & Mario, R.E., Abst 1979-P]. On the other hand, initiation of insulin was not associated with deterioration of patient satisfaction or quality of life [Legendre, J.L. et al., Abst 577-P], but according to some observations insulin alone fails to achieve target hemoglobin A1c levels [Elizabeth, B. et al., Abst 531-P]; predictors of reaching target hemoglobin A1c levels during insulin therapy were analyzed as a means for improving therapeutic planning, and were found to include baseline hemoglobin A1c levels, body mass index, dose of insulin and glycemic response at 8-12 weeks [Peters, A.L. et al., Abst 568-P]. In addition, a number of experimental insights into the pros and cons of insulin therapy were discussed, including a study that demonstrated that acute but not chronic insulin replacement restores glucokinase regulation [Kim, K. et al., Abst 1276-P], and a specific assessment of patients’ perceptions of insulin, in which prandial injection consistently fared less favorably than biphasic or basal regimens [Farmer, A.J. et al., Abst 487-P].

Continuous subcutaneous insulin infusion

Insulin pump treatment has been considered usually more effective than injection regarding glycemic control and hemoglobin A1c levels in patients with type 1 or 2 diabetes [Kinney, G.L. et al., Abst 1006-P; Jankovec, Z. et al., Abst 1991-PO], with glycemic improvements increasing with more prolonged time of use [Wilkinson, J.L. et al., Abst 1788-P]. Insulin pump treatment also showed potential for improving glycemic control in patients with type 2 diabetes [Edelman, S.V. et al., Abst 428-P] and in adolescents with newly diagnosed type 1 diabetes, in whom improvements in insulin resistance and ?-cell function were noted [Fox, L. et al., Abst 2468-PO]. Overall, insulin pumps were well accepted by patients [Samarasinghe, Y.P. et al., Abst 1990-PO], and compared to basal insulin glargine, continuous subcutaneous insulin infusion provided superior glucose control in a cohort of patients with type 1 diabetes, although without differences between the two strategies regarding glucose variability and a nonsignificant trend towards increased risk of hypoglycemia [Bragd, J. et al., Abst 229-OR]. Furthermore, continuous subcutaneous insulin infusion during pregnancy significantly reduced the risk of negative pregnancy outcomes, although with an increased risk for weight gain in both mother and offspring [Cyganek, K. et al., Abst 1814-P]. Nevertheless, it should be noted that independent studies identified a time lapse between starting subcutaneous insulin infusion and reaching a pharmacodynamic steady state, so that adjustments need to be carefully considered [Heinemann, L. et al., Abst 230-OR].

Over the long term, continuous subcutaneous insulin infusion may also offer some advantages in the management of type 2 diabetes, including improvements in the insulinogenic index and the proinsulin:insulin ratio [Noh, Y.H. et al., Abst 231-OR].

Inhaled insulins

While additional studies confirmed the glycemic benefit of inhaled human insulin [Heise, T. et al., Abst 2054-PO], the novel inhaled formulation Technosphere® insulin proved superior to oral therapy in terms of health-related quality of life and patient satisfaction [Peyrot, M. & Rubin, R.R., Abst 552-P], prevented the deterioration in health-related quality of life perceived by patients as compared to basal rapid-acting insulin [Rubin, R.R. & Peyrot, M., Abst 1881-P], and resulted in earlier, faster activity than insulin lispro or standard inhaled insulin in a further study [Potocka, E. et al., Abst 232-OR] (Fig. 1), with favorable patient acceptance and satisfaction [Howard, C.P. et al., Abst 551-P] and pharmacokinetic bioequivalence when comparing the same total dose administered as a single or divided doses [Cassidy, J.P. et al., Abst 425-P]. Rapid absorption in the lungs was demonstrated in further pharmacokinetic assessments, without pharmacokinetic alterations in patients with chronic obstructive pulmonary disease, although a portion of the agent was eliminated through proteolysis and ciliary clearance [Cassidy, J.P. et al., Abst 433-P; Potocka, E. et al., Abst 437-P]. Both combined with insulin glargine, this inhaled insulin offered comparable reductions of hemoglobin A1c with less weight gain and risk of hypoglycemia than rapid-acting insulin analogs [Bergenstal, R.M. et al., Abst 479-P]. In addition, no differences in lung function were noted between diabetes patients on inhaled Technosphere® insulin and usual antidiabetic therapy [Amin, N. et al., Abst 570-P].

Fig. 1. Time to endogenous glucose production suppression after a meal in patients receiving inhaled Technosphere® or standard (Exubera®) insulin or subcutaneous insulin lispro [Potocka, E. et al., Abst 232-OR].

Oral insulins

While absorption and retention of activity were demonstrated with oral insulin intake in patients with type 2 diabetes [Kidron, M. et al., Abst 434-P], buccal insulin spray was suggested effective for controlling postprandial hyperglycemia in subjects with oral glucose intolerance in a randomized, dose-finding study [Palermo, A. et al., Abst 233-OR]. According to a placebo-controlled trial, premeal administration of oral hepatic-directed vesicle insulin was safe and well tolerated, and markedly lowered postprandial glucose levels [Geho, B. et al., Abst 424-P]. A further oral insulin, IN-105, was associated with favorable responses and a therapeutic index superior to that of injected insulin in patients poorly controlled on metformin [Iyer, H. et al., Abst 442-P].

Novel insulins and insulin formulations

Beneficial properties were described for a number of novel insulin products during this year’s ADA meeting, including PC-DAC-based insulin, offering long-lasting activity with very low variability [Thibaudeau, K. et al., Abst 435-P] and percutaneous insulin, the high safety and therapeutic potential of which were commented [Ito, Y. et al., Abst 431-P].

Insulin analogs

Among the rapid-acting insulin analogs, insulin glulisine showed a faster onset of action than insulin aspart, with greater metabolic activity shortly after injection [Arnolds, S. et al., Abst 528-P; Bolli, G.B. et al., Abst 555-P], and was reported effective in the real-life clinical practice [Bouter, K.P. et al., Abst 2061-PO]; however, insulin aspart showed moderately better metabolic control, safety and patient satisfaction compared to human insulin in a systematic review and pooled analysis of published evidence [Rys, P. et al., Abst 449-P]. Biphasic insulin aspart showed efficacy in the IMPROVE and other trials [Esteghamati, A. et al., Abst 2012-PO; Gao, Y. et al., Abst 2013-PO; Gerö, L. et al., Abst 2051-PO; Esteghamati, A. et al., Abst 2050-PO; Landin-Olsson, M. et al., Abst 2056-PO; Shah, S. et al., Abst 2078-PO; Milenkovic, T. et al., Abst 2083-PO; Schroner, Z. & Uliciansky, V., Abst 2085-PO; Yang, W. et al., Abst 2089-PO] (with lower dose needs in Asian compared to non-Asian subjects [Valensi, P. et al., Abst 2068]) and was non-inferior to insulin glargine, with similar patient satisfaction rates, but incurred a higher risk for nocturnal hypoglycemia [Strojek, K. et al., Abst 546-P], but basal bolus insulin glargine/insulin glulisine may offer equiefficacy compared to biphasic insulin aspart at a lower cost [Vora, J.P. et al., Abst 451-P]. According to the IMPROVE trial, predictors of response to biphasic insulin aspart included shorter duration of diabetes, older age and lower baseline hemoglobin A1c levels, fasting plasma glucose and body mass index [Valensi, P. et al., Abst 567-P]. However, consider also that the in vitro stability of insulin aspart was deemed sufficient to allow continuous subcutaneous infusion [Senstius, J. et al., Abst 432-P], and intravenous in-hospital administration offers an alternative for urgent recovery from severe hyperglycemia [Udwaia, F. et al., Abst 2062-PO].

Pooled clinical trial data analyses demonstrated the superiority of insulin glargine over subcutaneous human insulin for lowering hemoglobin A1c levels in older subjects with type 2 diabetes [Lee, P.G. et al., Abst 576-P] and individual trial data suggested better glycemic and lipid control than thiazolidinediones [Hollander, P. et al., Abst 2034-PO; Meneghini, L.F. et al., Abst 2035-PO; Rosenstock, J. et al., Abst 2094-PO], superiority over subcutaneous insulin in women with gestational diabetes [Negrato, C.A. et al., Abst 2489-PO] and optimal results with basal-bolus insulin glargine combined with insulin glulisine [Fritsche, A. et al., Abst 2087-PO; Lankisch, M. et al., Abst 2086-PO], while mechanistic results demonstrated hepatic specificity with minimal effect on glucose flux, which explain the low risk for hypoglycemia with this insulin analog [Wang, Z. et al., Abst 559-P]. Although requiring higher insulin doses than insulin detemir to attain the same degree of reduction of hemoglobin A1c [Dailey, G. et al., Abst 480-P] (Fig. 2), at comparable hemoglobin A1c-lowering activity, insulin glargine showed markedly reduced rates of microvascular events during the treatment of type 2 diabetes [Fonseca, V.A. et al., Abst 23-LB], and as monotherapy effectively controlled glycemia and the first-phase insulin response in newly diagnosed type 2 diabetes patients [Zeng, L. et al., Abst 512-P]. Real-world data also suggested superiority of insulin glargine over insulin detemir in lowering hemoglobin A1c levels throughout one year of treatment [Blonde, L. et al., Abst 514-P] (Fig. 3), while retrospective data suggested no differences in the total daily insulin dose when using insulin glargine or insulin detemir [Luo, W. et al., Abst 1194-P]. Furthermore, a direct comparison in type 2 diabetes patients suggested greater reductions in hemoglobin A1c and reduced need for hospitalization with insulin glargine as compared to exenatide [Rosenstock, J. et al., Abst 515-P; Umpierrez, G.E. et al., Abst 2073-PO]. Insulin glargine-based treatment with metformin was described as a safe, effective regimen that can be combined with exenatide or sitagliptin if required [Arnolds, S. et al., Abst 526-P], and was related to improvements in postprandial oxidative stress [Bunck, M.C. et al., Abst 548-P]. Overall, insulin glargine combined with oral hypoglycemic therapies was able to reach equivalent glycemic control compared to biphasic insulin at a 30% lower cost [Owens, D. et al., Abst 527-P], with reduced healthcare expenditures also compared to exenatide [Herman, W.H. et al., Abst 2046-PO], resulting in additional benefits on emotional wellbeing [Hajos, T. et al., Abst 563-P] and being overall a cost-effective option for the treatment of type 2 diabetes [Evans, M. et al., Abst 2016-PO; Greiner, R.A. et al., Abst 2017-PO], with the added benefit of a lower risk for nocturnal hypoglycemia compared to regular insulin [Home, P.D. et al., Abst 2114-PO]. In addition, compared with subcutaneous insulin and insulin detemir, persistence with insulin glargine was better, resulting in marginal improvements in hemoglobin A1c [Gordon, J.P. et al., Abst 554-P]. However, insulin detemir remains an effective analog insulin option for the treatment of diabetes, as further demonstrated in the PREDICTIVE, LIGHT and other studies [Meneghini, L. et al., Abst 2008-PO; Némethyová, Z. et al., Abst 2025-PO; Kummaraganti, S. et al., Abst 2027-PO; Catrinoiu, D. et al., Abst 2029-PO; Tripathy, S. et al., Abst 2052-PO; Dimitrovski, C. et al., Abst 2084-PO], offering benefits on glycemic control and weight upon switch from regular human insulin [Martinka, E. & Lacka, J., Abst 2049-PO; Kesavadev, J. et al., Abst 2053-PO; Ramachandran, A. et al., Abst 2057-PO; Cokolic, M. et al., Abst 2058-PO; Hermansen, K. et al., Abst 2059-PO; Shestakova, M.V. & Glinkina, I.V., Abst 2060-PO; Hajos, T. et al., Abst 2088-PO; Fledelius, C. et al., Abst 2442-PO], and a trial in type 2 diabetes patients revealed equiefficacy of add-on insulin detemir compared to repaglinide/metformin with regular insulin in attaining glycemic control with improved cardiovascular risk profile [Liebl, A., Abst 524-P] (Fig. 4), and also in the case of type 1 diabetes in children and adolescents compared with subcutaneous regular insulin, although with a lower risk for hypoglycemia [Thalange, N.K.S. et al., Abst 1784-P]. On the other hand, besides improving glycemic control, intensive therapy with insulin detemir and insulin aspart improved nonalcoholic fatty liver disease in poorly controlled type 2 diabetes patients [Mathew, M. et al., Abst 532-P], and centrally administered insulin detemir induced body weight loss in experimental animals [Vasselli, J.R. et al., Abst 1533-P]. Furthermore, even via the subcutaneous route, insulin detemir was associated with attenuated weight gain in animal models of diet-induced obesity [Rojas, J.M. et al., Abst 1700-P].

Fig. 2. Doses of insulin required for 1% reduction in hemoglobin A1c in patients treated with insulin glargine or insulin detemir [Dailey, G. et al., Abst 480-P].

Fig. 3. Hemoglobin A1c levels at one year of treatment with insulin glargine or insulin detemir [Blonde, L. et al., Abst 514-P].

Fig. 4. Percent of patients reaching the target levels of hemoglobin A1c <7% after 12 or more months of treatment with insulin detemir or regular insulin, both combined with repaglinide and metformin [Liebl, A., Abst 524-P].

Combined use of rapid-acting (insulin glulisine, insulin aspart) and longer-acting (insulin glargine, insulin detemir) basal/bolus insulin therapy offers equivalent or better glycemic control compared to regular subcutaneous insulin, but at a lower risk for hypoglycemia [Umpierrez, G.E. et al., Abst 516-P] and, according to some studies, improved cardiovascular function [Von Bibra, H. et al., Abst 463-P]. In a specific case, insulin glulisine combined with insulin glargine resulted in better glycemic control than regular insulin, also with insulin glargine, in inpatients with type 2 diabetes or hospital-related hyperglycemia [Boron, A. et al., Abst 513-P].

In addition, note that according to a study in young patients with type 1 diabetes, mixing insulin lispro with insulin glargine results in flattened early pharmacodynamic response to insulin lispro, rightward shifting of the glucose response, which could limit the ability to control early post-meal glucose excursions [Cengiz, E. et al., Abst 19-OR].

BIGUANIDES

To the known benefits of metformin in the treatment of diabetes, which after the publication of the ADA/EASD guidelines for the treatment of diabetes resulted in increased overall prescription and use in the clinical practice [Huang, E.A. et al., Abst 2096-PO], new data described this year with the background sounds of jazz and blues indicated additional benefits in modestly but significantly reducing body weight, an effect maintained over at least 10 years of treatment in patients adhering to therapy [Bray, G. et al., Abst 286-OR]. The activity of metformin was further explored in two mechanistic studies that revealed suppression of hepatic gluconeogenesis and lowering of blood glucose through an effect on reactive nitrogen species [Fujita, Y. et al., Abst 303-OR] and improvements in skeletal myogenesis, hypertrophy and insulin resistance [Terruzzi, I. et al., Abst 566-P]. Furthermore, metformin offered improvements on dyslipidemia and metabolic parameters in pediatric obesity [Dall, T.L. et al., Abst 1767-P] and, in experimental diabetic animals, attenuated atherosclerosis [Zhang, M. et al., Abst 706-P]. However, some data suggested a high rate of low-normal to inadequate levels of cyanocobalamin during metformin therapy, cautioning against the risk of peripheral neuropathy [Braza, M. et al., Abst 569-P]. According to the Diabetes Prevention Program, metformin has limited activity against C-reactive protein and tissue plasminogen activator levels in patients with established diabetes, although with a lifestyle intervention program it did lower the levels of these markers in patients with or at risk for prediabetes [Goldberg, R., Abst 2160-PO].

Secondary failures were reported despite initial success with metformin in diabetes patients treated in the routine practice, with many patients requiring the addition of a second drug within the year, although such requirement could be delayed in patients starting metformin at earlier stages of the disease [Nichols, G.A. et al., Abst 46-OR].

Regarding novel experimental findings, metformin was shown to prevent isoprenaline-induced cardiac hypertrophy in experimental animals through an effect on interleukin-6, transforming growth factor-? and epithelial growth factor receptor kinase [Part, S.Y. et al., Abst 1750-P].

Gastrointestinal adverse events being the main tolerability concern of metformin, a glycinate derivative of the agent was developed that showed improved gastrointestinal tolerability and longer half-life than metformin in healthy volunteers [Garza-Ocañas, L. et al., Abst 2074-PO].

SULFONYLUREAS

While being a feasible initial option for the management of neonatal diabetes [Marshall, B.A. et al., Abst 590-P], the efficacy of sulfonylureas in the treatment of permanent neonatal diabetes resulting from KCNJ11 gene mutations was confirmed in a two-year observational study [Malecki, M.T. et al., Abst 1137-P]. In addition, experimental data suggested potential for nateglinide for stimulating glucagon-like polypeptide-1 release by L-cells through AMP-dependent potassium channel-independent mechanisms [Kitahara, Y. et al., Abst 1427-P] and, combined with sitagliptin, for suppressing triglyceride accumulation in the liver and improving insulin sensitivity [Mori, Y. et al., Abst 478-P]. In the laboratory, mitiglinide combined with miglitol normalized insulin responses and glucose excursions more effectively than mitiglinide alone in diabetic models [Itoh, Y. et al., Abst 491-P]. Also according to experimental studies, and at least in the case of glibenclamide, the efficacy of sulfonylureas may be superior in earlier stages of diabetes, whereas treatment in advanced disease may even result in worsening of the disease process [Remedi, M.S. & Nichols, C.G., Abst 1636-P]. However, tolbutamine, although not repaglinide or nateglinide, was shown to induce ?-cell apoptosis through an effect on protein kinase signaling [Ling, S. et al., Abst 2407-PO].

A-GLUCOSIDASE INHIBITORS

Only a scattering of clinical findings on a-glucosidase inhibitors were reported this year during ADA. Acarbose offered benefits on glycemic, metabolic and blood pressure profiles in patients with type 2 diabetes [Grzeszczak, W. & Wronka, M., Abst 2032-PO], improved blood glucose fluctuations and the risk of micro- and macrovascular complications [Rong, M.Y. et al., Abst 443-P] and was found as effective as nateglinide in improving postprandial glucose excursions in type 2 diabetes patients on optimized basal insulin glulisine therapy [Kwon, M.J. et al., Abst 565-P]. From a mechanistic viewpoint, it showed a comprehensive effect throughout the gastrointestinal tract, preventing transdifferentiation of mucosa cells, although not in patients with overt metabolic syndrome [Schmitz, G. et al., Abst 1122-P]. Both voglibose and miglitol reduced total 120-minute postprandial glucose AUC in patients with diabetes or impaired glucose tolerance, while only miglitol lowered 60-minute glucose load, which was related to improvements in hyperlipidemia and LDL particle size. However, none of the agents improved insulin resistance indices [Tsuchiya, M. et al., Abst 519-P]. On an independent basis, voglibose did not impair the pharmacokinetics or pharmacodynamics of sitagliptin when coadministered [Kato, Y. et al., Abst 609-P].

THIAZOLIDINEDIONES AND OTHER PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR AGONISTS

With an effect in enhancing glucose-induced insulin secretion and glucagon suppression even in nondiabetic subjects [Choi, E. et al., Abst 1463-P], improvements in LDL- and HDL-cholesterol, triglyceride and C-reactive protein levels and abdominal adiposity [McCall, T.B. et al., Abst 2213-PO; Takata, Y. et al., Abst 2218-PO; Moon, J.H. et al., Abst 2093-PO], a rejuvenation of ?-cells shifting towards earlier diabetes stages in patients with established but newly diagnosed, not pretreated diabetes [Kutoh, E., Abst 619-P] and benefits on glycemic and lipidic control in patients with micro- or macroalbuminuria [Shi, S.Y. et al., Abst 624-P], long-term reduction of carotid atherosclerosis progression was demonstrated with pioglitazone in placebo-controlled trials [Reaven, P.D. et al., Abst 15-LB] (Fig. 5). The agent also exhibited potential for attenuating endothelial dysfunction at equivalent glycemic potency compared to rosiglitazone and glipizide [Mishra, M. et al., Abst 493-P] and reduced the total medication burden of patients with type 2 diabetes [Shaqdan, W. & Abdulwahid, N.A., Abst 1999-PO]. However, in a comparison with glimepiride no differences in progression of coronary artery calcification were apparent [Davidson, M.H. et al., Abst 717-P]. Furthermore, the agent offered stable long-term glycemic activity [Lee, J. et al., Abst 2066-PO] and compared to metformin, pioglitazone increased pericardial and abdominal subcutaneous fat volume but decreased hepatic triglyceride levels [Jonker, J.T. et al., Abst 6-P], and showed no direct impact on postprandial fatty acid trafficking compared to glipizide [Basu, A. et al., Abst 1403-P]. In the same context, the thiazolidinedione reverted abnormalities in pro- and antiinflammatory marker expression in circulating monocytes of obese, diabetic individuals [Satoh, N. et al., Abst 339-OR], and according to the PIOace study, combined with ramipril offered improvements in low-grade inflammation in nondiabetic individuals with increased cardiovascular risk [Pfützner, A. et al., Abst 561-P] (Fig. 6). A fixed-drug combination of pioglitazone and metformin reportedly improved insulin resistance, glycemic control and C-reactive protein and adiponectin levels in type 2 diabetes [Perez, A. et al., Abst 2031-PO; Spanheimer, R. et al., Abst 2030-PO; Spanheimer, R. et al., Abst 2105-PO], and combinations of pioglitazone with insulin were feasible and therapeutically active in the clinical practice [Lundershausen, R. et al., Abst 2103-PO; Grueneberg, M. et al., Abst 2104-PO; Schoenauer, M. et al., Abst 2110-PO]. Furthermore, experimental results indicated an effect of pioglitazone in increasing islet neogenesis-associated protein expression [Pittenger, G.L. et al., Abst 2417-PO] and both pioglitazone and metformin/phenformin offered neuroprotection through inhibition of the mitochondrial permeability transition pore, but only the thiazolidinedione also prevented neuronal cell apoptosis through stimulation of the peroxisome proliferator-activated receptor-? [Okouchi, M. et al., Abst 656-P]. Response to pioglitazone showed pharmacogenomic associations with a number of markers, the strongest of which was rs1468322 single nucleotide polymorphism in the inward-rectifier potassium channel gene [Distefano, J.K. et al., Abst 1172-P]. As an additional issue, safe use of pioglitazone in patients with renal failure [Froehling, P.T. et al., Abst 2179-PO] or hepatitis B and/or C [Lin, K.D. et al., Abst 2047-PO] was documented, although thiazolidinediones in general showed untoward effects on brain natriuretic peptide levels [Shirabe, S. & Yamanouchi, T., Abst 2098-PO].

Fig. 5. Annual rate of change in the carotid intima-media thickness throughout 2 years of treatment with pioglitazone or placebo [Reaven, P.D. et al., Abst 15-LB].

Fig. 6. Change in adiponectin levels in nondiabetic patients at high cardiovascular risk receiving pioglitazone and/or ramipril [Pfützner, A. et al., Abst 561-P].

Improvements in insulin sensitivity and ß-cell function in obese adolescents [Cali, A. et al., Abst 1806-P] and rapid but reversible attenuation of high fat diet-induced inflammation and insulin resistance [Lu, W.J. et al., Abst 95-LB] were attained by treatment with rosiglitazone, with the agent, like pioglitazone, improving muscular insulin sensitivity independent of mitochondrial function, although both agents had divergent activity on mitochondrial content and function (decreased mitochondrial respiration during rosiglitazone but increased during pioglitazone treatment) [Rabol, R. et al., Abst 252-OR]. Moreover, addition of rosiglitazone to metformin was associated with reduced cost and fewer outpatient visits than addition of sulfonylurea, according to a retrospective analysis [Ma, L. et al., Abst 574-P]. Furthermore, analysis of the DREAM study results indicated that the improvements in insulin sensitivity and prevention of diabetes in prediabetic individuals can be attributed to improvements in ß-cell function [Hanley, A.J. et al., Abst 968-P], while confirming a reduction in visceral and hepatic fat content and an increase in adiponectin levels compared to placebo [Punthakee, Z. et al., Abst 1728-P]. In addition, rosiglitazone prevented fatty liver disease in experimental animal models through modulation of nuclear factors [Choi, E.A. et al., Abst 2441-PO]. However, rosiglitazone showed a cardiovascular protective effect apparently restricted to patients with shorter exposure to insulin, the effect being nonsignificant in patients with longer exposure [Wang, C.P. & Pugh, J., Abst 657-P].

On the other hand, despite reported increases in the risk of myocardial infarction in patients using thiazolidinediones, specifically rosiglitazone, a review of the data on 2,105 patients treated with metformin and either sulfonylureas, pioglitazone or rosiglitazone revealed no statistically significant differences in the incidence of death, or rather nonsignificant trends towards reduced mortality in patients using thiazolidinediones [Simpson, S.H. et al., Abst 1013-P] (Fig. 7). On the contrary, safety warnings and the consequent change in the pattern of use of thiazolidinediones resulted in poorer glycemic control, at least in older patients seen in a Veterans Administration facility [Shi, L. et al., Abst 17-P]. Bone loss after experimental ovariectomy was exacerbated by thiazolidinediones, but not sitagliptin [Kimmel, D.B. et al., Abst 1443-P], and a pooled analysis of clinical trials confirmed an increased risk for bone fractures during thiazolidinedione therapy [Aubert, R. et al., Abst 601-P]. On the contrary, periodontitis-related bone loss was attenuated by aldose reductase inhibition [Kador, P.F. et al., Abst 489-P].

Fig. 7. Death rates in patients receiving metformin combined with sulfonylureas, pioglitazone or rosiglitazone [Simpson, S.H. et al., Abst 1013-P].

Although not a thiazolidinedione, the selective peroxisome proliferator-activated receptor-? modulator INT-131 also showed potential as a glucose-lowering, insulin-sensitizing therapy for diabetes and insulin, but without the adverse events commonly associated with pioglitazone and rosiglitazone [Depaoli, A.M. et al., Abst 117-OR; Lee, D.H. et al., Abst 1306-P]. Also acting at least partially through peroxisome proliferator-activated receptor-? without being a thiazolidinedione, curcumin exhibited antidiabetic potential in experimental animal models [Mathews, S.T. et al., Abst 1301-P].

Regarding other agents acting on peroxisome proliferator-activated receptors, novel studies with the dual ?/? agonist aleglitazar confirmed beneficial effects on glycemic and lipidic control in patients with type 2 diabetes [Henry, R.R. et al., Abst 917-P, Liogier d’Ardhui, X. et al., Abst 924-P] (Fig. 8). A similar agent, ZYH-1 proved safe and well tolerated in phase I studies in healthy volunteers, and exhibited potential for improving lipid levels [Jani, R.H. et al., Abst 2206-PO; Patel, H. et al., Abst 2207-PO]. The pan-peroxisome proliferator-activated receptor agonist indeglitazar showed potential for improving insulin sensitivity and dyslipidemia in experimental animal models of obesity and insulin resistance [Perreault, M. et al., Abst 364-OR]. Also in the experimental setting, the dual peroxisome proliferator-activated receptor-d/? agonists DB-959 [Delmedico, M.K. et al., Abst 365-OR; Delmedico, M.K. et al., Abst 484-P] and DSP-8658 [Yamanaka, M. et al., Abst 1284-P] showed potential for improving metabolic abnormalities and HDL-cholesterol and triglyceride levels in experimental models of type 2 diabetes and dyslipidemia.

Fig. 8. Change in hemoglobin A1c, LDL-cholesterol and body weight after 16 weeks of treatment with aleglitazar, pioglitazone or placebo [Henry, R.R. et al., Abst 917-P].

INCRETIN-BASED THERAPIES

Incretin mimetics, analogs and agonists and incretin-degrading enzyme inhibitors have been developed for the treatment of diabetes, with the potential --at least in the experimental arena (but also confirmed in the clinical practice)-- for increasing ß-cell function and mass and reducing ß-cell apoptosis [Del Zotto, H.H. et al., Abst 2410-PO].

Glucagon-like polypeptide-1 analogs and agonists

With sustained effect on hemoglobin A1c, body weight, adiponectin levels and C-reactive protein [Kim, T. et al., Abst 159-OR; Christofides, E.A. et al., Abst 572-P; Bunck, M.C. et al., Abst 469-P], good tolerability [Bruce, S. et al., Abst 578-P; Iwamoto, k. et al., Abst 603-P] and no excess risk of pancreatitis compared to other antidiabetic therapies [Bloomgren, G. et al., Abst 158-OR], superior glycemic control with additional body weight reduction resulted from treatment with exenatide compared to maximum doses of sitagliptin or pioglitazone in DURATION-2, a 26-week trial in patients with type 2 diabetes presented as a Late Breaking contribution to this year’s ADA meeting in New Orleans. Patients were on stable metformin [Bergenstal, R. et al., Abst 6-LB], and compared to glibenclamide, both added to metformin, exenatide and the sulfonylurea improved glycemic control but only exenatide improved insulin resistance [Derosa, G. et al., Abst 500-P] (Fig. 9) (note that improvements in insulin resistance rather than enhanced ß-cell function were suggested as the main activity of exenatide in an open study [Preumont, V. et al., Abst 2042-PO]). Moreover, exenatide therapy was shown to bring about improvements in the cardiometabolic risk profile (blood pressure, lipid levels, hepatic enzymes) over one year of treatment [Bergenstal, R. et al., Abst 165-OR; Shen, L. et al., Abst 366-OR], without any negative impact on the QT interval duration [Linnebjerg, H. et al., Abst 597-P]. Furthermore, weekly treatment with exenatide improved hemoglobin A1c, body weight and the cardiometabolic profile across a wide range of body weights in additional studies [Okerson, T. et al., Abst 506-P; Hamdy, O. et al., Abst 539-P], and in fact exenatide was suggested as a feasible option for patients showing body weight gain during insulin therapy [Samarasinghe, Y.P. et al., Abst 530-P]. Add that in healthy subjects, exenatide induced unexpected glucose elevations during aerobic exercise, suggesting a very low risk of hypoglycemia during physical activity in diabetic individuals [Khoo, E.Y.H. et al., Abst 1079-P], and that a combination of exenatide and pioglitazone showed additional benefits on adiponectin levels, with synergistic benefit also on free fatty acid and triglyceride levels [Jogi, M. et al., Abst 615-P]. Also reported as late-breaking news during the meeting, continuous subcutaneous delivery of exenatide was validated as a strategy for lowering fasting and postprandial glucose in a phase Ib study [Luskey, K. et al., Abst 7-LB]. Furthermore, exenatide profoundly inhibited postprandial increases in triglycerides, which also contribute to vascular inflammation and atherosclerosis [Schwartz, E.A. et al., Abst 375-OR], and mechanistic studies in living animals and isolated hepatocytes revealed an effect in downregulating gluconeogenic gene expression and gluconeogenesis [Samson, S.L. et al., Abst 9-OR]. In addition, prandially administered exenatide showed also efficacy in lowering postprandial glycemia in young patients with type 1 diabetes [Raman, V. et al., Abst 20-OR]. However, although inducing an acute improvement of endothelial function after high-fat meals [Mullin, M.P. et al., Abst 640-P], administration of exenatide in experimental animals acutely increased blood glucose levels through activation of the sympathetic nervous system [Perez-Tilve, D. et al., Abst 508-P], and improved cholecystokinin- and cerulean-stimulated pancreatic enzyme secretion in normal animals [Smith, P. et al., Abst 1411-P], without impacting on amylase or lipase production after subchronic administration in further experimental studies in diabetic animals [Tatarkiewicz, K. et al., Abst 1438-P]. Other studies confirmed the anorectic effect of exenatide, but suggested it was independent from glucagon-like polypeptide-1 signaling, as the effect was not obtained with exogenous administration of glucagon-like polypeptide-1 even after inhibition of dipeptidyl peptidase-IV [Jessen, L. et al., Abst 1527-P]. New experimental insights into additional activities of exenatide revealed potential for preventing amyloid formation and improving ß-cell function and survival, at least in the in vitro setting [Ao, Z. et al., Abst 1577-P]. On the other hand, an extended half-life construct of exenatide containing a hydrophilic amino acid tail and coded VRS-859 was described and announced to be currently in clinical trials [Cleland, J.L. et al., Abst 1994-PO]. Another sustained-release exenatide product based on microsphere encapsulation exhibited favorable pharmacokinetics in experimental animals, thus suggesting potential for improving patient compliance, although this remains to be proven in clinical trials [Kwak, H.H. et al., Abst 2367-PO], and biological activity was reported with a further exenatide-angiopeptide conjugate with enhanced brain penetrability [Regina, A. et al., Abst 1997-PO].

Fig. 9. Change in the HOMA insulin resistance index after 9 months of treatment with exenatide or glibenclamide [Derosa, G. et al., Abst 500-P].

Sustained improvements in hemoglobin A1c and fasting plasma glucose levels and reductions in body weight also resulted from treatment with liraglutide, which over a two-year period proved superior to glimepiride in the treatment of type 2 diabetes [Garber, A.J. et al., Abst 162-OR; Matthews, D.R. et al., Abst 2064-PO] (Fig. 10) and proved equally effective and well tolerated regardless of the administration time [Kaku, K. et al., Abst 538-P]. Moreover, switch from exenatide to liraglutide was reported to improve glycemic control [Buse, J. et al., Abst 591-P]. The drug also lowered systolic blood pressure compared to placebo [Fonseca, V. et al., Abst 545-P] and was described as more effectively achieving a composite endpoint for hemoglobin A1c, systolic blood pressure and weight targets than other diabetes medications, based on the results of a meta-analysis [Zinman, B. et al., Abst 537-P] (Fig. 11). Furthermore, a comparative trial demonstrated significant superiority for liraglutide over glibenclamide in improving glycemia, insulin responses to meals, body weight and ß-cell function with a low risk for hyperglycemia [Seino, Y. et al., Abst 536-P; Kaku, K. et al., Abst 2371-PO], and additional comparative data suggested higher satisfaction and patient-perceived outcomes with liraglutide compared to exenatide [Schmidt, W.E. et al., Abst 1880-P] (Fig. 12). In addition, the smoother, less fluctuating pharmacokinetic profile of liraglutide compared to exenatide, which was demonstrated in a pharmacokinetic study in type 2 diabetes patients, was related to a lower risk for hypoglycemia and gastrointestinal adverse events [Rosenstock, J. et al., Abst 558-P], and the pharmacokinetic profile of subcutaneous liraglutide was unaffected by concomitant administration of sitagliptin [Nielsen, F.S. et al., Abst 2065-PO]. Trying to better define the role of liraglutide in therapeutics, a meta-analysis explored the relative benefits of add-on or switch to liraglutide, and demonstrated preference for the former [Nauck, M.A. et al., Abst 459-P]. In the experimental arena, both exenatide and liraglutide modulated gene expression in the pancreas, as well as pancreas mass, without increasing the risk for pancreatitis [Koehler, J.A. et al., Abst 9-LB; Herrera, V. et al., Abst 10-LB] (Fig. 13), and liraglutide induced ß-cell proliferation, prevented the antiproliferative effects of LDL, protected against interleukin-1ß-induced apoptosis [Rütti, s. et al., Abst 1592-P], delayed onset of diabetes and improved triglyceride levels in diabetic-prone animal models [Havel, P.J. et al., Abst 1408-P]. Add to this that liraglutide, but not vildagliptin, improved diabetes in Psammomys obesus, an animal model that closely resembles human type 2 diabetes with initial hyperinsulinemia concomitant with obesity and later hypoinsulinemia with hyperglycemia [Bodvarsdottir, T.B. et al., Abst 1425-P], a fact further supported by observations in obese individuals, in which liraglutide reversed indices of prediabetes [Finer, N. et al., Abst 1729-P]. To conclude, mechanistic data suggested that the protracted activity of liraglutide depended upon albumin binding, heptamer formation and dipeptidyl peptidase-IV stability, which resulted in delayed absorption and prolonged half-life [Knudsen, L.B. et al., Abst 2069-PO].

Fig. 10. Change in hemoglobin A1c levels after 16 weeks of treatment with liraglutide or glimepiride [Garber, A.J. et al., Abst 162-OR].

Fig. 11. Proportion of patients co-attaining hemoglobin A1c, systolic blood pressure and body weight targets after treatment with liraglutide and a variety of comparator antidiabetic medications [Zinman, B. et al., Abst 537-P].

Fig. 12. Proportion of patients satisfied with liraglutide or exenatide therapy according to the Diabetes Treatment Satisfaction Questionnaire scores [Schmidt, W.E. et al., Abst 1880-P].

Fig. 13. Change in hemoglobin A1c levels after 26 weeks of treatment with exenatide, sitagliptin or pioglitazone [Herrera, V. et al., Abst 10-LB].

Albiglutide, an additional long-acting glucagon-like polypeptide-1 receptor agonist, also improved glycemic control of diabetes with favorable tolerability and pharmacokinetic potential for biweekly maintenance [Rosenstock, J. et al., Abst 163-OR; Reusch, J.B. et al., Abst 461-P; Seino, Y. et al., Abst 581-P] (Fig. 14). Compared to biweekly and monthly regimens, as well as in comparison to exenatide, the 30-mg weekly regimen of albiglutide offered improved gastrointestinal tolerability in additional studies [Steward, M.W. et al., Abst 598-P].

Fig. 14. Percent of patients with fully controlled hemoglobin A1c (<7%) after one year of treatment with albiglutide, exenatide or placebo [Rosenstock, J. et al., Abst 163-OR].

With favorable safety and pharmacokinetics supporting weekly subcutaneous dosing [Barrington, P. et al., Abst 583-P], a novel glucagon-like polypeptide-1 analog, LY-2189265 proved effective in lowering hemoglobin A1c and fasting and postprandial glucose levels in patients with type 2 diabetes not adequately controlled by oral antihyperglycemic agents, without weekly titration impacting on the efficacy or safety profile [Umpierrez, G. et al., Abst 12-LB; Barrington, P. et al., Abst 161-OR] (Fig. 15). Another glucagon-like polypeptide-1 receptor agonist currently in development, lixisenatide also demonstrated benefits, with dose-dependent improvements in postprandial glucose, glucagon and insulin in type 2 diabetes patients undercontrolled with metformin [Rosenstock, J. et al., Abst 564-P] (Fig. 16), remaining safe without major pharmacokinetic deviations in patients with renal insufficiency [Lu, Y.H. & Ruus, P., Abst 557-P]. However, the agent altered the rate of absorption of concomitantly administered paracetamol or oral contraceptives, although without modifying total bioexposure [Liu, Y.H. et al., Abst 495-P]. Two further mimetics were described during the meeting: PF-04603629, which proved safe, well tolerated and pharmacodynamically active in type 2 diabetes patients, but increased heart rate and diastolic blood pressure [Gustavson, S.M. et al., Abst 497-P], and CJC-1134-PC, which safely lowered hemoglobin A1c levels and showed excellent gastrointestinal tolerability [Wang, M. et al., Abst 553-P].

Fig. 15. Change in hemoglobin A1c levels after 16 weeks of treatment with LY-2189265 (titrated every four weeks to the maximum specified doses) or placebo [Umpierrez, G. et al., Abst 12-LB].

Fig. 16. Change in two-hour postprandial glucose levels after 13 weeks of treatment with once- or twice-daily lixisenatide or placebo [Rosenstock, J. et al., Abst 564-P].

Developed as an alternative to injectable therapy, Technosphere®-based inhaled glucagon-like polypeptide-1 (MKC-253) induced insulin responses comparable to exenatide in nonsmokers with type 2 diabetes, but with faster responses and no major effect on gastric emptying, which was markedly delayed by exenatide [Baugham, R.A. et al., Abst 160-OR]. Pharmacodynamic modeling confirmed the activity of the agent on insulin, C-peptide, glucagon and glucose levels and gastric emptying [Costello, D.J. et al., Abst 445-P].

In the experimental arena, reductions in postprandial intestinal peptide responses in obese animals was demonstrated with taspoglutide, a novel glucagon-like polypeptide-1 analog with improved stability and potency and potential for weekly administration [Sewing, S. et al., Abst 323-OR; Sebokova, E. et al., Abst 594-P] that provided long-term glucose control in diabetic animal models [Sebokova, E. et al., Abst 593-P], while a further similar compound, ro1-GLP-1 reduced hemoglobin A1c levels and prevented excess body weight gain in models of type 2 diabetes [Wong, P.Y. et al., Abst 502-P].

Glucose-dependent insulinotropic polypeptide analogs

GIP1-42, a glucose-dependent insulinotropic polypeptide mimetic, demonstrated the ability to modulate production of proinflammatory cytokines and calcitonin peptides in adipocytes, suggesting potential in the setting of inflammation in obesity [Timper, K. et al., Abst 1359-P].

Dipeptidyl peptidase-IV inhibitors

Inhibition of dipeptidyl peptidase IV with drugs such as sitagliptin has shown correlation with improvements in glucose homeostasis in diabetes [Roy, R.S. et al., Abst 2373-PO]. Compared to placebo, sitagliptin offered activity as a treatment for type 2 diabetes in patients already in insulin therapy [Visboll, T. et al., Abst 588-P] (Fig. 17), with rapid reductions in glucose levels in the elderly [Barzilai, N. et al., Abst 587-P], and reduced total peptide YY and PYY3-36 whilst increasing PYY1-36 without effect on intact glucagon-like polypeptide-2 levels [Aaboe, K. et al., Abst 606-P]. Sitagliptin was non-inferior to the thiazolidinediones as third-line therapy for type 2 diabetes [Hsia, S.H. et al., Abst 544-P], was comparable overall to exenatide, both being superior to regular human insulin, in improving cardiovascular risk biomarkers [Horton, E.S. et al., Abst 611-P], and provided substantial glycemic benefits over the long term as monotherapy or in combination with metformin [Williams-Herman, D.E. et al., Abst 540-P], but had minimal, if any, effect in islet transplant recipients [Lagari-Libhaber, V. et al., Abst 542-P]. In addition, initial therapy with the fixed sitagliptin/metformin combination was superior to metformin alone regarding attainment of hemoglobin A1c target levels, but was associated with lower rates of abdominal pain and diarrhea [Reasner, C.A. et al., Abst 610-P] (Fig. 18). First-line therapy with sitagliptin plus pioglitazone also showed substantial improvements in glycemic control compared to pioglitazone monotherapy in a cohort of patients with type 2 diabetes, with favorable safety and tolerability [Yoon, K.H. et al., Abst 522-P] (Fig. 19). In the real world, sitagliptin seems to be well accepted, and is used especially in the management protocol of older patients with higher comorbidity burden [Zhang, Q. et al., Abst 2222-PO], and translated into improved body weight control comparable to exenatide and superior to regular insulin [Rosenstock, J. et al., Abst 2033-PO]. Mechanistic data confirmed the ?-cell-stimulating potential of sitagliptin in type 2 diabetes [Henry, R. et al., Abst 447], with improvement in ?-cell insulin-secreting capacity [Aaboe, K. et al., Abst 605-P], while studies in nondiabetic healthy volunteers demonstrated the activity of sitagliptin at enhancing insulin secretion and allowing increases in glucose infusion rate during hyperglycemic clamp [Migoya, E. et al., Abst 586-P]. Furthermore, sitagliptin, like exenatide, improved glucose homeostasis in experimental models of diet-induced insulin resistance [Massa, L. et al., Abst 616-P], and the dipeptidyl peptidase-IV inhibitor was reported safe in kidney transplant recipients, without negatively affecting immunosuppression [Odegaard, D. et al., Abst 2509-PO]. However, also in the experimental arena sitagliptin was related to ductal metaplasia, ductal cell turnover and pancreatitis [Matveyenko, A.V. et al., Abst 1601-P].

Fig. 17. Change in hemoglobin A1c levels during 24 weeks of add-on sitagliptin or placebo in patients on insulin with or without metformin [Vilsboll, T. et al., Abst 588-P].

Fig. 18. Percent of patients attaining target levels of hemoglobin A1c <7% after treatment for 18 weeks with sitagliptin/metformin or metformin monotherapy [Reasner, C.A. et al., Abst 610-P].

Fig. 19. Change in hemoglobin A1c levels during 24 weeks of first-line treatment with pioglitazone alone or combined with sitagliptin [Yoon, K.H. et al., Abst 522-P].

While also improving glycemic control with favorable tolerability [Defronzo, R.A. et al., Abst 547-P], low risk of hypoglycemia [Chen, R. et al., Abst 2082-PO] and no effect on the QT interval [Patel, C.G. et al., Abst 2072-PO], a meta-analysis of published trials suggested direct cardiovascular benefits of saxagliptin, which was associated with reduced rates of major adverse cardiovascular events compared to alternative therapies [Wolf, R. et al., Abst 8-LB] (Fig. 20).

Fig. 20. Rate of major adverse cardiovascular events (stroke, myocardial infarction or cardiovascular death), acute, clinically significant events (including cardiac revascularization procedures), cardiovascular death and all-cause death in patients treated or not with saxagliptin [Wolf, R. et al., Abst 8-LB].

Although no major news were discussed during the meeting on alogliptin, studies demonstrating improved glycemic control and enhancements in ?-cell function and insulin resistance when added to pioglitazone in patients naive to treatment of previously resistant to metformin was included in the abstract publication [DeFronzo, R.A. et al., Abst 2023-PO; DeFronzo, R.A. et al., Abst 2024-PO; Inzucchi, S.E. et al., Abst 2026-PO; Rosenstock, J. et al., Abst 2036-PO]. An additional agent within this group, linagliptin proved safe and effective in patients with type 2 diabetes insufficiently controlled with metformin [Uhlig-Laske, B. et al., Abst 535-P] (Fig. 21) and was shown to improve wound healing in obese animal models [Linke, A. et al., Abst 596-P]. A novel dipeptidyl peptidase-IV inhibitor currently in development, gosogliptin (PF-734200), proved safe and effective when added to metformin in a placebo-controlled trial in patients with type 2 diabetes [Terra, S.G. et al., Abst 504-P; Terra, S.G. et al., Abst 1996-PO] (Fig. 22); pharmacokinetic assessments revealed the need for reduced doses in patients with renal failure [Dai, H. et al., Abst 600-P] and no differences between Japanese and Western populations [Dai, H. et al., Abst 2075-PO]. In addition, favorable in vivo experimental activity was revealed with three further new agents: PSN-IV/119-1 (dual dipeptidyl peptidase-IV inhibitor and GPR119 agonist), which showed superior blood glucose-lowering activity compared to sitagliptin [Swain, S. et al., Abst 453-P]; MP-513, which prevented high-fat diet-induced visceral obesity [Takashina, Y. et al., Abst 543-P]; and DSP-7238, with favorable phase I clinical trial data [Woodruffe-Peacock, C. et al., Abst 2081-PO], favorable pharmacokinetics in experimental animals [Furuta, Y. et al., Abst 2022-PO] and higher reported selectivity than vildagliptin or sitagliptin [Nakagawa, T. et al., Abst 2021-PO].

Fig. 21. Change in postprandial glucose levels after 12 weeks of treatment with linagliptin or placebo [Uhlig-Laske, B. et al., Abst 535-P].

Fig. 22. Change in hemoglobin A1c levels after 12 weeks of treatment with PF-734200 or placebo [Terra, S.G. et al., Abst 504-P].

As additional information, the dipeptidyl peptidase-IV inhibitors saxagliptin and vildagliptin were reported effective in the treatment of one case each of maturity-onset juvenile diabetes (MODY) [Katra, B. et al., Abst 1161-P].

AMYLIN AGONISTS

Similar improvements in glycemic control but a lower risk of hypoglycemia resulted from adding pramlintide to basal insulin compared to add-on rapid-acting insulin in patients with type 2 diabetes, without the triple combination increasing the risk of hypoglycemia compared to pramlintide/insulin [Karounos, D. et al., Abst 118-OR]. Add-on pramlintide was reported safe without a risk for severe hypoglycemia in a further study in patients on mealtime insulin [Lutz, K. et al., Abst 579-P]. Pramlintide was also reported safe in the real world when added to mealtime insulin in the management of type 2 diabetes, with a low, acceptable risk for severe hypoglycemia [Pencek, R. et al., Abst 580-P], and in one additional 24-week study decreased glucose levels, reduced hypoglycemia, prevented weight gain and improved patient satisfaction and quality of life more effectively as add-on therapy than uptitration of rapid-acting basal insulin [Peyrot, M. et al., Abst 1842-P].

SODIUM-GLUCOSE TRANSPORTER-2 INHIBITORS

A placebo-controlled trial demonstrated the efficacy of dapagliflozin in improving glycemic control and body weight while reducing insulin requirements in type 2 diabetes [Wilding, J.P.H. et al., Abst 482-P] (Fig. 23), while a study in healthy volunteers ruled out an effect on the QT interval [Carlson, G.F. et al., Abst 483-P] and experimental animal studies confirmed a role in preventing pancreatic function loss after a high fat diet [MacDonald, R.F. et al., Abst 1468-P]. Phase I clinical trial data was reported in the jazz city by the Mississippi confirming the safety, favorable pharmacokinetics and glucose-lowering activity of remogliflozin in healthy volunteers and patients with type 2 diabetes [Kapur, A. et al., Abst 509-P; Dobbins, R.L. et al., Abst 573-P], without adverse interactions when coadministered with metformin [Hussey, E.K. et al., Abst 582-P]. In the preclinical arena, the novel sodium-glucose transporter-2 inhibitor JNJ-28431754/TA-7284 improved glycemia and body weight in models of diabetes and obesity [Liang, Y. et al., Abst 534-P], while BI-10773 showed marked selectivity for type 2 over type 1 sodium-dependent glucose cotransporter and exhibited an in vivo pharmacokinetic and pharmacodynamic profile supporting its development for the treatment of type 2 diabetes [Grempler, R. et al., Abst 521-P].

Fig. 23. Change in hemoglobin A1c levels after 12 weeks of treatment with dapagliflozin or placebo [Wilding, J.P.H. et al., Abst 482-P].

PROTEIN PHOSPHATASE-1B INHIBITORS

Although without efficacy-focused news, a pharmacokinetic assessment of trodusquemine reinforcing its potential in the treatment of diabetes and obesity was presented this year, with feasibility for subcutaneous administration based on half-life and exposure data [Ruiz-White, I.A. et al., Abst 556-P; Ellis, J. et al., Abst 2071-PO]. The agent was shown to improve glucose tolerance and body weight in obese animal models [McLane, M.P. et al., Abst 604-P].

NOVEL ANTIDIABETIC TARGETS

Novel drugs are being developed for the treatment of diabetes acting on newer therapeutic targets, and the efficacy of some of them was demonstrated in clinical trials presented during this year’s meeting. Examples of these include the glucokinase activator MK-0599, with potential for lowering glucose levels demonstrated in healthy, nondiabetic subjects [Migoya, E.M. et al., Abst 116-OR], the 11-?-hydroxysteroid dehydrogenase type 1 inhibitor INCB-13739, which was very well tolerated and significantly improved hemoglobin A1c and LDL-cholesterol levels compared to placebo in patients with type 2 diabetes [Rosenstock, J. et al., Abst 7-LB] (Fig. 24), the chemical chaperone sodium phenylbutyrate, which prevented free fatty acid-induced insulin resistance in nondiabetic volunteers [Xiao, C. et al., Abst 1457-P] (while butyrate improved insulin sensitivity through increasing the biogenesis of mitochondria in experimental animals [Gao, Z. et al., Abst 2387-PO] and increased exocrine pancreatic gene expression in embryonic stem cells [Ren, M. et al., Abst 2420-PO]), and the glucose-dependent insulinotropic receptor agonist MBX-2982, which improved glucose tolerance with good tolerability in healthy volunteers and patients with impaired glucose tolerance [Roberts, B. et al., Abst 164-OR]. Another example is the farnesoid-X receptor agonist INT-747, which was well tolerated and effectively improved glucose disposal rate and induced weight loss, also compared to placebo, in patients with type 2 diabetes and nonalcoholic hepatic steatosis [Henry, R.R. et al., Abst 13-LB] (Fig. 25). Two further examples are the fructose-1,6-bisphosphatase inhibitor MB-07803, which also attained reductions of fasting and postprandial glycemia compared to placebo in patients with poorly controlled type 2 diabetes [Gumbiner, B. et al., Abst 11-LB], and the so-called compound X, an inhibitor of diglyceride acyltransferase, which improved insulin sensitivity and insulin signaling in diabetic/obese animal models [Wertheimer, S.J. et al., Abst 1279-P]. In addition, the antiinflammatory agent salsalate was shown to improve glycemia in patients with type 2 diabetes, with benefits on hemoglobin A1c, fasting plasma glucose, triglyceride and adiponectin levels [Goldfine, A.B. et al., Abst 115-OR]. Bromocriptine was proven to increase insulin sensitivity and inhibit several hepatic inflammatory pathways leading to insulin resistance in experimental animal models [Luo, S. et al., Abst 1278-P] and in patients with type 2 diabetes an accelerated absorption formulation improved glycemic control after failure with thiazolidinediones [Scranton, R.E. et al., Abst 481-P]. To close this section, the NADPH oxidase inhibitor apocynin was noted to restore, at least partially, ?-cell secretory capacity [Koulajian, K. et al., Abst 1448-P]; an aloe vera whole leaf extract, UP-780, showed potential in a placebo-controlled study for lowering hemoglobin A1c and fasting blood glucose levels and improving lipid metabolism and insulin responses in white adipose tissue in patients with metabolic syndrome [Tseng-Crank, J. et al., Abst 1129-P]; a chalcone extracted from Artemisia dracunculus exhibited antidiabetic potential similar to metformin in experimental models [Ribnicky, D.M. et al., Abst 1995-PO]; and the Ayurvedic formulation Mersina showed mildly antihyperglycemic activity compared to placebo in patients with secondary failure to oral antidiabetic drugs [Addepalli, V. et al., Abst 2041-PO].

Fig. 24. Change in hemoglobin A1c levels after 26 weeks of treatment with INCB-13739 or placebo [Rosenstock, J. et al., Abst 7-LB].

Fig. 25. Change in glucosal disposal rate after 6 weeks of treatment with INT-747 or placebo in patients on high- or low-dose insulin [Henry, R.R. et al., Abst 13-LB].

Specifically in type 1 diabetes, treatment with GAD65-alum induced production of GADA-specific antibodies without adverse events, but enhanced C-peptide preservation [Cheramy, M. et al., Abst 23-OR].

In addition, a number of novel compounds showed potential in the preclinical arena, as exemplified by the insulin-sensitizing, weight-lowering effect of the selective glucocorticosteroid antagonist ADS-108297 [Azagami, T. et al., Abst 92-LB], the insulin-sensitizing activity of an antisense oligonucleotide inhibiting transthyretin expression, resulting in increased myocardial glucose uptake [Manchem, P. et al., Abst 76-LB], the insulin-sensitizing, glucose-lowering effect of the humanin analog HNGF6A [Huffman, D.M. et al., Abst 326-OR; Muzumdar, R.H. et al., Abst 1423-P], the glucose tolerance-improving activity of the epithelial growth factor receptor kinase inhibitor PD-153035 [Prada, P. et al., Abst 322-OR], a novel undisclosed glucokinase activator (compound B) with potential for preventing hydrogen peroxide-induced ?-cell death and treating sulfonylurea-nonresponding diabetes [Ohyama, S. et al., Abst 1537-P; Futamura, M. et al., Abst 1569-P] and the glucosuric effect of the SGLT2 antisense compound ISIS-388626 [Bhanot, S. et al., Abst 328-OR], all in obese animal models. In addition, studies in experimental animals also revealed that cotreatment with interleukin-2 and sirolimus is able to reverse type 1-like diabetes in nonobese conditions [Ramiya, V. et al., Abst 327-OR]. Reductions in glucose and lipid levels in experimental animal models was also attained with antisense inhibition of cyclic AMP response element-binding protein (CREB) expression, offering potential for new developments in the treatment of hyperglycemia and dyslipidemia in type 2 diabetes [Murray, S.F. et al., Abst 380-OR]. In addition, reductions in glucose levels with accompanying decreases in lymphocyte homing into the endocrine pancreas were demonstrated with the c-Jun N-terminal kinase (JNK) inhibitor XG-102 [Khoo, C.P. et al., Abst 1240-P]. Potential in other in vivo models was reported with DHPO, a small molecule that activates AMP-dependent protein kinase [Kandari, M.R. et al., Abst 1911-P] (although A-769662, a further AMP-dependent protein kinase activator, failed to stimulate glucose uptake by cardiomyocytes [Bertrand, L. et al., Abst 1923-P]), and with exogenous administration of D3 peptide [Simms, J.R. et al., Abst 1914-P]. In the in vitro laboratory setting, the advanced glycation endproduct inhibitor LR-90 showed potential for inhibiting high glucose-induced radical oxygen species, tumor necrosis factor-? and interleukin-6 production by endothelial cells [Stentz, F.B. et al., Abst 768-P], and prevention of palmitate-induced insulin-secreting cell death and recovery of the insulin signaling pathway were attributed to inhibition of I?B kinase inhibition by salicylate or aspirin [Lee, S.M. et al., Abst 1559-P] (to note, salicylate, like pioglitazone, reversed monocyte activation in obesity [Kim, M.S. et al., Abst 1756-P]). Additionally, protection against fatty acid-induced ?-cell death was reported with 2-bromopalmitate [Baldwin, A.C. et al., Abst 1639-P]. The antiulcer agent isrogladine stimulated insulin responses to glucose through an effect on gap junction channels [Matsumoto, T. et al., Abst 1626-P]. Moreover, the benefits of antisense blockade of retinol-binding protein-4 expression on hepatic and peripheral insulin sensitivity [Manchem, P. et al., Abst 1404-P], those of a monoclonal anti-CD3 antibody in delaying diabetes in nonobese diabetes- and obesity-prone animal models [Bevier, W.C. et al., Abst 1822-P] and the protection against glucolipotoxicity by lactogens [Nagesha, G.K. et al., Abst 1564-P] suggested new avenues to explore in the targeted treatment of type 2 diabetes.

Furthermore, active research into nutraceuticals resulted in demonstration of lowering of blood glucose, C-reactive protein, monocyte chemoattracting protein-1, intercellular cell adhesion molecule-1, oxidative stress and creatinine levels, inhibition of the nuclear factor ?B, Akt and glucose transporter Glut-2 and increases in insulin receptor substrate-1 activation in animal models of type 2 diabetes with chromium dinicocysteinate supplementation [Jain, S.K. et al., Abst 1672-P]. In a similar way, ingestion of lysine was related to attenuated glucose responses to a meal, without impacting on insulin responses [Kalogeropoulou, D. et al., Abst 1678-P]. On the contrary, glutamine supplementation was associated with increased probability of nocturnal and exercise-related hypoglycemia in adolescents with type 1 diabetes [Mauras, N. et al., Abst 1786-P].

IMMUNOTHERAPIES FOR DIABETES

A DNA plasmid vaccine encoding for full-length human insulin (BHT-3021) tested positive for preserving ?-cell function and improving glycemic control in a phase I/II study in patients with type 1 diabetes [Gottlieb, P. et al., Abst 114-OR] (Fig. 26). Another approach to immunotherapy is modulation with the anti-interleukin-1? antibody XOMA-052, which also lowered hemoglobin A1c, in this case in patients with type 2 diabetes [Donath, C.Y. et al., Abst 113-OR] (Fig. 27), and improved glucose control, ß-cell function and insulin sensitivity in experimental models of obesity [Owyang, A.M. et al., Abst 310-OR].

Fig. 26. Change in hemoglobin A1c levels after 15 weeks of treatment with BHT-3021 or placebo [Gottlieb, P. et al., Abst 114-OR].

Fig. 27. Median change in hemoglobin A1c levels during three months after a single dose of XOMA-052 or placebo [Donath, C.Y. et al., Abst 113-OR].

ISLET TRANSPLANTATION

A late-breaking contribution to this year’s meeting in New Orleans indicated potential for uncoupling protein-2 (UCP2) modulation to improve the function of transplanted islets [O’Sullivan, E.S. et al., Abst 110-LB]; improvements in islet graft survival were also notified with sitagliptin [Kim, S.J. et al., Abst 1948-P] and exenatide [Buss, J. et al., Abst 1957-P] administration in experimental animals. On the other hand, caution on the use of tacrolimus during transplantation derives from an experimental report describing impairments in ß-cell proliferation in animals exposed to the agent [Soleimanpour, S. et al., Abst 1602-P].

DIABETIC DYSLIPIDEMIA AND METABOLIC SYNDROME

Although chocolate induced improvements in the lipid profiles and body weight of patients with type 2 diabetes, with an understandable benefit on the patients’ quality of life [Mellor, D.D. et al., Abst 2208-PO], more intensive approaches are usually recommended for controlling the metabolic profile and associated cardiovascular risk.

While simvastatin induced antiinflammatory effects on adipokine levels, with marked decreases in proinflammatory/proatherosclerotic cytokines [Hu, Y. et al., Abst 642-P], an effect of atorvastatin in modulating insulin signaling was reported, which was related to inhibition of ? GTPase in adipocytes [Sato, K. et al., Abst 1319-P], and atorvastatin was further reported to protect the liver of diabetic, dyslipidemic patients when combined with metformin [Matafome, P. et al., Abst 1496-P]. Fluvastatin was also included in this year’s ADA reports, with a poster describing protective effects on the endothelium mediated by increases in nitric oxide [Hirama, N. et al., Abst 729-P].

Addition of ezetimibe offers a valid lipid-lowering strategy for patients not responding to statin monotherapy, and a fixed combination of ezetimibe and simvastatin proved superior to atorvastatin alone in cohorts of patients with metabolic syndrome, with greater reductions in LDL- and non-HDL-cholesterol, apolipoprotein B and also C-reactive protein levels [Ballantyne, C.M. et al., Abst 646-P; Robinson, J.G. et al., Abst 671-P] (Fig. 28). In addition, combination with ezetimibe was superior to uptitrating atorvastatin for lipid control in patients with type 2 diabetes or metabolic syndrome at high risk for coronary artery disease [Conard, S. et al., Abst 669-P]. Furthermore, mechanistic pharmacodynamic activity of ezetimibe in reversing hepatic insulin resistance was reported in high-fat diet-induced obesity models [Terauchi, Y. et al., Abst 1479-P]. However, analysis of apolipoprotein B target attainment with either ezetimibe/statin or statin monotherapy suggested the need for more aggressive therapies for patients with metabolic syndrome, aimed at lower LDL-cholesterol and higher HDL-cholesterol target levels than those currently recommended for high cardiovascular risk patients [Ballantyne, C.M. et al., Abst 670-P].

Fig. 28. Moderately high- and high-risk patients attaining target LDL-cholesterol and C-reactive protein levels after treatment with ezetimibe/simvastatin or atorvastatin [Ballantyne, C.M. et al., Abst 646-P].

Although effective in both genders, fenofibrate reduced LDL-cholesterol levels and prevented cardiovascular morbidity and mortality more in women than men in the FIELD trial [D’Emden, M. et al., Abst 662-P], and combined with rosuvastatin resulted in increased rates of target lipid level attainment [Rosenson, R.S. et al., Abst 936-P] (Fig. 29). Mechanistically, the agent was shown to protect microvascular endothelial cells against inflammation and apoptosis via activation of AMP-dependent protein kinase pathways [Tomizawa, A. et al., Abst 759-P], and protected the kidneys against high fat diet-related injuries [Tanaka, Y. et al., Abst 797-P]. Furthermore, in vitro studies revealed a link between inhibition of 11?-hydroxysteroid dehydrogenase type 1 by fenofibrate and depression of cortisone-dependent glucocorticosteroid signaling [Suri, V. et al., Abst 1415-P]. (As a side comment, it is worth mentioning that although chronic corticosteroid use has been related to hyperglycemia and insulin resistance, the effect of prednisone in experimental animals showed dependency on feeding status, with impairments of insulin sensitivity and glucose responses only during fast [Laskewitz, A.J. et al., Abst 1432-P].) However, independent mechanistic studies linked fenofibrate to a higher risk for hepatic hypertrophy [Joe, Y. et al., Abst 1480-P] and suggested better activity on blood pressure, liver function and glucose metabolism with bezafibrate than fenofibrate [Yaamaki, N. et al., Abst 921-P] (Fig. 30).

Fig. 29. Percent of subjects at LDL- and HDL-cholesterol and triglyceride target after treatment with combinations of fenofibrate (F) and rosuvastatin (R) [Rosenson, R.S. et al., Abst 936-P].

Fig. 30. Change in systolic blood pressure and hemoglobin A1c levels after 8 weeks of treatment with bezafibrate or fenofibrate [Yamaaki, N. et al., Abst 921-P].

Decreases in serum retinol-binding protein-4 levels were noted after treatment with niacin in patients with metabolic syndrome [Plaisance, E.P. et al., Abst 70-LB], and a fixed combination of extended-release niacin and simvastatin offered increased lipid-lowering activity, although with a transient increase in fasting blood glucose that should not preclude its use in patients with impaired blood glucose provided adequate monitorization is ensured [Ballantyne, C.M. et al., Abst 933-P]. In a similar way, a combination of niacin and fenofibrate improved dyslipidemia without altering intrahepatic triglyceride levels in patients with nonalcoholic hepatosteatosis [Fabbrini, E. et al., Abst 1475-P]. However, niacin induced untoward effects on glucose homeostasis, although these could be prevented by coadministration of pioglitazone [Dunbar, R.L. et al., Abst 621-P]. In experimental models, cholestyramine not only improved lipid levels, but also reversed hyperglycemia and enhanced glucagon-like polypeptide-1 release in fatty animals [Chen, L. et al., Abst 1407-P]. Treatment with colesevelam brought about improvements in the metabolic control and benefits on bile acid metabolism in healthy and diabetic subjects [Brufau, G. et al., Abst 498-P]. Furthermore, add-on colesevelam effectively and cost-effectively improved LDL-cholesterol and glycemic profiles in metformin-treated type 2 diabetes patients [Simons, W.R. & Hagan, M., Abst 1217-P; Simons, W.R. & Hagan, M., Abst 2304-PO]. Experimental studies in animal models confirmed improvements in insulin resistance after treatment with the agent [Shang, Q. et al., Abst 477-P].

As in the treatment of hypertension, control of the lipid profile may require intensive therapy with a combination of multiple drugs, and in addition to the known benefit of adding ezetimibe to statin therapy, results discussed in New Orleans demonstrated the benefit of a triple combination of ezetimibe, simvastatin and niacin in the management of dyslipidemia in subjects with diabetes or metabolic syndrome, resulting in incremental benefits in HDL-cholesterol, triglycerides, LDL-cholesterol, apolipoprotein B, albeit with a somewhat increased risk for inducing glucose abnormalities and new-onset diabetes in those patients without overt diabetes at baseline [Fazio, S. et al., Abst 696-P].

While adhering to a low-fat diet offered improvements not only in lipid but also glycemic control in women with type 2 diabetes, glycemic benefits being independent of lipid lowering and/or weight control [Neelima, G.R. et al., Abst 172-OR], benefits on the lipid profile and body weight of diabetic patients were obtained by dietary consumption of marine ?3-fatty acids, resulting in improved cardiometabolic risk profile [Belalcazar, L.M. et al., Abst 173-OR; Bays, H.E. et al., Abst 2444-PO]. In a similar way, chromium picolinate supplementation lowered muscular and hepatic lipid levels, thus improving insulin sensitivity [Luu, L.T. et al., Abst 174-OR], while dietary phytosphingosine improved both insulin sensitivity and cholesterol levels in patients with metabolic syndrome [Snel, M. et al., Abst 614-P]. On the other hand, supplementation with eicosapentanoic acid and docosahexaenoic acid in healthy volunteers was associated with a profile suggesting prevention of metabolic syndrome [Paniagua, J.A. et al., Abst 91-LB] (whereas docosahexaenoic acid was mechanistically related to prevention of palmitate-induced reductions in glucose transporter GLUT4 gene expression [Jung, J.G. et al., Abst 2388-PO]). In the experimental arena, ?-lipoic acid supplementation improved glucose tolerance in fructose-accelerated diabetes models [Cummings, B.P. et al., Abst 1389-P], while the effect of green tea (-)-epigallocatechin gallate preventing islet amyloidosis [He, L. et al., Abst 2404-PO] as well as increasing heme oxygenase-1 and reducing bone morphogenic protein-4 expression in endothelial cells suggested complementary cardiovascular and antiatherosclerosis protection [Pullikotil, P. et al., Abst 781-P]. As an additional comment, soy isoflavones were noted to improve endothelial dysfunction and prevent oxidized LDL-induced endothelial cell apoptosis [Kamiyama, M. et al., Abst 2397-PO], whereas lupin seeds exhibited metabolic benefits that were attributed to a specific component, conglutin-?, which according to experimental in vitro studies, in diabetic or insulin-resistant conditions offered additional benefit on muscle cell differentiation and growth [Terruzzi, I. et al., Abst 620-P].

Novel therapies are also being developed aimed at addressing lipid abnormalities in diabetic, prediabetic and patients in general with metabolic risk profiles. New clinical trials were reported on a number of such agents, including the partial adenosine A1 agonist CVT-3619, which safely and dose-dependently reduced free fatty acid levels in normal and overweight volunteers, with an antilipolytic effect starting at doses of 300 mg [Staehr, P. et al., Abst 72-LB], and the microsomal triglyceride transfer protein inhibitor AEGR-733, which lowered LDL-cholesterol and triglyceride levels while inducing weight loss in dyslipidemic, overweight individuals [Bays, H.E. et al., Abst 471-P].

DIABETES AND OVERWEIGHT/OBESITY

Weight, or rather overweight, is a major risk factor for type 2 diabetes and metabolic syndrome, and therapies have been developed to control body weight in people at risk. Effective weight reduction with acceptable tolerability was demonstrated in a new placebo-controlled clinical trial with lorcaserin, a selective serotonin 5-HT2C receptor agonist. Furthermore, rerandomization after one year of treatment revealed less weight gain during the second year of the study in lorcaserin- compared to placebo-treated individuals [Smith, S.R. et al., Abst 96-LB] (Fig. 31). Placebo-controlled clinical trial data supported the efficacy of phentermine in lowering body weight and waist circumference [Kang, J.G. et al., Abst 1716-P], and also topiramate, which induced weight loss without impacting on insulin sensitivity [Jazet, I.M. et al., Abst 622-P]; weight loss in overweight type 2 diabetes patients was also demonstrated with a fixed-drug combination of phentermine and controlled-release topiramate, with additional benefit in lowering hemoglobin A1c levels compared to placebo over the mid- and long term [Aronne, L.J. et al., Abst 119-OR; Garvey, W.T. et al., Abst 361-OR] (Fig. 32), and also with a fixed-drug combination of naltrexone and bupropion [Wadden, T. et al., Abst 37-OR; Wadden, T. et al., Abst 1731-P; Klein, S. et al., Abst 1730-P] (Fig. 33). Additional studies indicated improvements in insulin resistance and ß-cell function in obese individuals with glucose intolerance treated with a-lipoid acid [Han, P. et al., Abst 360-OR].

Fig. 31. Proportion of patients with >=5% and >=10% body weight loss after one year of treatment with lorcaserin or placebo [Smith, S.R. et al., Abst 96-LB].

Fig. 32. Change in hemoglobin A1c levels after six months of treatment with phentermine/controlled-release topiramate or placebo [Aronne, L.J. et al., Abst 119-OR].

Fig. 33. Change in the Impact of Weight on Quality of Life scores after 56 weeks of treatment with naltrexone/bupropion or placebo [Wadden, T. et al., Abst 1731-P].

In the experimental preclinical setting, a novel cannabinoid CB1 receptor blocker with the ability to improve diabetes and metabolic parameters without altering body weight and without the need for penetrating into the central nervous system was described: JD-5006 [McElroy, J.F. et al., Abst 325-OR]. Two further CB1 blockers, SR-141716 and CIS-565C, also showed benefits with improvements in insulin sensitivity and the metabolic profile in obese experimental animals [Olivieri, M. et al., Abst 1305-P; Kumagai, H. et al., Abst 475-P], whereas the soluble epoxide hydrolase inhibitor AR-9281 showed nitric oxide synthase-independent antiobesity, glucose homeostasis-improving potential [Vincelette, J. et al., Abst 1698-P] (favorable safety and pharmacokinetics and preliminary evidence of pharmacodynamic activity were documented in a phase I trial with AR-9281 in healthy volunteers [Whitcomb, R. et al., Abst 612-P]). In addition, the ?-opioid receptor blocker PSN-MOP-1 [Bloxham, J. et al., Abst 1715-P] and the selective peroxisome proliferator-activated receptor d agonist GW-501516 [Will, S. et al., Abst 1717-P] induced weight loss in overweight experimental animals. An undisclosed glucagon receptor agonist with the ability to reduce blood glucose and elevate glucagon-like polypeptide-1 levels in the blood [Jiang, G. et al., Abst 157-OR], a pegylated glucagon/glucagon-like polypeptide-1 co-agonist capable of reversing obesity [Tschoep, M.H. et al., Abst 313-OR], and an antisense fibroblast growth factor receptor-4 oligonucleotide that improved insulin sensitivity, body weight and adiposity [Yu, X.X. et al., Abst 312-OR] in animals with diet-induced obesity were also discussed. What is more, prevention of fatty liver disease without an effect on body weight was noted with the histone deacetylase SIRT1 inhibitor SRT-1720 [Yamazaki, Y. et al., Abst 1689-P]. In the in vitro laboratory, through blockade of AMP-dependent potassium channels, berberine repressed proinflammatory responses via downregulation of radical oxygen species and mitogen-activated protein kinase signaling in macrophages [Jeon, H.W. et al., Abst 1267-P] and prevented palmitate-induced lipoapoptosis [Tieyun, Z. et al., Abst 2403-PO], but also inhibited adipogenesis in vitro and in vivo [Hu, Y. & Davies, G.E., Abst 1718-P] and improved insulin and glucose balance in experimental models of diabetes [Zhao, H. et al., Abst 2394-PO].

DIABETIC CARDIOVASCULAR DISEASE

A meta-analysis of six studies including 10,117 patients revealed the same magnitude of cardiovascular preventive efficacy of aspirin in diabetic and nondiabetic populations at high overall cardiovascular risk, with effective prevention of myocardial infarction and stroke, although the former reached significance only in men [De Berardis, G. et al., Abst 90-OR]. Low-dose aspirin for cardiovascular prevention is not only effective, but also cost-saving for all patients with a cardiovascular risk of 4% or higher, which includes diabetic populations [Moeremans, K. et al., Abst 44-OR].

However, underdosing of aspirin seems to be common in the clinical practice [Law, E. & Simpson, S.H., Abst 2230-PO] and clinical aspirin resistance or underresponsiveness has been widely recognized, which was mechanistically related to an adverse effect on fibrin clot lysis only in hyperglycemic conditions [Ajjan, R.A. et al., Abst 644]. On the other hand, the efficacy of clopidogrel in patients with type 2 diabetes undergoing coronary stent placement was diminished upon cotreatment with proton pump inhibitors [Stanek, E.J. et al., Abst 1034-P]. The antiplatelet, agent, cilostazol exhibited antiinflammatory activity on vascular smooth muscle cells related to activation of AMP-dependent protein kinase signaling [Suzuki, K. et al., Abst 750-P] and was shown to inhibit plasminogen activator inhibitor-1 expression in vascular smooth muscle cells [Park, K.G. et al., Abst 650-P]. As additional observations, in postmenopausal women with type 2 diabetes prasterone inhibited platelet aggregation through an effect on nitric oxide production [Muñoz, Y.C. et al., Abst 754-P], whereas ursodeoxycholate was found to inhibit high glucose-induced plasminogen activator inhibitor-1 expression in endothelial cells, suggesting protection against ischemic cardiovascular events [Yokoi, T. et al., Abst 608-P].

Hypertension in diabetes

Calcium channel blockers are not the preferred options for the management of hypertension in diabetes, but remain effective agents for lowering blood pressure, and data supporting blood pressure- and albuminuria-lowering effects of benidipine was presented during this meeting, from a comparative trial that documented its superiority over amlodipine [Yamane, Y. et al., Abst 793-P]. However, amlodipine remains an effective antihypertensive, even in diabetic individuals, and a fixed combination with atorvastatin resulted in rapid co-achievement of blood pressure and lipid targets [Rivard, L. et al., Abst 2077-PO].

In addition to its known benefits on blood pressure, ramipril use in the DREAM trial was associated with reductions in total body and visceral fat and free fatty acid levels compared to placebo in patients with impaired fasting glucose or impaired glucose tolerance [Punthakee, Z. et al., Abst 1727-P]. Blood pressure and renal benefits derived from treatment with benazepril in further studies, without the need to reach high doses in order to obtain benefit in diabetes [Taureen, N. & Davidson, M.B., Abst 785-P]. However, a case-control study did not find evidence that angiotensin-converting enzyme inhibitors had any clinical effect on diabetic retinopathy [Khamseh, M.E. et al., Abst 2193-PO].

In a similar way, with established benefits on blood pressure, treatment with losartan brought about improvements in myocardial backscatter signal variability in hypertensive diabetic individuals, which was related to attenuation of myocardial fibrosis and regression of left ventricular hypertrophy [Fogari, R. et al., Abst 698-P], and in combination with hydrochlorothiazide proved an effective alternative for improving overt proteinuria [Okada, S. et al., Abst 2178-PO]. A related agent, valsartan not only offered activity on blood pressure, but also improved hyperglycemic responses to hydrochlorothiazide in obese African American individuals with hypertension [Ofili, E. et al., Abst 541-P], and proved superior to losartan, as it also improved insulin resistance and visfatin levels in overweight individuals [Fogari, R. et al., Abst 617-P]. In the case of candesartan, data from the DIRECT-2 trial demonstrated effective protection against vascular complications of type 2 diabetes in patients without cardiovascular disease or microalbuminuria [Tillin, T. et al., Abst 647-P], whereas in comparison with olmesartan, candesartan induced improvements in insulin resistance at comparable blood pressure reduction [Derosa, G. et al., Abst 2106-PO].

Besides lowering blood pressure, telmisartan improved glucose metabolism and leptin [De Luis, D. et al., Abst 1722-P] and, as opposed to valsartan, insulin resistance in patients with metabolic syndrome [Tasaki, H. et al., Abst 623-P] (Fig. 34). A combination of telmisartan and amlodipine was considered an effective option for the management of hypertension in diabetic individuals compared to the nondiabetic population [Littlejohn, T. et al., Abst 595-P]. Aliskiren, a direct renin inhibitor, offered antiproteinuric effects in patients with type 2 diabetes and hypertension [Persson, F. et al., Abst 549-P]. A novel angiotensin receptor blocker with insulin-sensitizing activity, K-868, was shown to improve and prevent diabetes and diabetic nephropathy in experimental animal models [Hamaguchi, A. et al., Abst 782-P], whereas the aldosterone antagonist spironolactone improved blood pressure but at the cost of deteriorating glomerular filtration rates in diabetic nephropathy, limiting its usefulness in patients with type 2 diabetes [Bountouvis, N. et al., Abst 796-P].

Fig. 34. Change in the HOMA insulin resistance index after 12 weeks of treatment with telmisartan or valsartan [Tasaki, H. et al., Abst 623-P].

DIABETIC NEPHROPATHY

With good tolerability, the addition of aliskiren to losartan improved renal outcomes and better preserved renal function compared to placebo in diabetic, hypertensive patients with diabetic nephropathy [Parving, H.H. et al., Abst 32-OR] (Fig. 35). Dose-dependent improvements in glycemic control and renal function in chronic kidney disease secondary to type 2 diabetes were also shown with bardoxolone [Schwartz, S.L. et al., Abst 112-OR; Schwartz, S.L. et al., Abst 362-OR] (Fig. 36).

Fig. 35. Change in the estimated glomerular filtration rate throughout 6-months of adding aliskiren or placebo to losartan therapy [Parving, H.H. et al., Abst 32-OR].

Fig. 36. Change in the estimated glomerular filtration rate during 28 days of treatment with add-on bardoxolone [Schwartz, S.L. et al., Abst 112-OR].

DIABETIC NEUROPATHY

While more advanced trials supported the benefits of tapentadol, with initial pain relief suggesting longer-term safety and efficacy in a placebo-controlled trial with open-label extension [Etropolski, M. et al., Abst 852-P], initial clinical studies suggested safety and potential for the vascular endothelial growth factor zing finger protein activator SB-509 in the management of diabetic neuropathy, with improvements in neurological outcomes in patients with moderately severe and severe disease [Benaim, E. et al., Abst 859-P].

In addition, note that an investigation in 42 patients did not find any link between diabetic neuropathy and either lipid levels or lipid-lowering therapy [Tapp, R.J. et al., Abst 840-P].

Diabetic neuropathic pain

Duloxetine and pregabalin are used in the management of neuropathic pain in diabetes, with real-world data suggesting more common use of pregabalin in women or patients with a diagnosis of fibromyalgia, hypertension, nephropathy or other neuropathic pains, or previously treated with citalopram, topiramate or venlafaxine [Sun, P. & Zhao, Y., Abst 848-P].

DIABETES AND BRAIN DISEASE

Although only in the experimental setting, an effect reported for memantine in preventing hyperglycemia-related brain damage could suggest novel possibilities for preventing early cognitive impairment in the diabetic population [Silverstein, J. et al., Abst 130-OR].

DIABETES AND THE SKIN

Improved wound healing in experimental models of diabetes was demonstrated with the CXCR4 receptor blocker NIBR-1816 [Mocci, A. et al., Abst 592-P].

DIABETES AND ERECTILE DYSFUNCTION

Improvements in erectile dysfunction in experimental models of diabetes were demonstrated with a combination of sildenafil and nebivolol, through potentiation of the nitric oxide and cyclic GMP pathways [Angulo, J. et al., Abst 324-OR], and also with a triple combination of trazodone, tadalafil and testosterone, which in an open-label trial resulted in higher satisfaction rates than usual in the clinical practice [Sakkal, S. et al., Abst 2190-PO].

MISCELLANEOUS

Mifepristone was reported to prevent risperidone-induced weight gain in healthy volunteers [Gross, C. et al., Abst 97-LB].

Through inhibition of mammalian target of rapamycin (mTOR), sirolimus counteracted hypoglycemia in a patient with metastatic pancreatic islet cell tumor resulting in malignant insulin secretion [Bourcier, M.E. et al., Abst 4-OR]. Also acting on mTOR, resveratrol suppressed amino acid-induced activation of the AMP-dependent protein kinase, resulting in enhanced insulin sensitivity [Li, H. & Zhang, M., Abst 74-OR], while also decreasing neointimal growth after arterial injuries in high-fat fed experimental animals [Guo, J. et al., Abst 722-P] and improving cardiac function through inhibition of nitrosoxidative stress in type 2 diabetes [Zhang, H. et al., Abst 575-P]. In a similar way, the glucagon-like polypeptide-1 blocker exendin9-39 suppressed insulin secretion and elevated fasting blood glucose levels in patients with ATP-dependent potassium channel mutations resulting in hyperinsulinism [Stanley, C.A. et al., Abst 2-OR].

Although with a risk for anaphylaxis upon repeated injections, a1-antitrypsin was shown to prevent type 1 diabetes in experimental animal models [Ma, H. et al., Abst 191-OR].

Observations in healthy volunteers and patients with type 1 diabetes suggested that immunization responses during rituximab-induced B-cell depletion in diabetics are attenuated and inhibited, calling for caution [Pescovitz, M.D. et al., Abst 195-OR].

Dimethyl fumarate was shown to inhibit vascular myocyte proliferation through activation of the nuclear factor E2-related factor-2 [Oh, C.J. et al., Abst 755-P].

Treatment with olanzapine induced postprandial hyperglycemia, hyperinsulinemia and hypertriglyceridemia in healthy volunteers independently of weight gain [Teff, K.L. et al., Abst 1467-P], but did not impair glucose-stimulated insulin secretion [Kim, S.H. et al., Abst 2372-PO].

Inhibition of matrix metalloproteinase-9 by GM-6001 increased islet amyloidosis and ß-cell apoptosis in animal models [Aston-Mourney, K. et al., Abst 1561-P].

St. John’s wort inhibited adipocyte differentiation from preadipocytes and induced insulin resistance [Doucet, J. et al., Abst 2330-PO].

A glucagon construct for the prevention of nocturnal hypoglycemia tested positive in experimental animal studies and was reported to be moving into clinical studies [Cleland, J.L. et al., Abst 2001-PO].