Therapies for and prevention of diabetes: A report from the American Diabetes Association 68^th Scientific Sessions

INTRODUCTION

By X. Rabasseda

Preventing diabetes is as important as treating it, and a possible way of doing so would be attending the annual ADA scientific sessions, not just because of the wealth of new information reported every year, but also because of the physical exertion entailed in trying to sample all the posters, broken up by sprints to oral sessions in between. As every year, nearly 2000 oral and poster presentations were selected for his year’s meeting in San Francisco, a classic location where the struggle to walk up and down Market Street against the wind also provides an opportunity for physical exercise. Does it matter? The benefits of walking, and in general of lifestyle interventions against sedentarism, obesity, smoking, adverse dietary habits, etc., are well recognized, and the novelties all attendees could gain first-hand from the researchers were worth all the effort. And among other news, worldwide studies discussed during the meeting confirmed the long-term benefits of lifestyle intervention in the prevention of diabetes and its complications.

However, and despite results from the FIELD study demonstrating that glycemic control can be maintained in most patients with type 2 diabetes using standard diabetes therapy with metformin, sulfonylureas and insulin [Best, J. et al., Abst 397-OR], the negative aspect of the issue is that more and more voices are speaking out about the lack of control of glycemia even in patients who are diagnosed with diabetes, and information piles up on the suboptimal control, suboptimal treatment and suboptimal monitorization of diabetic patients, while control, treatment and monitorization of prediabetes is even worse. As an example, up to 91% of patients from a survey of 53,774 people newly diagnosed from type 2 diabetes did not fill any prescription for oral antidiabetic drugs during the first year, and only about half of them had a test for hemoglobin A_1c performed, with adequate glucose control in only 61% of patients tested [Chapman, R.H. et al., Abst 341-OR].

Given that situation, and with the new data from the CARMELA study confirming the relationship between glycemic control, intim media thickness and cardiovascular disease [Escobedo, J. et al., Abst 623-P], spreading the news on diabetes prevention and treatment gains importance, and this is the main objective of the following report: to briefly summarize major news regarding these two issues as reported during this year’s ADA meeting. However, despite the benefits of intensive glucose-lowering intervention on the risk of serious complications in the ADVANCE trial, a note should be included on the negative results of the ACCORD trial, in which intensive glycemic control was associated with more effective reduction of hemoglobin A_1c levels compared to standard therapy, but also with an increased risk for severe hypoglycemia and higher hazard risk for all-cause mortality that forced discontinuation of the trial and recommended against such approach in the treatment of diabetes. Furthermore, intense blood glucose control yielded no significant effect on cardiovascular outcomes in an additional Veterans Administration Diabetes trial, although in this particular study common morbidities may have hindered the benefits of antidiabetic medication.

INSULIN THERAPY

Subcutaneous human insulin

Although early introduction of insulin may not be cost-effective compared to other recommended treatment options for type 2 diabetes [Willis, M. et al., Abst 342-OR], many patients with type 2 diabetes become insulin-dependent, and continuous subcutaneous insulin infusion in such patients was related to improvements in β-cell function and insulin sensitivity [Yang, Z. et al., Abst 349-OR]. Furthermore, continuous subcutaneous insulin infusion was concluded to be cost-effective compared to multiple daily injections in adolescents and adults with type 1 diabetes [St Charles, M.E. et al., Abst 1182-P]. While basal-only insulin may not offer adequate glycemic control in type 2 diabetes patients [Wolfe, G.S. et al., Abst 202-OR], basal/bolus subcutaneous insulin therapy was suggested to be advantageous regarding glycemic control and risk of hypoglycemia in the treatment of type 2 diabetes patients requiring insulin [Strange, P. et al., Abst 197-OR]. However, although basal bolus insulin has been reported beneficial also in the management of diabetic ketoacidosis [Smiley, D. et al., Abst 547-P], initiation of insulin therapy has been related to weight gain, mainly in younger, less overweight subjects [Nieznaj, M. et al., Abst 462-P].

Continuous insulin infusion

Continuous subcutaneous insulin infusion may offer a feasible approach for improving and maintaining metabolic control while also improving the quality of life of patients with unstable diabetes or poor metabolic control [Franciosi, M. et al., Abst 419-P; Alemzadeh, R. et al., Abst 1796-P; Szypowska, A. et al., Abst 1800-P]. Insulin is also used in the intensive-care unit to maintain glycemia, and computer-guided infusion protocols have been developed to improve glycemic control while reducing the risk of hypoglycemia [Newton, C.A. et al., Abst 76-OR]. Continuous insulin infusion protocols have also been developed for safe glycemic control outside of the intensive-care unit [Smiley, D. et al., Abst 77-OR].

Alternative insulin administration routes

Inhaled insulin can be effectively absorbed through the lungs [Angelo, R. et al., Abst 428-P], showing rapid absorption, with pharmacokinetics independent of smoking status [Baugham, R. et al., Abst 427-P]. However, some data suggested lower patient preference for inhaled compared to pen-delivered insulin [Borchert, M. et al., Abst 429-P]. In experimental animals, inhaled insulin offered prolonged enhancement of glucose disposal [Edgerton, D.S. et al., Abst 423-P].

In human patients with type 2 diabetes, intranasal insulin offered improved glycemic control compared to subcutaneous human insulin, without additional risk of hypoglycemia [Brandt, G. et al., Abst 424-P].

Oral insulin is a further effective option, with therapy reported to reach biological activity in healthy volunteers [Kidron, M. et al., Abst 425-P].

Similar reductions in glucose levels were attained comparing hepatic-directed vesicle insulin and subcutaneous insulin in experimental animals and patients with type 1 diabetes [Schwartz, S. et al., Abst 417-P; Geho, B. et al., Abst 421-P]. This particular form of insulin therapy was superior to placebo in lowering postprandial glucose excursions in patients with type 2 diabetes [Schwartz, S. et al., Abst 426-P] (Fig. 1).

Fig. 1. Incremental postprandial blood glucose area under the curve (AUC) in patients treated with oral, hepatic-directed vesicle-insulin (HDV-I) or placebo [Schwartz, S. et al., Abst 426-P].

A transdermal insulin patch was described as feasible in the treatment of type 1 diabetes [Smith, A. et al., Abst 309-OR].

Insulin analogs

A number of insulin analogs have been developed and overall have shown efficacy comparable to human insulin, while being associated with a lower risk of hypoglycemia, as confirmed by observational registries [Hutchinson, A. et al., Abst 582-P].

Compared to subcutaneous human insulin, insulin glargine offered improved glycemic control with a lower risk for hypoglycemia in patients with type 2 diabetes [Hsia, S.H., Abst 201-OR], while in type 2 diabetes insulin glargine was superior to lifestyle management [Blickle, J.F. et al., Abst 467-P] and as effective as oral antidiabetic therapy in controlling hemoglobin A_1c with greater reductions during the late-night and morning hours [Yale, J.F. et al., Abst 224-P]. Once-daily insulin glargine safely decreased insulin requirements while maintaining glycemic control without a risk for hypoglycemia in both diabetic and nondiabetic patients undergoing cardiac surgery [Garg, R. et al., Abst 71-OR; Dukatz, T. et al., Abst 78-OR]. Furthermore, insulin glargine attenuated intimal hyperplasia after balloon catheter injury in obese, nondiabetic experimental animals [Amanyam, S. et al., Abst 299-OR].

Although with reduced potency and necessary dose adjustments [Johnson, C.K. & Shimshi, M., Abst 8-LB], insulin detemir arose as a cost-effective option for the treatment of type 1 and 2 diabetes from Canadian and Australian perspectives [Kapor, J. et al., Abst 340-OR; Fulcher, G.R. & Agren, M.A., Abst 1188-P], with a glycemic profile almost identical to that of insulin glargine in a randomized comparative trial in 35 patients with type 2 diabetes [King, A.B. & Armstrong, D.U., Abst 436-P]. Further analysis confirmed the similar pharmacy costs of insulin detemir and insulin glargine at equivalent but not target hemoglobin A_1c control, but total diabetes-related and overall adjusted medical costs were lower with insulin detemir [Borah, B. et al., Abst 42-LB]. Furthermore, a regimen of basal/bolus insulin detemir plus mealtime insulin aspart offered similar glycemic control with lower risk for hypoglycemia compared to standard insulin regimens [Hor, T.K. et al., Abst 458-P] and combined use insulin detemir/insulin aspart markedly improved the atherogenic lipid profile in type 2 diabetes patients [Kumar, P. et al., Abst 881-P]. However, mixing insulin aspart with insulin detemir in a single injection resulted in negative pharmacodynamic interactions with loss of effectiveness [Swan, K.L. et al., Abst 1812-P]. On the other hand, insulin detemir increased body weight and fat mass less than regular human insulin or insulin glargine in experimental animals [Fledelius, C. et al., Abst 497-P], but whereas subcutaneous human insulin increased visceral fat mass, insulin detemir reduced visceral fat mass in patients with type 2 diabetes [Tinahones, F.J. et al., Abst 562]. In fact, mechanistic data suggested that insulin detemir has lower adipogenic and adipocyte survival-promoting activity than human insulin [Staiger, H. et al., Abst 1379-P].

With a lower risk of hypoglycemia compared to biphasic human insulin [Davidson, J. et al., Abst 575-P], biphasic insulin aspart offered a feasible switch approach to patients not adequately controlled on basal insulin analog therapy alone or combined with oral antidiabetic drugs [Hwa, C. et al., Abst 544-P], but changing from regular insulin to insulin aspart correction-dose sliding scales for inpatient use did not improve overall glycemic control in a single-center experience [Schmeltz, L., Abst 545-P].

Insulin glulisine brought about postprandial plasma glucose levels similar to those noted after insulin lispro following a standard meal in obese patients with type 2 diabetes [Wernsing, M. et al., Abst 200-OR], and also in young people with type 1 diabetes [Philotheou, A. et al., Abst 1791-P] (Fig. 2); prandial premixed insulin lispro mix was also as effective as basal/bolus  insulin glargine/insulin lispro therapy in 136 African American and Hispanic patients [Colon, G. et al., Abst 480]. On the other hand, coadministration of insulin lispro with recombinant human hyaluronidase resulted in faster, more complete absorption and enhanced metabolic effects of the insulin analog [Yocum, R.C. et al., Abst 2-LB].

Fig. 2. Change in hemoglobin A1c after 26 weeks of treatment with insulin glulisine or insulin lispro [Philotheou, A. et al., Abst 1791-P].

Improvements in glycemic control with good tolerability were reported from a large observational study of 3,295 elderly patients with type 2 diabetes using biphasic insulin aspart [Jang, H.C. et al., Abst 452-P].

Novel research into insulin therapies resulted in an insulin/albumin fusion protein that in experimental animals showed activity and offered long-acting insulin delivery [Williams, P. et al., Abst 468-P].

BIGUANIDES

With glycemic benefits when combined with exercise [Sharoff, C.G. et al., Abst 26-LB], besides lowering glucose levels and carbohydrate oxidation, treatment with metformin brought about improvements in fat oxidation and body mass index in prediabetic, obese subjects [Schaefer, E. et al., Abst 97-OR; Clarson, C.L. et al., Abst 392-OR], and in fact based on the ADA consensus statement, the vast majority of people with impaired fasting glucose and impaired glucose tolerance are candidates for diabetes prevention with metformin, which may amount to one in every 12 American adults [Rhee, M.K. et al., Abst 336-OR]. Further studies with the biguanide also demonstrated an effect in attenuating oxidative stress and increasing the number of circulating endothelial progenitor cells in patients with type 2 diabetes [Chen, L.L. et al., Abst 514-P], effects that were mechanistically related to induction of thioredoxin system via the AMP-activated protein kinase/fork head transcription factor-3 pathway [Li, X. et al., Abst 693]. In the experimental arena, metformin was noted to inhibit hepatic lactate gluconeogenesis in diabetes [Baverel, G. et al., Abst 38-OR] and the expression of hypoxia-inducible factor-1α and plasminogen activator inhibitor-1 in proximal tubular epithelial cells [Takiyama, Y. et al., Abst 739-P]. Mechanistic observations suggested an AMP-dependent protein kinase-independent effect in increased glu-4 translocation in obese, diabetic muscle [Son, L.S. et al., Abst 1275-P] but a mixed AMP-dependent protein kinase-dependent and -independent effect towards inhibited hepatic gluconeogenesis [Foretz, M. et al., Abst 1507-P].

SULFONYLUREAS

Cyclic AMP sensor Epac was identified as a regulator of tolbutamine sensitivity of ATP-dependent potassium channels [Leech, C.A. et al., Abst 179-OR].
A nonsulfonylurea that acts also on potassium channels as an insulin sensitizer, nateglinide showed insulin-dependent and -independent benefits on postprandial hyperlipidemia [Kitahara, Y. et al., Abst 880-P] and offered benefits on liver fat content, an effect shared by pioglitazone but not voglibose, without modifying adiponectin levels (as opposed to pioglitazone) in patients with type 2 diabetes or impaired glucose tolerance [Tsuchiya, M., Abst 516-P].

Α-GLUCOSIDASE INHIBITORS

Add-on acarbose was reported as successful in improving glycemic control in 102 patients on insulin and oral antidiabetic therapy, without significant adverse events [Ahammed, S. et al., Abst 438-P]. Furthermore, acarbose showed efficacy in improving prediabetic-like glucose excursions in prediabetic, obese adolescents. In mechanistic studies in early type 2 diabetes, acarbose improved postprandial glucose and downregulated abnormal oxidative stress and platelet activation, suggesting cardioprotective potential [Santilli, F. et al., Abst 395-OR]; an effect was also reported in increasing pancreatic islet blood flow in obese, glucose-intolerant animals [Iwase, M. & Iida, M., Abst 1467-P].

A further α-glucosidase inhibitor, miglitol induced prolonged, enhanced glucagon-like peptide-1 and reduced gastric inhibitory polypeptide responses in response to a meal in nine type 2 diabetes patients [Narita, T. et al., Abst 447-P].

THIAZOLIDINEDIONES

With novel data reaffirming its positive effects on insulin sensitivity, insulin secretory demand and progression of atherosclerosis [Han, S.J. et al., Abst 435-P], improvements in weight gain and fat distribution in patients also receiving insulin [Shah, P. et al., Abst 476-P] and a comparative assessment in a population of 6,372 patients with type 2 diabetes suggesting better glycemic control with pioglitazone or metformin compared to sulfonylureas [Wu, E. et al., Abst 457-P], further data from the PROactive study underlined the cardiovascular protective activity of pioglitazone against ischemic events in patients with type 2 diabetes regardless of baseline cardiovascular risk [Perez, A. et al., Abst 523-P; Kupfer, S. et al., Abst 535-P] and confirmed the benefits of pioglitazone in patients treated with nitrates, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers or insulin, without increasing the risk of all-cause death, myocardial infarction or stroke [Spanheimer, R. et al., Abst 296-OR], an extent that was further confirmed by the lower incidence of all-cause death in patients treated with thiazolidinediones in an observational study in 1,895 patients [Bilik, D. et al., Abst 300-OR]. Furthermore, observations in 71 patients with type 2 diabetes but no cardiac ischemia from a comparative study revealed beneficial effects of pioglitazone on cardiac metabolism and insulin sensitivity, that were only partly observed with metformin (improvements in insulin sensitivity but reduced myocardial glucose uptake and fatty acid oxidation and no improvements in diastolic function) [Rujzewijk, L.J. et al., Abst 394-OR]. Furthermore, pioglitazone was effectively used with hypocaloric diets for controlling weight, resulting in decreases in visceral fat [Kritchevsky, S.B. et al., Abst 1736-P]. Pioglitazone was suggested to upregulate adiponectin translation in adipocytes [Banga, A. et al., Abst 194-OR], and both pioglitazone and rosiglitazone improved flow-mediated vasodilatation and endothelial function in patients with metabolic syndrome [Kim, S.G. et al., Abst 548-P], with the addition of pioglitazone to atorvastatin offering synergistic antiinflammatory, endothelial function-improving and cardiovascular risk-lowering activity [Wilhelm, B. et al., Abst 654-P] (Fig. 3). Furthermore, treatment with pioglitazone brought about decreases in inflammatory cytokine expression in monocytes and lymphocytes, even in nondiabetic patients with impaired glucose tolerance [Zhang, W. et al., Abst 655-P], and in further experimental models delayed or prevented the small fiber dysfunction that leads to neuropathy [Sugimoto, K. et al., Abst 789-P] and showed synergy with exercise in improving adiponectin resistance in obesity [Piao, S.J. et al., Abst 1041-P]. Mechanistic experimental studies related the insulin-sensitizing activity of pioglitazone to upregulation of adiponectin receptor 2 in adipocytes [Kudo, A. et al., Abst 1278-P], with activity also in promoting recovery of adipose mass through an effect on lipogenic enzyme gene expression and protein activity [Takada, J. et al., Abst 1397-P]. In addition, enhanced β-cell function was demonstrated with pioglitazone in glucose-tolerant but insulin-resistant individuals [Choi, E. et al., Abst 61-LB].

Fig. 3. Percent change in highly sensitive C-reactive protein and tissue plasminogen activator levels in patients adding pioglitazone or placebo to atorvastatin therapy [Wilhelm, B. et al., Abst 645-P].

The addition of rosiglitazone to antidiabetic therapy reduced hospitalization rates and emergency room visits, and improved adherence in type 2 diabetes patients treated with metformin monotherapy [Bao, Y. et al., Abst 441-P], while addition of rosiglitazone to insulin did not result in increased body weight after adjustment for changes in hemoglobin A_1c [Henriksen, J.E. et al., Abst 456-P]. Rosiglitazone may be used associated with additional antidiabetic medications. Concomitant use of rosiglitazone and metformin increased adiponectin levels in direct correlation with HDL-cholesterol and glucose disposal rate [Kung, J.T. et al., Abst 1406-P]; a fixed drug combination of rosiglitazone and glimepiride has been developed, which offered higher adherence rates compared to dual therapy [Thayer, S. et al., Abst 1200-P]. Insulin-sensitizing responses to rosiglitazone were ethnic dependent, with greater responses in Asian Indian compared to Chinese patients [Tint, M.T. et al., Abst 303-OR]. In the experimental arena, an effect of rosiglitazone on signaling pathways in the pancreatic β-cell was related to protection against injury by free fatty acids [Landy, C. et al., Abst 1683-P]. However, rosiglitazone has been related to an increased risk for cardiovascular events, which could depend on increased atherogenic index of plasma in patients with the ATP-binding cassette transporter rs4149263 single nucleotide polymorphism [Park, S.E. et al., Abst 487-P]. On the other hand, troglitazone’s toxicity on mitochondrial DNA, resulting in hepatocyte apoptosis, is not shared by rosiglitazone [Rachek, L. & Wilson, G., Abst 558-P], whilst the most significant toxicity of rosiglitazone, volume expansion, was related to direct effects on the endothelium [Akiyama, T.E. et al., Abst 589-P], and in fact rosiglitazone was confirmed to increase the cardiovascular risk in an observational registry of 11,283 patients, the effect being more prominent in subjects with prior cardiovascular disease [Wang, C.P. et al., Abst 604-P].

A novel thiazolidinedione, rivoglitazone proved well tolerated and offered glycemic benefits comparable to or larger than those of pioglitazone in groups of 404 and 426 patients with type 2 diabetes [Chou, H.S. et al., Abst 304-OR; Truitt, K. et al., Abst 437-P] (Fig. 4).

Fig. 4. Change in hemoglobin A1c after treatment with rivoglitazone, pioglitazone or placebo [Chou, H.S. et al., Abst 304-OR].

A novel selective peroxisome proliferator-activated receptor-γ modulator, INT-131 was also described, which was reported to improve fasting glucose levels compared to placebo with a favorable tolerability profile [Dunn, F. et al., Abst 499-P] (Fig. 5). Although a nonthiazolidinedione, the peroxisome proliferator-activated receptor-&alpaha; and -γ agonist muraglitazar significantly improved glycemia, insulin sensitivity, β-cell function and hepatic and visceral fat deposits in 27 patients with type 2 diabetes [Gastaldelli, A. et al., Abst 348-OR; Tantiwong, P. et al., Abst 567-P]. In the experimental setting, the agent increased the expression of genes that participate in muscle mitochondrial function and fat oxidation [Coletta, D.K. et al., Abst 1310-P]. A related compound, P-1736-05 was markedly more effective than rosiglitazone in improving insulin sensitivity with a remarkable safety profile in experimental animals [Marita, A.R., Abst 196-OR].

Fig. 5. Change in fasting plasma glucose levels after 4 weeks of treatment with INT-131 or placebo [Dunn, F. et al., Abst 499-P].

INCRETIN-BASED THERAPIES

Incretin analogs

Exenatide, the first glucagon-like peptide-1 analog to be developed, significantly improved postprandial hyperglycemia, dyslipidemia and body weight in clinical studies and real-world practice [Bunck, M.C. et al., Abst 109-OR; Brixner, D. et al., Abst 454-P; Cervera, A. et al., Abst 464-P; Yoon, N. et al., Abst 482-P; Malloy, J. et al., Abst 484-P; Brodows, R. et al., Abst 485-P; Kim, T. et al., Abst 494-P; Kendall, D.M. et al., Abst 513-P; Brodows, R. et al., Abst 531-P], with similar effects on glycemic control when given after lunch or breakfast [Oliveira, J. et al., Abst 442-P], and offered tighter glycemic control than human insulin with additional benefits on the metabolic profile in 1,015 patients [Maggs, D. et al., Abst 5-LB] (Fig. 6). However, although it sensitized insulin-mediated glucose uptake in the skeletal muscle and liver [Zheng, D. et al., Abst 191-OR] and exerted a pancreatic compensation effect against insulin resistance [Bhole, D. et al., Abst 483-P], exenatide showed no major benefits in a real-world setting, with no significant improvement in hemoglobin A_1c and loss of most weight benefits at two years in 30 patients [Soh, J. & Clement, S.C., Abst 105-OR]. However, in the clinical trial setting, a weekly regimen was well tolerated over a period of 30 weeks in 295 patients using a long-acting release formulation compared to twice-daily treatment with standard exenatide [Drucker, D.J. et al., Abst 107-OR] and cost-effectiveness data suggested superiority over insulin glargine, with reduced hypoglycemia rates, better compliance and persistency and lower hypoglycemia-related costs [Nielsen, L. et al., Abst 1198-P; Fabunmi, R. et al., Abst 1213-P] (Fig. 7). An intranasal formulation of exenatide offered potential without serious adverse or hypoglycemic events compared to placebo in 20 patients [Blasé, E. et al., Abst 195-OR]. Furthermore, evidence of an effect of exenatide in preventing carotid intima hyperplasia after balloon catheter injury was documented in experimental animal studies [Murthy, S.N. et al., Abst 486-P]. However, no improvements in β-cell function could be demonstrated with exenatide alone or combined with daclizumab in 20 type 1 diabetes patients treated for six months [Rother, K.I. et al., Abst 471-P], although in the experimental setting the compound prevented tumor necrosis factor-α-induced β-cell apoptosis [Natalicchio, A. et al., Abst 1568-P]. On the other hand, experimental data confirmed the effect of exenatide on hepatic insulin signaling [Kwon, D.Y. et al., Abst 1036-P], with an antiinflammatory and insulin-sensitizing activity comparable to those of adiponectin [Sinha, S. et al., Abst 1266-P], and the agent was demonstrated to activate antiinflammatory and antiapoptotic pathways in pancreatic islets [Cechin, S.R. et al., Abst 1678-P], prevent renal injury and hypertension in experimental models of type 2 diabetes [Kume, S. et al., Abst 705-P] and to improve survival in experimental animals with dilated cardiomyopathy as effectively as rosiglitazone [Yang, K.C. et al., Abst 14-OR]. Exenatide was also shown to increase small intestinal mass as a consequence of stimulation of glucagon-like peptide-1 receptors [Simonsen, L. et al., Abst 1438-P], and in experimental models of obesity induced anorectic weight loss [Aulinger, B.A. et al., Abst 1551-P]. Furthermore, exenatide protected against oxidative β-cell death during experimental islet grafting, improving the outcome of islet transplantation [Ahn, Y.B. et al., Abst 1964-P].

Fig. 6. Percent of patients with hemoglobin A1c levels under 6.5% after treatment with exenatide or insulin [Maggs, D. et al., Abst 5-LB].

Fig. 7. Percent of patients with medication possession ratio (days of supply over 365 days) during treatment with exenatide or insulin glargine [Fabunmi, R. et al., Abst 1213-P].

A second glucagon-like peptide-1 analog, liraglutide offered a well-tolerated, active option for improving glycemic control in patients treated with a sulfonylurea [Marre, M. et al., Abst 13-OR] (Fig. 8), with benefits on postprandial glucose levels [Flint, A. et al., Abst 556-P], and was as effective as glimepiride but superior to insulin glargine in controlling glycemia whilst reducing body weight in patients treated with metformin [Nauck, M.A. et al., Abst 504-P; Russell-Jones, D. et al., Abst 536-P] (Fig. 9); superiority of liraglutide over glimepiride regarding glycemic control and weight reduction was noted in one additional trial in 746 type 2 diabetes patients [Garber, A. et al., Abst 7-LB] (Fig. 10). The agent offered natural slow subcutaneous absorption and long-lasting activity [Steensgaard, D.B. et al., Abst 552-P]. Liraglutide reduced fat content, visceral and subcutaneous adiposity and hepatic steatosis compared to placebo in 160 patients treated with metformin for type 2 diabetes [Jendle, J. et al., Abst 106-OR] (Fig. 11), and brought about reductions in hunger and energy intake [Flint, A. et al., Abst 555-P]. Liraglutide was also shown to reduce systolic blood pressure and cardiovascular risk in patients with type 2 diabetes [Colagiuri, S. et al., Abst 554-P], and from a mechanistic point of view was noted to increase β-cell function in patients with type 2 diabetes [Matthews, D. et al., Abst 505-P] and β-cell mass in experimental animals through a direct effect on cell kinetics but also by suppressing oxidative stress and interleukin-1β-induced β-cell apoptosis [Shimoda, M. et al., Abst 9-OR; Prazak, R. et al., Abst 1573-P], while additionally protecting cardiomyocytes from ischemia and improving survival and cardiac function after myocardial infarction [Noyan-Ashraf, H. et al., Abst 190-OR]. Furthermore, liraglutide brought about benefits on glucose-mediated induction of plasminogen activator inhibitor-1 expression [Simpson, R.W. et al., Abst 503-P], and improved engraftment and function of transplanted islets in experimental animal models [Merani, S. et al., Abst 1956-P]. However, because of its effect on gastric emptying, liraglutide modified the absorption kinetics of concomitantly administered drugs, although the effect was considered minor and devoid of clinical significance [Malm-Erjefält, M. et al., Abst 434-P].

Novel incretin analogs are being developed, such as the glucagon-like peptide-1 analogs albiglutide, a safe and well tolerated, long-acting agent shown to improve fasting and postprandial glucose in type 2 diabetes patients [Stewart, M.W. et al., Abst 519-P; Stewart, M.W. et al., Abst 522-P]; R-1583, which proved safe, well tolerated and active in phase II studies compared to placebo [Ratner, R. et al., Abst 10-OR; Balena, R. et al., Abst 108-OR] (Figs. 12 and 13) and showed prolonged activity, safety and good tolerability when administered every two weeks [Kapitza, C. et al., Abst 506-P]; the intranasally delivered analog MKC-253, which induced insulin secretion and reduced fasting glucose levels in healthy volunteers [Costello, D. et al., Abst 198-OR]; AVE-0010, a similar compound that dose-dependently improved glycemic control compared to placebo in 542 patients with type 2 diabetes inadequately controlled on metformin [Ratner, R.E. et al., Abst 433-P] (Fig. 14), with potential for once- and twice-daily dosing [Distiller, L. & Ruus, P.E., Abst 520-P] and improved glucose-stimulated insulin responses in in vitro studies [Werner, U. et al., Abst 11-OR]; and CNTO-736, which improved islet engraftment, function and β-cell proliferation in models of islet transplantation [Pileggi, A. et al., Abst 1586-P]. Furthermore, insights from experimental studies demonstrated that glycosylated glucagon-like peptide-1 may act as a dipeptidyl peptidase-IV-resistant incretin, which may be the basis for developing new incretin analogs [Asakura, K. et al., Abst 12-OR], and experimental data suggested antidiabetic benefits for consumption of a glucagon-like peptide-1-expressing rice [Jomori, T. et al., Abst 1456-P].

Fig. 12. Change in hemoglobin A1c levels at 8 weeks in patients receiving R-1583 5, 10 or 20 mg once weekly or 10 mg twice weekly, or placebo [Balena, R. et al., Abst 108-OR].

Fig. 13. Change in fasting plasma glucose levels in patients receiving maintenance therapy with R-1583 20, 30 or 40 mg once weekly for four weeks after four initial weekly doses of 20 mg, or placebo [Ratner, R. et al., Abst 10-OR].

Fig. 14. Percent of patients with hemoglobin A1c levels <7% after 13 weeks of treatment with AVE-0010 or placebo [Ratner, R.E. et al., Abst 433-P].

Dipeptidylpeptidase-IV inhibitors

By inhibiting degradation of endogenous incretins, dipeptidylpeptidase-IV inhibitors act as incretin enhancers with potential for β-cell preservation in type 2 diabetes, which has important long-term economic value because of prevention of complications [Tunis, S.L. et al., Abst 1211-P]. New results were reported with sitagliptin, which offered early responses on hemoglobin A_1c and fasting plasma glucose in patients with type 2 diabetes [Kanazu, S. et al., Abst 466-P; Williams, D. et al., Abst 495-P; Katzef, H.L. et al., Abst 496-P] (Fig. 15), and enhanced insulin responses to meals [Stafford, S. & Meneilly, G., Abst 550-P]. Initial combination therapy with sitagliptin and metformin also brought about significant improvements in β-cell function [Williams-Herman, D.A. et al., Abst 543-P] (Fig. 16). A meta-analytical approach suggested similar efficacy of sitagliptin, pioglitazone and rosiglitazone in lowering hemoglobin A_1c levels [Chapell, R. et al., Abst 512-P].

Fig. 15. Change in hemoglobin A1c levels after 18-24 weeks of treatment with sitagliptin or placebo depending on age and body mass index [Williams, D. et al., Abst 495-P].

Fig. 16. Dynamic disposition index as an index of β-cell function in patients receiving metformin and/or sitagliptin [Williams-Herman, D.A. et al., Abst 543-P].

Vildagliptin was also the subject of new studies discussed during the meeting this year in San Francisco, with confirmed benefits on postprandial glucose excursions in type 2 diabetes patients [Woerle, H.J. et al., Abst 511-P] and an effect reported in enhancing a-cell sensitivity to hyper- and hypoglycemia [Ahrén, B. et al., Abst 560-P]. Furthermore, vildagliptin was more effective and better tolerated than voglibose in the treatment of 380 patients with type 2 diabetes [Iwamoto, Y. et al., Abst 561-P] (Fig. 17), and showed synergistic activity with exenatide in experimental animals [Aulinger, B.A. et al., Abst 1545-P]. In mechanistic experimental studies, the effect of vildagliptin on increasing glucagon-like peptide-1 levels was more pronounced in portal than peripheral blood [Hjøllund, K.R. et al., Abst 1464-P]. An additional related report described partial restoration of pancreatic insulin content and correction of hyperglycemia in animals with recent-onset diabetes by cotreatment with vildagliptin and pantoprazole [Suarez-Pinzon, W.L. et al., Abst 1587-P].

Fig. 17. Change in the HOMA-B insulin sensitivity index after 12 weeks of treatment with vildagliptin or voglibose [Iwamoto, Y. et al., Abst 561-P].

Results were also presented on saxagliptin, which given as monotherapy improved glycemic control in therapy-naïve type 2 diabetes patients without inducing weight gain [Rosenstock, J. et al., Abst 517-P]. On the other hand, pharmacokinetic data revealed a gender-independent profile [Boulton, D.W. et al., Abst 551-P] and no need for adjusting doses of saxagliptin in patients with hepatic impairment [Patel, C. et al., Abst 537-P].

With pharmacokinetic/pharmacodynamic potential for once-daily dosing [Hirayama, M. et al., Abst 521-P] without need for adjustments based on renal function up to moderate failure [Karim, A. et al., Abst 538-P], add-on alogliptin further reduced hemoglobin A_1c compared to placebo without inducing weight gain or causing hypoglycemia in 390 patients with type 2 diabetes treated with insulin [Rosenstock, J. et al., Abst 444-P] (Fig. 18), 527 patients with type 2 diabetes treated with metformin [Nauck, M. et al., Abst 477-P], 500 patients with type 2 diabetes treated with glibenclamide [Pratley, R. et al., Abst 445-P] and 493 similar patients treated with pioglitazone [Pratley, R. et al., Abst 478-P]. Alogliptin monotherapy was also useful compared to placebo in controlling HbA_1c and fasting plasma glucose in 329 patients [Defronzo, R. et al., Abst 446-P].

Fig. 18. Change in hemoglobin A1c levels after 26 weeks of treatment with alogliptin or placebo [Rosenstock, J. et al., Abst 444-P].

Novel dipeptidylpeptidase-IV inhibitors currently under development also include ARI-2243, which in experimental animal models was also noted to act through dipeptidylpeptidase-IV-independent mechanisms, thus offering benefits exceeding those of other DPP-IV inhibitors, with a wide therapeutic index [Sanford, D.G. et al., Abst 448-P]; BI-1356, which was safe and pharmacodynamically active in healthy volunteers [Sesoko, S. et al., Abst 534-P] and patients with type 2 diabetes [Kanada, S. et al., Abst 533-P], was safe and devoid of pharmacokinetic interactions when combined with metformin [Graefe-Mody, U. et al., Abst 553-P] and effectively increased glucagon-like peptide-1 levels and improved glycemic control in experimental diabetic animal models [Thomas, L. & Mark, M., Abst 451-P]; SK-0403, which synergistically increased glucagon-like peptide-1 levels and improved glycemic control when combined with miglitol in models of type 2 diabetes and obesity [Goto, M. et al., Abst 470-P]; and LC15-0444, which significantly enhanced active glucagon-like peptide-1 and decreased glucagon and glucose excursions after an oral load [Hwang, D.M. et al., Abst 502-P].

AMYLIN ANALOGS

Add-on pramlintide was safe and improved postprandial glucose excursions and hemoglobin A_1c levels compared to placebo in adolescents with type 1 diabetes [Chase, P. et al., Abst 1802-P; Burdick, P. et al., Abst 1803-P] (Fig. 19), with accompanying benefits on body weight in patients treated with insulin glargine [Riddle, M. et al., Abst 524-P], resulting in reduced mealtime insulin requirements [King, A.B. et al., Abst 549-P]. The feasibility of subcutaneous pramlintide infusion in patients with type 1 diabetes was confirmed in a series of 11 patients, with mild postprandial hypoglycemia in most patients but no severe hypoglycemia episodes [Huffman, D.M. & McLean, G.W., Abst 199-OR]. On the other hand, a combination of pramlintide and metreleptin for obesity showed potential in 139 obese individuals [Weyer, C. et al., Abst 1738-P]. A novel amylin mimetic, AC-2307 showed potential in obese subjects by reducing 24-hour food intake compared to placebo [Nicandro, J.P.A. et al., Abst 1543-P] (Fig. 20).

Fig. 19. Plasma glucose incremental AUC0à3 after breakfast in patients treated with pramlintide or placebo [Chase, P. et al., Abst 1802-P].

Fig. 20. Change in food intake in two studies with AC-2307 [Nicandro, J.P.A. et al., Abst 1543-P].

Because of the benefits of incretins and amylin and the possibility of synergic activity of both, AC-164290, a hybrid peptide covalently linking a glucagon-like peptide-1 receptor agonist and an amylin mimetic, was developed. AC-164290 showed dual pharmacologic activity as an antidiabetic and antiobesity agent in experimental animal models [Mack, C. et al., Abst 1433-P].

SODIUM-GLUCOSE COTRANSPORTER-2 INHIBITORS

Dapagliflozin proved effective in improving glycemic control and body weight in patients with type 2 diabetes. With urinary tract infection, nausea, dizziness, headache, fatigue, back pain and nasopharyngitis as most common adverse events, dapagliflozin did not increase the risk of hypoglycemia compared to placebo [List, J.F. et al., Abst 329-OR; List, J.F. et al., Abst 461-P] (Fig. 21). Favorable results in the experimental setting were also reported with remogliflozin [Harrington, W.W. et al., Abst 529-P] and the antisense inhibitor ISIS-388626 [Wancewicz, E.V. et al., Abst 334-OR].

Fig. 21. Change in hemoglobin A1c levels after 12 weeks of treatment with dapagliflozin, metformin or placebo [List, J.F. et al., Abst 329-OR].

GLUCOKINASE ACTIVATORS

Potential in the treatment of diabetes from initial human trials and experimental studies were reported during this year’s meeting with the glucokinase activators piragliatin [Bonadonna, R.C. et al., Abst 332-OR] and TTP-355 [Bödvarsdóttir, T.B. et al., Abst 328-OR]. Preclinical research resulted in the discovery of a further glucokinase inhibitor, ARRY-588, that also showed promise for the treatment of type 2 diabetes [Aicher, T. et al., Abst 465-P]. An additional, undisclosed glucokinase activator was shown to increase β-cell mass in vitro but not in vivo [Nakamura, A. et al., Abst 493-P].

ADDITIONAL PUTATIVE THERAPIES

Advancements in clinical research resulted in clinical trials suggesting potential for novel antidiabetic therapies, including the 11b-hydroxysteroid dehydrogenase-1 inhibitor INCB-13739, which improved insulin sensitivity and also lowered total and LDL-cholesterol levels [Hawkins, M. et al., Abst 344-OR]; methylisocitrate, which enhanced glucose-stimulated insulin secretion from pancreatic islets [Liu, L. et al., Abst 1669-P]; an unnamed TGR5 agonist, which improved insulin resistance and reduced hyperglycemia in experimental models of diet-induced diabetes and obesity [Guha, M. et al., Abst 439-P]; the novel epoetin receptor agonist CNTO-530, which improved glucose tolerance and insulin sensitivity in experimental animals offering potential for the treatment of concomitant diabetes and anemia [Scully, M.S. et al., Abst 306-OR]; the anti-CD3 monoclonal antibody otelixizumab, which induced expansion of CD4-/FoxP3-positive cells suggesting potential for type 1 diabetes therapy [Forman, D. et al., Abst 518-P]; ginsenosides Rb1 and Rb2, which prevented diabetes through suppression of lipogenesis and enhancement of β-cell function and survival [Kwon, D.Y. et al., Abst 1685-P]; a fixed combination of phentermine and topiramate, which lowered hemoglobin A_1c and body weight compared to placebo [Garvey, W.T. et al., Abst 390-OR]; chromium picolinate supplementation, which improved insulin sensitivity and reduced fasting glucose levels [Qin, J. et al., Abst 1689] and combined with niacinate prevented vascular inflammation [Jain, S.K. et al., Abst 1690-P]; an ethanolic extract of Artemisia dracunculus, which in obese subjects improved carbohydrate metabolism and enhanced insulin activity through suppression of protepin phosphatase-1B [Coulter, A.A. et al., Abst 469-P]; and a Gynostemma pentaphyllum tea, which improved glycemia and insulin sensitivity in patients with type 2 diabetes [Huyen, V.T. et al., Abst 508-P]. Additionally, improvements in function and survival of cultured β-cells were reported by treatment with the amyloid-binding dye Congo red [Marzban, L. et al., Abst 1576-P], and “reversal” of type 1 diabetes in animals was observed with cotreatment with lisofylline and islet neogenesis-associated protein [Tersey, S.A. et al., Abst 1620-P].

Experimental studies confirmed the benefits of compounds currently in clinical research, including trodusquemine [Ruiz-White, I. et al., Abst 1325-P] and the fructose-1,6-bisphosphatase inhibitor MB-07803 [Van Poelje, P.D. et al., Abst 350-OR]. Currently under preclinical research, experimental results also suggested feasibility as novel therapies for diabetes for PSN-821, a compound targeting the GPR119 G-protein-coupled receptor in the pancreas and gut [Fyfe, M. et al., Abst 297-OR]; rottlerin, a protein kinase-Cδ inhibitor [Motoshima, H. et al., Abst 351-OR]; SRT-100, a SIRT1 activator [Perni, R.B. et al., Abst 540-P]; and a small-molecule GPR40 agonist named compound A [Zhou, Y.P. et al., Abst 541-P]. Additional experimental findings revealed potential for apocynin, a NADPH oxidase inhibitor, in preventing lipid infusion-induced hepatic and peripheral insulin resistance [Pereira, S. et al., Abst 1554-P], and epigallocatechin gallate in preventing the onset of type 1 diabetes in nonobese animals [Fu, Z. et al., Abst 1565-P].

Studies in experimental animals also suggested potential for gene therapy with an adeno-associated virus 1/cytomegalovirus engineered to express insulin and glucokinase [Mann, C.J. et al., Abst 420-P], while in vitro studies demonstrated the potent antidiabetic-like activity of cucurbitane triterpenoids from bitter melon [Ye, J. et al., Abst 1311-P]. Antibodies that antagonize glucagon receptor blockers have been developed, and proved to induce glucose lowering, which offers new putative targets for antidiabetic interventions [Yan, H. et al., Abst 1441-P].

Resveratrol deserves special mention, given the amount of information reported during this year’s meeting. Resveratrol was noted to suppress proinflammatory genes causing insulin resistance in healthy volunteers in a placebo-controlled trial, suggesting potential as insulin sensitizer [Dandona, P. et al., Abst 346-OR], while further studies demonstrated an effect in preventing muscle free fatty acid-induced insulin resistance through an effect on the mTOR and p70 S6K phosphorylation pathways [Sanli, T. et al., Abst 572-P]. Resveratrol also improved renal injuries and oxidative stress-induced nephropathy in experimental diabetes [Kasinath, B.S. et al., Abst 738-P; Kitada, M. et al., Abst 753-P], and mechanistic results suggested an effect in increasing LKB1-AMPK activity through increase of cytoplasmic localization mediated by K48 deacetylation and S428 phosphorylation [Ido, Y. et al., Abst 1463-P]. Furthermore, resveratrol-containing red wine in moderate quantities –like vodka, also moderately consumed– enhanced insulin sensitivity in insulin-resistant patients [Kim, S.H. & Reaven, G.M., Abst 354-OR]. In fact, moderate consumption of alcohol was noted to lower the risk for developing diabetes in the Diabetes Prevention Program [Polsky, S. et al., Abst 102-OR].

Also regarding dietary components, consumption of fructose- but not glucose-sweetened beverages was reported to induce glucose intolerance and insulin resistance, and to increase visceral adiposity in overweight/obese people [Stanhope, K.L. et al., Abst 352-OR]. On the contrary, consumption of pregerminated brown rice showed antidiabetic potential, improving hyperglycemia and preventing neuropathy of diabetes in experimental animals [Usuki, S. et al., Abst 791-P]. On the other hand, orange juice was noted to inhibit high fat/high carbohydrate meal-induced toll-like receptor hyperexpression and reduce plasma endotoxin levels [Ghanim, H. et al., Abst 698-P]; two Citrus polyphenols, naringenin and hesperetin, stimulated nitric oxide production by endothelial cells [Iantorno, M. et al., Abst 697-P].

NEWS ON ISLET TRANSPLANTATION AND CELL THERAPIES

Interest in pancreatic [Giannarelli, R. et al., Abst 379-OR] and islet [Wojtusciszyn, A. et al., Abst 380-OR; Tharavanij, T. et al., Abst 381-OR] transplantation as a treatment for diabetes remains active, and these approaches, if feasible, can have additional benefits. For example, reduced progression of retinopathy was documented after islet cell transplantation compared to intensive medical therapy in patients with proliferative retinopathy [Thompson, D.M. et al., Abst 378-OR]. Mechanistic observations related rosiglitazone to an effect in decreasing amyloid formation after transplantation of human islet amyloid polypeptide to transgenic islets, thus preventing β-cell loss following transplantation [Lakshmi, J. et al., Abst 268-OR]. Islet yield and viability in other experimental studies were enhanced by a fusion protein based on N-terminal mitochondrial localization sequence, DNA glycosylase and the TAT sequence from HIV [Wilson, G. et al., Abst 269-OR] or by B7-H4 overexpression through recombinant adenovirus-based gene intervention [Wang, X. et al., Abst 270-OR]. On the other hand, discontinuation of sirolimus as immunosuppressant for islet transplantation and switch to mycophenolate mofetil/tacrolimus proved well tolerated in patients not tolerating sirolimus [Koh, A. et al., Abst 1952-P] and stabilized renal function [Senior, P.A. et al., Abst 377-OR], and sirolimus was not related to effects on intrahepatic fat content or risk of liver steatosis in islet transplant recipients [Perseghin, G. et al., Abst 1947-P]. In that respect, it is worth mentioning that sirolimus counteracted insulin resistance, which was linked to chronic inhibition of the mTOR/S6K1 pathway in experimental studies [Brulé, S. et al., Abst 50-LB].

In the experimental setting, proinsulin-secreting fibroblasts offered protection against hypertriglyceridemia, microalbuminuria and aorta intima damage in diabetic animals [Zhang, M. et al., Abst 1511-P]. On the other hand, mobilization of autologous hematopoietic stem cells was feasible by targeting the CXCR4-SDF-1 axis with the selective blocker NIBR-1816 [Fiorina, P. et al., Abst 267-OR].

HYPERTENSION IN DIABETES

Tight control of blood pressure is required to prevent cardiovascular morbidity and mortality in patients with diabetes, with additional benefits on renal function, as demonstrated with perindopril/indapamide in the ADVANCE trial [De Galan, B.E. et al., Abst 752-P]. Furthermore, losartan also demonstrated benefits on urinary albumin excretion and vascular fitness [Yagi, K. et al., Abst 762-P], whilst the direct renin inhibitor aliskiren reduced albuminuria as effectively as irbesartan, the combination offering synergistic activity [Persson, F. et al., Abst 6-LB]. Data was also reported this year in San Francisco on the cost-effectiveness of adding aliskiren to losartan in patients with hypertension and nephropathy accompanying type 2 diabetes [Delea, T.E. et al., Abst 460]. On the other hand, antihypertensive therapy may have additional benefits on the cardiovascular status in patients with type 2 diabetes, and valsartan, for example, was shown to decrease aorta wall thickness as well as arterial compliance [Khaodhiar, L. et al., Abst 473-P].

DIABETES AND CARDIOVASCULAR DISEAS

As in nondiabetic subjects, antiplatelet drugs have a role in preventing cardiovascular morbidity and mortality in diabetic individuals, and aspirin was confirmed beneficial in diabetic individuals on hemodialysis in the DOPPPS study [Hayashino, Y., et al., Abst 611-P]. Cilostazol was further suggested to protect arterial stiffness and lower pulse-wave velocity more effectively than aspirin [Kim, C. et al., Abst 609-P].

Significant reductions in the risk for myocardial infarction, stroke and cardiovascular death in patients with type 2 diabetes were obtained with bromocriptine in a quick-release formulation [Scranton, R. et al., Abst 331-OR]; in the experimental arena, the drug offered improvements in obesity, hypertension, insulin resistance and proinflammatory mediators [Ezrokhi, M. et al., Abst 593-P]. On the other hand, the antiinflammatory agent AGI-1067 improved insulin sensitivity in experimental animals [Sundell, C.L. et al., Abst 345-P], delayed progression to type 2 diabetes in 6,144 patients with acute coronary syndrome compared to placebo [Tardif, J.C. et al., Abst 335-R] and improved glycemic control in patients with established type 2 diabetes when added to background therapy, regardless of the individual treatment (metformin, sulfonylurea, thiazolidinedione, insulin or other) [Klug, E. et al., Abst 443-P], and the radical scavenger bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)decandioate reduced oxidative stress and improved glucose-stimulated insulin secretion in isolated islets [Mancarella, R. et al., Abst 1943-P]. In mechanistic experimental studies, the compound inhibited activation of JNK,1RS-1 serine phosphorylation and cytokine production by adipocytes [Chen, X. et al., Abst 1262-P].
In the experimental arena, inhibition of glycogen synthase kinase-3 with lithium attenuated high fat diet-induced atherosclerosis in experimental animal models [Jung, J.G. et al., Abst 692-P].

THERAPIES FOR DIABETIC DYSLIPIDEMIA

Significant improvements in HDL kinetics were described with rosuvastatin [Vergès, B. et al., Abst 84-OR]. Furthermore, beside improvements in lipid levels, statin therapy has been associated with additional benefits on a number of issues in patients with diabetes, including prevention of chronic kidney disease [Tong, P. et al., Abst 724-P]. Specific studies with high-dose atorvastatin confirmed the benefits in lowering the cardiovascular risk in patients with diabetes or metabolic syndrome [Deedwania, P. et al., Abst 15-LB].

Among the fibrates, fenofibrate improved lipid profiles in 45 hypertriglyceridemic individuals, while also decreasing waist circumference and free fatty acid levels and significantly lowering insulin resistance [Li, Y. et al., Abst 475-P]; fenofibrate also improved glycemic control through improvements in insulin resistance and downmodulation of retinol-binding protein-4 gene expression [Wei, L. et al., Abst 1712-P]. Furthermore, a combination of fenofibrate with rosiglitazone showed triglyceride- and non-HDL-cholesterol-lowering activity even in diabetic patients treated with statins [Dhindsa, S. et al., Abst 871-P] (Fig. 22). Although not a fibrate, the peroxisome proliferator-activated receptor-δ agonist KD-3010 also showed potential for the treatment of dyslipidemia and insulin resistance in healthy, normal and obese volunteers [Multani, P. et al., Abst 569-P], while in animals an enhancing effect was noted on glucose-stimulated insulin secretion [Ghia, M. et al., Abst 1478-P].

Fig. 22. Changes in non-HDL-cholesterol levels in patients on statin therapy receiving rosiglitazone combined with fenofibrate or placebo [Dhindsa, S. et al., Abst 871-P].

Concomitant use of the choline fenofibrate and rosuvastatin improved the lipid profiles of 1,445 patients with type 2 diabetes more comprehensibly than either drug in monotherapy [Jones, P.H. et al., Abst 85-OR] (Fig. 23). Another combination that offered improved activity against dyslipidemia was niacin/laropiprant, which was as equally effective in patients with or without metabolic syndrome [Bays, H.E. et al., Abst 86-OR] (Fig. 24).

Fig. 23. Change in lipid levels in patients treated with choline fenofibrate, rosuvastatin or the combination [Jones, P.H. et al., Abst 85-OR].

Fig. 24. Change in lipid levels in patients treated with extended-release niacin alone or combined with laropiprant, or placebo in patients with or without metabolic syndrome [Bays, H.E. et al., Abst 86-OR].

The cholesterol absorption inhibitor ezetimibe has been effective in enhancing the cholesterol-lowering effect of statins, despite low activity in itself, but in experimental models of obese insulin resistance reversed hepatic steatosis and improved hepatic insulin sensitivity [Muraoka, T. et al., Abst 564-P]. A fixed combination of ezetimibe and niacin was superior to atorvastatin monotherapy in improving atherogenic lipoprotein subfractions [Mazzone, T. et al., Abst 870-P] (Fig. 25). Furthermore, a triple combination of ezetimibe, simvastatin and niacin was confirmed effective in improving atherogenic lipid levels in dyslipidemic patients with or without diabetes and/or metabolic syndrome [Guyton, J.R. et al., Abst 869-P].

Fig. 25. Change in LDL-, IDL- and VLDL-cholesterol levels after treatment with ezetimibe/simvastatin or atorvastatin [Mazzone, T. et al., Abst 870-P].

Niacin is a further option for the treatment of selected forms of dyslipidemia, and offers additional activity in stimulating adiponectin secretion through an effect on the GPR109A receptor [Plaisance, E.P. & Judd, R.L., Abst 1395-P].

Compared to placebo, colesevelam induced significant reductions in both LDL-cholesterol and hemoglobin A_1c in patients with type 2 diabetes; hence, although mainly a lipid-modifying compound, colesevelam also improved glycemic control, and such effect was related to activity on glucose absorption [Schwartz, S. et al., Abst 440-P; Jialal, I. et al., Abst 459-P] (Fig. 26). Detailed gene expression analyses demonstrated targeted activity of colesevelam in the gut to revert transcriptional alterations associated with diabetes [Forman, B.M. et al., Abst 1098-P]. As a further option for treating lipid abnormalities in diabetes, acipimox offered benefits in subjects on a very-low-calorie diet, being able to partly reverse myocardial diastolic dysfunction associated with an increase in nonesterified fatty acids [Hammer, S. et al., Abst 588-P]. An alternative approach, ω₃ polyunsaturated fatty acid therapy induced a reduction in the cardiovascular risk of diabetic individuals independently of LDL particle and apolipoprotein A1 and B changes [Hartweg, J. et al., Abst 626-P]; in experimental animal models of prediabetes both exogenous eicosapentaenoate, fish oil and lipoic acid and endogenous hyperproduction of ω₃ polyunsaturated fatty acids offered in fact glycemic benefits [Cummings, B. et al., Abst 1414-P; Wei, D. et al., Abst 1415-P] and ω3 fatty acids offered antiapoptotic effects [Park, E.M. et al., Abst 1720-P].

Fig. 26. Change in hemoglobin A1c and LDL-cholesterol levels in placebo-controlled trials with colesevelam [Jialal, I. et al., Abst 459-P].

THERAPIES FOR OBESITY

Lifestyle management is the most immediate aid against obesity, through its effect on burning calories as well as increasing plasma adiponectin levels and reducing visceral adiposity [Cote, M. et al., Abst 1386-P]. However, pharmacotherapy is required in many patients if the aim is to control cardiovascular risk. A combination of sibutramine and pramlintide or phentermine induced marked weight loss in 244 overweight/obese patients [Aronne, L.J. et al., Abst 99-OR] (Fig. 27).

Fig. 27. Change in body weight after treatment with pramlintide alone or combined with sibutramine or phentermine, or placebo [Aronne, L.J. et al., Abst 99-OR].

Besides lowering body weight and waist circumference, rimonabant also improved fasting plasma glucose over two years in nondiabetic overweight/obese patients in the RIO-Europe study [Scheen, A.J. et al., Abst 101-OR] (Fig. 28), and detailed analysis in experimental animals demonstrated additional benefits on insulin resistance, with the corresponding compensatory changes in β-cell function [Richey, J.M. et al., Abst 570-P]. Rimonabant’s weight loss-independent effects on insulin activity were related to changes in resting substrate utilization [Stefanovski, D. et al., Abst 1430-P]. Furthermore, according to the ARPEGGIO trial, rimonabant also improved glycemic control compared to placebo in 365 patients with type 2 diabetes treated with insulin [Hollander, P.A. et al., Abst 330-OR] (Fig. 28). Some additional effects of rimonabant, such as improvements in insulin resistance, but not its weight-lowering activity, were found to be dependent on adiponectin [Migrenne, S. et al., Abst 100-OR]. New research into the endocannabinoid system as a target for the treatment of obesity resulted in MJ-15 and CP-945598, two potent, selective CB1 receptor blockers that showed potential as an obesity treatment in experimental studies [Wang, L.L. et al., Abst 515-P; Patterson, T.A. et al., Abst 1733-P].

Fig. 28. (Left) Change in fasting plasma glucose levels in patients treated with rimonabant or placebo in the RIO-Europe study [Scheen, A.J. et al., Abst 101-OR]. (Right) Change in hemoglobin A1c levels in patients treated with rimonabant or placebo in the ARPEGGIO trial [Hollander, P.A. et al., Abst 330-OR].

Search for new antiobesity options in experimental studies suggested the use of sodium butyrate, a histone deacetylase inhibitor, for treating obesity and associated insulin resistance [Jung, D.Y. et al., Abst 565-P; Rumberger, J.M. et al., Abst 1384-P]. Similarly, benefits on insulin resistance and hepatic steatosis were attributed in experimental animals to propagermanium, a chemokine CCR2 receptor blocker used in the treatment of chronic hepatitis B [Tamura, Y. et al., Abst 568-P], and benefits comparable to those of sibutramine on body weight were described with the serotonin 5-HT1A agonist PSN-602 [Babbs, A.J. et al., Abst 1744]. Antiobesity and antidiabetic activity was reported in further animal studies with the melanocortin receptor-modulating agent AP-1030 [Jonassen, T.E. et al., Abst 72-LB], and preservation of β-cell function while reducing hyperglycemia in models of diet-induced obesity were noted with the anti-interleukin-1β monoclonal antibody XOMA-052 [Owyang, A.M. et al., Abst 75-LB]. On the contrary, chronic phosphodiesterase V inhibition with PF-581253 did not prevent obesity progression, although it enhanced insulin-dependent glucose uptake in muscle [Ayala, J.E. et al., Abst 1555-P]. On the other hand, an undisclosed fatty acid synthase inhibitor suppressed de novo lipogenesis but induced hepatic steatosis and dermatitis without enhancing insulin sensitivity in obese animals [Wallenius, K. et al., Abst 58-LB].

THERAPIES FOR DIABETIC NEPHROPATHY

Data from 21 diabetic and 21 nondiabetic men treated with the albumin glycosylation inhibitor GLY-230 or placebo demonstrated a positive correlation between albuminuria and nephrinuria reductions, with the treatment resulting in repair of the filtration barrier [Kennedy, L. et al., Abst 728-P].

THERAPIES FOR DIABETIC EYE DISEASE

Similar progression of diabetic retinopathy was noted in patients receiving insulin glargine and regular human insulin over the long term [Rosenstock, J. et al., Abst 301-OR].

Regarding prevention, the aldose reductase inhibitor fidarestat was shown to prevent diabetic eye disease in diabetic animal models [Kakehashi, A. et al., Abst 807-P]. Additional experimental studies with ISO and GPI-1542 suggested potential for poly(ADP-ribose) polymerase inhibition in preventing cataract formation and early retinal changes in diabetes [Obrosova, I.G. et al., Abst 51-OR], findings that were also reported in experimental animals with KIOM-79, an ethanol extract of Pueraria lobata root, Magnolia officinalis bark, Glycyrrhiza uralensis root and Euphorbia pekinensis root [Kim, Y.S: et al., Abst 396-OR].

DIABETIC NEUROPATHY

Pregabalin was confirmed effective in safely improving signs and symptoms of peripheral diabetic neuropathy [Freeman, R. et al., Abst 507-P] and effectiveness in the clinical trial setting was also reported with lacosamide [Wymer, J. et al., Abst 532-P]. High-frequency external muscle stimulation was reported to significantly improve symptoms of diabetic polyneuropathy [Kempf, K. et al., Abst 489-P].

Regarding mechanistic observations, the aldose reductase inhibitor epalrestat suppressed serum N-carboxymethyl lysine repressing deterioration of diabetic peripheral neuropathy through an effect on the polyol pathway and prevention of advanced glycated endproduct formation [Kasai, T. et al., Abst 774-P].

As a further putative option for the treatment of diabetic neuropathy, experimental studies suggested potential and feasibility for bone marrow-derived mesenchymal stem cell-based therapy [Kim, M.O. et al., Abst 796-P].

THERAPIES FOR OTHER DIABETIC COMPLICATIONS

The ghrelin agonist TZP-101 offered activity in accelerating gastric emptying of solid foods and improving symptoms of gastroparesis in 10 patients with diabetes [Ijskjaer, N. et al., Abst 298-OR]. Diabetic lipodystrophy in 25 patients improved with recombinant human leptin therapy [Chong, A.Y. et al., Abst 347-OR].

MISCELLANEOUS

Opioid receptor blockade with naloxone prevented autonomic failure during hypoglycemia [Leu, J. et al., Abst 20-OR], while activation of GABAA receptors with alprazolam blunted hemodynamic response to hypoglycemia [Davis, S.N. et al., Abst 21-OR].

High doses of salicylate, an IKKβ inhibitor, restored peripheral but not hepatic insulin sensitivity after protracted lipid infusion in experimental animals [Pereira, S. et al., Abst 288-OR] but had no effect on insulin sensitivity in overweight/obese nondiabetic people, although it improved the first-phase insulin response [Xiao, C. et al., Abst 154-OR].
α-Lipoic acid improved lipid levels independently of peripheral insulin sensitivity in women with polycystic ovary syndrome [Gjerde, C. et al., Abst 492-P].

Improvements in hemoglobin A_1c levels were obtained with the antianginal agent ranolazine when used in patients with diabetes and coronary artery disease [Chrisholm, J.W. et al., Abst 528-P].
Aminoguanidine prevented changes in trabecular bone structure in experimental diabetes without affecting bone mineral density [Gogas, D. et al., Abst 1080-P].

Risperidone- and olanzapine-induced diabetes were counterbalanced by prolactin and estrogen [Park, S. et al., Abst 1457-P].