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Meeting Reports

American Diabetes Association's 70th Scientific Sessions (ADA)
June 25 - 29, 2010
Orlando, Florida


Describing Orlando would be a very difficult task, as it represents many different forms for many people. From a manicured landscape devoid of interest, to a land where everything is possible (including entering houses upside down); from a place where hectic meetings are held, to the site of Disney World where child fantasies are realized. Not for everybody, but a dreamland for many! However, if sweet is one of the adjectives that may be used to describe the greater Orlando area, sweet, at least sweet food, is one of the enemies of diabetes, and Orlando is also a place where food is available, but is not particularly healthy. Fat and sugar galore! Obviously strategies to prevent and treat diabetes have been and continue to be intensely researched, although not always feasible. The finding that the prevalence of diabetes is lower in marijuana users [Rajavashisth, T.B. et al., Abst 659-P], for example, does not open a feasible strategy for preventing diabetes, but does suggest targets and opens research avenues that may eventually result in clinically relevant findings.


Although without preventing the loss of C-peptide and without a negative impact on the quality of life [Nishigaki, Y. et al., Abst 1973-P], insulin is a major asset in the treatment of diabetes and the control of glycemia [Badaru, A. et al., Abst 1908-P], despite the increased risk for macrosomia when used as continuous subcutaneous infusion to manage gestational diabetes [Skalli, S. et al., Abst 121-LB]. A number of recombinant products, formulations and analogous have been developed. However, besides hypoglycemia, excessive doses of insulin may also result in cardiac conduction defects leading to serious, even life-threatening arrhythmias [Yagi, K. et al., Abst 682-P]. In addition, recombinant human insulin resulted in similar control of hemoglobin A1c in patients with type 2 diabetes, compared to regular human insulin [Rodbard, H.W. et al., Abst 36-OR].

Looking for alternatives to subcutaneous insulin administration, inhaled insulin offered meal-independent control of glycemia with a low risk for hypoglycemia [Zisser, H. et al., Abst 554-P] and was safe without a meaningful impact on pulmonary function [Rossiter, A. et al., Abst 523-P], but resulted in greater inactivating antibody responses than subcutaneous insulin [Yu, W. et al., Abst 216-OR]. Without the kinetics of insulin response being negatively affected by salbutamol or fluticasone propionate treatment in patients with asthma [Cassidy, J.P. et al., Abst 522-P; Baughman, R.A. et al., Abst 528-P] inhaled insulin showed an optimal sigmoid pharmacokinetic profile [Potocka, E. et al., Abst 624-P], with observations from the real-world clinical practice indicating suboptimal control of hemoglobin A1c after one year of initiation of inhaled insulin therapy [Freemantle, N. et al., Abst 623-P]. However, compared to insulin lispro, inhaled insulin resulted in faster, greater benefits on free fatty acids, glucagon and postprandial glucose [Potocka, E. et al., Abst 1561-P]. An oral insulin has also been developed, with potential for preprandial intake to safely improve glycemic responses to a meal [Eldor, R. et al., Abst 521-P]. An investigational nasal insulin offered faster pharmacodynamic responses during meal intake than insulin lispro, in healthy volunteers with an attenuated risk of hypoglycemia [Stote, R. et al., Abst 520-P].

Among rapid-acting insulin analogous, similar effectiveness was reported comparing premixed insulin lispro and insulin aspart [Ikeda, S. et al., Abst 526-P], thrice-daily biphasic insulin aspart 50 being more effective than twice-daily biphasic insulin aspart 30 in obtaining glycemic control [Gao, Y. et al., Abst 560-P]. Add-on insulin aspart was in fact described as a feasible, effective form of intensification therapy in patients on once-daily basal insulin detemir [Meneghini, L.F. et al., Abst 730-P], while basal insulin lispro protamine showed efficacy for improving glycemic control with minimal weight gain in patients suboptimally controlled with metformin, sulfonylurea, pioglitazone and exenatide [Blevins, T.C. et al., Abst 19-B]. It should be added, however, that a monomeric formulation of human insulin exhibited a faster onset of action than insulin lispro [Heise, T. et al., Abst 622-P], with potential also for reducing weight gain and the risk of hypoglycemia compared to standard human insulin [Hollander, P. et al., Abst 642-P]. Monomeric insulin also allowed for longer-lasting effects [Jackson, J.A. et al., Abst 14-LB] resulting in improved control of glycemia in patients requiring large doses of insulin, with acceptable weight gain but a risk for hypoglycemia that requires careful vigilance [Ziesmer, A. et al., Abst 741-P].

Regarding long-acting insulin analogous, which were not more costly to the healthcare system than standard human insulin [Gungaard, J. et al., Abst 1296-P], insulin glargine was one of the compounds reported effective in the management of diabetes [Davis, S.N. et al., Abst 541-P], with better control of glycemia and longer delay to intensified therapy but lower risk for hypoglycemia compared to human insulin [Pan-Wei, M. et al., Abst 637-P; Quinzler, R. et al., Abst 1295-P]. It also showed potential as a treatment for diabetic ketoacidosis [Heneghan, M.A. et al., Abst 1907-P] and additional benefit by improving myocardial function in patients with coronary artery disease [Von Bibra, H. et al., Abst 627-P], without a propensity case-control study indicating increased risk of cancer [Chuang, L.M. et al., Abst 619-P]. However, insulin glargine elicited antiapoptotic insulin-like growth factor-mediated signaling [Yehezkel, E. et al., Abst 620-P]. Compared to human insulin, insulin detemir and insulin glargine offered superiority in the control of morning glycemia in type 2 diabetes, although insulin glargine offered better control in the afternoon [Porcellati, F. et al., Abst 35-OR] (Fig. 1). Detailed mechanistic analysis revealed the efficacy of insulin glargine metabolites on glycemic control without the growth-promoting activity of insulin [Sommerfeld, M. et al., Abst 561-P]. However, insulin detemir remained an effective treatment modality over the long term [Norberg, B. et al., Abst 688-P], and was demonstrated to improve glycemic control in patients on background sitagliptin/metformin/sulfonylurea [Hollander, P. et al., Abst 549-P], with a lower risk of hypoglycemia compared to neutral protamine insulin [Pieber, T.R. et al., Abst 687-P]. Furthermore, a regimen of basal insulin detemir with mealtime insulin aspart was as effective as biphasic insulin aspart in patients requiring insulin intensification [Liebl, A. et al., Abst 558-P].


Fig. 1 Glucose infusion rate during an euglycemic clamp in patients receiving insulin glargine, insulin detemir or human insulin [Porcellati, F. et al., Abst 35-OR].


Insulin degludec was described as a new-generation soluble ultra-long basal insulin with low insulin-like growth factor receptor-1 affinity and a low mitogenic:metabolic ratio, a pharmacokinetic profile that was attributed to the multihexamer formulation resulting in slow release of monomers with potential for preventing hypoglycemia while providing improved dosing flexibility [Jonassen, I.B. et al., Abst 39-OR; Nishimura, E. et al., Abst 1406-P]. Compared to insulin glargine, insulin degludec offered comparably favorable safety and tolerability and similar glycemic control, with potential for even lower risk of hypoglycemia [Zinman, B. et al., Abst 40-OR; Meneghini, L.F. et al., Abst 559-P] (Fig. 2).


Fig. 2 Change in fating plasma glucose levels after 16 weeks of subcutaneous insulin degludec or insulin glargine [Zinman, B. et al., Abst 40-OR].

Long-lasting control of glycemia with novel insulin-based strategies was demonstrated feasible with insulin lispro protamine/insulin lispro, which was noninferior to insulin glargine plus insulin lispro as intensification therapy [Oliveira, J.H. et al., Abst 628-P].

As an additional, particular topic, randomized trial confirmed the superiority of basal-bolus insulin over sliding scale regular insulin for managing glycemia during hospitalization in patients with type 2 diabetes undergoing general surgical procedures [Umpierrez, G.E. et al., Abst 33-OR]. Nevertheless, additional data suggested an increased risk for hypoglycemia during hospitalization regardless of the use of basal-bolus insulin degludec with insulin aspart bolus boost or maintenance insulin glargine [Heise, T. et al., Abst 34-OR]. Note that insulin degludec/insulin aspart was also suggested effective and well tolerated for controlling postprandial glycemia in patients on sitagliptin [Retnakaran, R. et al., Abst 38-OR].

A miscellaneous additional observation related to insulin analogue therapy was that coinjection of hyaluronidase accelerated the pharmacokinetic and pharmacodynamic activity of the three rapid-acting insulin analogues: insulin glulisine, insulin lispro and insulin aspart [Morrow, L. et al., Abst 353-OR].


Metformin has long been used in the treatment of diabetes, and is still the background agent for many antidiabetic combinations, although responses to the agent were improved in younger male patients with lower body mass index [Wang, C.P., Abst 709-P]. Besides improving glycemia in diabetes, metformin also prevented hepatocellular carcinoma in patients with cirrhotic hepatitis C [Cosson, E. et al., Abst 1089-P]. Mechanistically, treatment with metformin was related to improvement in leukocyte inflammation and senescence through an effect on the sirtuin-7 pathway [Zeng, W. et al., Abst 882-P], while the agent was reported to prevent calcium-induced opening of the mitochondrial permeability transition pore in obese animal models [Lin, C.T. et al., Abst 1603-P]. Metformin has been associated with tolerability issues that, according to new data discussed in Orlando, have been overcome by a gastro-retentive formulation that was well tolerated in patients previously intolerant to the standard formulation [Sweeney, M. et al., Abst 729-P]. Furthermore, the addition of thiazolidinediones, sulfonylureas and glinides to metformin was noted to be associated with increased body weight, whereas metformin combined with incretin mimetics, a-glucosidase inhibitors or dipeptidylpeptidase-4 inhibitors was neutral or resulted in weight loss [Phung, O.J. et al., Abst 567-P].

A combination of metformin and colesevelam was at least as effective as metformin, but resulted in an improved tolerability profile with a marked reduction in metformin-related diarrhea, offering a safe option for first-line treatment of hypercholesterolemic diabetes [Abby, S.L. et al., Abst 633-P]. Furthermore, colesevelam was associated with increased levels of glucagon-like polypeptide-1, helping restore the incretin effect in type 1 diabetes [Ritchie, P.J. et al., Abst 808-P]. In the experimental setting, metformin was demonstrated to stimulate glucagon-like peptide-1 production by intestinal L-cells through an effect on Wnt signaling [Kim, M.H. et al., Abst 278-OR]. In addition, although without being potent inhibitors of the apical sodium-dependent bile acid transporter, both metformin and phenformin increased bile acid content in the intestine, an effect that contributes to the glucose-lowering activity of these biguanides [Yao, X. et al., Abst 611-P].


Initial treatment of diabetes with sulfonylureas was associated with faster, greater need for insulin compared to initial metformin therapy [Zhao, C. et al., Abst 685-P], while maintaining sulfonylureas and/or glinides in patients on prior treatment with these agents plus metformin initiating basal insulin resulted in excess risk of hypoglycemia, suggesting the need for maintaining only metformin [Sanne, G. et al., Abst 37-OR]. Among the sulfonylureas, gliclazide and mitiglinide, but not tolbutamide, showed increased potency on the K23/A1369 variant of the ATP-dependent potassium channel [Lang, Y. et al., Abst 1239-P], while hypoglycemic responses to all sulfonylureas were reduced in patients carrying the T-cell transcription factor 7-like-2 (TCF7L2) rs7903146 allele variant [Holstein, A et al., Abst 1279-P]. In addition, experimental studies with nateglinide revealed an effect in suppressing postprandial fatty acid synthesis [Kitahara, Y. et al., Abst 1572-P] and upregulating ATP-binding cassette transporter and scavenger receptor type B class I expression in macrophages, while improving the lipid profile in apolipoprotein E-deficient animal models [Kitahara, Y. et al., Abst 1060-P].


Besides improving postprandial hyperglycemia, treatment of impaired glucose tolerance with acarbose resulted in a lower likelihood for developing hypertension and protection against endothelial dysfunction [Hanefeld, M. et al., Abst 325-OR]. A dual a-glucosidase inhibitor that also activates sodium-glucose cotransporter-3, miglitol prevented postprandial rises in glucose and decreases remnant-like particle levels in patients with type 2 diabetes controlled with insulin lispro [Kimura, T. et al., Abst 702-P]. Miglitol was further demonstrated to reduce liver fat content in patients with nonalcoholic fatty liver disease and impaired glucose tolerance or overt type 2 diabetes [Tsuchiya, M. et al., Abst 703-P].


Compared to biguanides and a-glucosidase inhibitors, thiazolidinediones showed potential for preventing type 2 diabetes in patients at risk [Phung, O.J. et al., Abst 658-P]. Compared to placebo, pioglitazone improved b-cell function, insulin secretion and insulin resistance in patients with impaired glucose tolerance [Tripathy, D. et al., Abst 317-OR] (Fig. 3), the agent specifically improving insulin sensitivity in the adipose tissue [Tripathy, D. et al., Abst 1491-P]. Pioglitazone treatment in type 2 diabetes was also accompanied by reductions in hepatic triglyceride content and cholesteryl ester transfer protein mass [Jonker, J.T. et al., Abst 1061-P], along with increases in adiponectin and decreases in osteoprotegerin and C-reactive protein levels [Park, J.S. et al., Abst 723-P]. Proteomic analysis of the effect of the agent on subcutaneous adipocytes revealed increased lipid disposal through increased fatty acid oxidation and energy production and decreased lipolysis [Xie, X. et al., Abst 84-LB]. However, pioglitazone was associated with increased body weight that was not seen with telmisartan and was related to increased low-molecular-weight adiponectin, while increases in high- and middle-molecular weight adiponectin brought about by both pioglitazone and telmisartan were related to insulin sensitization [Satoh, H. et al., Abst 88-LB]. Pioglitazone has further been associated with a loss of bone mineral density that, in experimental ovariectomized animals, was not exacerbated by sitagliptin [Glantschnig, H. et al., Abst 1628-P]. A fixed-drug combination of pioglitazone and metformin has been developed the use of which resulted in marked improvements in markers of lipid metabolism, b-cell function, visceral adipose tissue activity, chronic systemic inflammation and platelet activity at similar glycemic control compared to glimepiride plus metformin [Pfutzner, A.H. et al., Abst 735-P; Forst, S. et al., Abst 739-P] (Fig. 4).


Fig. 3. Change in the Matsuda insulin sensitivity index after 2.8 years of treatment with pioglitazone or placebo in patients with impaired glucose tolerance [Tripathy, D. et al., Abst 317-OR].

Fig. 4. Change in hemoglobin A1c and C-reactive protein levels after 6 months of treatment with pioglitazone or glimepiride, both combined with metformin [Pfutzner, A.H. et al., Abst 735-P].


Compared to glipizide, treatment of type 2 diabetes with rosiglitazone resulted in decreased bone mineral density in female, but not male patients [Banerji, M.A. et al., Abst 648-P]. As initial therapy, a fixed combination of rosiglitazone and metformin proved superior to metformin in maintaining glycemic control over the long term [Borges, J. et al., Abst 713-P]. Furthermore, rosiglitazone attenuated the increase in monocyte chemoattractant protein-1 resulting from increased advanced glycation endproducts, although the effect was restricted to renal mesangial, but not tubular cells [Sun, Z. et al., Abst 924-P]. Mechanistically, rosiglitazone was also related with induction of 6-phosphofructo-2-kinase [Guo, X. et al., Abst 1480-P] and prevention of casein-induced endoplasmic reticulum stress in the liver of obese animals [Kang, S.B. et al., Abst 1087-P]. However, experimental findings revealed prevention of b-cell apoptosis [Xue, Y. et al., Abst 1689-P] but induction of osteoblast apoptosis by rosiglitazone through activation of glycogen synthase kinase 3b [Sheng, H. et al., Abst 751-P], although glycogen synthase 3b activators are being developed as a novel target for diabetes treatment, with favorable preclinical results having already been reported with RO-5289867 [Bolin, D. et al., Abst 1389-P].

A novel thiazolidinedione, rivoglitazone improved glycemic control as effectively as pioglitazone [Chou, H.S. et al., Abst 671-P] (Fig. 5) and ameliorated lipid levels and inflammatory biomarkers as or more effectively than pioglitazone in patients with type 2 diabetes [Truitt, K.E. et al., Abst 668-P]. A further agent, mitoglitazone, induced brown adipose tissue differentiation in in vitro studies, suggesting potential for controlling diabetes without causing weight gain [McDonald, W.G. et al., Abst 1453-P] whereas the peroxisome proliferator-activated receptor-γ-sparing thiazolidinedione MSCD-0160 improved insulin resistance in islet cells by activation of the AMP-dependent protein kinase and deactivation of the mammalian target for rapamycin systems [Rohatgi, N. et al., Abst 1706-P].


Fig. 5. Change in hemoglobin A1c levels after 26 weeks of treatment with rivoglitazone or placebo [Chou, H.S. et al., Abst 671-P].

As an alternative approach, the peroxisome proliferator-activated receptor-γ agonist T-131, improved glycemic control as effectively as pioglitazone in type 2 diabetes, without causing significant peripheral edema compared to placebo [Depaoli, A.M. et al., Abst 315-OR].


A pooled analysis of clinical trials along with postmarketing data confirmed the cardiovascular safety of pramlintide in the treatment of type 2 diabetes [Burns, C. et al., Abst 647-P].


Glucagon-like polypeptide-1 analogues have been developed as a treatment for diabetes, with activity against oxidative stress comparable to biguanides and thiazolidinediones although through different mechanism of action (transactivation of the epithelial growth factor receptor/phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin/GCL signaling, inhibition of permeability transition pore opening and upregulation of Bcl-2, respectively), all of which offer promise for treating and preventing diabetic encephalopathy [Okouchi, M. et al., Abst 662-P].

The glucagon-like polypeptide-1 mimetic agonist exenatide, provided effective control of glycemia in type 2 diabetes, accompanied by improvements in body weight, cardiovascular risk markers, hepatic injury and quality of life [Horton, E. et al., Abst 582-P; Bergenstal, R.M. et al., Abst 673-P; Kadowaki, T. et al., Abst 683-P; Best, J.H. et al., Abst 712-P]. Weekly treatment resulted in improved or sustained glycemic benefits, accompanied by weight loss in patients switching from maximal doses of daily sitagliptin or pioglitazone [Wysham, C. et al., Abst 594-P], and offering a valid alternative to twice-daily injection [Blevins, T. et al., Abst 8-LB], but exenatide remained safe in patients concomitantly receiving thiazolidinediones [Norwood, P. et al., Abst 715-P]. Furthermore, weight loss during exenatide therapy was not associated with a negative impact on bone mineral density [Eliasson, B. et al., Abst 644-P], but contributed to the hemoglobin A1c-lowering activity, whereas the negative impact of insulin on body weight adversely affected improvements in hemoglobin A1c levels [Paul, S.K. et al., Abst 664-P]. In addition, exenatide, but not sitagliptin, increased adiponectin levels [Xu, L. et al., Abst 1479-P]. While demonstrating superiority over sitagliptin, pioglitazone and insulin glargine in lowering hemoglobin A1c and plasma glucose, and reducing body weight with a lower risk for hypoglycemia [Diamant, M. et al., Abst 59-OR; Horton, E. et al., Abst 597-P; Holcombe, J.H. et al., Abst 674-P; Van Gaal, L. et al., Abst 763-P] (Fig. 6), as well as equal efficacy compared to insulin aspart but superiority regarding weight control and the risk of hypoglycemia [Gallwitz, B. et al., Abst 557-P], a pooled analysis of the DURATION studies confirmed the favorable safety and tolerability profile of exenatide in the treatment of type 2 diabetes [Bruce, S. et al., Abst 61-OR]. Furthermore, treatment of diabetes with exenatide was associated with lower healthcare resource utilization compared to insulin glargine [Pawaskar, M. et al., Abst 1294-P], whilst the addition of exenatide to insulin glargine therapy, or that of insulin glargine to an exenatide regimen resulted in improvements of glycemic control and body weight [Levin, P. et al., Abst 652-P; Buse, J. et al., Abst 10-LB]. Additional data corroborated the positive impact of exenatide on body weight and glycemic control of diabetes [Smith, S.R. et al., Abst 542-P].

Fig. 6. Percent of patients with hemoglobin A1c levels fewer than 7.0% or 6.5% after 26 weeks of biweekly exenatide or daily sitagliptin, pioglitazone or insulin glargine [Horton, E. et al., Abst 597-P].


Furthermore, studies with exenatide indicated protection against glucocorticosteroid-induced glucose intolerance and islet cell-dysfunction [Van Raalte, D.H. et al., Abst 233-OR]. Exenatide was also tested in combination with metformin, resulting in increased rates of glycemic control [Riddle, M. et al., Abst 18-LB], and in combination with pioglitazone, resulting in improved glycemic control and b-cell function without the weight gain observed with pioglitazone alone [Chavez, A.O. et al., Abst 320-OR; Chavez, A.O. et al., Abst 744-P]. Note that improvements in b-cell disposition index gained with long-term exenatide were maintained for at least four weeks after discontinuation [Bunck, M.C. et al., Abst 728-P]. In experimental studies, treatment with the agent prevented b-cell apoptosis through an effect on the protein kinase A/phosphatidylinositol 3-kinase pathway [Wang, L. et al., Abst 1673-P], and also protected the cells against amyloid peptide-induced damage through an effect on the Akt pathway and mitochondrial biogenesis [Fan, R. et al., Abst 1674-P; Aston-Mourney, K. et al., Abst 1677-P] (note that protection against amyloid-induced b-cell apoptosis resulted also from treatment with a peptide Jun kinase inhibitor [Subramanian, S.L. et al., Abst 1675-P]), and against sulfonylurea-induced apoptosis through an effect on calcium-dependent endoplasmic reticulum stress [Kim, J.Y. et al., Abst 1678-P]. An important observation related to exenatide came from a simulated comparison versus intensive therapy with traditional therapies, according to which the incidence of cardiovascular morbidity and mortality was reduced by the incretin mimetic, which was also associated with better protection against diabetic neuropathy and nephropathy [Peskin, B.R. et al., Abst 592-P]. On the other hand, chart and claim reviews did not demonstrate any association between use of exenatide and an increased risk of acute pancreatitis [Bloomgren, G. et al., Abst 543-P; Pendergrass, M. and Chen, W., Abst 587-P; Wenten, M. et al., Abst 596-P], whereas in animal models of obesity exenatide rather attenuated or had no impact on experimental pancreatitis [Tatarkiewicz, K. et al., Abst 1627-P; Villescaz, C. et al., Abst 1633-P]. Similarly, use of exenatide was not associated with increased incidence of acute renal failure [Pendergrass, M. and Chen, W., Abst 11-LB].

While oral administration of exenatide was documented feasible with a novel technology [Eldor, R. et al., Abst 6-LB] and a novel continuous subcutaneous delivery proved as effective as twice-daily subcutaneous injection [Cuddihy, R. et al., Abst 7-LB], modification of the exenatide molecule by adding a XTEN peptide to prolong stability and allow for reduced frequency of dosing resulted in VRS-859, which, along with a similar construct with glucagon, showed potential as a treatment for obesity and diabetes in the experimental arena [Cleland, J.L. et al., Abst 617-P]. A further exenatide-based construct with immunoglobulin G Fc fragment also offered benefits by preventing immunogenicity against the compound [Liang, Y. et al., Abst 1652-P].

A recently developed related agent, lixisenatide showed potential for restoring insulin release in type 2 diabetes patients, thus also improving glycemic control [Becker, R.H.A. et al., Abst 552-P].

With only a transient, short-lived effect on gastric emptying [Knudsen, L.B. et al., Abst 591-P] but a significant effect in improving b-cell function [Matthews, D. et al., Abst 1513-P] and superiority over traditional therapies regarding the percent of patients with full glycemic control without hypoglycemia or weight gain [Charbonnel, B. et al., Abst 593-P], a direct comparative trial in patients with type 2 diabetes concluded on the superiority of liraglutide versus sitagliptin for lowering hemoglobin A1c levels regardless of baseline values [Davies, M. et al., Abst 57-OR; Pratley, R. et al., Abst 16-LB] (Figs. 7 and 8). Liraglutide was also superior to sitagliptin in promoting weight loss [Garber, A. et al., Abst 697-P], the effect on weight loss being independent on the presence of nausea as an adverse event to the treatment [Russell-Jones, D. et al., Abst 1886-P], but added to metformin reduced blood pressure and weight more effectively than glimepiride at similar effect on hemoglobin A1c but a lower risk for hypoglycemia [Yang, W. et al., Abst 698-P; Yang, W. et al., Abst 699-P; Gough, S. et al., Abst 764-P]. Furthermore, treatment with liraglutide was accompanied by decreases in body mass index and waist circumference [Park, J.S. et al., Abst 1893-P], improvements in endothelial dysfunction and markers of atherogenesis [Simpson, R.W. et al., Abst 595-P], reductions in systolic blood pressure even in patients on antihypertensive therapy [Fonseca, V. et al., Abst 296-OR], as well as modulated appetite-related signals in the hypothalamus of experimental animals resulting in reduced food intake [Vrang, N. et al., Abst 583-P; Raun, K. et al., Abst 584-P]. Liraglutide was also safe in the sense that it did not impact on bone mineral density even in type 2 diabetes patients already at risk for fractures [Pratley, R. et al., Abst 1634-P]. With pharmacodynamic activity closely depending on plasma levels [Flint, A. et al., Abst 1590-P], overall patients were willing to pay the extra cost associated with liraglutide compared to glimepiride, an effect driven mostly by the impact of the agent on weight and blood pressure [Jendle, J. et al., Abst 1312-P]. However, the antihyperglycemic activity of liraglutide tended to diminish with disease duration, suggesting the need for early therapy to better control glucose [Garber, A. et al., Abst 722-P]. Used in combination therapy, liraglutide plus metformin improved metabolic control with less risk for hypoglycemia and greater weight loss than liraglutide plus glimepiride, although with a higher frequency of nausea [Courreges, J.P. et al., Abst 737-P]. In addition, no pharmacokinetic interaction was demonstrated by coadministering liraglutude and insulin detemir, suggesting potential as combination therapy [Morrow, L. et al., Abst 653-P]. Liraglutide also was less immunogenic than exenatide even after switch from the latter, while persisting antibodies to exenatide for up to one year after discontinuation did not limit the efficacy of liraglutide [Buse, J. et al., Abst 676-P]. In the mechanistic experimental arena, effects of liraglutide in reducing high glucose-induced oxidative stress in endothelial cells [Schisano, B. et al., Abst 680-P] and protecting the brain against neuropathologic traumatic injuries [Della Valle, B. et al., Abst 15-LB] were described, whilst like exenatide, the agent did not induce pancreatitis in preclinical animal models [Nyborg, N.C.B. et al., Abst 23-LB].

Fig. 7. Mean hemoglobin A1c levels after 26 weeks of treatment with liraglutide or sitagliptin based on baseline levels [Davies, M. et al., Abst 57-OR].

Fig. 8.Mean changes in hemoglobin A1c levels after 1 year of treatment with liraglutide or sitagliptin [Pratley, R. et al., Abst 16-LB].

Favorable pharmacokinetics and tolerability in patients with type 2 diabetes were reported with reduced-dosing albiglutide, supporting the use of weekly or less frequent dosing regimens [Bush, M.A. et al., Abst 598-P].

A more recent drug within this group, taspoglutide proved superior to placebo [Hollander, P. et al., Abst 858-P] and was as effective as exenatide in improving postprandial glucose and glucagon levels, but also significantly increased insulin output in patients with type 2 diabetes [Rosenstock, J. et al., Abst 719-P]. Taspoglutide was as effective as insulin glargine regarding glycemic control in type 2 diabetes pretreated with metformin, but was associated with a lower risk for hypoglycemia and better weight loss [Nauck, M. et al., Abst 60-OR] (Fig. 9 and 10). Taspoglutide was superior to sitagliptin [Bergenstal, R. et al., Abst 58-OR] and exenatide [Rosenstock, J. et al., Abst 62-OR] (Fig. 11) according to additional comparative studies, and compared to placebo exerted an insulin-sensitizing effect that was more pronounced on the first-, but was also maintained in the second-phase response [Pellanda, C. et al., Abst 588-P]. In the experimental mechanistic arena, taspoglutide was associated with protective effects on b-cell survival [Uhles, S. et al., Abst 544-P].

Fig. 9. Change in hemoglobin A1c levels after 24 weeks of treatment with taspoglutide or daily insulin glargine [Nauck, M. et al., Abst 60-OR].

Fig. 10. Percent of patients at target hemoglobin A1c levels <7.0% after 24 weeks of treatment with taspoglutide, sitagliptin or placebo [Nauck, M. et al., Abst 60-OR].



Fig. 11. Percent of patients at target hemoglobin A1c levels <7.0% after 24 weeks of treatment with weekly taspoglutide or twice-daily exenatide [Rosenstock, J. et al., Abst 62-OR].

Novelties in the area of incretin analogues included: the novel compounds LY-2189265, which showed higher hemoglobin A1c-lowering activity in Hispanic compared to non-Hispanic populations [Bastyr, E.J. et al., Abst 589-P] without impairing gastric emptying in healthy volunteers [Chien, J.Y. et al., Abst 600-P]; SKL-18287, which exhibited potent pharmacodynamic activity in preclinical studies with favorable pharmacokinetics and stability while showing resistance to hydrolysis by dipeptidylpeptidase-4 [Okamoto, M. et al., Abst 586-P; Tamura, M. et al., Abst 599-P], and DA-15864 [Kim, M.K. et al., Abst 590-P]; and ZP-2929 [Daugaard, J.R. et al., Abst 1630-P], the pharmacological profile of which was demonstrated in experimental animals. In addition, a novel glucose-dependent insulinotropic receptor agonist, MBX-2982, proved well tolerated and improved glucose tolerance in a phase I trial in subjects with prediabetes [Roberts, B. et al., Abst 603-P], while among two similarly acting drugs, AS-153907 improved insulin responses  in experimental studies [Yoshida, S. et al., Abst 615-P] and PSN-821 proved superior in improving glycemic control and inducing body weight in obese animal models compared to exenatide and sitagliptin [Cock, T.A. et al., Abst 1625-P]. A further glucose-dependent insulinotropic receptor agonist, NBI-104, markedly reduced postprandial glucose excursions, but rapid tachyphylaxis resulted in loss of effect and increases in hemoglobin A1c levels [Barnes, W.G. et al., Abst 679-P].


Sitagliptin and pioglitazone were both identified as potent drugs for improving the glycemic control of type 2 diabetes in patients insufficiently controlled with metformin [Handayan, O. et al., Abst 667-P]. In addition, when compared to placebo, sitagliptin also effectively improved glucose control in patients with type 1 diabetes [Ellis, S.L. et al., Abst 9-LB]. In experimental models of diet-induced obesity, sitagliptin suppressed accelerated gluconeogenesis, delaying or preventing the development of type 2 diabetes [Lu, Y. & Guo, Z., Abst 640-P].

Saxagliptin offered a body weight-independent pharmacokinetic profile in healthy volunteers and patients with type 2 diabetes supporting once-daily dosing [Zhang, L. et al., Abst 675-P]. As add-on therapy, in patients suboptimally controlled with metformin, saxagliptin was noninferior to glipizide, but carried significantly lower risk for hypoglycemia, so that considering the target of reduction in hemoglobin A1c without hypoglycemia or weight gain, sitagliptin proved superior to glipizide [Göke, B. et al., Abst 578-P; Seck, T.L. et al., Abst 580-P]. First-line treatment of type 2 diabetes with sitagliptin/metformin proved superior to pioglitazone in improving glycemic control while lowering body weight, although incurring in a higher incidence of gastrointestinal adverse events [Katz, L. et al., Abst 546-P] (Fig. 12). Mechanistically, both agents increased active glucagon-like polypeptide-1 levels by different mechanisms, sitagliptin preventing hydrolysis without increasing total levels of the protein, whereas metformin increased total output, without altering the active fraction [Migoya, E. et al., Abst 572-P]. Sitagliptin was similarly found effective and well tolerated for managing glycemia, when added to voglibose [Tajima, N. et al., Abst 575-P].

Fig. 12. Proportion of patients with hemoglobin A1c under 7% after 32 weeks of treatment with sitagliptin/metformin or pioglitazone [Katz, L. et al., Abst 546-P].

With good tolerability, saxagliptin improved glycemic control of type 2 diabetes compared to placebo in patients with renal failure [Nowicki, M. et al., Abst 550-P]. A fixed combination of saxagliptin and metformin offered sustained glycemic control with good tolerability as first-line therapy for type 2 diabetes [Pfutzner, A. et al., Abst 64-OR] (Fig. 13).

Fig. 13. Change in hemoglobin A1c levels after 76 weeks of treatment with saxagliptin, metformin or placebo mono- or combination therapy [Pfutzner, A. et al., Abst 64-OR].

Improvements in the b-cell capacity and glycemic control in previously untreated patients with type 2 diabetes and mild hypertriglyceridemia were demonstrated with vildagliptin compared to placebo [Bunck, M.C. et al., Abst 63-OR], the drug showing no impact on bone resorption markers or calcium homeostasis in patients with mild hyperglycemia [Diamante, M. et al., Abst 706-P].

Add-on alogliptin provided superior glycemic control and improved b-cell function compared to pioglitazone uptitration in patients with type 2 diabetes, suboptimally controlled with pioglitazone plus metformin [Bosi, E. et al., Abst 545-P] (Fig. 14). Thus, the agent improved early insulin responses and inhibited glucagon secretion, while promoting less insulin secretion than pioglitazone in experimental animal models [Mori, Y. et al., Abst 724-P]. Dulogliptin, a dipeptidylpeptidase-4 inhibitor scarcely metabolized in the body and predominantly eliminated through the feces with minimal retention [Li, J. et al., Abst 701-P] and devoid of pharmacokinetic interaction with metformin [Li, J. et al., Abst 705-P], proved superior to placebo in improving hemoglobin A1c and fasting plasma glucose levels in patients with early-stage type 2 diabetes [Rosenberg, N. et al., Abst 581-P] (Fig. 15). In the experimental setting, alogliptin induced acute vascular relaxation through an effect on endothelial nitric oxide synthase and potassium channels [Shah, Z.I. et al., Abst 641-P], and inhibited toll-like receptor-4 mediated extracellular signal-regulated kinase activation and the resulting expression of matrix metalloproteinases, suggesting anti-inflammatory activity [Ta, N.N. et al., Abst 843-P]. Furthermore, in cotreatment with pioglitazone preserved or normalized b-cell function [Kawashima, S. et al., Abst 655-P].

Fig. 14. Glycemic control rates in patients on background metformin adding alogliptin or uptitrating pioglitazone [Bosi, E. et al., Abst 545-P].

Fig. 15. Change in hemoglobin A1c levels after 12 weeks of adding dulogliptin or placebo to background metformin therapy [Rosenberg, N. et al., Abst 581-P].


Improvements in glycemic control and b-cell function were likewise reported with linagliptin [Del Prato, S. et al., Abst 695-P; Kawamori, R. et al., Abst 696-P; Shah, P. et al., Abst 1742-P] (Fig. 16), which in patients not controlled with metformin alone or combined with sulfonylurea was not associated with weight gain or a risk for hypoglycemia [Owens, D.R. et al., Abst 548-P; Taskinen, M.R. et al., Abst 579-P] (Fig. 17). Furthermore, linagliptin monotherapy was superior to voglibose in controlling glycemia [Kawamori, R. et al., Abst 632-P], and first-line therapy with linagliptin plus pioglitazone offered synergistic activity, proving a well-tolerated option for inadequately controlled type 2 diabetes [Gomis, J. et al., Abst 551-P]. In the experimental setting, linagliptin improved hepatic steatosis [Klein, T. et al., Abst 577-P] and counteracted diabetic interferences with healing by improving dipeptidylpeptidase-4 expression in the skin [Schurmann, C. et al, Abst 576-P]. Additionally, chronic renal disease had no negative impact on the pharmacokinetics of linagliptin, while increasing exposure to alogliptin and sitagliptin according to experimental animal studies [Chaykovska, L. et al., Abst 937-P].

Fig. 16. Proportion of patients with hemoglobin A1c <7% after 26 weeks of treatment with linagliptin or voglibose [Kawamori, R. et al., Abst 632-P].


Fig. 17 Glycemic control rates (hemoglobin A1c <7%) by 24 weeks in patients on treated with linagliptin or plcebo [Owens, D.R. et al., Abst 548-P].


A novel dipeptidylpeptidase-4 inhibitor, tenegliptin was safe and effective for improving glycemic control of type 2 diabetes [Kadowaki, T. et al., Abst 573-P], and demonstrated pharmacodynamic activity with favorable pharmacokinetics and good tolerability in healthy volunteers [Kumagai, Y. et al., Abst 708-P]. Tengliptin also ameliorated energy consumption and prevented adiposity in animal models of diet-induced obesity [Fukuda, S. et al., Abst 547-P]. Another drug within this group is LC-15-0444, which was also able to improve glycemic control, b-cell function and insulin sensitivity with once-daily dosing [Rhee, E.J. et al., Abst 638-P].






Studies reported during this year’s ADA meeting in Orlando confirmed the benefits of dapagliflozin on glycemic control of type 2 diabetes, with reductions in hemoglobin A1c and body weight in patients poorly controlled with insulin [Wilding, J.P.H. et al., Abst 78-OR; Wilding, J. et al., Abst 21-LB] (Fig. 18) and activity independent of disease stage [Parikh, S. et al., Abst 563-P] (Fig. 19).


Fig. 18. Change in hemoglobin A1c levels and body weight after 24 weeks of adding dapagliflozin or placebo to insulin therapy [Wilding, J.P.H. et al., Abst 78-OR].

Fig. 19. Change in hemoglobin A1c levels in patients treated with dapagliflozin 10 mg as mono- or combination therapy with metformin or insulin [Parikh, S. et al., Abst 563-P].


Without safety concerns and no apparent risk of hypoglycemia, canagliflozin  exerted glycemic benefits in patients with type 2 diabetes [Sha, S. et al., Abst 568-P], including subjects not well controlled with insulin [Schwartz, S. et al., Abst 564-P]. Improvements in glycemic control were also demonstrated in type 2 diabetes patients with canagliflozin or sitagliptin compared to placebo in patients on prior metformin therapy, but only canagliflozin also improved body weight [Rosenstock, J. et al., Abst 77-OR] (Fig. 20). Canagliflozin was also demonstrated to improve b-cell function in type 2 diabetes [Polidori, D. et al., Abst 646-P] and to induce dose-dependent increases in glucosuria in healthy volunteers [Sha, S. et al., Abst 76-OR] and obese individuals (in whom reductions in body weight were noted) [Sarich, T. et al., Abst 567-P]. In the experimental mechanistic arena, canagliflozin progressively improved hepatic glucose metabolism by a beneficial effect on glucokinase expression, thus preventing hyperglycemic glucotoxicity [Ueta, K. et al., Abst 608-P].

Fig. 20. Change in hemoglobin A1c levels and body weight after 12 weeks of treatment with canagliflozin or sitagliptin [Rosenstock, J. et al., Abst 77-OR].

A novel sodim/glucose cotransporter-2 inhibitor, ASP-1941 also offered glycemic benefits on hemoglobin A1c and fasting blood glucose levels with good safety and tolerability in patients with type 2 diabetes [Kashiwagi, A. et al., Abst 75-OR; Schwartz, S. et al., Abst 566-P] (Fig. 21), an extent that was further confirmed in experimental animal models using monotherapy or a combination with metformin or pioglitazone [Takasu, T. et al., Abst 562-P]. Furthermore, ASP-1941 induced a dose-dependent glucosuric effect in healthy volunteers without impacting on mean plasma glucose levels [Veltkamp, S.A. et al., Abst 565-P]. Experimental animal studies confirmed the role of ASP-1941 as a sodium-glucose cotransporter-2 inhibitor with glucosuric and antihyperglycemic activity [Kurosaki, E. et al., Abst 570-P].

Fig. 21. Change in fasting blood glucose levels after 28 days of treatment with ASP-1941 or placebo [Schwartz, S. et al., Abst 566-P].

Similar glycemic benefits, also in patients with type 2 diabetes, were described with one more novel drug, LX-4211, with dual activity on cotransporter-1 and -2 [Freiman, J. et al., Abst 17-LB]. Favorable pharmacokinetics, pharmacodynamics and tolerability results in healthy volunteers were reported with an additional sodium-glucose cotransporter-2 inhibitor, BI-10773 [Port, A. et al., Abst 569-P], which was also tested positive over the short-term in patients with type 2 diabetes [Seman, L. et al., Abst 571-P; Heise, T. et al., Abst 629-P] (Fig. 22) and induced body weight reduction by decreasing body fat in experimental models of obesity [Grempler, R. et al., Abst 1793-P].


Fig. 22. Change in plasma and mean daily glucose levels after 4 weeks of treatment with BI-10773 or placebo [Heise, T. et al., Abst 629-P].


Treatment of healthy volunteers and type 1 diabetes with lisofylline was safe and well tolerated, and significantly downregulated STAT4 expression in T cells, but not monocytes [Ma, K. et al., Abst 666-P].


A natural anthraquinone from rhubarb, emodin, showed potential for protecting the endothelium against high glucose attack [Gao, Y. et al., Abst 672-P].


Favorable safety, tolerability and pharmacokinetics were described for the GPR119 agonist GSK-1292263 in healthy volunteers, the agent decreasing glucose levels after an oral load without modifying gastric emptying [Nunes, D.J. et al., Abst 80-OR], while increasing glucagon without affecting insulin action in preclinical animal models [Ayala, J.E. et al., Abst 1391-P]. Proof of pharmacodynamic activity on glucose levels in healthy volunteers was also obtained with a glucagon receptor antisense oligonucleotide [Morgan, E.S. et al., Abst 79-OR], whilst a small-molecular-weight glucagon receptor blocker coded GRA1, showed activity in preclinical animal models [Mu, J. et al., Abst 1533-P].

More advanced studies in patients with type 2 diabetes confirmed the therapeutic activity of the antisense phosphatase-1B inhibitor ISIS-113715 on control of glycemia and lipidemia, with a prominent effect in rising adiponectin levels [Brandt, T.A. et al., Abst 316-OR]. Favorable phase I/II data on glucose levels with good tolerability was similarly reported with the glucokinase activator MK-0941 [Migoya, E. et al., Abst 607-P; Migoya, E. et al., Abst 635-P] (which was also confirmed active in experimental animal models [Zhang, B.B. et al., Abst 1511-P]) and the glucocorticosteroid receptor blocker KB-003305 [Jax, T. et al., Abst 605-P; Kapitza, C. et al., Abst 694-P].

Proof of concept studies in obese, type 2 diabetes patients, confirmed that rectal administration of sodium taurocholate increased incretin responses by stimulating intestinal L-cells, and reduced fasting plasma glucose and spontaneous food intake, suggesting potential for the bile acid TGR5 receptor as a new target for intervention in diabetes [Adrian, T.E. et al., Abst 602-P].

Experimental animal studies revealed glycemic benefits of additional novel compounds, including notably the glucokinase activators GKA-23 [Charles, A.D. et al., Abst 609-P], SKL-191014 [Makino, M. et al., Abst 614-P; Yamashita, T. et al., Abst 631-P] and MTBL1 [Baverel, G. et al., Abst 618-P], the free fatty acid receptor agonists TAK-875 [Tsujihata, Y. et al., Abst 606-P] (which was also tested positive in healthy volunteers for safety, tolerability and pharmacodynamic activity without hypoglycemia [Vakily, M. et al., Abst 630-P; Matsuno, K. et al., Abst 707-P]) and ESN-284 [Bernard, J. et al., Abst 612-P], the natural fatty acid synthase inhibitor platensimycin isolated from Streptomyces platensis [Wu, M. et al., Abst 742-P], the anthraquinone diacerrhein [Tobar, N. et al., Abst 743-P] and an extract from Gymnostemma pentaphyllum [Yassin, K. et al., Abst 745-P]. Improvements in multiple diabetes-related outcomes in experimental models by exogenous administration of COMP-Ang1, a variant of angiopoietin-1, also suggested potential to explore in the domain of gene therapy [Kim, W. et al., Abst 656-P] and the anti-interleukin-1b antibody XOMA-052, which decreased b-cell apoptosis and increased proliferation in synergy with sitagliptin but not exenatide (given probably the potency of the latter) [Lee, S. et al., Abst 1811-P; Owyang, A.M. et al., Abst 1820-P]. Furthermore, ranolazine improved b-cell survival and glucose homeostasis in animal models of diabetes [Ning, Y. et al., Abst 710-P]. Also in the preclinical arena, potential as targets for intervention in diabetes was described for phosphodiesterase-8B inhibition [Houseknecht, K.L. et al., Abst 94-OR], adenylate cyclase type 5 inhibition [Ho, D.W. et al., Abst 172-OR] and phospharidylinositol 3-kinase inhibition [Azzi, J.R. et al., Abst 332-OR], whilst an undisclosed synthetic interleukin-1 receptor blocker prevented inflammatory fat-induced b-cell dysfunction in diabetic-prone animal models [Tang, C. et al., Abst 232-OR]. In addition, the identification of small molecules, such as glyphosine with potential for enhancing anti-insulin peptide T-cell receptor signaling, suggested new targets for pharmacological intervention [Michels, A.W. et al., Abst 335-OR].


Advances in research for immunotherapeutics for type 1 diabetes resulted in the proinsulin-based plasmidic vaccine BHT-3021, which proved well tolerated while preserving b-cell function in a placebo-controlled trial [Gottlieb, P. et al., Abst 66-OR] (Fig. 23).


Fig. 23. Change in C-peptide levels at 6 and 12 months after 12 weekly doses of BHT-3021 or placebo [Gottlieb, P. et al., Abst 66-OR].


Without much detail, undue in a report like this, some mention of the benefits of individual dietary approaches on the prevention and/or treatment of diabetes were presented during the meeting, including: studies concluding on the lower risk of type 2 diabetes in adolescents with higher dairy intake [Malik, V.S. et al., Abst 1766-P]; the benefits of blueberry powder [Stull, A.J. et al., Abst 1769-P] or ω3-polyunsaturated fatty acid supplementation [Dondoi, C.I. et al., Abst 1774-P] on insulin sensitivity; those of chokeberry extract on postprandial apolipoprotein B-containing lipoproteins [Qin, B. and Anderson, R.A., Abst 39-LB]; the advantageous effect of a catehcin-rich caffeine-free beverage on high-molecular-weight adiponectin levels [Takeshita, M. et al., Abst 116-LB] (although caffeine was associated with increased glucose output during exercise, preventing exertional hypoglycemia in patients with type 1 diabetes [Gallen, I.W. et al., Abst 1184-P]); the positive impact of phytosterols on the cardiovascular risk profile [McIntosh, M.S. et al., Abst 1775-P]; and the favorable effect of magnesium supplementation on biomarkers and genes related to inflammation in overweight subjects [Chacko, S. et al., Abst 109-LB]. As an additional curious observation, vinegar-based pickles were noted to reduce mealtime glycemia in healthy adults, although not in women in the third trimester of pregnancy [Appel, C.L. et al., Abst 1947-P].


Islet transplantation offered an alternative to intensive insulin therapy in patients with type 1 diabetes, with potential for insulin independence [Locher, R. et al., Abst 139-OR]. Pretreatment of islet donors with exenatide improved graft function compared to post-transplant treatment of recipients only [Buss, J.L. et al., Abst 141-OR]. At an experimental mechanistic level, inhibition of interleukin-21 signaling pathway prolonged graft survival after islet transplantation, suggesting an innovative alternative for preventing alloimmune rejection [Petrelli, A. et al., Abst 162-OR]. In addition, a combination of thymoglobulin and CTLA4-Ig prevented autoimmunity recurrence after islet transplantation, reverting ongoing autoimmune diabetes in animal models [Vergani, A. et al., Abst 336-OR]. On the other hand, some immunosuppressive therapies, notably ciclosporin and tacrolimus, may induce insulin resistance and hyperglycemia and/or impair b-cell function and proliferation [Delgado, T.C. et al., Abst 2042-P; Velazquez, S.A. et al., Abst 2052-P]. However, metformin was effectively used for reversing immunosuppressant-induced hyperglycemia in experimental animal models [Shivaswamy, V. et al., Abst 2038-P].

As an alternative to islet transplantation, implantation of alginate-encapsulated insulin-producing cells differentiated from embryonic stem cells was demonstrated feasible and viable in diabetic animal models [Gao, Y. et al., Abst 2033-P], although bone marrow transplantation per se also improved islet function through increases in nerve growth factor [Hathout, E. et al., Abst 2041-P].


Sibutramine was confirmed effective in inducing body weight loss [Prajapati, R. et al., Abst 1878-P], but combination with levocarnitine provided additional, faster, greater benefits on inflammatory marker and hemoglobin A1c levels [Derosa, G. et al., Abst 1843-P], whereas initial observations with lorcaserin confirmed its benefits on body weight accompanied by improvements in lipid and glucose levels and blood pressure [Anderson, C.M. et al., Abst 1845-P; Fidler, M.C. et al., Abst 1855-P]. Reductions in body weight and additional decreases in hemoglobin A1c in obese patients with type 2 diabetes on stable metformin were also obtained with the microsomal triglyceride transfer protein inhibitor SLx-4090 [Tong, W. et al., Abst 651-P]. Although no news were reported on the use of rimonabant for obesity, the agent was shown to improve fatty acid flux in peripheral organs from animal models even in the absence of weight loss [Vaidyanathan, V. et al., Abst 1472-P].

Substantial, sustained reductions in body weight and adiposity and improvements in hemoglobin A1c levels in obese patients with type 2 diabetes resulted from treatment with phentermine/topiramate [Gadde, K. et al., Abst 382-OR] (Fig. 24) or naltrexone/bupropion [Hollander, P. et al., Abst 56-OR; Smith, S.R. et al., Abst 1848-P], the former offering additional benefits on insulin sensitivity, lipid levels, glycemic control and the overall cardiometabolic risk profile [Garvey, W.T. et al., Abst 1083-P; Garvey, W.T. et al., Abst 1842-P; Ryan, D.H. et al., Abst 1846; Gadde, K. et al., Abst 1847-P; Ryan, D.H. et al., Abst 1879-P] (Fig. 25), while naltrexone/bupropion also offered benefits on depressive symptoms in obese patients with major depression [McElroy, S.L. et al., Abst 1851-P]. In addition, weight loss without information being provided on any effect on hemoglobin A1c was reported with zonisamide/bupropion [Fujioka, K. et al., Abst 1841-P].

Fig. 24. Percent change in body weight after 56 weeks of treatment with phentermine/topiramate or placebo [Gadde, K. et al., Abst 382-OR].

Fig. 25. Change in the HOMA insulin resistance index and hemoglobin A1c levels after 56 weeks of treatment with phentermine/topiramate or placebo [Garvey, W.T. et al., Abst 1842-P; Gadde, K. et al., Abst 382-OR].


Treatment of overweight individuals with insulin resistance with resveratrol resulted in improved glucose metabolism and mitochondrial function [Kehlenbrink, S. et al., Abst 310-OR], the compound attenuating oxidative stress and exerting insulin-like activity on inflamed endothelium [Ko, S.H. et al., Abst 2028-P] and also improving glucose metabolism in older adults with impaired glucose tolerance [Crandall, J.P. et al., Abst 736-P]. and, incorporated in a nutraceutical preparation also containing polyphenols, improved oxidative and inflammatory responses to a high-fat, high-carbohydrate meal [Ghanim, H. et al., Abst 1583-P]. In a similar way, polyphenols from green tea inhibited adipogenesis, resulting in reduced ectopic fat deposits in obese-prone animal models [Tan, Y. et al., Abst 1063-P] and fumagillin, an inhibitor of methionine aminopeptidase-2, improved experimental obesity through an effect on fat metabolism and food intake [Hughes, T.E. et al., Abst 1803-P] and normalized glucose tolerance in obese animal models [Hughes, T.E. et al., Abst 24-LB].

In the experimental arena, selective inhibitors of hepatic atypical protein kinase C that improved lipid and carbohydrate metabolism during hyperinsulinemic obesity were described [Sajan, M.P. et al., Abst 738-P], whereas a fatty acid-binding protein-4 inhibitor with ability for improving diabetes and atherosclerosis but with deleterious effects on the cardiac function, was announced [Lamounier-Zepter, V. et al., Abst 1850-P]. In addition, bardoxolone [Saha, P.K. et al., Abst 1393-P] and the herbal product liuweidihuang-wang [Xue, Y. et al., Abst 1519-P] showed antidiabetogenic potential in animal models of diet-induced obesity, whereas chronic inhibition of the mammalian target of rapamycin (mTOR) with sirolimus caused a diabetes-like syndrome by stimulating gluconeogenesis and impairing insulin secretion [Houde, V. et al., Abst 1395-P], although the agent protected insulinoma cells from apoptosis [Farrelly, A.M. et al., Abst 1683-P].

As additional topics, while sebacic acid supplementation ameliorated fasting blood glucose and hemoglobin A1c levels, as well as glucose tolerance in obese animal models [Membrez, M. et al., Abst 1576-P], improvements in insulin resistance brought about by berberine in adipocytes long exposed to high-glucose concentrations were attributed to an effect on the inhibitor of nuclear factor κB kinase pathway [Yi, P. et al., Abst 747-P], the agent also reducing hydroxymethylgluratyl-coenzyme A reductase protein expression [Sui, Y. et al., Abst 1579-P]. Improvements in insulin resistance in glucose-fed animals were also obtained with the nonpeptide kinin B1 receptor blocker SSR-240612 [Pena Dias, J. and Couture, J., Abst 1636-P], which also prevented septic shock complications in diabetes [Tidjane, N. et al., Abst 1647-P], whilst sulfuretin isolated from Rhus verniciflua prevented cytokine-mediated streptozotocin diabetogenesis at the b-cell level [Song, M.Y. et al., Abst 1681-P].


Although largely underused in patients with type 2 diabetes [Fu, A.F. et al., Abst 1077-P], statins are among the best established therapies for atherogenic dyslipidemia, with pleiotropic benefits on lipid-independent phenomena, in which respect at equivalent lipid-lowering activity atorvastatin had a more pronounced effect on C-reactive protein levels than simvastatin [Sathyapalan, T. et al., Abst 1076-P]. Significant regression of thoracic and aortic abdominal plaques was demonstrated by cotreatment with atorvastatin and etidronate [Kawahara, T. et al., Abst 718-P]. However, untoward effects of atorvastatin on glycemic control and cutaneous microvascular reactivity were noted in patients with type 1 diabetes [Tehrani, S. et al., Abst 1070-P].

Complementing the activity of statins in combination regimens, the cholesterol absorption inhibitor ezetimibe showed an effect per se in reducing liver X receptor activity, thus improving the metabolic profile [Sugizaki, T. et al., Abst 42-LB], and ameliorating glucose tolerance and reducing chylomicron production in animal models of dyslipidemic insulin resistance [Naples, M. et al., Abst 1069-P].

Fibrates also have value in the management of dyslipidemia in diabetes, with a marked benefit on postprandial triglyceride levels, as demonstrated with fenofibrate in the ACCORD trial [Reyes-Soffer, G. et al., Abst 1075-P].

While niacin exerted a direct antilipolytic effect in healthy individuals [Nelson, R.H. 1399-P], a fixed-drug combination of niacin and laropiprant exerted meaningful phosphorus-lowering activity in dyslipidemic type 2 diabetes patients with hyperphosphatemic renal disease, offering a putative option for the management of stage 4 or 5 chronic kidney disease [Bostom, A.G. et al., Abst 1081-P].

Colesevelam brought about significant decreases in LDL-cholesterol levels in patients with type 1 diabetes accompanied by transient initial reductions in hemoglobin A1c that were not maintained over the long term [Garg, S.K. et al., Abst 654-P]. First-line therapy with a fixed combination of colesevelam and metformin offered meaningful cardiometabolic benefits on glycemia and cholesterolemia in patients with type 2 diabetes [Rosenstock, J. et al., Abst 0648-P] (Fig. 26).

Fig. 26. Percent of patients with hemoglobin A1c levels <7% and LDL-cholesterol levels <100 mg/dl after 16 weeks of treatment with metformin combined with colesevelam or placebo [Rosenstock, J. et al., Abst 0648-P].


Significant lipid-improving and antiatherosclerotic activity in preclinical models was demonstrated with the novel cholesteryl ester transfer protein inhibitor DRL-17822 [Alikunju, S. et al., Abst 616-P]. Phase I safety and tolerability data with the agent in healthy volunteers demonstrated safety, tolerability and pharmacokinetic feasibility, with dose-dependent increases in HDL-cholesterol without modifying triglycerides and total cholesterol [Hasham, S.N. et al., Abst 634-P; Bapat, A. et al., Abst 714-P].

Favorable initial human data were also reported with the peroxisome proliferator-activated receptor-a/δ/γ agonist GFT-505, which safely improved atherogenic dyslipidemia, and lipid and glucose homeostasis in prediabetic individuals [Hanf, R. et al., Abst 677-P; Hanf, R. et al., Abst 12-LB] and the adenosine A1 partial agonist, which lowered free fatty acid levels in otherwise healthy overweight individuals [Staehr, P. et al., Abst 13-LB].


Hypertension is a risk factor for developing diabetes, but some antihypertensive therapies have also been associated with an increased likelihood for diabetes, including b-blockers. Treatment with angiotensin-converting enzyme inhibitors may have a preventive role, as was demonstrated with trandolapril in the placebo-controlled PEACE trial [Vardeny, O. et al., Abst 1088-P], whereas spironolactone administered to high fructose-fed animal models improved hepatic steatosis [Wada, T. et al., Abst 1578-P]. In addition, the angiotensin receptor blocker valsartan improved glucose-stimulated insulin secretion and insulin sensitivity in normotensive patients with impaired glucose tolerance [van der Zijl, N.J. et al., Abst 22-LB]. On the other hand, the renin inhibitor aliskiren was demonstrated to penetrate into adipose and muscular tissue and reduce renin-angiotensin system activity, whereas amlodipine increased renin-angiotensin system activity without significantly affecting angiotensin II levels [Boschmann, M. et al., Abst 1839-P].

With mild to moderate adverse events only, a triple combination of olmesartan, amlodipine and hydrochlorothiazide offered significant blood pressure-lowering activity, resulting in significant proportions of patients with or without diabetes achieving target control [Oparil, S. et al., Abst 670-P], whereas individual antihypertensive agents, such as azelnidipine, showed antioxidant and insulin-sensitizing effects [Tatsumi, F. et al., Abst 1486-P]. On the other hand, in obese, normotensive patients without dyslipidemia, treatment with losartan did not improve skeletal muscle glucose metabolism or insulin-mediated vasodilatation, suggesting benefits restricted to patients with overt hypertension and insulin resistance [Gilbert, K. et al., Abst 845-P].

An additional information related improvements in blood pressure in adults with type 2 diabetes receiving vitamin supplements during months of low light exposure [Jarvandi, S. et al., Abst 1758-P].


Used to slow renal progression in patients with advanced-stage type 2 diabetes and chronic kidney disease, the spherical carbon adsorbent AST-120 prolonged survival, while reducing healthcare costs [Hayashino, Y. et al., Abst 939-P]. Improvements in renal function in diabetic nephropathy patients were demonstrated with benfotiamine [Constantin, C.G. et al., Abst 953-P].

Improvements in renal function in diabetic animal models resulted from treatment with pentosan polysulfate and pyridoxamine, suggesting potential for the prevention or management of diabetic nephropathy [Grosjean, F. et al., Abst 923-P], while vorinostat attenuated oxidative stress during experimental diabetic nephropathy through endothelial nitric oxide synthase-dependent mechanisms [Advani, A. et al., Abst 961-P]. On the contrary, clinical results indicated no benefit of cilostazol in patients with diabetic nephropathy [Luk, A.O.Y. et al., Abst 934-P].


While duloxetine proved noninferior to pregabalin for controlling pain in patients with diabetic neuropathy not responding to gabapentin [Tanenberg, R.J. et al., Abst 969-P] (Fig. 27), a phase II study confirmed the feasibility of treatment with SB-509, a plasmid DNA encoding a zinc finger DNA-binding protein transcription factor designed to upregulate vascular endothelial growth factor A gene, resulting in regenerative potential of even severe diabetic neuropathy [Benaim, E. et al., Abst 348-OR] (Fig. 28). In fact, mechanistic studies with the agent confirmed an effect in enhancing regeneration of epidermal nerve fibers and blood vessels [Ebenezer, G. et al., Abst 346-OR]. At an experimental preclinical level, potential as a treatment for diabetic neuropathy was suggested for ranirestat [Kakehashi, A. et al., Abst 1017-P] and exenatide [Himeno, T. et al., Abst 977-P], the latter especially in the case of central neuropathy and encephalopathy [Jin, H.Y. et al., Abst 349-OR], while a related aldose reductase inhibitor, epalrestat, improved diabetic wound healing by increasing nerve growth factor expression [Nakagaki, O. et al., Abst 1213-P]. In addition, chronic insulin therapy was shown able to improve central neuronal damage during severe hypoglycemia in diabetic animal models [Tanoli, T.S. et al., Abst 765-P]. In that context, dichloroacetate was shown to promote brain metabolism during acute hypoglycemia, with a neuroprotective effect [Herzog, R.I. et al., Abst 767-P]. Further preclinical studies suggested potential use against diabetic neuropathy for the metabotropic glutamate type 2 and 3 receptor agonist LY-379268 [Muragundla, A. et al., Abst 978-P] and the low-molecular-weight heparin sulodexide [Jin, H.Y. et al., Abst 997-P].

Fig. 27. Change in pain scores in patients receiving duloxetine alone or combined with gabapentin, or pregabalin [Tanenberg, R.J. et al., Abst 969-P].

Fig. 28. Response rates (improvement in nerve conduction velocity or reappearance of nonconducting nerves) after 120 days of treatment with SB-509 or placebo [Benaim, E. et al., Abst 348-OR].



In the experimental setting, the kallikrein inhibitor ASP-440 normalized retinal vascular permeability in models of diabetes, suggesting potential for preventing diabetic retinopathy [Chilcote, T.J. et al., Abst 610-P].


Cilostazol safely improved skin oxygenation in patients with type 2 diabetes and peripheral ischemic disease [Xiao, Z. et al., Abst 1214-P]. In addition, greater protection against cerebrovascular disease in diabetes was attributed to cilostazol compared to aspirin, because of the beneficial effect of the phosphodiesterase inhibitor on circulating endothelial progenitor cells and small, dense LDL particles [Ueno, H. et al., Abst 811-P].


Improved nitric oxide production in endothelial cells by the citrus polyphenol hesperidin indicated benefits on endothelial dysfunction, which translated into improved systemic inflammation in patients with metabolic syndrome [Rizza, S. et al., Abst 791-P]. Protection against endothelial oxidative stress was also reported with ω3-polyunsaturated fatty acids [Ishikado, A. et al., Abst 884-P], which on the negative side were associated with blunted benefits of exercise on nonalcoholic fatty liver disease and accompanying insulin resistance [Borengasser, S. et al., Abst 1555-P].


Daily or on-demand udenafil for treating erectile dysfunction in diabetes resulted in improvements in endothelial function [Han, K.A. et al., Abst 645-P].


Bromocriptine, a dopamine D2 receptor agonist, improved vascular oxidative stress and aortic stiffness in experimental animal models of hypertension [Ezrokhi, M. et al., Abst 252-OR].

The nuclear factor κB inhibitor salsalate prevented free fatty acid-induced insulin resistance in the skeletal muscle [Liu, J. et al., Abst 312-OR].

In patients with recent-onset type 1 diabetes, calcitriol had no benefit on residual b-cell function, metabolic control or insulin requirements [Bizzarri, C. et al., Abst 329-OR].

Nausea and vomiting secondary to gastroparesis were significantly improved by the ghrelin agonist TZP-101 [Ejskjaer, N. et al., Abst 613-P].

Local insulin delivery inhibited repair responses in the vessel wall, suggesting potential for insulin-releasing stents in the prevention of restenosis [Breen, D.M. et al., Abst 621-P].

Blockade of diabetes-induced thioredoxin-interacting protein (TXNIP) transcription resulted from treatment with verapamil through an effect on the nuclear factor Y [Cha-Molsatd, H. et al., Abst 734-P].

The use of an undisclosed somatostatin receptor-2 blocker improved and prevented hypoglycemia in animal models of recurrently hypoglycemic diabetes through an effect on glucagon [Yue, J.T.Y. et al., Abst 754-P].

Regardless of cotreatment with proton pump inhibitors, higher rates of platelet hyperreactivity despite concomitant treatment with aspirin and clopidogrel was identified in patients with diabetes [Khochtali, I. et al., Abst 854-P].

The diabetogenic profile of olanzapine was related to dysregulation of hepatic lipid metabolism [Park, J. et al., Abst 1532-P] but showed dependence on UDP-glucoronyltransferase 2B1067Y and 1A448V variants [Erickson, K.K. et al., Abst 1252-P].

Through elevation of nitric oxide availability, sildenafil improved hyperglycemia in experimental animals [Li, H. et al., Abst 1516-P].

Islet function in aged experimental models was improved by dehydroepiandrosterone replacement therapy [Almeida, F.N. et al., Abst 1743-P].