September 29 - October 2 , 2009
Vienna
INTRODUCTION
September 29-October 2, 2009
Vienna, Austria
Although the FIELD study demonstrated that it is possible to maintain glycemic control in type 2 diabetes, as evidenced in a large cohort of patients treated with standard therapy with metformin, sulfonylureas and insulin over a 5-year period [Best, J.D. et al., Abst 211], the fact is that many patients require additional therapies, and despite the large number of treatment options available, many patients still develop complications directly related to long-term glycemic imbalance. On that basis, new research discussed this year by the Prater, which in itself is a place for fun (theme parks) and relaxation (walks around the park and the Danube banks), but also for scientific discussions at the Messe (convention center), pointed towards improved therapies for a better future. And Vienna is indeed a good place to start thinking seriously about diabetes, being as it is renowned for not just Sacher Torte, but for an endless array of Contitorei serving sweets and pastries; these are lovely to look at and taste great, but are also very easy to abuse, thus increasing the chances of developing type 2 diabetes. Happily, most of these contain chocolate, which, at least in the case of dark chocolate, contains polyphenols that improve endothelial function [Mellor, D. et al., Abst 1291]; furthermore, sweets and pastries are normally combined with a superb selection of coffees, and coffee has been shown to have a favorable impact on diabetic pathophysiology. Most locals and visitors are also smart enough to enjoy a taste of sweets without overeating, and education is in fact of utmost importance for both prevention and treatment of diabetes, as emphasized in a number of presentations during the meeting. Vienna is very much worth a visit. But if discussions such as those held during the European Association for the Study of Diabetes annual meeting are added to the lot, the satisfaction of the visit is multiplied to a great Heurigen. Let’s help increase the success of such a meeting by summarizing and reviewing some of the most outstanding findings on antidiabetic therapies presented and discussed during the meeting. And in addition to new information on established and potential novel therapeutic options detailed in the following report, we would like to point out an interesting finding: besides the known role of abdominal visceral fat as a marker for metabolic syndrome, data from a cross-sectional study identified neck fat as a subcutaneous fat deposit of particular importance for whole-body insulin resistance [Thamer, C. et al., Abst 670].
INSULIN
Insulin remains the mainstay in the treatment of type 1 diabetes, and is required by the vast majority of patients with type 2 diabetes, in whom while consistently improving hemoglobin A1c levels [Liebl, A. et al., Abst 964], basal insulin therapy was related to better satisfaction and healthy-related quality of life compared to alternative treatments [Boltri, J.M. et al., Abst 911], although frequent dose self-adjustments by well-educated outpatients did not translate into improved metabolic control [Beluchin, E. et al., Abst 212]. Overall, insulin therapy has brought about significant benefits on hemoglobin A1c levels without a negative impact on patient satisfaction [Raskin, P. et al., Abst 969], the glycemic response depending mostly on age, gender, body mass index, baseline hemoglobin A1c levels and the particular insulin regime utilized [Idris, I. et al., Abst 905; Jovanovic, L. et al., Abst 909], and in that respect, real-life data revealed a preference for insulin analogs over human insulins, although human insulins are still widely used in the population [Heintjes, E.M. et al., Abst 908]. As a reminder, intensified insulin therapy was described as remarkably active, particularly in type 2 diabetes patients with overt obesity [Jackson, J.A. et al., Abst 910], and basal insulin therapy in such patients was self-perceived as beneficial, with increased satisfaction and health-related quality of life [Boltri, J.M. et al., Abst 911].
A particular form of insulin therapy, continuous subcutaneous infusion, was associated with improved glycemic control and health-related quality of life in patients with type 2 diabetes [Chen, X. et al., Abst 941; Edelman, S.V. et al., Abst 943], at the cost of a non-irrelevant incidence of hypoglycemia, especially nocturnal hypoglycemia, if too-tight glucose control was attempted [Li, M., Abst 940]M; subcutaneous insulin remained effective and safe in the management of type 1 diabetes during pregnancy [Cyganek, K. et al., Abst 1193]. Furthermore, continuous subcutaneous insulin infusion was superior to intensified insulin therapy in improving family cohesion, wellbeing and coping with type 1 diabetes [Liouri, E. et al., Abst 944], without differences between the two approaches regarding attainable glycemic control in properly educated patients [Howorka, K. et al., Abst 945; Halter, C. et al., Abst 956]. In addition to continuous subcutaneous infusion, continuous peritoneal insulin delivery also proved feasible, resulting in improved insulin-like growth factor-I activity [Hedman, C.A. et al., Abst 958].
Noninjectable formulations of insulin have been developed to facilitate administration and improve patient compliance. One such is inhalable Technosphere/insulin, which with a two-component (fast followed by proteolysis- and mucociliary clearance-dependent reduced) profile of insulin absorption [Gotfried, M. et al., Abst 955], improved glycemic control and did not induce meaningful changes in lung function or radiological appearance during up to four years of treatment in adults with type 1 or 2 diabetes [Amin, N. et al., Abst 215; Petrucci, R. et al., Abst 919; Phillips, M. et al., Abst 920; Rossiter, A. et al., Abst 921] and showed faster suppression of endogenous glucose production than insulin lispro [Potocka, E. et al., Abst 952], while remaining feasible without pharmacokinetic alterations in patients with chronic obstructive pulmonary disease [Richardson, P. et al., Abst 954]. Additional studies confirmed the equiefficacy of Technosphere/insulin with rapid-acting insulin, both combined with insulin glargine [Kapsner, P. et al., Abst 982], whilst documenting the low likelihood for hypoglycemia during treatment with the inhaled insulin [Howard, C. et al., Abst 983], while yet further trials confirmed the satisfaction and benefits of a further inhalable insulin formulation: rDNA-origin human insulin monomer powder [Peyrot, M. & Rubin, R.R., Abst 1009]. Other novel insulin formulations include intranasal insulin, which had no impact on neuronal brain processing of food pictures in obese subjects [Guthoff, M. et al., Abst 502], buccal insulin spray, which in a proof-of-concept study proved of value for reducing postprandial hyperglycemia in obese patients with impaired glucose tolerance [Palermo, A. et al., Abst 950], and alginate-coated, chitosan-polyethylene glycol-albumin-based [Damge, C. et al., Abst 947] and poly(lactide-co-glycolide) acid-based [Reix, N. et al., Abst 948] oral insulin nanoparticle formulations that showed optimal pharmacological and pharmacokinetic profiles and, in the case of the former, prolonged antidiabetic effects in the experimental arena.
INSULIN ANALOGS
Without increasing treatment costs [Gundgaard, J. et al., Abst 216], insulin analogs may offer equivalent or improved glycemic control compared to standard insulin while being associated with a lower risk for hypoglycemia, particularly nocturnal and severe hypoglycemia [Caballero-Corchuelo, J. et al., Abst 987], and while being associated, according to a retrospective chart analysis, with superior renal outcomes in patients with renal failure [Hasslacher, C. & Moecks, J., Abst 1065]. The improved glycemic control during treatment with insulin analogs was also associated with better cardiac function compared to intensive conventional insulin therapy with human insulin [Siegmund, T. et al., Abst 1244].
With equiefficacy or slight superiority compared to rapid-acting human insulin but a lower risk of nocturnal hypoglycemia [Lorber, D. et al., Abst 918; Skrzekowska-Baran, I. et al., Abst 986], biphasic insulin aspart was associated with improved glycemic control in elderly type 2 diabetes patients [Borzi, Y. et al., Abst 888] and better control of postprandial hyperglycemia compared to insulin glargine, both combined with metformin and glimepiride, in patients with type 2 diabetes, although the similar low rates of hypoglycemia were accompanied by a somehow increased risk for nocturnal hypoglycemia during treatment with biphasic insulin aspart [Franek, E. et al., Abst 213] (Fig. 1). In fact, biphasic insulin aspart was confirmed as an effective therapy for type 2 diabetes regardless of initial or final injection regimen in the IMPROVE observational study, albeit with twice-daily regimens showing increased potential for controlling glycemia [Ligthelm, R.J. et al., Abst 214]. However, insulin glargine remains an effective option for improving glycemic outcomes in patients suboptimally controlled with oral therapies [Hajos, T.R.S. et al., Abst 973], with equiefficacy to insulin detemir in type 1 diabetic patients on continuous glucose monitoring [Tsujimo, D. et al., Abst 951]; although it exhibited a lower probability for reaching hemoglobin A1c levels under 7.0% in patients with higher baseline levels, this was not related with differing risks for hypoglycemia, which were low across all quintiles of hemoglobin A1c in a large study [Zhou, R. et al., Abst 893], and in fact better control of hemoglobin A1c was demonstrated with insulin glargine relative to human insulin in a pooled analysis of four randomized trials [Lee, P.G. et al., Abst 971]. It was also superior compared to exenatide in U.S. surveys and pharmacoeconomic analyses [Bhushan, R. et al., Abst 746; Herman, W.H. et al., Abst 1044]; furthermore, relative to thiazolidinediones [Dandona, P. et al., Abst 895] and compared to insulin detemir, basal-bolus insulin glargine in the treatment of type 2 diabetes required lower doses [Swinnen, S.G.H. et al., Abst 966], was equieffective on a weight:hemoglobin A1c ratio according to some assessments [Dailey, G. et al., Abst 970], incurred lower overall costs of care [Bierwirth, R.A., Abst 889] and, in experimental models, better preserved signaling in the hippocampus and cortex and promoted memory and learning [Sasaoka, T. et al., Abst 1235], although compared to human insulin, insulin aspart was also associated with reduced costs and risk for cardiovascular complications [Pollock, R.F. et al., Abst 891]. Insulin glulisine is another fast-acting option, actually faster-acting than insulin aspart according to a comparative study in healthy volunteers [Hövelmann, U. et al., Abst 890], the use of which was related with lower glucose levels immediately after a meal in diabetic, obese patients because of the faster subcutaneous absorption compared to insulin aspart [Bolli, G.B. et al., Abst 968] (Fig. 2).
Fig. 1. Change in hemoglobin A1c levels after 26 weeks of treatment with biphasic insulin aspart or insulin glargine, both combined with metformin and glimepiride [Franek, E. et al., Abst 213].
Fig. 2. Postprandial glucose AUC during the first hour and first 6 hours after a meal in patients treated with insulin aspart or insulin glulisine [Bolli, G.B. et al., Abst 968].
With duration of action comparable to neutral protamine insulin lispro, single-dose insulin detemir showed a flatter, more even metabolic effect over a 32-hour period, as well as showing less variability [Korsatko, S. et al., Abst 499], while compared with insulin glargine, both shared similar impact on hepatic glucose metabolism [Moore, M.C. et al., Abst 892], although insulin glargine was associated with better improvements in hemoglobin A1c in absence of increased risk for hypoglycemia [Blonde, L. et al., Abst 894]. Overall, insulin detemir offered comparable or superior glycemic control compared to human insulin, but at a lower risk for hypoglycemia and a better impact on body weight [Hermansen, K. et al., Abst 914; Szypowska, A. et al., Abst 984; Thalange, N. et al., Abst 985]. Furthermore, experimental animal studies correlated the more moderate but consistent glucose-lowering effects of insulin detemir with the lower risk for hypoglycemia [Vasselli, J.R. et al., Abst 501], while in vitro studies suggested better stimulation of glucose uptake in visceral adipocytes and less adipogenesis of subcutaneous and visceral adipocytes compared to human insulin [Cignarelli, A. et al., Abst 694]. Moreover, insulin detemir was related to weight-sparing effects associated with increased adiponectin levels and decreased adiposity [Fledelius, C. et al., Abst 727]. These were also advantages of insulin glargine compared to natural human insulin, which also arose as an effective therapy with a much lower risk for hypoglycemia, and particularly nocturnal hypoglycemia [Home, P.D. et al., Abst 915].
INSULIN MIMETICS
Although in very early stage of development, promising results were described with the insulin mimetic VO(dmmp)2, an oxyvanadium compound that mimicked insulin action on glucose uptake by adipocytes and showed synergism with insulin at low concentrations [Passadouro, M. et al., Abst 512]. In addition, D-chiro-inositol was reported to act as an insulin mimetic on epinephrine-stimulated hepatic glucose output [Loomes, K.M. et al., Abst 511].
BIGUANIDES
By activating the cyclic AMP-dependent protein kinase pathway, metformin prolonged survival of L-cells without a direct effect on glucagon-like polypeptide-1 secretion [Lauffer, L.M. et al., Abst 198]. Mechanistically, the agent was also shown to improve natural killer cell activity in type 2 diabetes faster and to a greater extent than gliclazide [Piatkiewicz, P.J. et al., Abst 494]. Whether or not related to these mechanisms, a combination of metformin and pioglitazone improved diabetic control as effectively as pioglitazone plus sitagliptin, but only the combination with metformin improved insulin resistance-related parameters in type 2 diabetes [Derosa, G. et al., Abst 530] (Fig. 3), although high-dose metformin was related to reduced glycation and oxidative damage to apolipoprotein B100, which by decelerating atherosclerosis further improved the cardiovascular health of patients [Rabbani, N. et al., Abst 1293]. Further observations related to metformin’s actions included observations of an inhibitory effect on nitric oxide production independent of MyD88 signaling in macrophages [Kato, Y. et al., Abst 699], a down-modulatory effect on von Willebrand’s factor, adhesion molecules, tissue plasminogen activator and C-reactive protein levels suggesting antiinflammatory activity and improvements of endothelial regulation of hemostasis, leukocyte adhesion and fibrinolysis [Kooy, A. et al., Abst 861] and, in the clinical trial setting, improvements in proatherogenic lipid levels [Lund, S.S. et al., Abst 1260]. Regarding toxicity issues, concern about the use of metformin in patients with moderate renal failure derived from observations of increased levels despite dose adjustments, and of accumulation in erythrocytes [Briet, C. et al., Abst 858].
Fig. 3. Change in adiponectin and resistin levels in type 2 diabetes patients treated with pioglitazone combined with either metformin or sitagliptin [Derosa, G. et al., Abst 530].
SULFONYLUREAS
Over a two-year period, switch from insulin to sulfonylureas proved effective in maintaining control of patients with permanent neonatal diabetes carrying mutations of the ATP-sensitive potassium channel KCNJ11 gene [Malecki, M.T. et al., Abst. 347].
Intensive therapy with modified-release gliclazide in the ADVANCE trial resulted in effective control of hemoglobin A1c levels irrespective of age, duration of disease, body mass index or baseline degree of glycemic control [Chalmers, J. et al., Abst 903]. Add to this that according to cross-sectional and cohort studies, gliclazide in the treatment of type 2 diabetes was associated with a lower risk for cardiovascular morbidity and mortality than glibenclamide [Khalangot, M.D. et al., Abst 1315], while differential effects of glibenclamide and gliquidone were demonstrated in beta-cells, with the latter stimulating insulin release but closing ATP-dependent potassium channels more quickly [Liu, S.Y. et al., Abst 431].
When combined with metformin, nateglinide improved glucose tolerance, insulin sensitivity and first-phase insulin secretion in beta-cells of patients with new onset type 2 diabetes [Chang, B.C. et al., Abst 902], whereas residual beta-cell capacity in patients with established type 2 diabetes was stimulated by nateglinide, leading to improved glucose tolerance in such patients [Reusch, J. et al., Abst 576].
THIAZOLIDINEDIONES
While new mechanistic data regarding pioglitazone in the treatment of type 2 diabetes indicated a relationship between increases in plasma adiponectin and HDL-cholesterol and decreases in liver triglyceride levels, at least partly through activation of the AMP-dependent protein kinase, which stimulates fatty acid oxidation in the liver [Nagasawa, K. et al., Abst 661; McCall, T. et al., Abst 1285], a fixed combination of pioglitazone and metformin was shown to significantly improve glycemic control in previously untreated patients compared to the respective monotherapies [Zhao, Z. et al., Abst 854] (Fig. 4), although pioglitazone, but not metformin, reduced fat content [Rijzewijk, L.J. et al., Abst 857], while also improving C-reactive protein and adiponectin levels through a specific effect of pioglitazone [Perez, A. et al., Abst 866] (Fig. 5), which also exhibited an modulatory effect on mature adipocyte proliferation resulting in decreased visceral fat and increased subcutaneous fat [Ishizuka, T. et al., Abst 859]. Furthermore, compared to the lack of effect of ramipril, pioglitazone improved thrombocyte function and reduced inflammation in nondiabetic patients with increased cardiovascular risk [Pfützner, A. et al., Abst 855]. However, the possibility of unfavorable effects of pioglitazone on brain natriuretic peptide levels in patients with type 2 diabetes was described based on the results of a prospective randomized trial, in which the superiority of pioglitazone over miglitol regarding hemoglobin A1c and fasting plasma glucose was accompanied by a significant increase in levels of the cardiovascular risk marker [Shirabe, S. et al., Abst 853] (Fig. 6), while further studies showed relationships between on-treatment edema and salt sensitivity [Nakamura, A. et al., Abst 863] and between on-treatment weight gain and shift from visceral to subcutaneous adipose tissue [Taneda, S. et al., Abst 864]. Furthermore, thiazolidinedione therapy, but not sitagliptin, exacerbated ovariectomy-induced bone loss in experimental animals [Cusick, T. et al., Abst 856].
Fig. 4. Percent of patients with hemoglobin A1c 7% or less after 24 weeks of treatment with pioglitazone, metformin or the fixed-drug combination [Zhao, Z. et al., Abst 854].
Fig. 5. Change in C-reactive protein and adiponectin levels during 24 weeks of treatment with pioglitazone, metformin or the fixed-drug combination [Perez, A. et al., Abst 866].
Fig. 6. Change in hemoglobin A1c, fasting plasma glucose and brain natriuretic peptide levels after treatment with pioglitazone or miglitol [Shirabe, S. et al., Abst 853].
Rosiglitazone was also demonstrated to prevent the degeneration of islets isolated from obese, diabetic-prone animals [Jones, H.B. et al., Abst 71], while clinical data suggested further benefits by protecting against cognitive decline in the elderly with type 2 diabetes and mild cognitive impairment [Abbatecola, A.M. & Paolisso, G., Abst 148]. From a mechanistic point of view, the favorable impact of rosiglitazone on insulin sensitivity in muscle was related to changes in plasma lipid levels, specifically relative increases of monounsaturated fatty acids and particularly palmitoleic acid [Jelenik, T. et al., Abst 658]. However, rosiglitazone, but not pioglitazone, promoted lipogenesis and increased hepatocyte lipid content, suggesting better overall improvement in the lipid profile in diabetic patients with pioglitazone compared to rosiglitazone [Degrace, P. et al., Abst 852]. Regarding biomarker studies, the fact that rosiglitazone improved insulin sensitivity but did not reduce plasma levels of retinol-binding protein-4 suggested the unlikeliness of the latter as a useful marker of insulin resistance in type 2 diabetes [Renzhe, L. et al., Abst 865].
Before turning to novel agents in development, a population-based retrospective survey suggested benefits of the currently available thiazolidinediones in lowering the risk of cancer mortality in patients with type 2 diabetes compared to patients treated only with sulfonylureas [Bowker, S.L. et al., Abst 899].
A novel thiazolidinedione in early clinical research, BLX-1002 was shown to potentiate high-glucose-, glucagon-like polypeptide-1- and tolbutamine-induced insulin secretion in beta-cells from diabetic and obese, but not normal animals [Zhang, F. et al., Abst 438].
In relation with thiazolidinediones, while the selective peroxisome proliferator-activated receptor-gamma modulator T-131, pharmacodynamic activity of which was confirmed in preclinical models [Higgins, L.S. et al., Abst 1259], improved glycemic control and insulin sensitivity in patients with poorly controlled type 2 diabetes [DePaoli, A.M. et al., Abst 871], the peroxisome proliferator-activated receptor-alpha/gamma modulator aleglitazar showed glucose-lowering and insulin-sensitizing potential in experimental animal models [Hansen, B.C. et al., Abst 867] while DSP-8658 proved a promising option for the treatment of type 2 diabetes, with a gene expression regulation profile distinct from that of drugs such as pioglitazone [Hirota, K. et al., Abst 508].
AMYLIN AGONISTS
Although no major news was discussed in Vienna on pramlintide, a study was presented revealing similar improvements in glycemic control compared to rapid-acting basal insulin therapy but with lower risk of hypoglycemia and no weight gain, pointing to two clinically significant advantages of pramlintide for type 2 diabetes [Karounos, D. et al., Abst 912].
INCRETIN ANALOGS AND MIMETICS
While new observations suggested long-term tolerability [Wintle, M. et al., Abst 768], even in very elderly patients [Linnebjerg, H. et al., Abst 782], maintenance of glycemic and weight benefits over a two-year period [Trautmann, M. et al., Abst 730] and no increased risk for acute pancreatitis in patients initiating exenatide compared to other antidiabetic therapies [Bloomgren, G. et al., Abst 6] (with improvements rather than worsening of pancreatic enzyme secretion at least in experimental models [Parkes, D. et al., Abst 771]), and other studies suggested effective glycemic control with minimal weight gain compared to insulin glargine in overweight, type 2 diabetes patients [Davies, M.J. et al., Abst 738] and maintained glycemic control with significant weight loss upon switch from premeal rapid-acting insulin to exenatide in well controlled type 2 diabetes patients [Cusi, K. et al., Abst 248], improvements in beta-cell function following exenatide therapy were confirmed in patients with type 2 diabetes for at least five weeks after treatment discontinuation [Bunck, M.C. et al., Abst 1]. Comparatively, weekly exenatide was well tolerated and improved glucose and hemoglobin A1c levels more effectively than pioglitazone or sitagliptin, with a more favorable impact on body weight [Wysham, C. et al., Abst 739; Best, J.H. et al., Abst 745] (Fig. 7), and real-life data further supported the overall effectiveness of exenatide in the management of type 2 diabetes [Ryder, R.E.J. et al., Abst 741]. Moreover, a direct relationship was demonstrated between weight loss and improvements in blood pressure and the overall cardiovascular risk profile during treatment with exenatide across a broad range of body mass index at baseline in overweight and obese individuals [Berria, R. et al., Abst 755; Ruggles, J. et al., Abst 756], with consistent cardiometabolic benefits maintained over the long term [Bergenstal, R. et al., Abst 758; Shen, L. et al., Abst 759], including beneficial changes of adiponectin and leptin levels in obese patients compared to the untoward effects of glimepiride [Gallwitz, B. et al., Abst 795], and meaningful reductions of systolic, diastolic and central pulse pressure and other cardiovascular risk factors not obtained by other treatment modalities such as insulin glargine [Cohen, A. et al., Abst 757, Horton, E.S. et al., Abst 760]. Furthermore, with additive effects on glycemic control, the combination of exenatide and rosiglitazone offset the weight gain effects of the thiazolidinedione [Glass, L.C. et al., Abst 729]. Furthermore, mechanistic data in experimental animals and isolated beta-cells confirmed the potential of exenatide for attenuating endoplasmic reticulum stress-mediated beta-cell damage and apoptosis [Yamane, S. et al., Abst 67; Cunha, D.A. et al., Abst 357], while in vitro data indicated an effect activating the calcium-calmodulin-dependent protein kinase cascade resulting in enhanced expression of ATP-binding cassette transporter A1 in beta-cells [Imachi, H. et al., Abst 193], whereas in the insulin-resistant state treatment increased glucose transporter-4 expression in the skeletal muscle and adipose tissue [Moreno, P. et al., Abst 194; Gutierrez-Rojas, I. et al., Abst 805]. In addition, treatment with exenatide enhanced proliferation of coronary artery endothelial cells independently of any effect on the glucagon-like polypeptide-1 receptor [Erdogdu, Ö. et al., Abst 252] and showed nephroprotective activity in diabetic animal models by downregulation of NADPH oxidase-4 and 8-hydroxy-2’-deoxyguanosine expression [Kodera, R. et al., Abst 1069]. A novel formulation of exenatide for continuous subcutaneous infusion was validated in a phase Ib study as feasible over extended periods of time and therapeutically active in the setting of type 2 diabetes [Luskey, K. et al., Abst 780].
Fig. 7. Percent of patients reaching hemoglobin A1c levels <7.0% or <6.5% during 26 weeks of treatment with exenatide, pioglitazone or sitagliptin [Wysham, C. et al., Abst 739].
A related agent still under clinical research, lixisenatide also proved effective, with dose-dependent improvements in postprandial glucose, glucagon and insulin levels in patients with type 2 diabetes not adequately controlled with metformin [Ratner, R.E. et al., Abst 131] (Fig. 8). However, because of slowing gastric emptying, concomitant lixisenatide and oral contraceptives resulted in adverse pharmacokinetic interactions requiring a 1-hour interval between the latter and the former, although the absorption of paracetamol was unchanged [Liu, Y.H. & Ruus, P., Abst 776].
Fig. 8. Change in postprandial glucose, glucagon and insulin AUC0-4 after 12 weeks of treatment with once- (solid bars) or twice-daily (hatched bars) lixisenatide or placebo [Ratner, R.E. et al., Abst 131].
Without safety or tolerability concerns, switch from exenatide to liraglutide resulted in additional glycemic and beta-cell function benefits in patients with type 2 diabetes on oral antidiabetic medications, reflecting the superiority of liraglutide over exenatide [Buse, J. et al., Abst 2] (Fig. 9), which was confirmed by an analysis of patient willingness-to-pay [Ridderstråle, M. et al., Abst 1040]. Confirmation of the optimal activity of liraglutide was obtained in studies in which, given alone or combined with metformin or sulfonylurea, liraglutide was as effective as or superior to glimepiride or glibenclamide, but associated with a lower risk for hypoglycemia as well as weight loss rather than the weight gain noted with the sulfonylureas [Frid, A. et al., Abst 3; Garber, A.J. et al., Abst 734; Seino, Y. et al., Abst 744], and in a meta-analysis of six large randomized trials, which concluded that add-on liraglutide improved glycemic control whether the prior therapy had been metformin, sulfonylureas, combinations thereof and/or lifestyle interventions [Holst, J.J. et al., Abst 736]. Comparatively, a pooled analysis of the LEAD studies demonstrated higher rates of glycemic control in the absence of weight gain or hypoglycemia in patients treated with liraglutide than subjects receiving exenatide, insulin glargine, glimepiride or rosiglitazone [Zinman, B. et al., Abst 743] and further meta-analysis data confirmed the potential of liraglutide for lowering blood pressure and improving the lipid profile and overall cardiovascular risk profile compared to placebo [Fonseca, V. et al., Abst 761; Plutzky, J. et al., Abst 762] (Fig. 10), although the benefits on triglyceride levels were not accompanied by an impact on adipose tissue lipolysis in patients with impaired fasting glucose [Nelson, R.H. et al., Abst 796l]. Note that the improvements in hemoglobin A1c levels during treatment with liraglutide were independent of weight loss, which was similarly maintained over placebo regardless of extent of glycemic control [Schmidt, W.E. et al., Abst 737]. Furthermore, liraglutide proved superior to glimepiride in patients with best preserved beta-cell function, suggesting enhanced clinical benefits if initiated early [Matthews, D.R. et al., Abst 4]. Liraglutide also showed potential for lowering body weight and reducing the prevalence of prediabetes in obese individuals [Finer, N. et al., Abst 12] (Fig. 11). Turning to new experimental findings, studies in normoglycemic animals and in vitro studies in isolated islets indicated that besides enhancing glucose responsiveness, liraglutide is able to increase beta-cell mass by accelerating cell differentiation and proliferation [Shimoda, M., Abst 68; Rütti, S. et al., Abst 458], while experiments in animal models of type 2 diabetes confirmed the potential for liraglutide in delaying onset of diabetes [Havel, P.J. et al., Abst 784]. On the other hand, along with pharmacokinetic characterization as an agent with delayed absorption and long plasma half-life resulting in protracted activity [Bjerre Knudsen, L. et al., Abst 775], subcutaneous liraglutide was devoid of pharmacokinetic interactions with sitagliptin in experimental animals [Nielsen, F.S. et al., Abst 777] and a dipeptidyl peptidease-4 active metabolite of liraglutide was identified: (gamma-L-glutamyl)(N-alpha-hexadecanoyl)-Lys26-Arg34-glucagon-like polypeptide-19-37 [Tomaselli, K. et al., Abst 774]. In addition to clinical data, studies in diabetic, obesity-prone animals confirmed the normoglycemic benefits of liraglutide, which were not attained by vildagliptin [Heller, R. et al., Abst 801].
Fig. 9. Change in fasting plasma glucose levels (upper panel) and the HOMA-B beta-cell function scores (lower panel) after 26 weeks of treatment with liraglutide or exenatide, and after 14 weeks of continued liraglutide or switch from exenatide to liraglutide [Buse, J. et al., Abst 2].
Fig. 10. Change in lipid levels (upper panel) and other cardiovascular risk markers (lower panel) after 26 weeks of treatment with liraglutide, comparator antidiabetic medications or placebo [Plutzky, J. et al., Abst 762].
Fig. 11. Percent of obese patients switching from prediabetes to normal or from normal to prediabetes status during 20 weeks of treatment with liraglutide, orlistat or placebo [Finer, N. et al., Abst 12].
News was also discussed in Vienna regarding albiglutide, which was shown to consistently and stably improve glycemic control in type 2 diabetes after weekly or biweekly administration with a favorable safety and tolerability profile [Bush, M.A. et al., Abst 742], with the 30-mg weekly dose being associated with less fasting glucose fluctuations than the 50-mg biweekly dose, both, along with the 100-mg monthly dose being comparable to exenatide and superior to placebo regarding overall control of the disease [Yang, F. et al., Abst 130; Rosenstock, J. et al., Abst 735] (Fig. 12). Furthermore, albiglutide 30 mg once weekly showed a favorable gastrointestinal tolerability profile comparable to that of exenatide [Stewart, M.W. et al., Abst 767].
Fig. 12. Change in hemoglobin A1c levels after 16 weeks of treatment with albiglutide, exenatide or placebo [Yang, F. et al., Abst 130].
While only experimental data were reported on taspoglutide, demonstrating potential for lowering postprandial glucose and improving glycemic control [Sebokova, E. et al., Abst 783] and pharmacodynamic activity in reducing post-glucose challenge-induced peptide YY and glucose-dependent insulinotropic peptide secretion [Sewing, S. et al., Abst 794], the further novel glucagon-like polypeptide-1 analog LY-2189265 proved safe, well tolerated and pharmacokinetically feasible in patients with type 2 diabetes [Barrington, P. et al., Abst 781] and significantly improved hemoglobin A1c and fasting and postprandial glucose levels in patients suboptimally controlled on oral medications [Umpierrez, G. et al., Abst 129; Hardy, T.A. et al., Abst 731] (Fig. 13), while a similarly acting novel compound, DMB, showed potential in experimental animal models [Patterson, S. et al., Abst 787] and a another new drug candidate, Val8-glucagon-like polypeptide-1 readily crossed the blood-brain barrier and enhanced synaptic plasticity [Hölscher, C. et al., Abst 790]. In addition, an inhaled preparation of glucagon-like polypeptide-1 showed glucose-dependent pharmacodynamic activity [Costello, D. et al., Abst 779], although the mechanism by which it reduced postprandial glucose excursions seemed to be different to that of subcutaneous exenatide [Baughman, R. et al., Abst 778]. A further advancement in that area was the obtainment of fatty acid derivatized forms of glucose-dependent insulinotropic polypeptide derivatives that showed longer-lasting biological activity and could expand the field of mimetic analogs into novel agents [Gault, V.A. et al., Abst 786].
Fig. 13. Change in hemoglobin A1c levels in patients treated with weekly LY-2189265 (initial dose for 4 weeks) or placebo for a total of 16 weeks [Umpierrez, G. et al., Abst 129].
DIPEPTIDYL PEPTIDASE-IV INHIBITORS
Important new data were discussed this year on sitagliptin, which was shown to improve glucose tolerance by enhancing endogenous glucagon-like polypeptide-1 activity while also enhancing the effects of glucose-dependent insulinotropic peptide [Kutscherauer, G. et al., Abst 5] (Fig. 14). Trials corroborating the benefits of sitagliptin mono- or combination therapy on glycemic control in type 2 diabetes were presented in Vienna [Aaboe, K. et al., Abst 748; Williams-Herman, D. et al., Abst 754] and a study to determine the impact of the agent on cardiovascular outcomes, the TECOS study, was announced to be underway [Bethel, M.A. et al., Abst 1245]. Compared with the respective monotherapies, a fixed combination of sitagliptin and metformin upregulated the expression of genes associated with glucose control, underlying the superiority of the combination over both monotherapies regarding glycemic outcomes in diabetes [Han, S. et al., Abst 69], and the fixed sitagliptin/metformin combination was reported superior to metformin alone as initial therapy regarding efficacy and tolerability issues [Reasner, C.A. et al., Abst 751]. Sitagliptin showed also potential in combination with pioglitazone, improving the glycemic control with favorable tolerability as first-line therapy compared to pioglitazone alone [Yoon, K. et al., Abst 747]. Furthermore, sitagliptin was used to demonstrate the effectiveness of add-on dipeptidyl peptidase-IV inhibitors in patients with hepatocyte nuclear factor-1 homeobox A mutation-dependent maturity-onset diabetes of the young [Katra, B. et al., Abst. 342]. Interestingly, real-world data suggested that sitagliptin is usually prescribed to older, predominantly male patients with higher rates of macrovascular complications and renal failure, but less frequently obese as compared to patients prescribed exenatide [Radican, L. et al., Abst 732].
Fig. 14. Postprandial glucose (mg/dl) and insulin (U/ml) levels after treatment with sitagliptin or placebo in patients with type 2 diabetes receiving or not the glucagon-like polypeptide-1 receptor blocker exendin9-39 [Kutscherauer, G. et al., Abst 5].
As with sitagliptin, studies were also discussed during this year’s meeting to confirm the glycemic benefits of vildagliptin. In that sense, improvements in glycemic control and reduced glycemic excursions were shown upon addition of vildagliptin to basal insulin glargine [Brooks, J. et al., Abst 750], while compared to the increase noted with glimepiride, vildagliptin was associated with a decrease in prandial glucagon levels [Ahrén, B. et al., Abst 798]. This was obtained without any increase in the risk of cardio- and cerebrovascular events according to a meta-analysis of 20 phase III double-blind controlled trials [Schweizer, A. et al., Abst 763], and without immune-related adverse events [Foley, J. et al., Abst 773] or an increased risk for pancreatitis [Ligueros-Saylan, M. et al., Abst 769] or hepatic adverse events despite mild hepatic enzyme elevations [Kothny, W. et al., Abst 764]. A combination of vildagliptin and metformin also proved well tolerated and effective in the early treatment of type 2 diabetes [Meier, J.J. et al., Abst 772], while a combination of vildagliptin and pioglitazone improved insulin resistance-related parameters, adiponectin, resistin and inflammatory markers more effectively than either monotherapy [Fogari, R. et al., Abst 799].
New studies were also presented with saxagliptin, which besides improving beta-cell function in both fasting and postprandial states and decreasing postprandial glucagon levels [List, J.F. et al., Abst 806], when added to metformin also improved glycemic control in patients inadequately controlled with metformin alone, offering clinically relevant glycemic benefits that were sustained for over 102 weeks without tolerability concerns or a risk of hypoglycemia or weight changes [Ravichandran, S. et al., Abst 132]. Saxagliptin also proved effective as add-on therapy in patients treated with metformin or sulfonylurea or as initial therapy combined with metformin in additional studies [Chen, R. et al., Abst 753], and showed similar efficacy and safety profiles in elderly and nonelderly patients [Maheux, P. et al., Abst 766].
New studies and data were also discussed relative to alogliptin, which used as initial therapy with pioglitazone induced significant glycemic improvements in patients with type 2 diabetes not controlled with diet and exercise [Fleck, P. et al., Abst 749] (Fig. 15), or in patients showing suboptimal control during prior metformin therapy [DeFronzo, R. et al., Abst 752], the combination improving beta-cell function and insulin resistance in further studies in patients pretreated with metformin [Burant, C. et al., Abst 800]. Furthermore, alogliptin provided similar benefits in elderly compared to other patients with type 2 diabetes [Pratley, R. et al., Abst 765].
Fig. 15. Change in hemoglobin A1c levels in patients treated with alogliptin and/or pioglitazone [Fleck, P. et al., Abst 749].
Research into novel dipeptidyl peptidase-4 inhibitors continues with favorable preclinical pharmacology data reported during the meeting with DSP-7238 [Furuta, Y. et al., Abst 869] and PKD-275-055, the latter specifically in models of diabetic neuropathy in which the agent showed potential for treating established neuropathy [Bianchi, R. et al., Abst 1142].
SODIUM/GLUCOSE COTRANSPORTER INHIBITORS
With demonstrated efficacy and tolerability regarding overall glycemic control in patients previously uncontrolled with metformin monotherapy [Bailey, C.J. et al., Abst 169] (Fig. 16) and in patients showing resistance to insulin [Wilding, J.P.H. et al., Abst 170], dapagliflozin prevented the acquisition of diabetes in experimental animals [Zinker, B.A. et al., Abst 11] and improved islet disruption in obese, diabetic-prone animals [Peel, J.E. et al., Abst 72]. A further sodium/glucose cotransporter inhibitor, BI-10773 also improved glucose levels and glycemic control in experimental animal models of diabetes [Eickelmann, P. et al., Abst 873].
Fig. 16. Proportion of patients with hemoglobin A1c levels <7% after 24 weeks of adding dapagliflozin or placebo to metformin [Bailey, C.J. et al., Abst 169].
FRUCTOSE-1,6-BISPHOSPHATASE INHIBITORS
The candidate drug CS-917 was shown to reduce mitochondrial oxidation and lactate clearance through inhibition of gluconeogenesis, suggesting potential, if not for the drug itself, for derivatives or metabolites sharing activity and potential usefulness in the treatment of diabetes [van Poelje, P.D. et al., Abst 874]. Such was the case with the second-generation inhibitor MB-07803, which induced statistically and clinically significant improvements in glycemia in patients with type 2 diabetes [Gumbiner, B. et al., Abst 875] (Fig. 17).
Fig. 17. Placebo-adjusted change in 24-hour glucose AUC in patients treated with increasing doses of MB-07803 [Gumbiner, B. et al., Abst 875].
11-BETA-HYDROXYSTEROID DEHYDROGENASE-1 INHIBITORS
The first agent in this group, INCB-13739, proved safe and well tolerated in patients with type 2 diabetes treated with insulin, and significantly improved hemoglobin A1c levels compared to placebo [Huber, R. et al., Abst 172] (Fig. 18).
Fig. 18. Change in hemoglobin A1c levels after 12 weeks of adding INCB-13739 or placebo to metformin [Huber, R. et al., Abst 172].
INSULIN SENSITIZERS
Insulin sensitizers are currently under clinical research, and a representative compound, VVP-808, was confirmed active in sensitizing hepatic cells to the activity of insulin on gene expression and glucose production, while also offering in vivo activity in experimental animal models [Walder, K.R. et al., Abst 505]. Insulin-sensitizing and lipid-lowering activity in experimental animals was also attributed to extracts of Labisia pumila, a Malaysian herb [Fazliana, M. et al., Abst 506].
NOVEL PUTATIVE THERAPEUTIC AGENTS AND TARGETS
A novel target for intervention in diabetes and nonalcoholic fatty liver disease, farnesoid X receptor, was validated in tests with the agonist agent INT-747, which proved well tolerated while improving glucose disposal rate and body weight in a first clinical study [Mudaliar, S. et al., Abst 174]. Similarly, promise as an agent for the treatment of type 2 diabetes was reported with the glucokinase activator ARRY-403, which was announced to have moved into phase I clinical testing [Hinklin, R.J. et al., Abst 872], while initial phase I results with a further similar inhibitor, MK-0599, demonstrated lowering of plasma glucose levels in healthy, nondiabetic volunteers [Migoya, E.M. et al., Abst 876]. Benefits on insulin secretion, hepatic glucose uptake and glycogen synthesis were noted with a small-molecule glucokinase inhibitor coded compound C [Camacho, R.C. et al., Abst 577], whereas blockade of the glucagon receptor by a compound 15 brought about reductions in blood glucose and increases in circulating glucagon-like polypeptide-1 levels in experimental models of obesity [Zhang, B.B. et al., Abst 582], further widening the range of therapeutic targets being researched for the treatment of diabetes. Coming also as a novelty during this year’s meeting, a synthetic peptide termed D3 with intrinsic kinase-inhibitory activity that was able to increase residual pancreatic beta-cell mass and improve glycemic control in genetically diabetic animal models [Gelber, C. & Simms, J.R., Abst 396] and the insulin resistance-reversing activity of silibinin through inhibition of the glucose-6-phosphate and pyruvate kinase pathways [Sanchez-Martin, C. et al., Abst 870] were reported. In addition, undisclosed small compounds that mimic the insulin-like activity of black tea theaflavins were identified, which could expand the therapeutic options for the treatment of type 2 diabetes [Cameron, A.R. et al., Abst 504].
Prevention of diabetes in experimental animal models was feasible with an undisclosed IKKbeta inhibitor from Novo Nordisk [Friberg, J. et al., Abst 10].
IMMUNOTHERAPIES FOR DIABETES
A vaccine candidate for type 1 diabetes, the DNA plasmid BHT-3021, was tested positive in a phase I/II trial in which the safety and tolerability of the immunotherapy was associated with preserved beta-cell function and improved glycemic control over a 12-week period compared to placebo [Gottlieb, P. et al., Abst 188]. Favorable mechanistic data was also reported in type 1 diabetes patients with rhGAD65, a further recombinant diabetes vaccine [Ludvigsson, J. et al., Abst 474; Axelsson, S. et al., Abst 478; Hjorth, M. et al., Abst 479; Casas, R. et al., Abst 482], while the peptide vaccine AVE-0277 induced favorable C-peptide responses in subjects with new-onset type 1 diabetes [Buzzetti, R. et al., Abst 477].
But besides vaccines, other immunotherapeutic approaches have been devised, including the anti-CD3 monoclonal antibody otelixizumab, which induced favorable pharmacokinetic/pharmacodynamic changes without safety concerns in patients with type 1 diabetes [Rosenzweig, M. et al., Abst 476] and the interleukin-1beta-regulating antibody XOMA-052, which by regulating rather than blocking the cytokine’s activity, showed differential effects on receptors responsible for signaling, neutralizing and clearing interleukin-beta [Roell, M.K. et al., Abst 370].
INSIGHTS INTO GENE THERAPIES
Adenoviral gene transfer of phospholipase D1 D4 C-terminal domain in experimental animal models proved feasible and enhanced skeletal muscle insulin sensitivity and glucose tolerance [Cassese, A. et al., Abst 121].
ISLET AND PANCREAS TRANSPLANTATION
The feasibility of restoring glycemic control by islet after kidney transplantation was demonstrated in 10 patients in the GRAGIL 1 trial [Wojtusciszyn, A. et al., Abst 466], while pancreas/kidney transplantation in patients with type 1 diabetes improved the cardiovascular risk profile [Teh, M.M. et al., Abst 473] and resulted in normal fasting and postprandial liver glycogen stores despite systemic insulin secretion [Stadler, M. et al., Abst 471]. In the experimental arena preliminary favorable results were described with transendoscopic islet transplantation to the gastric submucosa [Wszola, M. et al., Abst 470]. However, additional insight into the potential of islet transplantation suggested superiority for small islet-cell aggregates compared to full islets [O’Sullivan, E.S. et al., Abst 467], while yet further data suggested no impact of the donor’s age on transplantation outcomes, although better islet graft function was obtained with younger donors [Benhamou, P.Y. & Berney, T., Abst 469]. Also in the setting of pancreas or islet transplantation, immunosuppressive drugs were reported to inhibit islet cell proliferation, suggesting a risk for islet graft dysfunction [Parnaud, G. et al., Abst 472].
DIET, DIETARY SUPPLEMENTS AND DIABETES CONTROL
Miscellaneous information on the impact of diet and dietary components on diabetic outcomes reported during this year’s meeting in Vienna included an observation of the insulin resistance-minimizing, food intake-decreasing, antiatherosclerotic effects of fish oil/omega 3-polyunsaturated fatty acids [Corporeau, C. et al., Abst 509; Dragomir, A.D. et al., Abst 816], accompanied by better maintenance of endothelial function than oleic acid [Nandrean, S. et al., Abst 1243], prevention of metabolic alterations secondary to carbohydrate overfeeding [Allain, G. et al., Abst 534] and, specifically reported with docosahexaenoic acid, a property also shared with lutein, preventive activity against cortical lipid peroxidation in diabetic animal models [Miranda, M. et al., Abst 1234], although, also in the experimental arena, muscle type- and gender-specific differences were noted in the effects of omega 3-polyunsaturated fatty acids on the expression of genes related with energy metabolism in the muscle [Jilkova, Z.M. et al., Abst 807]. Other reports included a description of the protein kinase Cξ-dependent stimulation of glucagon-like polypeptide-1 secretion in the ileum by oleic acid ingestion [Iaboubov, R. et al., Abst 195], the antiinflammatory benefits of linoleic acid supplementation on monocytes [Herrmann, J. et al., Abst 808], the restorative potential for hydrolyzed casein on impaired intestinal permeability in diabetes [Visser, J.T.J. et al., Abst 810], the superiority of whey protein over casein and gluten for improving postprandial lipidemia after a fat-rich meal [Mortensen, L.S. et al., Abst 814], the favorable impact of antioxidants on postprandial endothelial function [Zavaroni, I. et al., Abst 812] and results apparently ruling out an effect of supplementation with trypsin/bromelain/rutoside, a mixture of proteases and flavonols, in reducing the prevalence of type 1 diabetes in persons at risk [Schloot, N.C. et al., Abst 475]. Turning to the experimental setting, Aloe vera phytosterols were shown to improve hyperglycemia, hyperlipidemia and visceral fat obesity in diabetic animals [Eriko, M. et al., Abst 706] whereas alpha-linolenic and oleic acid were noted to correct hypothalamic signaling in diet-induced obesity [Cintra, D.E. et al., Abst 681] and to protect against renal palmitic acid toxicity [Katsoulieris, E. et al., Abst 1067], and berberine offered activity in models of nonalcoholic fatty liver disease by decreasing methylation of the microsomal triglyceride transfer protein promoter [Chang, X.X. et al., Abst 1242].
Regarding additional dietary issues, a vegetarian, low-fat meal was associated with a reduction in the need for antidiabetic medications and improvements in beta-cell function [Kahleova, H. et al., Abst 817], while a regular three-meal-a-day schedule was related to lower body mass index but not better glycemic control as compared with more erratic patterns [Kim, S. et al., Abst 818]. Overall, dieting was noted to improve lipids, inflammatory status and insulin resistance in diabetics more effectively than in nondiabetic populations [Golan, R. et al., Abst 821], while both diet and general lifestyle counseling related to physical activity had a positive impact on the cardiovascular risk in type 2 diabetes [Price, H.C. et al., Abst 824]. The fact that the DEPLAN study confirmed the feasibility of implementing a lifestyle intervention program to prevent type 2 diabetes in the community [Makrilakis, K. et al., Abst 825] and the development and validation of a mathematical model to predict the effects of lifestyle and pharmacological intervention on the progression of type 2 diabetes [De Gaetano, A. et al., Abst 833] opened hope for the future.
DIABETES AND CARDIOVASCULAR DISEASE
Hypertension is a major cardiovascular risk factor in patients with diabetes, but, at least with telmisartan, the benefits of the agent on blood pressure were accompanied by improvements in glucose metabolism, lipid profile and adiponectin levels, which were related to an effect of the agent on peroxisome proliferator-activated receptor-gamma [Mori, H. et al., Abst 1093], while in the case of valsartan an antiatherosclerotic effect independent from the blood pressure-lowering activity was described [Uno, Y. et al., Abst 1210]. In a comparable manner, additional benefits were attributed to olmesartan on dorsal root sensory neuron insulin receptors resulting in improved sensory nerve conduction and slowing of myelin pathology in models of diabetic neuropathy [Sugimoto, K. et al., Abst 1145]. Add-on aliskiren preserved renal function and improved prior dysfunction and the urinary albumin:creatinine ratio better than add-on placebo in patients with type 2 diabetes and diabetic nephropathy already treated with losartan [Parving, H.H. et al., Abst 48; Persson, F. et al., Abst 1206], but pharmacogenomic dependency was reported with the latter, with reduced blood pressure-lowering response in A1166C AT1 receptor gene variant-carrying subjects [Andersen, S. et al., Abst 1071]. On the other hand, losartan demonstrated renoprotective activity in animal models of diabetic nephropathy [Sumita, T. et al., Abst 1205], while lisinopril prove to reduce E-selectin and increase adiponectin levels in patients with diabetic nephropathy [Astrup, A.S. et al., Abst 1204], which also added to the blood pressure-lowering activity of this angiotensin-converting enzyme inhibitor. Another related antihypertensive drug, ramipril, also showed additional benefits in type 2 diabetes patients by improving arterial stiffness and endothelial dysfunction [Vikulova, O.K. et al., Abst 1211], whereas perindopril attenuated the expression of genes related to pathogenetic processes involved in chronic vascular complications in type 1 diabetes [Flekac, M. et al., Abst 1239] and similar activity was described with quinapril in experimental animal models of diabetes [Watson, A.M.D. et al., Abst 1230]. Last but not least, a fixed combination of aliskiren and valsartan was reported to effectively lower blood pressure regardless of the diagnosis of diabetes, with superiority over the two respective monotherapies [Yarows, S.A. et al., Abst 1208].
According to ACTION, a large randomized trial in 1,113 patients with coronary artery disease and diabetes, addition of nifedipine-GITS for angina on top of the best available cardiovascular therapy in high-cardiovascular-risk situations was safe but did not improve blood pressure control, reduce cardiovascular risk or prevent major adverse cardiovascular events [Meredith, P.A. & Elliott, H.L., Abst 47].
Regarding antiplatelet therapies for coronary artery disease in diabetes, response to clopidogrel in diabetic patients showed dependency on fibrinogen levels and type of diabetes, but not on diabetic control. Higher platelet reactivity was demonstrated in type 2 compared to type 1 diabetes [Darmon, P. et al., Abst 698]. On the other hand, cilostazol demonstrated antiinflammatory activity in vascular smooth muscle in vitro and in vivo, which was related to activation of the AMP-dependent protein kinase pathway [Hattori, Y. et al., Abst 1246].
DIABETIC DYSLIPIDEMIA
In addition to lowering cholesterol levels, pravastatin therapy brought about improvements in hemoglobin A1c levels [Nishimura, R. et al., Abst 1250] and fluvastatin reduced oxidative stress in diabetic state [Irat, A. et al., Abst 1254], whereas atorvastatin was confirmed beneficial for improving lipid levels in patients with type 2 diabetes, lowering remnant-like particle-cholesterol [Dullaart, R.P.F. et al., Abst 1251] and inducing a shift in the relationship between fasting LDL- and non-HDL-cholesterol with apolipoprotein B towards lower cholesterol levels outside from the apolipoprotein B guideline targets [Kappelle, P.J.W. et al., Abst 1249]. However, in addition to its known pleiotropic effects, atorvastatin was also shown to slow the loss of residual beta-cell function in patients with newly diagnosed type 1 diabetes in the DIATOR study [Martin, S. et al., Abst 496] and to protect against nephropathy in patients with type 2 disease [Rutter, M.K. et al., Abst 1207]. Furthermore, a case-control analysis from the CARDS trial revealed reductions in neopterin and monocyte chemoattracting protein-1 levels in patients with diabetes treated with atorvastatin, although neither could be considered a valid marker for cardiovascular events [Colhoun, H.M. et al., Abst 1247]. However, an instance of acute rhabdomyolisis was reported in a patient treated with atorvastatin and fusidic acid [Francois, M., Abst 703]. Rosuvastatin, like simvastatin, was associated with an increase in fasting glucose and hemoglobin A1c levels when used in patients with type 2 diabetes, an effect that in the case of rosuvastatin was related to impaired insulin sensitivity. However, both statins improved vascular reactivity and inflammatory biomarkers, with a more profound effect by rosuvastatin [Bellia, A. et al., Abst 531].
The combination of ezetimibe and simvastatin proved superior to atorvastatin and rosuvastatin monotherapies in improving total, LDL- and HDL-cholesterol and apolipoprotein B levels in high-risk dyslipidemic patients with or without type 2 diabetes not controlled with prior statin therapy (rosuvastatin study) or in patients with metabolic syndrome and moderately high to high coronary artery disease risk (atorvastatin study) [Vaverkova, H. et al., Abst 712; Rosen, J.B. et al., Abst 1253]. A triple combination of ezetimibe, simvastatin and extended-release niacin further improved lipid and lipoprotein profiles with good tolerability in patients with diabetes and metabolic syndrome [Fazio, S. et al., Abst 1252] (Fig. 19).
Fig. 19. Change in LDL- (dark colors) and HDL-cholesterol levels (light colors) during 64 weeks of treatment with ezetimibe/simvastatin alone or combined with extended-release niacin in patients with diabetes, metabolic syndrome without diabetes, or neither [Fazio, S. et al., Abst 1252].
A paradoxical untoward effect similar to that previously described for rosuvastatin and simvastatin was described in Vienna with extended-release niacin, which despite lowering triglyceride levels, but with a trend towards increasing nonesterified fatty acids, increased insulin resistance in patients with abdominal obesity and dyslipidemia [Blond, E. et al., Abst 535].
While fenofibrate suppressed microvascular inflammation and apoptosis through activation of the AMP-dependent protein kinase [Hattori, S. et al., Abst 1288] and showed potential for improving the barrier function of retinal pigment epithelium [Garcia-Ramírez, M. et al., Abst 1121], at least in a patient with type 2 diabetes, bezafibrate suppressed transforming growth factor-beta and type IV collagen production by mesangial cells exposed to remnant lipoprotein, suggesting potential for the control not just of lipid alterations but also diabetic nephropathy [Eto, M. et al., Abst 1052]. Because of the different mechanisms of action of fibrates and statins, a combination of both, namely fenofibrate and atorvastatin, was tested in patients with type 2 diabetes, resulting in more comprehensive improvements in the overall lipid profile compared to either monotherapy [Sleep, D.J. et al., Abst 1248] (Fig. 20).
Fig. 20. Percent change in total, LDL- and HDL-cholesterol, triglyceride and apolipoprotein B levels after 12 weeks of treatment with fenofibrate, atorvastatin or their combination [Sleep, D.J. et al., Abst 1248].
Besides improving lipid levels, treatment of patients with type 2 diabetes with colesevelam resulted in improvements in hemoglobin A1c and fasting plasma glucose levels and glucose clearance during fast without increasing endogenous glucose production [Beysen, C. et al., Abst 171]. Such improvements could be related to the benefits of treatment with the agent on insulin resistance in experimental models of diet-induced obesity, which were related to increased release of glucagon-like polypeptide-1 [Xu, G. et al., Abst 877].
While effectively improving lipid profiles in patients with diabetes or metabolic syndrome comparably to those in patients without such metabolic abnormalities, favorable tolerability was documented also with dalcetrapib in a safety analysis of a randomized, placebo-controlled trial in patients with type 2 diabetes or metabolic syndrome [Kallend, D. et al., Abst 1261; Stalenhoef, A.F.H. et al., Abst 1262].
Further to the aforementioned drugs and therapies, the bile acid sequestrant and cholesterol absorption inhibitor colestilan proved effective for managing metabolic syndrome abnormalities in patients with diabetes, with favorable effects on obesity and insulin resistance while lowering atherogenic lipid and atherosclerosis markers at least as effectively as pitavastatin [Itoh, M. et al., Abst 1276] (Fig. 21). In addition, elevation of plasma HDL-cholesterol levels was demonstrated with isosteviol in experimental animals, suggesting potential for pharmacological cardiovascular risk modification [Jeppesen, P.B. et al., Abst 1272].
Fig. 21. Change in hemoglobin A1c levels in patients treated for 24 weeks with colestilan or pitavastatin [Itoh, M. et al., Abst 1276].
OBESITY AND DIABETES
Cotreatment with phentermine and topiramate in a fixed-drug combination resulted in sustained and meaningful reductions in hemoglobin A1c, fasting and postprandial glucose and body weight in a placebo-controlled study in patients with type 2 diabetes who were candidates for weight loss [Garvey, W.T. et al., Abst 173].
In the preclinical arena, a novel estradiol derivative, PE-0607 improved insulin sensitivity and decreased visceral obesity in models of high fat diet-induced overweight [Gorbenko, N. et al., Abst 616].
DIABETIC NEPHROPATHY
In the experimental arena, aldosterone blockade with spironolactone improved diabetic, hypertensive nephropathy [Pessõa, B.S. et al., Abst 1070] and the antifibrotic agent FT-011 attenuated functional and structural progression of experimental diabetic nephropathy [Gilbert, R.E. et al., Abst 1047], while the cannabinoid CB1 receptor inverse agonist 4'-I-SR-141716A improved diabetic proteinuria [Barutta, F. et al., Abst 1068] and the antioxidant tempol reduced albuminuria through prevention of poly(ADP-ribose) polymerase-mediated podocyte apoptosis [Peixoto, E.B.M. et al., Abst 1048]. In addition, the Chinese herbal product Yu-qui-qing downregulated advanced glycation endproduct-induced monocyte chemoattractant protein-1 and fractaline production and the consequent stimulation of monocyte transmigration through renal mesangial cells, suggesting nephroprotective potential [Sun, Z.I. et al., Abst 1049].
DIABETIC RETINOPATHY
Ranibizumab was confirmed active in the treatment of diabetic macular edema in the 12-month RESOLVE study, in which intravenous therapy to 151 patients confirmed superiority over placebo with continuous improvements in best-corrected visual acuity and optical coherence tomography outcomes [Engelmann, K., Abst 60] (Fig. 22).
Fig. 22. Change in the best-corrected visual acuity over 12 months in patients treated with intravitreal ranibizumab or placebo [Engelmann, K., Abst 60].
In the experimental arena, both thiamine and benfotiamine prevented and high glucose-induced retinal pericyte apoptosis, suggesting promising potential for the management of diabetic retinopathy [Berrone, E. et al., Abst 59].
DIABETIC NEUROPATHY
An unnamed aldose reductase inhibitor proved effective in improving peripheral muscle sympathetic nerve function and activity in models of diabetes, suggested potential for preventing diabetic autonomic neuropathy [Kusunoki, M. et al., Abst 1133], while additional experimental studies in models of diabetic neuropathic pain confirmed the benefit of tapentadol against disease-related thermal hyperalgesia [Christoph, T. et al., Abst 1149]. A third interesting presentation related to diabetic neuropathy confirmed the potential for methylcobalamin, although with higher effectiveness the less advanced the disease [Jiambo, L. et al., Abst 1144]. In addition, a pan-European study presented as a poster during the meeting corroborated the analgesic effectiveness of a 5% lidocaine medicated plaster compared to pregabalin regarding improvement of neuropathic pain symptoms with a low frequency of adverse events [Baron, R. et al., Abst 1168].
DIABETIC FOOT ULCERS
Among miscellaneous presentations related to diabetic feet, a pooled analysis of randomized trials corroborating the potential for recombinant human platelet-derived growth factor gel in healing diabetic neuropathic foot ulcers was presented [Shi, J. et al., Abst 1157]. Similarly, an individual trial suggested potential for MF-125, a protein-free metabolically active hemoderivative containing extracts of calf blood, for accelerating the healing of wounds after surgical removal of infected diabetic foot ulcers [Parhimovich, R.M. et al., Abst 1159].
MISCELLANEOUS
The Ginkgo biloba extract EGb761 was shown to prevent palmitate-induced insulin resistance in the in vitro setting [Ha, E.S. et al., Abst 507]. On the contrary, acetylcysteine did not reverse hepatic insulin resistance after protracted lipid infusions in experimental animals [Pereira, S. et al., Abst 537], but reduced gluconeogenesis without impacting on hepatic lipid accumulation in experimental models of nonalcoholic fatty liver disease [Lockman, K.A. et al., Abst 539].
The endocannabinoid receptor blocker rimonabant was shown to modulate insulin secretion and correct metabolic abnormalities in animal models of fructose-rich diet-induced diabetes [Flores, L.E. et al., Abst 510].
Like dexamethasone [Jensen, D.H. et al., Abst 570], prednisone dose-dependently lowered insulin sensitivity in healthy lean volunteers, even over the short term [Kauh, E.A. et al., Abst 528]. Ciclosporin, tacrolimus and sirolimus shared dexamethasone’s inhibitory activity on insulin-stimulated glucose uptake by hepatocytes [Pereira, M.J.R. et al., Abst 702]. Similarly, bromocriptine depressed glucose-stimulated insulin secretion in experimental animals [de Leeuw van Weenen, J.E. et al., Abst 575].
Dextrose tablets and liquid sugar jelly were reported effective for rapidly increasing plasma glucose levels, whereas oral glucose spray had a minimal impact within 30 minutes of use and was not recommended for the management of hypoglycemia [Chlup, R. et al., Abst 813].
Administration of calcitriol to young patients with recent onset type 1 diabetes was associated with reduced bone remodeling and turnover, contributing to prevention of diabetes-related osteopenia [Napoli, N. et al., Abst 886].
Coadministration of recombinant human hyaluronidase accelerated prandial insulin lispro pharmacokinetics and improved glycemic control in type 1 diabetes [Hompesch, M. et al., Abst 953].
Use of diazoxide in patient with newly diagnosed type 1 diabetes had no impact on beta-cell function, but improved glycemic control over a 6-month period [Radtke, M. et al., Abst 980].