Educate the Patients But Also Physicians and Educators: A Report from the 20th World Diabetes Congress

October 18-22, 2009

Montreal, Canada

As the global diabetes epidemic explodes, the International Diabetes Federation has launched an urgent call for more education, and has drawn up global education guidelines to help provide health professionals with an educational framework. This call seemed to be taken up for those directly off the airplaine, since the screens in the immigration and customs area of the Montreal international airport included, among other information, a message on the expected 380 million people who will have developed diabetes by 2025. One of the major messages pronounced during the meeting itself was the need for population-wide measures addressing diet, physical activity and smoking to reduce the risk of obesity, diabetes and cardiovascular disease [Unwin, N., Abst 0336], a cohort usually termed diabesity. This was accompanied by evidence that population-wide educational and interventional campaigns do work.

This was a relevant issue discussed during this year’s meeting that led to discussions on whether it is more important to prevent diabetes or to diagnose unrecognized diabetes [Bell, E., Abst 0193; Beecham, K.A. et al., Abst 0194]. It was quite evident to all attendees that it is equally important to treat diabetes, diagnose previously unrecognized diabetes and prevent diabetes in the population at risk, but given that the population at risk includes everyone, the complexity resides in how to distribute resources in order to better address the problem as a whole. An important message is that a healthy lifestyle can prevent premature death in both the diabetic and nondiabetic populations [Saydah, S. et al., Abst O-0196], which brings us back to the initial recommendation of education and promotion of health as a priority for public interventions in the area of diabetes prevention, awareness and treatment. In that context, along with many other interesting reports discussed at the meeting site, the feasibility of culturally appropriate diabetes education programs for rural communities was documented in a phase I study [Ardena, G.J.R. et al., Abst O-0253], leaving the issue of educating the educators and the physicians at large open to discussion. Is this not one of the objectives of the International Diabetes Federation and one of the reasons why physicians from over the world attended the meeting in Montreal? Better patient education with better physician training should be key to modifying the current increasing trends in the diabetes pandemic. On a very minor scale, this report aims to reinforce these ideals and offer clues as to what was discussed at the meeting for the benefit of all those who could not attend the meeting or for those who attended, but could not or did not see or hear it all.

The International Diabetes Federation’s World Diabetes Congress also included information on the treatment of established diabetes, with regard to which an updated review of the ACCORD study is worth mentioning. The study initially demonstrated that intensive therapy aimed at reducing hemoglobin A1c levels did not prevent, but rather worsened cardiovascular mortality. However, novel analyses have now revealed that adverse cardiovascular outcomes occurred not in patients reaching target, but rather in patients on intensive therapy who were unable to attain the hemoglobin A1c targets. Furthermore, epidemiologic relationship analyses between mortality and the rate and degree of improvement of hemoglobin A1c levels confirmed prior knowledge of an association between higher levels of the marker and higher risk of death [Riddle, M., Abst 0527]. Indeed, this finding was independently confirmed by the ADDITION study, which demonstrated an increased risk of death in patients with hemoglobin A1c levels over 6.4% regardless of glucose tolerance status, while also revealing a two-fold increase in mortality in patients with concomitant impaired glucose tolerance and impaired fasting glucose, even in the presence of hemoglobin A1c levels under 6.0% [Lauritzen, T. et al., Abst O-0530], and was further corroborated by an analysis of mortality in patients with type 2 diabetes and prior myocardial infarction, which demonstrated higher death rates in patients with higher postprandial glycemia or hemoglobin A1c levels compared to those with fasting or lower levels [Dundua, M. et al., Abst D-0673]. On the other side of the scale, a meta-analysis presented as a poster during the meeting suggested superiority of insulin secretagogues and thiazolidinediones for reducing hemoglobin A1c compared to other oral antidiabetic agents (excluding insulin and insulin analogs), but confirmed the overall efficacy of all currently available oral antidiabetic drug families [Sherifali, D. et al., Abst D-0840] (Fig. 1). Specific data on the antidiabetic effectiveness profiles of individual agents and other relevant therapeutic information discussed during the meeting is summarized in the following report.

Insulin is the gold standard in the management of type 1 diabetes, with the used of premixed insulins offering a viable option for increasing adherence and compliance despite the increased likelihood for diabetic ketoacidosis [Van Walleghem, N. et al., Abst D-0893], and is the most readily available means to lower acute hyperglycemia in the hospital setting; a triple basal bolus booster regimen proved reliable, effective and well-tolerated in this respect [Harding, A. et al., Abst P-1391]. However, the use of insulin analogs was associated with fewer treatment changes in real-life conditions [Thomsen, T.L. et al., Abst P-1447] and could also outcompete human insulin for in-hospital hyperglycemic crises [Bhattacharyya, A. et al., Abst P-1393], as effectively demonstrated in the case of insulin aspart [Udwadia, F. et al., Abst P-1462]. Furthermore, although insulin therapy remains a requirement in many patients with type 2 diabetes, and although benefits can be expected on endothelial function at least using an injectable formulation of ultrarapid recombinant human insulin (VIAject^TM) [Pfützner, A. et al., Abst P-1428], real-life data revealed initiation of such treatment mostly in patients with advanced disease, worst glycemic control and a high prevalence of micro- and macrovascular complications [Picard, S. et al., Abst D-0674]. In contrast to this, data from the IMPROVE^TM study confirmed that while improving glycemic control and patients’ quality of life without excess risk of hypoglycemia or weight gain [Valensi, P. et al., Abst D-0837; Esteghamati, A.R. et al., Abst P-1445; Kim, S.W. et al., Abst P-1449], initiation of biphasic insulin aspart in patients with type 2 diabetes improved life expectancy, delayed the onset of complications and reduced the life-long cumulative incidence of complications compared to continued oral therapy [Gumprecht, J.G. et al., Abst D-0727], resulting in an attractive and cost-effective rapid-acting alternative to human insulin [Pollock, R.F. et al., Abst P-1598]. Furthermore, switch to insulin aspart showed a positive impact on the patients’ satisfaction with insulin therapy and on physicians’ resources [Brod, M. et al., Abst P-1425; Shaban, J. et al., Abst P-1426], biphasic insulin aspart being associated with superior outcomes compared to insulin glargine in a further study [Kalra, S. et al., Abst P-1435]. Lower risk for hypoglycemia compared with standard human insulin was also demonstrated with insulin detemir, which was likewise associated with lower fasting and postprandial glycemia [Amirkhanashvili, K. et al., Abst D-0894] and was confirmed effective in independent studies in patients with type 1 or 2 diabetes [Fuji, H. et al., Abst P-1439; Ko, K.S. et al., Abst P-1457; Ko, K.S. et al., Abst P-1458], although real-life observations suggested higher patient satisfaction and lower treatment costs with insulin glargine than insulin detemir [Moock, J. et al., Abst D-0962; Landgraf, W. et al., Abst D-0963]. Insulin glargine was effective for glycemic control, as confirmed in alternative studies [Pathan, F. et al., Abst P-1429; Ascic Buturovic, A.B.B. et al., Abst P-1432; Pathan, M.F. et al., Abst P-1700], and, although additional studies did not find differences in glycemic control comparing the two analog insulins [McAdam-Marx, C. et al., Abst P-1450], according to pharmacoeconomic insights, the increased quality-adjusted life expectancy and the reduced risk of hypoglycemia using insulin glargine compared to human insulin translated into clear benefits in terms of reduced number-needed-to-treat (NNT) to avoid one case of hypoglycemia, and, hence, in superior cost-effectiveness [Rosenstok, J. et al., Abst O-0058; Greiner, R.A. et al., Abst P-1595], despite the lower direct costs for human insulin compared to the analog in yet other studies [Saler, T. et al., Abst P-1455]. Aside from the previously mentioned differences comparing the two long-acting insulin analogs, total doses of insulin glargine and insulin detemir in the real-world treatment of type 2 diabetes seemed to be similar matched for baseline glycemic profile [McAdam-Marx, C. et al., Abst P-1437], and insulin detemir, like insulin glargine, also arose as a cost-effective initial insulin therapy for type 2 diabetes, without expected differences comparing the life expectancy, quality-adjusted life years, glycemic control and total lifetime cost per patient [Aagren, M., Abst P-1597].

However, it is not only which insulin or insulin analog to use, but which regimen offers better chances of a good diabetes control, with less risk of hypoglycemia and weight gain and better long-term prognosis. This was the question analyzed by the T-4 study which, according to already published one-year results, which were discussed in Montreal by A. Farmer in an unscheduled presentation, demonstrated higher decreases in hemoglobin A1c with biphasic (twice daily) and prandial (thrice daily) insulin compared to basal insulin (once daily, with a second dose at bedtime only if required), although the risk of hypoglycemia was higher with prandial insulin compared to the other two regimens. No major differences were noted comparing quality of life and patient satisfaction, although basal insulin fared better regarding flexibility and prandial dosing showed overall lower scores. However, the three-year results of the T-4 study, which were scheduled to be presented in one of the most popular sessions during this year’s World Diabetes Congress, turned the earlier results around. After the first year, patients continued the same insulin regimen but, as the objective of the study was Treating To Target in Type 2 diabetes (hence the name of 4-T), patients on biphasic and basal insulin regimens could add a minor prandial dose (only midday in the biphasic group), whereas patients on prandial insulin could add a minor basal bedtime dose to reach glycemic control. With this individualized to target strategy, which resulted in approximately 75% of patients across groups adding a second insulin, no differences were apparent by the end of the third year regarding glycemic control, but patients initially on prandial or basal insulin showed better target attainment rates and control of blood glucose, and patients on basal insulin showed less risk for hypoglycemia and less weight gain and increase in waist circumference. Hence, over the long term, basal insulin offered efficacy comparable to biphasic or prandial insulin, with a lower risk for serious outcomes that also included a lower rate of all-cause and cardiovascular death [Holman, R.R. et al., Abst 0526] (Fig. 2).

In relation with subcutaneous insulin therapy, and at least in the case of insulin lispro, the recombinant human hyaluronidase rHuPH20 acted as a potent permeation enhancer, resulting in higher exposure and maximm effect of the insulin analog [Vaughn, D. et al., Abst D-0964]. A specific modality of subcutaneous insulin, continuous insulin infusion offered improved lifestyle flexibility to both children with type 1 diabetes and their parents, with favorable results in terms of glycemic control and quality of life [Danne, T. et al., Abst 0528; Alsaleh, F.M. et al., Abst P-1452; González-Molero, I. et al., Abst P-1454] and an overall low risk of hypoglycemic excursions [Didangelos, T. et al., Abst P-1459]. Continuous subcutaneous insulin infusion also proved a feasible approach to the management of hyperglycemia and diabetes during pregnancy [González-Molero, I. et al., Abst P-1468]. However, alternatives to injectable insulin have been actively researched, and a number of innovative formulations are now available or under advanced clinical research. One example is buccal insulin spray, which in proof-of-concept studies demonstrated glycemic improvements in patients with type 2 diabetes suboptimally controlled with oral agents [Talwalkar, P. et al., Abst P-1446] and had a significant effect on postprandial hyperglycemia in obese patients with impaired glucose tolerance [Napoli, N. et al., Abst D-0965]. Another alternative that was successfully tested in human patients was an insulin for instillation into the auditory channel, with or without using a piezoelectric pump [Pirkalani, K., Abst P-1465; Pirkalani, K. & Talaei Rad, Z., Abst P-1466]. Furthermore, experimental animal studies suggested potential for an oral long-lasting insulin-containing hydrofoam [Smolko, E. et al., Abst D-0966].

A randomized, controlled study demonstrated an effect for metformin in decreasing plasma levels of von Willebrand’s factor, vascular cell adhesion molecule-1, tissue plasminogen activator, plasminogen activator inhibitor-1, C-reactive protein and intercellular adhesion molecule 1, suggesting improvements in endothelial regulation of hemostasis, leukocyte adhesion and fibrinolysis and an overall reduction in low-grade inflammation associated with diabetes [Kooy, A. et al., Abst D-0772]. A second study confirmed the antiinflammatory potential of metformin by demonstrating reductions in C-reactive protein levels in patients treated with metformin plus insulin glargine, but not in those treated with the insulin analog alone [Velija-Asimi, Z. et al., Abst P-1460]. Furthermore, metformin, but not sitagliptin combined with pioglitazone improved insulin resistance and adiponectin levels at equivalent glycemic control in patients with type 2 diabetes [Derosa, G. et al., Abst D-0833] (Fig. 3), although both agents proved similarly effective for controlling glucose levels in patients with glucocorticosteroid-induced diabetes [Georgiadi, E. et al., Abst P-1481]; metformin was also reported effective in preventing and/or reverting metabolic abnormalities in patients with polycystic ovary syndrome [Refaie, M.R. et al., Abst P-1527]. As a novel addition, a sustained-release formulation of metformin was shown to improve glycemic control in type 2 diabetes patients showing poor adherence to the immediate-release formulation [Hsiao, S.H. et al., Abst P-1163]. Mechanistically, treatment with metformin normalized the depressed activity of natural killer cells, the number of which was increased in hyperglycemic conditions [Piatkiewicz, P. et al., Abst P-1155] although, in experimental animals, the agent increased oxidative stress, indicating the need for antioxidant vitamin supplementation [Adaramoye, O. et al., Abst P-1160].

New results from the ADVANCE study ─ which along with other major trials mentioned in this report were presented in a special session of the World Diabetes Congress devoted to the latest clinical trials in diabetes ─ confirmed the safety and efficacy of intensive gliclazide therapy in lowering hemoglobin A1c and improving glycemic control [Marre, M. et al., Abst D-0696], while confirming a log-linear relationship between hemoglobin A1c levels and clinical outcomes translating into a 20% to 25% reduction in the risk of death or vascular or renal events for each 1% reduction in glycosylated hemoglobin levels [Chalmers, J. et al, Abst 0529], further clarifying the issue of the benefits associated with intensive glycemic control derived from novel analysis of the ACCORD and ADDITION studies previously mentioned.

According to a meta-analysis of randomized controlled trials, alpha-glucosidase inhibitors are able to improve glycemic control as effectively as other oral antidiabetic medications, with a low risk for hypoglycemia and an increased risk for adverse gastrointestinal events [Chen, H. et al., Abst D-0839]. Among these agents, the prototype drug, acarbose, was shown to improve hyperglycemia in patients submitted to gastric bypass surgery by decreasing insulin and glucagon-like polypeptide-1 responses [Valderas, J.P. et al., Abst D-0993], while voglibose allowed for less stringent dietary control in patients with type 2 diabetes, which could be important when good dietary guidance from a professional nutritionist is not available [Shankhdhar, L.K. et al., Abst P-1138]. However, switch from acarbose or voglibose to miglitol in patients with type 2 diabetes previously showing suboptimal glycemic control improved glucose fluctuations and hemoglobin A1c levels and was associated with a decrease in the expression of genes coding for inflammatory cytokines and mediators in leukocytes [Mochizuki, K. et al., Abst D-0838].

Thiazolidinediones have shown a number of benefits in the treatment of type 2 diabetes, which now include, according to a new population-based retrospective study, a reduced risk for cancer mortality and adverse cancer outcomes [Bowker, S. et al., Abst D-1000]. However, although clinical data confirmed its potential for improving glycemic control [Seguchi, T. et al., Abst P-1168] and further reducing urinary albumin excretion in diabetic, hypertensive patients on renin-angiotensin system-blocking antihypertensive therapy [Morikawa, A. et al., Abst D-0819], and new mechanistic data reported during the World Diabetes Congress confirmed an effect of pioglitazone in improving post-oral glucose challenge glucose levels [Liu, J. et al., Abst P-1157] (Fig. 4), decelerating pancreatic S-cell metabolism and reducing insulin secretion at submaximal glucose concentrations through an effect on AMP-dependent protein kinase [Lamontagne, J. et al., Abst D-0791] and improving the overall cardiovascular risk profile of hypertensive, nondiabetic patients [Pfützner, A. et al., Abst P-1164], the agent was associated with dose-dependent weight gain and fluid retention paralleling benefits on glycemic control [Panikar, V. et al., Abst P-1166]. While a fixed-drug combination of pioglitazone and metformin improved glycemic control, insulin resistance and markers of inflammation in patients with type 2 diabetes compared to either monotherapy [Perez, A. et al., Abst D-0835; Spanheimer, R. et al., Abst P-1158] (Fig. 5) and ablated glucotoxicity and induced “pharmacological remission” of type 2 diabetes in patients with newly diagnosed disease [Panikar, V. et al., Abst P-1165], a fixed triple-drug combination of pioglitazone, metformin and glimepiride tested favorably in the PRIDE III study for improving glycemic control in patients not responding favorably to mono- and dual therapies, while also enhancing compliance and reducing insulin requirements [Joshi, S.R. et al., Abst D-0834].

The results of the RECORD1 trial presented during the meeting in Montreal confirmed the association between use of rosiglitazone and increased risk for heart failure and fractures, the latter at least in women, but did not confirm an association between the agent and the risk of myocardial infarction or overall cardiovascular morbidity and mortality [Beck-Nielsen, H., Abst 0125].

A novel thiazolidinedione currently in development, BLX-1002 was shown to enhance glucose-, glucagon-like polypeptide-1 and tolbutamide-induced insulin secretion in experimental diabetes models [Zhang, F. et al., Abst D-0794]. A further novel peroxisome proliferator-activating receptor-gamma-sparing drug candidate sharing most of the benefits of pioglitazone, according to a comparative trial, was MSDC-0160 [Colca, J.R. et al., Abst D-0773] (Fig. 6).

With benefits on glycemic control and body weight through enhancement of glucose-dependent insulin secretion, suppression of excess glucagon secretion, reduction of food intake and slowing of gastric emptying [Kadir, S. et al., Abst P-1411], exenatide may exert a disease-modifying approach to the treatment of diabetes [Disoteo, O. et al., Abst P-1414]. Weekly and twice-daily administration of exenatide provided similar efficacy in reducing exposure to glucose in patients with type 2 diabetes, the extended-action formulation given weekly resulting in improved glucose stability [Mazze, R. et al., Abst O-0544]. Insight into the effect of exenatide on body weight concluded on a higher impact in heavier patients reaching better on-treatment glycemic control, whereas initial body weight gains could be possible in patients with very poor glycemic control, turning to weight loss as exenatide progressively improves glycemia [Ryder, R.E.J. et al., Abst P-1736]. In the experimental setting, exenatide prevented diabetes in diabetic-prone animal models [Juang, J.H. et al., Abst O-0396]. Furthermore, while both exenatide and glibenclamide improved the glycemic profiles of patients suboptimally controlled with prior metformin therapy, only exenatide improved insulin resistance and body weight [Derosa, G. et al., Abst D-0909], while combined use of exenatide and pioglitazone resulted in enhanced control of glucose, free fatty acid and triglyceride levels [Bajaj, M. et al., Abst P-1407]. In addition to the prior new reported findings, a theoretical study confirmed the possibility of predicting glycemic responses to exenatide, and possibly other incretin mimetics, through an in silico simulation program based on continuous glucose monitoring using the Karlsburg Diabetes Management System software [Augstein, P. et al., Abst O-0546].

With an overall benefit on hemoglobin A1c and body weight without meaningful risk for hypoglycemia [Zinman, B. et al., Abst D-0910; Pratley, R. et al., Abst P-1401] and benefits on beta-cell function [Seino, Y. et al., Abst D-0912], use of liraglutide in the management of type 2 diabetes resulted in improved lipid, blood pressure and overall cardiovascular risk profiles [Plutzky, J. et al., Abst O-0542; Fonseca, V. et al., Abst D-0908] (Fig. 7), while improving mealtime insulin responses and overall glycemic control as or more effectively than glibenclamide or glimepiride at a lower risk for hypoglycemia [Kaku, K. et al., Abst P-1262; Garber, A. et al., Abst P-1397; Matthews, D. et al., Abst P-1399; Nauck, M. et al., Abst P-1402], with improved patient satisfaction as compared to exenatide [Christiansen, J.S. et al., Abst P-1403] and offering a better glycemic control upon switch from prior exenatide therapy [Buse, J. et al., Abst P-1405]. To note, according to a meta-analysis of the LEAD trials, the effect of liraglutide on hemoglobin A1c levels was related to baseline levels, with increased efficacy in patients with poorer prior glycemic control [Nauck, M. et al., Abst P-1400]. In addition, treatment with liraglutide in obese prediabetic individuals resulted in benefits on body weight and systolic blood pressure and reversed the prediabetic status [Van Gaal, L. et al., Abst D-0986], although in established type 2 diabetes, the glycemic benefit of the treatment showed no dependence on degree of weight loss [Schmidt, W.E. et al., Abst P-1398]. While further data confirmed the lack of effect of concomitant sitagliptin on the pharmacokinetics of liraglutide in preclinical species [Nielsen, F. et al., Abst P-1404], in experimental animal models the agent showed potential for delaying or preventing the onset of type 2 diabetes through effects on body weight gain and energy and lipid metabolism [Cummings, B. et al., Abst D-0907], promoting S-cell proliferation while protecting against interleukin-1beta- and LDL-induced apoptosis [Rütti, S. et al., Abst P-1270] and restoring normoglycemia in the sand rat (Psammomys obesus), an effect not accomplished with vildagliptin [Bodvarsdottir, T.B. et al., Abst P-1520]. The long-lasting activity of the glucagon-like polypeptide-1 analog was related to its stability against dipeptidyl peptidase-4, formation of heptamers and binding to plasma albumin [Bjerre Knudsen, L. et al., Abst D-0911]. With favorable safety, tolerability and pharmacokinetics [Seino, Y. et al., Abst P-1408], and especially a low risk for gastrointestinal adverse events [Yang, F. et al., Abst P-1409], improvements in glycemic profile in patients with type 2 diabetes were also obtained with albiglutide, with reductions in hemoglobin A1c and fasting plasma glucose numerically greater than those obtained with exenatide in a comparative study [Rosenstock, J. et al., Abst O-0545; Reusch, J. et al., Abst P-1410] (Fig. 8). A further similar agent, taspoglutide exerted protective effects on islet integrity and pancreatic S-cells resulting in enhanced insulin secretion, prevention of apoptosis and induction of proliferation in the experimental arena [Wang, H. et al., Abst D-0906; Bénardeau, A. et al., Abst P-1396].

A novel long-acting glucagon-like polypeptide-1 analog, LY-2189265, proved effective in controlling glycemia in type 2 diabetes patients previously uncontrolled on oral medications, the reductions in hemoglobin A1c being accompanied by modest reductions in body weight and all other metabolic outcomes assessed and without an excess risk of hypoglycemia compared to placebo [Umpierrez, G. et al., Abst O-0543] (Fig. 9).

By inhibiting the enzyme that degrades glucagon-like polypeptide-1, dipeptidyl peptidase-4 inhibitors raise endogenous incretin concentrations and are able to improve glycemic control in diabetes with a very favorable safety and tolerability profile [Deacon, C.F., Abst 0506]. These agents seem to be more effective when administered in earlier stages of the diabetes process, and can be used as monotherapy or combined with metformin and/or sulfonylureas [Navarrete, R.E.T. et al., Abst P-1412].

As opposed to pioglitazone and rosiglitazone, sitagliptin did not exacerbate ovariectomy-induced bone loss in experimental animals [Cusick, T. et al., Abst D-0832] while in the clinical arena improved glycemic control and beta-cell function whether used in mono- or combination therapy with metformin [Williams-Herman, D. et al., Abst D-0913]. Overall, real-world data demonstrated generalized use of sitagliptin in older patients with more complications and comorbidities compared to other oral antidiabetic therapies [Zhang, Q. et al., Abst P-1152]. Without feedback effects on endogenous incretin hormone production or effects on somatostatin secretion [Aaboe, K. et al., Abst O-0547], initial treatment of type 2 diabetes with a fixed-drug combination of sitagliptin and metformin proved superior to treatment with only metformin regarding control of hemoglobin A1c in a randomized trial [Olansky, L. et al., Abst O-0535] (Fig. 10). In a similar way, a combination of sitagliptin and pioglitazone proved as well tolerated as pioglitazone monotherapy as initial treatment for type 2 diabetes, but led to substantially incremented glycemic control [Yoon, K.H. et al., Abst P-1153] (Fig. 11) and improved both beta- and alpha-cell function [Alba, M. et al., Abst P-1740] (Fig. 12). Vildagliptin offered glycemic improvements comparable to those obtained with sitagliptin, as demonstrated in a direct comparative trial [Gama, M. et al., Abst P-1413] (Fig. 13). A similar combination of pioglitazone with vildagliptin was as effective as glimepiride combined with vildagiptin regarding glycemic control, but only pioglitazone/vildagiptin improved insulin resistance-related parameters [Derosa, G. et al., Abst P-1156], vildagliptin having been proved safe and well tolerated also in patients with renal impairment in the GALIANT study [Francis, B. et al., Abst P-1395].

As first-line therapy of type 2 diabetes not controlled with diet and exercise, a combination of alogliptin and pioglitazone improved glycemic control while also improving insulin resistance and beta-cell function [Rosenstock, J. et al., Abst O-0548] (Fig. 14). The combination was also superior to pioglitazone alone in patients previously uncontrolled on metformin therapy [DeFronzo, R. et al., Abst D-0914].

Pre- and clinical data were reviewed with a novel dipeptidyl peptidase-4 inhibitor, DSP-7238, which, with selectivity versus other dipeptidyl peptidases, showed pharmacokinetic/pharmacodynamic potential for prolonged activity and sustained exposure [Nakagawa, T. et al., Abst P-1151]; clinical results were also discussed with melogliptin, a novel dipeptidyl peptidase-4 inhibitor that proved safe in a phase II study while also improving the metabolic profile and insulin resistance in patients with type 2 diabetes [Efthimiou, J. et al., Abst P-1739] (Fig. 15). Only preclinical results were discussed in the meeting with teneligliptin, which improved glucose tolerance and prevented diet-induced obesity, specifically abdominal adiposity, in experimental animals, offering benefits beyond glycemia-improving activity [Ishii, S. et al., Abst P-1737].

Through lowering of postprandial and fasting plasma glucose levels and body weight due to calories lost as glucose, sodium/glucose cotransporter-2 inhibitors may have a role in the treatment of type 1 and 2 diabetes and obesity [Henry, R. et al., Abst 0450]. In that respect, the previous favorable findings with dapagliflozin were corroborated and extended in a phase III trial and a pooled analysis of three randomized, placebo-controlled trials reported in Montreal that demonstrated meaningful decreases in hemoglobin A1c levels over 12- to 24-week periods regardless of baseline status and background medication and with favorable safety and tolerability [Seck, T. et al., Abst O-0536; Bastien, A. et al., Abst D-0765] (Fig. 16). To note that despite causing glucosuria, treatment with dapagliflozin was not associated with an increased risk for urinary tract infections compared to placebo, although a nonsignificant trend towards increased rates of genital infections was noted [Bastien, A. et al., Abst D-0766].

In the experimental arena, the profile of canagliflozin was also confirmed, with increases in urinary glucose excretion associated with reductions in body weight and increases in fatty acid oxidation resulting in improvements in hyperglycemia and hemoglobin A1c levels and enhanced insulin responses to glucose challenge [Liang, Y. et al., Abst D-0767; Liang, J. et al., Abst D-0768].

Glucokinase activators are another family of agents with putative antidiabetic activity in the preclinical arena, although efficay remains to be fully validated in clinical trials [Matschinsky, F.M. et al., Abst 0452]. Within that group of putative drugs, piragliatin [Doliba, N. et al., Abst O-0537] and YH-9425 [Lee, D. et al., Abst P-1738] were shown to exert pharmacodynamic activity, suggesting potential for improving insulin secretion and glucose metabolism in patients with type 2 diabetes.

Experimental preclinical studies have suggested potential for glucagon receptor blockade as an approach to the treatment of type 2 diabetes [Moller, D.E., Abst 0351]. Benefits in the experimental arena were also described with the 11beta-hydroxysteroid dehydrogenase inhibitor carbenoxolone, which improved insulin resistance by increasing glucose transporter-4 expression in the muscle [Mori, R.C. et al., Abst P-1554]. In relation with the latter, monosubstituted vanadium compounds aimed at improving glucose transporter-4 expression were developed that also tested positive in the preclinical arena [Seraphim, P.M. et al., Abst P-1169].

As in other diseases with an immunoinflammatory background, targeted biological therapies have been developed for diabetes based on the identification of markers and mediators in the pathophysiology of the disease. A good example is otelixizumab, a chimeric humanized aglycosylated anti-CD3 monoclonal antibody that in patients with type 1 diabetes was shown to be safe and well tolerated while pharmacodynamically active, with evidence of improved residual beta-cell function [Rosenzweig, M. et al., Abst O-0397].

Diabetes has an inflammatory component, and the possibility of improving the disease through drugs acting on inflammatory pathways has been explored. In that sense, the antiinflammatory activity of salsalate, a prodrug of acetylsalicylic acid, in patients with type 2 diabetes translated into improved glycemia in a pilot study [Goldfine, A. et al., Abst 0539], and additional studies to confirm such activity, such as the TINSAL-CVD trial, are currently underway [Fonseca, V., Abst 0541]. In a similar way, initial favorable results were obtained with interleukin-1 receptor-blocking antibodies [Donath, M., Abst 0540; Feldstein, J.D. et al., Abst D-0856], and antiinflammatory activity accompanied by increased insulin activity in muscle was demonstrated in experimental animal models after treatment with quercetin [Anhe, G.F. et al., Abst D-0713].

Regarding prevention issues, effective control of hypertension through blockade of the renin-angiotensin system was shown to be mechanistically related to improvements in renal function and/or prevention of diabetic nephropathy, as demonstrated with losartan and perindopril in experimental animals [Chan, J.S.D. et al., Abst D-0597]. Other experimental studies described inhibition of organic cation transporter-1- and -2-mediated uptake of MPP+ and metformin with carvedilol and propranolol, but not bisoprolol or metoprolol [Bachmakov, I. et al., Abst D-0769], and reported renal benefits with chromium histidinate [Dogukan, A. et al., Abst D-0609]. In addition, quick-release bromocriptine was associated with enhanced glycemic control in patients already treated with thiazolidinediones, with accompanying benefits on blood pressure and the negative consequences of hypertension in hypertensive patients with type 2 diabetes, reducing the overall risk of cardiovascular adverse events by 40% over 52 weeks of treatment [Scranton, R. et al., Abst D-0770] (Fig. 17). On the contrary, dietary supplementation with omega 3-polyunsaturated fatty acids had no impact on the risk of incident microalbuminuria [Lee, C.C. et al., Abst D-0600], although it had a positive impact on the prevention of cardiometabolic abnormalities and oxidative stress in patients with metabolic syndrome [Dragomir, A. et al., Abst D-0636] without a negative impact on glycemic control [Khandelwal, S. et al., Abst P-1121].

Improvements in diabetic neuropathy in patients treated with epalrestat correlated with changes in taurine levels, which were suggested to be a reliable objective marker of response to treatment [Suzuki, D. et al., Abst D-0825].

Regarding symptomatic therapies, tramadol/paracetamol was found as effective as gabapentin for relieving diabetic neuropathic pain in a six-week randomized trial, without differences between the two treatment options regarding safety and tolerability issues [Cha, B.Y. et al., Abst O-0218] (Fig. 18). In addition, a placebo-controlled study confirmed the effectiveness of tapentadol, which was well tolerated and significantly and sustainably improved moderate neuropathic pain in patients with diabetes [Etropolski, M. et al., Abst O-0221; Etropolski, M. et al., Abst D-0830; Okamoto, A. et al., Abst D-0831] (Fig. 19).

Helium/neon laser therapy was suggested as an effective approach to the treatment of lower limb diabetic angiopathy, provided therapies aimed at glycemic control were also administered [Hairapetyan, E. et al., Abst D-0606]. In addition, use of bosentan offered rapid relief from diabetic skin ulcers with good tolerability in one patient, and although this should be confirmed in the randomized clinical trial setting, these observations support a role for endothelin in the pathogenesis of diabetic skin ulceration [Luna Gomez, C. et al., Abst P-1735].

Education and lifestyle modification are becoming a pressing matter to attenuate the current rapid spread of the diabetes pandemic worldwide. Starting with the DPP study, which demonstrated a clear benefit for lifestyle interventions in preventing diabetes [Nathan, D.D., Abst 0171], other studies have confirmed similar benefits across the world [Ramachandran, A. et al., Abst 0172; Saaristo, T. et al., Abst 0173], while additional studies have corroborated the favorable impact of physical activity, healthy diet and an overall “antidiabetic” lifestyle in patients with established diabetes [Fernando, T.A. et al., Abst 0174]. In addition, reports presented during one of the meeting’s oral sessions revealed a favorable impact of meditation on the risk for developing type 2 diabetes [Wijesuriya, M., Abst 0182], and that of yoga in the overall health status of patients with the disease [Woo, J., Abst 0183; Sreelakshmi, H. et al., Abst P-1741] and well as patients with prediabetes [Arpana, G. et al., Abst D-0789].

Food for thought could be the story of the westernization of the Cree from Northern Quebec, which by abandoning the traditional diet and assuming a more sedentary lifestyle have markedly increased their risk for type 2 diabetes. Many factors contribute to this, but amazingly, when looking into the traditional herbal pharmacopoeia, a plant component of their traditional diet, coded W7, was discovered, extracts of which showed antiobesity and antidiabetic effects in the experimental arena [Harbilas, D. et al., Abst O-0372]; research into the Cree’s herbal remedies continues, and other plants and plant components also demonstrating antidiabetic/antiobesity potential were identified and are further being investigated [Haddad, P., Abst O-0375]. In that same context, a variety of benefits were attributed to other natural products, including notably fasting glucose, insulin levels- and insulin resistance-lowering by resistant starch from wild-type banana [Ble, J. et al., Abst P-1562], gluconeogenic gene upregulation by resveratrol [Park, J. et al., Abst P-1244], glucose utilization- and insulin responsiveness-improving effect of Myricaria alopecuroides extracts [Khookhor, O. et al., Abst O-0374], the insulin-secreting activity of Gymnema sylvestre extract [Alromaiyan, A. et al., Abst O-0376], the antidiabetic activity of okra and hibiscus mucilages [Peerkhan, N., Abst P-1136], oyster mushroom (Pleurotus sp.) [Chopra, A. et al., Abst P-1140], licorice root extract [Shahabinejad, M. et al., Abst P-1522], Pongamia pinnata-derived cycloart-23-ene-3s,25-diol [Badole, S. et al., Abst O-0377], Tapinanthus butungii [Osinubi, A.A. et al., Abst P-1016], Eugenia jambolana [Sharma, S.B. et al., Abst P-1019], Brassica rapa (Chinese cabbage) [Islam, M.S. et al., Abst P-1023], Trichosanthes dioica [Bairy, L. et al., Abst P-1031] and Tulbaghia violacea [Davison, C. et al., Abst P-1033] extracts, Qei-fu-di-huang-wan [Chang, C.J. et al., Abst O-0378] and various plants from Bangladesh, including Trichosanthes kirilowii, Psidium guajava, Coix lacryma-jobi, Scoparia dulcis, Murraya koenigii, Syzygium cumini and many more [Mollik, M. et al., Abst P-1017; Mollik, M. et al., Abst P-1024; Mollik, M. et al., Abst P-1028; Mollik, M. et al., Abst P-1029; Mollik, M. et al., Abst P-1030]. Also reported were the antihyperglycemic activity of Ocimum sanctum [Hanran, J.M.A. et al., Abst D-0608] and Trigonella foenumgraecum [Junaida, K. et al., Abst D-0611] extracts, the antidiabetic and antioxidant profile of Emblica officinalis [Begum, R. et al., Abst D-0610], the antiatherosclerosis potential of Cassia auriculata leaf extracts [Gupta, S. et al., Abst D-0607], the vasorelaxant effects of Anacardium occidentale (cashew tree) leaf extracts [Guilet, D. et al., Abst O-0373], the insulin resistance- and dyslipidemia-improving activity of Spirulina platensis (demonstrated in patients with HIV infection ) [Loni Ekali, G. et al., Abst D-0632] and the antiinflammatory activity of the Chinese herbal product Yu-Qui-Qing [Sun, Z. et al., Abst D-0612] and thiamine supplementation [Ramos-Zavala, M.G. et al., Abst D-0637]. Add to all this information the results of a controlled trial that demonstrated a favorable impact on glycemic control and insulin requirements, without increasing the risk of hypoglycemia, of camel milk [Mohta, N. et al., Abst P-1135], while yet a further study confirmed the favorable impact of vanadium supplementation in the diet on insulin resistance and tissue damage markers [Mukhamedova, F. et al., Abst P-1159].

However, not only specific dietary complements and supplements had an impact on the risk of developing or on the progression and control of established diabetes, but the general dietary pattern also impacts on such risk. The favorable health-promoting results of a fiber-rich diet have long been known, but novel mechanistic studies analyzed the relationship between dietary fiber and type 2 diabetes to clarify the favorable impact of short-chain fatty acids resulting from fermentation of fiber in the colon and the levels of free fatty acids, glucagon-like polypeptide-1 and ghrelin, which offered an explanation of the benefits of fiber on insulin resistance [Tarini, J. & Wolever, T.M.S., Abst D-0638]. Analogously, benefits on parameters such as medication requirements and oxidative stress in patients with type 2 diabetes were attributed to a low-fat vegetarian diet [Kahleova, H. et al., Abst D-0639].

Atherosclerosis is common in patients with type 2 diabetes, and although no major therapeutic news were discussed in Montreal during the World Diabetes Congress, a study suggested benefits of pomegranate juice, which increased paraoxonase-1 gene expression and significantly lowered glucose and cholesterol levels in an experimental study in animal models [Betanzos-Cabrera, G. et al., Abst P-1058].

In addition, a mechanistic ex vivo study in patients with type 2 diabetes demonstrated greater synergism between collagen and adrenaline in inducing platelet aggregation in diabetic compared to nondiabetic states, but also the possibility of yohimbine, an alpha_2A-receptor blocker, in inhibiting such synergism and hence offering enhanced antiplatelet activity in diabetic patients also treated with aspirin and clopidogrel [Lahiri, P. et al., Abst D-0594].

Diabetes carries an excess risk of cardiovascular disease that is closely linked to the occurrence of dyslipidemia, to a point that experts state that although “it is important that conventional risk factors for cardiovascular disease like hypertension, smoking, sedentary lifestyles, etc. are addressed, …statins are mandatory” based on the economics of preventing cardiovascular disease, and call for urgent interventions to improve poor compliance with statins through aggressive educational activities or even, if feasible, free drug distribution [Kesavadev, J. et al., Abst D-0728]. In fact, treatment with rosuvastatin of patients with type 2 diabetes brought about marked reductions in LDL-cholesterol levels without adverse events in an open-label study, leading the investigators to recommend statin therapy of most, if not all, diabetic individuals [Kim, S.R. et al., Abst P-1040]. Specific information on atorvastatin indicated benefits on glucose-induced endothelial dysfunction in patients also treated with metformin [Koniari, K. et al., Abst D-0929].

Beyond statins, other therapies have also been developed for the management of dyslipidemia. Among these, fenofibric acid showed additive activity combined with simvastatin, resulting in more comprehensive improvements in lipid parameters in diabetic patients with mixed dyslipidemia [Mohiuddin, S. et al., Abst D-0813] (Fig. 21). Niacin has also shown potential efficacy, but has been associated with increases in glucose levels and flushing that, according to new results presented in Montreal, can be prevented by aspirin [Padley, R.J. et al., Abst D-0807].

Obesity is a major contributor to cardiovascular risk and is also a major risk factor for type 2 diabetes, and therapies for obesity have a favorable impact on the risk of developing diabetes as well as the progression of established disease. In that sense, while treatment with sibutramine reduced adiposity and improved diastolic blood pressure and uric acid levels in obese women without impacting on insulin sensitivity, coadministration with levocarnitine markedly improved the body mass index and waist circumference [Hernandez-Gonzalez, S. et al., Abst P-1162].

Outcomes after pancreas and islet transplantation have been progressively improving, with favorable long-term survival and functional outcomes after pancreas and simultaneous kidney/pancreas transplantation [Misra, A., Abst 0330; Sutherland, D.E.R., Abst 0494]. Technical advances in immunomodulatory strategies and micro-/nanoencapsulation [Ricordi, C. et al., Abst 0492; Bilodeau, S. et al., Abst D-0752; Tam, S.K. et al., Abst D-0755; Langlois, G. et al., Abst P-1271], including notably the development of nonrejectable indoleamine-2,3-dioxygenase-containing allografts [Jalili, R.B. et al., Abst D-0751] and scientific insight into the feasibility of creating insulin-secreting cells from neonatal porcine islets [Korbutt, G., Abst 0493] augur renewed potential for and interest in isolated islet transplantation. In addition, the wide availability of stem cells would make this a feasible approach for transplantation therapies in diabetes, provided stem cells could be forced to differentiate into beta-cells [Dominguez-Bendala, J. & Ricordi, C., Abst 0317; Macfarlane, W., Abst 0331]. This is still something open to research and debate, although initial clinical trials in type 1 diabetes patients have confirmed benefits on glycemic control [Larijani, B. et al., Abst P-1431]. In relation with the latter, observations of the improved graft survival in athymic animal models receiving pancreatic islets concomitantly with neural stem cells, an effect attributed to the release of neurotrophic factors [Olerud, J. et al., Abst D-0753], also offer novel insight into better outcomes after transplantation.

An alternative approach to transplantation, which is also subject of research at present, is specific immunotherapy to develop antigen-specific tolerance and avoid islet destruction. Favorable initial feasibility results were reported with GAD65, auguring hopes for breaking type 1 diabetes pathogenesis [Pozzili, P. et al., Abst 0318].

Acetylcysteine was suggested effective in preventing contrast-induced nephropathy in type 2 diabetic patients without nephropathy receiving iohexaol for imaging procedures [Sar, F. et al., Abst D-0881].

No clear benefit on bone turnover in type 1 diabetes could be demonstrated with calcitriol in a placebo-controlled trial, but the agent did reduce bone turnover marker levels during puberty [Napoli, N. et al., Abst D-0895].

Olanzapine was associated with marked decreases in adiponectin levels and increases in body weight when used in the treatment of schizophrenia; these were numerically superior to abnormalities seen during treatment with risperidone [Scheen, A. et al., Abst P-1476].

The hepatotoxicity of paracetamol was worsened in experimental animals with drug-induced diabetes [Debri, K. et al., Abst P-1521].

By inducing a gastric bypass surgery-like effect on the gut hormones that control for insulin secretion, ranitidine induced body weight loss and improved lipid and insulin levels in otherwise obese individuals [Pudar, G. et al., Abst P-1575].