Partly cloudy skies and weather that was not as hot as expected greeted attendees at this year's ADA meeting in San Diego's Glasslamp District, where the 5th Avenue became a corridor linking Hillcrest with the Convention Center's seating by the bay. Many new research findings were discussed during the meeting's oral and poster sessions, including new trials with drugs currently available or in advanced clinical research corroborating or expanding previous findings on the usefulness of specific therapies in particular types of patients. Others covered new clinical and preclinical studies delineating novel putative therapeutic modalities that need to be further explored in future research, the results of which may hopefully be presented at future ADA meetings.
Although not the main issue reported, many of the clinical trials and observations described during this year's ADA meeting in San Diego included patients "suboptimally controlled” with prior therapies, including insulin or oral antidiabetic drugs. As a particular reflection of this, and to show that the situation is not different in Asian compared to Western countries, baseline data from the FINE study indicated delayed treatment intensification and insulin, despite local treatment guidelines for diabetes and other metabolic abnormalities and risk factors, while also documenting higher risks of hypoglycemia in countries with higher percentages of patients reaching goal hemoglobin A1c levels [Tsai, S.T. et al., Abst 1073-P; Ji, L. et al., Abst 1096-P]. Yet, at least in the case of type 1 diabetes, early intensive insulin therapy was associated with better beta cell preservation, regardless of the use of intravenous or multiple daily subcutaneous injections [Enander, R. et al., Abst 1222-P]. These are not mere side messages from the meeting highlights, because they reflect the clinical inertia against initiating or intensifying insulin therapy also documented in other studies [Khunti, K. et al., Abst 1115-P]. They further emphasize that, even in patients diagnosed with diabetes and treated for the disease, glycemic control is not attained in a vast majority, despite the availability of effective drugs and treatment strategies that should be able to provide full control of glycemia without unacceptable untoward effects in a large proportion of patients. In fact, and just as an example, a particular study comparing basal insulin versus basal plus prandial insulin indicated that patients with type 2 diabetes can achieve glycemic goals without body weight gain [Raccah, D. et al., Abst 1059-P].
However, can achieve does not always translate into achievement, further exemplified by the results of a survey that observed modest changes in clinical practice but still high hemoglobin A1c levels at initiation of metformin, despite the evidence and recommendations, leading the investigators to question whether this is a matter of clinical inertia, failure to diagnose type 2 diabetes, or lack of trust in available evidence [Boudreau, D. et al., Abst 1337-P].
As a consequence, new drugs and therapeutic strategies are being actively researched to offer further therapeutic tools with which to help patients with type 1 or 2 diabetes attain glycemic control without weight gain and without an excess risk of hypoglycemia. It will remain in the practitioners' field to decide on the best treatment for each particular patient and ensure his or her full control of glucose and all other cardiovascular risk factors.
Insulin remains the cornerstone of the treatment for type 1 diabetes, and is an indispensable component of treatment for type 2 diabetes, in which regard basal insulin combined with oral antidiabetic drugs improved glycemic control and beta cell function more efficiently than oral therapy alone in patients with newly diagnosed disease [Mu, P.W. et al., Abst 1051-P]. However, insulin may also offer additional advantages, among which a study presented during ADA 2011 indicated efficacy for preventing new-onset diabetes after kidney transplant, an effect related to improved endogenous insulin secretion [Hecking, M. et al., Abst 0072-OR].
Continuous subcutaneous insulin infusion was shown to be effective for maintaining glycemia while improving the quality of care in diabetes [AMD Annals Study Group, Abst 0925-P]. In type 2 diabetes, such treatment improved hemoglobin A1c levels and the proportion of normoglycemic time throughout the day, even in patients with severe hemoglobin A1c elevations [Rodbard, D. et al., Abst 0924-P], with the initial response in patients with newly diagnosed type 2 diabetes predicting long-term euglycemia [Liu, J. et al., Abst 1106-P] and a delay in disease progression [Liu, J. et al., Abst 1111-P]. Insulin therapy has been associated with stress and fear, especially in patients prone to severe hypoglycemia, in which case the use of multiple daily injections or continuous subcutaneous insulin infusion was associated with a reduced risk of death compared to other forms of insulin therapy [Grubina, R. et al., Abst 0491-P].
Novel formulations of insulin include oral enteric capsules, which in healthy volunteers exhibited hypoglycemic activity with an action-time profile comparable to subcutaneous NPH insulin, although with wide interindividual variability in absorption [Li, J.Q. et al., Abst 0075-OR]; inhaled insulin, which improved glycemic control of type 1 diabetes [Garg, S.K. et al., Abst 0941-P], proved safe regarding cardiovascular events [Bilheimer, D.W. et al., Abst 0922-P; Baughman, R.A. et al., Abst 0933-P] and improved hemoglobin A1c levels as effectively as insulin lispro, but was associated with lower fasting and postprandial glucose levels, a reduced risk for hypoglycemia and increased patient satisfaction in patients also receiving multiple daily injections with insulin glargine [Garg, S.K. et al., Abst 0917-P; Petrucci, R.E. et al., Abst 0940-P] (Fig. 1); and chromium insulin, which restored glucose homeostasis in experimental animal models of type 1 diabetes [Sahim, K. et al., Abst 1129-P]. In addition, a needleless jet injector of rapid-acting insulin analogues with faster glucose-lowering activity was described, which also reduced the duration of hyperinsulinemia [De Galan, B.E. et al., Abst 0028-LB].
Fig. 1. Rates of hypoglycemia during 16 weeks of adding inhaled insulin or insulin lispro to multiple daily injections with insulin glargine [Garg, S.K. et al., Abst 0917-P].
Among rapid-acting insulin analogues, insulin aspart was reported to be safe and effective, with a low likelihood for minor or major hypoglycemia in elderly patients with type 2 diabetes [Upgrade Italian Study Group, Abst 0499-P].
Based on published evidence reviewed during ADA, premixed insulin lispro is a cost-effective option for treating type 2 diabetes [Pollock, R. et al., Abst 0418-PP], with the additional benefit of being one of the insulin analogues with less anti-insulin antibody responses, hence requiring less progressive dose increases [Morita, S. et al., Abst 1022-P]. Another rapid-acting recombinant human insulin proved effective for maintaining hemoglobin A1c levels without hypoglycemia or excessive body weight gain in patients with type 1 or 2 diabetes [Hollander, P. et al., Abst 1024-P; Rodbard, H.W. et al., Abst 1025-P]. An additional rapid-acting analogue, insulin glulisine, was associated with improved micro- and macrovascular and cardiovascular outcomes compared to NPH insulin in real-life clinical practice [Kress, S. et al., Abst 0066-LB].
Insulin glargine-based antidiabetic therapy was considered feasible as a standard of care based on experience from a healthcare institution [Wynja, L. et al., Abst 1015-P], and switch from NPH insulin to insulin glargine resulted in reduced glucose fluctuations, without increasing the risk of hypoglycemia [Kvapil, M. et al., Abst 1037-P]. Insulin glargine combined with prandial insulin glulisine was associated with a comparable effect on body weight but improved fasting plasma glucose-lowering activity, higher glycemia control rates, a lower likelihood for hypoglycemia and greater benefits on the patients' quality of life than other insulin-based regimens, including premixed biphasic insulin aspart [Rosenstock, J. et al., Abst 0073-OR; Riddle, M.C. et al., Abst 0409-PP] and NPH plus regular human insulin [Bueno, E. et al., Abst 1082-P]. In fact, a modest weight loss not impairing the patients' quality of life was demonstrated in additional studies using insulin glargine [Hajos, T.R.S. et al., Abst 0845-P], insulin glargine remaining effective and improving the quality of life also in patients with diabetic nephropathy on hemodialysis [Tanaka, E. et al., Abst 0942-P], and being as safe as NPH insulin during pregnancy [Lepercq, J. et al., Abst 0949-P]. Furthermore, although NPH insulin was also active, insulin glargine exerted greater, longer-lasting enhancing effects on nitric oxide release, resulting in attenuation of oxidative vascular and renal endothelial stress [Mason, R.P. et al., Abst 0578-P]. However, the addition of insulin glargine to continuous subcutaneous insulin infusion was associated with worsened glucose variability, calling for caution in children with type 1 diabetes [Tridgell, A.H. et al., Abst 1220-P]. Pharmacokinetic insight into the profile of subcutaneous insulin glargine indicated rapid, dose-independent conversion to an active metabolite accounting for almost all the pharmacodynamic effect of the insulin analogue, with only marginal exposure to the unmetabolized compound [Bolli, G.B. et al., Abst 0071-OR; Lucidi, P. et al., Abst 1092-P]. Regarding mechanistic pharmacodynamics, insulin glargine was associated with insulin receptor phosphorylation comparable to but delayed with respect to human insulin, whereas insulin aspart resulted in higher phosphorylation levels for longer periods of time, neither of the compounds inducing phosphorylation of insulin-like growth factor 1 receptor [Tennagels, N. et al., Abst 1562-P].
Another long-acting insulin analogue, insulin detemir, was as effective as other basal insulin regimens, but was associated with less weight gain at relatively higher insulin doses compared to NPH insulin or insulin glargine, although the latter was associated with a lower incidence of hypoglycemia and insulin detemir showed lower pharmacodynamic potency requiring higher doses, especially in the presence of increased adiposity [Li, S. et al., Abst 0938-P; Porcellati, F. et al., Abst 0948-P; Sheldon, B. et al., Abst 0963-P]. In fact, compared to NPH insulin, insulin detemir was associated with a decrease in waist circumference and fewer episodes of hypoglycemia at doses resulting in comparable effects on hemoglobin A1c levels [Tinahones, F.J. et al., Abst 1125-P], but also resulted in greater increases in cerebral glucose metabolism, which may be related to the weight gain-sparing effect of insulin detemir [Van Golen, L.W. et al., Abst 1540-P], although compared to insulin NPH, insulin detemir was also associated with a food switch towards reduced protein and fat intake, which may also be related to the lower propensity of the long-acting analogue for inducing weight gain [Zachariah, S. et al., Abst 1539-P]. As a complement, in vitro studies in adipose stem cells indicated less adipogenesis and lipid droplet accumulation during exposure to insulin detemir compared to human insulin [Cignarelli, A. et al., Abst 1602-P]. Furthermore, additional studies indicated higher doses of insulin detemir compared to insulin glargine across a wide range of body mass indices [Holleman, F. et al., Abst 1046-P], while other observations suggested comparable maternal and fetal outcomes but a lower total cost using insulin detemir as a treatment for type 1 diabetes during pregnancy compared to continuous subcutaneous insulin infusion [Ottanelli, S. et al., Abst 1279-P], whereas compared to NPH insulin, the use of insulin detemir during pregnancy was associated with comparable outcomes and hemoglobin A1c levels but lower fasting plasma glucose at similar rates of hypoglycemia [Mathiesen, E.R. et al., Abst 0061-LB; Hod, M. et al., Abst 0062-LB]. In addition, insulin detemir with insulin aspart was associated with improved postprandial glucose control and better cardiac function compared to human insulin in patients with type 2 diabetes [Von Bibra, H. et al., Abst 1522-P]. On the other hand, the results of the A1chieve study using insulin detemir, insulin aspart and biphasic insulin aspart indicated poor control of diabetes at the moment patients with type 2 diabetes were started on insulin analogue therapy, regardless of prior use of other insulins [Soewondo, P. et al., Abst 1045-P], but independent data from other trials indicated better control of oxidative stress with once-daily insulin detemir than insulin aspart three times a day [Naruse, R. et al., Abst 1061-P].
With a multi-hexameric soluble structure resulting in ultra-long glucose-lowering effects [Kurtzhals, P. et al., Abst 0042-LB] due to a half-life twice as long as that of insulin glargine (25.4 hours vs. 12.5 hours) and more consistent pharmacokinetics [Heise, T. et al., Abst 0037-LB], such that extended dosing intervals of up to 40 hours maintained glycemic control with flexibility in the time of administration (whereas insulin glargine required consistent administration at the same time every day) [Meneghini, L. et al., Abst 0035-LB], the novel long-acting insulin analogue insulin degludec offered sustained, flat, control of glucose levels [Nosek, L. et al., Abst 0049-LB], and was safe and as or more effective than biphasic insulin aspart and insulin glargine in terms of glycemic control, but was associated with lower risk of nocturnal hypoglycemia than either comparator in patients with type 2 diabetes [Heller, S. et al., Abst 0070-OR; Garber, A.J. et al., Abst 0074-OR; Vaag, A. et al., Abst 1141-P] (Fig. 2), and exhibited less pharmacodynamic variability over a 24-hour period than insulin glargine [Heise, T. et al., Abst 0960-P]. Furthermore, a combination of basal insulin degludec plus insulin aspart bolus boosts was associated with less nocturnal hypoglycemia and a reduced total number of daily injections than conventional bolus insulin therapy [Hirsch, I.B. et al., Abst 1064-P]. In addition, insulin degludec enhanced counterregulatory hormone responses to an induced hypoglycemia compared to insulin glargine, further explaining the lower risk of hypoglycemia during treatment with the novel long-acting analogue [Pieber, T. et al., Abst 0498-P].
Fig. 2. Proportion of patients with hemoglobin A1c (HbA1c) < 7% and rate of nocturnal hypoglycemia during 1 year of treatment with insulin degludec or insulin glargine [Heller, S. et al., Abst 0070-OR].
A further putative long-acting insulin-like product, proinsulin-transferrin fusion protein was effectively converted to insulin by hepatocytes, resulting in a hepato-specific hypoglycemic agent with a protracted half-life [Wang, Y. et al., Abst 0937-P].
With an effect in accelerating prandial insulin pharmacokinetics and hence glucodynamics [Muchmore, D.B. et al., Abst 0965-P], the addition of human hyaluronidase to recombinant human insulin increased the dispersion and absorption of the insulin moiety, resulting in reduced early absorption variability [Morrow, L. et al., Abst 0027-LB], with activity comparable to insulin lispro on postprandial glucose excursions and control without safety and tolerability concerns [Buse, J.B. et al., Abst 0069-OR]. However, pegylated recombinant hyaluronidase per se was able to reverse diet-induced insulin resistance in experimental animal models through an effect on increased extracellular matrix deposition, which has been related with insulin resistance in the skeletal muscle [Kang, L. et al., Abst 1526-P].
Compared to sulfonylureas, the treatment of type 2 diabetes with metformin was associated with longer time to and a lower risk of cardiovascular events, especially ischemic heart disease [Fu, A.Z. et al., Abst 0038-OR] (Fig. 3). In this regard, metformin was found to be particularly safe and effective in the treatment of diabetes in patients with comorbid heart failure [Eurich, D. et al., Abst 0953-P]. Furthermore, metformin exhibited notable advantages in the treatment of type 2 diabetes during pregnancy, as it lowered insulin requirements and facilitated the return to previous weight after labor, compared with the persistent weight gain in women receiving insulin alone [Pernicova, I. et al., Abst 1280-P]. On the other hand, metformin was reported to be safe even in patients with reduced glomerular filtration rate, although with a risk for lactic acidosis in older patients [Frid, A. et al., Abst 0364-OR]. In addition, meta-analysis data indicated a lower risk of cancer in diabetes patients receiving metformin [Noto, H. & Noda, M., Abst 1112-P], while the combined use of metformin and statin synergistically prevented prostate cancer in patients with type 2 diabetes [Wang, C.P. & Lehman, D.M., Abst 0944-P]. Furthermore, metformin also appeared to attenuate muscle mass loss, at least as measured by appendicular lean mass, in older men with diabetes [Lee, C.G. et al., Abst 1294-P]. However, metformin has contraindications (including advanced heart failure and renal and hepatic failure), although registry data indicated frequent use of the agent even in patients in which the drug is not recommended by the current guidelines [Marcin, K. et al., Abst 1134-P]. Also in relation to metformin, a preclinical study in diabetic fatty animals revealed a renal gluconeogenesis-inhibiting effect independent of the activity of key gluconeogenic enzymes [Baverel, G. et al., Abst 1672-P]. A final mechanistic study with metformin demonstrated dipeptidyl peptidase 4-independent induction of glucagon-like peptide 1 receptor release from intestinal L-cells through a not fully clarified mechanism involving the parasympathetic nervous system, but not the vagus nerve [Mulherin, A.J. et al., Abst 1791-P].
Fig. 3. Incidence of cardiovascular events, specifically cardiovascular disease (CVD) and ischemic heart disease (IHD), during 2 years of treatment with metformin or sulfonyl-urea [Fu, A.Z. et al., Abst 0038-OR].
Metformin also offered advantages in nondiabetic patients at risk for type 2 diabetes, in whom it improved inflammation, endothelial function and coagulation parameters as effectively as intensive lifestyle intervention [Temprosa, M. et al., Abst 0119-OR]. Furthermore, the use of metformin or an intensive lifestyle intervention represented comparable cost-effective alternatives for preventing type 2 diabetes [Herman, W.H. et al., Abst 0136-LBOR].
Although with a higher risk of hypoglycemia than other antidiabetic medications [Tschöpe, D. et al., Abst 1293-P] and a higher likelihood of cancer than metformin [Sun, G. et al., Abst 1350-P], sulfonylureas are still valuable treatment options for diabetes. While mechanistic comparative data demonstrated higher selectivity for gliquidone for pancreatic beta cells compared to cardiac ATP-dependent potassium channels, suggesting similar efficacy but higher cardiac safety [Liu, S.Y. et al., Abst 1074-P], improvements in myocardial dysfunction in animal models of obesity undergoing experimental ischemic injury were demonstrated with gliclazide [Bao, Y.G. et al., Abst 0952-P]. As a side comment, ATP-dependent potassium channel opening was identified as a possible mechanism of the antidiabetic activity of rimonabant and ipinabant [Lynch, C.J. et al., Abst 2011-P], whereas improvements in glycemic control were also documented with the non-brain-penetrant cannabinoid CB1 receptor inverse agonist JD-5037 [Tam, J. et al., Abst 0038-LB].
Although not a sulfonylurea, the potassium channel-blocking insulin secretagogue nateglinide controlled postprandial glycemia as effectively as acarbose, but offered greater improvements in the postprandial lipid profile through restoration of the early-phase insulin response, suggesting a cardiovascular risk advantage for the alpha-glucosidase inhibitor [Lu, J. et al., Abst 1062-P].
Although effective for improving the control of glycemia in diabetes without impacting on sodium excretion, at least after single doses in healthy volunteers [Foucher, C. et al., Abst 0612-P], peroxisome proliferator-activated receptor-gamma agonist thiazolidinediones were associated with an increased likelihood for diabetic macular edema [Idris, I. et al., Abst 0135-OR].
Novel studies indicated the benefit of pioglitazone on insulin requirements and glycemic and lipid control, even in type 2 diabetes patients on hemodialysis [Pfützner, A.H. et al., Abst 1148-P], with the additional benefit compared to metformin of lowering blood pressure and albuminuria and improving the overall cardiovascular risk profile [Forst, T. et al., Abst 1159-P; Hanefeld, M. et al., Abst 1156-P] (Fig. 4). Additional studies corroborated the lipid benefits of pioglitazone, which prevented recurrences of new-onset hyperglycemic crises, delaying the need for insulin therapy in overweight African American individuals [Smiley, D. et al., Abst 0369-OR], and demonstrated decreases in small dense LDL particles towards a less atherogenic potential when used in combination with insulin glargine [Fuchs, W. et al., Abst 0054-OR]. Furthermore, pio-glitazone combined with metformin improved insulin sensitivity, which was reflected by increases and decreases in a number of amino acid metabolites [Weymiller, A.J. et al., Abst 1701-P]. Similarly, pioglitazone, but not metformin/insulin glargine without pioglitazone, improved insulin resistance and the cardiometabolic profile, although the triple combination maintained the benefits with an additional decrease in hemoglobin A1c levels [Pfützner, A. et al., Abst 1160-P] (Fig. 5). Finally, pioglitazone also exerted an insulin-sensitizing effect in nondiabetic obese subjects with insulin resistance [Shankar, S.S. et al., Abst 1531-P], prediabetic subjects with impaired glucose tolerance (an effect that was accompanied by increased adiponectin and decreased proinflammatory adipocytokine levels) [Tripathy, D. et al., Abst 1597-P] and women with polycystic ovary syndrome that was related to an antiinflammatory effect on the muscle [Ciaraldi, T.P. et al., Abst 1158-P]. However, independently of the impact of treatment on other metabolic risk factors, pioglitazone exerted activity against carotid atherosclerosis progression in patients with impaired glucose tolerance and/or hypertriglyceridemia [Saremi, A. et al., Abst 0036-OR; Schwenke, D.C. et al., Abst 0037-OR], and prevented myocardial steatosis and diabetic cardiomyopathy in diabetic animal models of early-stage diabetes [Abdurrachim, D. et al., Abst 0946-P], effects that were complemented by increased glucose-dependent insulinotropic receptor expression in adipocytes [Sideleva, O. et al., Abst 1604-P], although pioglitazone did not modify glucose-dependent insulinotropic peptide-stimulated insulin secretion in type 2 diabetes patients with well-controlled glycemia [Tharp, W.G. et al., Abst 1630-P]. In experimental animal models, the insulin-sensitizing activity of pioglitazone resulted in improved muscle oxidative capacity and reduced intramyocellular lipid levels [Wessels, B. et al., Abst 1100-P], while it induced adrenomedullin expression in pancreatic islets, hence attenuating endoplasmic reticulum stress in beta cells [Ohta, Y. et al., Abst 1949-P]. On the other hand, the proapoptotic effect of pioglitazone on osteoblasts was prevented by estrogens, at least in in vitro studies [Sheng, H. et al., Abst 0943-P].
Fig. 4. Change in hemoglobin A1c (HbA1c) levels and the HOMA insulin resistance (HOMA-IR) index after treatment with pioglitazone and/or metformin [Hanefeld, M. et al., Abst 1156-P].
Fig. 5. Change in hemoglobin A1c (HbA1c), adiponectin and C-reactive protein (CRP) levels after treatment with combinations of pioglitazone and metformin with insulin glargine [Pfützner, A. et al., Abst 1160-P].
Regarding rosiglitazone, a study in patients with impaired glucose tolerance suggested a transient insulin-sensitizing effect for the thiazolidinedione combined with metformin, which resulted in a non-sustained reduction in incident type 2 diabetes not maintained over time [Retnakaran, R. et al., Abst 0366-OR], whereas a mechanistic study indicated upregulation of LDL lipoprotein receptor-related protein 1 expression in brain microvessels, restoring impaired clearance of beta-amyloid in diabetes [Kim, H.J. et al., Abst 1155-P] (low-dose insulin also suppressed beta-amyloid precursor protein expression [Dandona, P. et al., Abst 1519-P]). On the other hand, a study in experimental animals demonstrated improvements in sirolimus-induced hyperglycemia after treatment with rosiglitazone [Shivaswamy, V. et al., Abst 1482-P].
Concerning balaglitazone, a comparative, placebo-controlled study demonstrated effective lowering of hemoglobin A1c levels in patients with type 2 diabetes on stable insulin therapy, although less potently than pioglitazone, but with less fluid and fat accumulation than the reference thiazolidinedione [Henriksen, K. et al., Abst 1150-P] (Fig. 6).
Fig. 6. Placebo-corrected changes in hemoglobin A1c after 26 weeks of treatment with balaglitazone or pioglitazone [Henriksen, K. et al., Abst 1150-P].
A novel non-thiazolidinedione dual peroxisome proliferator-activated receptor-delta/gamma agonist, DB-959 proved safe and pharmacokinetically feasible in healthy volunteers upon single daily dosing [Delmedico, M.K. et al., Abst 1044-P].
A study of aleglitazar in experimental animals indicated potential for preventing diabetes progression and protecting against end-organ diabetic damage and dysfunction [Bénardeau, A. et al., Abst 1058-P].
Pramlintide was a useful add-on therapy for improving glycemic control in type 1 diabetes patients on subcutaneous insulin [Herrmann, K. et al., Abst 1065-P], and was effective for lowering hemoglobin A1c levels in patients with type 2 diabetes as well [Herrmann, K. et al., Abst 1063-P], according to pooled analyses of randomized and open-label trials, which also documented a favorable impact on body weight and insulin dose requirements. Pharmacodynamic activity was reported with pramlintide, which delayed peak postprandial glucose levels while reducing the amplitude of glucose excursion after a meal [Weinzimer, S.A. et al., Abst 0926-P]. In the preclinical setting, anorexigenic activity was also demonstrated with UGP-281, a peptidic amylin receptor agonist [Mehta, N. et al., Abst 0115-LB].
Glucagon-like peptide 1 receptor agonists such as exenatide and liraglutide have been associated with beneficial effects on glycemic control associated with substantial weight loss in patients with or without type 2 diabetes and reduced insulin requirements, with a very low risk of hypoglycemia [Vilsbøll, T. et al., Abst 1146-P; Vilsbøll, T. et al., Abst 1076-P; Lind, M. et al., Abst 1075-P]. This was further corroborated by the sustained improvement in glycemic control and weight loss over a 3-year treatment period in patients receiving exenatide [MacConell, L. et al., Abst 0969-P], while in fact, real-world clinical practice data indicated comparable glycemic control with exenatide and insulin, but weight loss and less hypoglycemia with the incretin analogue [Guerci, B. et al., Abst 1032-P]. In addition, while both exenatide and glimepiride improved glycemic control in patients with uncontrolled type 2 diabetes who could not tolerate high-dose metformin, only exenatide also improved insulin resistance [Derosa, G. et al., Abst 1071-P] (Fig. 7). Moreover, intensified therapy with exenatide and insulin glargine improved previously poor glycemic control in patients with type 2 diabetes, without increasing the risk for hypoglycemia [Levin, P. et al., Abst 0972-P], the addition of exenatide to the insulin analogue preventing the increase in body weight noted with insulin glargine alone [Buse, J. et al., Abst 0973-P]. In addition, while pioglitazone had no effect on fibroblast growth factor 21 levels despite reducing hepatic fat content in patients with type 2 diabetes, the addition of exenatide significantly reduced both hepatic fat content and fibroblast growth factor 21 levels, suggesting benefits in nonalcoholic steatohepatitis [Sathyanarayana, P. et al., Abst 0410-PP]. Moreover, the addition of exenatide to other glucose-lowering therapies, especially insulin, reduced the risk of developing heart failure [Best, J.H. et al., Abst 1133-P], and the agent exerted a direct antiatherogenic effect by suppressing inflammatory macrophage responses [Liang, C.P. & Tall, A.R., Abst 0005-LB]. However, exenatide, like tretinoin, did not prevent or rescue diabetes after islet transplant in genetically diabetic-prone animal models [Juang, J.H. & Van, Y.H., Abst 1478-P], although exenatide did improve pancreatic beta cell function, at least in experimental models of obese type 2 diabetes [Ionut, V. et al., Abst 1784-P]. In addition, treatment of diabetic animals with exenatide also resulted in attenuation of hyperglycemia-related cardiomyocyte apoptosis [Younce, C.W. & Ayala, J.E., Abst 1785-P], as well as increased bone mineral density [Kim, J.Y. et al., Abst 1786-P], while in vitro exposure to the agent upregulated the expression of protein Wnt-4, a beta cell proliferation regulator [Heller, C. et al., Abst 2034-P] and improved handling of pro-islet amyloid polypeptide, suggesting potential for reducing islet amyloidosis [Chen, H. et al., Abst 1930-P]. A particular study focused on the benefits of adding exenatide to dietary interventions in the management of prediabetes, but concluded that intensified dietary management alone yielded comparable results without an added benefit for the incretin mimetic [McLaughlin, T. et al., Abst 0034-LB]. On the other hand, an analysis of an insured population of patients treated with exenatide did not find any association with such treatment and an increased risk of pancreatitis, contradicting recent concerns [Romley, J. et al., Abst 0045-LB].
Fig. 7. Change in hemoglobin A1c (HbA1c) and the HOMA insulin resistance (HOMA IR) index after 12 months of treatment with exenatide or glimepiride [Derosa, G. et al., Abst 1071-P].
Weekly exenatide was associated with improved glycemic control regardless of background antidiabetic therapy [Malone, J. et al., Abst 1066-P], and as monotherapy was associated with similar tolerability and control of hemoglobin A1c and fasting blood glucose levels and body weight [Brunell, S.C. et al., Abst 1034-P; Pencek, R. et al., Abst 1033-P; Moretto, T. et al., Abst 1038-P], both being superior to standard metformin, pioglitazone or sitagliptin therapy in previously untreated type 2 diabetes patients and associated with a low risk for hypoglycemia [Cuddihy, R.M. et al., Abst 0280-OR] (Fig. 8), whereas the addition of weekly exenatide to ongoing metformin or metformin/sulfonylurea therapy achieved better glycemic control than add-on insulin glargine, also with a more favorable impact on body weight and a lower risk of hypoglycemia [Diamant, M. et al., Abst 0277-OR] (Fig. 9). Weekly exenatide was also demonstrated to be safe, without an effect on the QT interval [Sager, P. et al., Abst 1070-P], but was associated with a reduction in blood pressure closely related to the glucose- and body weight-lowering activity [Paul, S. et al., Abst 1077-P]. Furthermore, exenatide appeared to protect the kidney from diabetic nephropathy, with better maintained renal function compared to placebo in a randomized, controlled trial [Tuttle, K. et al., Abst 0971-P], the agent also preventing neointima formation after balloon injury [Kang, S.M. et al., Abst 0956-P] and inducing systemic cellular and molecular antiinflammatory activity [Chaudhuri, A. et al., Abst 0970-P]. Exenatide also protected beta cells against palmitate-induced apoptosis, an effect mediated by downmodulation of free fatty acid receptor expression [Natalicchio, A. et al., Abst 0470-PP]. However, significant decreases in hemoglobin A1c during exenatide therapy were associated with accelerated progression of diabetic retinopathy, requiring frequent monitoring [Shminarayanan, L. et al., Abst 0137-OR], and the benefits of exenatide on the lipid profile were lost in patients with optimally controlled lipid levels at treatment initiation [Alattar, M. et al., Abst 0542-P]. On the other hand, exenatide proved effective for reducing adiposity and improving the cardiometabolic profile of nondiabetic young subjects with obesity [Kelly, A.S. et al., Abst 0420-PP], in which regard an anorexic effect of the agent was identified, which was not mediated by changes in the endogenous glucagon-like peptide 1 pathways in the central nervous system [Jelsing, J. et al., Abst 1083-P]. Furthermore, exenatide stimulated beta cell replication regardless of age in animal donors, but in the case of human donors the replication-stimulating effect was limited to younger subjects under 22 years of age [Tian, L. et al., Abst 0165-OR]. The agent also prevented the cytotoxic effects of diabetes on retinal pigment epithelial cells by reducing advanced glycosylation end product-specific receptor and intercellular adhesion molecule 1 and vascular cell adhesion protein 1 expression [Dorecka, M. et al., Abst 0671-P]. Finally, intravenous exenatide was a feasible option for intensive care unit patients with sustained hypoglycemia, with efficacy comparable to that of intravenous insulin but no risk for hypoglycemia [Marso, S.P. et al., Abst 0275-OR].
Fig. 8. Change in hemoglobin A1c (HbA1c) levels and body weight after 26 weeks of treatment with weekly exenatide or daily metformin, pioglitazone or sitagliptin [Cuddihy, R.M. et al., Abst 0280-OR].
Fig. 9. Proportion of patients (pts) on metformin (MET) or metformin plus sulfonylurea (MET/SU) with hemoglobin A1c (HbA1c) levels < 7% during 84 weeks of treatment with weekly exenatide or insulin glargine, and the proportion of patients with minor hypoglycemia [Diamant, M. et al., Abst 0277-OR].
Like weekly exenatide, monthly treatment with a novel suspension formulation also offered robust improvements in glycemia in patients with type 2 diabetes [MacConell, L. et al., Abst 0046-LB] (Fig. 10), but effective control of glycemic parameters and body weight with positive cardiovascular benefits was also demonstrated with continuous subcutaneous exenatide infusion [Rosenstock, J. et al., Abst 0135-LBOR] (Fig. 11). Furthermore, a construct of exenatide with the recombinant polypeptide XTEN to generate a monthly dosing formulation of exenatide for type 2 diabetes (half-life of 120 hours), VRS-859, was shown to be well tolerated in patients with type 2 diabetes, resulting in improved glycemic control, with significant decreases in fasting plasma glucose levels at 4 and 8 days after dosing [Cleland, J.L. et al., Abst 1016-P].
Fig. 10. Change in hemoglobin A1c levels after 3 months of treatment with weekly (wk) or monthly (mo) exenatide [MacConell, L. et al., Abst 0046-LB].
Fig. 11. Change in hemoglobin A1c (HbA1c) levels and body weight after 48 weeks of treatment with increasing doses of continuous subcutaneous exenatide infusion [Rosen-stock, J. et al., Abst 0135-LBOR].
With an advantage over glycemic control and body weight compared to exenatide and sitagliptin [Zinman, B. et al., Abst 1055-P] (Fig. 12), resulting in an increased proportion of patients achieving hemoglobin A1c goals upon switch from exenatide [Buse, J. et al., Abst 1117-P], effective glycemic control of type 2 diabetes with weight loss at a low incidence of hypoglycemia in a clinical practice audit [McLaughlin, C. et al., Abst 1084-P] and a direct weight-lowering effect added to the benefits of diet [Wadden, T.A. et al., Abst 1859-P], significant benefits in patients with type 2 diabetes derived from the addition of liraglutide to oral antidiabetic drugs or insulin, with improvements in hemoglobin A1c levels, body weight and glycemic variability over time accompanied by a decrease in insulin requirements [Anholm, C. et al., Abst 1142-P; Ghosal, S., Abst 1144-P; Varanasi, A. et al., Abst 0411-PP; Taniguchi, Y. et al., Abst 1128-P]. In fact, switch from sitagliptin plus metformin to liraglutide plus metformin also resulted in improved glycemic control, weight loss and increased patient satisfaction [Montanya, E. et al., Abst 1118-P; Pratley, R. et al., Abst 1119-P]. Nevertheless, liraglutide demonstrated greater efficacy in untreated or patients treated with only one oral antidiabetic medication compared to patients receiving two or more prior therapies [Garber, A. et al., Abst 0967-P]. On the other hand, besides improving glycemia, liraglutide exerted favorable effects on the endothelium, resulting in improved retinal microvascular responses to flicker light [Mitry, M. et al., Abst 0966-P]. In addition, liraglutide inhibited gastric emptying through central effects independent from vagal afferents [Vrang, N. et al., Abst 1126-P], while a switch of food preference was noted upon initiation of liraglutide, which in a cohort of regular alcohol drinkers was associated with a marked drop in alcohol intake [Kalra, S. et al., Abst 1029-P].
Fig. 12. Change in hemoglobin A1c (HbA1c) and body weight after 26 weeks of treatment with liraglutide, exenatide or sitagliptin [Zinman, B. et al., Abst 1055-P].
The novel, long-acting glucagon-like peptide 1 mimetic albiglutide also induced glycemic benefits, accompanied by direct benefits on cardiac metabolic efficiency and energetic, which resulted in improved myocardial function during experimental ischemic injury [Bao, W. et al., Abst 0459-PP]. Another novel glucagon-like peptide 1 receptor agonist, lixisenatide, improved glycemic control in patients with type 2 diabetes insufficiently controlled with insulin alone or combined with sulfonylurea [Seino, Y. et al., Abst 0278-OR], and exerted cardioprotective activity against ischemia-reperfusion injury in experimental conditions [Huber, J. et al., Abst 0968-P]. Compared to exenatide, lixisenatide was noninferior in terms of drop in hemoglobin A1c levels, but was associated with less common hypoglycemia, slightly reduced weight gain and better gas-trointestinal tolerability [Rosenstock, J. et al., Abst 0033-LB] (Fig. 13). Another experimental compound, LY-2189265, was safe and well tolerated in healthy volunteers and devoid of untoward effects on the QT interval even at supratherapeutic doses [Loghin, C. et al., Abst 1089-P]. In patients with type 2 diabetes, the compound dose-dependently lowered hemoglobin A1c and blood glucose levels with an acceptable safety and tolerability profile [Grunberger, G. et al., Abst 1094-P] (Fig. 14).
Fig. 13. Proportion of patients with hemoglobin A1c (HbA1c) levels < 7% and symptomatic hypoglycemia during 24 weeks of treatment with lixisenatide or exenatide [Rosenstock, J. et al., Abst 0033-LB].
Fig. 14. Percent of patients with hemoglobin A1c levels < 7% after 12 weeks of treatment with LY-2189265 or placebo [Grunberger, G. et al., Abst 1094-P].
With a glucose-lowering effect mediated by reduced glucose absorption, decreased postprandial glucose excursions and attenuated glucagon responses [Muscelli, E. et al., Abst 0975-P] and activity against type 1 and advanced type 2 diabetes in patients with insulin deficiency mediated by mechanisms other than inhibition of dipeptidyl peptidase 4 [Kutoh, E., Abst 1056-P], sitagliptin was confirmed to be an effective therapy for type 2 diabetes, with additional antiinflammatory activity reflected in decreases in C-reactive protein, interleukin-6 and TNF-alpha levels [Dandona, P. et al., Abst 1114-P]. However, mechanistic data indicated that the effects of sitagliptin were mediated not only by inhibition of dipeptidyl peptidase 4, but also by stimulation of glucagon-like peptide 1 secretion from intestinal L-cells [Sangle, G.V. et al., Abst 1769]. Effective suppression of ghrelin in patients with diabetes was demonstrated with the agent and metformin alone or in combination [Seyoum, B. et al., Abst 1800-P], sitagliptin, but not metformin, also stimulating reverse cholesterol transport in experimental animal models, adding a further beneficial effect on the cardiovascular risk profile [Briand, F. et al., Abst 0684-P]. In fact, add-on sitagliptin significantly improved glycemic control in patients on metformin [Yang, W. et al., Abst 1113-P] or metformin plus pioglitazone [Fonseca, V. et al., Abst 1120-P], and a fixed-drug combination of sitagliptin and metformin has been developed, which, according to new evidence reported in San Diego, provided superior glycemic control over metformin monotherapy [Seck, T.L. et al., Abst 1057-P]. However, the complementary but independent glucose-lowering activity of both compounds in previously untreated type 2 diabetes resulted in synergistic activity, reinforcing the use of fixed-drug combination therapy [Migoya, E. et al., Abst 0980-P] (Fig. 15). Furthermore, improved glycemic control in experimental animal models resulted from a combination of sitagliptin and colesevelam [Shang, Q. et al., Abst 1122-P]. At least in experimental models, prolonged exposure to sitagliptin was not associated with exocrine pancreatic abnormalities [Hull, R.L. et al., Abst 0976]. On the other hand, sitagliptin can be used at correspondingly adjusted doses in patients with renal failure, and the high correlation found between estimated glomerular filtration rate and estimated creatinine clearance in patients treated with the agent facilitated the dose selection process [Arjona Ferreira, J.C. et al., Abst 1079-P].
Fig. 15. Change in serum insulin, C-peptide and glucagon levels after treatment with sitagliptin and/or metformin [Migoya, E. et al., Abst 080-P].
New studies and observations were also reported on saxagliptin, which offered a safe, well tolerated treatment for improving glycemia in patients suboptimally controlled on insulin monotherapy [Kadowaki, T. et al., Abst 1019-P]. In fact, adding saxagliptin to ongoing metformin therapy resulted in more patients at hemoglobin A1c goal without hypoglycemia or weight gain than adding glimepiride [Bouzamondo, H. et al., Abst 1109-P] (Fig. 16) or glipizide [Göke, B. et al., Abst 1110-P], while compared to placebo saxagliptin improved glycemic control in patients uncontrolled on insulin alone or combined with metformin [Charbonnel, B. et al., Abst 1108-P]. Furthermore, saxagliptin proved as safe and well tolerated as placebo over a 4-year follow-up in patients already receiving metformin or sulfonylureas [Rosenstock, J. et al., Abst 1086-P; Allen, E. et al., Abst 1087-P], and as an add-on medication it improved glycemic control of type 2 diabetes more effectively than uptitrated metformin in patients with poorly controlled disease [Fonseca, V. et al., Abst 1018-P] (Fig. 17).
Fig. 16. Proportion of patients with hemoglobin A1c < 7% without hypoglycemia during 52 weeks of add-on saxagliptin or glimepiride to patients with hemoglobin A1c levels of 7-8.5% during prior metformin therapy [Bouzamondo, H. et al., Abst 1109-P].
Fig. 17. Proportion of patients with hemoglobin A1c < 7% after 18 weeks of adding saxagliptin to metformin 1500 mg or uptitrating metformin to 2000 mg [Fonseca, V. et al., Abst 1018-P].
New information was likewise available on alogliptin, reported to improve glucose metabolism as effectively as voglibose, while also, as opposed to the glucosidase inhibitor, improving lipid levels and LDL particle size in patients with type 2 diabetes or impaired glucose tolerance [Tsuchiya, M., Abst 1021-P]. In the preclinical stage, a combination of alogliptin and pioglitazone significantly improved glycemic control of type 2 diabetes while enhancing beta cell function [Akiyama, M. et al., Abst 1028-P].
With pleiotropic vasodilating and antioxidant activity not shared by other dipeptidyl peptidase 4 inhibitors [Schuff, A. et al., Abst 0981-P], linagliptin was confirmed to be an effective, well-tolerated option for the treatment of type 2 diabetes in patients with poor glycemic control in a meta-analysis of three randomized trials [Del Prato, S. et al., Abst 1067-P]. A combination of linagliptin and metformin resulted in effective gly-cemic control without weight gain and with a low risk of hypoglycemia in type 2 diabetes, with superiority over either drug as monotherapy [Haak, T. et al., Abst 0279-OR] (Fig. 18). In addition, linagliptin was safe and remained clinically effective in diabetic patients with severely impaired renal function [Sloan, L. et al., Abst 0413-PP]. The overall comparative impact of the agent or glimepiride on cardiovascular outcomes in patients with type 2 diabetes and increased cardiovascular risk will be further determined in the CAROLINA trial [Rosenstock, J. et al., Abst 1103-P], but results from a comparative study already indicated similar reductions in hemoglobin A1c levels, but less hypoglycemia, weight loss rather than gain and less cardiovascular events with the dipeptidyl peptidase 4 inhibitor [Gallwitz, B. et al., Abst 0039-LB] (Fig. 19), while a meta-analysis of randomized, double-blind studies also indicated lower cardiovascular event rates with linagliptin versus comparators (placebo, glimepiride and voglibose) [Johansen, O.E. et al., Abst 0030-LB]. In experimental mechanistic studies, linagliptin preserved beta cell function and delayed diabetes in genetically prone animals [Jelsing, J. et al., Abst 1123-P], and it was further shown to reduce intramyocellular and hepatic lipid accumulation brought about by a fat-rich diet in models of obesity [Klein, T. et al., Abst 0415-PP], and to reduce urinary albumin excretion in animals resistant to angio-tensin receptor blockade, suggesting potential as a treatment for refractory diabetic nephropathy [Alter, M. et al., Abst 0978-P]. Linagliptin also proved active in experimental animal models for improving glycemia, reducing adipocyte size and body weight, and preserving beta cell mass [Takahashi, T. et al., Abst 0983-P; Uchida, S. et al., Abst 1000-P]. Moreover, linagliptin was not only neutral on weight in experimental animals, but inhibited weight gain upon withdrawal of exenatide [Vickers, S.P. et al., Abst 0979-P]. In addition, the agent increased active glucagon-like peptide 2 levels, resulting in decreased colonic cytokine levels in models of inflammatory bowel disease [Klein, T. et al., Abst 1124-P]. As a final comment on linagliptin, it should be noted that studies in experimental animals suggested safe use in combination with other therapies, including metformin, pioglitazone and the sodium/glucose cotransporter 2 inhibitor BI-10773 [Thomas, L. et al., Abst 1035-P].
Fig. 18. Change in hemoglobin A1c levels after 24 weeks of treatment with linagliptin and/or metformin [Haak, T. et al., Abst 0279-OR].
Fig. 19. Cardiovascular event rates during 2 years of treatment with linagliptin or glimepiride [Gallwitz, B. et al., Abst 0039-LB].
Compared to glimepiride, the use of vildagliptin as a treatment for type 2 diabetes was associated with better outcomes considering patients achieving glycemic control (hemoglobin A1c levels under 7%), without hypoglycemia or weight gain, during a 2-year period [Ferrannini, E. et al., Abst 1017-P] (Fig. 20). In the preclinical arena, vildagliptin improved glucose tolerance and beta cell mass in insulin receptor substrate 2-deficient animals [Sato, K. et al., Abst 1929-P], and combined with rosiglitazone it significantly reduced hepatic steatosis and triglyceride levels, suggesting potential as a treatment for non-alcoholic fatty liver disease [Mookkan, J. et al., Abst 1036-P].
Fig. 20. Proportion of patients with hemoglobin A1c < 7% without hypoglycemia or weight gain during 2 years of treatment with vildagliptin or glimepiride [Ferrannini, E. et al., Abst 1017-P].
A novel dipeptidyl peptidase 4 inhibitor currently in development, the xanthine derivative BI-14361, exerted cardioprotective activity against ischemia, reducing infarct size and myocardial fibrosis and improving cardiac function in experimental animal models [Sharkovska, Y. et al., Abst 0974-P]. Another novel compound, SK-0403, improved glucose tolerance, insulin resistance and body weight in high-fat diet-fed animals [Nakaya, K. et al., Abst 2020-P].
With selective inhibition of the sodium/glucose cotransporter 2 over other glucose transporters [Bellamine, A. et al., Abst 0987-P; Poucher, S.M. et al., Abst 1041-P] resulting in an effective decrease in postprandial glucose used as mono- or combination therapy with glimepiride or pioglitazone [Salsali, A. et al., Abst 1104-P], and with a low propensity to induce hypoglycemia [Rohwedder, K. et al., Abst 1042-P], dapagliflozin has been previously shown to reduce glucose reabsorption in the kidneys, providing an effective glucose-lowering therapy for type 2 diabetes. Further mechanistic data confirmed the safety of dapagliflozin regarding hypoglycemia, as the agent showed a ceiling effect in lowering glucose levels in experimental hyperglycemic animals, without affecting glucose levels in normoglycemic animals [Zinker, B. et al., Abst 0995-P]. Experimental animal studies also revealed that chronic control of hyperglycemia with dapagliflozin resulted in enhanced hepatic insulin action, inhibiting endogenous glucose production and enhancing beta cell function [Zinker, B. et al., Abst 1031-P], and modulation of hepatic fatty acid metabolism-related gene expression without upregulation of glucose transporters in the kidney [Guan, B. et al., Abst 1137-P]. Combined treatment with dapagliflozin and metformin offered an effective, well-tolerated therapy for type 2 diabetes, with benefits on glycemia and body weight superior to those obtained with the respective monotherapies [Henry, R.R. et al., Abst 0307-OR] (Fig. 21), and in fact, additional evidence demonstrated sustained improvements in glycemic control accompanied by reductions in body weight without an excess risk of hypoglycemia upon adding dapagliflozin compared to placebo to ongoing treatment with metformin [Bailey, C.J. et al., Abst 0988-P] (Fig. 22). In that regard, add-on dapagliflozin improved glycemic control more effectively than glipizide in patients suboptimally controlled with metformin, with additional weight loss and a lower risk for hypoglycemia [Nauck, M. et al., Abst 0040-LB] (Fig. 23). Dapagliflozin was also effectively combined with pioglitazone, resulting in enhanced therapeutic activity while mitigating body weight gain, with a low risk for hypoglycemia [Rosenstock, J. et al., Abst 0986-P] (Fig. 24). Furthermore, a modest decrease in plasma uric acid levels, a recognized independent cardiovascular risk factor, after treatment with dapagliflozin in patients with normal levels at baseline was reported [Hardy, E. et al., Abst 1043-P].
Fig. 21. Proportion of patients with hemoglobin A1c levels < 7% after 24 weeks of treatment with dapagliflozin and/or metformin in two independent trials [Henry, R.R. et al., Abst 0307-OR].
Fig. 22. Change in hemoglobin A1c levels after 102 weeks of adding dapagliflozin or placebo to metformin [Bailey, C.J. et al., Abst 0988-P].
Fig. 23. Change in hemoglobin A1c levels after (left chart) and proportion of patients with hypoglucemia during (right chart) 2 years of treatment with dapagliflozin or glipizide [Nauck, M. et al., Abst 0040-LB].
Fig. 24. Change in hemoglobin A1c levels after 24 weeks of adding dapagliflozin or placebo to pioglitazone [Rosenstock, J. et al., Abst 0986-P].
A related sodium/glucose cotransporter inhibitor, canagliflozin, also improved glycemic control and body weight in patients with type 2 diabetes compared to placebo [Inagaki, N. et al., Abst 0999-P] (Fig. 25), with an exposure-dependent effect similar in Japanese and Western patients [Polidori, D. et al., Abst 1072-P]. Mechanistically, the glucose excretion-promoting effect of canagliflozin was related to a decrease in the renal glucose threshold [Liang, Y. et al., Abst 1090-P]. However, compared to placebo or sitagliptin, canagliflozin was associated with an increased likelihood for Candida colonization or symptomatic vulvovaginal candidiasis [Nyirjesy, P. et al., Abst 0032-LB], although without increasing the risk for bacteriuria or urinary tract infections [Nicolle, L. et al., Abst 0043-LB].
Fig. 25. Change in fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) levels and body weight after 12 weeks of treatment with canagliflozin or placebo [Inagaki, N. et al., Abst 0999-P].
Clinical trial data supporting the use of ipragliflozin were also discussed during ADA 2011, the results of a placebo-controlled trial indicating improvements in fasting and postprandial glucose levels accompanied by an increase in urinary glucose excretion in patients with type 2 diabetes [Akiyama, N. et al., Abst 1023-P] (Fig. 26). However, the presence of renal failure increased exposure to the agent, although it remained well tolerated, but resulted in lower urinary glucose excretion in patients with diabetes and impaired renal function [Veltkamp, S.A. et al., Abst 1127-P]. Preclinical research with ipragliflozin indicated increased fatty acid oxidation and antiobesity activity in models of diet-induced obesity [Takasu, T. et al., Abst 1814-P].
Fig. 26. Change in fasting plasma glucose (FPG) levels, 24-hour urinary glucose excretion (UGE) and body weight after 14 days of treatment with ipragliflozin or placebo [Akiyama, N. et al., Abst 1023-P].
Glucose-lowering activity accompanied by a decrease in blood pressure resulted from PF-04971729, another sodium/glucose cotransporter 2 inhibitor, in type 2 diabetes patients with high blood pressure [Amin, N.B. et al., Abst 0048-LB] (Fig. 27). Significant increases in urinary glucose excretion were demonstrated in healthy volunteers with the experimental inhibitor TS-071, the agent being well tolerated, with feasible pharmacokinetics [Sasaki, T. et al., Abst 1140-P] unaffected by the presence of renal failure [Friedrich, C. et al., Abst 1105-P], and proving effective for improving glycemia and body weight in patients with type 2 diabetes [Seino, Y. et al., Abst TS-071], with favorable renal safety and maintained effectiveness in patients with renal failure [Cooper, M. et al., Abst 1068-P]. Favorable pharmacokinetics and dose-dependent decreases in hemoglobin A1c levels and body weight were similarly described for BI-10773, another sodium/glucose cotransporter 2 inhibitor that was pharmacodynamically active and well tolerated in patients with type 2 diabetes [Rosenstock, J. et al., Abst 0989-P] (Fig. 28), and in experimental animals it prevented pioglitazone-induced weight gain when used concomitantly [Grempler, R. et al., Abst 1851-P], whereas another dual inhibitor, LX-4211, effectively improved glycemic control in patients with type 2 diabetes while increasing glucagon-like peptide 1 and peptide YY levels [Powell, D. et al., Abst 0982-P].
Fig. 27. Change in 24-hour systolic (SBP) and diastolic blood pressure (DBP) after 4 weeks of treatment with PF-04971729, hydrochlorothiazide or placebo [Amin, N.B. et al., Abst 0048-LB].
Fig. 28. Change in hemoglobin A1c levels after 12 weeks of adding BI-10773, sitagliptin or placebo to ongoing metformin therapy [Rosenstock, J. et al., Abst 0989-P].
In the experimental arena, improvements in pancreatic and renal function in models of type 2 diabetes were reported with two further sodium/glucose cotransporter 2 inhibitors, tofogliflozin [Fukuzawa, T. et al., Abst 1135-P; Suzuki, M. et al., Abst 1136-P], and BI-38335 (combined with linagliptin) [Chen, L. et al., Abst 2001-P].
While LY-259906 proved effective for improving fasting and postprandial glycemia in patients with type 2 diabetes without affecting glucagon levels [Bue-Valleskey, J.M. et al., Abst 0993-P], at least at the experimental level, the glucokinase activator piragliatin normalized insulin release from and energy production in beta cells from diabetic islets [Doliba, N. et al., Abst 0473-PP], and whereas the dual glucagon-like peptide 1 and gastrin agonist ZP-3022 prevented diabetes in diabetes-prone experimental animals [Fosgerau, K. et al., Abst 1653-P], another glucokinase activator, named compound A, prevented beta cell apoptosis during endoplasmic reticulum stress, suggesting potential for preventing type 2 diabetes in diabetes-prone animal models [Shirakawa, J. & Terauchi, Y., Abst 0185-OR], and compound C preserved beta cell mass under obese, diabetic conditions [Berger, J. et al., Abst 1012-P].
Favorable pharmacokinetics and pharmacodynamic activity resulting in improved fasting and postprandial glycemia in patients with type 2 diabetes were demonstrated using the free fatty acid receptor agonist TAK-875 [Araki, T. et al., Abst 0312-OR; Leifke, E. et al., Abst 0414-PP; Viswanathan, P. et al., Abst 0134-LBOR] (Fig. 29) (activation of the free fatty acid receptor by TAK-875 combined with metformin [with a beta cell function-improving effect] [Ito, R. et al., Abst 1002-P] and SAR1 [Herling, A.W. et al., Abst 0452-PP] also reduced blood glucose levels via a glucose-dependent effect on insulin levels in experimental animal models), whereas in vitro exposure to another free fatty acid receptor agonist, TUG-469, stimulated insulin secretion [Ullrich, S. et al., Abst 2023], and in vitro and in vivo results with CNX-011-67 also indicated benefits on fasting and nonfasting glycemia [Jagannath, M.R. et al., Abst 0031-LB]. Moreover, the glucagon receptor blocker MK-0893 inhibited glucagon-induced hyperglycemia compared to placebo in healthy volunteers, without meaningfully interfering with recovery from hypoglycemia, at least at the dose of 200 mg [Troyer, M.D. et al., Abst 0494-P], and, along with LY-2409021, another glucagon receptor blocker that also lowered glucose levels in healthy volunteers and patients with type 2 diabetes [Kelly, R.P. et al., Abst 1004-P] (Fig. 30) (as well as human glucagon receptor-transfected experimental animal models [Farb, T.B. et al., Abst 1673-P]), resulted in improved glycemic control, with decreases of fasting plasma glucose and hemoglobin A1c levels in patients with type 2 diabetes, although, at least in the case of MK-0893, at the cost of untoward effects on LDL cholesterol and transaminase levels and body weight [Kelly, R.P. et al., Abst 0305-OR; Engel, S.S. et al., Abst 0309-OR; Ruddy, M. et al., Abst 0311-OR; Tham, L.S. et al., Abst 0416-PP] (Fig. 31). Preclinical findings further confirmed the benefits of glucagon receptor blockade on lipid and glucose metabolism [Li, X. et al., Abst 0103-LB]. Efficacy and safety as a treatment for type 2 diabetes were similarly reported with the chemokine CCR2 receptor blocker CCX-140, which improved hemoglobin A1c levels compared to placebo, without detrimental effects on monocyte chemoattractant protein 1 levels or monocyte counts [Hanefeld, M. et al., Abst 0310-OR] (Fig. 32), and the anti-interleukin-1beta neutralizing antibodies canakinumab [Rissanen, A. et al., Abst 0036-LB] and LY-2189102 [Sloan-Lancaster, J. et al., Abst 0047-LB] (Fig. 33), which effectively lowered hemoglobin A1c and C-reactive protein levels, with a favorable safety and tolerability profile. Chemokine receptor blockade in experimental diabetic, obese animal models also resulted in metabolic and renal improvements [Sullivan, T. et al., Abst 0606-P], whereas activation of NAD-dependent deacet-ylase surtuin-1 by SRT-2104 improved insulin sensitivity while promoting glucose utilization and normalizing cardiac, hepatic and muscular function in experimental conditions [Qi, Y. et al., Abst 1007-P; Suri, V. et al., Abst 1706]. Because of the inflammatory component of type 2 diabetes, improved glycemic control in patients with the disease also resulted from add-on treatment with diacerein [Pei, D. et al., Abst 0308-OR]. In addition, without suggesting direct therapeutic utility, inhibition of lysine deacetylase by vorinostat and givinostat protected beta cells against inflammatory activity resulting from nuclear factor NF-kappab pathway activation, suggesting potential to be explored [Christensen, D.P. et al., Abst 0477-PP], whereas inhibition of 12-lipoxygenase by small-molecule inhibitors exhibited beta cell-preserving activity on isolated islets [Taylor, D.A. et al., Abst 1006-P].
Fig. 29. Change in fasting (FPG) and post-oral glucose tolerance test plasma glucose (post-OGTTG) levels in patients treated with TAK-875 or placebo [Araki, T. et al., Abst 0312-OR].
Fig. 30. Change in fasting plasma glucose levels 24 hours after a single dose of LY-240921 or placebo in patients with type 2 diabetes [Kelly, R.P. et al., Abst 1004-P].
Fig. 31. Change in fasting plasma glucose (FPG), hemoglobin A1c (HbA1c) and LDL cholesterol (LDL-C) levels after 12 weeks of treatment with MK-0893, metformin or placebo [Engel, S.S. et al., Abst 0309-OR].
Fig. 32. Change in hemoglobin A1c levels after 28 days of treatment with CCX-140, pioglitazone or placebo [Hanefeld, M. et al., Abst 0310-OR].
Fig. 33. Change in hemoglobin A1c levels after 12 weeks of treatment with LY-2189102 or placebo [Sloan-Lancaster, J. et al., Abst 0047-LB].
While the glucose-dependent insulinotropic receptor agonist PSN-821 stimulated basal and postprandial glucose-dependent insulinotropic peptide, glucagon-like peptide 1 and peptide YY secretion in the gut of experimental animals [Mace, O.J. et al., Abst 1132-P], hence effectively lowering glucose levels and decreasing energy intake in patients with type 2 diabetes in a placebo-controlled trial [Goodman, M.L. et al., Abst 0306-OR] (Fig. 34), another similarly acting compound, GSK-1292263, was well tolerated and pharmacokinetically feasible, without drug-drug interactions with sitagliptin, but was not meaningfully effective on glycemic control, regardless of cotreatment with sitagliptin or metformin [Nunez, D.J. et al., Abst 0996-P]. In the preclinical arena two other glucose-dependent insulinotropic receptor agonists, AR-231453 and AS-1790091, stimulated stimulated beta cell replication and improved islet graft function, suggesting therapeutic utility [Tian, L. et al., Abst 0166-OR], and improved insulin resistance and beta cell function while reducing body weight in type 2 diabetes animal models [Yoshida, S. et al., Abst 1001-P], whereas, without intrinsic activity, the glucagon receptor blocker ZP-2929 maintained the improved glycemic control of insulin glargine or insulin detemir but prevented weight gain [Fosgerau, K. et al., Abst 1527-P]. Also in the preclinical arena, prevention of hyperglycemic insulinitis, inflammation and beta cell apoptosis was noted after treatment with 11-keto-boswellic acid [Ammon, H.P.T. et al., Abst 1014-P] and the small-molecule selective cytokine suppressor BRD-0476 [Hung-Chieh, D. et al., Abst 1937-P], putative improvements in plasma glucose levels in experimental animal models were demonstrated with an antisense nucleotide against pyruvate carboxylase [Kumashiro, N. et al., Abst 1693-P], improvements in lipid and glucose homeostasis were shown in animal models of diet-induced insulin resistance by adding the adenosine A1 receptor partial agonist GS-9677 (which inhibited adipocyte lipolysis [Chisholm, J.W. et al., Abst 1611-P]) to sitagliptin [Ning, Y. et al., Abst 0977-P] and by administering curcumin [Shao, W. et al., Abst 1617-P] (curcumin also improving skeletal muscle atrophy by inhibiting protein ubiquitination [Ono, T. et al., Abst 1717-P]), amelioration of glucose metabolism but decreases in gallbladder emptying were reported with a G-protein coupled bile acid receptor 1 agonist compound A [Hubert, J. et al., Abst 1003-P] and prolonged antidiabetic activity was revealed with the long-acting fibroblast growth factor 21 construct CVX-343 [Huang, J. et al., Abst 1040-P], pointing towards a novel therapeutic target for type 2 diabetes. Improved beta cell regeneration via an effect on cyclin D3 and p57Kip2 expression in further animal models after treatment with the novel lysophospholipid analogue LP-2008, leading to insulin-free diabetes in the animals, suggested novel putative treatment strategies to be further explored [Zhao, Z. & Ma, Z.A., Abst 0188-OR]. Furthermore, bromocriptine synergistically improved glucose tolerance in experimental animals also treated with exenatide [Ezrokhi, M. et al., Abst 1633-P], while the glutathione peroxidase mimetic ebselen increased beta cell mass while preventing fasting hyperglycemia and loss of insulin secretion in obese animals [Mahadevan, J. et al., Abst 0994-P], further expanding potential therapies, the efficacy of which needs to be assessed. Additional antidiabetic activity in experimental animal models was described with zinc oxide nanoparticles [Umrani, R.D. & Paknikar, K.M., Abst 1147-P], whereas in vitro observations of an effect on type 2 diabetes of inducible nitric oxide synthase and preliminary observations with small molecules targeting cyclic AMP generation supported a role for adenylate cyclase and phosphodiesterase modulators [Balhuizen, A. et al., Abst 2016-P].
Fig. 34. Change in fasting plasma glucose levels and body weight after 14 days of treatment with PSN-821 alone or combined with metformin, or placebo [Goodman, M.L. et al., Abst 0306-OR].
Specifically in type 1 diabetes, the anti-CD3 monoclonal antibody teplizumab induced lymphocytopenia by inducing migration and sequestration of regulatory T lymphocytes to the small intestine, suggesting a role in the development of tolerance to the agent [Waldron-Lynch, F. et al., Abst 0329-OR]. Further clinical findings related to putative novel therapeutic strategies for type 1 diabetes included a study that revealed sustained increases in interleukin-2 responsiveness and transient decreases in C-peptide levels after treatment with sirolimus plus interleukin-2, indicating no promotion of regulatory T-cell isolation by increases in natural killer and effector T-cell responses [Long, S.A. et al., Abst 0332-OR]. Regarding preclinical findings, reversion of recent-onset diabetes was demonstrated after cotreatment with anti-interleukin-1beta antibody and GAD65 DNA vaccine [Pagni, P.P. & Von Herrath, M.G., Abst 0331-OR].
Regarding preventive strategies, a placebo-controlled trial indicated a reduced likelihood for developing type 2 diabetes in veterans with impaired glucose tolerance or impaired fasting glucose treated with salsalate, with a significant negative correlation between serum salicylate levels and the change in fasting glucose levels [Goldfine, A. et al., Abst 0050-OR]. Furthermore, salsalate was associated with reduced insulin secretion during fasting due to increased insulin responses to glucose load in patients with impaired glucose tolerance [Koska, J. et al., Abst 1640-P], and exhibited a neutral effect on the cardiovascular risk profile, suggesting benefits in diabetogenesis and atherogenesis, without untoward cardiac effects [Halperin, F. et al., Abst 0541-P]. In the preclinical scenario, prevention of lipid-induced inflammation and insulin resistance by the protectin D1 analogue 10(S),17(S)-DiHDoHE [White, P.J. et al., Abst 0336-OR] also suggested potential preventive strategies to be explored, whereas an anti-CD20 monoclonal antibody and proinsulin plasmid synergistically prevented type 1 diabetes in genetically prone animals [Sarikonda, G. et al., Abst 1009-P]. Prevention of renal injuries in animal models of diabetes was demonstrated with two novel plasminogen activator inhibitor 1 inhibitors, TM-5275 and TMS-5441 [Jeong, B.Y. et al., Abst 0004-OR].
Diet and dietary supplements have a major impact on glycemia, and in addition to improving control of established diabetes, they may also help prevent type 2 diabetes in patients at risk. As an example, flaxseed intake in subjects with prediabetes improved glucose and insulin levels and insulin sensitivity in a placebo-controlled trial [Hutchins, A. et al., Abst 0122-OR] (canola/flax oil supplementation [Hanke, D.P. et al., Abst 1677], as well as the lipolysis inhibitor acipimox [Lee, E.Y. et al., Abst 0111-LB], were associated with reduced hepatic steatosis in experimental models of obesity), whereas resveratrol induced improvements in insulin signaling in insulin-resistant, but not insulin-sensitive, conditions [Lee, D.H. et al., Abst 1559-P], and omega 3-polyunsaturated fatty acids improved the adipocytokine profile [Dragomir, A.D. et al., Abst 0021-LB] and protected against fatty diet-induced glucose intolerance, possibly by modifying ceramide content in the muscle [Lanza, I. et al., Abst 1839-P]. In addition, according to in vitro and in vivo experimental studies, conjugated linoleic acid stimulates insulin secretion, the effect also depending on an effect on free fatty acid receptors [Ullrich, S. et al., Abst 0284-OR], whereas lignin-rich fractions from Schisandra chinensis (magnolia vine) fruits improved insulin sensitivity through an effect on the peroxisome proliferator-activated receptor-gamma pathway [Park, S. et al., Abst 0784-P], stem extracts from Schisandra arisanensis prevented inflammatory cytokine-mediated cytotoxicity of beta cells through antiapoptotic and insulinotropic activity [Liu, H.K. et al., Abst 1097-P], and levocysteine supplementation decreased insulin resistance and vascular inflammation by increasing blood levels of hydrogen sulfide and nitrite [Jain, S.K. & Bull, R., Abst 0780-P]. In addition, the antioxidant terpene phytochemical astaxanthin improved in vitro glucose metabolism through modulation of insulin signaling [Ishiki, M. et al., Abst 1500-P], whereas triterpenes from Panax notoginseng (tienchi) showed antidiabetic activity [Iwasaki, H. et al., Abst 0109-LB], bioactives from Artemisia dracunculus (tarragon) exerted an insulin-sensitizing effect [Obanda, D.N. et al., Abst 1501] and triterpenoids isolated from Momordica charantia (bitter melon) activated the calcium/calmodulin-dependent protein kinase kinase alpha [Iseli, T.J. et al., Abst 1504-P].
The advanced glycosylation end product-specific receptor antagonist PF-04494700 proved safe and well tolerated in a placebo-controlled trial in patients with diabetic nephropathy, but had no effect on the urinary albumin:creatinine ratio in patients already receiving maximal doses of angiotensin-converting enzyme inhibitors or angio-tensin receptor blockers [Bell, J. et al., Abst 0957-P]. In the preclinical stage, the advanced glycosylation end product-specific receptor blocker KIOM-VN-118 exerted pharmacodynamic activity suggestive of potential therapeutic activity for preventing diabetic nephropathy [Jung, D.H. et al., Abst 0955-P].
Besides treatments for diabetic nephropathy, the use of epoetin for managing anemia in patients with diabetes on hemodialysis did not modify survival or cardiovascular events, with harmful rather than a beneficial effect [Zhang, Y. et al., Abst 1338-P].
Two phase III trials discussed in San Diego corroborated the benefits and safety of intravitreous ranibizumab as a treatment for diabetic macular edema, with important gains in visual acuity and a reduction in the need for laser therapy [Boyer, D.S. et al., Abst 0132-LBOR] (Fig. 35). At least in the experimental setting, the liver X receptor agonist GSK-3965 prevented hyperglycemic endothelial cell dysfunction, resulting in a reduced likelihood for inflammation and diabetic retinopathy [Grant, M.B. et al., Abst 0390-PP]. In the in vitro setting, prevention of 4-hydroxynonenal-induced cytotoxicity in retinal Müller cells was demonstrated for berberine, through interference with the AMP-dependent protein kinase/peroxisome proliferator-activated receptor alpha/nuclear factor NF-kappaB phosphorylation pathway, depending on stimulation of mitogen-activated protein kinase 1/3 [Zhang, J. et al., Abst 0703-P].
Fig. 35. Mean letters gained on best corrected visual acuity at 3 months in patients treated with ranibizumab or placebo in the RISE and RIDE trials [Boyer, D.S. et al., Abst 0132-LBOR].
Amitriptyline and alpha-lipoic acid were similarly effective in the treatment of peripheral diabetic neuropathy, although the tricyclic antidepressant was associated with greater improvement in the quality of life despite a higher frequency of adverse events [Psurek, A. et al., Abst 0638-P] (Fig. 36). Improvement in pain in patients with diabetic neuropathy also resulted from topical application of clonidine gel [Campbell, J.N. et al., Abst 0951-P] (Fig. 37), whereas improvement in symptoms and inflammation resulted from treatment with a combination of l-methylfolate, pyridoxal-5'-phosphate and methylcobalamin [Fonseca, V.A. et al., Abst 1053-P]. However, in experimental animal models pioglitazone was considered to be superior to alpha-lipoic acid, although the combination afforded increased benefits on nerve preservation [Park, T.S. et al., Abst 0657-P].
Fig. 36. Proportion of patients with 50% reduction in pain scores after treatment with amitriptyline or alpha-lipoic acid [Psurek, A. et al., Abst 0638-P].
Fig. 37. Mean change in the numeric pain rating scale for pain after 12 weeks of treatment with topical clonidine or placebo [Campbell, J.N. et al., Abst 0951-P].
In experimental animal models, the loop diuretic bumetanide had beneficial effects on peripheral diabetic neuropathy, increasing the thermal pain threshold at nondiuretic doses [Fernandes-Conti, F. et al., Abst 0639-P]. A pegylated C-peptide with potential as a therapeutic agent for diabetic neuropathy was characterized in experimental animal models [Callaway, J. et al., Abst 1049-P]. In patients with type 1 diabetes, subcutaneous C-peptide improved erectile function compared to placebo [Wahren, J. et al., Abst 1039-P]. Potential as a treatment for diabetic neuropathy based on experimental studies was similarly reported with exogenous ghrelin [Nagamine, K. et al., Abst 1138-P].
A late-breaking presentation on the treatment of diabetic foot ulcer indicated the cost-effectiveness of a human fibroblast-derived dermal substitute, which markedly improved and shortened healing rates compared to conventional therapy and "paid for itself” within 6 months from a U.S. payer perspective [Zhang, Y. & Hogan, P., Abst 0053-LB] (Fig. 38).
Fig. 38. Healing rates (left chart) and time to healing (right healing) in patients receiving a human fibroblast-derived dermal substitute (HFDS) or conventional therapy [Zhang, Y & Hogan, P. et al., Abst 0053-LB].
Regarding scattered information on statins, among the extralipidic pleiotropic effects of atorvastatin, a study in patients with type 2 diabetes indicated improvements in baroreflex sensitivity in normal-weight but not obese individuals [Grigoropoulou, P. et al., Abst 0642-P]. In addition to lowering LDL cholesterol levels, rosuvastatin improved serum YKL-40 levels and urinary albumin excretion, indicating benefits on stabilizing atherosclerotic plaque and prevention of nephropathy and other vascular complications of type 2 diabetes [Suzuki, Y. et al., Abst 0518-P]. Concerning pitavastatin, a study identified a nephroprotective effect as measured by changes in glomerular filtration rate in dyslipidemic patients with or without type 2 diabetes and increased cardiovascular risk [Sponseller, C.A. et al., Abst 1085-P].
With comparable activity on cholesterol and phytosterols in diabetic and nondiabetic, as well as obese and nonobese individuals [Ai, M. et al., Abst 0706-P], but insulin sensitivity- and lipid level-improving effects confirmed in hypercholesterolemic subjects [Morinaga, Y. et al., Abst 0692-P], ezetimibe without the combination with statins improved postprandial lipid and insulin profiles in hyperlipidemic, hyperglycemic individuals [Kikuchi, K. & Terauchi, Y., Abst 0690-P] and exerted nephroprotective activity derived from inhibition of cholesterol absorption and the resulting attenuation of oxidative stress. However, the addition of pitavastatin improved kidney damage by also facilitating nitric oxide release independent of the lipid-lowering activity [Mori, Y. & Hirano, T., Abst 0614-P].
In addition to improving the lipid profile, especially in combination with statins [Kelly, M.T. et al., Abst 0699-P], fenofibrate improved insulin sensitivity [Ida, Y.D. et al., Abst 1060-P] and brought about reductions in microvascular and cerebrovascular complications in type 2 diabetes, which were related to an effect on inflammation and oxidative stress [Jenkins, A.J. et al., Abst 0033-OR]. In this regard, improvements in diabetic retinopathy were observed, which were related to blockade of the Wnt pathway [Chen, Y. et al., Abst 0412-PP], although fenofibric acid per se also prevented interleukin-1beta-induced disruptions in the retinal pigment epithelium through suppression of AMP-dependent protein kinase activation [Simo, R. et al., Abst 0672-P]. In experimental models of obesity, fenofibrate also exerted a cholecystokinin receptor-mediated anorexigenic effect, possibly mediated by upregulation of cholecystokinin receptor expression in the small intestine [Han, Y. et al., Abst 1831-P]. In addition, like pioglitazone, fenofibrate upregulated adipose triglyceride lipase expression, resulting in decreased triglyceride levels in the skeletal muscle and improved insulin sensitivity [Wei, L. et al., Abst 1830-P].
With synergistic activity combined with simvastatin resulting in benefits on HDL and LDL cholesterol levels compared to atorvastatin monotherapy [Toth, P et al., Abst 0701-P] (Fig. 39), in addition to its known lipid benefits, niacin was associated with both increased levels of plasma adiponectin and insulin resistance in the skeletal muscle, although increased adiponectin blunted the negative effect on peripheral insulin resistance [Fraterrigo, G. et al., Abst 1872-P]. Mechanistically, intravenous niacin exerted additional lipolysis suppression and prevented fractional fatty acid spillover in subjects with adipose tissue lipolysis already suppressed by insulin [Nelson, R.H. et al., Abst 1533-P]. However, continuous exposure to niacin in experimental animals resulted in free fatty acid rebound and insulin resistance due to a gene expression switch towards increased basal lipolysis [Oh, Y. et al., Abst 1594-P].
Effective improvements in cholesterol levels and body weight accompanied by antihyperglycemic activity in obese patients with diabetes were similarly reported with the bile acid sequestrant colestilan [Kurioka, S., Abst 1088-P], which was also shown to be active in apolipoprotein E-deficient animal models of diet-induced obesity, in which it reduced visceral obesity by increasing the flux of free fatty acids from adipose tissue to the liver [Shimada, H. et al., Abst 0990-P].
Improved fasting and postprandial tissue glucose metabolism with accompanying improvements in hemoglobin A1c levels resulted from treatment with colesevelam in patients with type 2 diabetes, without such treatment having an effect on insulin sensitivity or insulin and glucagon levels [Beysen, C. et al., Abst 0370-OR; Smishkin, G. et al., Abst 1664-P] (Fig. 40). However, the agent improved oral but not intravenous glucose tolerance, the effect being independent from insulin sensitivity or beta cell function, suggesting an effect on glucose absorption or glucagon release [Marina, A.L. et al., Abst 0408-PP].
Fig. 39. Change in HDL and LDL particle levels after 12 weeks of treatment with ezetimibe/simvastatin or atorvastatin [Toth, P. et al., Abst 0701-P].
Fig. 40. Change in hemoglobin A1c levels after treatment with colesevelam or placebo [Smishkin, G. et al., Abst 1664-P].
As a different strategy for managing body weight and the lipid profile, the peroxisome proliferator-activated receptor-gamma-sparing thiazolidinedione MSCD-0160 showed potential as an insulin sensitizer and promoted the development of brown adipose tissue in experimental animal models [McDonald, W.G. et al., Abst 0092-OR]; in vitro studies indicated the effect of the agent to be mediated by activated AMP-dependent protein kinase and downregulated mammalian target of rapamycin (mTOR) expression [Rohatgi, N. et al., Abst 1973-P]. Also in the experimental laboratory, inhibition of fatty acid-binding protein 4/5 by BMS-309403 [Lan, H. et al., Abst 0685-P], inhibition of diacylglycerol O-acyltransferase in the jejunum [Leininger, M. et al., Abst 0179-OR] and supplementation with reduced-bitterness fenugreek [Muraki, E. et al., Abst 0693-P] prevented metabolic abnormalities on the lipid profile brought about by a high-fat diet, suggesting novel targets for intervention, whereas the interleukin-6/TNF-alpha production inhibitor BLX-1002 shower promising activity on body weight, liver enzyme levels and insulin resistance in models of nonalcoholic fatty liver disease [Narayanan, S. et al., Abst 1052-P] and the AMP-dependent protein kinase activator A-769662 increased fatty acid oxidation and depleted the liver of lipodystrophic animals of fat deposits [Foretz, M. et al., Abst 1679-P]. In this regard, inhibition of ceramide synthesis by myriocin also improved high-cholesterol diet-related lipidemia and adiposity, but not hepatic lipid levels, suggesting an effect on lipogenesis [Dekker, M.J. et al., Abst 0679-P], whereas inhibition of malonyl-CoA decarboxylase exerted antiobesity and antidiabetic activity related to suppression of fatty acid oxidation, but resulted in ectopic fat deposition [Wallenius, K. et al., Abst 1153-P]. In addition, inhibition of 11-beta-hydroxysteroid dehydrogenase type 1 reduced stress-related hepatic glucose output [Winnick, J. et al., Abst 0991-P], improved metabolic syndrome parameters in diet-induced obese conditions [Han, H.Y. et al., Abst 0089-LB] and showed atheroprotective activity in apolipoprotein E-deficient animal models [Hübschle, T. et al., Abst 0381-PP]; furthermore, AZD-4017 was shown to inhibit 11-beta-hydroxysteroid dehydrogenase type 1 in the liver, but only transient inhibition of enyzme activity in adipose tissue was seen [Sjöstrand, M. et al., Abst 1161-P].
Significant benefits on body weight compared to placebo, accompanied by improvements in glycemic control, were demonstrated during 1 year of treatment with the 5-HT2C receptor agonist lorcaserin in patients with type 2 diabetes [O'Neil, P.M. et al., Abst 1878-P; Anderson, C.M. et al., Abst 0466-PP] (Fig. 41). Effective weight loss was maintained in type 2 diabetes patients treated with metformin or sulfonylurea, although with an increased likelihood for hypoglycemia in subjects treated with the latter [Fidler, M.C. et al., Abst 1908-P].
Fig. 41. Proportion of patients with ³ 5% body weight (BW) loss (left top chart) and change in hemoglobin A1c (HbA1c; right top chart) and fasting plasma glucose (FPG) levels (right bottom chart) and the HOMA insulin resistance (HOMA IR) index (right bottom chart) after 1 year of treatment with lorcaserin or placebo [O'Neil, P.M. et al., Abst 1878-P; Anderson, C.M. et al., Abst 0466-PP].
With nausea, constipation, headache, dry mouth and insomnia as the most common but normally mild and acceptable adverse events, sustained-release naltrexone/bupropion also improved body weight, the overall metabolic profile, physical health and weight-related quality of life in overweight and obese individuals [Kolotkin, R.L. et al., Abst 1877-P; Rubino, D. et al., Abst 1868-P; Fujioka, K. et al., Abst 1928-P] (Fig. 42), with a favorable effect on eating control resulting in reduced craving [Hill, J.O. et al., Abst 1874-P]. In obese/overweight individuals with type 2 diabetes, naltrexone/bupropion also improved hemoglobin A1c levels, adding to the weight-lowering benefit and resulting in a decrease in the need for rescue medications for hyperglycemia [Hollander, P. et al., Abst 1862-P; Bays, H. et al., Abst 1866-P] (Fig. 42).
Fig. 42. Change in the Impact of Weight on Quality of Life (IWQL) scores (left chart) and proportion of patients reaching hemoglobin A1c (HbA1c) levels < 7% (right chart) after 56 weeks of treatment with naltrexone/bupropion 32/360 mg or placebo [Kolotkin, R.L. et al., Abst 1877-P; Hollander, P. et al., Abst 1862-P].
Similar benefits on body weight, in this case accompanied by resolution of metabolic syndrome criteria in most patients, were demonstrated after treatment with phentermine/topiramate [Garvey, W.T. et al., Abst 1875-P] (Fig. 43), such treatment offering long-term benefits on weight and glycemic control in patients with type 2 diabetes [Kushner, R.F. et al., Abst 1906-P].
Fig. 43. Change in systolic blood pressure (SBP) and fasting plasma glucose (FPG) and triglyceride (TG) levels after 56 weeks of treatment with phentermine/topiramate or placebo [Garvey, W.T. et al., Abst 1875-P].
A proof-of-concept trial with the selective methionine aminopeptidase inhibitor ZGN-433 indicated effective weight loss in obese subjects accompanied by improvements in LDL cholesterol and C-reactive protein levels, also suggesting potential value in the treatment of obesity [Hughes, T.E. et al., Abst 0050-LB] (Fig. 44). With no efficacy outcomes reported, the results of a trial in healthy volunteers indicated no untoward effects of a product containing cyclo[His-Pro] plus zinc on zinc or copper levels, which, along with preclinical observations of improved insulin sensitivity, indicated therapeutic potential [Song, M.K., Abst 0797-P].
Fig. 44. Change in body weight and percent change in LDL cholesterol (LDL-C) and C-reactive protein (CRP) levels after 26 days of treatment with ZGN-433 or placebo [Hughes, T.E. et al., Abst 0050-LB].
In the preclinical scenario, weight loss and improved insulin resistance were demonstrated after treatment with the melanin-concentrating hormone receptor blocker ALB-127158 [Surman, M.D. et al., Abst 0108-LB], while increased satiety leading to decreased body weight resulted from treatment with tropomyosin-related kinase B agonists through direct activation of satiety centers in the central nervous system [Gareski, T. et al., Abst 1853-P].
Olmesartan- and amlodipine-based antihypertensive therapy was effective for controlling blood pressure in patients with type 2 diabetes uncontrolled on prior therapy [Nesbitt, S.D. et al., Abst 0947-P], whereas another angiotensin receptor blocker, valsartan, exerted an insulin-sensitizing effect that was related to changes in microvascular function [Van Der Zijl, N.J. et al., Abst 1152-P], and telmisartan, but not olmesartan, inhibited endotoxin-induced resistin expression as effectively as pioglitazone, but whereas the effect of pioglitazone was prevented by blockade of peroxisome proliferator-activated receptor-gamma, that of telmisartan was not [Morioka, T. et al., Abst 1610-P] (as a side comment, protection against endotoxin-induced lipid-mediated muscular inflammation was demonstrated with the toll-like receptor 4 inhibitor TAK-242 [Hussey, S.E. & Musi, N., Abst 0104-LB]). It should be added that losartan attenuated insulin resistance and improved microvascular neogenesis [Wang, N. et al., Abst 1745-P], combined with simvastatin also brought about improvements in visceral adiposity that were superior to those obtained with a combination of amlodipine and the statin in patients with steatohepatitis [Fogari, R. et al., Abst 1690-P] (Fig. 45), and combined with sitagliptin enhanced differentiation of pancreatic progenitor cells into mature beta cells through an effect on pancreas/duodenum homeobox protein 1 (PDX-1) and peroxisome proliferator-activated receptor-gamma expression [Liang, J. & Leung, P.S.].
Fig. 45. Percent change in the degree of steatosis and visceral adiposity in patients treated with simvastatin plus either losartan or amlodipine [Fogari, R. et al., Abst 1690-P].
The renin inhibitor also improved insulin sensitivity and glucose tolerance in animal models of obesity [Henriksen, E.J. et al., Abst 1489-P]. Furthermore, reductions of QT interval dispersion in hypertensive, diabetic individuals independent of blood pressure-lowering activity were demonstrated after treatment with aliskiren [Fogari, R. et al., Abst 0537-P]. According to phase I clinical trial data, the novel experimental direct renin inhibitor, VTP-27999, was more effective than aliskiren, and possibly angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, in inhibiting renal renin, suggesting potential for superior nephroprotection in diabetes [Gregg, R. et al., Abst 1013-P].
In the experimental arena, a novel undisclosed dual neutral endopeptidase/endothelin-converting enzyme inhibitor improved renal function as effectively as losartan in animal models of diabetic nephropathy [Reiche, D. et al., Abst 1011-P].
An effect of cilostazol inhibiting transforming growth factor-beta-induced plasminogen activator inhibitor 1 expression was reported [Kim, M.K. et al., Abst 1698-P].
With variable activity in diabetes due to alterations in megakaryopoiesis as part of the disease [Pitocco, D. et al., Abst 0533-P], high doses of aspirin were found to be required for interfering with the fibrin network structure in patients with type 1 diabetes, especially in subjects with poor glycemic control [Tehrani, S. et al., Abst 0363-OR].
In addition to its antianginal activity, the use of ranolazine in patients with coronary artery disease and treated type 2 diabetes resulted in significant reductions in hemoglobin A1c levels [Kipnes, M.S. et al., Abst 1149-P], while in experimental prediabetic animal models it prevented the development of type 2 diabetes [Chisholm, J.W. et al., Abst 0044-LB].
By suppressing the nuclear factor NF-kappab pathway, chromium picolinate and chromium histidinate protected the brain against diabetic damage in experimental animal models [Sahin, K. et al., Abst 1030-P].
The use of dexamethasone as antiemetic prophylaxis in patients undergoing surgery was associated with deterioration of postoperative glucose control in patients with insulin-treated type 2 diabetes [Baldwin, D. et al., Abst 1047-P].
Omalizumab was effectively used in a patient with severe insulin allergy, resulting in inadequately controlled type 2 diabetes [Cavelti-Weder, C.R. et al., Abst 1116-P].
Improved survival and sepsis-induced insulin resistance in animal models resulted from treatment with diacerrhein [Calisto, K.L. et al., Abst 1157-P].
Preclinical in vitro studies in embryos concluded that Ophiopogon japonicus (dwarf lilyturf) tuber, a Chinese medicine, prevented hyperglycemia-induced abnormalities [Tong, Y. et al., Abst 1274-P].