From Insulin to Incretins: A Report from the 67th Scientific Sessions of the American Diabetes Association

INTRODUCTION

Diabetologists and endocrinologists from all over the world attended the annual scientific sessions of the ADA, where more than 2,000 oral and poster presentations were discussed. New topics, especially reflected in a symposium debate on the cardiovascular safety of rosiglitazone (see box below), offered ample opportunities for discussion of new evidence that may change how patients with diabetes and the disease complications are treated. The following report reviews many of the new research results disclosed during this year’s ADA meeting, and complements information available at the DiabetesPRO website (http://professional.diabetes.org), including webcast files of many of the oral sessions during the meeting, with audio synchronized to slide presentations.

INSULIN IN THE TREATMENT OF DIABETES

Insulin is still the mainstay in the treatment of type 1 diabetes, and is also highly effective in improving health and economic outcomes in patients with type 2 diabetes [Lee, W.C. et al., Abst 458-P]. Benefits continued to be reported with continuous subcutaneous insulin infusion during this year’s meeting [Peyrot, M. & Rubin, R.R., Abst 461-P; Horvath, K. et al., Abst 464-P; Pankowska, E. et al., Abst 470-P; Johnson, S.L. et al., Abst 558-P], and initiation of pump therapy at the time of diagnosis was feasible and successful in a randomized trial in 49 adolescents [Siafarikas, A. et al., Abst 204-OR]. Novel insulins and insulin delivery systems have been developed throughout the years to improve glycemic control and patient comfort. News regarding these novel approaches discussed during ADA this year included mention of superior postprandial glucose control with less postprandial hyperglycemia following use of a novel regular human insulin formulation (VIAject^®) compared to standard subcutaneous human insulin [Steiner, S.S. et al., Abst 34-OR], confirmation of improved glycemic control without weight gain with inhaled insulin [Tu, N. et al., Abst 471-P] and the pulmonary safety of inhaled insulin delivery [Hollander, P. et al., Abst 472-P; Cefalu, W. et al., Abst 473-P], as well as confirmation of the superior metabolic control with oral compared to subcutaneous insulin therapy [Guevara-Aguirre, J. et al., Abst 474-P], reports of the effective glucose-lowering effect of oral insulin [Luzio, S.D. et al., Abst 37-OR; Goldberg, M. et al., Abst 457-P], the feasibility of intranasal insulin spray regardless of smoking status [Leary, A.C. et al., Abst 467-P; Schwartz, S.L. et al., Abst 02-LB] and description of the glycemic benefits and lack of impact of mild asthma on inhaled insulin requirements compared to nonasthmatic individuals [Wolzt, M. et al., Abst 35-OR; Schwartz, S. et al., Abst 36-OR]. Another formulation of insulin, for which efficacy in improving glycemic control was reported during the meeting, is intraperitoneal insulin, which in 19 subjects with poorly controlled type 1 diabetes offered significant benefits on hemoglobin A1c and other outcomes [Logtenberg, S.J. et al., Abst 451-P]. On the other hand, observations in 141 patients suggested reduced perception of burden and restrictions and improved treatment satisfaction with continuous subcutaneous insulin infusion compared to multiple daily injections [Nicolucci, A. et al., Abst 452-P].

Insulin delivery and guidance software have been developed to improve glycemic control in intensively insulin-treated type 1 or 2 diabetic patients over the long term [Ellis, S.L. et al., Abst 31-OR; Soni, S. et al., Abst 202-OR; Strange, P. et al., Abst 454-P; Carr, J.B. et al., Abst 455-P; Newton, C.A. et al., Abst 460-P; Dunn, K. et al., Abst 463-P].

Risk of hypoglycemia has been one of the major drawbacks of insulin therapy, but data from a controlled study in six patients suggested a preventive effect against nocturnal hypoglycemia when a very low dose of glucagon was infused continuously throughout the night [Edelman, S. et al., Abst 32-OR].

Regarding experimental insights into insulin activity and physiology, experimental studies suggested no increase in the sympathoadrenal response to hypoglycemia after intrahypothalamic insulin administration [Ishihara, K.K. et al., Abst 629-P].

INSULIN ANALOGS

With confirmation of benefits in patients with type 2 diabetes in the PREDICTIVE study [Meneghini, L. et al., Abst 197-OR; Gallwitz, B. et al., Abst 550-P], insulin detemir therapy was associated with enhanced hemoglobin A1c goal attainment rates and less weight gain than standard subcutaneous insulin [Philis-Tsimikas, A. et al., Abst 487-P; Hermansen, K. et al., Abst 489-P] as well as counterregulatory changes in hormone responses and increased sweating and symptom awareness during hypoglycemia [Tschritter, O. et al., Abst 171-OR]. Moreover, switch from basal insulin to insulin detemir improved glycemic control in 71 children with type 1 diabetes, with no tolerability concerns umník, Z. et al., Abst 1884-P], while switch from insulin glargine to insulin detemir resulted in a lapse in glycemic control, increased insulin requirements and augmented costs [Kabadi, U.M., Abst 07-LB]. Furthermore, insulin detemir was not associated with weight gain in the ADAPT and PREDICTIVE studies [Le Floch, J.P. et al., Abst 546-P; Sreenan, S. et al., Abst 549-P].

The efficacy of insulin glargine in improving glycemic control in patients with type 2 diabetes without increasing body weight was further demonstrated in the RABBIT 2 and other trials [Smiley, D.D. et al., Abst 193-OR; Tadros, L. et al., Abst 547-P; Korytkowski, M. et al., Abst 564-P], and compared to regular insulin, insulin glargine was associated with a reduced risk of hypoglycemia in patients on oral antidiabetic therapy [De Mattia, G. et al., Abst 555-P; Mullins, P. et al., Abst 603-P]. Insulin glargine was as effective as insulin detemir in improving glycemia, but insulin detemir had lower antilipolytic activity and was associated with reduced glucose metabolism at the end of the dosing period [Porcellati, F. et al., Abst 201-OR]. However, switch from twice-daily insulin lispro to once-daily insulin glargine reduced the odds for glycemic control after one year according to a retrospective chart review [Sun, P. & Wang, R., Abst 466-P]. On the other hand, insulin glargine had a similar or higher benefit than pioglitazone and higher benefit than rosiglitazone on free fatty acid levels in diabetic individuals [Schwartz, S. et al., Abst 889-P; McGill, J. et al., Abst 890-P]. In the experimental arena, insulin glargine did not induce proliferation of pancreatic carcinoma cells, and human data suggested no effect in reducing survival in patients with pancreatic carcinoma [Erbel, S. et al., Abst 583-P].

Regarding insulin glulisine, addition to basal insulin with oral antidiabetic therapy improved response rates  in 316 type 2 diabetic patients [Lankisch, M. et al., Abst 198-OR], and both insulin glulisine and insulin glargine offered higher bioavailability than regular human insulin [Richardson, A. et al., Abst 407-P].

Confirmation of the benefits of mealtime insulin aspart in type 2 diabetes was obtained in a two-year follow-up of 371 patients [Henriksen, J.E. et al., Abst 195-OR], while results in 7,317 patients with type 2 diabetes demonstrated improvements in glycemic control with a reduced risk for hypoglycemia in subjects poorly controlled on oral antidiabetic drugs  [Shestakova, M.V. et al., Abst 632-P]. Cross-immunity against insulin aspart and human insulin was demonstrated in children, but resulted in no compromise in safety or efficacy [Holmberg, H. et al., Abst 1885-P].

Intensive treatment with prandial insulin lispro combined with regular insulin also offered optimal glycemic control with a low risk of hypoglycemia in patients with type 2 diabetes previously uncontrolled with insulin glargine combined with oral hypoglycemic agents [Rosenstock, J. et al., Abst 196-OR]. Continuous insulin lispro infusion was reported as an attractive alternative to standard insulin therapy for type 2 diabetes, based on results in eight healthy volunteers [Rave, K. et al., Abst 453-P], and was as effective as continuous insulin aspart in 298 children with type 1 diabetes [Weinzimer, S. et al., Abst 1892-P].

BIGUANIDES

While the ADOPT trial suggested superiority and cost-effectiveness of metformin over glibenclamide in the treatment of new-onset type 2 diabetes [Herman, W.H. et al., Abst 548-P; Willis, M. et al., Abst 1227-P] (Fig. 1), metformin was also associated with improvements in HDL-mediated cholesterol efflux through an effect on HDL glycation [Matsuki, K. et al., Abst 572-P] and reduced the cardiovascular risk profile while preventing weight gain compared to placebo in 390 intensively insulin-treated patients [Kooy, A. et al., Abst 578-P]. In adolescents, metformin markedly improved the metabolic and cardiovascular risk profiles associated with obesity [Burgert, T.S. et al., Abst 1867-P]. Reduced mortality during metformin therapy for type 2 diabetes was confirmed in a population-based study in Quebec [Gregoire, J.P. et al., Abst 915-P]. Pharmacogenomic data suggested an effect greater insulin-sensitizing effect in type 2 diabetes patients carrying the ENPP Q¹²¹ polymorphic variant [De Cosmo, S. et al., Abst 334-OR].

Fig. 1. Percentage of patients on monotherapy with controlled hemoglobin A1c levels after 4 years of starting metformin or glibenclamide [Herman, W.H. et al., Abst 548-P].

THIAZOLIDINEDIONES

Despite recent controversies on the cardiovascular safety of rosiglitazone, which were a major focus of interest during the meeting and resulted in a special debate symposium which is summarized in the box below, thiazolidinediones are extensively used in the treatment of diabetes, and new studies have revealed more and more benefits of these drugs, including a newly discovered effect of pioglitazone on coupling of electro transport to ATP synthesis in the skeletal muscle of experimental animals [Moellering, D.R. et al., Abst 327-OR] as well as improving adiponectin levels and improving glycemic control while lowering plasminogen activator inhibitor-I levels [Aso, Y. et al., Abst 333-OR]. Furthermore, while pioglitazone was not associated with an increased risk of hospitalization in the PROactive study, a reduction in the need for hospitalization because of ischemic cardiac events and a special reduction in major adverse cardiovascular outcomes in patients with renal dysfunction were noted during the three-year follow-up, in parallel with significant improvements in lipid levels compared to placebo [Spanheimer, R. et al., Abst 553-P; Erdmann, E. et al., Abst 671-P; Spanheimer, R. et al., Abst 905-P], so that pioglitazone arose as a cost-effective option for diabetes [Palmer, A.J. et al., Abst 1209-P; Benedetti, M.M. et al., Abst 1220-P], although according to some evidence, the use of thiazolidinediones can increase the cost of managing heart failure in patients with type 2 diabetes [Delea, T.E. et al., Abst 1223-P]. While both pioglitazone and metformin improved insulin action in the presence of free fatty acids, only metformin prevented the inhibitory effects of free fatty acids on insulin-induced glucose uptake, while pioglitazone enhanced insulin-induced suppression of endogenous glucose production [Basu, R. et al., Abst 250-OR]. Pioglitazone also showed an effect in improving vascular dysfunction to an extent similar to ramipril, but with benefits on adiponectin that were not attained with the angiotensin-converting enzyme inhibitor, although only the latter improved endothelin-1 levels [Fernandez, M. et al., Abst 264-OR]. Additional benefits reported with pioglitazone include lowering of the intima-media thickness [Bierwirth, R.A. et al., Abst 494-P], improvements in plaque stability with reduced inflammation in patients with coronary artery disease [Forst, T. et al., Abst 647-P], downregulation of monocyte/macrophage inflammatory protein mRNA expression and secretion [Pfützner, A. et al., Abst 713-P], inhibition of fibroblast and vascular endothelial growth factor-induced endothelial cell proliferation [Desouza, C.V. et al., Abst 714-P], and improvements in hepatic and visceral fat deposition in normoglycemic subjects with metabolic syndrome [Tsuchiya, M. et al., Abst 577-P]; however, treatment with pioglitazone in patients with impaired glucose tolerance or type 2 diabetes and nonalcoholic steatohepatitis resulted in increased body weight that was related to an increase in whole body fat, but not total body water [Balas, B. et al., Abst 617-P]. An in vitro study in human skeletal muscle demonstrated a role for pioglitazone in upregulating the expression of genes involved in mitochondrial function and fat oxidation, which could be the mechanism by which the drug improves insulin sensitivity [Coletta, D.K. et al., Abst 241-OR], and in fact improvements in insulin resistance have been documented in treated diabetic individuals [Kutoh, E. & Wajs, J., Abst 609-P], which has been related to an effect on ferritin-A levels [Mori, K. et al., Abst 611-P] but not to modulation of retinol-binding protein-4 expression [Schöndorf, T. et al., Abst 613-P]. Overall, a combination of pioglitazone and glimepiride improved cardiovascular risk profile in 98 type 2 diabetic subjects switching from insulin [Hohberg, C. et al., Abst 612-P], while the thiazolidinedione had superior activity in the CHICAGO trial on the lipoprotein subfraction profile [Meyer, P.M. et al., Abst 906-P]. On the other hand, pioglitazone showed more favorable effects than rosiglitazone on triglycerides and HDL-cholesterol, with greater benefit in women, while rosiglitazone improved HDL-cholesterol in both genders, but significantly increased triglycerides in men [Perez, A. et al., Abst 902-P; Perez, A. et al., Abst 903-P; Chahil, T. et al., Abst 910-P] (Fig. 2). Further data regarding the benefits of rosiglitazone were reported this year during the meeting, with studies suggesting an effect in improving adiponectin levels, inflammation and nitrosative stress [Harte, A.L. et al., Abst 551-P; Pop-Busui, R. et al., Abst 600-P], reducing C-reactive protein more effectively than glibenclamide and metformin [Haffner, S.M. et al., Abst 664-P], and also improving inflammation and neuroprotective activity in diabetic subjects with Alzheimer’s disease [Solerte, S.B. et al., Abst 621-P].

Fig. 2. Change in triglyceride and HDL-cholesterol levels in men and women after 6 months of treatment with pioglitazone or rosiglitazone [Perez, A. et al., Abst 902-P].

Α-GLUCOSIDASE INHIBITORS

New data presented during the ADA meeting in Chicago confirmed the safety and cost-effectiveness of add-on acarbose to biphasic insulin therapy, suggesting it to be the “poor man’s insulin analog” [Shankhdhar, L.K. et al., Abst 522-P]. Benefits on arterial stiffness and postprandial hyperglycemia in obese individuals with type 2 diabetes were reported with voglibose, a related drug [Satoh, N. et al., Abst 652-P].

INCRETIN-BASED THERAPIES

Glucagon-like peptide-1 (GLP-1) analogs

Exenatide was associated with good glycemic control and weight reduction in type 2 diabetic subjects [Buse, J. et al., Abst 283-OR], although less favorable experiences were reported in a real-world setting [Loh, J.A. & Clement, S.C., Abst 570-P]. Exenatide offered a reduced risk of hypoglycemia compared to insulin glargine, while inducing similar glycemic benefits in type 2 diabetic patients treated with metformin [Trautmann, M. et al., Abst 172-OR] (Fig. 3) and a marked improvement in the cardiovascular risk profile, as demonstrated over a 3.5-year period in 151 patients [Kendall, D. et al., Abst 557-P]. Treatment with exenatide also offered improvements in hepatic function [Nielsen, L. et al., Abst 561-P]. The efficacy of exenatide was higher in patients with greater β-cell responsiveness to insulin [Davis, S. et al., Abst 518-P]. The agent showed usefulness for controlling glucose and weight, especially if thiazolidinedione therapy was discontinued [Oyer, D.S. et al., Abst 585-P]. A long-acting protected graft copolymer nanocarrier-based formulation of an exenatide analog has been developed that reduces the likelihood for neutralizing antibodies while allowing for less frequent administration because of a longer half-life and higher bioavailability after subcutaneous administration [Reichstetter, S. et al., Abst 540-P; Sakamuri, S. et al., Abst 567-P]. A closely related derivative, PC-DAC:exendin-4, offered favorable safety at pharmacodynamically active doses in healthy volunteers [Wang, M. et al., Abst 498-P], and proved safe and effective when added to metformin in lowering glucose levels in 70 patients [Wang, M. et al., Abst 06-LB]. Another GLP-1 analog, liraglutide, showed a pharmacokinetic profile compatible with once-daily dosing [Jonker, D. et al., Abst 605-P] independent of renal or hepatic function, such that renal and hepatic impairment were not associated with an increased risk of adverse events even in severe cases on dialysis [Jacobsen, L.V. et al., Abst 513-P; Flint, A. et al., Abst 545-P]. Once-daily treatment with liraglutide effectively improved the glycemic control in 226 type 2 diabetes patients compared to placebo [Seino, Y. et al., Abst 520-P] (Fig. 4). A GLP-1 receptor agonist currently under clinical research, ZP-10A showed enhanced protection against cytokine- and fatty acid-induced β-cell apoptosis in in vitro studies [Tews, D. et al., Abst 279-OR], while a further compound, AVE-0010, prevented glucose excursions in normoglycemic animals undergoing oral glucose tolerance tests with no risk of hypoglycemia [Werner, U. et al., Abst 486-P]. A related compound, the bivalent GLP-1 mimetic CVX-73 created by fusing a dipeptidyl peptidase-4-resistant GLP-1 analog with a proprietary monoclonal antibody, was also tested in animals, showing optimal pharmacokinetic and pharmacodynamic profile [Huang, J. et al., Abst 527-P].

Fig. 3. Incidence of hypoglycemia in patients adding exenatide or insulin glargine to metformin- or sulfonylurea-based therapy [Trautmann, M. et al., Abst 172-OR].

Fig. 4. Placebo-adjusted change in hemoglobin A1c levels after treatment with increasing doses of liraglutide [Seino, Y. et al., Abst 520-P].

A similar alternative is the use of native GLP-1 formulated in protected graft copolymers, to prevent degradation by dipeptidyl peptidase-4. Such a strategy proved feasible in experimental studies [Castillo, G. et al., Abst 475-P].

Dipeptidyl peptidase-4 inhibitors

While being well tolerated and effective in improving glycemic control over the long term with a low risk of hypoglycemia and benefits on weight loss when combined with metformin and/or sulfonylureas [Karasik, A. et al., Abst 523-P; Williams-Herman, D. & Xu, L., Abst 533-P; Stein, P.P. et al., Abst 534-P; Hermansen, K. et al., Abst 535-P] (Fig. 5), complementary activity was reported with sitagliptin and metformin in increasing glucagon-like peptide-1 levels in a placebo-controlled study in 16 healthy adults [Migoya, E.M. et al., Abst 286-OR], and initial therapy with the combination offered durable, substantial glycemic improvements with good tolerability in a randomized trial in 1,091 patients [Williams-Herman, D.E. et al., Abst 04-LB]. Sitagliptin was also demonstrated to improve islet cell mass and function in experimental animals, whereas the comparator, glipizide, improved glycemic control only transiently with no effects on pancreatic islets [Mu, J. et al., Abst 10-LB].

Fig. 5. Change in hemoglobin A1c levels after 54 weeks of treatment with sitagliptin, metformin, combination therapy or placebo [Williams-Herman, D. & Xu, L., Abst 533-P].

With benefits on hyperglycemia and hemoglobin A1c levels in treatment-naïve patients with type 2 diabetes [Scherbaum, W.A. et al., Abst 503-P; Rosenstock, J. et al., Abst 506-P] (Fig. 6) resulting in high goal achievement rates compared to placebo whether used as monotherapy or combined with metformin or pioglitazone [Pratley, R.E. et al., Abst 504-P], improvements in β-cell function by vildagliptin were sustained over 52 weeks of treatment in 306 patients with mild hyperglycemia [Mari, A. et al., Abst 284-OR], with no differences between morning and evening administration over a 28-days in a placebo-controlled study of 38 patients [He, Y.L. et al., Abst 493-P]. Vildagliptin was also reported to improve insulin sensitivity and β-cell function in nondiabetic patients with impaired fasting glucose [Utzschneider, K.M. et al., Abst 515-P], and to decelerate gastric emptying in 18 patients with type 2 diabetes after a single dose [Woerle, H.J. et al., Abst 500-P] and offered similar benefits on glycemic excursions in patients with impaired glucose tolerance [Rosenstock, J. et al., Abst 505-P]. No effect of vildagliptin on satiety and nutrient intake was noted in a double-blind, placebo-controlled study in 14 type 2 diabetic individuals [Vella, A. et al., Abst 575-P]. Moreover, treatment with vildagliptin also lowered blood pressure, as demonstrated in a double-blind comparison with metformin [Bosi, E. et al., Abst 521-P]. Regarding combination therapies, vildagliptin with concomitant sulfonylurea was effective and well tolerated, and was devoid of weight gain with a minimal risk of hypoglycemia compared to placebo in 144 patients [Garber, A.J. et al., Abst 501-P]. In fact, a trend towards reduced body weight was apparent in elderly subjects, which showed higher benefit than younger individuals regarding glycemic control, with good tolerability [Pratley, R.E. et al., Abst 507-P].

Fig. 6. Change in hemoglobin A!c levels after treatment with increasing doses of vildagliptin in a meta-analysis of 5 studies [Rosenstock, J. et al., Abst 506-P].

Initial pharmacokinetic, pharmacodynamic and tolerability data with alogliptin in healthy males and patients with type 2 diabetes confirmed the potential of the drug as a well-tolerated dipeptidyl peptidase-4 inhibitor for decreasing postprandial glucose [Christopher, R. et al., Abst 495-P; Christopher, R. et al., Abst 499-P]. In the experimental setting, effective improvement of β-cell function was demonstrated in obese animals [Moritoh, Y. et al., Abst 511-P].

A fourth dipeptidyl peptidase-4 inhibitor, saxagliptin showed favorable pharmacokinetic and pharmacodynamic properties in healthy volunteers [Boulton, D.W. & Geraldes, M., Abst 606-P]. Addition of saxagliptin to metformin therapy resulted in improved glycemic control compared to placebo in 743 patients with type 2 diabetes [Defronzo, R.A. et al., Abst 285-OR].

Novel dipeptidyl peptidase-4 inhibitors in development, new results with which were reported during the meeting, include PHX-1149, which was safe and well tolerated and effectively reduced hemoglobin A1c levels compared to placebo in type 2 diabetes patients [Guler, H.P., Abst 09-LB] (Fig. 7), SK-0403, which proved safe and well tolerated up to 400 mg in healthy subjects with optimal pharmacokinetic and pharmacodynamic profiles [Sunami, Y. et al., Abst 482-P], PF-734200, which induced nonlinear increases in glucagon-like peptide-1 levels in healthy adults [Dai, H. et al., Abst 508-P], ABT-279 and BI-1356, which proved active and well tolerated in healthy volunteers [Zhu, T. et al., Abst 562-P; Huettner, S. et al., Abst 586-P; Heise, T. et al., Abst 588-P; Forst, T. et al., Abst 594-P]. Dipeptidyl peptidase-4 inhibitors under preclinical development, for which results of experimental studies in animals demonstrated favorable activity, included S-40010 [Combettes, M.M. et al., Abst 597-P] and ARI-2243 [Sanford, D.G. et al., Abst 604-P].

Fig. 7. Change in postprandial glucose area under the curve after treatment with increasing doses of PHX-1149 or placebo [Guler, H.P., Abst 09-LB].

Other incretin-based therapies

Native GLP-1 was effectively delivered through nonimmunogenic nanocarriers,  resulting in long-acting therapy that offered efficacy in controlling glycemia and weight in animals [Reichstetter, S. et al., Abst 282-OR]. On the other hand, reversal of diabetes in experimental animals was attained with a gene therapy using adeno-associated virus vectors encoding for GLP-1 injected directly into the pancreas [Xue, S. et al., Abst 280-OR], and studies are ongoing to determine long-term impact on islet cell mass, β -cell apoptosis and proliferation.

NATURAL AND NONPHARMACOLOGICAL THERAPIES FOR DIABETES

To the known benefits of red wine polyphenols on the cardiovascular function and risk, experimental data presented during the meeting of the ADA in Chicago added positive effects of resveratrol in suppressing hepatic glucose production through an effect on the hypothalamic Sirt1-dependent pathway [Knight, C.M. et al., Abst 38-LB] and inhibiting neointimal growth and decreasing vascular smooth muscle cell migration [Breen, D.M. et al., Abst 711-P], and improving renal hypertrophy [Lee, M.J. et al., Abst 779-P]. In that respect, and despite not being from natural sources, the synthetic polyphenol and AMP-dependent protein kinase activator S-17834 improved diet-induced obesity, insulin resistance, hyperlipidemia and atherosclerosis in experimental animals [Zang, M. et al., Abst 727-P; Xu, S. et al., Abst 730-P]. Other diet and dietary supplements reportedly beneficial in diabetes include chromium picolinate (enhancement of phosphatidyl inositol-3 kinase and decrease in protein tyrosine phosphatase-1B activity, resulting in improved insulin sensitivity and glycemic control) [Wang, Z. et al., Abst 1765-P; May, J.A. et al., Abst 1891-P], chromium/niacinate (decrease of proinflammatory cytokines and lipid peroxidation) [Jain, S.K. et al., Abst 1784-P], curcumin (enhancement of insulin secretion and improvement in glucose homeostasis-related enzyme activity) [Seo, K.I. et al., Abst 1766-P], Korean red ginseng (activation of AMP-dependent protein kinase in liver and muscle) [Lee, H.J. et al., Abst 1775-P], cod proteins (improvements in insulin sensitivity and muscle phosphatidyl inositol-3 kinase activity) [Ouellet, V. et al., Abst 1771-P] and a low-fat, vegetarian diet (sustained improvements in glycemic, lipid and weight control) [Barnard, N. et al., Abst 1774-P].

Immunoprevention of type 1 diabetes is another area of interest, and rhGAD65, a recombinant human glutamic acid decarboxylase 65-kD isoform-based vaccine, proved safe and immunologically active in 2,096 type 2 diabetes patients [Agardh, C.D. et al., Abst 1240-P; Casas, R. et al., Abst 1242-P]. Prevention of the immune pathways related with diabetes pathogenesis was also suggested with interferon beta [Bagher, L., Abst 1241-P].

A further option that has repeatedly been reported feasible for the treatment of diabetes is pancreas or islet transplantation, and new studies reported in Chicago in summer 2007 confirmed the benefits on glycemia, especially for patients with severe hypoglycemia and unstable glycemic control despite optimal insulin therapy [Gorn, L. et al., Abst 446-P; Lauria, M.W. et al., Abst 2053-P; Jung, H.S. et al., Abst 2055-P; Lauria, M.W. et al., Abst 2056-P], while studies in animals suggested a role for a further option: transplantation of embryonic progenitor-derived insulin-producing cells [Shao, S. et al., Abst 2057-P]. Related alternatives include skeletal myoblast transplantation, which improved hyperglycemia and insulin sensitivity in experimental studies [Ye, L. et al., Abst 2071-P]. On the other hand, immunosuppressants such as tacrolimus and sirolimus cause hypergluycemia and insulin resistance [McClure, M. et al., Abst 2066-P], but a study in 22 pancreas graft recipients suggested that treatment with exenatide during transplantation reduces mycophenolate and tacrolimus toxicity to insulin secretion [Ao, Z. et al., Abst 2061-P], while results in nine patients suggested improved outcomes after islet infusion with compared to without concomitant exenatide therapy [Faradji, R.N. et al., Abst 49-LB]; α₁-antitrypsin administration, but not α₁-antitrypsin gene therapy, also improved transplant outcomes in experimental animals [Song, S. et al., Abst 2076-P], but did not prevent recurrence of islet autoimmunity [Song, S. et al., Abst 2077-P].

OTHER ANTIDIABETIC MEDICATIONS

With further human data suggesting long-term efficacy of recombinant leptin in improving insulin resistance in subjects with lipodystrophy and type 1 diabetes [Park, J.Y. et al., Abst 622-P], pramlintide, an amylin analog, has been available since 2005 for the treatment of diabetes. Observations reported during this year’s meeting suggested improvements in glycemic control with no added risk of hypoglycemia compared to placebo in 211 insulin glargine-treated patients [Lutz, K. et al., Abst 536-P; Riddle, M. et al., Abst 538-P] (Fig. 8); improvements were also apparent in weight loss and C-reactive protein levels [Lush, C. et al., Abst 541-P; Edelman, S. et al., Abst 1826-P], and a sustained weight benefit throughout one year of therapy was also demonstrated in 209 obese individuals [Smith, S. et al., Abst 335-OR]. Pramlintide decelerated gastric emptying in type 1 diabetic and healthy subjects [Woerle, H.J. et al., Abst 574-P], and proved beneficial when added to insulin/thiazolidinedione-based therapy compared to placebo in 54 patients [Lorenzi, G. et al., Abst 552-P].

Fig. 8. Hypoglycemia rates in patients adding pramlintide or placebo to basal insulin glargine [Lutz, K. et al., Abst 536-P].

Currently in advanced clinical research, the fructose 1,6-bisphosphatase inhibitor managlinat enhanced the activity of insulin and improved lactate metabolism when combined with thiazolidinediones [Yoshida, T. et al., Abst 490-P], and was shown to suppress gluconeogenesis in human hepatocytes, whereas the effect of metformin was that of stimulating glycolysis [Okuno, A. et al., Abst 488-P]. As opposed to metformin, managlinat lowered blood glucose in diabetic, obese animals through an effect on gluconeogenesis [Van Poelje, P.D. et al., Abst 543-P].

Currently in phase II/III clinical research, the SGLT-2 inhibitor dapagliflozin reduced fasting serum glucose levels and postprandial glucose excursions compared to placebo in a cohort of 47 type 2 diabetic patients [Komoroski, B. et al., Abst 188-OR] (Fig. 9) and brought about improvements in glucose homeostasis in experimental animals [Whaley, J. et al., Abst 559-P]. Similarly, the clinical safety and tolerability of sergliflozin in patients with type 2 diabetes and healthy volunteers was reported, along with reports of predictable, consistent pharmacodynamic effects regardless of body weight and initial pharmacodynamic demonstration of an effect in lowering plasma glucose levels [Hussey, E.K. et al., Abst 189-OR; Hussey, E.K. et al., Abst 491-P]. Dose optimization of sergliflozin was deemed beneficial based on in vivo human pharmacodynamic data [O’Connor-Semmes, R.L. et al., Abst 480-P].

Fig. 9. Change in fasting blood glucose levels after 13 days of treatment with dapagliflozin or placebo [Komoroski, B. et al., Abst 188-OR].

Phase II studies are also ongoing with the cortisol synthesis inhibitor (-)-ketoconazole, which was reported as a well-tolerated option for improving glycemic control and lipid profiles compared to placebo in 37 type 2 diabetic patients [Schwartz, S. et al., Abst 191-OR] (Fig. 10), while administration of bromocriptine reduced the cardiovascular risk compared to placebo and improved glycemic control in diabetic subjects with suboptimal control during metformin and sulfonylurea [Gaziano, J.M. et al., Abst 50-LB]. Benefits on postprandial glycemia were described in a further study in 49 patients with a Salacia oblonga root extract [Williams, J.A. et al., Abst 43-LB].

Fig. 10. Change in fructosamine levels after 14 days of treatment with (-)-ketoconazole, ketoconazole or placebo [Schwartz, S. et al., Abst 191-OR].

EXPERIMENTAL PUTATIVE THERAPIES FOR DIABETES

In the experimental arena, normalization of glycemia and insulin production was demonstrated with exogenous stromal cell-derived factor-1 [Cheng, H. et al., Abst 187-OR], while an insulin-sensitizing effect was reported with the adenosine A_2B receptor blocker ATL-801 [Zhang, Z. et al., Abst 247-OR] and sodium butyrate prevented type 1 diabetes in genetically prone animals [Escobar-Douglas, M. et al., Abst 1238-P]. Normalization of glycemia and improved insulin sensitivity resulted from treatment with the tyrosine kinase inhibitor PD-153035 in further experimental studies [Prada, P.O. et al., Abst 252-OR]. Further compounds in preclinical research as putative therapies for diabetes reported during the meeting include the glycogen phosphorylase inhibitor CP-320626 [Zibrova, D. et al., Abst 502-P], the sodium-dependent glucose cotransporter inhibitors SGL-5083, SGL-5085 and SGL-5094 [Yamamoto, K. et al., Abst 509-P; Kumeda, S. et al., Abst 510-P], sodium-dependent glucose cotransporter antisense oligonucleotides [Wancewicz, E.V. et al., Abst 542-P], the glucose-dependent insulinotropic receptor agonist PSN-119-1 [Fyfe, M. et al., Abst 532-P], GKA-50 and another unnamed small-molecular-weight glucokinase activator [Nakamura, A. et al., Abst 529-P; Johnson, D. et al., Abst 592-P], the hepatic gluconeogenesis inhibitor and muscle glucose uptake enhancer EMD-387008 [Raynal, S. et al., Abst 590-P; Bozec-Hallakou, S. et al., Abst 591-P; Baverel, G. et al., Abst 593-P] and ISIS-113715, an antisense oligonucleotide targeting protein tyrosine phosphatase-1B [Havel, P.J. et al., Abst 11-LB]. Experimental data also revealed benefits on glucose metabolism with the Sinocrassula indica extract shilianhua, which was reported to act through glycogen synthase kinase-3β [Yin, J. et al., Abst 544-P], and an Artemisia dracunculus extract that improved insulin sensitivity and insulin-dependent intracellular signaling [Wang, Z.Q. et al., Abst 610-P].

OBESITY AND DIABETIC DYSLIPIDEMIA

Obesity and dyslipidemia are common in patients with diabetes, and antiobesity and lipid-lowering are required by a high proportion of patients. Among other alternatives, the results of the SERENADE study demonstrated improvements in body weight, atherogenic lipid levels and glycemia with the use of rimonabant compared to placebo [Rosenstock, J. et al., Abst 190-OR] (Fig. 11), resulting in a cost-effective addition to the management of overweight and obesity in diabetic subjects [Getsios, D. et al., Abst 1196-P]. However, data from a study in nine patients suggested a body weight-independent direct effect of rimonabant on insulin sensitivity, not correlated with reductions in body weight or omental fat content [Richey, J.M. et al., Abst 248-OR]. These observations were confirmed by improved insulin sensitivity in obese animals after treatment with rimonabant [Harrison, L.N. et al., Abst 372-OR].

Fig. 11. Change in hemoglobin A1c levels after treatment with rimonabant 20 mg or placebo [Rosenstock, J. et al., Abst 190-OR].

Another weight-lowering pharmacological strategy is that based on topiramate, which induced reduction in body mass index without improving insulin sensitivity or adiposity compared to placebo in 20 obese adults [Llamas-Moreno, J.F. et al., Abst 1833-P]. Weight loss was also reported after treatment with bupropion and naltrexone, which also improved insulin resistance markers [Greenway, F.L. et al., Abst 45-LB] (Fig. 12).

Fig. 12. Change in body weight after 24 weeks of treatment with bupropion, naltrexone, the combination of both or placebo [Greenway, F.L. et al., Abst 45-LB].

Lipid-lowering drugs have been extensively used to maximize benefits of glycemic control in patients with diabetes, resulting in improved cardiovascular risk profiles in patients with concomitant coronary artery disease and chronic kidney disease as demonstrated with high-dose atorvastatin in new analyses of the TNT study results [Shepherd, J. et al., Abst 265-OR] (Fig. 13) or in patients with impaired renal function as demonstrated in the CARDS study [Colhoun, H.M. et al., Abst 524-P], while the SPARCL trial confirmed the benefits of intensive atorvastatin therapy in preventing cardio- and cerebrovascular events in high-risk patients with type 2 diabetes or metabolic syndrome [Callahan, A. et al., Abst 266-OR]. Rosuvastatin, on the other hand, improved neuropathy and microvascular function in 15 type 2 diabetic individuals [Parson, H.K. et al., Abst 801-P], while pitavastatin proved not inferior to atorvastatin in 251 Japanese hypercholesterolemic patients, and was more efficient in patients with concomitant metabolic syndrome [Yokote, K. et al., Abst 892-P].

Fig. 13. Major adverse cardiovascular event rates in patients with type 2 diabetes and coronary artery disease on atorvastatin 10 or 80 mg depending on the presence or absence of chronic kidney disease [Shepherd, J. et al., Abst 265-OR].

Fenofibrate represents a different approach to the treatment of dyslipidemia, and in experimental studies in diabetic animals showed an effect in upmodulating the expression of ABCG1, which plays a major role in HDL-mediated cholesterol efflux and reverse cholesterol transport [Tanabe, J. et al., Abst 514-P]. A combination of fenofibrate and metformin induced weight loss and improved the cardiovascular risk profile compared to placebo in 148 obese individuals [Crimet, D. et al., Abst 1836-P]. A related fibrate, bezafibrate, improved both glycemic and lipid outcomes in the 6,407 patients with diabetic dyslipidemia included in the J-BENEFIT trial [Teramoto, T. et al., Abst 888-P] and exhibited milder mitochondrial toxicity than fenofibrate [Yamada, K. et al., Abst 899-P], but showed no additive activity when combined with pioglitazone, and rather blunted the reduction in liver and muscle triglyceride content [Balasubramanian, R. et al., Abst 616-P]. Another peroxisome proliferator-activated receptor (PPAR)-α agonist, KRP-101, is also under active development for the treatment of diabetes and lipoprotein disorders, and studies reported during ADA in Chicago suggested significant activity in in vitro assays [Nagasawa, M. et al., Abst 215-OR], while data from animal studies suggested efficacy in improving fat-induced insulin resistance, suppressing adiposity and preventing fatty liver disease [Kobayashi, N. et al., Abst 492-P; Tsunoda, M. et al., Abst 516-P]. Three further compounds currently under preclinical research are CP-900691, which improved lipids, lipoproteins and glycemic control and reduced body weight in diabetic animal models [Flynn, M. et al., Abst 517-P], LR-90, which prevented insulin resistance, nephropathy and diabetic macrovascular complications in diabetic experimental models [Rahbar, S. et al., Abst 554-P; Figarola, J. et al., Abst 05-LB], and DRL-17564, which is also a modulator of PPARy receptors and showed antidiabetic and lipid-lowering effect without the weight gain or hemotoxicity associated to thiazolidinediones [Chakrabarti, R. et al., Abst 897-P].

Effectiveness in lipid and lipoprotein control in experimental animals was also demonstrated with the thyroid hormone receptor agonist MB-07811 [Linemeyer, D.L. et al., Abst 565-P], the stearoyl-CoA desaturase-1 inhibitor A-572 [Mika, A. et al., Abst 907-P] and a cinnamon extract [Qin, B. et al., Abst 911-P]; novel putative strategies under development for the treatment of obesity and lipoprotein disorders include the PPAR-δ agonist KD-3020, which in experimental studies presented during the meeting showed promise as a treatment for nonalcoholic steatohepatitis and resulting cirrhosis [Guha, M. et al., Abst 497-P], and an unnamed 11β-hydroxysteroid dehydrogenase type 1 inhibitor, which improved the overall metabolic profile of diabetic animals [Veniant, M. et al., Abst 891-P]. On the other hand, the alkaloid berberine, currently in initial clinical research for the treatment of lipoprotein disorders and obesity, was shown to activate the AMP-dependent protein kinase through mechanisms independent of ATP levels in in vitro assays [Turner, N. et al., Abst 618-P]. Benefits on body weight were also reported in experimental studies with the monoamine reuptake inhibitors/serotonin 5HT_1A receptor agonists PSN-S1 and PSN-S2 [Thomas, G.H. et al., Abst 1827-P], the cannabinoid-1 receptor inverse agonist MK-0364 [Addy, C. et al., Abst 1828-P], which also reduced food intake in overweight/obese human volunteers [Stevens, C. et al., Abst 1830-P], the melanocortin-4 receptor agonist MK-0493 [Stevens, C. et al., Abst 1829-P] and a nondisclosed lipoic acid synthase inducer [Padmalayam, I. et al., Abst 1832-P].

TREATMENTS FOR DIABETIC COMPLICATIONS

Diabetic nephropathy

According to the TRIAD study, nephropathy is common and progressive in diabetic individuals, especially those who are overweight or with a history of hypertension, hyperlipidemia or retinopathy [Onyemere, K. et al., Abst 219-OR]. Improvements in microalbuminuria in patients with diabetes were reported this year during the ADA scientific sessions with the heparin-related glycosaminoglycan sulodexide [Lewis, E.J. et al., Abst 573-P], the growth factor modulator FG-3019 [Schwartz, S. et al., Abst 566-P] and the angiotensin receptor blocker telmisartan [Bakris, G. et al., Abst 601-P]. Experimental in vitro studies suggested benefits for a methanolic extract of Cassiae semen [Jung, D.H. et al., Abst 581-P].

Regarding anemia in diabetic nephropathy, improvements in hemoglobin levels were obtained in diabetic and nondiabetic end-stage renal disease patients with the continuous erythropoiesis receptor activator R-744 [Lunde, N.M. et al., Abst 748-P].

On the other hand, the angiotensin-I-converting enzyme-related carboxypeptidase (ACE2) inhibitor MLN-4760 worsened albuminuria and renal injury and upregulated ACE expression in experimental diabetic animals [Soler, M.J. et al., Abst 781-P].

Diabetic neuropathy

Among the treatments reported effective in the treatment of diabetic neuropathy, α-lipoic acid was described as well tolerated and effective against some neuropathic deficits and symptoms, but not nerve conduction, in the NATHAN 1 trial [Ziegler, D. et al., Abst 7-OR] (Fig. 14), while gabapentin was highly effective in reducing pain compared to placebo in 147 patients [Schwartz, S.L. et al., Abst 608-P] (Fig. 15). The NMDA-glycine site blocker lacosamide is currently in advanced clinical research, and data from a randomized study in 370 patients with painful distal diabetic neuropathy demonstrated significant reductions in pain scores with favorable safety and tolerability [Wymer, J. et al., Abst 596-P].

Fig. 14. Change in the Neuropathy Impairment Scores after 4 years of treatment with a-lipoic acid or placebo [Ziegler, D. et al., Abst 7-OR].

Fig. 15. Change in the average daily pain scores after treatment with gabapentin or placebo [Schwartz, S.L. et al., Abst 608-P].

According to observational data, lipid-lowering therapy with statins or fibrates has a protective effect against peripheral sensory neuropathy [Davis, T.M. et al., Abst 4-OR].

Aldose reductase inhibitors are used in the treatment of diabetic neuropathy, and experimental data with a novel compound, lidorestat, suggested benefits on mortality [Noh, H.L. et al., Abst 560-P].

In the experimental arena, mitigation of diabetic neuropathy was reported with pregerminated brown rice intake [Usuki, S. et al., Abst 744-P] and bone marrow-derived mesenchymal stem cell transplantation [Shibata, T. et al., Abst 785-P], and islet cell transplantation prevented myelinated nerve fiber pathology in experimental animals [Mojaddidi, M.A. et al., Abst 804-P].

Diabetic retinopathy

While experimental studies revealed the benefits of periocular insulin injection in improving degenerative and inflammatory changes in diabetic retinopathy [Singh, R.S. et al., Abst 476-P], new studies have confirmed the benefits of intravitreal pegaptanib in inducing regression of proliferative retinopathy and macular edema compared to photocoagulation, with reduced risk of adverse iatrogenic effects [Gonzalez, V.H. et al., Abst 100-OR]. Another effective therapy for diabetic retinopathy, ruboxistaurin improved visual acuity compared to placebo in a series of 685 patients followed up for 36 months [Sheetz, M.J. et al., Abst 481-P] (Fig. 16). In the experimental arena, benefits were reported with topical naltrexone [Zagon, I.S. et al., Abst 817-P] and topical nipradilol [Kakehashi, A. et al., Abst 822-P], but no impact on retinal abnormalities were noted with the protein kinase C inhibitor JTT-010 [Sasase, T. et al., Abst 813-P].

Fig. 16. Change of visual acuity at 12 months in patients on ruboxistaurin or placebo [Sheetz, M.J. et al., Abst 481-P].

Diabetic ulcers

Restoration of ischemia-induced angiogenesis by sildenafil was reported in experimental models of diabetes [Kevil, C.G. et al., Abst 739-P].

Diabetic dyslipidemia and atherosclerosis

Treatment with colesevelam improved lipid profiles with no negative impact on triglycerides in 316 adults with type 2 diabetes, while also improving glycemic control of the disease [Goldberg, R.B. et al., Abst 484-P; Bays, H.E. et al., Abst 485-P].

Vascular disease in diabetes

Controlling blood pressure is crucial for preventing cardiovascular morbidity and mortality and diabetes, and antihypertensive drugs are required in many patients. Overall attainment of glycemic, blood pressure and lipid targets was feasible with aggressive treatment in a large proportion of patients using combination therapies [Mulcahy, M.P. et al., Abst 531-P]. However, negative effects on fat redistribution, intrahepatic lipid accumulation and insulin resistance resulted from hydrochlorothiazide therapy, which were not noted after treatment with candesartan or placebo in a crossover study including 26 nondiabetic, obese subjects [Eriksson, J.W. et al., Abst 336-OR]. Olmesartan also showed benefits, with activity suppressing oxidative stress and inflammation in subjects with coronary artery disease or risk for atherosclerosis [Dandona, P. et al., Abst 607-P]. The direct renin inhibitor aliskiren provided effective blood pressure control with an excellent safety and tolerability in diabetic individuals, according to a meta-analysis including 8,076 patients [Taylor, A.A. et al., Abst 483-P]. Benefits on endothelial function and oxidative stress  were obtained with carvedilol, but not metoprolol therapy in further studies in patients with type 2 diabetes [Kelly, A.S. et al., Abst 659-P].

In the experimental arena, prevention of hypertension, type 2 diabetes, obesity and vascular oxidative stress was reported with α-lipoid acid in diabetes-prone animals [El Midaoui, A. et al., Abst 732-P], while magnesium lithospermate B was shown to prevent diabetic vascular complications through antioxidant and aldose reductase-inhibiting activity [Hur, K.Y. et al., Abst 734-P]. Exposure to (-)-epigallocatechin gallate resulted in depressed expression of endothelin-1 in vascular endothelial cells [Reiter, C. et al., Abst 52-OR].

Other diabetic complications

A trial in 33 patients suggested the feasibility of intensive treatment with subcutaneous insulin aspart in the management of diabetic ketoacidosis [Gupta, R.A. & Baldwin, D., Abst 528-P], while results in two subjects with diabetic gastroparesis suggested acceleration of gastric emptying with the ghrelin receptor agonist TZP-101 [Madsen, J.L. et al., Abst 599-P]. In vitro data in cultured lens epithelial cells suggested a role in preventing diabetic cataract for the Pueraria lobata extract PO41-14-42-K1 [Kim, Y.S: et al., Abst 580-P].

MISCELLANEOUS

The anti-tumor necrosis factor-α drug etanercept improved insulin resistance in patients with rheumatoid arthritis, and attenuated the risk for atherosclerosis; infliximab had a similar, but transient, effect [Sayo, Y. et al., Abst 614-P]. The recombinant human interleukin-1 receptor antagonist anakinra prevented high fat diet-induced diabetes in experimental animals [Sauter, N.S. et al., Abst 101-OR].

Fluoxetine was reported to improve autonomic counterregulatory responses to hypoglycemia in subjects with type 1 diabetes [Briscoe, V.J. et al., Abst 165-OR].

The cannabinoid CB₁ and vanilloid VR₁ receptor agonist anandamide depressed apolipoprotein A1 gene expression in in vitro assays [Ligaray, K. et al., Abst 214-OR].

According to a meta-analysis, perioperative insulin infusion reduced mortality but increased hypoglycemia in patients undergoing surgical procedures [Gandhi, G.Y. et al., Abst 539-P]. Intravenous insulin infusion is also commonly used to maintain euglycemia in the intensive care unit, and a nurse titration protocol was reported feasible, safe and effective [Garnica, P. et al., Abst 579-P].

Rosiglitazone was suggested as superior in improving endothelial function and endocrine function in patients with polycystic ovary syndrome compared to metformin, but had no effect on ovarian volume [Jude, E. et al., Abst 584-P].

Pharmacological stress with prednisone during three days increased insulin requirements in type 1 diabetic individuals [Bevier, W.C. et al., Abst 615-P].

Quetiapine and olanzapine, but not risperidone, increased total and LDL-cholesterol and triglyceride levels an the cholesterol:HDL and triglyceride:HDL ratios in patients treated for schizophrenia [Ratner, R.E. et al., Abst 620-P].

A favorable impact of raloxifene on glycemic and lipid control was reported in 37 postmenopausal women with osteoporosis and type 2 diabetes [Nakatani, Y. et al., Abst 895-P].

Acadesine inhibited palmitate-induced osteoblast apoptosis through upregulation of ERK [Park, S.Y. et al., Abst 904-P].

Regarding the treatment of hypoglycemia in children with type 1 diabetes, saccharose was as effective but less expensive than glucose tablets, both being superior to fructose [Husband, A. et al., Abst 1882-P].

Report prepared by: X. Rabasseda, Prous Science Medical Information Department