Walking the streets in Lisbon is not a matter of inertia, at least when going uphill through the small streets crowding the slopes around the Alfama and Bairro Alto neighborhoods. However, when treating diabetes, clinical inertia seems to be the rule, despite the availability of effective therapies and recommendations for early insulin replacement to improve glucose control and prevent diabetes complications. This was further confirmed in the SOLVE study presented during EASD [Khunti, K. et al., Abst 377], highlighting the importance of understanding healthcare habits to implement policies aimed at appropriate treatment intensification and even initiation to achieve earlier glycemic control of type 2 diabetes.
However, preventing type 2 diabetes is crucial. Physical activity has been repeatedly reported to reduce the risk of acquiring type 2 diabetes, and does so independently of its impact on general and abdominal adiposity [Ekelund, U. et al., Abst 225], resulting in a clearly cost-effective option to avoid the disease and the need for treatments. Although physical activity improves fitness but not glycemic control in type 1 diabetes [Valletta, J.J. et al., Abst 602], this is feasible through educational campaigns aimed at improving eating habits, routine physical exercise and healthy lifestyles, which, as demonstrated among students in Mexico, reduced the incidence of obesity and overweight [Martínez, M.E., Abst 858].
Nevertheless, type 2 diabetes is a reality that is actually on the rise and requires treatments aimed at maintaining glycemic control, thus avoiding diabetic complications, while minimizing the risk of hypoglycemia and its consequences. Reducing hemoglobin A1c levels below 7%, as recommended by most guidelines for the treatment of diabetes, was confirmed to be associated with a reduced risk of death and diabetes-related morbidity in a population study in patients with type 2 diabetes [Skriver, M.V. et al., Abst 54]. Hence, treatments are critical for achieving glycemic goals and preventing deaths. A wide range of therapies are currently available, but new drugs under research may potentially improve outcomes with a lower risk for adverse events, or may offer efficacy in patients currently not at goal because of insufficient efficacy of the drugs they are receiving, or because the doses they would require would cause excessive toxicity or an undue risk for hypoglycemia. New findings with currently available drugs and drugs in research that were reported during this year's EASD meeting in the beautiful city of Lisbon are summarized in the following report.
A general finding related to insulin therapy for diabetes was that in subjects requiring high-dose injections of over 60 units of insulin, splitting the dose and injecting in two sites resulted in improved metabolic control [Saryusz-Wolska, M. et al., Abst 109]. Furthermore, initiation of insulin in patients with type 2 diabetes helped control not only hemoglobin A1c levels, but also the hypofibrinolytic status noted in such patients, without overtly affecting coagulation [Holleman, F. et al., Abst 1251]. However, the use of insulin or insulin secretagogues, but not long-acting insulin analogues, as a treatment for type 2 diabetes was associated with an increased risk of all-cause and cancer-related death compared to biguanide monotherapy according to an observational registry [Ioacara, S. et al., Abst 219], whereas independent retrospective analyses from additional registry data suggested a higher risk for adverse diabetes-related cardiovascular events in patients on insulin alone compared to other regimens, particularly incretin-based therapies [Currie, C.J. et al., Abst 773] (Fig. 1). This was found despite the recognized fact that insulin replacement is actually required by many patients with type 2 diabetes.
Fig. 1. Relative risk for diabetes-related endpoints (cardiovascular morbidity or mortality, stroke, cancer or death) in patients receiving insulin, insulin-based combinations or alternative therapies compared to metformin (reference). GLP-1, glucagon-like peptide 1 analogues/agonists; DPP IV, dipeptidyl peptidase 4 inhibitors [Currie, C.J. et al., Abst 773].
Long-acting insulin analogues such as insulin glargine and insulin detemir have been associated with similar or improved glycemic control but a lower risk for hypoglycemia than other insulin regimens [Pontiroli, A.E. et al., Abst 110; Riddle, M.C. et al., Abst 1036]. While improving not only hemoglobin A1c levels but also, like metformin, diastolic function and blood pressure in patients with impaired glucose tolerance or early type 2 diabetes and coronary artery disease [Siegmund, T. et al., Abst 1057], compared to insulin detemir, insulin glargine was associated with a greater likelihood for treatment adherence, resulting in superior glycemic outcomes according to a retrospective real-world survey in the U.S. [Xie, L. et al., Abst 1020]. Furthermore, switch from insulin glargine to human insulin in patients completing the ACCORD trial resulted in a marked increase in the frequency of severe hypoglycemia, although without direct translation into greater healthcare resource utilization [Berard, L.D. & Woo, V.C., Abst 1058]. On the other hand, available evidence from published studies comparing insulin glargine versus standard human insulin did not reveal safety concerns during pregnancy [Lin, J. et al., Abst 1210]. This was also demonstrated with insulin detemir in pregnant women with type 1 diabetes [Mathiesen, E.R. et al., Abst 1208; Hod, M. et al., Abst 1209], while in patients with type 2 diabetes early intensification with insulin detemir improved glycemia without weight gain (rather sustained weight loss in some studies) and rare severe adverse events, including hypoglycemia [Bain, S.C. et al., Abst 73; Dornhorst, A. et al., Abst 1032; Ross, S.A. et al., Abst 1039] (Fig. 2). In this regard, it should be noted that insulin detemir exerted an insulin-sensitizing effect related to hepatic-selective reduction of brown adipose tissue hyperinsulinism and/or weight loss [Alsini, N. et al., Abst 574], but was associated with a neutral effect on body weight, which, as in the case of insulin glargine, was not the result of altered caloric intake or systemic satiety factors such as leptin, ghrelin and peptide YY [Burge, M.R. et al., Abst 1048]. This effect could be explained by the greater increase in cerebral glucose metabolism induced by insulin detemir compared to human insulin in patients with type 1 diabetes [van Golen, L.W. et al., Abst 707]. In addition, insulin detemir combined with insulin aspart offered advantages over human insulin regarding postprandial glucose control and cardiac function in type 2 diabetes patients requiring intensive insulin therapy [von Bibra, H. et al., Abst 1246], whereas compared to long-acting human insulin, the activity of insulin detemir translated into reduced waist circumference at equivalent glycemic control with less common hypoglycemia [Tinahones, F.J. et al., Abst 671]. Furthermore, comparing the two long-acting insulin analogues, equiefficacy for targeting hyperglycemia was obtained with twice-daily insulin detemir and once-daily insulin glargine, the higher doses required with the former being associated with less weight gain [Simon, A.C.R. et al., Abst 1034]. This was at least partly explained by the lower pharmacodynamic potency of insulin detemir compared to both insulin glargine or long-acting human insulin [Porcellati, F. et al., Abst 1054], and the delayed onset of hypo-glycemic activity of insulin glargine compared to human insulin, explaining the lower risk for hypoglycemia [Tennagels, N. et al., Abst 570]. This despite the rapid conversion of insulin glargine to the active metabolite, with marginal, if any, in vivo exposure to insulin glargine in patients with type 1 or 2 diabetes [Frick, A. et al., Abst 572; Lucidi, P. et al., Abst 1056]. On the other hand, compared to insulin-like growth factor I, insulin glargine, like [AspB10]-insulin (an insulin analogue discontinued because it increased the risk of breast cancer in experimental animals) showed increased mitogenic activity on mammary epithelial cells in vitro, which, in the case of insulin glargine, appeared to be independent of its interaction with the insulin receptor and not associated with carcinogenicity [Schmidt, N. et al., Abst 571; Werner, U. et al., Abst 576]. However, insulin glargine exhibited no carcinogenicity in preclinical studies [Stammberger, I., Abst 766]. As an alternative long-acting insulin analogue, a basal-bolus regimen with insulin lispro protamine once daily was noninferior to insulin glargine [Giugliano, D. et al., Abst 1037].
Fig. 2. Proportion of patients attaining hemoglobin A1c levels < 7% with no weight gain or hypoglycemia after 1 year of intensification with insulin detemir or continuation of metformin/liraglutide alone. (Patients not controlled with metformin with or without sulfonylurea were treated with add-on liraglutide. Those patients attaining glycemic control were maintained on that therapy. Only patients not attaining glycemic control with add-on liraglutide were randomized to continuation with the same regimen or insulin detemir intensification) [Bain, S.C. et al., Abst 73].
Another ultra-long-acting insulin analogue, the multihexamer structure of which is the basis for its very long, flat, stable glucose-lowering activity after subcutaneous injection [Kurtzhals, P. et al., Abst 1049; Nosek, L. et al., Abst 1055], insulin degludec was characterized by longer, more consistent pharmacokinetics than insulin glargine [Heise, T. et al., Abst 1046], offering feasibility for flexibly dosing at intervals between 8 and 40 hours without loss of glycemic control or increase in the risk of hypoglycemia compared to fixed dosing at the same time of day [Birkeland, K.I. et al., Abst 1041], without flexible dosing with the analogue compromising its safety or glycemic control compared to fixed daily dosing of basal insulin glargine [Atkin, S.L. et al., Abst 112], but rather resulting in improved quality of life [Home, P.D. et al., Abst 941] (Fig. 3). In fact, once-daily insulin degludec combined with insulin aspart with additional mealtime insulin aspart injections offered similar glycemic control but a lower risk for hypoglycemia than basal insulin glargine or insulin detemir combined with mealtime insulin aspart [Hollander, P.A. et al., Abst 1035; Russell-Jones, D.L. et al., Abst 1045; Hirsch, I. et al., Abst 1050] (Fig. 4), In addition, in case of hypoglycemia, insulin degludec was associated with greater counterregulatory hormone responses compared to insulin glargine, further reducing the risk of severe hypoglycemia [Heller, S.R. et al., Abst 640]. Furthermore, insulin degludec/insulin aspart proved to be safe and well tolerated, resulting in equiefficacy compared to biphasic insulin aspart in patients on maintenance metformin, although biphasic insulin aspart was associated with a greater likelihood for hypoglycemia [Vaag, A. et al., Abst 1040] (Fig. 5). Moreover, insulin degludec showed a pharmacokinetic profile in children and adolescents comparable to that previously seen in adults, offering potential as a treatment for diabetes in young subjects that needs to be further explored [Danne, T. et al., Abst 1047], while in adults two formulations of the insulin at 100 and 200 U/mL proved pharmacokinetically bioequivalent, resulting in similar interchangeable pharmacodynamic profiles [Korsatko, S. et al., Abst 1051].
Fig. 3. Change in the Short Form-36 physical and mental quality of life scores in patients treated for 16 weeks with insulin degludec or insulin glargine [Home, P.D. et al., Abst 941].
Fig. 4. Change in hemoglobin A1c (HbA1c) levels (left chart) and incidence of hypoglycemia (right chart) during 52 weeks of treatment with insulin degludec or insulin glargine [Hollander, P.A. et al., Abst 1035].
Fig. 5. Percent of patients attaining hemoglobin A1c levels < 7% without hypoglycemia during 16 weeks of treatment with biphasic insulin aspart or insulin degludec/insulin aspart [Vaag, A. et al., Abst 1040].
In patients on basal insulin glargine, adding one to three bolus injections of insulin glulisine improved glycemic control without significantly increasing body weight or the risk of hypoglycemia [Raccah, D. et al., Abst 1023]. Insulin glulisine was also effectively combined with human insulin, with glycemic benefits compared to a combination of regular and long-acting human insulin [Wang, E. et al., Abst 1042]. Another short-acting insulin analogue was effectively formulated in a 25/75 combination with the corresponding protamine suspension to result in a longer duration and higher rates of glycemic control than insulin glargine in elderly type 2 diabetes patients [Jovanovic, L. et al., Abst 1052]. Another short-acting insulin analogue, insulin aspart, showed more rapid absorption when combined with hyaluronidase, resulting in superior glycemic control of type 1 diabetes [Hompesch, M. et al., Abst 1043], but a biphasic formulation of insulin aspart improved glycemic control more effectively than insulin glargine, without increasing the risk of hypoglycemia in patients with type 2 diabetes receiving oral antidiabetic drugs [Schubert, A. et al., Abst 1033].
Although implantable insulin pumps may avoid the need for multiple daily injections and total insulin requirements, while in fact improving metabolic control in patients with poor glucose control despite multiple daily injections of insulin [Guerrero Vázquez, R. et al., Abst 975; Courrèges, J.P. et al., Abst 977; Pankowska, E. et al., Abst 978; Anhalt, H. et al., Abst 982], noninjectable insulins have also been developed, including inhalable insulin, which improved fasting and postprandial glucose and hemoglobin A1c levels in type 2 diabetes [Mehta, R.J. et al., Abst 1025], an oral enteric long-acting insulin that proved pharmacodynamically active with suitable pharmacokinetics in healthy volunteers [Li, J., Abst 893], and a buccal insulin spray that was safely and effectively used for lowering hemoglobin A1c levels in patients with impaired glucose tolerance [Palermo, A. et al., Abst 111].
Besides the already known glycemic benefits that resulted in as cost-effective a treatment option as lifestyle intervention for the prevention of type 2 diabetes [Herman, W. et al., Abst 904], persistence of initial treatment with metformin or sulfonylureas was far from optimal according to registry data presented as a meeting poster [Jermendy, G. et al., Abst 937]. Nevertheless, treatment of type 2 diabetes with metformin was associated with a reduced risk for cardiovascular events compared to frontline therapy with sulfonylureas [Fu, A.Z. et al., Abst 156], an effect that could be related to glycometabolic effect-independent improvement in endothelial function demonstrated in patients with type 1 diabetes [Scavone, G. et al., Abst 912], and it also counteracted the increased risk of cancer found in type 2 diabetes patients [Rizza, S. et al., Abst 767]. Indeed, metformin possesses antineoplastic activity that was confirmed in studies demonstrating inhibition of insulin-like growth factor I-induced proliferation and signaling of non-small cell lung cancer cells [Salani, B. et al., Abst 768] and inhibition of insulin-driven oncogene AKT and mammalian target of rapamycin (mTOR) pathway activation leading to proliferation of endometrial epithelial cells [Selen, D.J. et al., Abst 769]. In addition, at least in preclinical models, metformin also exhibited cholesterol-lowering activity by promoting VLDL clearance in brown adipose tissue rather than affecting hepatic production [Guigas, B. et al., Abst 692]. On the other hand, although inducing vitamin B12 deficiency, metformin was not associated with an increased likelihood for silent myocardial ischemia or overt hematological abnormalities [Gastaldi, G. et al., Abst 1242].
Although with a higher risk for hypoglycemia, at least in the elderly, and the corresponding healthcare costs [Yang, H. et al., Abst 649], sulfonylureas remain a commonly used therapeutic strategy for diabetes. For example, glimepiride alone or especially combined with metformin (using a lower dose of the sulfonylurea) was an effective add-on therapy to early insulin glargine in patients with type 2 diabetes poorly controlled with alternative oral drugs, with benefits on hemoglobin A1c and postprandial glucose levels, reduced insulin requirements and a low propensity for hypoglycemia [Lee, J.M. et al., Abst 1038]. However, pharmacogenomic insight indicated lower efficacy for sulfonylureas in subjects carrying the T allele in the transcription factor 7-like 2 (TCF7L2) rs7903146 polymorphism [Schroner, Z. et al., Abst 280].
Based on the results of a randomized clinical trial, compared to acarbose, nateglinide better suppressed postprandial hyperglycemia in patients with type 2 diabetes and maintained insulin secretion, but in patients with decreased insulin secretion acarbose could be preferred because its activity was independent of insulin secretion [Shimura, H. et al., Abst 911].
In patients suboptimally controlled with insulin glargine, adding pioglitazone, but not metformin, improved insulin sensitivity, reduced matrix metalloproteinase 9, C-reactive protein and E-selectin and leukocyte counts, and increased adiponectin levels independently of glycemic control, although triple therapy with pioglitazone, metformin and prior insulin glargine was associated with improved glycemic control, but also an increased risk of hypoglycemia [Kleine, I.E. et al., Abst 915] (Fig. 6). In fact, biomarker analyses from the ACTNOW study confirmed insulin-sensitizing activity for pioglitazone [Tripathy, D. et al., Abst 55]. Moreover, the addition of pioglitazone, but not metformin, to insulin glargine was associated with a favorable impact on the LDL particle size towards a less atherogenic profile [Koehler, C. et al., Abst 916]. Furthermore, pio-glitazone improved insulin sensitivity in adipocytes, whereas exenatide did not just lack such an effect, but attenuated the benefit of pioglitazone [Chavez, A.O. et al., Abst 513]. Pioglitazone also exerted favorable biological effects on isolated endothelial progenitor cells, suggesting vascular protective activity with potential therapeutic implications on endothelial health [Dei Cas, A. et al., Abst 917].
Fig. 6. Change in hemoglobin A1c (HbA1c) levels and incidence of hypoglycemia after adding pioglitazone, metformin or both to prior therapy with insulin glargine [Kleine, I.E. et al., Abst 915].
The mitochondrial biogenesis-inducing activity of rosiglitazone in white adipose tissue was related to activation of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) coactivator 1-alpha (PGC-1-alpha), which was not linked to insulin sensitivity but was required for activation of the mitochondrial brown fat uncoupling protein 1 (thermogenin) [Villena, J.A. et al., Abst 24].
Beneficial effects on the lipid profile in patients with type 2 diabetes were also observed with other PPAR agonists, such as the PPAR-alpha/gamma-selective compound aleglitazar [Chognot, C. et al., Abst 890] (Fig. 7), while a novel thiazolidinedione, PNU-91325, induced brown adipocyte differentiation and increased adiponectin production according to in vitro observations [McDonald, W.G. et al., Abst 21]. Another dual PPAR- alpha/gamma agonist, GFT-505, also exerted beneficial effects in animal models of nonalcoholic steatohepatitis that were mediated by PPAR-alpha-dependent but also -independent mechanisms, highlighting the role of PPAR-delta activation in the hepatoprotective activity [Hanf, R. et al., Abst 1269].
Fig. 7. Change in LDL (LDL-C) and HDL cholesterol (HDL-C) and triglyceride (TG) levels in statin-treated and -untreated patients receiving aleglitazar, pioglitazone or placebo [Chognot, C. et al., Abst 890].
While mechanistic data corroborated that continuous exposure to exenatide increased insulin sensitivity and glucose disposal index even after partial pancreatectomy [Casiraghi, F. et al., Abst 514] and retrospective analyses indicated a reduced risk for heart failure in patients treated with the agent [Best, J.H. et al., Abst 803], data from the DURATION-1, -3 and -4 studies confirmed the long-term benefits of exenatide on the cardiovascular risk profile in patients with type 2 diabetes, with significant reductions in systolic and diastolic blood pressure, LDL cholesterol levels and C-reactive protein levels. In DURATION-4 particularly, weekly exenatide fared superior to pioglitazone and sitagliptin in achieving glycemic control without hypoglycemia or weight gain, or hemoglobin A1c, systolic blood pressure and LDL cholesterol goals [Diamant, M. et al., Abst 778; Boardman, M.K. et al., Abst 779] (Fig. 8), whereas in DURATION-1 the robust antihyperglycemic activity of the agent was maintained over 3 years regardless of background antidiabetic therapy [Maggs, D. et al., Abst 783], without an impact on the QT interval [Sager, P. et al., Abst 802]. Overall, analyses of the DURATION trials confirmed significant improvements in glycemic control without hypoglycemia or weight gain after treatment with weekly exenatide compared to alternative glucose-lowering therapies, the effect being accompanied by improvements in systolic blood pressure and LDL cholesterol levels in patients not at goal [Wintle, M. et al., Abst 781]. Similar conclusions, along with independence from age, gender, body mass index, race and duration of diabetes, were reached in a pooled analysis of clinical trial data [Blickensderfer, A. et al., Abst 782], while simulation and modeling analyses indicated superiority of weekly exenatide over insulin and pioglitazone regarding life years, quality-adjusted life years, healthcare cost savings and the overall cost-effectiveness profile [Alperin, P. et al., Abst 806]. Furthermore, twice-daily exenatide also improved glycemic parameters regardless of age, gender, body mass index and duration of diabetes [Pencek, R. et al., Abst 777], whereas both twice-daily and once-weekly treatment induced favorable effects on lipoprotein particle levels and size distribution, although the weekly regimen was associated with a more robust effect [Chilton, R. et al., Abst 799], without differences between the two regimens regarding safety and tolerability [Ridge, T. et al., Abst 801] and kidney function and renal events [Anderson, P.W. et al., Abst 823]. Moreover, weekly exenatide was consistently beneficial regarding improved metabolic control in patients on a number of background therapies, including diet and exercise and metformin alone or combined with a thiazolidinedione or sulfonylurea [Malone, J. et al., Abst 780]. Likewise, monthly dosing with exenatide suspension improved glycemic control and body weight as effectively as weekly injections, offering new putative treatment regimens for type 2 diabetes [MacConell, L. et al., Abst 76] (Fig. 9). Mechanistically, the cardiovascular benefits of subcutaneous exenatide, particularly increased cardiac output and decreased peripheral resistance, were also confirmed in healthy nondiabetic volunteers [Mendis, B. et al., Abst 800]. As a further alternative, a miniature subcutaneous implanted pump for continuous, consistent delivery of exenatide (code-named ITCA-650) provided dose-proportional exposure with rapid steady-state levels of the drug [Dahms, J. et al., Abst 790], resulting in sustained glycemic and weight control over 48 weeks in patients on background metformin [Luskey, K. et al., Abst 77], and was at least as effective as exenatide injection, but was associated with higher patient satisfaction [Alessi, T. et al., Abst 789] (Fig. 10).
Fig. 8. Percent of patients achieving glycemic control without weight gain or hypoglycemia (goal A), or hemoglobin A1c, systolic blood pressure, and LDL cholesterol targets (goal B) [Boardman, M.K. et al., Abst 779].
Fig. 9. Percent of patients attaining hemoglobin A1c levels < 7% after 20 weeks of treatment with monthly or weekly exenatide [MacConell, L. et al., Abst 76].
Fig. 10. Change in hemoglobin A1c (HbA1c) levels and body weight after 12 weeks of treatment with ITCA-650 or subcutaneous exenatide injection twice daily [Alessi, T. et al., Abst 789].
Exenatide was effectively combined with insulin glargine for improving glycemic control in patients suboptimally controlled with either drug alone, with additional benefits on the lipid profile [Levin, P. et al., Abst 1030]. However, both exenatide and lira-glutide had a lower impact on hemoglobin A1c levels, although with greater impact on body weight, in patients on background insulin therapy, especially those receiving higher doses or with a longer history of type 2 diabetes [Walton, C. et al., Abst 805]. In the mechanistic domain, liraglutide protected against palmitate-induced beta cell apoptosis through an effect on GPR40 expression [Natalicchio, A. et al., Abst 142]. In addition, exenatide improved endothelial function in animal models of obesity [Han, L.N. et al., Abst 68], while in human coronary artery endothelial cells the agent prevented lipo-apoptosis, supporting such endothelial protective activity [Erdogdu, Ö. et al., Abst 69]. In addition, prolonged exposure of diabetic animals to supratherapeutic levels of the agent had no untoward effect on the exocrine pancreas structure and function, rather resulting in improved survival [Tatarkiewicz, K. et al., Abst 818]. Further mechanistic studies in experimental animals confirmed that the glucagon-like peptide 1 receptor is essential for the activity of exenatide, but that these receptors are also involved in exenatide clearance [Parkes, D.G. et al., Abst 813].
Liraglutide is another incretin receptor agonist that, besides improving glycemia and body weight through an anorectic effect not mediated by glucagon-like peptide 1-expressing neurons in the brainstem [Jelsing, J. et al., Abst 586], exerted favorable benefits on the retinal endothelial function and vascular risk profile in patients with type 2 diabetes initially well controlled with metformin monotherapy [Mitry, M. et al., Abst 1123]. Moreover, liraglutide's benefit on weight were maintained in obese nondiabetic individuals [Woo, V.C. et al., Abst 78] (Fig. 11), while its favorable impact on hemo-globin A1c levels and body weight was superior to that of sitagliptin and exenatide [Davies, M. et al., Abst 792; Matthews, D.R. et al., Abst 793; Bailey, T. et al., Abst 794; Zinman, B. et al., Abst 798] and better maintained across a broad range of beta cell mass values than the effect of alternative drugs, including exenatide and sitagliptin, as well as sulfonylureas and thiazolidinediones, particularly in early stages of diabetes in which other drugs are less effective [Meier, J.J. et al., Abst 795] (Fig. 12). This superior effect of liraglutide resulted in a reduced dose of insulin in patients with type 1 diabetes regardless of the presence of residual beta cell function [Kielgast, U. et al., Abst 74]. Furthermore, liraglutide was associated with greater reductions in hemoglobin A1c levels and weight loss than weekly exenatide, at the cost of a higher frequency of gastrointestinal adverse events [Buse, J.B. et al., Abst 75] (Fig. 13), while switch from sitagliptin to liraglutide resulted in improved overall satisfaction in patients also receiving metformin [Montanya Mias, E. et al., Abst 796]. On the other hand, the glycemic benefits of liraglutide and its low risk of hypoglycemia were not affected by the presence of renal impairment [Gough, S. et al., Abst 822]. In the mechanistic arena, liraglutide was found to activate the fibroblast growth factor 21 signaling pathway, reverting insulin resistance in low adiponectin conditions [Lu, C. et al., Abst 510]. This was confirmed in independent in vivo studies that also documented the benefits of liraglutide on insulin resistance in hypoadiponectinemic and high-fat diet conditions [Miao, Z. et al., Abst 515]. In addition, in vitro assays determined a stimulating effect of the agent on islet secretion of vascular endothelial growth factor that could be related to an increased islet viability in case of transplant [Langlois, A. et al., Abst 430]. Additional studies confirmed the effects of liraglutide on gastric emptying and weight loss, but suggested such anorectic activity not to be related with vagal afferents or neurons in the area postrema, but other possibly centrally located glucagon-like peptide 1 receptors [Vrang, N. et al., Abst 587]. As an additional finding of interest, incretin therapy with liraglutide was associated with improvements in psoriasis severity in patients with diabetes and psoriasis [Ahern, T. et al., Abst 797].
Fig. 11. Proportion of obese, nondiabetic patients losing and maintaining at least 5% of body weight during 56 weeks of treatment with liraglutide or placebo in the SCALE trial [Woo, V.C. et al., Abst 78].
Fig. 12. Patients with the highest quartile of beta cell mass at target after 26 weeks of treatment with liraglutide or comparators [Meier, J.J. et al., Abst 795].
Fig. 13. Change in hemoglobin A1c levels and body weight after 26 weeks of adding daily liraglutide 1.8 mg or weekly exenatide 2 mg to oral antidiabetic drugs [Buse, J.B. et al., Abst 75].
Improved glycemic control in patients with type 2 diabetes insufficiently responding to metformin was likewise reported with lixisenatide, which given once daily was noninferior to twice-daily exenatide but resulted in less hypoglycemia and better gastrointestinal tolerability [Rosenstock, J. et al., Abst 786] (Fig. 14). Once-daily lixisenatide was also superior to placebo in further studies in patients insufficiently controlled with metformin that further confirmed the lack of hypoglycemia and the benefit of weight loss during treatment with the incretin mimetic [Bolli, G.B. et al., Abst 784; Ratner, R.E. et al., Abst 785] (Fig. 14). Furthermore, at least in the experimental preclinical arena, lixisenatide showed cardioprotection against myocardial ischemia/reperfusion injury in isolated hearts [Ruetten, H. et al., Abst 810]. Another incretin mimetic, dulaglutide, also dose-dependently lowered hemoglobin A1c and blood glucose levels in patients with type 2 diabetes with an acceptable safety and tolerability profile [Grunberger, G. et al., Abst 788] (Fig. 15).
Fig. 14. Proportion of patients achieving hemoglobin A1c levels < 7% after treatment with lixisenatide once daily versus exenatide twice daily (24-week data) [Rosenstock, J. et al., Abst 786] or placebo (12-week data) [Ratner, R.E. et al., Abst 785].
Fig. 15. Percent of patients with hemoglobin A1c levels < 7% after 12 weeks of treatment with dulaglutide or placebo [Grunberger, G. et al., Abst 788].
Besides exenatide, liraglutide, lixisenatide and dulaglutide, an innovative analogue of exenatide, a fusion protein containing the low hydrophilic tail XTEN, was tested favorable as a treatment for type 2 diabetes in a phase I trial [Cleland, J.L. et al., Abst 787]. A novel pegylated glucagon-like peptide 1 analogue coded compound 23 also offered putative therapeutic-like activity in experimental animal models that was comparable to but different from that of an anti-glucagon receptor monoclonal antibody [Gu, W. et al., Abst 809].
While their glycemic benefits were confirmed in numerous clinical trials, as a group, a meta-analysis of randomized, controlled trials suggested a cardioprotective effect for dipeptidyl peptidase 4 inhibitors in patients with type 2 diabetes, with a significant 32% reduction in the risk of major adverse cardiovascular events [Lamanna, C. et al., Abst 244]. However, no such effect could be demonstrated on the risk of cancer or pancreatitis [Monami, M. et al., Abst 770]. Nevertheless, differences exist between individual drugs, and new information with each dipeptidyl peptidase 4 inhibitor reported in Lisbon during EASD 2011 is summarized below.
While lowering not only hemoglobin A1c levels but also insulin sensitivity, triglyceride and remnant lipoprotein cholesterol levels and beta cell glucose sensitivity in patients with type 2 diabetes [Muscelli, E. et al., Abst 815; Eto, M. & Saito, M., Abst 836], like exenatide, treatment with sitagliptin prevented the metabolic abnormalities resulting from a high-fructose diet in experimental animals [Massa, L.M. et al., Abst 517]. Mechanistically, sitagliptin increased intact glucagon-like peptide 1 levels without affecting the production of incretins, whereas acarbose increased glucagon-like peptide 1 but suppressed glucose-dependent insulinotropic peptide secretion after a meal and sulfonylureas had no effects on incretin production [Yabe, D. et al., Abst 838]. Using an analogue, des-F-sitagliptin, suppression of diabetes progression by preventing beta and alpha cell death in experimental animal models was demonstrated [Takeda, Y. et al., Abst 516].
While add-on saxagliptin resulted in sustained improvements in glycemic control in patients on prior insulin, metformin or combined insulin/metformin therapy, in the case of the biguanide at submaximal doses with equiefficacy compared to uptitrated metformin but better gastrointestinal tolerability [Barnett, A.H. et al., Abst 243; Hermans, M.P. et al., Abst 828], frontline therapy with saxagliptin combined with metformin proved superior to metformin monotherapy regarding the proportion of patients with type 2 diabetes attaining sustained glycemic control [Frederich, R. et al., Abst 829] (Fig. 16). Moreover, switch from insulin to saxagliptin/metformin offered a therapeutic option in patients with residual beta cell function [Pfützner, A.H. et al., Abst 830]. Furthermore, the use of saxagliptin plus metformin was associated with more patients achieving glycemic control but fewer patients suffering from hypoglycemia compared to adding glipizide to metformin [Allen, E. & Berglind, N., Abst 827] (Fig. 17).
Fig. 16. Proportion of patients attaining sustained glycemic responses to saxagliptin plus metformin (Met) versus metformin monotherapy [Frederich, R. et al., Abst 829].
Fig. 17. Percent of patients attaining glycemic control (hemoglobin A1c < 7%) with no weight gain (< 2%) and no hypoglycemia during 52 weeks of add-on saxagliptin or glipizide to background metformin [Allen, E. & Berglind, N., Abst 827].
While a study with alogliptin in patients with type 2 diabetes indicated reductions in hemoglobin A1c accompanied by decreases in fasting and postprandial triglyceride and triglyceride-rich lipoprotein levels, suggesting a benefit on the cardiovascular risk profile [Eliasson, B. et al., Abst 837], novel studies with vildagliptin discussed in Lisbon confirmed the benefits of the dipeptidyl peptidase 4 inhibitor on hemoglobin A1c levels and insulin requirements in patients with type 2 diabetes and severe renal impairment [Kothny, W. et al., Abst 819; Lukashevich, V. et al., Abst 820]. Furthermore, vildagliptin was associated with greater glycemic benefits, less hypoglycemic events and better adherence than sulfonylureas during a Ramadan fasting in patients on background metformin [Hanif, W. et al., Abst 839; Shete, A.V.V., Abst 840], and in fact, a direct comparison to glimepiride demonstrated a higher proportion of patients at hemoglobin A1c target without hypoglycemia during treatment with vildagliptin [Bader, G. et al., Abst 833] (Fig. 18). In vivo assessments in experimental animals confirmed the increases in beta cell mass brought about by the agent in nondiabetic conditions, which was directly related to accelerated cell proliferation and differentiation [Hamamoto, S. et al., Abst 807], documented a beta cell-preserving activity in transgenic beta cell-failing animal models [Shimizu, S. et al., Abst 808], demonstrated an antiinflammatory effect on the exocrine pancreas devoid of duct cell proliferation [Takahashi, K. et al., Abst 817], and suggested potential for preventing or reverting neuropathic changes associated with diabetes [Mizukami, H. et al., Abst 1126]. However, additional mechanistic studies using selective blockers of the glucagon-like peptide 1 receptor indicated that some, but not all, effects of vildagliptin and possibly other dipeptidyl peptidase 4 inhibitors are mediated by glucagon-like peptide 1 [Nauck, M.A. et al., Abst 241], while ex vivo assessments in patients with type 2 diabetes did not reveal an impact of the drug on monocyte and T-cell cytokine responses [van Poppel, P.C.M. et al., Abst 825]. Also in the preclinical arena, linagliptin showed activity against left ventricular fibrosis and dysfunction in models of uremic cardiomyopathy [Chaykovska, L. et al., Abst 824] and reduced infarct size and improved postischemic cardiac function after experimental myocardial ischemia/reperfusion [Pfab, T. et al., Abst 811] , while clinical trial results with the drug confirmed its long-lasting benefits on hemoglobin A1c levels regardless of baseline insulin sensitivity, the time since diagnosis of type 2 diabetes, response to prior metformin or the presence of severe renal impairment [Schlosser, A. et al., Abst 242; Newman, J. et al., Abst 821; Rafeiro, E. et al., Abst 831; Patel, S. et al., Abst 832] (Fig. 19).
Fig. 18. Percent of patients attaining glycemic control (hemoglobin A1c < 7%) with no weight gain and no hypoglycemia during 2 years of treatment with vildagliptin or glimepiride [Bader, G. et al., Abst 833].
Fig. 19. Proportion of patients with 5% or greater drop in hemoglobin A1c levels after 12 weeks of adding linagliptin or placebo to prior metformin therapy [Rafeiro, E. et al., Abst 831].
The glucose-dependent insulinotropic receptor agonist PSN-821 showed favorable tolerability and fasting and postprandial glucose-lowering activity in overweight/obese patients with type 2 diabetes, with an additional effect on energy intake suggesting potential (but not demonstrated) weight-lowering activity associated with favorable benefits on leptin and adiponectin levels [Goodman, M.L. et al., Abst 188]. A similarly acting compound, AR-7947, induced preclinical effects suggestive of glucose- and lipid-normalizing activity in type 2 diabetes [Fell, J.B. et al., Abst 889].
With selective activity on the sodium/glucose cotransporter SGLT2 over SGLT1, SMIT, SGLT4, SGLT6, GLUT-1, GLUT-2 and GLUT-4 [Poucher, S.M. et al., Abst 842], compared to placebo, treatment of type 2 diabetes with dapagliflozin brought about significant improvements in the overall glucose disposal rate and insulin responses to glucose over a 12-week period, resulting in improvements in hemoglobin A1c levels with a very low propensity for hypoglycemia [Rohwedder, K. et al., Abst 853; Mudaliar, S. et al., Abst 854] (Fig. 20). Dapagliflozin was also a well-tolerated, effective add-on option for improving glycemic control without weight gain or increased risk of hypoglycemia in patients suboptimally controlled on prior metformin therapy, in which case it also fared superior to placebo and glipizide regarding weight loss and a lower risk of hypo-glycemia [Bailey, C.J. et al., Abst 146; Del Prato, S. et al., Abst 852] (Fig. 21), or prior pioglitazone therapy [Vico, M. et al., Abst 851]. As a consequence, treatment of type 2 diabetes with the agent resulted in high patient satisfaction rates [Medin, J. et al., Abst 848]. Treatment with dapagliflozin also reduced serum uric acid levels, not observed with placebo or glimepiride [Hardy, E. et al., Abst 843]. In addition, the combination of dapagliflozin with metformin resulted in additive benefits on hemoglobin A1c and fasting plasma glucose levels versus either monotherapy, with an additional marginal benefit on body weight compared to metformin alone [Henry, R.R. et al., Abst 145] (Fig. 22).
Fig. 20. Percent change in glucose disposal rate after 12 weeks of treatment with dapa-gliflozin or placebo [Mudaliar, S. et al., Abst 854].
Fig. 21. Change in hemoglobin A1c levels and body weight after 2 years of adding dapagliflozin versus placebo [Bailey, C.J. et al., Abst 146] or glipizide [Del Prato, S. et al., Abst 852] to suboptimal background metformin.
Fig. 22. Percent of patients treated with metformin (maximum tolerated dose), dapagli-flozin (5 or 10 mg/day) or the combination attaining hemoglobin A1c levels < 7% at week 24 in two studies [Henry, R.R. et al., Abst 145].
The BRIGHTEN trial with ipragliflozin demonstrated its safety, tolerability and superiority over placebo in reducing hemoglobin A1c levels in patients with type 2 diabetes. The drug also brought about benefits on fasting plasma glucose, adiponectin and fasting insulin levels, as well as body weight [Kashiwagi, A. et al., Abst 149] (Fig. 23). A further placebo-controlled study confirmed the safety and tolerability of the novel sodium/glucose cotransporter inhibitor in patients on stable metformin therapy, without drug-drug interactions with the biguanide and no apparent risk of hypoglycemia [Veltkamp, S.A. et al., Abst 849]. Contrarily, increased exposure to ipragliflozin resulted from concomitant renal impairment in patients with type 2 diabetes, although the drug remained safe and well tolerated in patients with moderate renal failure, despite showing reduced efficacy on plasma glucose compared to subjects with normal renal function [Kadokura, T. et al., Abst 847].
Fig. 23. Percent change in hemoglobin A1c levels after 16 weeks of treatment with ipragliflozin 50 mg or placebo [Kashiwagi, A. et al., Abst 149].
A comparative, placebo-controlled study with empagliflozin demonstrated dose-dependent reductions in hemoglobin A1c levels, fasting blood glucose and body weight in patients already treated with metformin, empagliflozin being at least as effective as open-label sitagliptin [Seman, L. et al., Abst 147] (Fig. 24). Placebo-controlled clinical trial results were likewise reported supporting the glycemic benefits of luseogliflozin, which dose-dependently increased glucosuria, decreased plasma glucose and hemoglobin A1c levels and reduced body weight with favorable safety and pharmacokinetics in patients with type 2 diabetes [Seino, Y. et al., Abst 148; Sasaki, T. et al., Abst 846] (Fig. 25). The latter sodium/glucose cotransporter inhibitor also proved effective in preclinical animal models, in which improvements in glycemic parameters were associated with preservation of beta cell mass [Teisuke, T. et al., Abst 845].
Fig. 24. Placebo-corrected percent change in hemoglobin A1c levels after 12 weeks of treatment with empagliflozin or open-label sitagliptin [Seman, L. et al., Abst 147].
Fig. 25. Change in hemoglobin A1c levels after 12 weeks of treatment with luseogliflozin or placebo [Seino, Y. et al., Abst 148].
Another sodium/glucose cotransporter inhibitor, PF-04971729, meaningfully improved glycemic parameters as effectively as sitagliptin in patients with type 2 diabetes suboptimally controlled with metformin [Nucci, G. et al., Abst 850] (Fig. 26). The agent also exerted blood pressure-lowering activity in spontaneously hypertensive animal models that was accompanied by increased diuresis and reduction in body weight [Knight, D.R. et al., Abst 1105]. Such blood pressure-lowering activity was confirmed in patients with type 2 diabetes, reaching values comparable to hydrochlorothiazide accompanied by improvements in glycemic control [Amin, N.B. et al., Abst 8440] (Fig. 27). An additional, dual sodium/glucose cotransporter 1/2 inhibitor, LX-4211, induced favorable effects on glycemia and incretin levels in patients with type 2 diabetes, with equivalent pharmacokinetics and pharmacodynamics comparing tablet and liquid formulations [Powell, D. et al., Abst 150].
Fig. 26. Change in hemoglobin A1c levels after 12 weeks of treatment with PF-04971729, sitagliptin or placebo [Nucci, G. et al., Abst 850].
Fig. 27. Change in fasting plasma glucose (FPG) levels and 24-hour systolic blood pressure (SBP) after 4 weeks of treatment with PF-04971729, hydrochlorothiazide or placebo [Amin, N.B. et al., Abst 844].
As a side comment to sodium/glucose cotransporter inhibition, lifestyle intervention in prediabetic individuals was associated with reduced expression of GLUT-4, further confirming the preventive benefits of diet and exercise interventions on the risk of developing type 2 diabetes [Bernat-Karpińska, M.A. et al., Abst 903].
While placebo-controlled trials with LY-2599506 demonstrated improvements in fasting and postprandial glucose levels in patients with type 2 diabetes [Bue-Valleskey, J.M. et al., Abst 189] and reductions in blood glucose in patients with the disease, as well as healthy control volunteers [Deeg, M.A. et al., Abst 886], a study in healthy volunteers demonstrated the tolerability and dose-proportional pharmacokinetics of AZD-1656 [Leonsson-Zachrisson, M. et al., Abst 883]. The agent was also demonstrated to be well tolerated, pharmacodynamically active and pharmacokinetically feasible in patients with type 2 diabetes, resulting in dose-dependent glucose-lowering activity [Morrow, L. et al., Abst 885]. AZD-1565, like the similarly acting compound AZD-6370, was biologically active and pharmacologically active in facilitating counterregulatory responses to hypoglycemic clamps in healthy volunteers [Norjavaara, E. et al, Abst 884].
Improvements in hemoglobin A1c with a favorable safety and tolerability profile were demonstrated in a placebo-controlled study with the chemokine CCR2 receptor blocker CCX-140 [Hanefeld, M. et al., Abst 192] (Fig. 28). Likewise, antihyperglycemic and hypoglucosuric effects in experimental animal models were demonstrated with CCX-417, another small-molecule CCR2 receptor blocker [Jaen, J.C. et al., Abst 894], while reductions in plasma glucose through inhibition of hepatic glucose production in patients with type 2 diabetes resulted from blockade of glucocorticosteroid receptors in the liver by KB-003305 [Jax, T. et al., Abst 892]. Potent glucose-lowering activity was demonstrated in healthy volunteers and patients with type 2 diabetes with the glucagon receptor blocker LY-2409021 in placebo-controlled studies [Prince, M.J. et al., Abst 190; Kelly, R.P. et al., Abst 887] (Fig. 29). In addition, while the glucagon receptor blocker MK-0893 was effectively combined with metformin, offering significant glycemic improvements comparable to those obtained by adding sitagliptin to metformin [Engel, S.S. et al., Abst 191] (Fig. 30), two glucagon analogues, des-His1-Pro4-Glu9-glucagon and des-His1-Pro4-Glu9-Lys12-glutamyl-PAL-glucagon amide effectively acted as antagonists of the glucagon receptor, resulting in antidiabetic activity in experimental animal models [O'Harte, F.P.M. et al., Abst 130].
Fig. 28. Change in hemoglobin A1c levels after 4 weeks of treatment with CCX-140, pioglitazone or placebo [Hanefeld, M. et al., Abst 192].
Fig. 29. Change in hemoglobin A1c levels after 28 days of treatment with LY-2409021 or placebo [Prince, M.J. et al., Abst 190].
Fig. 30. Change in hemoglobin A1c and fasting plasma glucose (FPG) levels after 4 weeks of treatment with combinations of MK-0893 40 mg o.d., sitagliptin 100 mg o.d. and metformin 1000 mg b.i.d. [Engel, S.S. et al., Abst 191].
Although independent studies confirmed only a modest hemoglobin A1c-lowering effect in patients treated with metformin [Hensen, J. et al., Abst 895] (Fig. 31), a favorable impact on insulin secretion rate in patients with type 2 diabetes treated with insulin with or without metformin or subjects with impaired insulin tolerance was demonstrated with the anti-IL-1beta antibody canakinumab [Rissanen, A. et al., Abst 896]. Improved glycemic control with good tolerability and pharmacokinetic feasibility with 6-weekly administration was similarly reported after treatment with LY-2189102, another IL-1beta-neutralizing antibody [Abu-Raddad, E. et al., Abst 897; Sloan-Lancaster, J. et al., Abst 898] (Fig. 32). A study in patients with metabolic syndrome demonstrated benefits for an alpha-linolenic acid-enriched diet on body weight, endothelial function and inflammation marker levels, suggesting benefits of such intervention on energy metabolism and the cardiovascular risk profile [Baxheinrich, A. et al., Abst 879]. On the contrary, genistein and daidzein had no effects on glycemia or lipidemia in patients with prediabetes or untreated early type 2 diabetes, as demonstrated in Chinese women [Ye, Y.B. et al., Abst 881].
Fig. 31. Change in hemoglobin A1c levels after 4 months of adding canakinumab or placebo to metformin monotherapy [Hensen, J. et al., Abst 895].
Fig. 32. Change in hemoglobin A1c levels after 12 weeks of treatment with LY-2189102 or placebo [Sloan-Lancaster, J. et al., Abst 898].
Benefits on endothelial function and systemic inflammation in subjects with impaired glucose metabolism were demonstrated with bilberry combined with a whole grain-enriched diet and fatty fish consumption, suggesting potential for dietary intervention in metabolic syndrome [de Mello Laaksonen, V.D.F. et al., Abst 871].
Preclinical studies in animal models similarly confirmed the insulin-sensitizing potential of LIM-0705, which inhibited glucose production by hepatocytes and resulted in antiglycemic effects comparable to those of rosiglitazone. The agent also proved pharmacodynamically active in healthy volunteers [Chang, M.P. et al., Abst 891]. Likewise, glucose reduction in additional experimental studies was demonstrated with the alpha2-adrenoceptor blocker efaroxan through such blockade, but also because of closure of ATP-dependent potassium channels [Lehner, Z. et al., Abst 591], whereas the insulin sensitizer VVP-808 suppressed endogenous hepatic glucose production, improving glycemia in diabetes- and obesity-prone animal models [Walder, K.R. et al., Abst 616] and the 11beta-hydroxysteroid dehydrogenase 1 inhibitor SAR-184841 significantly improved microvascular reactivity and function in hypertensive animal models as effectively as irbesartan, while also improving metabolic parameters as effectively as rosiglitazone and relieving peripheral neuropathy independently of the effect on blood glucose [Chamiot-Clerc, P.J. et al., Abst 70; Noah, L. et al., Abst 1128]. Inhibition of hepatic glucose production and lipid synthesis in further studies was demonstrated with YL-01, an undisclosed natural compound [Leng, Y. et al., Abst 612].
A Boswellia serrata extract and 11-keto-beta-boswellic acids proved active for preventing streptozotocin-induced diabetes [Ammon, H.P.T. & Shehata, A.M., Abst 437], while the chemical chaperone 4-phenylbutyric acid prevented hepatic and insulin resistance after prolonged lipid infusion [Pereira, S. et al., Abst 120]. With a different approach, a GAD65 autoantibody-targeted monoclonal antibody was described with potential for preventing insulinitis and type 1 diabetes in genetically diabetes-prone animal models, suggesting novel putative targets for therapeutic intervention [Wang, X. et al., Abst 198]. With similar results, the glutamate dehydrogenase activator 2-aminobicyclo-heptan-2-carboxylic acid improved glycemic control in diabetic, obese animals by preserving beta cell mass and enhancing insulin secretion [Han, S. et al., Abst 500].
Also in the preclinical arena, in vitro studies demonstrated an antioxidant and antiapoptotic effect for ZnCl2 in isolated islets exposed to high glucose concentrations [Duprez, J. et al., Abst 497]. Additional in vitro studies indicated protection by aminoguanidine against the negative effects of advanced glycation end products on fibroblasts [Serban, A.I. et al., Abst 1131], and improved beta cell survival and function by the free fatty acid receptor FFA1 agonist TUG-469 [Ullrich, S. et al., Abst 493], while a study in vivo in experimental animals confirmed the benefits of another free fatty acid receptor agonist, TAK-875, on glycemic parameters and beta cell preservation [Matsuda-Nagasumi, K. et al., Abst 888]. A randomized, placebo-controlled study in patients with type 2 diabetes confirmed the hemoglobin glucose- and A1c-lowering activity of TAK-875, which was also safe and well tolerated [Viswanathan, P. et al., Abst 187]. Further studies documented a glucose-lowering effect for Cinnamomum zeylanicum (Ceylan cinnamom) (accompanied by reduced food intake and lipid levels) [Ranasinghe, P. et al., Abst 874], as well as the benefits of green tea on nitric oxide bioavailability [Faria, A.M. et al., Abst 1070].
Scarce miscellaneous news was discussed on the subject of islet transplant for type 1 diabetes during the meeting in Lisbon, but the results of an interesting study were reported that indicated comparable benefits of single islet transplant (with retransplant only in case of glycemic deterioration) compared to multiple initial islet transplant, the former approach requiring less donors and resulting in equal glycemic control and risk of severe hypoglycemia despite a higher demand for exogenous insulin [Gerber, P.A. et al., Abst 229]. In relation with islet transplant, pretreatment of isled donors with deferoxamine and treatment of recipients with the drug reduced post-transplant apoptosis and increased beta cell mass [Stokes, R.A. et al., Abst 232], whereas treatment of experimental islet graft recipients with sitagliptin did not improve transplanta outcomes [Juang, J.H. et al., Abst 429]. On the other hand, tacrolimus and ciclosporin as immunosuppression for pancreas/kidney transplant were not associated with changes in glucose metabolism during the late post-transplant period [Havrdova, T. et al., Abst 428].
Besides the nephroprotective activity of spironolactone, which reduced urinary albumin excretion in patients with diabetic microalbuminuria [Nielsen, S. et al., Abst 1099], preclinical studies indicated potential as therapeutic agents for alternative compounds. For example, at least in experimental animals, telmisartan exhibited nephroprotective activity through antioxidative and antiinflammatory mechanisms resulting from activation of the PPAR-gamma pathway [Kajitani, N. et al., Abst 1092]. However, greater improvements in progressive diabetic nephropathy were observed with the novel angiotensin AT1 receptor blocker and PPAR-gamma agonist K-21299 [Sekimoto, R. et al., Abst 1069].
While the safety of ranibizumab in the treatment of diabetic macular edema was corroborated in a pooled analysis of the RESOLVE and RESTORE trials [Bandello, F. et al., Abst 1122] and the aldosterone synthase inhibitor FAD-286 was confirmed to be effective for reducing retinal neovascularization in ex vivo studies [Deliyanti, D. et al., Abst 1110], in the experimental in vitro and in vivo arena, polyphenol-enriched cocoa exhibited activity against retinal oxidative activity and claudin-1 expression in diabetic conditions, indicating retinal protective activity [Rosales, M.A.B. et al., Abst 1115]. Retinal protection against oxidative stress and glutamate transporter expression during exposure to high glucose concentrations was also demonstrated with green tea polyphenols [Silva, K.C. et al., Abst 1114], while studies in diabetic animal models indicated prevention of retinopathy and retinal advanced glycation end product accumulation by HM-VN118, an herbal medicine [Kim, J. et al., Abst 1113].
While amitriptyline and alpha-lipoic acid were both effective for relieving pain in patients with diabetic neuropathy, with the former having a greater beneficial impact on the patients' quality of life but also a greater likelihood for adverse events [Psurek, A. et al., Abst 1140], the use of epalrestat in the treatment of patients with type 2 diabetes and polyneuropathy resulted in protection against the development of myocardial infarction according to retrospective observations from diabetes centers in Japan [Kajiwara, T. et al., Abst 1241]. In a similar way, treatment with lipoic acid improved heart rate variability and exercise tolerance in patients with diabetic cardiovascular autonomic neuropathy resulting in heart failure [Pochinka, I. et al., Abst 1148].
Although no clinical trial results were discussed on treatments for diabetic foot ulcers, preclinical results suggesting potential therapeutic usefulness for Astragalus polysaccharides for promoting fibroblast proliferation but inhibiting matrix metalloproteinase 2 and 9 expression [Dingyu, C. et al., Abst 1173] and mesenchymal stem cells for improving diabetic foot ulcer healing [Kato, J. et al., Abst 1169] were reported.
Sustained weight loss in patients with metabolic syndrome was demonstrated with phentermine/topiramate, resulting in improvements in glycemia outcomes in patients with type 2 diabetes [Van Gaal, L.F. et al., Abst 906] and resolution of the metabolic syndrome diagnostic criteria in a significant proportion of patients compared to placebo [Toplak, H. et al., Abst 905] (Fig. 33). In the experimental arena, improved mitochondrial dysfunction and insulin sensitivity in diabetic obesity was suggested after cyclo-oxygenase-2 inhibition with celecoxib, which increased mitochondrial density in the diabetic skeletal muscle [Kang, S. et al., Abst 538].
Fig. 33. Proportion of patients with metabolic syndrome losing diagnostic criteria and percent of patients without but progressing to metabolic syndrome after 108 weeks of treatment with phentermine/topiramate or placebo [Toplak, H. et al., Abst 9095].
While in the preclinical arena atorvastatin combined with insulin protected retinal cell function by reducing oxidative stress and restoring the ubiquitin proteasome pathway [Fernandes, R. et al., Abst 1111], low-dose pravastatin was effective for preventing coronary and cerebrovascular events in patients with diabetic hypercholesterolemia [Sasaki, J. et al., Abst 1258].
No other information was reported during this year's meeting on statins, but news was discussed on alternative lipid-lowering drugs. In that regard, data from the FIELD study using fenofibrate demonstrated slowing of glomerular filtration rate loss, prevention and reversion of early-stage neuropathy and maintained cardiovascular benefits without renal injury in patients with diabetes [Ting, R. et al., Abst 41; Keech, A.C. et al., Abst 180], and results with colesevelam indicated decreases in endogenous glucose production that were not mediated by the incretin system, despite the agent mildly increasing glucagon-like peptide 1 production, possibly through its effects on gastrointestinal motility, and interacting to further lower glucose levels during treatment with sitagliptin [Smushkin, G. et al., Abst 835]. On the other hand, rimonabant had no additive effect to insulin on nonesterified fatty acid levels in nondiabetic subjects with abdominal obesity, although it exerted beneficial effects compared to placebo on body weight, waist circumference and fat mass [Triay, J.M. et al., Abst 663].
Studies in obese individuals indicated that omega 3-polyunsaturated fatty acid supplementation resulted in an increased production of lipid-derived adipokines and improvement in systemic inflammation [Itariu, B.K. et al., Abst 738], while reductions in obesity-associated disorders in experimental animals were superior with omega 3-polyunsaturated fatty acids administered as phospholipids compared to marine triglycerides [Rossmeisl, M. et al., Abst 878]. Furthermore, in the preclinical arena, polyunsaturated fatty acid supplementation magnified the beneficial effects of calorie restriction after a high-fat diet [Zouhar, P. et al., Abst 677]. However, a study in older subjects with impaired glucose regulation did not find any effect of fish oil supplementation on endogenous glucose production or glucose disposal [Clark, L.F. et al., Abst 317]. Concerning other dietetic supplements, mixed carotenes from vegetable-based soups and salads reduced oxidized LDL levels, with the consequent cardiovascular benefits [Bradley, R. et al., Abst 882]. On the contrary, Lactobacillus casei supplementation did not affect insulin sensitivity of beta cell function in patients with metabolic syndrome [Tripolt, N.J. et al., Abst 613].
Although not widely used in the treatment of hypertension, the beta-adrenoceptor blocker carvedilol not only reduced blood pressure, but also helped prevent insulin resistance in high sucrose- and fat-fed experimental animals, indicating a role for the sympathetic nervous system in the pathogenesis of diet-related metabolic disturbances [Guarino, M.P. et al., Abst 592].
Angiotensin-converting enzyme inhibitors, particularly ramipril, exerted protective activity against obesity and insulin resistance in experimental animal models through an effect on adipose tissue independent of the blood pressure-lowering effects [Kavalkova, P. et al., Abst 679].
With a possible additional advantage of irbesartan, angiotensin receptor blockers were identified as effective drugs for lowering blood pressure and the albumin:creatinine ratio in patients with type 2 diabetes [Bilo, H.J.G. et al., Abst 1093], while at least in the case of valsartan, adding the angiotensin receptor blocker was superior to uptitrating the dose of prior enalapril in suppressing aldosterone, thus preventing cardiac fibrosis and ventricular remodeling [Yasuda, G. et al., Abst 1095]. On the other hand, at least in the case of valsartan, the lack of effect on osteoprotegerin and receptor activator of nuclear factor NF-κB ligand (RANKL) levels suggested that these mediators were not related to the cardioprotective activity of angiotensin receptor blockade in type 2 diabetes [Karalliedde, J. et al., Abst 1096], whereas irbesartan negatively influenced the glycosylation gap (difference between hemoglobin A1c and glycosylated protein levels) [Thornalley, P.J. et al., Abst 1097]. Furthermore, as demonstrated with candesartan, blockade of the angiotensin receptor induced antiapoptotic and anti-senescent activity on retinal pericytes submitted to hyperglycemic conditions, suggesting potential for preventing diabetic retinopathy [Berrone, E. et al., Abst 1109].
Direct renin inhibition with aliskiren proved effective for lowering blood pressure regardless of the presence of diabetes in patients with hypertension [Sowers, J.R. et al., Abst 1106]. Moreover, in hypertensive individuals with metabolic syndrome, both aliskiren and amlodipine improved peripheral blood pressure, insulin sensitivity and endothelial function, but aliskiren had a stronger benefit on urinary albumin and endothelin-1 levels, central systolic, diastolic and mean blood pressure and beta cell function, with fewer patients receiving the renin inhibitor progressing to overt diabetes [Troum, O.M. et al., Abst 584] (Fig. 34). Furthermore, adding aliskiren to losartan-based optimal antihypertensive therapy improved urinary albumin:creatinine ratio more effectively than placebo, especially in patients with poorly controlled type 2 diabetes [Persson, F. et al., Abst 1098].
Fig. 34. Change in central systolic and diastolic blood pressure (upper chart) and endothelin-1 and urinary albumin levels (lower chart) after 12 weeks of treatment with aliskiren or amlodipine [Troum, O.M. et al., Abst 584].
Phase III clinical trial data were reported indicating the effectiveness of avanafil as a treatment for erectile dysfunction in patients with type 1 or 2 diabetes [Goldstein, I. et al., Abst 1153] (Fig. 35). In the preclinical setting, improvements in erectile dysfunction associated with diabetes were demonstrated with the urotensin receptor blocker SB-657510 [Olukman, M. et al., Abst 1130].
Fig. 35. Percent of patients reporting successful insertion or intercourse after 12 weeks of on-demand avanafil or placebo [Goldstein, I. et al., Abst 1153].
Administration of alpha-lipoic acid to patients with type 1 diabetes resulted in attenuated platelet reactivity, supporting a benefit on the cardiovascular risk that should be evaluated in randomized clinical trials [Scalone, G. et al., Abst 1250].
At a dose of 0.6 g/kg, isomaltulose with a 50% reduction in the dose of rapid-acting insulin produced less glycemic responses but maintained exercise performance as effectively as full-dose rapid-acting insulin in actively exercising type 1 diabetes patients [Bracken, R.M. et al., Abst 618].
While aspirin had no significant impact on oxidative stress, paraoxonase activity or nitric oxide levels regardless of the presence of diabetes [Lopez, L.R. et al., Abst 757], resistance to the antiplatelet activity of aspirin in diabetes was independent from glucose control, and could be overcome by twice-daily administration better than doubling the dose [Zaccardi, F. et al., Abst 72].