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Meeting Reports

46th Annual Meeting of the European Association for the Study of Diabetes (EASD)
September 20 - 24, 2010
Stockholm, Sweden

INTRODUCTION

Old and modern architecture go hand in hand along the many waterfronts in Stockholm, just as old (established) and new (investigational) drugs for treating diabetes shared time and space at the oral and poster sessions during this year's EASD meeting in Älfsjö. Old and new drugs shared the spotlight at the meeting, the main declared objective of which was to promote excellence in diabetes care through research and education. Although it is important to attend the EASD meeting in order to obtain information on what's new firsthand ¾new drugs, new indications, new treatment modalities… as well as news on negative aspects and limitations of drug therapy¾, not all healthcare professionals can attend so many annual meetings, and those who can, cannot attend many of the parallel sessions, and thus alternative sources of information are needed.

Indeed, education has a major role in the management and prevention of diabetes, obesity and related disorders, all of which carry a high cardiovascular risk, but if educating patients and the general population is essential, so is informing healthcare professionals about new therapies and new findings related with the management of diabetes. In line with the previously stated attendance limitations and alternative sources of information ¾or education¾, this is the scope of the following report, which complements other information on subjects discussed during the EASD meeting in Stockholm available on line through other channels.

INSULIN AND INSULIN ANALOGUES

Insulin remains the cornerstone in the treatment of diabetes, in which sense, in the case of type 2 diabetes, earlier initiation of insulin could have greater benefits, as more favorable effects on hemoglobin A1c levels with a lower risk for hypoglycemia were noted in patients taking less oral antidiabetic medications [Leahy, J. et al., Abst 960], although observations in the real world practice suggest that suboptimal dose titration is common, resulting in poor glycemic control [Home, P. et al., Abst 954]. Furthermore, according to data discussed this year during EASD, insulin is also useful in the treatment of gestational diabetes, against which it was as effective as metformin regardless of the presence of obesity [Rönnemaa, T. et al., Abst 1091]. In that specific case, better glycemic control during pregnancy was demonstrated with continuous subcutaneous insulin infusion compared to multiple daily injection therapy, without differences in perinatal outcomes [Neff, K. et al., Abst 1084].

Comparing the pharmacokinetic and pharmacodynamic profiles of regular human U-500 and U-1000 insulins, the former had significantly lower peak concentrations resulting in somewhat attenuated effects on insulin and glucose parameters. Both exhibited prolonged time to peak effect and duration of activity, but U-500 was longer acting [Linnebjerg, H. et al., Abst 964].

As an alternative to subcutaneous insulin injection, prandial inhaled insulin offered equivalent glycemic control but a numerical reduction in hypoglycemic events compared to usual diabetes care, with equivalent safety and tolerability during 24 months of continued use [Boss, A.H. et al., Abst 5].

Continuous subcutaneous insulin infusion has arisen as an option for the treatment of type 1 diabetes in children, resulting in improved metabolic control compared with multiple daily insulin injections over the long term [Szypowska, A. et al., Abst 929]. Overall, insulin pump therapy was described as a feasible means of improving glycemic control in patients with type 2 diabetes suboptimally controlled with multiple daily insulin injections [Frias, J.P. et al., Abst 1008]. Furthermore, continuous subcutaneous insulin infusion, at least over the short term, was able to improve insulin sensitivity in patients with type 2 diabetes [Jing, D. et al., Abst 593].

Insulin analogues have been developed to overcome the limitations of human insulin therapy, with rapid-acting analogues such as insulin lispro, insulin aspart and insulin glulisine improving prandial insulin therapy, especially in novel formulations containing EDTA and citrate [Pohl, R. et al., Abst 963] and offering cost-effective benefits compared to regular insulin despite increased direct drug costs, which were offset by lower hospital-related costs [Gundgaard, J. et al., Abst 1061]. One particular insulin analogue, insulin lispro, offered longer durability of treatment compared to insulin glargine despite the need for twice-daily injection, compared to once-daily injection with insulin glargine [Wolffenbuttel, B.H.R. et al., Abst 961]. Moreover, coinjection of rapid insulin analogues with hyaluronidase resulted in faster, shorter insulin exposure and activity [Muchmore, D. et al., Abst 965], and coinjection of insulin lispro with human hyaluronidase improved postprandial glucose control over insulin lispro alone during liquid meal testing [Hompesch, M. et al., Abst 2]. Another rapid-acting analogue, insulin aspart, proved effective as an intensifying stepwise addition to insulin detemir for control of postprandial glycemia [Hermansen, K. et al., Abst 957]. However, faster onset of action compared to insulin lispro was obtained with a monomeric formulation of recombinant human insulin [Nosek, L. et al., Abst 6], offering alternatives to the use of insulin analogues that were further explored and demonstrated pharmacologically stable and suitable for continuous subcutaneous insulin infusion therapy [Flacke, F. et al., Abst 969].

Long-acting insulin analogues may have advantages over human insulin, especially regarding the risk of hypoglycemia. Indeed, the GINGER study demonstrated lower rates of hypoglycemia at equivalent overall glycemic control with basal-bolus insulin glargine/insulin glulisine compared to premixed insulin therapy [Fritsche, A. et al., Abst 573], whereas a meta-analysis of nine trials revealed similar glycemic goal attainment with insulin glargine versus comparators (oral antidiabetic drugs, human insulin or insulin lispro) [Banerji, M.A. et al., Abst 976]. On the other hand, once-daily insulin glargine with premeal insulin glulisine offered better glycemic control with less risk for complications upon general surgical interventions compared to sliding-scale regular insulin [Umpierrez, G.E. et al., Abst 232], although switch from once- to twice-daily insulin glargine resulted in improved glycemic control in independent studies [Dhatiriya, K. & Yeong, J., Abst 977]. Moreover, both insulin glargine and insulin detemir offered better control of morning plasma glucose than regular human insulin, although insulin detemir was less potent than both comparators in controlling glycemia in the afternoon [Lucidi, P. et al., Abst 980], whereas switch to basal-bolus insulin glargine plus a rapid-acting insulin in the ATLANTIC study resulted in significant improvements in glycemic control in patients suboptimally treated with premixed insulin [Storms, G. et al., Abst 962]. Furthermore, basal insulin glargine-supported oral therapy was associated with lower cost than exenatide plus oral antidiabetic drugs in the real-world practice [Fuchs, S.M. et al., Abst 1063], intensified therapy with insulin glargine also offering cost advantages over regular human insulin or insulin detemir considering total annual treatment costs [Bierwirth, R.A. et al., Abst 1064]. In addition, insulin glargine, like insulin detemir, improved endothelial damage and facilitated regeneration in patients with type 2 diabetes, with potential benefits in case of established cardiovascular disease [Fadini, G. et al., Abst 42]. On the other hand, insulin detemir improved glycemic control in patients on background sitagliptin/metformin [Hollander, P.A. et al., Abst 866], and offered advantages over alternative regimens, as switch therapy incorporating insulin detemir plus sitagliptin in patients on prior sulfonylurea therapy improved the glycemic control, with limited impact on body weight and a low risk of hypoglycemia, as compared to adding sitagliptin alone to the prior sulfonylurea regimen [Rašlová, K. et al., Abst 912]. Insulin detemir also induced weight loss upon switch from human insulin, while improving urinary sodium excretion and extracellular volume [Hendriksen, K.V. et al., Abst 41], and showed a low mitogenic potential with well-balanced binding to insulin-like growth factor-1 and insulin receptors [Hansen, B.F. et al., Abst 38]. Furthermore, insulin detemir was less adipogenic than other available insulins, while insulin glargine was the least antilipolytic of the insulins [Garcia-Escobar, E. et al., Abst 707].

Insulin degludec, an ultralong-acting, peakless multihexameric insulin analogue [Jonassen, I. et al., Abst 972], proved as effective as insulin glargine regarding tolerability and glycemic control in type 2 diabetes [Mathieu, G. et al., Abst 4; Meneghini, L. et al., Abst 973; Nishimura, E. et al., Abst 974], but was associated with less pharmacodynamic variability at steady state [Heise, T. et al., Abst 971]. Insulin degludec was tested in a fixed combination with insulin aspart in a proof-of-concept trial that demonstrated safety and tolerability as well as clinical activity comparable to insulin glargine [Cuddihy, R. et al., Abst 975] (Fig. 1).

Fig. 1. Percent of patients with hemoglobin A1c levels <7.0% after 16 weeks of treatment with insulin degludec/insulin aspart or insulin glargine [Cuddihy, R. et al., Abst 975].

Insulin lispro protamine suspension was noninferior to insulin glargine regarding control of hemoglobin A1c in patients also receiving exenatide and/or oral antidiabetic drugs, but was associated with higher rates of nocturnal hypoglycemia, although without differences in severe hypoglycemia and minimal impact on weight [Arakaki, R.F. et al., Abst 979].

BIGUANIDES

Although effective and commonly used to treat diabetes, contraindicated use of metformin in patients with renal impairment, even severe disease, was noted in a retrospective database, suggesting an undue risk for lactic acidosis in that population [Sun, S.X. et al., Abst 1264]. Furthermore, metformin was not able to prevent gestational diabetes in women with polycystic ovary syndrome compared to placebo [Carlsen, S.M. & Vanky, E., Abst 12]. However, compared to insulin secretagogues, adding metformin to insulin therapy improved atherogenic cholesterolemia [Lund, S.S. et al., Abst 1297] and use of metformin in diabetic patients with cirrhotic hepatitis C was associated with a reduced risk of hepatocellular carcinoma and liver-related death or transplantation in a retrospective study [Nkontchou, G. et al., Abst 898].

SULFONYLUREAS AND RELATED ANTIDIABETIC AGENTS

An antioxidant effect of gliclazide was reported, resulting in prevention of hydrogen peroxide-induced cytotoxicity [Sliwinska, A. et al., Abst 905].

Repaglinide significantly improved glucose control in previously untreated type 2 diabetes patients, but the benefits were significantly greater upon combination with metformin without negatively impacting the tolerability profile [Wang, W. et al., Abst 897].

Α-GLUCOSIDASE INHIBITORS

Compared to placebo, acarbose was associated with faster, better glycemic and lipid control and improvements in insulin resistance biomarkers and inflammatory parameters, especially after an oral fat load [Maffioli, P. et al., Abst 902; Derosa, G. et al., Abst 903]. Matching its mechanism as α-glucosidase inhibitor, miglitol significantly reduced postprandial glucose levels, especially after dinner [Nagasaka, S. et al., Abst 904], and proved superior to voglibose in enhancing postprandial incretin responses in patients with type 2 diabetes, although both α-glucosidase inhibitors were effective and improved glucose excursions after a meal tolerance test [Narita, T. et al., Abst 865].

THIAZOLIDINEDIONES

While novel results from the ACTNOW study confirmed the benefit of insulin on ß-cell function and insulin sensitivity in patients with impaired glucose tolerance, preventing the conversion to type 2 diabetes [Tripathy, D. et al., Abst 185], at lower glycemic control compared to metformin but with lower insulin requirements, pioglitazone added to insulin glargine in the PIOcomb trial improved insulin resistance, systemic inflammation and cardiometabolic syndrome and vascular function in patients with type 2 diabetes [Stratmann, B. et al., Abst 901; Pfützner, A. et al., Abst 899] (Fig. 2). Results were also disclosed of the PIOren trial, which demonstrated the tolerability of adding pioglitazone to a stable insulin regimen in type 2 diabetes patients on hemodialysis for endstage kidney disease, resulting in reduced need for insulin doses and improvements in triglyceride levels [Galle, J. et al., Abst 900]. An additional major trial with pioglitazone, the PIOfix study, in which pioglitazone or glimepiride were added to metformin, demonstrated an effect of the thiazolidinedione in improving erythrocyte flexibility paralleling improvements in adiponectin and intact proinsulin levels, these effects being independent of glycemic control [Forst, S. et al., Abst 1265]. Besides clinical information from new major trials assessing the role of pioglitazone in the treatment of diabetes, mechanistic data was also reported from new investigational efforts. In that sense, pioglitazone was noted to increase the aerobic capacity of skeletal muscle's high-energy phosphate metabolism in conditions of insulin resistance, indicating improvements in fatty acid oxidation [Yokota, T. et al., Abst 687].

Fig. 2. Change in C-reactive protein levels after 6 months of adding pioglitazone, metformin or both to once-daily insulin glargine [Stratmann, B. et al., Abst 901].

While having an effect on proteinuria and intrarenal nitric oxide bioavailability in patients with overt diabetic nephropathy [Pistroch, F. et al., Abst 1226], add-on rosiglitazone improved and maintained better control of glycemia in type 2 diabetes during an 80-week follow-up compared to metformin monotherapy, with additional benefits on insulin sensitivity [Nino, A.J. et al., Abst 896]. A nephroprotective effect of rosiglitazone in experimental animal models was related to the upregulated expression of pigment epithelium-derived factor and matrix metalloproteinase-2 and decreased transforming growth factor-ß1 [Tan, L.X. et al., Abst 1218]. On the other hand, a fixed-drug combination of rosiglitazone and metformin significantly improved glycemia compared to metformin alone in treatment-naive patients with type 2 diabetes, with marked benefits on insulin sensitivity but an untoward effect on bone mineral density [Jones, A. et al., Abst PS-082]. However, concerns regarding the cardiovascular safety of rosiglitazone resulted in the European Medicines Agency suspending the marketing authorization for the drug, a decision that came during the EASD meeting and prompted a joint statement by EASD and ADA on the need to prioritize care of patients currently receiving the drug and to look for suitable alternatives, without stopping antidiabetic medication and causing even worse health risks [Press Conference with C. Bailey, U. Smith, D. Kendall and D. Matthews].

SODIUM-GLUCOSE COTRANSPORTER TYPE 2 INHIBITORS

Data discussed during this year's meeting in Stockholm confirmed significant insulin-independent improvements in glycemic control by dapagliflozin across various stages of type 2 diabetes progression, from treatment-naive to insulin- and/or metformin-treated patients [Parikh, S. et al., Abst 869] (Fig. 3); through an insulin-sparing effect, dapagliflozin also reduced the rate of insulin uptitration or study discontinuation for lack of glycemic control over a 48-week period in patients with type 2 diabetes suboptimally controlled with insulin [Soler, N.G. et al., Abst 872]. Administered once daily, no differences in glycemic control or tolerability were noted in patients receiving morning or bedtime treatment with the agent [Salsali, A. et al., Abst 868]. A randomized study also confirmed the benefit of adding dapagliflozin to glimepiride for improving glycemic control in patients with type 2 diabetes not controlled with sulfonylurea monotherapy [Strojek, K. et al., Abst 870] (Fig. 4), dapagliflozin also being confirmed as noninferior to glimepiride regarding glycemic control in a 52-week study that suggested lower likelihood of weight gain and hypoglycemia with the sodium-glucose cotransporter inhibitor, although with a higher tendency to be associated with urinary tract and genitourinary infections [Nauk, M. et al., Abst 241].

Fig. 3. Change in hemoglobin A1c levels after 24 weeks of treatment with dapagliflozin mono- or combination therapy with metformin or insulin in placebo-controlled studies [Parikh, S. et al., Abst 869].

Fig. 4. Change in hemoglobin A1c levels after 24 weeks of treatment with dapagliflozin or placebo plus background glimepiride [Strojek, K. et al., Abst 870].

The results of a phase Ib study with canagliflozin presented during this year's EASD meeting in Stockholm confirmed the therapeutic activity of the agent, which lowered the renal threshold for glucose excretion resulting in decreased plasma glucose levels without causing hypoglycemia, and also induced body weight loss and improved ß-cell function in patients with type 2 diabetes [Sarich, T. et al., Abst 874; Rothenberg, P.L. et al., Abst 876] (Figs. 5 and 6). The results of further studies indicated improved glycemic control without the need for increasing daily insulin doses, resulting in weight loss in patients poorly controlled with insulin [Wilding, J.P.H. et al., Abst 871]. Canagliflozin was further confirmed to improve glycemic control, lower body weight and potentiate ß-cell function in a study in type 2 diabetes patients on background metformin [Rosenstock, J. et al., Abst 873] (Fig. 7), while mechanistic studies corroborated an effect in lowering the renal threshold for glucose excretion [Polidori, D. et al., Abst 875].

Fig. 5. Change in body weight after 16 days of treatment with canagliflozin or placebo [Sarich, T. et al., Abst 874].

Fig. 6. Change in fasting plasma glucose levels after 16 days of treatment with canagliflozin or placebo [Rothenberg, P.L. et al., Abst 876].

Fig. 7. Change in hemoglobin A1c levels after 12 weeks of treatment with canagliflozin, sitagliptin or placebo [Rosenstock, J. et al., Abst 873].

Favorable clinical trial results were also reported with the novel agent BI-10773, which induced clinically relevant improvements in glycemic control as effectively as metformin in a placebo-controlled trial in patients with insufficiently controlled type 2 diabetes [Ferrannini, E. et al., Abst 877] (Fig. 8).

Fig. 8. Change in hemoglobin A1c levels after 12 weeks of treatment with BI-10773, metformin (open-label control arm) or placebo [Ferrannini, E. et al., Abst 877].

INCRETIN ANALOGUES, MIMETICS AND AGONISTS

Incretin analogues, mimetics and receptor agonists and dipeptidylpeptidase-4 inhibitors share a common site of action within the pathophysiology of diabetes. According to a meta-analysis comparing both approaches, the former, specifically glucagon-like polypeptide-1 receptor agonists, cause greater reductions in hemoglobin A1c and body weight [Aroda, V.R. et al., Abst 836].

Exenatide was further confirmed superior to placebo regarding glycemic control in type 2 diabetes, specifically, as demonstrated in new clinical studies discussed in Stockholm, when given as add-on to thiazolidinedione therapy with or without background metformin [Liutkus, J. et al., Abst 833]. At similar improvements in hemoglobin A1c, greater benefits were demonstrated with exenatide compared to insulin glargine regarding body weight and the cardiovascular risk profile in patients with type 2 diabetes [Bunck, M.C. et al., Abst 848; Diamant, M. et al., Abst 863] (Fig. 9). Exenatide was likewise noninferior to insulin aspart for glycemic control in patients pretreated with metformin, but offered a superior profile regarding body weight and control of hypoglycemia, although exenatide fared slightly worse than insulin aspart for glycemic control in patients on prior metformin plus sulfonylurea, probably because of a more advanced disease with poorer ß cell reserve [Gallwitz, B. et al., Abst 862]. Also in patients on background metformin, add-on exenatide improved diabetic control as effectively as glimepiride, but offered greater benefits on insulin resistance-related parameters, adiponectin levels, inflammatory status and body weight [Salvadeo, S.A.T. et al., Abst 852], while the addition of exenatide to insulin glargine further improved hemoglobin A1c levels and fasting and postprandial glycemic control of type 2 diabetes with favorable weight loss and no apparent risk for hypoglycemia [Bergenstal, R.M. et al., Abst 73]. Moreover, compared to sitagliptin, exenatide offered superior control of average 24-hour and postprandial glucose levels, in association with a better insulinogenic index [Shenouda, S.K. et al., Abst 831]. Furthermore, according to the DURATION-5 study, weekly exenatide at doses of 2 mg resulted in significantly better glycemic control but lower likelihood for gastrointestinal adverse events than twice-daily administration of 10-µg doses [Pullman, J. et al., Abst 843] (Fig. 10), while switch to once-weekly exenatide improved glycemic control regardless of prior therapy [Mondick, J.T. et al., Abst 841; Wysham, C.H. et al., Abst 842] (Fig. 11); in another study, continuous subcutaneous exenatide infusion offered substantial decreases in hemoglobin A1c levels comparable to twice-daily injectable therapy, offering an alternative with guaranteed compliance and good tolerability [Henry, R.R. et al., Abst 78]. On the subject of body weight during exenatide therapy as opposed to insulin, a comparison between the incretin analogue and bedtime insulin glargine or insulin detemir revealed a decrease in resting energy expenditure after treatment with the insulin analogues, which could explain the lack of body weight benefits with these agents compared to exenatide [Gonzalez, C. et al., Abst 867]. Mechanistically, treatment of type 2 diabetes with exenatide was related to improvements in central responses to food ingestion [Nathan, Y. et al., Abst 225], while in animal models of obesity the agent normalized the deleterious glucose metabolism and hepatic handling of glycogen [Gutiérrez-Rojas, I. et al., Abst 637; Moreno, P. et al., Abst 649]. Furthermore, the agent prevented palmitate-induced ß cell apoptosis [Natalicchio, A. et al., Abst 571] and, in in vitro studies, stimulated proliferation of coronary artery endothelial cells [Erdogdu, Ö. et al., Abst 1315], while also preventing apoptosis of islet endothelial cells in high-glucose conditions [Miceli, I. et al., Abst 161]. A specific topic regarding the use of exenatide as a treatment for type 2 diabetes is the need for adjusting prior insulin therapy. According to an audit, continuing insulin upon initiation of exenatide is safe, whereas a progressive dose reduction of insulin resulted in increasing weight loss at the expense of losing benefit on hemoglobin A1c, without a clear threshold being identified to support any specific recommendations at present [Thong, K.Y. et al., Abst 74; Jose, B. et al., Abst 861]. Furthermore, although anti-exenatide antibodies may develop during therapy, early peaks and progressive decline prevent them from impairing the safety and efficacy of the agent, and as such antibodies do not cross-react with endogenous incretins and glucagon, they lack clinical consequence [Fineman, M. et al., Abst 858]. On the negative side, experimental findings indicated that exenatide increases collagen production by hepatic stellate cells, suggesting potential for inducing liver fibrosis [Firneisz, G. et al., Abst 854], while clinical observations confirmed an effect in lowering glycemia and increasing satiety in patients with Prader-Willi syndrome, suggesting possibilities for expanding the clinical use of the agent [Viardot, A. et al., Abst 144].

Fig. 9. Change in C-reactive protein levels after 26 weeks of treatment with exenatide or insulin glargine [Diamant, M. et al., Abst 863].

Fig. 10. Percentage of patients with improvement of both hemoglobin A1c levels and body weight after 24 weeks of treatment with weekly or twice-daily exenatide [Pullman, J. et al., Abst 843].

Fig. 11. Change in hemoglobin A1c levels after 26 weeks of treatment with exenatide, sitagliptin or pioglitazone, and another 26 weeks of switch to exenatide [Wysham, C. et al., Abst 842].

VRS-859, a derivative of exenatide with the peptidic chain fused to the long hydrophilic tail XTEN to prolong its half-life, proved feasible for improving glycemic control in animal models upon monthly subcutaneous dosing [Cleland, J. et al., Abst 844].

New studies were also reported on liraglutide, which compared to glimepiride offered similar glycemic benefits but additional improvements in body weight and systolic blood pressure, and a lower risk for hypoglycemia, so that patients on liraglutide were more likely to reach hemoglobin A1c goals without weight gain or hypoglycemia [Wenying, Y. et al., Abst 829] (Fig. 12), although according to other studies the benefit of the agent on systolic blood pressure was not associated with meaningful effects on body weight [Fonseca, V.A. et al., Abst 1292] despite weight loss being confirmed in a meta-analysis of placebo-controlled studies of liraglutide [Russell-Jones, D. et al., Abst 835]. Furthermore, liraglutide improved ß-cell function more effectively than exenatide, glimepiride or rosiglitazone based on determinations of the HOMA-B index and proinsulin:insulin ratio during a 26-week treatment period [Matthews, D.R. et al., Abst 851] (Fig. 13). In addition, liraglutide was associated with greater weight loss and higher patient satisfaction than sitagliptin, the treatment being associated with superior perception of efficacy on glycemia and body weight [Montanya Mias, E. et al., Abst 832; Garber, A. et al., Abst 834]. Because of improvements in ß-cell function, use of liraglutide in subjects with type 1 diabetes and residual ß-cell function reduced insulin dose requirements while maintaining or even improving glycemic control [Kielgast, U. et al., Abst 853]. Mechanistically, the activity of liraglutide was further expanded to glucagon-like polypeptide-1 receptor-dependent antiatherosclerosis benefits on tumor necrosis factor-α-induced intercellular adhesion protein expression [Dear, A.E. et al., Abst 158], while the agent was further demonstrated to attenuate endothelial cell endoplasmic reticulum stress in hyperglycemic conditions [Schisano, B. et al., Abst 1313]. The agent was further demonstrated to improve insulin sensitivity in experimental animal models through an effect on adiponectin levels [Zhang, Z. et al., Abst 636]. As an additional issue, it should be noted that a head-to-head comparison demonstrated lower incidence and levels of antidrug antibodies in patients receiving liraglutide compared to exenatide, high-titer anti-exenatide antibodies negatively affecting glycemic responses to the treatment [Buse, J.B. et al., Abst 857]. On the other hand, liraglutide also showed activity in nonalcoholic fatty liver disease, and treatment with the agent of patients with such disease brought about decreases in alanine aminotransferase levels, liver fibrosis scores and body weight accompanied by an increase in platelet counts [Armstrong, M.J. et al., Abst 1349]. In the experimental scenario, the agent modulated appetite by acting on the brainstem and hypothalamic neuronal circuitry [Vrang, N. et al., Abst 159; Raun, K. et al., Abst 847], with only short-lived effects on gastric emptying [Bjerre Knudsen, L. et al., Abst 860], and also showed protective activity against traumatic brain injury-related neuropathological inflammation and oxidative stress [Della Valle, B. et al., Abst 855]. Experimental animal studies also suggested no risk of pancreatitis during treatment with liraglutide in several species [Mølck, A.M. et al., Abst 856].

Fig. 12. Percent of patients with hemoglobin A1c <7.0% after 16 weeks of adding liraglutide or glimepiride to metformin [Wenying, Y. et al., Abst 829].

Fig. 13. Change in the HOMA-B index and proinsulin:insulin ratio after 26 weeks of treatment with liraglutide, rosiglitazone, glimepiride, exenatide or placebo [Matthews, D.R. et al., Abst 851].

With glycemic benefits demonstrated against placebo in randomized, controlled trials that substantiated its favorable tolerability [Raz, I. et al., Abst 839], new clinical results with taspoglutide, a further glucagon-like polypeptide-1 analogue, indicated superiority over exenatide regarding insulin secretion and glycemic control without differences in glucose tolerance, glucagon responses, body weight or tolerability [Bolli, G.B. et al., Abst 75; Ratner, R. et al., Abst 840] (Fig. 14), and superiority over sitagliptin regarding glycemic control and body weight, although with a higher incidence of gastrointestinal adverse events [Chiasson, J.L. et al., Abst 838] (Fig. 15). Weekly taspoglutide was equieffective compared to daily insulin glargine as add-on to metformin in patients not controlled with metformin plus a sulfonylurea, but the similar glycemic control with taspoglutide was accompanied by a much larger drop in body weight [Ampudia-Blasco, F.J. et al., Abst 864] (Fig. 16). Moreover, experimental studies with the agent demonstrated prevention of ß-cell apoptosis and islet inflammation in diabetic-prone, insulin-resistant animal models [Uhles, S. et al., Abst 162]. A further analogue currently in advanced clinical trial research, LY-2189265, demonstrated greater decreases in hemoglobin A1c levels and postprandial glucose excursions in Hispanic compared to non-Hispanic Caucasian patients with type 2 diabetes [Bastyr, E.J. et al., Abst 845].

Fig. 14. Change in fasting plasma glucose levels after 16 days of treatment with dapagliflozin or placebo [Ratner, R. et al., Abst 840].

Fig. 15. Change in body weight after 24 weeks of treatment with weekly taspoglutide, sitagliptin or placebo [Chiasson, J.L. et al., Abst 838].

Fig. 16. Change in body weight after 24 weeks of treatment with weekly taspoglutide or daily insulin glargine [Ampudia-Blasco, F.J. et al., Abst 864].

An additional glucagon-like polypeptide-1 receptor agonist, lixisenatide, also improved glycemic control of type 2 diabetes, as demonstrated in placebo-controlled trials [Gerich, J.E. et al., Abst 830] (Fig. 17), the agent restoring insulin release as well, thus accelerating glucose disposal after an intravenous glucose challenge [Becker, R.H.A. et al., Abst 850].

Fig. 17. Change in hemoglobin A1c levels after 12 weeks of treatment with lixisenatide or placebo. Lixisenatide was administered at final doses of 20 µg adjusted from 10 µg daily for the first week in a one- or two-step titration regimen, the latter including a second week of 15 µg daily [Gerich, J.E. et al., Abst 830].

In the preclinical arena, the glucagon-like polypeptide-1 receptor agonist TAK-875 effectively potentiated glucose-dependent insulin secretion in human pancreatic islets and living animal models of diabetes [Yashiro, H. et al., Abst 243; Takeuchi, K. et al., Abst 882], whereas the novel agent ZP-2929, which possesses dual agonist activity on glucagon and glucagon-like polypeptide-1 receptors, was confirmed to improve glucose control, body weight gain and lipid profiles in animal models of obese insulin resistance [Daugaard, J.R. et al., Abst 886].

AMYLIN ANALOGUES

Integrated analyses of randomized controlled trials in patients with type 2 diabetes confirmed the cardiovascular safety of pramlintide, which did not increase the risk of cardiovascular adverse events during up to 52 weeks of follow-up [Chen, S. et al., Abst 1266].

DIPEPTIDYLPEPTIDASE-4 INHIBITORS

The known clinical efficacy of sitagliptin was corroborated in new clinical trials and observations reported during this year's EASD meeting, which demonstrated hemoglobin A1c-lowering and insulin-sparing activity in type 1 as well as type 2 diabetes [Ellis, S.L. et al., Abst 77], with similar glycemic efficacy compared to glimepiride but with a more favorable impact on body weight and risk of hypoglycemia in type 2 diabetes patients on background metformin [Goldstein, B.J. et al., Abst 819]. A combination of sitagliptin and metformin synergistically increased glucagon-like polypeptide-1 levels more effectively than either monotherapy, offering unique benefits to patients with type 2 diabetes [Migoya, E.M. et al., Abst 818]. In fact, the combination proved superior to pioglitazone in improving glycemic control while lowering body weight in a comparative trial [Pérez-Monteverde, A. et al., Abst 820] (Fig. 18).

Fig. 18. Change in body weight after 28 weeks of treatment with sitagliptin/metformin or pioglitazone [Pérez-Monteverde, A. et al., Abst 820].

The glycemic efficacy of saxagliptin was confirmed in a meta-analysis that demonstrated the superiority of this dipeptidylpeptidase IV inhibitor over placebo regardless of gender, body mass index, age, diabetes duration and other demographic and pathologic variables [Allen, E. et al., Abst 826], although greater drops in hemoglobin A1c levels were noted in patients with higher baseline levels, but higher rates of full glycemic control were obtained in patients with lower baseline levels [Maheux, P. et al., Abst 825] (Fig. 19). In experimental mechanistic studies, saxagliptin, as well as sitagliptin, improved not only glycemic control but also ß-cell mass preservation and pancreatic degeneration in diabetic animal models [Poucher, S.M. et al., Abst 567].

Fig. 19. Percent of patients reaching target hemoglobin A1c levels <7.0% without hypoglycemia after 24 weeks of treatment with saxagliptin or placebo [Maheux, P. et al., Abst 825].

A further dipeptidylpeptidase-IV inhibitor, alogliptin, also showed efficacy in the treatment of type 2 diabetes. As an example, the results of a randomized trial in patients inadequately controlled with metformin plus pioglitazone indicated superiority of adding alogliptin over uptitrating pioglitazone regarding glycemic control and ß-cell function [Bosi, E. et al., Abst 827] (Fig. 20). Alogliptin alone or combined with usual antidiabetic medications such as metformin, pioglitazone, glimepiride or voglibose proved effective for lowering hemoglobin A1c levels in additional studies in patients with type 2 diabetes [Seino, Y. & Kaku, K., Abst 828].

Fig. 20. Change in hemoglobin A1c levels after 52 weeks of adding alogliptin 25 mg or uptitrating pioglitazone from 35 to 45 mg in patients also receiving metformin [Bosi, E. et al., Abst 827].

Mechanistic studies with vildagliptin in preclinical animal models confirmed a role in preserving ß-cell mass and function and inducing ß-cell proliferation in spontaneously diabetic animals through various mechanisms, including direct kinetic cell regulation but also suppression of oxidative and endoplasmic reticulum stress [Yagibashi, S. et al., Abst 569; Hamamoto, S. et al., Abst 849].

Comparing early to delayed treatment of type 2 diabetes in patients not optimally controlled with metformin and/or thiazolidinediones, dulogliptin was superior to placebo, and offered a greater impact on hemoglobin A1c in patients with shorter disease duration, suggesting potential for early treatment of the disease with dipeptidylpeptidase-4 inhibitors [Rosenberg, N. et al., Abst 824] (Fig. 21).

Fig. 21. Change in hemoglobin A1c levels after 12 weeks of treatment with dutogliptin or placebo [Rosenberg, N. et al., Abst 824].

While proving effective for managing hyperglycemia in patients not suitable for metformin therapy [Barnett, A.H. et al., Abst 823] or inadequately controlled with sulfonylureas [Lewin, A.J. et al., Abst 821] (Fig. 22), pharmacokinetic assessments in patients with varying degrees of renal function suggested no need for dose adjustment of linagliptin, even in patients with moderate to severe renal failure [Graefe-Mody, U. et al., Abst 822].

Fig. 22. Percentage of patients with hemoglobin A1c levels <7.0% after 18 weeks of treatment with linagliptin or placebo. Data from two independent studies [Barnett, A.H. et al., Abst 823; Lewin, A.J. et al., Abst 821].

Results were reported with a further novel agent, LC15-0444, which improved glucose and hemoglobin A1c control after an oral glucose tolerance test and also improved ß-cell function and insulin sensitivity in patients with type 2 diabetes [Kim, S.W. et al., Abst 885] (Fig. 23).

Fig. 23. Change in hemoglobin A1c levels after 12 weeks of treatment with LC15-0444 or placebo [Kim, S.W. et al., Abst 885].

OTHER ANTIDIABETIC DRUG FAMILIES

With favorable phase I clinical trial results, the investigational glucokinase activator MK-0941 was also tested positive in phase II studies, supporting further development as a candidate antidiabetic drug [Meininger, G.E. et al., Abst 242].

Glimins are a new class of oral antidiabetic agents targeted at insulin resistance and ß-cell failure through decreasing mitochondrial oxidation. The first glimin to be developed, imeglimin proved as effective as metformin in lowering glucose and hemoglobin A1c levels when administered as monotherapy for type 2 diabetes in two phase II studies [Pirags, V. et al., Abst 884] (Fig. 24).

Fig. 24. Change in glucose AUC during an oral glucose test in patients treated with imeglimin or metformin [Pirags, V. et al., Abst 884].

IMMUNOTHERAPY OF DIABETES

Currently in phase III clinical research, the polypeptide diabetic vaccine AVE-0277 showed potential for preserving ß-cell function and improving glycemic control in type 1 diabetes, according to a pooled analysis of data from individual studies, although without completely abolishing the loss of C-peptide levels over time [Dagan, S. et al., Abst 456] (Fig. 25). A currently ongoing, larger phase III study was announced, interim results of which confirmed the very favorable safety profile of the agent [Ziegler, A.G. et al., Abst 461]. In addition, the good tolerability so far supported continuing the DIAPREV-IT study, in which immunotolerance with alum-GAD is being studied for preventing type 1 diabetes in nondiabetic children with islet autoantibodies [Elding Larsson, H. et al., Abst 458]. In the preclinical scenario, combined use of a CD3 antibody and fingolimod improved ß-cell survival and reduced apoptosis without immune cell infiltration in an animal model of type 1 diabetes [Jörns, A. et al., Abst 428].

Fig. 25. Change in C-peptide AUC six months after a 12-month treatment with AVE-0277 or placebo [Dagan, S. et al., Abst 456].

With a different approach, the CD3ε monoclonal antibody otelixizumab significantly increased regulatory and effector T cells, with the former showing reduced inhibitory potential, playing an immunoregulatory effect in the pathophysiology of type 1 diabetes [Apostolon, I. et al., Abst 443].

GENE THERAPIES FOR DIABETES

At least in the experimental setting, potential in terms of safety and activity was described for skeletal muscle cells engineered to produce insulin and glucokinase [Callejas, D. et al., Abst 1] and lentivirus-vectored furin-cleavable human insulin gene into hepatocytes from immune diabetic animals [Elsner, M. et al., Abst 470].

NOVEL DRUGS IN DEVELOPMENT

Favorable experimental results regarding improvements in metabolic function and adequate pharmacokinetics with good safety and tolerability were the attributes described for the oral chemokine CCR2 receptor blocker CCX-140 [Sullivan, T. et al., Abst 883]. On the other hand, the apical sodium-dependent bile transport inhibitor SC-435 stimulated glucagon-like polypeptide-1 secretion, resulting in improvements in plasma glucose levels, body weight and distal bowel bile acid content in obese, diabetic animals, indicating potential as a therapy for diabesity [Gedulin, B.R. et al., Abst 735]. Also in the preclinical arena, improvements in plasma glucose were associated to treatment with pegylated peptide YY3-36 [Konkar, A. et al., Abst 572], shikonin, a naphthoquinone from Lithospermum erythrorhizon [Yassin, K. et al., Abst 754] and an extract of Lomatogonium rotatum [Khookhor, O. & Sato, Y., Abst 752], whereas safety, tolerability and glucose-stabilizing activity were demonstrated in both experimental animals and healthy volunteers with a product containing Juglans regia (English walnut), Olea europea (common olive), Urtica dioica (great nettle) and Atriplex halimus (sea orache) [Zaid, H. et al., Abst 751]. Clinical data with a further herbal supplement, Gynostemma pentaphyllum (jiaogulan) indicated add-on glycemic benefits to sulfonylurea in patients with type 2 diabetes [Vu, H.T.T. et al., Abst 890]. In addition, favorable in vitro and in vivo results were reported with P-1738, a peroxisome proliferator-activator receptor-α/γ-independent insulin sensitizer that improved glycemic and extraglycemic parameters with a favorable weight profile [Marita, R.A. et al., Abst 881], and with YL-01, a potent AMP-dependent protein kinase activator that improved glucose uptake and fatty acid oxidation in animal models of obesity [Leng, Y. et al., Abst 739]. Furthermore, although not a treatment for diabetes, the natural antioxidant astaxanthin exhibited an insulin-enhancing effect while preventing ß-cell apoptosis in in vitro studies [Ishiki, M. et al., Abst 178], whereas Bifidobacterium lactis 420, a probiotic, reversed high-fat diet-induced diabetes in experimental animals by reducing endotoxemia and adipose tissue inflammation [Burcelin, R. et al., Abst 738]. Finally, resveratrol was associated with improved insulin sensitivity [Brasnyó, P. et al., Abst 755], a reduction in hepatic gluconeogenesis [Sanz, M.N. et al., Abst 892] and enhanced glucose-dependent insulin secretion in insulinoma cells [Vetterli, L. et al., Abst 92] in isolated cell studies, whereas in in vivo studies, the red wine polyphenol improved skeletal muscle mitochondrial function, but paradoxically increased markers of inflammation [Lambert, K. et al., Abst 949].

TRANSPLANTATION

At least in the experimental preclinical arena, cotransplantation of pancreatic islets with endothelial progenitor cells [Kang, S. et al., Abst 127] or mesenchymal stem cells [King, A.J.F. et al., Abst 485] enhanced islet engraftment, vascularization, transplantation outcomes and survival.

Although not the main focus of this report, it should be noted that sirolimus and mycophenolate mofetil used in tacrolimus-based steroid-free immunosuppressive regimens for pancreas/kidney transplantation did not result in meaningful differences in glucose metabolism [Havrdova, T. et al., Abst 462], although sirolimus was noted to impair proliferation of transplanted ß cells [Parnaud, G. et al., Abst 481].

DIABETES COMPLICATIONS AND COMORBIDITIES

Obesity

Obesity is a major risk factor for diabetes and a common comorbidity that worsens cardiovascular risk and requires specific management. Phentermine/topiramate has been shown effective in improving body weight, lipid levels and the cardiovascular risk profiles of obese patients, and new data also indicated benefits on glucose impairment and glycemic control in patients with impaired fasting glucose or impaired glucose tolerance [Van Gaal, L.F. et al., Abst 773], while in patients with type 2 diabetes, treatment with the combination led to improved glycemic control and a resulting decrease in the number of antidiabetic medications required [Garvey, W.T. et al., Abst 774]. On the contrary, no benefit on insulin sensitivity could be demonstrated in obese individuals treated with the interleukin-1 receptor blocker anakinra [van Asseldonk, E.J.P. et al., Abst 597].

Within the experimental preclinical chapter, improvements in glucose homeostasis, insulin secretion and body weight accompanied by benefits on fat metabolism markers were obtained with the anorexigenic oxyntomodulin analogue (d-Ser2)Oxm[mPEG-PAL] [Gault, V.A. et al., Abst 20]. Similar improvements in glycemia, glucose tolerance and insulin levels were demonstrated with the bradykinin type 1 receptor blocker SSR-240612 in further experimental models of obesity [Sörhede Winzell, M. et al., Abst 126], whereas SAR-707 and related hexahydropyrrolopyrole heterocyclic inhibitors of stearoyl-coenzyme A desaturase improved body weight and glucose and triglyceride levels [Voss, M.D. et al., Abst 764] and the the dipeptidylpeptidase-IV inhibitor A desfluorositagliptin prevented ß-cell apoptosis and glucolipotoxicity in animal models of diet-induced obesity [Shirakawa, J. et al., Abst 568]. Fat-eliminating effects and improvements in fat metabolism and food intake were likewise demonstrated with fumagillin [Hughes, T.E. et al., Abst 244]. In addition, downregulation of 11ß-hydroxysteroid dehydrogenase type 1 and corticosterone levels by Labisia pumila extract in ovariectomized animal models also suggested potentially beneficial antiobesity activity [Fazliana, M. et al., Abst 786].

Diabetic nephropathy

Although intensive glucose control per se is renoprotective in diabetes [Zoungas, S. et al., Abst 221], additional therapies for protecting the kidneys and avoiding diabetic nephropathy have been tested for efficacy and/or have an established role in therapy. Angiotensin-converting enzyme inhibitors are considered suitable candidates for the management of hypertensive and diabetic nephropathy, but the results of the J-MIND study demonstrated similar protective activity of nifedipine retard in a cohort of hypertensive patients with type 2 diabetes treated for two years [Yoshino, G. et al., Abst 1227].

Experimental findings in animal models corroborated the benefits of telmisartan in preventing diabetic renal injuries through inhibition of the Notch signaling pathway [Koshizaka, M. et al., Abst 1224], although results of clinical trials with irbesartan, another drug with demonstrated nephroprotective activity in prior studies, had no impact on Nε(carboxymethyl)lysine and Nε(carboxyethyl)lysine, two advanced glycation endproducts, in patients with microalbuminuric type 2 diabetes [Engelen, L. et al., Abst 1203], but nonsignificantly (at ultralow doses) reduced markers of tubular damage such as kidney injury molecule-1 and urinary neutrophil gelatinase-associated protein [Nielsen, S.E. et al., Abst 1225]. A third angiotensin receptor blocker, losartan, also showed nephroprotective activity in diabetes, reducing albuminuria more effectively than the direct renin inhibitor aliskiren, although the combination of both maximized the benefit [Pankiv, V.I. et al., Abst 187; Parving, H.H. et al., Abst 1286]. The combination of losartan and aliskiren was further demonstrated superior to losartan monotherapy for lowering aldosterone levels in patients with type 2 diabetic nephropathy [Persson, F. et al., Abst 224], whereas an additional sartan, olmesartan, significantly reduced the risk and prolonged the time to microalbuminuria onset in patients with type 2 diabetes and at least one additional cardiovascular risk factor [Haller, H. et al., Abst 222] (Fig. 26). Protection against diabetic nephropathy in hypertensive animal models was also demonstrated with spironolactone [Shanmuganathan, M.V. et al., Abst 1221]. Improvements in diabetic proteinuria in experimental animal models were likewise demonstrated with the cannabinoid CB2 receptor agonist AM-1241 [Barutta, F. et al., Abst 103].

Fig. 26. Cumulative incidence of microalbuminuria during 48 months of treatment with olmesartan or placebo [Haller, H. et al., Abst 222].

Anemia is common in chronic kidney disease, but according to observations discussed in Stockholm, treatment with epoetin of diabetic chronic kidney disease patients on hemodialysis improved hemoglobin levels, while also lowering hemoglobin A1c levels but without affecting glucose levels [Ng, J.M. et al., Abst 1202].

Diabetic retinopathy

Clinical study results reported during this year's EASD meeting in Stockholm confirmed the benefit of ranibizumab alone or as adjunct to laser photocoagulation compared to laser photocoagulation alone in patients with diabetic macular edema [Massin, P. et al., Abst 1192] (Fig. 27).

Fig. 27. Change in best corrected visual acuity after treatment with ranibizumab, laser photocoagulation or the combination of both [Massin, P. et al., Abst 1192].

New experimental findings in the setting of diabetic retinopathy indicated prevention of oxidative damage and activation of nitric oxide synthase in the diabetic retina by Camellia sinensis (green tea), suggesting a potential preventive effect against this diabetic complication [Silva, K.C. et al., Abst 1193]. In the same context, the natural isoflavone puerarin prevented advanced glycation endproduct-induced retinal pericyte apoptosis in diabetic animal models [Kim, J. et al., Abst 1190]. Although not a drug developed for the treatment of diabetic retinopathy, experimental studies in human retinal pigment epithelial cells cultured under diabetic-like conditions revealed reduced overexpression of fibronectin upon exposure to fenofibrate, suggesting potential for reducing blood-retinal barriers leakage associated to diabetic retinopathy [Roy, S. et al., Abst 1189]. In a similar way, improved survival of retinal epithelial cells by prevention of stress kinase activation resulted from exposure to fenofibric acid [Valverde, A.M. et al., Abst 1188].

Diabetic neuropathy

Duloxetine, amitryptiline and pregabalin are among the agents that may offer subjective improvements in patient with painful diabetic neuropathy, although according to new clinical trial evidence only duloxetine also improves pain interference, sleep and mood [Gribble, L. et al., Abst 26].

Diabetic foot

Intravenous or oral moxifloxacin proved equieffective to intravenous piperacillin/tazobactam combined followed by oral amoxicillin/clavulanate in the treatment of diabetic foot infections, offering a valid alternative for patients with moderate to severe disease [Schaper, N.C. et al., Abst 1167]. On the contrary, the results of a randomized controlled trial could not confirm the superiority of soluble ß-1,3/1,6-glucan over placebo in the treatment of diabetic foot ulcers [Jeffcoate, W.J. et al., Abst 119], whereas a further controlled study could not demonstrate any benefit of a phenytoin-containing dressing on ulcer closure time or area [Shaw, J. et al., Abst 1168].

Dyslipidemia and metabolic syndrome in diabetes

While a triple combination of fenofibrate, pravastatin and ezetimibe improved the atherogenic lipid profile in type 2 diabetes as or more effectively than ezetimibe/simvastatin, with a greater benefit on triglyceride and fibrinogen levels [Farnier, M. et al., Abst 1296] (Fig. 28), the increased effectiveness of ezetimibe/simvastatin over atorvastatin in atherogenic lipid levels in patients with metabolic syndrome with or without atherosclerotic vascular disease translated into a lower risk for cardiovascular events [Rosen, J. et al., Abst 1260].

Fig. 28. Change in lipid and fibrinogen levels after 12 weeks of treatment with fenofibrate 160 mg/pravastatin 40 mg plus ezetimibe 10 mg or ezetimibe 10 mg/simvastatin 49 mg [Farnier, M. et al., Abst 1296].

While niacin use was associated with a decrease in triglyceride levels that resulted from increased vascular lipolysis and increased reverse cholesterol transport [Krempf, M. et al., Abst 1262], treatment of diabetic dyslipidemia with niacin/laropiprant resulted in a switch towards a less atherogenic lipid profile, with marked decreases in very small and small and relatively smaller decreases in large LDL particles, but significant decreases in LDL-cholesterol and triglyceride and increases in HDL-cholesterol levels [O'Neil, E. et al., Abst 1299].

With efficacy for reducing LDL-cholesterol in patients with type 2 diabetes [Garg, S.K. et al., Abst 18], adding colesevelam also improved glycemic control compared to metformin alone in Hispanic patients with type 2 diabetes [Hernandez-Triana, E. et al., Abst 894]. Furthermore, colesevelam also lowered LDL-cholesterol levels while improving the overall metabolic profile in hypercholesterolemic individuals with prediabetes [Handelsman, Y. et al., Abst 1294].

A further concept in the management of atherogenic dyslipidemia, specifically in prediabetic patients with impaired glucose tolerance, the peroxisome proliferator-acivated receptor-α/δ agonist GFT-505 arose in initial clinical trials as a safe drug candidate for improving insulin resistance while effectively improving the lipid profile [Hanf, R. et al., Abst 880]. On the other hand, the δ agonist GW-501516 enhanced mitochondrial energy metabolism and uncoupling, resulting in attenuated insulin secretion in ß cells exposed to palmitate [Jiang, L. et al., Abst 498].

As complementary information, ω3-polyunsaturated fatty acids proved superior to triacylglycerols for improving hepatic steatosis in animal models of high fat-induced obesity [Jelenik, T. et al., Abst 943], and in fact ω3-polyunsaturated fatty acid-enriched diets improved the overall metabolic profile and reduced the cardiovascular risk in patients with metabolic syndrome [Dragomir, A.D. et al., Abst 944]. Improvements in fatty liver in similar animal models were likewise demonstrated with berberine [Chang, X. et al., Abst 760], whereas silibinin reversed high-fructose diet-induced insulin resistance in additional experimental models through an inhibitory effect on glucose-6-phosphatase [Sánchez-Martín, C. et al., Abst 891]. Also in the context of dietary supplements, octyl-d-carnosine showed potential usefulness in the prevention of atherosclerosis and renal disease in experimental animals [Menini, S. et al., Abst 65], while d-carnosine supplementation offered also protection against diabetic nephropathy in diabetic/obese animal models [Iacobini, C. et al., Abst 106].

Hypertension

Hypertension is another highly prevalent cardiovascular risk factor that frequently coexists with diabesity. Although no major news on the treatment of hypertension were reported other than a study corroborating the superiority of aliskiren/hydrochlorothiazide over amlodipine regarding blood pressure control rates [Townsend, R.R. et al., Abst P1285], this being a meeting on diabetes rather than hypertension, a number of important news related to antihypertensive medications were discussed. These included clinical observations that revealed improvements in insulin sensitivity and ß-cell function brought about by valsartan without resulting in improved microvascular function in patients with impaired glucose metabolism [Van der Zijl, N.J. et al., Abst 595; Moors, C.C.M. et al., Abst 596], the results of a study that demonstrated improvements in adipose tissue function in normotensive subjects with impaired glucose metabolism treated with valsartan [Goossens, G.H. et al., Abst 600], and those of an experimental study that revealed a preventive effect of cilnidipine against progression of diabetic renal failure [Matsuura, K. et al., Abst 1223]. Also at an experimental level, irbesartan induced an insulin-sensitizing effect that resulted in increased insulin-induced capillary density in mild hypertension [Jonk, A.M. et al., Abst 740], whereas losartan was noted to protect pancreatic islets against glucotoxicity and endoplasmic reticulum oxidative stress, which could have important implications on type 2 diabetes and islet transplantation [Pan, Y. et al., Abst 518].

Coronary artery disease and atherosclerosis

Diabetes carries an increased risk for cardiovascular events, and in fact hyperglycemia has been associated with increased platelet reactivity and poor antiplatelet response to aspirin, although good glycemic control and increased doses of aspirin may be able to overcome insufficient responses in such patients [Lemkes, B.A. et al., Abst 1325]. A study in platelets from nondiabetic patients on chronic aspirin therapy demonstrated loss of response to the antiplatelet agent in vitro upon exposure to high glucose levels, further explaining the role of hyperglycemia on reduced aspirin sensitivity [Russo, I. et al., Abst 1326].

Independently of atherosclerotic coronary artery disease, suggestions of a benefit of benfotiamine on diabetes-associated myocardial damage were discussed based on observations of an effect for the vitamin B1 analogue on survival and proliferation of cardiac stem cells in diabetic or hyperglycemic conditions [Katare, R.G. et al., Abst 1339].

DIET, GLUCOSE, INSULIN AND METABOLIC SYNDROME

Diet is a major risk factor for diabetes, insulin resistance, obesity and the metabolic syndrome, and a brief summary of a number of observations supporting such a role and offering strategies to overcome the negative impact of diet on health are worth including in this report. Among these, a nine-year survey in French volunteers identified an inverse relationship between dairy product consumption and calcium intake and the incidence of insulin resistance and most individual components of the metabolic syndrome, supporting increased dairy product intake as a strategy for lowering cardiovascular risk [Fumeron, F. et al., Abst 357]. Add that fermented milk intake was also related with decreased risk for type 2 diabetes and improved insulin sensitivity [Sonestedt, E. & Orho-Melander, M., Abst 358], whereas direct high-dose vitamin D supplementation significantly increased regulatory T cell counts in healthy volunteers, further suggesting a link between vitamin D deficiency and autoimmune diabetes [Prietl, B. et al., Abst 441].

Diet is not only important for preventing diabetes, obesity, atherosclerosis and metabolic syndrome, but also as component of the management of these diseases. In the specific case of diabetes, results from the DAFNE study were reported in Stockholm, indicating a reduction in insulin requirements in patients with type 1 diabetes participating in a lifestyle educational program that included recommendations on diet and physical activity [Leelarathna, L. et al., Abst 1026].

MISCELLANEOUS

Compared to alfacalcidol and no intervention, use of raloxifene in postmenopausal women with diabetes improved not only bone metabolism, but also LDL-cholesterol levels and the overall lipid metabolism profile [Mori, H. et al., Abst 1267].

Chronic caffeine ingestion reversed age-related insulin resistance in experimental animals independently of any effect on body weight, visceral fat and oxidative stress [Conde, S.V. et al., Abst 753].

Modafinil improved hypoglycemia-related warning signals compared to placebo without differences on hormonal responses or cognitive function [Thomakos, P. et al., Abst 590].

By inhibiting endoplasmic reticulum stress as a consequence of inhibiting CYP2E1, α-lipoid acid exerted a positive effect on nonalcoholic fatty liver disease in experimental animal models [Kim, M. et al., Abst 1351].