Close to 3000 oral, poster or publication-only contributions constituted the new research disclosed to this year's American Diabetes Association (ADA) scientific sessions, which heated the not so warm weather around the harbor in San Diego's Convention Center. New data on epidemiology, risk, prognosis, treatment and management of diabetes and diabetes complications was discussed during the meeting, as summarized in this report. Newsbites contained herein are supplemented by full abstract information available through the ADA's Web site (www.diabetes.org), while selected news is also included in the daily medical news of this Web site. DailyDrugNews.com contains information on antidiabetic drugs in development, and detailed pharmacological, pharmacokinetic and clinical data presented during the meeting is or will soon be made available through the comprehensive Web database Integrity at integrity.prous.com. Selected sessions, including special highlight sessions from the meeting, are available as on-demand webcasts at webcasts.prous.com/ada2005/.
Insulin injection remains the most common treatment for type 1 diabetes, even for in-hospital hyperglycemia [Garnica, P. et al. Abst. 438-P] or in patients on waiting lists for transplantation [Hung, L.Y. et al. Abst. 2844-PO], and pharmacodynamic assays with standard human insulin have demonstrated activity for at least 5 hours even in toddlers [Buckingham, B.A. Abst. 1889-P]; continuous subcutaneous insulin infusion also effectively controlled hemoglobin A1c in diabetic children [Wallach, E.J. et al. Abst. 2770-PO]. However, new insulin formulations and insulin analogues have been developed to improve patient care with a better efficacy/tolerability profile.
Inhaled insulin therapy demonstrated safety and efficacy, with a fast onset of action and significant muscle glucose uptake [Leary, A.C. et al. Abst. 430-P; Edgerton, D.S. et al. Abst. 435-P; Thule, P.M. et al. Abst. 444-P]. Inhaled insulin resulted in no airway sensitization or adverse immunological response [Dumas, R. et al. Abst. 437-P], and in animals rapid absorption and lung clearance was demonstrated [Laureano, R.T. et al. Abst. 445-P]. Equiefficacy in terms of tight control of glycemia with similar tolerability was shown compared with subcutaneous insulin in 226 and 259 patients included in two trials, with no major impact on lung function [Dumas, R. et al. Abst. 355-OR; Garg, S. et al. Abst. 361-OR], but inhaled insulin acted faster than subcutaneous insulin in 15 further patients [Petersen, A.H. et al. Abst. 359-OR]. Equivalent results were obtained with inhaled insulin and subcutaneous insulin lispro in a pharmacokinetic and glucodynamic study [Rave, K. et al. Abst. 360-OR]. Continuous subcutaneous insulin infusion effectively prevented hypoglycemia in an open trial [Thomas, R. et al. Abst. 2216-PO], and diabetes-related complications in a populational survey [Zakrzewska, K. et al. Abst. 2533-PO]. Transdermal patch administration of insulin has also been studied, with transfer of significant amounts of insulin through skin [Heinemann, L. et al. Abst. 362-OR].
Novel insulin analogues have been developed with improved pharmacokinetic and pharmacodynamic profiles [Burke, B.V. et al. Abst. 561-P]. Insulin glargine offered superior control compared with standard insulin, offering higher patient flexibility in case of missed dosing [Rosak, C. et al. Abst. 587-P; Donaubauer, B. et al. Abst. 2151-PO; D'annunzio, G. et al. Abst. 2769-PO], and was as effective as continuous subcutaneous insulin infusion, but exhibited higher patient satisfaction [Boaz, M. et al. Abst. 2425-PO]. However, insulin glargine used once daily resulted in a loss of basal insulin action, indicating the need for twice-daily dosing [Idampitiya, C. et al. Abst. 2048-PO]. Twice-daily insulin glargine combined with meal-time insulin aspart demonstrated optimal control of insulin levels, despite higher nighttime glucose levels, compared with once-daily administration [Ashwell, S.G. et al. Abst. 483-P], but morning dosing prevented nocturnal ketosis when subcutaneous insulin lispro infusion was interrupted postdinner [Von Dobeln, A. et al. Abst. 495-P] and observations of a reproducible, individual glucose raise in mid-afternoon suggested the need for better optimized therapy [Porcellati, F. et al. Abst. 524-P]. Both insulin aspart and regular insulin given intranasally exerted effects on insulin utilization in the central nervous system, with improvements in memory function [Kern, W. et al. Abst. 51-LB]. Use of insulin glargine resulted in lower total healthcare costs than those with the use of standard insulin [Orsini, L.S. and Huse, D.M. Abst. 582-P].
Insulin aspart in basal-bolus therapy with NPH insulin was as effective as insulin lispro or regular insulin in 378 children treated for 24 weeks [Arslanian, S. et al. Abst. 2150-PO]. Insulin glargine plus insulin aspart given as basal-bolus therapy provided superior glycemic control compared with NPH insulin in a group of 64 Japanese children [Kawamura, T. et al. Abst. 1890-P]. Insulin glargine could be mixed with rapid-acting insulin in the same syringe, with no deleterious effects on glycemic control [Fiallo-Scharer, R. et al. Abst. 1879-P]. The analogue proved cost-effective because of the decreased complication rates and improved quality-adjusted life expectancy in 1070 patients [Palmer, A.J. et al. Abst. 1236-P]. Safety of insulin aspart during pregnancy was demonstrated in 10 women [Balaji, V. et al. Abst. 537-P], and the drug was superior to soluble human insulin in controlling glycemia in 20 pregnant patients [Kinsley, B.T. et al. Abst. 1918-P].
Insulin detemir also proved at least as effective as NPH insulin in reducing hemoglobin A1c levels, according to a meta-analysis [Heller, S. et al. Abst. 487-P], but was associated with a lower risk of hypoglycemia [Kolendorf, K. and Kim, H. Abst. 489-P] and weight gain, which has been related to enhanced hypothalamic activity [Hennige, A.M. et al. Abst. 1387-P].
Use of insulin glulisine, an insulin analogue with predictable pharmacokinetics [Frick, A.D. et al. Abst. 2154-PO], resulted in lower dose requirements than did pre- and postmeal regular insulin in a cohort of 832 patients treated over 12 weeks [Garg, S. et al. Abst. 581-P], with activity independent of the body mass index [Heise, T. et al. Abst. 588-P]. Similar end-organ metabolic effects were noted for insulin glulisine, insulin lispro and regular human insulin in a crossover trial in 17 patients [Horvath, K. et al. Abst. 1368-P], with no increased mitogenic potential compared with standard insulin [Seipke, G. and Stammberger, I. Abst. 1400-P; Stammberger, I. and Seipke, G. Abst. 1401-P].
Regarding adjuvant therapy, add-on pioglitazone was not effective in improving the glycemic control compared with placebo in 35 adolescents [Zdravkovic, V. et al. Abst. 1882-P], but in 265 patients not reaching glycemic targets with insulin therapy, add-on pramlintide further decreased hemoglobin A1c levels and body weight, suggesting potential for the treatment of type 1 diabetes [Guthrie, R. et al. Abst. 478-P]. Pramlintide offered improvements in diabetes management, with patients and/or parents perceiving benefit from the therapy [Marrero, D. et al. Abst. 2091-PO].
Novel experimental approaches
Gene constructs that are able to tightly regulate insulin production in response to glucose levels were developed and successfully tested in animals [Han, J. et al. Abst. 436-P]. Preclinical studies have demonstrated the feasibility of gene delivery to supply glucagon-like peptide-1 [Parsons, G.B. et al. Abst. 589-P]. The results of a double-blind, placebo-controlled trial suggested a tolerability for islet neogenesis gene-associated protein, despite no relevant changes in glycemia or insulin requirements after 90 days in 63 type 1 diabetic patients [Ratner, R.E. et al. Abst. 11-LB; Ratner, R.E. et al. Abst. 12-LB].
Research continues in transplantation as a cure for diabetes, and smaller islets have been noted to survive and function better than larger islets in animal models [Stehno-Bittel, L. et al. Abst. 2022-P]. However, data with tacrolimus and sirolimus suggested an induction of insulin resistance in animals [Larsen, J.L. et al. Abst. 2020-P].
Insulin is widely used in the treatment of type 2 diabetes, with sustained effects over the long term, although insulin alone is seldom able to effectively control glucose and hemoglobin A1c levels [Nijpels, G. et al. Abst. 2123-PO; Lawrence, I. et al. Abst. 2129-PO; Bretzel, R.G. et al. Abst. 2156-PO; Lundershausen, R. et al. Abst. 2518-PO; Sclar, D.A. et al. Abst. 2519-PO]. Novel formulations are being developed to improve the pharmacokinetic and pharmacodynamic profiles [Kohn, W. et al. Abst. 2124-PO; Micanovic, R. et al. Abst. 2128-PO]. Insulin proved superior to uptitration of oral agents in patients not controlled with standard therapies [Wan Mohamad, W.B. Abst. 2117-PO]. Continuous subcutaneous insulin infusion and multiple daily injections of insulin have both been shown to be effective in controlling hemoglobin A1c levels in patients with type 2 diabetes [Herman, W.H. et al. Abst. 504-P; Jankovec, Z. et al. Abst. 2053-PO; Block, J. et al. Abst. 2064-PO; Motaghedi, R. et al. Abst. 2077-PO], but formulations for alternative administration routes and insulin analogues with improved pharmacokinetic/pharmacodynamic profiles have been developed and tested in preclinical and clinical trials.
Inhaled insulin proved safe and well tolerated over 2 years, and offered continued glycemic control to patients with type 2 diabetes [Cefalu, W. et al. Abst. 356-OR]; a pharmacokinetic analysis revealed a relative bioavailability of 10.7%, with a time to peak of 10-20 minutes for doses of 80 and 160 U [Liao, Z. et al. Abst. 2072-PO]. Technosphere pulmonary insulin treatment also proved superior to placebo in improving hemoglobin A1c levels in 119 type 2 diabetic patients (Fig. 1) [Rosenstock, J. et al. Abst. 357-OR]. The approach was superior to subcutaneous insulin during the first 3 hours after administration [Boss, A.H. et al. Abst. 358-OR]. Inhaled formulations of insulin analogs have also been proved to be effective in clinical trials [Leung, F.K. et al. Abst. 2058-PO; Leung, F.K. et al. Abst. 2060-PO; Leung, F.K. et al. Abst. 2061-PO].
Fig. 1. Change in hemoglobin A1c levels treatment with pulmonary insulin or placebo [357-OR].
Other insulin formulations
Oral insulin proved bioavailable [Whitelaw, D.C. et al. Abst. 5-LB] and effective combined with standard treatments in a placebo-controlled trial in 26 type 2 diabetic patients [Raz, I. et al. Abst. 2063-PO], and was effective in 104 children and adolescents with type 2 diabetes during 1 year of multistep therapy [Hathout, E. et al. Abst. 2778-PO]. Oral insulin offered effective glucose-lowering effects with optimal pharmacokinetics in animals [Leung, F.K. et al. Abst. 2057-PO; Leung, F.K. et al. Abst. 2062-PO], and bioavailability was also demonstrated for an intravenous formulation of insulin [Leung, F.K. et al. Abst. 2059-PO].
Among the novel insulin analogues, insulin detemir was superior to NPH insulin in terms of change in body weight, especially in overweight/obese individuals, with similar glycemic control [Hermansen, K. and Tamer, S.C. Abst. 271-OR], and showed a lower risk for hypoglycemia (Fig. 2) [Garber, A.J. et al. Abst. 479-P]. Efficacy and quality-of-life analysis suggested cost-effectiveness for insulin detemir compared with NPH insulin [Tucker, D.M. et al. Abst. 2528-PO; Valentine, W.J. et al. Abst. 2529-PO]. No pharmacokinetic or pharmacodynamic differences were noted in African Americans, Hispanics or Latinos compared with Caucasian subjects [Troupin, B. et al. Abst. 458-P].
Fig. 2. Hypoglycemia rate in younger and older patients treated with insulin detemir or NPH insulin [479-P].
Biphasic insulin aspart given twice daily offered high patient satisfaction rates [Ushakova, O. et al. Abst. 2085-PO] and was as effective as a basal bolus plus four daily injections of NPH insulin in a 4-month trial in 394 patients [Ligthelm, R.J. et al. Abst. 496-P]; effective control of glycemia was obtained in 96 nonobese patients not adequately controlled with oral hypoglycemic drugs [Lund, S.S. et al. Abst. 511-P], and efficacy was also demonstrated compared with regular human insulin in patients with gestational diabetes [Jovanovic, L. et al. Abst. 2808-PO]. Insulin aspart proved of benefit in patients with type 2 diabetes, with high glycemic control rates when added to oral antidiabetic drugs in undercontrolled patients [Jain, R. et al. Abst. 278-OR]. Premixed insulin aspart proved superior to human insulin in improving the quality of life of 52 patients [Yamada, S. et al. Abst. 481-P]. Used twice daily, it offered similar patient satisfaction rates to once-daily insulin glargine injection in 233 insulin-naive individuals [Brod, M. et al. Abst. 461-P]. Overall, insulin aspart was cost-effective compared with insulin glargine from a Medicare perspective [Palmer, A. et al. Abst. 2543-PO]. Using continuous subcutaneous infusion, insulin aspart acted faster, with lower dose requirements than with human soluble insulin [Li, Y. et al. Abst. 432-P].
Insulin lispro is a further effective insulin analogue with benefits on glycemic control and cardiovascular risk factors [Yano, M. et al. Abst. 424-P; Ceriello, A. et al. Abst. 550-P; Del Prato, S. et al. Abst. 552-P]. Given as multiple daily injection, it was as effective as insulin aspart or regular human insulin in terms of glycemic control, without significant risk of hypoglycemia [Numann, C. et al. Abst. 272-OR], but in a direct comparison, insulin lispro 75/25 offered better 24-hour and postprandial glucose control than insulin glargine in 20 patients (Fig. 3) [Roach, P. and Malone, J.K. Abst. 544-P].
Fig. 3. 24-Hour and postprandial glycemia after treatment with insulin lispro or insulin glargine [544-P].
Insulin glargine is a further insulin analogue with which safety and efficacy has been demonstrated in reducing hemoglobin A1c levels and improving health-related quality with a very low risk of hypoglycemia in patients with type 2 diabetes [Gerstein, H.C. et al. Abst. 273-OR; Vinik, A.I. et al. Abst. 574-P; Schreiber, S. et al. Abst. 579-P; Janka, H.U. et al. Abst. 580-P; Davies, M. et al. Abst. 585-P; Zick, R. et al. Abst. 2045-PO; Ruhnaua, K.J. et al. Abst. 2152-PO; Hammer, H. et al. Abst. 2153-PO; Gallen, I.W. et al. Abst. 2328-PO]. Insulin glargine was superior to pioglitazone in offering glycemic control with a better tolerability profile, despite a higher risk for hypoglycemia [Meneghini, L.F. et al. Abst. 10-LB]. Its use combined with oral hypoglycemic drugs was as effective as twice-daily premixed insulin [Kutoh, E. and Wajs, J. Abst. 2050-PO], and the combination with glimepiride proved effective in an open trial [Eliaschewitz, F.G. et al. Abst. 2158-PO] and was as effective as a combination of pioglitazone plus nateglinide in terms of metabolic efficacy, with no effect on insulin sensitivity [Brehm, A. et al. Abst. 2191-PO]. Combination of insulin glargine plus metformin, but not insulin glargine plus sulfonylurea, was as effective in terms of glycemic control as triple oral therapy with thiazolidinedione plus metformin plus sulfonylurea [Hollander, P. et al. Abst. 9-LB]. This analogue was effective upon discontinuation of thiazolidinediones and metformin in a series of 258 patients uncontrolled on oral therapies, while add-on insulin glargine had efficacy independent of age, race, duration of diabetes or body mass index in the GOAL A1c trial [Herman, W.H. et al. Abst. 568-P; Kennedy, L. et al. Abst. 570-P]. Insulin glargine favorably exerted glycemic control on fasting glycemia in diabetic patients scheduled for surgery when given the evening before at 50-100% the regular dose, with no risk of hypoglycemia [Dukatz, T. et al. Abst. 464-P; Yeldandi, R.R. et al. Abst. 512-P]. Insulin glargine also demonstrated efficacy in preventing transient postoperative hyperglycemia in patients undergoing bariatric surgery compared with regular insulin [Baldwin, D. et al. Abst. 275-OR]. No cytotoxic activity was demonstrated in an in vitro experiment against human breast epithelial cells [Staiger, K. et al. Abst. 451-P], and in animals benefits were noted on hepatic inflammation during critical illness [Emanuele, M.A. et al. Abst. 1355-P].
Insulin glulisine also proved effective in improving glycemic control in type 2 diabetic patients, with no ethnic differences [Dailey, G. et al. Abst. 2155-PO]. Two further insulin analogues with long-lasting efficacy in preclinical models are CJC-1525 and CJC-1575, which, compared with insulin glargine, showed glycemic effects beyond 24 hours [Robitaille, M. et al. Abst. 446-P].
Oral antidiabetic agents offered superiority over insulin monotherapy in the treatment of type 2 diabetes [Janka, H.U. et al. Abst. 583-P; Bretzel, R.G. et al. Abst. 584-P]. Metformin has shown insulin-sensitizing activity in patients with type 2 diabetes, obesity and impaired glucose tolerance [Tamura, Y. et al. Abst. 1555-P]. Compared with sulfonylurea monotherapy, metformin alone or in combination brought about significant improvements in clinical outcomes in 1833 patients with type 2 diabetes and heart failure included in a registry [Eurich, D.T. et al. Abst. 457-P], with increases in both β-cell function and insulin sensitivity compared with the benefit of sulfonylureas on β-cell function, but not insulin sensitivity [Holman, R. et al. Abst. 596-P]. Metformin also improved vascular reactivity and microcirculation in first-degree relatives of patients with diabetes who had metabolic syndrome but normal glucose tolerance [Aguiar, L.G.K. et al. Abst. 607-P; Aguiar, L.G.K. et al. Abst. 2170-PO]. Furthermore, treatment with metformin was related to a lower risk of cancer-related death compared with sulfonylureas and insulin in a follow-up of 10,309 new users of the drugs [Bowker, S.L. et al. Abst. 521-P].
Sulfonylurea benefits type 2 diabetic patients receiving insulin therapy [Nybäck-Nakeli, Å. et al. Abst. 454P], and compared with metformin, patients on sulfonylurea monotherapy before metformin plus sulfonylurea combination therapy had a higher likelihood of requiring insulin in two registries of 6616 and 11,992 patients [Zhang, Q. et al. Abst. 1214-P; Pietri, G. et al. Abst. 1215-P]. Glimepiride was as safe and effective in reducing hemoglobin A1c levels as metformin in 263 children with type 2 diabetes in a single-blind comparison (Fig. 4) [Gottschalk, M. et al. Abst. 264-OR]. The agent regulated endothelial nitric oxide synthase phosphorylation in endothelial cells through an Akt-dependent mechanism [Salani, B. et al. Abst. 545-P]. A pharmacokinetic analysis in children confirmed the favorable tolerability profile of glimepiride, with extent of absorption comparable to that of adult volunteers [Connor, J.D. et al. Abst. 571-P]. Repaglinide demonstrated no insulin-sparing effects over the long term, so that after 3 years of therapy initiation of twice-daily insulin mixture with metformin was required [Subramanian, B. et al. Abst. 516-P], but was superior to gliclazide regarding β-cell responses to meals at comparable fasting glycemia [Dunseath, G. et al. Abst. 597-P]. Glibenclamide was safe and effective in treating gestational diabetes in a cohort of 71 patients [Barbour, L.A. et al. Abst. 2794-PO], and experimental data suggested enhancement of the calcium-dependent second phase of insulin secretion independently of membrane potassium channels [Geng, X. et al. Abst. 1716-P], while assays with gliclazide demonstrated protection against a hydrogen peroxide-induced insulin resistance and restoration of glucose transporter activity [Shimoayama, T. et al. Abst. 2563-PO].
Fig. 4. Change in hemoglobin A1c levels 26 weeks of treatment with glimepiride or metformin [264-OR].
A postmarketing surveillance suggested usefulness for nateglinide in the treatment of early-stage diabetes, especially in the elderly, with a low risk for hypoglycemia and no significant impact on body weight [Taki, H. et al. Abst. 462-P]. Added to metformin therapy, nateglinide was superior to glibenclamide in controlling glycemia in 428 patients, with a lower risk of hypoglycemia over a 2-year follow-up [Gerich, J.E. et al. Abst. 266-OR]. Nateglinide showed benefits in preventing fatty liver [Kitahara, Y. et al. Abst. 959-P] and increased pancreatic islet blood flow [Iwase, M. et al. Abst. 1535-P] in experimental animal models of diabetes. Mitiglinide exhibited a quick, short-lived insulin secretory effect in animal models, limiting postglucose challenge hyperglycemia [Mori, Y. et al. Abst. 486-P].
Add-on acarbose proved safe and improved glycemic control in 30 patients failing premix insulin therapy [Shankhdhar, L.K. et al. Abst. 453-P]. In the 5-year EDIP trial, the agent improved postprandial glycemia and slowed the progression of early type 2 diabetes compared with placebo in 95 patients [Shankar, R.R. et al. Abst. 535-P]. In the PREDIAP trial, acarbose effectively prevented progression to type 2 diabetes over 3 years in 444 patients with impaired glucose metabolism [Costa, B. et al. Abst. 608-P]. Another α-glucosidase inhibitor, voglibose, also improved early insulin secretion and early postprandial hyperglycemia in 30 patients with impaired glucose tolerance or type 2 diabetes, resulting in decreased postprandial triglyceridemia [Tsuchiya, M. et al. Abst. 476-P]. Compared with diet therapy, addition of the drug reduced systemic inflammation and oxidative stress in 24 patients with type 2 diabetes [Satoh, N. et al. Abst. 647-P].
Pioglitazone is an effective drug for lowering glucose and hemoglobin A1c levels in patients with type 2 diabetes [Rajagopana, R. et al. Abst. 2135-PO; Rajagopalan, R. et al. Abst. 2136-PO], with a positive impact also on inflammatory markers [Udquhart, R. et al. Abst. 2149-PO]. The benefit of pioglitazone on glycemia was largely due to a decrease in gluconeogenesis [Gastaldelli, A. et al. Abst. 595-P], and the drug also improved fat redistribution and insulin sensitivity [Ravikumar, B. et al. Abst. 612-P; Raji, A. et al. Abst. 2183-PO; Zisser, H. et al. Abst. 2203-PO], adiponectin levels [Rasouli, N. et al. Abst. 1510-P; Nakashima, Y. et al. Abst. 2185-PO] and upregulated adiponectin receptor expression [Kudoh, A. et al. Abst. 1322-P]; C-reactive protein levels appeared as predictor of insulin sensitization and antiinflammatory effects after pioglitazone therapy [Kim, H. et al. Abst. 613-P]. Besides improving metabolic control, blood pressure and heart rate variability and the overall cardiovascular risk profile [Schoenauer, M. et al. Abst. 505-P; Hohberg, C. et al. Abst. 605-P; Pahler, S. et al. Abst. 23189-PO], treatment with pioglitazone resulted in improved β-cell function, with enhanced insulin sensitivity, in treatment-naive patients with type 2 diabetes compared with metformin and gliclazide in 2406 subjects included in two 1-year trials [De Winter, W. et al. Abst. 265-OR]; improved β-cell function was also noted in patients with impaired glucose tolerance [Rasouli, N. et al. Abst. 1538-P]. Preservation of β-cells during treatment with pioglitazone was further noted in a double-blind, placebo-controlled trial in another group of 38 patients [Hamdy, O. et al. Abst. 592-P]. Add-on pioglitazone improved the glycemic control of 1269 patients on metformin, maintaining stable, controlled hemoglobin A1c levels that progressively deteriorated with other treatments [Post, T. et al. Abst. 15-OR], and triple combination with glimepiride and metformin offered efficacy with good tolerability in patients uncontrolled on two oral hypoglycemic drugs [Desai, A.A. et al. Abst. 2093-PO]. The drug improved lipid-induced insulin resistance in obese nondiabetic individuals, but not in lean subjects [Yu, J.G. et al. Abst. 43-OR], and was safe and effective in type 2 diabetic patients on hemodialysis [Degenhardt, S. et al. Abst. 2112-PO]. Pioglitazone also proved effective in improving endothelial function, inflammation, homocysteine levels and markers of metabolic syndrome in patients with type 2 diabetes [Kunhiraman, B.P. et al. Abst. 449-P; Kutoh, E. and Wajs, J. Abst. 2163-PO] and in women with polycystic ovary syndrome [Lucidi, S. et al. Abst. 84-OR; Berria, R. et al. Abst. 1406-P], and in nondiabetic individuals with metabolic syndrome the drug also improved high-density lipoprotein (HDL) cholesterol levels and the general lipid profile compared with placebo [Szapary, P. et al. Abst. 963-P]. In the PRACTICAL study, a maintained efficacy with good general and hepatic tolerability was demonstrated in 22,943 patients treated for 18 months with pioglitazone [Kawamori, R. et al. Abst. 452-P]. First-line therapy with pioglitazone offered better lipid control than glibenclamide in 502 patients initiating therapy for type 2 diabetes [Kupfer, S. et al. Abst. 554-P; Perez, A. et al. Abst. 2138-PO], with superior benefits on insulin resistance in 24 patients [Kuriyama, G. et al. Abst. 2095-PO]. Pioglitazone has been related to an increased risk of edema, mainly due to an increase in interstitial water [Urquhart, R. et al. Abst. 520-P], but the drug had no ubiquitous effects on capillary filtration capacity and did not increase vascular endothelial growth factor levels [Tooke, J.E. et al. Abst. 573-P]. The increase in weight gain during treatment with pioglitazone reached a stable plateau after 36 months of therapy in 19 patients treated continuously for 5 years (Fig. 5) [King, A.B. et al. Abst. 468-P]; furthermore, diet intervention effectively controlled weight gain during treatment with the thiazolidinedione [Armand, B. et al. Abst. 2747-PO]. Combination with metformin appeared to be superior to the combination of pioglitazone with sulfonylureas regarding risk of weight gain and body mass index in the clinical practice, but both combinations were superior to metformin plus sulfonylurea in terms of glycemic control, lipid control and reduction in blood pressure and the atherogenic index of plasma [Rodriguez, A. et al. Abst. 2175-PO; Reviriego, J. et al. Abst. 2176-PO; Rodriguez, A. et al. Abst. 2177-PO; Julian, I. et al. Abst. 2178-PO; Polavieja, P. et al. Abst. 2179-PO]. In experimental studies, improved insulin sensitivity with pioglitazone correlated with reduced expression of suppressor of cytokine signaling mRNA [Kanatania, Y. et al. Abst. 2583-PO].
Fig. 5. Change in body weight during 60 months of continuous treatment with pioglitazone [468-P].
Low-dose rosiglitazone was associated with improved glycemic control compared with placebo in 421 patients with type 2 diabetes not sufficiently controlled on insulin, without incurring adverse events (Fig. 6) [Hollander, P. et al. Abst. 12-OR]; the drug offered significant benefits also in children with type 2 diabetes [Dabiri, G. et al. Abst. 1904-P]. Furthermore, rosiglitazone has shown efficacy in improving blood pressure [Home, P.D. et al. Abst. 542-P] and the thrombotic state [Khanolkar, M. et al. Abst. 546-P], and in increasing skeletal muscle uncoupling protein-3 levels [Hesselink, M.K. et al. Abst. 1587-P]. The benefits of rosiglitazone on glycemic control and insulin sensitivity have been confirmed in further trials [Sarafidis, P.A. et al. Abst. 2168-PO; Deng, H.-C. and Deng, H.-M. Abst. 2188-PO; Cho, M.H. et al. Abst. 2190-PO] and in animal models, in which no recovery of insulin-mediated capillary recruitment and glucose uptake was noted [Wheatley, C. et al. Abst. 2665-PO]. Addition of rosiglitazone to glimepiride improved the glycemic control compared with glimepiride uptitrated monotherapy in 361 patients [Rosenstock, J. et al. Abst. 549-P] and resulted in better metabolic control, β-cell function and insulin sensitivity than with placebo in 174 patients (Fig. 7) [Schöndorf, T. et al. Abst. 606-P]. Added to metformin, rosiglitazone was superior to glibenclamide in improving blood pressure and urinary albumin/creatinine ratio in 389 subjects [Bakris, G.L. et al. Abst. 543-P]. A fixed-dose combination of rosiglitazone and metformin proved safe and effective as first-line therapy in 190 patients with severe hyperglycemia, attaining rapid glycemic control [Rosenstock, J. et al. Abst. 515-P]; combinations of rosiglitazone with sulfonylureas have also been beneficial, according to the RESULT and other trials [Arondekar, B. et al. Abst. 517-P]. Further antiatherogenic potential was demonstrated for rosiglitazone, in inhibiting actin polymerization in monocytes [Singh, N. et al. Abst. 148-OR], and the compound showed protective effects on endothelial cells challenged with induced high glucose [Piconi, L. et al. Abst. 150-OR]. Furthermore, rosiglitazone brought about reductions in urinary albumin excretion and improved adipokine levels in 29 patients [Miyazaki, Y. et al. Abst. 455-P]. In animal studies, rosiglitazone showed benefits on fat distribution [Park, S. et al. Abst. 2603]. Treatment with rosiglitazone has been associated with a favorable hepatic toxicity profile as compared with placebo or sulfonylurea/metformin-insulin combinations in the Years of rosiglitazone Clinical Trial Experience [Krebs, J. et al. Abst. 82-OR]. However, in 24 type 2 diabetic patients with close to normal lipid levels, neither rosiglitazone nor pioglitazone had an effect on absolute lipid values, while rosiglitazone reduced very low-density lipoprotein (VLDL) apolipoprotein B through an unexplained mechanism [Brackenridge, A.L. et al. Abst. 957-P], but the effect on large VLDL and small LDL was greater for pioglitazone than with rosiglitazone in further studies [Deeg, M.A. et al. Abst. 960-P]. Moreover, rosiglitazone has been associated with an increased risk for fluid retention, which can be treated with spironolactone [Karalliedde, J. et al. Abst. 81-OR], but in patients with concomitant type 2 diabetes and congestive heart failure, no negative effect on cardiac structure of function was noted after treatment with rosiglitazone [Wilding, J. et al. Abst. 80-OR]. Thiazolidinediones have also proved safe and effective in posttransplant diabetes [Asnani, S. et al. Abst. 2027-P], and rosiglitazone was safely used to decrease blood glucose and enhance insulin sensitivity in diabetic kidney transplant recipients [Simos, A. and Obayashi, P. Abst. 2023-P]. Rosiglitazone was safe in hypertensive patients, although the risk of edema and heart failure has to be considered [Sarafidis, P.A. et al. Abst. 2167-PO]. In in vivo studies in animals and a preliminary trial in type 2 diabetic patients, rosiglitazone has improved blood pressure, endothelial dysfunction and C-reactive protein levels, while reversing insulin resistance [Potenza, M.A. et al. Abst. 1317-P; Medlej, R.C. et al. Abst. 2119-PO], and in in vitro studies, downregulation of adhesion molecule expression was observed [Won, H.S. et al. Abst. 2271-PO]. However, some data suggest no effect on insulin resistance in free fatty acid-loaded obese animal models [Sanalkumar, N. et al. Abst. 1471-P], while a benefit was noted in preventing glucagon elevation under fat-rich diet [Yang, W. et al. Abst. 1516-P] and islet cell apoptosis and loss of insulin production under human islet amyloid polypeptide challenge [Lin, C.Y. et al. Abst. 1611-P].
Fig. 6. Change in hemoglobin A1c levels after adding rosiglitazone or placebo to insulin therapy [9-OR].
Fig. 7. HOMA insulin resistance score after treatment with rosiglitazone or placebo added to glimepiride [606-P].
With either pioglitazone or rosiglitazone, activation of the PPARγ receptor resulted in depressed telomerase activation in vascular myocytes [Ogawa, D. et al. Abst. 85-OR], with beneficial fat remodeling in animal models [Velasquez, M.T. et al. Abst. 17-LB]. Both drugs reduced the coronary heart disease-related risk in adult patients with type 2 diabetes to a level equivalent to that after treatment with metformin plus sulfonylurea [Johannes, K.B. et al. Abst. 1053-P].
A related compound that was discontinued, troglitazone activated AMP-activated protein kinase in animal studies [Kelly, M. et al. Abst. 1592-P] and enhanced glucose-induced insulin secretion through an effect on G-protein-coupled cell-surface receptor-40 [Haag-Diergarten, S. et al. Abst. 2716-PO]. A novel non-thiazolidinedione drug, MBX-102, also demonstrated insulin-sensitizing properties and improved glycemia with no edema or weight gain compared with placebo in 217 patients [Rosenstock, J. et al. Abst. 44-OR], while a new thiazolidinedione with no affinity for PPAR receptors, BLX-1002, exhibited antidiabetic properties with no effect on weight, fluid retention or hepatotoxicity [Dey, D. et al. Abst. 8-LB].
Despite benefits on lipid levels [Rosenson, R.S. et al. Abst. 979-P], the PPARα agonist fenofibrate had no effect on plasma adiponectin levels, insulin sensitivity or muscle AMP-activated protein kinase activity in six patients with type 2 diabetes [Bajaj, M. et al. Abst. 611-P], but effectively modulated ubiquinol-1 levels in patients with diabetic dyslipidemia [Asano, A. et al. Abst. 965-P]. Fenofibrate showed modest additive effects with thiazolidinediones on triglyceride levels [Kashyap, S. et al. Abst. 2353-PO]. Experimental observations with a novel PPARα agonist, RWJ-667567, suggested beneficial effects on triglycerides, LDL and HDL cholesterol and free fatty acids, along with improvements in insulin sensitivity [Chen, X. et al. Abst. 2355-PO].
Muraglitazar was well tolerated and effective compared with placebo [Mohideen, P. et al. Abst. 518-P] and more effective than pioglitazone, both combined with metformin, regarding glycemic control in a series of 1159 patients (Fig. 8) [Defronzo, R.A. et al. Abst. 14-OR; Rubin, C.J. et al. Abst. 2113-PO]. Muraglitazar 5 mg in monotherapy induced greater benefits on triglycerides and non-HDL and HDL cholesterol levels than pioglitazone (Fig. 9) [Frederich, R. et al. Abst. 967-P], while added to glibenclamide it proved superior to placebo in improving the same parameters [Mohideen, P. et al. Abst. 968-P]. Gender-independent pharmacokinetics were observed in 18 healthy volunteers, with a modest increase in AUC in the elderly compared with younger subjects not needing dose adjustment [Moore, K.T. et al. Abst. 519-P]; no pharmacokinetic interaction was demonstrated with glibenclamide, metformin or statins [Darbenzio, R. et al. Abst. 2114-PO; Turner, K.C. et al. Abst. 2115-PO; Swaminathan, A. et al. Abst. 2116-PO]. In animals, glucose lowering by muraglitazar was not associated with changes in body weight, hematocrit or sodium homeostasis-related gene expression [Harrity, T. et al. Abst. 569-P].
Fig. 8. Change in hemoglobin A1c levels after adding muraglitazar or pioglitazone to metformin therapy [14-OR].
Fig. 9. Change in triglyceride and non-HDL and HDL cholesterol levels after treatment with muraglitazar or pioglitazone [967-P]
A related compound, tesaglitazar, improved glycemic and lipid profiles in a dose-dependent manner in 418 patients included in a comparative trial, with significant reductions in fasting plasma glucose levels and improvements in insulin sensitivity [Goldstein, B.J. et al. Abst. 83-OR]. Such observations were confirmed in a group of 222 patients undergoing postprandial lipid and glucose testing after treatment with tesaglitazar (Fig. 10) [Fagerberg, B. et al. Abst. 614-P]. Treatment with tesaglitazar has been related to improved apolipoprotein abnormalities and a reduced risk of metabolic syndrome and impaired fasting glucose in nondiabetic patients with insulin resistance [Schuster, H.M. et al. Abst. 615-P; Schuster, H.M. et al. Abst. 972-P]. Tesaglitazar showed once-compartment, linear pharmacokinetics, with no pharmacokinetic interaction with concomitantly administered glibenclamide or metformin in healthy volunteers [Ågren, A.C. et al. Abst. 2145-PO; Ågren, A.C. et al. Abst. 2146-PO; Manrén, B. et al. Abst. 2199-PO]. Experimentally, the compound prevented atherosclerosis in prone animal models [Havekes, L.M. et al. Abst. 956-P].
Fig. 10. Placebo-corrected changes in glucose levels after an oral tolerance test in patients receiving increasing doses of tesaglitazar [614-P].
Preclinical assays suggested antidiabetic efficacy for other PPARα/γ agonists currently under development: CKD-501, C1, D1, compound A and AK-109 [Kwon, Y.M. et al. Abst. 501-P; Gregoire, F.M. et al. Abst. 566-P; Nagano, T. et al. Abst. 1353-P; Umeno, H. et al. Abst. 2172-PO; Umeno, H. et al. Abst. 2173-PO].
Exenatide enhanced endogenous insulin production in a glucose-dependent manner [Parkes, D. et al. Abst. 1523-P] and reduced hemoglobin A1c in patients with type 2 diabetes or obesity [Blonde, L. et al. Abst. 477-P] with minimal nausea or adverse gastrointestinal effects [Maggs, D. et al. Abst. 485-P] and demonstrated potential as a therapy for type 2 diabetes in patients on metformin/sulfonylurea [Mari, A. et al. Abst. 482-P], with efficacy comparable to that of insulin glargine in terms of reducing hemoglobin A1c levels (Fig. 11) [Heine, R.J. et al. Abst. 9-OR]. According to a meta-analysis of three trials, exenatide improved glycemic and weight control, and significantly reduced cardiovascular risk over 82 weeks of treatment [Kendali, D.M. et al. Abst. 16-OR]. A pharmacokinetic study revealed no need for dose adjustments in patients with mild to moderate renal dysfunction, but the need for reduced doses of exenatide in patients with end-stage renal disease [Linnebjerg, H. et al. Abst. 469-P]. In animal models, exenatide improved insulin sensitivity in prediabetic states [Jeong, I.K. et al. Abst. 538-P] and prolonged survival of islet allografts but promoted hypoglycemia in the early posttransplant period [Crutchlow, M.F. et al. Abst. 100-OR], but failed to prevent diabetes in nonobese animal models [Hadjiyanni, I. and Drucker, D.J. Ast. 1499-P]. In vitro, exenatide, but not glibenclamide, maintained β-cell secretory capacity [Alarcon, C. and Rhodes, C.J. Abst. 2721-PO].
Fig. 11. Change in hemoglobin A1c levels after treatment with exenatide or insulin glargine [9-OR].
Another glucagon-like receptor-1 analogue, liraglutide, reversed hyperglycemia onset in animal models, resulting in β-cell regeneration and decreased insulitis in in vivo studies [Suarez-Pinzon, W.L. et al. Abst. 232-OR; Bodvarsdottir, T.B. et al. Abst. 500-P], and in humans revealed similar pharmacokinetic profiles in young and elderly subjects [Damholt, B.B. et al. Abst. 460-P]. In a phase II trial using the CORE diabetes model, combination of liraglutide and metformin was deemed superior to metformin monotherapy or metformin plus sulfonylurea in preventing diabetic complications, offering longer overall and quality of life-adjusted life expectancy [Valentine, W.J. et al. Abst. 2545-PO]. A further compound, DAC-GLP:1 demonstrated efficacy in 47 patients with type 2 diabetes treated with metformin, with significant reductions in hemoglobin A1c levels compared with placebo and no increased risk for hypoglycemia [Ratner, R.E. et al. Abst. 10-OR].
A third compound within that group, LY-548806, offered rapid onset of action with a favorable safety, tolerability and pharmacokinetic profile after intravenous administration to 36 patients [Jackson, K. et al. Abst. 562-P]. Favorable preclinical effects were noted in animal studies [Millican, R.L. et al. Abst. 1504-P]. A further drug, CJC-1131, was bioavailable after subcutaneous administration and induced no immunogenicity in animal models [Wen, S.Y. et al. Abst. 2106-PO; Lawrence, B. et al. Abst. 2107-PO].
Pramlintide, an amylin analogue, showed efficacy in decreasing hemoglobin A1c levels and body weight when added to insulin in a double-blind trial in 166 type 2 diabetic patients [Karl, D.M. et al. Abst. 48-OR].
Leptin replacement with recombinant human leptin significantly improved glycemia, dyslipidemia and steatosis in patients with type 2 diabetes and generalized lipodystrophy [Javor, E.D. et al. Abst. 47-OR; Kusakabe, T. et al. Abst. 610-P].
Dipeptidyl peptidase IV inhibitors
Vildagliptin increased β-cell neogenesis and diminished islet apoptosis in animal models of β-cell rapid turnover [Duttaroy, A. et al. Abst. 572-P]. In direct comparison, vildaglitin was as effective as exendin in terms of glycemic control and β-cell function in animal models of β-cell injury [Duttaroy, A. et al. Abst. 267-OR]. Vildagliptin had no adverse pharmacokinetic interactions with pioglitazone, the combination being safe in 12 patients with type 2 diabetes [Serra, D.B. et al. Abst. 2192-PO].
Data with the novel compound sitagliptin, which proved well tolerated with similar pharmacokinetics in lean and obese subjects [Herman, G.A. et al. Abst. 497-P], suggested efficacy in controlling glycemia in a cohort of 28 patients compared with placebo when added to baseline metformin therapy (Fig. 12) [Brazg, R. et al. Abst. 11-OR]. The compound increased glucagon-like peptide-1 levels in 34 healthy volunteers [Stevens, C. et al. Abst. 493-P], and given in monotherapy offered an effective and well-tolerated option to control glycemia with no significant risk of hypoglycemia or weight gain in 552 patients [Herman, G. et al. Abst. 541-P]. Preliminary data from a further, ongoing study in 743 patients suggesting efficacy and good tolerability in monotherapy have also been reported [Scott, R. et al. Abst. 41-OR]. A further new compound, DP-893 proved orally effective in preclinical models [Parker, J.C. et al. Abst. 450-P], while a pharmacodynamic and pharmacokinetic characterization suggested favorable potency in animals for BI-B [Tadayyon, M. et al. Abst. 656-P]. Pharmacokinetic characterization suggested a profile consistent with once-daily dosing [Bergman, A. et al. Abst. 2100], independently of age, gender or obesity [Bergman, A. et al. Abst. 2101-PO], with no pharmacokinetic interaction for the coadministration of sitagliptin and metformin [Herman, G. et al. Abst. 2099-PO].
Fig. 12. Change in fasting plasma glucose levels after adding MK-0431 or placebo to metformin therapy [11-OR].
Initial preclinical results with MP-513, compound A, GRC-8200 and KR-62436, four more long-acting dipeptidyl peptidase-IV inhibitors, suggested suitability for the treatment of type 2 diabetes and lipid abnormalities [Abe, Y. et al. Abst. 1493-J; Farb, T. et al. Abst. 1500-P; Mika, A. et al. Abst. 1501-P; Vaakkalanka, S.K.V.S. et al. Abst. 1529-P; Kim, K.R. et al. Abst. 2096-PO].
Novel therapies in development
Fructose 1,6-bisphosphatase inhibition has been deemed a target for intervention in diabetes, and a compound, CS-917, demonstrated improvements in postprandial and fasting glycemic control in animal models without causing weight gain or hypoglycemia [Yoshida, T. et al. Abst. 472-P; Van Poelje, P. et al. Abst. 503-P]. Inhibition of protein phosphatase-1b also proved effective, with suppression of endogenous glucose production and improved insulin resistance with PTP-3848 in animals [Dean, D. et al. Abst. 617-P]; the compound prevented diet-induced obesity and insulin resistance in preclinical models [Balkan, B. et al. Abst. 618-P]. Inhibition of phosphatase-1b with the antisense oligonucleotide ISIS-113715 also improved the glucose-lowering effects of rosiglitazone and metformin [Murray, S.F. et al. Abst. 1545], while the drug showed insulin-sensitizing activity in a phase I study in healthy volunteers [Kjems, L. et al. Abst. 2201-PO]. Another pharmacological target is sodium-dependent glucose cotransporter. SGL-0010 and T-1095 have been identified, with potential in experimental studies [Kumeda, S.I. et al. Abst. 473-P; Yamamoto, K. et al. Abst. 474-P; Fujimoto, Y. et al. Abst. 591-P]. Preclinical data also suggest a role for glycogen phosphorylase, as exemplified by the results obtained with GPI-688, PSN-357 and CP-368296 in animal models [Bartlett, J.B. et al. Abst. 492-P; Woing-Kai-In, P. et al. Abst. 567-P; Shiota, M. et al. Abst. 594-P], while two glucokinase activators, PSN-105 and PSN-010, demonstrated alternative strategies to glycemic control [Fyfe, M.C.T. et al. Abst. 522-P]. Acadesine is a further compound in development, which new experimental data suggested to overcome insulin suppression of hepatic glucose output [Camacho, R.C. et al. Abst. 1542-P] and reversed lipotoxicity-induced β-cell dysfunction [Kim, J.W. et al. Abst. 1731-P], while the phosphodiesterase 11A inhibitor BAY-65-6207 induced glucose-dependent insulin secretion in in vitro experiments [Wang, Y. et al. Abst. 1707-P; Claus, T. et al. Abst. 1708-P]. By inhibiting histone deacetylase, trichostatin A also protected β cells from inflammatory cytokine-induced cytotoxicity [Fueger, P.T. et al. Abst. 1757-P]. Experimental animal studies have demonstrated improved insulin resistance for dehydroepiandrosterone, which also improved adiponectin levels and prolonged survival [Ishizuka, T. et al. Abst. 2169-PO].
Diet and diet supplement therapies
Vitamin E-enriched diets have been correlated with pancreatic compensation for insulin resistance, with no effect on insulin response [Costacou, T. et al. Abst. 1763-P], while dietary supplements of fish oil have demonstrated antiinflammatory activity and benefits on the lipid profile of type 2 diabetic subjects [Mayman, G.A. et al. Abst. 1767-P]. Administration of the soy isoflavones genistein and daidzein exhibited antidiabetic properties through enhanced glucose and lipid metabolism in animal models [Park, S.A.E. et al. Abst. 1768-P], while administration of conjugated linoleic, but not linolenic, acid to animals reduced adiponectin expression, resulting in insulin resistance [Sörhede, M. et al. Abst. 39-OR; Nelson, T.L. et al. Abst. 88-LB]. Magnesium supplements helped control plasma glucose and raise HDL cholesterol, according to a meta-analysis of nine randomized trials in type 2 diabetic patients [Song, Y. et al. Abst. 526-P]. In animal studies, insulin sensitization was noted with panax ginseng supplements [Lee, H.J. et al. Abst. 2200]. On the other hand, low vitamin D intake has been associated with an increased risk of developing type 2 diabetes [Pittas, A.G. et al. Abst. 1772-P].
Antihypertensive therapies have an effect on insulin resistance and the development of new-onset diabetes, as has been demonstrated for trandolapril/verapamil in the INVEST trial [Cooper-Dehoff, R.M. et al. Abst. 1047-P]. Studies with another angiotensin-converting enzyme inhibitor, ramipril, suggested improvements in insulin sensitivity mediated by a decrease in protein phosphatase 1B activity [Lee, J.M. et al. Abst. 2594]. Losartan proved direct nephroprotective in type 2 diabetes, independently of the blood pressure-lowering effect [Sawaki, H. et al. Abst. 2273]. At equivalent blood pressure reduction, losartan had greater antiproteinuric effects compared with quinapril in 40 patients, but neither treatment influenced plasma or urinary transforming growth factor-β levels [Lim, S.C. et al. Abst. 456-P], but quinapril restored insulin-mediated muscle capillary recruitment in diabetic animals [Clerk, L.H. et al. Abst. 1581-P]. A trial with valsartan demonstrated improved resting skin blood flow in 13 patients with type 2 diabetes that was attributed to reduced poly(ADP-ribose)polymerase activity [Shrikhande, G. et al. Abst. 686-P]. Used as an antihypertensive, telmisartan enhanced glucose uptake and the glucose transporter-4 protein expression [Fujimoto, M. et al. Abst. 1418-P] and increased adiponectin levels in a cohort of 30 patients with type 2 diabetes [Miura, Y. et al. Abst. 45-OR]; the drug improved insulin resistance and glycemic control in 38 patients [Koshiyama, H. et al. Abst. 2164-PO]. Irbesartan has shown efficacy in reducing both microalbuminuria and blood pressure in patients with diabetic nephropathy [De Luis, D. et al. Abst. 2079-PO], and in the INCLUSIVE study, irbesartan/hydrochlorothiazide effectively lowered blood pressure in patients with metabolic syndrome [Sowers, J. Abst. 492-P; Bakris, G.L. Abst. 2098-PO]. A further angiotensin receptor blocker, candesartan, lowered blood pressure and improved insulin resistance when added to diet therapy [Kawai, T. et al. Abst. 2187-PO]. Experimentally, olmesartan was shown to improve platelet-derived and vascular endothelial growth factor responses to glycosylated albumin [Yokota, T. et al. Abst. 906-P] and combined with azelnidipine improved insulin sensitivity [Matsuda, M. et al. Abst. 2180-PO], while omapatrilat showed insulin-sensitizing activity dependent on hemodynamic effects [Wong, V. and Lewis, G.F. Abst. 2171-PO]. Regarding quality of life, carvedilol scored better than metoprolol in the GEMINI trial [Bell, D.H. et al. Abst. 556-P]; carvedilol also had a more favorable impact on insulin resistance [Fonseca, V. et al. Abst. 557-P], while metoprolol worsened glycemic control, especially in females, the elderly and Caucasian subjects [Bell, D.H. et al. Abst. 558-P]. On the other hand, neither carvedilol nor allopurinol was superior to placebo in reducing oxidative stress in diabetes [Larijani, B. et al. Abst. 2132-PO].
Regarding atherosclerosis and metabolic syndrome, use of fenofibrate in patients with metabolic syndrome has resulted in antiinflammatory effects on a number of markers, including adhesion molecules and C-reactive protein [Rosenson, R.S. et al. Abst. 590-P], and the compound has shown protective effects on islets in models of lipotoxicity [Zhang, L. et al. Abst. 1712-P]. Experimental data suggested a role for cilostazol in downregulating nuclear factor κB-mediated vascular cell adhesion molecule-1 expression [Wang, F. et al. Abst. 696-P], while in preclinical models of obese diabetes in advanced age, combination of rosiglitazone and enalapril resulted in regression of complex lesions and stabilization of remaining lesions [Collins, A.R. et al. Abst. 733-P]. Pioglitazone increased HDL and apolipoprotein A1 levels, reduced VLDL particle classes and switched the LDL profile to larger, more buoyant particles [Shadid, S. et al. Abst. 975-P; Berhanu, P. et al. Abst. 2139-PO; Perez, A. et al. Abst. 2140-PO; Johnson, K. et al. Abst. 2141-PO; Khan, M. et al. Abst. 2142-PO; Kupfer, S. et al. Abst. 2143-PO] and led to reduced progression of intimal lesions and decreased matrix metalloproteinase, adhesion molecule and connective tissue growth factor expression in LDL receptor-deficient animals, slowing plaque progression [He, L. et al. Abst. 738-P; Game, B.A. et al. Abst. 750-P]. Added to statin therapy, pioglitazone improved triglyceride, total, LDL and HDL cholesterol levels in men and women with type 2 diabetes [Johnson, K. et al. Abst. 2137-PO]. Rosiglitazone also had proangiogenesis effects through vascular tubule formation, an effect mediated by vascular endothelial growth factor [Collinson, D.J. et al. Abst. 754-P], and reduced glucose-induced oxidative stress and inflammation [Aljada, A. et al. Abst. 771-P], while troglitazone suppressed oxidized LDL-induced macrophage proliferation through an effect on ERK1/2 nuclear translocation [Matsumura, T. et al. Abst. 759-P]. An aldose reductase inhibitor, epalrestat, restored nitric oxide production by endothelial cells, suggesting benefits on endothelial dysfunction in hyperglycemia [Umemoto, T. et al. Abst. 775-P], while a related compound, fidarestat, counteracted nitrosative stress and poli(ADP-ribose)polymerase activation in renal cortex and mesangial cells during diabetes or high glucose-exposure [Obrosova, I.G. et al. Abst. 809-P]. In in vitro assays, epigallocatechin gallate inhibited ATP-dependent potassium channels [Lee, H.Y. et al. Abst. 2715-PO] and stimulated nitric oxide production through Src- and phosphatidylinositol 3-kinase-dependent mechanisms [Kim, J.A. et al. Abst. 753-P], while in in vivo studies, tea extract showed antiobesity and antidiabetic effects [Kim, J.Y. et al. Abst. 2741-PO]. The PPARδ activator GW-501516 improved glycemic control and reduced nitric oxide production with no effect on endothelial nitric oxide synthase expression [Kim, J. et al. Abst. 774-P; Wulff, E.M. et al. Abst. 978-P]. A synthetic flavonoid that activates AMP-dependent kinase and inhibits lipid accumulation in insulin-resistant hepatocytes and atherogenesis in LDL receptor-deficient animals has been characterized, suggesting a new potential target for intervention in diabetic, dyslipidemic vascular disease [Zang, M. et al. Abst. 969-P; Xu, S. et al. Abst. 970-P].
In diabetes, like in obesity and cardiovascular disease, treatment with sildenafil had no effect on the inflammatory state, according to data from a randomized trial of 30 patients [Theuma, P. et al. Abst. 463-P]; however, sildenafil improved insulin action in high-fat fed animal models [Ayala, J.E. et al. Abst. 1582-P]. Two related drugs, vardenafil and tadalafil, proved effective in treating erectile dysfunction compared with placebo in diabetic individuals [Ziegler, D. et al. Abst. 514-P; Engel, S. et al. Abst. 2469-PO].
Phytotherapy and exercise interventions
Chinese herbal medicine with Salvia miltorrhiza, Rehmannia glutinosa, Paeonia lactiflora, Ophiopogon sp., cornus officinalis, Atractylodes sp., Schisandra sp. and Poria sp. offered a cost-effective approach to improve treatment of type 2 diabetes [Zhao, H.L. et al. Abst. 2159-PO], with an effect on repair and regeneration of β cells and insulin production in animal models [Li, S. et al. Abst. 2695-PO]. Pinitol, a compound isolated from several Pinus sp. and bougainvillea spectabilis, modified glucose metabolism but not lipid or adiponectin levels in a cohort of 20 patients [Kim, M.K. et al. Abst. 385-P]. Stevioside, a further phytotherapeutic compound, stimulated insulin secretion through upregulation of the acetyl-CoA carboxylase 1, offering a putative innovative approach to diabetes [Xiao, J. et al. Abst. 536-P]. An extract of Pterocarpus marsupium and Tinospora cordifolia prevented or induced regression of pancreatic atrophy in eight long-standing diabetic patients [Ojha, J. et al. Abst. 2084-PO]. Peanut oil intake was related with a reduction in blood glucose in type 2, but not type 1 diabetes [Chakraborty, G. et al. Abst. 2678-PO]. On the other hand, regular consumption of coffee was associated with a reduced risk of developing type 2 diabetes according to a survey of 28,812 postmenopausal women [Pereira, M.A. et al. Abst. 1056-P], while increased alcohol intake was related to loss of insulin production in animals [Chung, C.H. et al. Abst. 2735-PO].
Regarding exercise, additive effects were demonstrated in patients treated with metformin or glibenclamide [Cunha, M.R. et al. Abst. 1090-P], with a positive effect on body weight and blood pressure [Dasgupta, K. et al. Abst. 2472-PO], and adiponectin multimer ratio [Nardi, A.E. et al. Abst. 1092-P] and endothelial function [Miyamoto, Y. et al. Abst. 1097-P]. Beneficial metabolic effects were noted for progressive resistance training in older patients with type 2 diabetes compared with regular aerobic exercise [Goh, S.Y. et al. Abst. 1089-P]. Concomitant use of rosiglitazone prolonged submaximal exercise duration in diet-treated patients [Gallen, I.W. and Qazi, S. Abst. 2485-PO].
Pioglitazone offered antiinflammatory effects [Bandyopadhyay, A. et al. Abst. 2110-PO] and proved superior to rosiglitazone in decreasing the atherogenic index and triglyceride levels and increasing HDL cholesterol levels, with a similar impact on hemoglobin A1c and insulin sensitivity in 802 patients with diabetic dyslipidemia (Fig. 13) [Ta, M.H. et al. Abst. 1-OR], and a switch from rosiglitazone to pioglitazone improved lipid control in 304 patients on stable statin therapy [Khan, M. et al. Abst. 533-P; Berhanu, P. et al. Abst. 555-P]. Combined with nicotinic acid, pioglitazone better improved HDL cholesterol and triglyceride levels, with evidence of hepatotoxicity in 18 patients [King, A.B. et al. Abst. 467-P]. Pioglitazone also demonstrated effect in patients with nonalcoholic steatohepatitis [Belfort, R. et al. Abst. 79-OR]. Pioglitazone also lowered blood pressure independently of concomitant antihypertensive therapy [Pahler, S. et al. Abst. 533-P].
Fig. 13. Change in the atherogenic index of plasma after treatment with pioglitazone or rosiglitazone [1-OR].
Antiinflammatory and organ-protective effects have also been demonstrated for rosiglitazone [Ghanim, H. et al. Abst. 2111-PO], which in a series of 30 patients was associated with reversed endothelial cell dysfunction nearing matched nondiabetic controls [Cuneo, M. et al. Abst. 527-P]. The compound effectively reduced C-reactive protein levels and modestly raised HDL cholesterol in nondiabetic patients with metabolic syndrome [Samaha, F.F. et al. Abst. 609-P]. Detailed studies with rosiglitazone demonstrated increases in large, buoyant LDL, but without decreases in small dense LDL particles in type 2 diabetic patients [Lautamäki, R. et al. Abst. 498-P]. The compound improved autonomic nervous system function, resulting in reduced cutaneous vascular reactivity in a further trial [Almarty, A. et al. Abst. 529-P], and in human fibroblasts promoted matrix component production and reduced cytokine release [Solini, A. et al. Abst. 530-P].
Dyslipidemia and atherosclerosis are common in patients with diabetes, and treatment with statins has been recommended. Using simvastatin, atorvastatin and rosuvastatin, equal or superior efficacy was observed in diabetic compared with nondiabetic subjects [Insull, W. et al. Abst. 2358-PO]; statins showed a role in increasing skeletal muscle free fatty acid oxidation and utilization and reducing triglyceride stores [Kim, D.L. et al. Abst. 2612-PO]. However, unlike in nondiabetic subjects, in diabetic patients treatment with statins showed dependence on the apolipoprotein E genotype, with improved lipid-lowering response in the ε3/4 genotype [Koh, A.F.Y. et al. Abst. 961-P]. Both atorvastatin and fluvastatin offered benefits in lipid control, with slight increases in plasma glucose and hemoglobin A1c in diabetic patients [Okayama, N. et al. Abst. 2080-PO]. New data with low-dose atorvastatin suggested additional antiinflammatory activity, reducing C-reactive protein and monocyte chemoattractant protein-1 levels [Takebayashi, K. et al. Abst. 490-P; Von Eynatten, M. et al. Abst. 559-P], with no adverse pharmacokinetic interaction upon coadministration with gemfibrozil or fenofibrate [Whitfield, L.R. et al. Abst. 547-P], but a meta-analysis of 49 trials suggested similar adverse event profiles for 10- and 80-mg doses of the drug, with a slight increase in the incidence of liver function test elevations [Newman, C. et al. Abst. 577-P]. These effects could explain the improvements in glomerular filtration rate observed after treatment with low-dose atorvastatin in the CARDS trial, although with no improvements in albuminuria [Neil, H.A.W. et al. Abst. 502-P]. Furthermore, in the ACTFAST study, targeted dosing of atorvastatin allowed most patients to safely reach LDL cholesterol targets [Leiter, L.A. et al. Abst. 2357-PO; Martineau, P. et al. Abst. 2360-PO]. Atorvastatin was also associated with decreased elevated hepatic lipase activity in the treatment of diabetes [Schneider, J.G. et al. Abst. 2364-PO]. Regarding simvastatin, efficacy was demonstrated in patients on on-going thiazolidinedione therapy in improving lipid profiles [Plotkin, D.J. et al. Abst. 951-P]. Addition of ezetimibe to treatment with simvastatin improved the hypocholesterolemic efficacy in patients with metabolic syndrome [Feldman, T. et al. Abst. 601-P], and the ezetimibe/simvastatin combination was superior to atorvastatin in improving LDL, total and HDL cholesterol in the VYVA trial (Fig. 14) [Ballantyne, C.M. et al. Abst. 962-P]. Rosuvastatin demonstrated antiatherosclerotic effects in apolipoprotein E-deficient animal models of diabetes [Jandeleit-Dahm, K.A.M. et al. Abst. 779-P] and induced insulin sensitization in animal models of diabetes [Federico, L. et al. Abst. 2181-PO].
Fig. 14. Percent change in lipid values after treatment with ezetimibe/simvastatin or atorvastatin [962-P].
Novel drugs under development for diabetic dyslipidemia include the apolipoprotein B-100 inhibitor ISI-301012, which dose dependently reduced LDL and total cholesterol levels in a double-blind, placebo-controlled trial [Bradley, J.D. et al. Abst. 977-P].
Pioglitazone improved the albumin/creatinine ratio more effectively than insulin alone in animal models of diabetic nephropathy [Nicholas, S.B. et al. Abst. 224-OR]. Improvements in albuminuria and glomerular filtration rate were obtained with the protein kinase Cb inhibitor ruboxistaurin in 123 patients with type 2 diabetes and nephropathy [Tuttle, K.R. et al. Abst. 223-OR]. By nuclear factor κB-dependent mechanisms, kremezin delayed progression of diabetic nephropathy in type 2 diabetic patients treated over 6 months [Shimizu, H. et al. Abst. 815-P]. Diacylglycerol oil supplementation stabilized renal function and hypertriglyceridemia when added to diet therapy in patients with diabetic nephropathy, offering improved quality of life [Tomonobu, K. et al. Abst. 89-LB].
Experimental preclinical studies demonstrated reduced renal cortical integrin expression and improved extracellular matrix accumulation with a synthetic cyclic Arg-Gly-Asp peptide in animal models of diabetes [Nicholas, S.B. et al. Abst. 603-P], while the prostanoid TP receptor blocker S-18886, but not aspirin, decreased 12-lipoxygenase expression, 12-HETE production and oxidant stress in the kidney of apolipoprotein E-deficient diabetic animals [Zuccollo, A. et al. Abst. 828-P], and the AT2 receptor blocker CGP-42112A induced migration and inhibited proliferation of mesangial cells after kidney injury in further diabetic models [Takeuchia, Y. et al. Abst. 842-P]. Protective effects against diabetic nephropathy were demonstrated for lithospermate B in other animal models [Lee, G.T. et al. Abst. 843-P].
Substantial relief of neuropathic pain associated with diabetic neuropathy was noted for duloxetine in placebo-controlled trials, independently of baseline status [Hardy, T. et al. Abst. 465-P; Chappell, A.S. et al. Abst. 508-P; Raskin, J. et al. Abst. 509-P; Pritchett, Y.L. et al. Abst. 510-P]. Efficacy was also demonstrated for pregabalin, which by reducing pain improved sleep in 1346 patients compared with placebo. The drug offered significant gains in clinical status and health-related quality of life [Rosenstock, J. et al. Abst. 539-P; Freeman, R. et al. Abst. 551-P; Brandenburg, N. et al. Abst. 563-P; Stacey, B. et al. Abst. 602-P]. Pregabalin proved effective in 81 treatment-refractory patients [Durso de Cruz, E. et al. Abst. 564-P]. A further antiepileptic drug with efficacy in diabetic neuropathy is topiramate, which improved epidermal nerve fiber morphology over 18 weeks in an open trial [Pittenger, G.L. et al. Abst. 901-P]. Lamotrigine also relieved pain in diabetic neuropathy, with no deleterious effects on glucose and weight control [Vinik, A.I. et al. Abst. 2147].
Efficacy against deterioration of diabetic neuropathy was also demonstrated for the aldose reductase inhibitor epalrestat compared with conventional therapy in a series of 594 patients in a 3-year trial (Fig. 15) [Hotta, N. et al. Abst. 872-P]. In experimental models, improvement in sorbitol accumulation and sensory nerve conduction velocity were demonstrated for ranirestat [Matsumoto, T. et al. Abst. 475-P]; the compound improved nerve function and sensation during a 52-week trial in patients with diabetic sensorimotor polyneuropathy [Bril, V. and Buchanan, R.A. Abst. 488P].
Fig. 15. Change in nerve conduction velocity during 3 years of therapy with epalrestat or conventional therapy [872-P].
Given intravenously or orally, α-lipoic acid also offered symptomatic benefits to 45 outpatients with diabetic polyneuropathy [Lee, H. et al. Abst. 491-P] and improved skin wound healing and muscle regeneration capacity in animal models [Stevens, M. et al. Abst. 891-P; Jurisic-Erzen, D. et al. Abst. 2666-PO], while early manifestations of the disease were improved by cariporide, an Na + /H + ATPase-1 inhibitor [Drel, V.R. et al. Abst. 875-P], and the associated neurovascular dysfunction was improved by the I k B kinase-2 inhibitor AS-602868 [Cameron, N.E. et al. Abst. 893-P], suggesting new targets for intervention.
Experimental studies suggested a role of gliclazide in preventing progression of diabetic retinopathy in animal models of diabetes [Kakehashi, A. et al. Abst. 2316-PO]. Nonsteroidal antiinflammatory drugs have been shown to prevent progression of diabetic retinopathy in the early stages [Zheng, L. and Kern, T.S. Abst. 929-P]. Prevention of capillary loss in animal models of diabetic retinopathy was demonstrated in an experimental study with aspirin, but not clopidogrel [Sun, W. et al. Abst. 907-P], while α-lipoic acid prevented retinal histopathology via regulation of mitochondrial superoxide production [Kowluru, R.A. and Basak, S. Abst. 908-P]. Trials are ongoing to assess the potential of sandostatin in the treatment of diabetic retinopathy [Collins, W. et al. Abst. 2089-PO].
Mitemcinal effectively improved diabetic gastroparesis compared with placebo in a double-blind trial [Faichney, J.D. et al. Abst. 2126-PO]. Safety and efficacy as a copper chelator was demonstrated for trientine, an agent for diabetic myocardiopathy, in both diabetic and nondiabetic subjects [Chan, Y.K. et al. Abst. 2105-PO].
The nonsteroidal compound CP4-72555-01 injected intracerebroventricularly to animals prevented hypoglycemia exacerbation during repeated insulin administration in animal models [Kale, A.D. et al. Abst. 104-OR].
Overweight diabetic subjects lose weight more slowly than nondiabetic patients during treatment with sibutramine, with less benefits on laboratory parameters [Barratt, R. et al. Abst. 2742-PO]. However, effective decrease in triglycerides levels was demonstrated for sibutramine in overweight and obese individuals [Aronne, L. et al. Abst. 1821-P; Long, B. et al. Abst. 1822-P; Fennoy, I. et al. Abst. 1824-P; Fujioka, K. et al. Abst. 1825-P]. Efficacy in the treatment of obesity was also demonstrated with rimonabant, which increased adiponectin levels besides reducing body weight in the RIO-Lipids trial [Després, J.P. et al. Abst. 7-LB], while a pooled analysis of all RIO trials suggested metabolic improvements in prediabetic individuals [Rosenstock, J. et al. Abst. 13-LB]. Efficacy was demonstrated for topiramate in reducing body weight, but also hemoglobin A1c levels in a placebo-controlled trial in 111 patients (Fig. 16) [Rosenstock, J. et al. Abst. 46-OR]. In a mechanistic, in vitro study, topiramate enhanced glucose transport through an AMP-activated protein kinase-dependent mechanism [Jung, K.H. et al. Abst. 45-LB]. Other news in the treatment of obesity revealed initial clinical efficacy for AOD-9604 [Wittert, G. et al. Abst. 1835-P], while an effect in increasing food intake was demonstrated for the antipsychotic olanzapine [Fountaine, R.J. et al. Abst. 1849-P].
Fig. 16. Percent change in body weight and hemoglobin A1c levels after treatment with topiramate or placebo [46-O
Genistein showed effective protection of human endothelial cells against oxidative stress in an in vitro diabetes model [Zhong, J. et al. Abst. 598-P].
Treatment with pioglitazone improved adiponectin levels and reduced liver fat and inflammatory markers in patients with nonalcoholic steatohepatitis [Belfort, R. et al. Abst. 600-P].
Use of infliximab in the treatment of rheumatoid arthritis improved insulin resistance [Sayo, Y. et al. Abst. 604-P].
Data suggesting benefits of insulin glargine in patients with cystic fibrosis was obtained in five diabetic patients [Minucci, L. et al. Abst. 2160-PO].
Potential for metformin in preventing weight gain in children treated with atypical neuroleptic was suggested in a trial in 35 patients [Klein, D.J. et al. Abst. 2198-PO].
Insulin infusion did not prevent mortality in patients with acute myocardial infarction, despite the relationship between glucose levels and mortality [Cheung, W. et al. Abst. 6-LB].
Report prepared by: Xavier Rabasseda
Affiliation: Medical Information Department, Prous Science