September 8 - 11, 2008
Rome, Italy
INTRODUCTION
Rome is eternal, or so it claims, but the hope is that the fight against diabetes can be won and the disease rendered noneternal (meaning curable). Currently, therapies are available for gaining glycemic control in diabetes, thus preventing complications, but observational registries of patients with type 2 disease still reveal a gradual increase in the risk for chronic heart failure, stroke, cardiovascular disease and death directly and independently related to increasing levels of hemoglobin A1c, as exemplified by a registry of 17,691 patients reported during this year’s meeting in Rome [Eed-Olofsson, K. et al., Abst 191]. Although no cure for diabetes has yet been identified, new therapies are available to help patients carry on normal lives with no or minimal risk for adverse outcomes (namely hypoglycemia) while preventing diabetic complications that may reduce the chances of a full, happy life. In that respect, the benefits of an intensive, multifactorial, treat-to-target intervention strategy in the MIND.IT study was confirmed to significantly improve all major cardiovascular risk factors in patients with type 2 diabetes [Rivellese, A.A. et al., Abst 1117; Ardigò, D. et al., Abst 1387], demonstrating that treatments are available and feasible, though going beyond what is usually achieved in the real world practice, and calling for intensive campaigns to improve patient care and clinical outcomes.
Furthermore, curable or not curable, diabetes may still be preventable, and the DEPLAN study, also reported during this year’s meeting in the Eternal City, demonstrated the ability of the FINDRISK questionnaire for identifying impaired glucose metabolism in young and middle-aged working populations, thus focusing on those at risk for developing type 2 diabetes who could benefit from education and lifestyle interventions [Grammatikou, S. et al., Abst 348]. Meanwhile, the EPIC-Norfolk study --also discussed during the meeting-- indicated that energy-dense diets carry an increased risk for developing type 2 diabetes [Wang, J. et al., Abst 349], pointing to the need for societal/populational instruction on lifestyles, education and awareness of the risks of diabetes. However, observations from the ADDITION Netherlands study led to the conclusion that lifestyle factors and socioeconomic status are not able to identify at-risk subjects to be screened for diabetes [Janssen, P.G.H. et al., Abst 353], although measurements of fasting triglycerides 3-5 years apart were suggested as able to identify healthy young men at risk for developing diabetes independently of traditional risk factors related to body mass index and lifestyle in the MELANY study [Tirosh, A. et al., Abst 407], such that screening strategies need to be designed encompassing all subjects at risk and all reliable risk indicators. In that respect, identifying prediabetic states should be a priority, and according to the ACT NOW study insulin and C-peptide levels during glucose tolerance testing are primary determinants of worsening glucose tolerance in prediabetic subjects, with impaired early insulin secretion being the major defect in subjects with isolated impaired fasting glucose and insulin resistance and impaired early- and late-phase insulin response being the drivers of post-glucose load hyperglycemia [DeFronzo, R.A. et al., Abst 650].
Nevertheless, whether future efforts will or will not reduce the dramatic impact of diabetes on the general population, diabetes carries an increased risk for death that was further confirmed in the ENTRED study [Simon, D. et al., Abst 416], and current patients need therapies, especially with reminders such as those from a review of 8,743 patients treated by specialists or primary care practitioners in Germany and the U.K. that demonstrated a large proportion of patients not meeting target hemoglobin A1c levels despite widespread awareness of the need for better control [Gough, S. et al., Abst 981].
A number of approaches were reported and discussed during this year’s EASD meeting and are summarized in the following report, complemented by observations from the aforementioned ADDITION Netherlands study, which also suggested that multifactorial, intensified treatment for diabetes does not impair health-related quality of life in screen-detected type 2 diabetes, suggesting the feasibility of intensive therapies without the fear for negative effects on the patients’ wellbeing and feelings [Van den Donk, M. et al., Abst 431].
INSULIN- AND INSULIN ANALOG-BASED THERAPIES
Insulin replacement is required for most patients with type 2 diabetes, although it carries a risk for increasing weight not shared by all patients but mostly in younger, less overweight subjects [Czupryniak, L. et al., Abst 973], and increase in body weight during insulin therapy deteriorates the cardiovascular risk profile [Jansen, H.J. et al., Abst 974]. According to observational data from 130,228 patients from the U.K., most patients start insulin at hemoglobin A1c levels over 9% and have been poorly controlled for a long period prior to insulin initiation, whilst oral antidiabetic drug escalation is usually associated to higher mean hemoglobin A1c levels at insulin initiation, which identifies insulin as the most effective hemoglobin A1c-lowering therapy and calls for awareness on the need for earlier insulin initiation [McEwan, P. et al., Abst 152] (Fig. 1). Furthermore, analysis of published data confirmed poor glycemic control in most type 2 diabetes patients on oral combination therapy, while immediate initiation of insulin was related to improvements in survival and diabetes-related complication rates compared to delayed insulin initiation [Sarpong, E. et al., Abst 184] (Fig. 2). However, early insulin treatment in 38 patients with latent autoimmune diabetes did not improve residual β-cell function or metabolic control [Thunander, M. et al., Abst 972]. Many insulin-based treatment strategies have been assayed, with some data suggesting better adherence when premixed insulins are used compared to basal-only therapy [Eldrup, E. & Toft, A.D., Abst 998], although other studies suggest superiority for once-daily basal insulin combined with oral drugs [Van AVendonk, M.J.P. et al., Abst 999].
Fig. 1. Hemoglobin A1c levels in insulinized and noninsulinized patients related to the number of oral antidiabetic drugs administered [McEwan, P. et al., Abst 152].
Fig. 2. Time to onset of diabetes-related complications in patients receiving immediate or delayed insulin therapy [Sarpong, E. et al., Abst 184].
An ultrarapid formulation of recombinant human insulin has been developed that in phase III trials induced weight loss and lowered insulin requirements with a lower risk for hypoglycemia compared to standard human insulin in patients with type 2 diabetes [Flacke, F.M. et al., Abst 677; Steiner, S. et al., Abst 678].
Continuous and algorithm-based bolus subcutaneous insulin infusion pumps have been effective and cost-effective in maintaining glycemic control and residual β-cell function in patients with type 1 and 2 diabetes [Pankowska, E. et al., Abst 948; Groele, L. et al., Abst 989; Choi, S.B. et al., Abst 990; Zoupas, C.S. et al., Abst 983; Cernea, S. et al., Abst 984; Hirose, M. et al., Abst 985; Lombardo, F. et al., Abst 986; Pumprla, J. et al., Abst 987; Tubiana-Rufi, N. et al., Abst 988; Lynch, P. et al., Abst 1002; Hebda-Szydlo, A. et al., Abst 1121; Pancani, F. et al., Abst 1122], while pump-delivered bolus doses related to meals were effective in lowering postprandial hyperglycemia [Scaramuzza, A.E. et al., Abst 949]; pregnancy outcomes in patients with type 1 diabetes were more favorable, with better glycemic control and less severe hypoglycemia, by using continuous subcutaneous insulin infusion compared to multiple daily injections [Hammond, P.J. et al., Abst 1125]. Continuous intraperitoneal insulin infusion through an implantable pump has also been confirmed as a safe strategy [Bilo, H.J.G. et al., Abst 1076], and, as reported in 24 patients with type 1 diabetes, improves glycemic control with a trend towards lowering hypoglycemic events and increasing time spent in euglycemia compared to multiple subcutaneous insulin injections [Logtenberg, S.J.J. et al., Abst 182].
Oral insulin has been validated as feasible and biologically active in healthy volunteers [Kidron, M. et al., Abst 1006]. An orally bioavailable insulin (Capsulin®) has been developed and tested for clinical effectiveness in trials that demonstrated improvements in glycemic control during and between meals without meaningful risk for hypoglycemia in 16 male patients with type 2 diabetes [Broke-Smith, T.P. et al., Abst 4]. Inhalable insulins have also been developed and shown to be safe and effective with absorption independent of smoking status [Heinemann, L. et al., Abst 1012; Angelo, R. et al., Abst 1013; Baughman, R. et al., Abst 1014; Hompesch, M. et al., Abst 1015].
Insulin analogs have been developed to overcome the limitations of insulin therapy (including risks of hypoglycemia and significant weight gain), and have been reported to offer additional benefits by attenuating the progressive decline in hemoglobin in diabetic patients with impaired renal function [Hasslacher, C. et al., Abst 1200]. Among long-acting insulin analogs, insulin detemir and insulin glargine showed an equivalent duration of action of approximately 24 hours [Bock, G. et al., Abst 968] (Fig. 3), with similar effects on glycemic control according to a crossover trial in 35 type 2 diabetes patients [King, A., Abst 993]; however, a deleterious effect was reported upon abrupt transition from insulin glargine to insulin detemir in 24 patients with type 1 diabetes, suggesting no bioequivalence [Kabadi, U.M., Abst 970]. Insulin detemir was effectively and safely used in patients with type 1 or 2 diabetes [Levy, J.C. et al., Abst 961; Pinget, M. et al., Abst 963; Niskanen, L. et al., Abst 965; Dornhorst, A. et al., Abst 966; Norberg, B. & Jendle, J. et al., Abst 969; Franco, D.R. et al., Abst 979] (Fig. 4), with a lower risk for hypoglycemia at similar levels of hemoglobin A1c compared to human isophane insulin [Shaw, J.E. et al., Abst 971] and a reduced body weight gain also compared to human isophane insulin or insulin glargine in experimental animals [Fledelius, C. et al., Abst 975]; in fact, initiation of insulin detemir in insulin-naïve type 2 diabetes patients with increased body mass index was associated with significant weight loss in the PREDICTIVE study [Hanaire, H. et al., Abst 976]. Moreover, while all intermediate- to long-acting insulin analogs offered comparable efficacy and safety regarding rates of cardiovascular events in type 2 diabetes patients, insulin glargine was associated with a lower risk for acute myocardial infarction [Juhaeri, J. et al., Abst 980]. Furthermore, a direct comparison between insulin detemir plus insulin aspart and isophane plus regular insulin in patients with type 2 diabetes, the DEAN study, confirmed the equivalent glycemic control with minimal risk for hypoglycemia by using insulin analog therapy [Umpierrez, G. et al., Abst 964] (Fig. 5). Mechanistically, insulin detemir showed effects on the insulin-like growth factor-1 axis comparable to those of regular human insulin despite attaining higher plasma insulin levels [Porcellati, F. et al., Abst 183] and stimulated glucose uptake in visceral adipocytes more efficiently than regular insulin [Perrini, S. et al., Abst 850], offering a safe and effective method for improving glycemic control in poorly controlled type 2 diabetes patients whilst improving glucotoxicity, glucose-stimulated insulin secretion and the atherogenic apolipoprotein profile [Cusi, K. et al., Abst 852]. On the other hand, insulin glargine improved glycemic goal attainment rates in type 2 diabetes patients [Misurski, D. et al., Abst 960; Blickle, J.F. et al., Abst 992] and clinical outcomes in children and adolescents with cystic fibrosis and early glucose abnormalities [Franzese, A. et al., Abst 951], while having no effect on other metabolic and cardiac risk factors or left ventricular function in diabetic patients with left ventricular dysfunction [Masi, S. et al., Abst 982], but did reduce carotid intima hyperplasia after experimental balloon injury in fatty animal models through insulin-like growth factor-1-mediated suppression of oxidative stress [Kadowitz, P.J. et al., Abst 806]. Insulin glargine was identified as offering higher patient satisfaction rates at improved glycemic control and equivalent or lower cost compared to isophane insulin in real-life conditions [Scholten, T. et al., Abst 1000; Leahy, J.L. et al., Abst 1001]; insulin glargine also arose as slightly more effective at marginal cost savings compared to insulin detemir, according to some evidence [Tetlow, A.P. et al., Abst 1004], although other analyses did not find differences in efficacy and cost between the two long-acting insulin analogs [Alemayehu, B. et al., Abst 1005], and a combination of insulin glargine and insulin glulisine also offered improved glycemic control [Del Prato, S. et al., Abst 1112] with no additional cost compared to premixed insulins [Lee, F. et al., Abst 1003].
Fig. 3. Duration of action of insulin detemir and insulin glargine after single doses and at steady state [Bock, G. et al., Abst 968].
Fig. 4. Changes in hemoglobin A1c levels during 52 weeks of treatment with insulin detemir in elderly patients included in the PREDICTIVE study [Pinget, M. et al., Abst 963].
Fig. 5. Percent of readings with glucose levels under 3.3 or 2.2 mmol/l during treatment with insulin detemir/insulin aspart or isophane/regular insulin [Umpierrez, G. et al., Abst 964].
Regarding rapid-acting insulin analogs, which were reported feasible when injected immediately after a meal without advantages of preprandial administration [Gelber, A. et al., Abst 1073], the DURABLE and other trials confirmed the safety and efficacy of insulin lispro in patients with type 2 diabetes, with significant decreases in hemoglobin A1c levels comparable to those obtained with regular insulin or insulin glargine but with a lower risk for nocturnal hypoglycemia [Wolffenbuttel, B.H.R. et al., Abst 959; Martin, S. et al.,, Abst 977; Jiang, H. et al., Abst 997] (Fig. 6). Observations confirming the benefits of insulin glulisine intensification administered at breakfast or mealtime for improving glycemic profiles in patients suboptimally controlled on basal insulin were reported from a 26-week study in 316 patients, with a trend towards higher number of patients at goal with meal- compared to breakfast-time administration [Lankisch, M. et al., Abst 185]; addition of insulin glulisine was also beneficial in 393 patients not optimally controlled with oral antidiabetic drugs [Woo, J.T. et al., Abst 991] (Fig. 7). Mealtime insulin glulisine combined with once-daily insulin glargine was also reported superior to twice-daily premixed insulin injection regarding glycemic control in the GINGER study [Fritsche, A. et al., Abst 186] (Fig. 8); basal-bolus insulin glulisine was also as effective and safe as insulin lispro over a 26-week period in 727 children and adolescents [Philotheou, A. et al., Abst 950] (Fig. 9). Favorable results were also reported with insulin aspart, which in the IMPROVE study showed improvements in glycemic control with reduced risk for hypoglycemia regardless of prior therapies [Kawamori, R. et al., Abst 978] and in the NICE study improved postprandial glucose and reduced the risk of cardiovascular events in 374 patients with type 2 diabetes [Nishimura, H. et al., Abst 1349]; biphasic insulin aspart offered a reasonable approach for early insulin therapy in the elderly or all people with high bedtime plasma glucose levels [Fonseca, V. et al., Abst 994], and given thrice daily was reported to mimic physiological insulin secretion [Kikuchi, M. et al., Abst 995] and improve glycemic control without a risk for hypoglycemia [Kadowaki, T. et al., Abst 996].
Fig. 6. Percent of patients attaining hemoglobin A1c levels <7.0% during 24 weeks of insulin lispro or insulin glargine intensification of oral antihyperglycemic therapy [Wolffenbuttel, B.H.R. et al., Abst 959].
Fig. 7. Change in hemoglobin A1c levels in subjects receiving insulin glulisine and/or oral antidiabetic drugs [Woo, J.T. et al., Abst 991].
Fig. 8. Change in daytime, postprandial and fasting blood glucose levels after 52 weeks of treatment with once-daily insulin glargine plus mealtime insulin glulisine or twice-daily premixed insulin in patients with type 2 diabetes [Fritsch, A. et al., Abst 186].
Fig. 9. Change in fasting glucose levels in subjects receiving insulin glulisine or insulin lispro as basal-bolus regimen [Philotheou, A. et al., Abst 950].
A further insulin analog, IN-105 proved safe, well tolerated and effective in dose-dependently lowering glucose levels in 14 patients with type 2 diabetes, with plasma levels of the drug decreasing from morning to evening but sustained glucodynamic effects throughout the day [Iyer, H. et al., Abst 5] (Fig. 10).
Fig. 10. Dose-dependent change in 2-hour postprandial glucose levels after treatment with IN-105 [Iyer, H. et al., Abst 5].
BIGUANIDES
Noninsulin oral antidiabetic medications are available for the treatment of diabetes, but according to Medicare data, type 2 diabetes patients treated with oral antidiabetic drugs still have a prevalence of stroke without transient ischemic attack ranging from 3.4-5.1%, and a prevalence of strike with transient ischemic attack ranging from 5.3-7.0%, suggesting the need for greater awareness of stroke in the elderly diabetic population [Shaya, F. et al., Abst 923].
Biguanides (metformin) and sulfonylureas are the classic oral antidiabetic drug families, still widely used in the clinical practice, and specific data related to metformin, namely a review of 13 published clinical trials, suggested favorable outcomes regarding cardiovascular disease and mortality when used as first-line antihyperglycemic agent for type 2 diabetes [Ruige, J.B. et al., Abst 924]. Additional observations indicated reductions in asymmetric dimethylarginine levels [Boyle, J.G. et al., Abst 941] and also folate and vitamin B12 levels without a significant increase in homocysteine but an increased risk of vitamin B12 deficiency [Kooy, A. et al., Abst 940]. Glycemic control in type 2 diabetes with metformin therapy was enhanced by concomitant exogenous administration of glucagon-like peptide-1, suggesting feasibility for combination therapy with incretin-based approaches [Cuthbertson, J. et al., Abst 943]. Improvements in natural killer cell-mediated immune activity in patients with type 2 diabetes were reported after treatment with metformin, adding a new pleiotropic action to this frequently used antidiabetic drug [Czech, A. et al., Abst 835]. Metformin was reported to improve metabolic and cardiovascular risk factors (blood pressure, fasting blood glucose and total cholesterol) in 324 nondiabetic upper-body obese subjects considered prediabetic in the placebo-controlled BIGPRO1 trial [Fontbonne, A. et al., Abst 939] (Fig. 11). Mechanistically, the activity of metformin in hepatocytes was related to activation of AMP-dependent protein kinase and production of reactive nitrogen species [Fujita, Y. et al., Abst 942].
Fig. 11. Changes in systolic blood pressure and fasting blood glucose and total cholesterol levels after 1 year of treatment with metformin or placebo in patients with impaired glucose tolerance/impaired fasting glucose (according to World Heart Organization; subset A [solid bars]) and patients fulfilling inclusion criteria for the Diabetes Prevention Program (subset B [hatched bars]) in the BIGPRO1 trial [Fontbonne, A. et al., Abst 939].
SULFONYLUREAS
Miscellaneous information on sulfonylureas was reported during this year’s meeting in Rome, with observational data supporting the concept that sulfonylureas prevent the progressive decline in β-cell function in type 2 diabetes [Nybäck-Nakell, Å. et al., Abst 938]. Drugs such as glibenclamide and glimepiride were described as having an effect on gene expression in insulin-producing cells affecting signaling pathways involved in cell homeostasis and death, whilst gliclazide exhibited a more selective effect on the SUR1 receptor with less impact on gene regulation [Magnusson, N.E. et al., Abst 466]. Additional data was reported on the benefits of repaglinide on β-cell function and metabolism, whilst also improving glucose control as effectively as gliclazide [Zhang, H. et al., Abst 937] (Fig. 12). On the other hand, the therapeutic effect of repaglinide was associated with the KCNJ11 E23K variant of the ATP-dependent potassium channel gene, whereas insulin sensitivity after treatment was related to the ABCC8 exon 16 -3T/C variant [He, Y. et al., Abst 936].
Fig. 12. Change in the HOMA insulin resistance index after 4 weeks of treatment with repaglinide or gliclazide [Zhang, H. et al., Abst 937].
THIAZOLIDINEDIONES
Thiazolidinediones such as pioglitazone and rosiglitazone were a later addition to the oral antidiabetic armamentarium, with benefits on glycemic, lipid and overall metabolic profile but an effect also in increasing bone resorption and losing bone mass [Cartenì, B. et al., Abst 926].
While beneficial effects of pioglitazone were noted on cardiac metabolism and insulin sensitivity compared to metformin in absence of myocardial ischemia in type 2 diabetes patients [Rijzewijk, L.J. et al., Abst 114], new mechanistic data with the drug reported this year demonstrated an effect in reducing downmodulation of proinflammatory genes and proteins in peripheral monocytes and lymphocytes and attenuation of inflammatory cross-talk between inflammatory cells and adipose tissue, resulting in metabolic improvements in patients with impaired glucose tolerance [Reaven, P.D. et al., Abst 72]. Initial combination therapy with pioglitazone and metformin increased the likelihood for glycemic control compared to sequential augmentation therapy as a strategy for type 2 diabetes, according to results in 561 patients [Pandya, B.J. et al., Abst 921].
While continued use in older patients with type 2 diabetes was related to sustained glycemic control [Florez, H.J. et al., Abst 925] and discontinuation of rosiglitazone brought about an increase in fasting plasma glucose and a loss of glycemic control [Weissman, P. et al., Abst 918], mechanistic insight into rosiglitazone’s activity demonstrated modulation of multiple signaling pathways in β-cells protecting against detrimental effects of palmitate and showing enhanced viability and function [Ali, T. et al., Abst 486] and attenuating advanced glycation endproduct-induced monocyte chemoattractant protein-1 upregulation [Yuan, Y. & Sun, Z., Abst 1182]. Thiazolidinediones were also reported to enhance insulin activity in skeletal muscle and liver cells through an effect on protein kinase Cδ [Brutman-Barazani, T. et al., Abst 684], and rosiglitazone remained effective in improving insulin sensitivity in nondiabetic patients with nonalcoholic fatty liver disease [Szymanska-Garbacz, et al., Abst 919]. On the other hand, fixed combination of rosiglitazone and glimepiride offered improved adherence with less reduction in medication possession ratio compared to dual therapy [Menditto, L. et al., Abst 920].
A novel thiazolidinedione with no affinity for peroxisome proliferator-activated receptors, BLX-1002 showed potential to stimulate AMP-activated protein kinase activity, raise intracellular calcium levels and enhance glucose-stimulated insulin secretion in pancreatic islets from genetically obese animals [Zhang, F. et al., Abst 654]. The contrary case, T-131, a nonthiazolidinedione compound and selective peroxisome proliferator-activated receptor-γ modulator, caused no fluid retention, weight gain, cardiac hypertrophy or hepatic toxicity in experimental animals [DePaoli, A.M. & Higgins, L.S., Abst 922].
INCRETIN ANALOGS
Clinical trial and observational evidence accumulates on the effectiveness of exenatide, which besides being confirmed to improve glucose and lipid control and body weight over the long term [Buse, J. et al., Abst 146; Bunck, M.C. et al., Abst 879; Wintle, M. et al., Abst 881; Schroeder, B. et al., Abst 882; Govindan, J.P. et al., Abst 884; Samarasinghe, Y.P. et al., Abst 885; Kendall, D. et al., Abst 886], acute-phase insulin responses to meals [Han, J. et al., Abst 863] and insulin-mediated glucose uptake in the liver and skeletal muscle [Zheng, D. et al., Abst 864; Arnés, L. et al., Abst 900], was superior to insulin glargine in improving β-cell function, glycemic control and body weight, as well as better compliance and persistency [Corner, A. et al., Abst 878; Fabunmi, R. et al., Abst 883] and better than sitagliptin in improving postprandial glycemia and insulin responses [MacConell, L. et al., Abst 872]. Superiority was furthermore demonstrated for exenatide combined with metformin over the respective monotherapies regarding improvements in the metabolic profile in women with polycystic ovary syndrome while also inducing a marked insulin-sensitizing effect [Bhushan, R. et al., Abst 147] (Fig. 13). Exenatide was reported to slow gastric emptying and reduce endogenous glucose production [Cersosimo, E. et al., Abst 865] and to improve albuminuria and renal damage in experimental animal models of type 1 diabetes through an effect on intercellular cell adhesion molecule-1 and hypoxia-inducible factor, suggesting direct antiinflammatory and antiischemic effects [Kodera, R. et al., Abst 92]. Furthermore, exenatide was superior to insulin in attaining tight glycemic control with a better effect on body weight, blood pressure and the metabolic profile in pools of 1,015 and 1,050 patients [Maggs, D. et al., Abst 876; Okerson, T. et al., Abst 877] (Fig. 14) and reduced within- and between-day glucose variability and postprandial glucose excursions more effectively than biphasic insulin aspart in series of 463 and 478 patients suboptimally controlled on metformin and sulfonylurea [Glass, L.C. et al., Abst 873; Malone, J.K. et al., Abst 874], while a meta-analysis of two trials suggested superiority regarding fasting serum glucose regardless of body mass index and clinically meaningful benefits on systolic blood pressure and body weight with exenatide compared to insulin glargine or insulin aspart [Trautmann, M. et al., Abst 875]. Experimental studies also suggested an effect of exenatide in upregulating endothelial nitric oxide synthase phosphorylation, promoting proliferation of coronary endothelial cells [Tütüncü, Ö. et al., Abst 207] and preventing free fatty acid- and autoimmune insulinitis-induced β-cell apoptosis [Cunha, D.A. et al., Abst 509; Segundo, C. et al., Abst 538]; furthermore, exenatide, like insulin, also stimulated proliferation of glucagon-like peptide-1-secreting cells [Miller, C.B. et al., Abst 633], restored sirolimus-induced apoptosis of β-cells [Kawasaki, Y. et al., Abst 902] and enhanced pancreatic compensation in insulin-resistant diabetic animal models [Bhole, D. et al., Abst 901]. However, further experimental studies suggested that exenatide lacks the vascular protective activity against lipid-induced endothelial dysfunction of natural glucagon-like peptide-1 [Nyström, T. et al., Abst 206]. On the other hand, the feasibility and favorable pharmacokinetic and pharmacodynamic effects of intranasal administration of exenatide in patients with type 2 diabetes was confirmed in a placebo-controlled trial, which also underlined the safety and tolerability of the treatment [Blase, E. et al., Abst 866]; weekly injection was also deemed feasible and afforded patient satisfaction, according to observations in 51 subjects [Boye, K.S. et al., Abst 880].
Fig. 13. Change in the HOMA insulin resistance index after 24 weeks of treatment with exenatide or metformin in insulin-resistant obese women with polycystic ovary syndrome [Bhushan, R. et al., Abst 147].
Fig. 14. Percent of patients with hemoglobin A1c levels £6.5% after treatment with exenatide or insulin [Maggs, D. et al., Abst 876].
A further glucagon-like peptide-1 analog, liraglutide also demonstrated improvements in β-cell function, fasting and postprandial glycemic control and body weight in type 2 diabetes regardless of baseline hemoglobin A1c levels and prior therapies [Vaag, A. et al., Abst 149; Flint, A. et al., Abst 887; Schmitz, O. et al., Abst 888; Matthews, D.R. et al., Abst 892; Zinman, B. et al., Abst 898], with superiority over insulin glargine when added to metformin/sulfonylurea in a series of 581 patients [Russell-Jones, D. et al., Abst 148] (Fig. 15), equiefficacy versus or superiority over glimepiride in 746 patients previously on lifestyle intervention [Bode, B.W. et al., Abst 894; Garber, A. et al., Abst 896] and 1,091 patients on prior oral antidiabetic drug monotherapy [Hermansen, K. et al., Abst 895], superiority over rosiglitazone in 1,041 patients on prior oral antidiabetic mono- or combination therapy [Marre, M. et al., Abst 897] and an especially pronounced effect on visceral fat [Jendle, J. et al., Abst 797] (Fig. 16). The GLP-1 analog also lowered blood pressure [Colagiuri, S. et al., Abst 899]; however, liraglutide also decreased hunger and slowed gastric emptying [Horowitz, M. et al., Abst 889], resulting in a shift in the absorption kinetics of oral drugs, although not clinically significant [Zdravkovic, M. et al., Abst 890]. Mechanistically, the agent prevented hyperglycemia-induced plasminogen activator inhibitor-1 and vascular adhesion molecule expression [Dear, A.E. et al., Abst 893] while enhancing β-cell mass in diabetic animal models and protecting β-cells through acute and chronic effects on cell kinetic regulation, oxidative stress, glucolipotoxicity and interleukin-1-induced apoptosis [Shimoda, M. et al., Abst 511; Prazak, R. et al., Abst 518]. On the other hand, liraglutide, like native glucagon-like peptide-1, is cleared by dipeptidyl peptidase-IV and probably neutral endopeptidase, but a much slower rate [Bjørnsdottir, I. et al., Abst 891].
Fig. 15. Percent of patients showing hemoglobin A1c levels £6.5% upon addition of liraglutide, insulin glargine or placebo to metformin/glimepiride for 26 weeks [Russell-Jones, D. et al., Abst 148].
Fig. 16. Percent change in fat and lean body mass after treatment with liraglutide or glimepiride [Jendle, J. et al., Abst 797].
While new phase II clinical data confirmed the safety and effects of taspoglutide (long-acting glucagon-like peptide-1 analog) in improving β-cell function [Berria, R. et al., Abst 871] (Fig. 17), safety, feasibility and pharmacodynamic activity were reported also with albiglutide, a further long-acting glucagon-like peptide-1 mimetic currently in phase II clinical trial development [Stewart, M.W. et al., Abst 870], and MKC-253, an inhalable formulation of glucagon-like peptide-1 using Technosphere powder technology currently in phase I [Cassidy, J. et al., Abst 867; Costello, D. et al., Abst 868], both for the treatment of type 2 diabetes. A further investigational incretin analog, ZP-10A is a direct glucagon-like peptide-1 receptor agonist that offered significant, dose-dependent improvements in glycemic control and meaningful decreases in hemoglobin A1c compared to placebo in 542 patients with type 2 diabetes inadequately controlled with metformin [Rosenstock, J. et al., Abst 145] (Fig. 18). In the experimental arena, pharmacodynamic effects were reported with oral encapsulated G001 and G002, two further glucagon-like peptide-1 analogs [New, R.R.C. & Broke-Smith, T.P., Abst 869], and a further, undisclosed dipeptidyl peptidase-IV-stabilized analog increased β-cell replication and improved metabolic evolution after transplantation of insufficient islet mass [Joanny, G. et al., Abst 904].
Fig. 17. Change in hemoglobin A1c levels after treatment with taspoglutide [Berria, R. et al., Abst 871].
Fig. 18. Changes in hemoglobin A1c levels after 13 weeks of treatment with increasing doses of ZP-10A or placebo [Rosenstock, J. et al., Abst 145].
DIPEPTIDYL PEPTIDASE-IV INHIBITORS
With data confirming good tolerability for up to two years of administration [Williams-Herman, D. et al., Abst 912], studies with sitagliptin revealed superiority over placebo in lowering hemoglobin A1c levels in metformin- and pioglitazone-treated type 2 diabetes patients, regardless of age, gender, body mass index or baseline β-cell function [Alba, M. et al., Abst 909; Maegawa, H. et al., Abst 910] (Fig. 19), and substantial and sustained glycemic improvements over two years in type 2 diabetes patients using sitagliptin plus metformin as initial therapy [Qi, D.S. et al., Abst 73]. In that respect, addition of sitagliptin to metformin was more cost-effective than adding a sulfonylurea according to analyses from the U.K. [Brandle, M. et al., Abst 1095]. A triple combination of sitagliptin, metformin and rosiglitazone also offered substantial glycemic improvements with good tolerability compared to metformin/rosiglitazone alone in a randomized study in 178 patients [Arjona Ferreira, J.C. et al., Abst 911] (Fig. 20).
Fig. 19. Change in hemoglobin A1c levels after 18-24 weeks of treatment with sitagliptin or placebo according to body mass index [Alba, M. et al., Abst 909].
Fig. 20. Change in the HOMA-b index after 18 weeks of adding sitagliptin or placebo to metformin/rosiglitazone [Arjona Ferreira, J.C. et al., Abst 911].
Studies were also discussed evaluating the safety (including cardiovascular safety) and improved glycemic and lipidic control and insulin secretion with vildagliptin [Goodman, M. et al., Abst 913; Kothny, W. et al., Abst 915; Boschmann, M. et al., Abst 916; Foley, J.E. et al., Abst 917], underlying its activity in sensitizing α-cells to the suppressive effects of hyperglycemia and the stimulatory effects of hypoglycemia [Ahrén, B. et al., Abst 75] and its safety, tolerability and efficacy in patients with normal or mildly or moderately impaired renal function [Thuren, T. et al., Abst 74]. Furthermore, the GALIANT primary care-based study suggested vildagliptin to be as effective as thiazolidinediones in lowering hemoglobin A1c in patients failing metformin [Braceras, R. et al., Abst 914] (Fig. 21).
Fig. 21. Change in hemoglobin A1c levels after 12 weeks of adding vildagliptin or thiazolidinedione to metformin in the GALIANT study [Braceras, R. et al., Abst 914].
Regarding alogliptin, use in monotherapy significantly improved glycemic control in 329 patients inadequately controlled with diet and exercise [Mekki, Q. et al., Abst 862], while addition to ongoing treatment with glibenclamide resulted in significant improvements in glycemic control compared to placebo in 500 patients with type 2 diabetes, without weight gain or increased risk for hypoglycemia [Fleck, P. et al., Abst 76]. Similarly, addition of alogliptin to ongoing insulin in 390 patients, to ongoing pioglitazone in 493 patients or to ongoing metformin in 527 patients resulted in incremental reductions of hemoglobin A1c without increased weight gain or hypoglycemia rates [Rendell, M. et al., Abst 77; Pratley, R. et al., Abst 860; Ellis, G. et al., Abst 861] (Fig. 22).
Fig. 22. Change in hemoglobin A1c levels after 26 weeks of adding alogliptin or placebo to insulin, metformin, glibenclamide or pioglitazone [Fleck, P. et al., Abst 76; Rendell, M. et al., Abst 77; Pratley, R. et al., Abst 860; Ellis, G. et al., Abst 861; Mekki, Q. et al., Abst 862].
As with other dipeptidyl peptidase-4 inhibitors, initial combination therapy with saxagliptin and metformin was suggested safe and effective for improving glycemic control in a 24-week study in 1,306 patients with type 2 diabetes, with superiority over the respective monotherapies [Chen, R. et al., Abst 78] (Figs. 23 and 24). A combination of saxagliptin and glibenclamide also proved superior to uptitration of the sulfonylurea in improving glycemic control in 768 patients uncontrolled by standard glibenclamide therapy [Ravichandran, S. et al., Abst 858], while addition of saxagliptin to rosiglitazone or pioglitazone was safe and well tolerated and offered clinically meaningful and statistically significant improvements in glycemic control in 565 patients suboptimally controlled with thiazolidinediones [Allen, E. et al., Abst 859].
Fig. 23. Change in hemoglobin A1c levels after 26 weeks of treatment with saxagliptin and/or metformin [Chen, R. et al., Abst 78].
Fig. 24. Change in hemoglobin A1c and fasting and postprandial glucose levels after 24 weeks of treatment with saxagliptin and/or glibenclamide [Chen, R. et al., Abst 78].
AMYLIN ANALOGS
With favorable pharmacokinetics and tolerability in adolescents [Lorenzi, G. et al., Abst 1009], data from a trial in 112 patients with type 2 diabetes was reported in Rome that suggested similar glycemic control with pramlintide compared to titrated rapid-acting insulin, both added to basal insulin therapy [Riddle, M. et al., Abst 1007]. Continuous subcutaneous pramlintide infusion was tested over a 16-week period in 11 patients with type 1 diabetes, suggesting good tolerability and effective improvements in hemoglobin A1c and postprandial glucose excursions, offering additional favorable changes on body weight and lipid profiles [Huggman, D.M. & McLean, G.W., Abst 1008]. Further data in groups of 28 and 211 patients with type 2 diabetes also suggested improvements in hemoglobin A1c levels and body weight upon addition of pramlintide to insulin therapy [Darsow, T. et al., Abst 1010; Wilhelm, K. et al., Abst 1011] (Fig. 25).
Fig. 25. Change in hemoglobin A1c levels and body weight after 16 weeks of adding pramlintide or placebo to insulin glargine-based therapy [Wilhelm, K. et al., Abst 1011].
GLUCOSE TRANSPORTER INHIBITORS
New clinical trials with dapagliflozin discussed during this year’s EASD meeting revealed improvements in glycemic control and weight loss compared to placebo and metformin in patients with type 2 diabetes [List, J.F. et al., Abst 40; Woo, V. et al., Abst 796] (Fig. 26).
Fig. 26. Change in hemoglobin A1c levels after 12 weeks of treatment with dapagliflozin, metformin or placebo [List, J.F. et al., Abst 40].
NOVEL PUTATIVE THERAPIES
Benefits in type 1 diabetes maintenance were attributed to alfacalcidol, which in 54 children and adolescents treated for two years reduced insulin requirements [Piekarski, R. et al., Abst 116] (Fig. 27). Data from 3,070 patients with type 2 diabetes included in a placebo-controlled trial demonstrated the safety and effectiveness of an oral, quick-release formulation of bromocriptine as a treatment, with significant improvements in hemoglobin A1c levels regardless of concomitant use of metformin or sulfonylureas [Cincotta, A.H. et al., Abst 39; Scranton, R.E. et al., Abst 930] (Fig. 28).
Fig. 27. Percent of patients with insulin requirements <0.5 U/kg after two years of treatment with alfacalcidol [Piekarski, R. et al., Abst 116].
Fig. 28. Percent of patients with hemoglobin A1c levels <7.0% after 24 weeks of treatment with bromocriptine or placebo in type 2 diabetes patients on oral antidiabetic therapy [Cincotta, A.H. et al., Abst 39].
Currently in phase II clinical development, the carnitine O-palmitoyltransferase-1 inhibitor teglicar demonstrated reductions in insulin resistance and a trend towards reduced fasting blood glucose compared to placebo after only 15 days in 40 patients with type 2 diabetes [Valentini, G. et al., Abst 41] (Fig. 29).
Fig. 29. Change in the HOMA insulin resistance index and fasting blood glucose levels after 15 days of treatment with teglicar or placebo [Valentini, G. et al., Abst 41].
Also currently in phase II development, the glucokinase activator RO-4389620 exhibited rapid, dose-dependent glucose-lowering activity lasting over 24 hours in three placebo-controlled trials in 24 healthy volunteers and groups of 15 and 59 patients with type 2 diabetes, with dose-independent headache and mild to moderate hypoglycemia as only side effects, suggesting potential for the treatment of the disease [Zhi, J. et al., Abst 42; Bonadonna, R.C. et al., Abst 927; Zhai, S. et al., Abst 928] (Fig. 30); a further glucokinase activator currently in phase II clinical development, TTP-355 was reported active in preclinical studies [Valcarce, C. et al., Abst 929], while another drug currently in preclinical testing, GKA-50 increased cellular glucose metabolism and insulin secretion in in vitro studies [Mullooly, N. et al., Abst 488].
Fig. 30. Fasting plasma glucose levels after a single dose of RO-4389620 or placebo [Bonadonna, R.C. et al., Abst 927].
Phase II clinical trial data also supported the use of BHT-3021, a human insulin-encoding plasmid that proved safe and effective in suppressing immune responses and preserving pancreatic function in 14 patients with type 1 diabetes [Gottlieb, P. et al., Abst 574] (Fig. 31); experimental studies with mutant proinsulin plasmids were reported, with activity limited by gene transfer efficiency and immune responses [Niessen, S.J.M. et al., Abst 600].
Fig. 31. Change in C-peptide levels at 15 weeks and 6 months after immunotherapy with BHT-3021 or placebo [Gottlieb, P. et al., Abst 574].
Phase I clinical data evidence of an effect of XOMA-052, an anti-interleukin-1β antibody, was obtained from two clinical studies that demonstrated the favorable safety and pharmacokinetic profile of the agent, with a half-life of 15-21 days and potential for monthly or longer administration intervals [Donath, M.Y. et al., Abst 1] (Fig. 32).
Fig. 32. Change in β-cell function (insulin secretion after intravenous glucose) during 91 days of treatment with XOMA-052 or placebo [Donath, M.Y. et al., Abst 1].
In the experimental setting, the AMP-activated protein kinase activator AICAR improved glucose tolerance despite diminished β-cell mass in experimental animal models [Pold, R. et al., Abst 788] and exposure of adipocytes to the adenosine A1 receptor agonist CVT-3619 potentiated the antilipolytic effects of insulin [Dhalla, A.K. et al., Abst 6862], while inhibition of poly(ADP-ribose) polymerase with isoquinoline-1,5-diol or GPI-15427 induced improvements in type 1 diabetic nephropathy markers [Obrosova, I.G. et al., Abst 95]. Furthermore, preclinical data with BGP-15, an insulin-sensitizing poly(ADP-ribose) polymerase inhibitor currently in phase II research, demonstrated potential for controlling antipsychotic drug-associated weight gain and metabolic abnormalities [Tory, K. et al., Abst 714] (Fig. 33), while experimental animal studies with a small-molecule antagonist of the glucagon receptor coded MB-09975 suggested potential for lowering hemoglobin A1c without weight gain [Potter, S.C. et al., Abst 931]. A number of novel insulin sensitizer acting on glucose transport and incorporation into adipocytes were described, including VVP-808 and VVP-326 (palmatine) , which exhibited in vitro and in vivo antidiabetic activity [Molero, J.C. et al., Abst 37; Walder, K.R. et al., Abst 935]. On the other hand, the development of nuclear receptor- and peroxisome proliferator-activated receptor-sparing insulin sensitizers was deemed feasible, and a number of compounds including GW-7627 and GW-0742 were obtained that exhibited antidiabetic-like properties [Colca, J.R. et al., Abst 38].
Fig. 33. Change in the HOMA insulin resistance index and body weight in patients receiving BGP-15 or placebo added to olanzapine [Tory, K. et al., Abst 714].
DIET AND DIET SUPPLEMENT THERAPIES
Diet, risk of developing diabetes and diabetes control are intimately related, and new studies have been performed to clarify issues such as glycemic, lipid and metabolic control based on dietary intervention. The DIRECT study, reported during this year’s EASD meeting in the Eternal City, suggested that Mediterranean and low-carbohydrate diets are effective and safe alternatives to a low-fat diet with improved effects on lipid (low-carbohydrate diet) and glycemic (Mediterranean) control, offering newer options for tailored management based on individual patient profiles [Shai, I. et al., Abst 246]. However, fat-modifying diet still confers a benefit, as further demonstrated in the LIPGENE study that demonstrated preintervention dietary fat intake-dependent benefits on lipid markers in 417 subjects with metabolic syndrome following several fat-modified dietary approaches [Tierney, A.C. et al., Abst 247]. Nevertheless, the most successful effect on diabetes could be obtained with low-carbohydrate diets, although according to the DIRECT study the benefit depends on concurrent weight loss in spouses and household dietary patterns [Golan, R. et al., Abst 958]. On the other hand, observations from the LIPGENE dietary intervention study related high-saturated-fat diets to increases and low-fat diets to decreases in pulse and systolic blood pressure in men but not women with metabolic syndrome [Gjestad, I.M.F. et al., Abst 1219].
Further to the known benefits of resveratrol, which were expanded to improvements in insulin-induced insulin resistance in skeletal muscle cells through an effect on mTOR and p70 S6K phosphorylation [Tsiani, E. et al., Abst 696] and to improve oxidative stress through an effect on Mn-superoxide dismutase dysfunction [Koya, D. & Kitada, M., Abst 1184], significant improvements in inflammatory and metabolic parameters in 32 patients with type 2 diabetes at high cardiovascular risk were noted after four-week supplementation with grape seed extract compared to placebo [Kar, P. et al., Abst 6]. In a similar way, the flavonoid silibinin was shown to reverse metabolic alterations related to insulin resistance in high fructose-fed experimental animals through an effect against hepatic gluconeogenesis and glycolysis [Sánchez, C. et al., Abst 934]. Benefits were also related to berberine, an alkaloid that showed protective activity against vascular dysfunction [Wang, Y. et al., Abst 1287], while a traditional Chinese preparation, qinghuoyihao, was suggested effective in protecting endothelial cells from high glucose-induced oxidative stress and endothelial dysfunction in experimental studies [Gao, X. et al., Abst 1286].
Polyunsaturated ω3-fatty acids also have metabolic benefits that extend to patients with diabetes, with prevention and improvements in diabetic cardiomyopathy accompanied by significant improvements in lipid profiles and EEG parameters [Serhiyenko, A.A. et al., Abst 955]. Mechanistically, oleoylethanolamide was related to stimulate glucagon-like peptide-1 secretion through an effect on the G protein-coupled receptor GPR119, suggesting potential as nutraceutical approach for type 2 diabetes [Lauffer, L.M. et al., Abst 125]. Furthermore, experimental results suggesting antiinflammatory benefits of conjugated linoleic acid on LDL-induced adhesion molecule expression in endothelial cells were reported [Schrezenmeir, J. et al., Abst 1290].
Further insights into natural therapies for diabetes and diabetes-related complications in experimental studies revealed potential against diabetic retinopathy and production and retinal accumulation of advanced glycation endproducts for an ethanolic extract of Pueraria montana root, Magnolia officinalis bark, Glycyrrhiza uralensis root and Euphorbia pekinensis root containing puerarin, glycyrrhicin, honokiol and magnolol and acting mostly against nuclear factor κβ kinase [Kim, J. et al., Abst 196], and against endothelial dysfunction during gestational diabetes for extracts of Centella asiatica [Di Pietro, N. et al., Abst 1291].
EDUCATION IN DIABETES AND DIABETES MANAGEMENT
That education improves clinical, cognitive and psychological outcomes in patients with type 2 diabetes was further confirmed by the results of the ROMEO study, which compared group to one-on-one care in 815 patients and suggested better results with continuous systemic group education [Trento, M., Abst 151]. The PREPARE study also demonstrated benefits on ambulatory activity, glucose tolerance and inflammatory cytokine levels in patients with impaired glucose tolerance receiving personalized structured education [Yates, T. et al., Abst 1035], while the HyPOS study confirmed the highly distressing impact of severe hypoglycemia in diabetic patients and the improvements in glycemic control while reducing the incidence of severe hypoglycemia obtained in 135 subjects with a specific education program for insulin-treated patients [Kulzer, B. et al., Abst 229]. Other studies and observations confirmed the overall benefits and cost-effectiveness of education on body weight, diet, physical activity and diabetes management [Dencker, L. et al., Abst 1036; George, J.T. et al., Abst 1108]. Furthermore, “modular” patient education programs centered on metabolic and body weight control were feasible and effective with less time required compared to standard programs while affording similar benefits on diabetes control in inpatients with type 2 diabetes on intensified insulin therapy [Nauck, M.A. et al., Abst 231]. However, the reality, as suggested by baseline data from the DESMOND study, is that newly diagnosed patients with type 2 diabetes present with lower hemoglobin A1c levels, suggesting earlier diagnosis, but higher body mass index and worse cardiovascular risk profiles, as a reflect of the increasing prevalence of obesity and dyslipidemia and the need for general education on lifestyles in the general population and specific education in the diabetic and diabetic-prone population [Dallosso, H.M. et al., Abst 962].
EXERCISE AND LIFESTYLES IN DIABETES MANAGEMENT
Although corpulence may limit activity to a greater extent than activity reduces corpulence [Metcalf, B. et al., Abst 670], exercise clearly has a role in the management of diabetes and body fat accumulation [Mokhtari, I. et al., Abst 1037], as well as in improving expression of genes involved in fatty acid metabolism in skeletal muscle [Hansson, O. et al., Abst 669] and restoring coronary vascular function [Ghosh, S. et al., Abst 1334], although moderate exercise and walking may not be sufficient for lowering hemoglobin A1c levels [Gram, B. et al., Abst 1038]. Moderately intensive exercise was reported as effective in lowering body fat and improving weight in patients with type 2 diabetes, with superiority over vigorous exercise, although the latter offered greater benefit regarding improvements in insulin resistance [Han, K. et al., Abst 668]; two resistance training sessions per week were reportedly effective in improving lipid profiles in hypercholesterolemic, obese women, despite significant decreases in circulating adiponectin levels [Forga, L. et al., Abst 851]. On the other hand, improvements in abdominal fat by lifestyle interventions in obese, nondiabetic women also brought about benefits on urinary albumin excretion [Invitti, C. et al., Abst 1212].
DYSLIPIDEMIA IN DIABETES
Dyslipidemia is a common co-occurrence in patients with dysglycemia, and is directly related to an increased risk for cardiovascular death in patients with fasting hyperglycemia or impaired fasting glucose, as further confirmed by the DECODE study [Zhang, L. et al., Abst 415] (to note: the ZODIAC-12 study suggested no relationship between cholesterol and mortality in older patients with type 2 diabetes [Houweling, S.T. et al., Abst 1391]). Statins have induced marked benefits on lipid profiles in patients with diabetes, which with atorvastatin resulted in reductions in the cardiovascular risk in patients with diabetes or metabolic syndrome [Deedwania, P. et al., Abst 1357] whilst in the case of rosuvastatin brought about benefits on HDL apolipoprotein A1 kinetics [Vergès, B. et al., Abst 855] and overall benefits that were complemented by addition of colestimide, the combination offering greater benefits than either monotherapy in 40 patients [Takebayashi, K. et al., Abst 808]. However, statins also offer broad pleiotropic beneficial effects, including activation of the nuclear factor E2-related factor-2 (Nrf2)-antioxidant response element pathway-dependent antioxidant effects [Ziros, P.G. et al., Abst 807], downregulation of CD36 scavenger receptor and nuclear factor κβ expression in monocytes from type 2 diabetes patients, as noted with atorvastatin [Mandosi, E. et al., Abst 1312], improvement in arterial stiffness in type 2 diabetes, also after treatment with atorvastatin [Grigoropoulou, P. et al., Abst 1348], and prevention of chronic hyperglycemia-induced reduction in islet microvascular endothelial cell death through modulation of the serine/threonine Akt kinase pathway, as demonstrated with pravastatin [Favaro, E. et al., Abst 1297].
Addition of a cholesterol absorption inhibitor to statin therapy has been devised as a means to improve the cholesterol-lowering activity, and a fixed combination of ezetimibe and simvastatin lowered atherogenic lipoprotein subfractions more effectively than atorvastatin in 1,013 hypercholesterolemic patients with type 2 diabetes [Tomassini, J.E. et al., Abst 853] (Fig. 34).
Fig. 34. Change in LDL-, IDL- and VLDL-cholesterol levels after 6 weeks of treatment with increasing doses of simvastatin (combined with ezetimibe 10 mg) or atorvastatin (monotherapy) [Tomassini, J.E. et al., Abst 853].
Nonstatin approaches to the treatment of dyslipidemia include fibrates, and protection of endothelial cells was reported with fenofibrate, which was related to an effect on AMP-activated protein kinase and endothelial nitric oxide synthase [Atsuko, T. et al., Abst 1315]. Niacin is a further drug with benefits against dyslipidemia, which was reported to improve serum total and phosphorylated fetuin A levels in direct correlation with changes in triglycerides in subjects with metabolic syndrome [Mathews, S.T. et al., Abst 933]. A fixed combination of extended-release niacin and laropiprant offered marked improvements in LDL- and HDL-cholesterol and triglycerides in 1,387 dyslipidemic patients with or without metabolic syndrome [Bays, H.E. et al., Abst 1388] (Fig. 35); a triple combination of ezetimibe, simvastatin and niacin improved lipid and lipoprotein profiles in hypercholesterolemic patients with or without diabetes or metabolic syndrome, but niacin-containing regimens tended to worsen fasting glucose levels compared to ezetimibe/simvastatin alone [Guyton, J.R. et al., Abst 854] (Fig. 36).
Fig. 35. Change in LDL- and HDL-cholesterol and triglyceride levels after 20 weeks of treatment with extended-release niacin alone or combined with laropiprant, or placebo in patients with (solid bars) or without (hatched bars) metabolic syndrome [Bays, H.ER. et al., Abst 1388].
Fig. 36. New-onset diabetes rates (as defined by 2 consecutive fasting glucose determinations of 126 mg/dl or over) in patients with metabolic syndrome (MS) or without diabetes or metabolic syndrome (no MS/DM) treated with ezetimibe/simvastatin, niacin or the triple combination [Guyton, J.R. et al., Abst 854].
OBESITY IN DIABETES: DIABESITY
New data was reported this year in Rome regarding rimonabant, an antiobesity agent that induced clinically significant improvements in glycemic control and overall cardiometabolic risk in 363 type 2 diabetes patients compared to placebo [Hollander, P.A. et al., Abst 3] (Fig. 37), and in experimental animals reduced body weight and adiposity independently of food intake and resting metabolic rate [Woolcott, O.O. et al., Abst 792] and induced hepatoprotective effects through upregulation of adiponectin in obese, insulin-resistant animal models [Kabir, M. et al., Abst 732]. A substudy of the ADAGIO-LIPIDS study was also discussed, according to which diabetic patients with atherogenic dyslipidemia treated with rimonabant showed improvements in glycemic control and the cardiometabolic profile associated to reductions in abdominal and hepatic fat [Despres, J.P. et al., Abst 1016]. Furthermore, experimental data suggested a role of rimonabant in the prevention and treatment of diabetic neuropathy, the drug preventing allodynia as effectively as duloxetine and gabapentin but without causing interferences with spontaneous locomotor activity [Chamiot-Clerc, P. et al., Abst 1242].
Fig. 37. Change in hemoglobin A1c levels after 48 weeks of treatment with rimonabant or placebo [Hollander, P.A. et al., Abst 3].
A combination of pramlintide and metreleptin (recombinant human leptin) was tested for activity in a 24-week, randomized study in 177 obese/overweight patients, demonstrating enhanced weight loss compared to either monotherapy [Koda, J. et al., Abst 83] (Fig. 38). Pramlintide combined with sibutramine or phentermine also resulted in enhanced weight loss in 244 overweight or obese individuals [Halseth, A. et al., Abst 798] (Fig. 39).
Fig. 38. Weight loss rate during week 12-20 after starting treatment with pramlintide or metreleptin combined with placebo, or the two-drug combination [Koda, J. et al., Abst 83].
Fig. 39. Weight loss after 24 weeks of treatment with pramlintide alone or combined with sibutramine or phentermine, or placebo [Halseth, A. et al., Abst 798].
According to further miscellaneous observations, the antianginal agent trimetazidine improved left ventricular function and reduced fatty acid oxidative metabolism in obese subjects [Bucci, M. et al., Abst 760].
In the experimental arena, antiobesity and antidiabetic potential was reported with the melanocortin receptor-modulating agent AP-1030 [Jonassen, T.E.N. et al., Abst 736] and the glucose-dependent insulinotropic polypeptide receptor antagonist SKL-14959 [Tsubamoto, Y. et al., Abst 932], and antiobesity activity was attributed to highly purified icosapentaenoate in animal models of high-fat/high-saccharose diet-induced obesity, an effect that was related to hepatic lipogenesis [Sato, A. et al., Abst 84]. The antioxidant compound α-lipoic acid prevented increases in food intake, body weight, blood glucose levels, urinary protein excretion and renal transforming growth factor-β expression in experimental models of obesity [Lee, S. et al., Abst 1186].
HYPERTENSION, DIABETES AND CARDIOVASCULAR RISK
Along with diabetes, hypertension is another major determinant of cardiovascular risk, both going together in a huge proportion of patients, and mere reductions in blood pressure have also induced benefits on diabetes, as exemplified by reductions in the incidence and progression of retinopathy by blood pressure lowering with perindopril/indapamide in patients with type 2 diabetes in the ADVANCE trial [Beulens, J.W. et al., Abst 1175]. On the other hand, because of the common coexistence of hypertension and dyslipidemia, a fixed combination of amlodipine and atorvastatin has been developed that in clinical trials was able to simultaneously control blood pressure and LDL-cholesterol in a high proportion of patients with and without diabetes, with favorable tolerability [Jenssen, T.G. et al., Abst 1220].
The β-blocker agent nebivolol was shown to prevent insulin resistance in saccharose-fed animals, an effect that was not shared by atenolol and correlated to benefits on nitric oxide production [Guarino, M.P. et al., Abst 688].
Angiotensin-converting enzyme inhibitors have shown kidney-protecting activity in diabetic nephropathy, and data from a study with lisinopril in 58 normoalbuminuric, 45 persistently microalbuminuric and 45 persistently macroalbuminuric type 1 diabetes patients and 55 healthy controls suggested additional benefits on glomerular and tubulointerstitial damage early in the disease [Nielsen, S. et al., Abst 46].
Angiotensin receptor blockers share the nephroprotective activity of angiotensin-converting enzyme inhibitors, and such benefits were demonstrated with irbesartan in the IDNT trial, in which at equivalent blood pressure-lowering activity, greater reduction in estimated glomerular filtration rate compared to amlodipine was demonstrated in 1,715 patients with type 2 diabetic nephropathy [Bilous, R.W. et al., Abst 1216] (Fig. 40). On the other hand, data from a double-blind trial in hypertensive patients treated with telmisartan alone or combined with hydrochlorothiazide suggested reduced albumin excretion rate responses to angiotensin receptor blockers with high sodium chloride intake or with salt supplementation in patients on low-sodium diets [Ekinci, E.I. et al., Abst 1215]. Experimental data with candesartan also demonstrated attenuation of renal vascular pathology in hypertensive diabetic animal models [Wilkinson-Berka, J.L. et al., Abst 193].
Fig. 40. Rate of loss in estimated glomerular filtration rate at months 21-48 in patients from the IDNT trial treated with irbesartan, amlodipine or placebo [Bilous, R.W. et al., Abst 1216].
Safe, blood pressure lowering-independent nephroprotective activity was demonstrated with aliskiren compared to hydrochlorothiazide in 396 hypertensive, obese patients [Schmieder, R.E. et al., Abst 1222] and compared to losartan in a trial in 599 patients with type 2 diabetes and nephropathy [Parving, H.H. et al., Abst 45], while the combination of aliskiren and valsartan offered higher blood pressure-lowering activity than either monotherapy [Yarrows, S.A. et al., Abst 1221] and a combination of aliskiren and irbesartan offered greater benefits than either monotherapy on albuminuria [Frandsen, E. et al., Abst 1217; Persson, F. et al., Abst 1218] (Fig. 41).
Fig. 41. Change in albumin excretion rate after 2 months of treatment with aliskiren, irbesartan or the combination of both [Persson, F. et al., Abst 1218].
ISLET AND PANCREAS TRANSPLANTATION
No major news was reported this year regarding islet and pancreas transplantation, but a number of miscellaneous findings are worth summarizing. In that respect, results from a comparative study suggested more favorable glucose metabolism with mycophenolate mofetil compared to sirolimus once transplant recipients reached a corticosteroid-free status [Havrdova, T. et al., Abst 592], while ciclosporin induced deleterious effects on isolated islets [Bugliani, M. et al., Abst 597]. To note also that long-term inhibition of mTOR with sirolimus exacerbated insulin resistance and high fat-induced glucose intolerance in experimental animals [VeyratDurebex, C. et al., Abst 697]. Furthermore, studies in nonhuman primates suggested feasibility for exenatide as potent antirejection therapy after islet cell allotransplantation [Buss, J.L. et al., Abst 598]. On the other hand, an in vitro study suggested feasibility for perfluorocarbons in preserving pancreatic islets and protecting them from hypoxia [Maillard, E. et al., Abst 591].
DIABETIC NEPHROPATHY AND ANEMIA
Combined use of epoetin beta and testosterone replacement improved hemoglobin levels in males with diabetes on hemodialysis [Lepetukhin, A. et al., Abst 659]. Improvements in hemoglobin levels in patients with diabetic nephropathy were also reported with epoetin zeta [Scigalla, P. & Koytchev, R., Abst 1201]. On the other hand, data from the SURE study suggested benefits of structured care targeted to hemoglobin A1c, glucose, blood pressure, LDL-cholesterol and triglyceride goals on renal endpoints in type 2 diabetes [So, W.Y. et al., Abst 1214].
DIABETIC NEUROPATHY
Without specific clinical news on the treatment of diabetic neuropathy during this year’s discussions and presentations other than further confirmations of the long-term safety and efficacy of pregabalin [Murphy, K. & Emir, B., Abst 1246] and duloxetine [Skljarevskyt, V. et al., Abst 1247; Wernicke, J.F. et al., Abst 1248], benefits in experimental animal models of diabetic neuropathy were associated to treatment with the vascular endothelial growth factor zinc finger protein activator SB-509 [Ando, D.G. et al., Abst 1249] and tretinoin [Park, J. et al., Abst 1245]. Furthermore, adipose tissue-derived stem cell transplantation arose as a promising strategy for the treatment of advanced-stage diabetic neuropathy, according to experimental observations [Mizukami, H. et al., Abst 1243].
MISCELLANEOUS
Nelfinavir-induced adipocyte insulin resistance was related to impairment of protein kinase B-sensing of inositol triphosphate [Maissel, A. et al., Abst 86]; glucosamine-induced insulin resistance was related to endoplasmic reticulum stress [Raciti, G.A. et al., Abst 691]. Thiazide-type diuretics can also cause insulin resistance through alterations of adipose tissue distribution, inflammation and gene expression [Palming, J. et al., Abst 836].
An effect of recombinant human prolactin in enhancing β-cell survival and inhibiting apoptosis was reported [Labriola, L. et al., Abst 215].
Mass- and glucose-dependent effects of diazoxide on β-cell mitochondrial function were demonstrated [Larsson-Nyrén, G. et al., Abst 498].
The phosphodiesterase V inhibitor zaprinast acutely enhanced insulin-mediated capillary recruitment and glucose disposal in experimental animals [Genders, A.J. et al., Abst 628].
Potential was suggested for bisperoxovanadate in preventing free fatty acid-induced β-cell dysfunction [Oprescu, A.I. et al., Abst 655].
Without affecting hepatic or peripheral insulin sensitivity, prednisolone increased fasting glucose and insulin levels in experimental animals [Laskewitz, A.J. et al., Abst 662]; in healthy humans, acute and short-term prednisolone exposure induced β-cell abnormalities leading to insulin resistance and diabetogenic effects [van Raalte, D.H. et al., Abst 663].
A glucose RapidSpray® has been developed and tested safe and effective for rapid management of hypoglycemia in children up to 5 years of age [Pronina, E. et al., Abst 952].
Tempol, an antioxidant free radical scavenger, was reported to prevent NADPH oxidase-induced oxidative stress in early-stage diabetes and hypertension [Peixoto, E.B.M. et al., Abst 1183].
Vitamin D replacement using active 1,25-dihydroxyvitamin D3 reverted basement membrane thickening in diabetic animal models with no effect on mesangial expansion [Wogensen, L. et al., Abst 1188].
By antagonizing the glucocorticosteroid receptor, metyrapone attenuated hippocampal neuronal loss and protected β-cells during early diabetes development in experimental animals [Orlovsky, M.A. et al., Abst 1244].
A superoxidized solution was reported effective in the postsurgical management of diabetic foot [Goretti, C. et al., Abst 1273]; healing of diabetic foot ulcers was enhanced by high-dose atorvastatin [Johansen, O.E. et al., Abst 1278].
Ursodeoxycholate was noted to inhibit expression of plasminogen activator inhibitor-1 in endothelial cells through an effect on high glucose-mediated transforming growth factor signaling [Yokoi, T. et al., Abst 1293].
Treatment of rheumatoid arthritis with infliximab or etanercept reduced the risk of atherosclerosis progression and improved insulin resistance continuously in the case of etanercept but only transiently in that of infliximab [Sayo, Y. et al., Abst 1338].
Desflurane was shown to induce phosphorylation of protein kinase B/Akt and glycogen synthase kinase-3b, thus inducing cardioprotective effects, only in the diabetic, but not nondiabetic myocardium [Lemoine, S. et al., Abst 1341]. In relation to that, inhibition of glycogen synthase kinase-3 by lithium chloride prevented high fat diet-induced atherosclerosis in apolipoprotein E-deficient animal models [Jang, H.J. et al., Abst 1371].