September 17 - 21, 2007
Amsterdam, The Netherlands
INTRODUCTION
Rainy and cloudy, misty over the canals, Amsterdam is still a beautiful city, rendered more beautiful by the interesting scientific meetings held once and again at the RAI. Late this summer, it was the turn of EASD, and diabetologists from Europe and beyond to crowd the meeting site during the day… and restaurants, coffee shops, shopping districts and other hotspots during the evening. Among the more than 1,200 abstracts presented this year during the meeting, a significant number of papers on pharmacotherapies for diabetes and diabetic complications are briefly summarized in the following report.
INSULIN
Data on human insulin was discussed in Amsterdam this year, including studies that suggested greater reduction in hemoglobin A1c and better prevention of albumin excretion rate increase in type 1 diabetes with continuous infusion rather than multiple daily insulin injections [Lepore, G. et al., Abst 0215; Horvath, K. et al., Abst 0221], so that continuous subcutaneous insulin infusion may be preferable for patients with poor glycemic control under treatment with multiple daily insulin injections [Taki, K. et al., Abst 0328], while a relationship was demonstrated between diabetes disease duration and daily insulin dose that was linked to the reduction of islet function in type 1 diabetes [Khalangot, M.D. et al., Abst 0327]. In fact, the benefits of insulin pump in adults, elderly and children with type 1 or 2 diabetes were confirmed in additional studies that suggested a low rate of hypoglycemic episodes even during pregnancy and a low risk for poor metabolic control [Pankowska, E. et al., Abst 0922; Ignatova, N. et al., Abst 0931; Gratzer, T.W. et al., Abst 0932; Giménez, M. et al., Abst 0949; Quester, W. et al., Abst 0950; Noh, Y.H. et al., Abst 0952; Jankovec, Z. et al., Abst 0951; Hoogma, R. et al., Abst 0953; Ferri, J. et al., Abst 0955].
Looking for novel administration routes, new data has confirmed the benefits of inhaled insulin, with improved glycemic control, sustained weight reduction, favorable overall, immunological and respiratory tract safety and equiefficacy compared to insulin glargine with higher preference compared to injectable insulin, although patients with asthma may require higher doses [Tu, N. et al., Abst 0968; Wolzt, M. et al., Abst 0969; Burge, M.R. et al., Abst 0970; Hompesch, M. et al., Abst 0971; Skyler, J. et al., Abst 0972; Fineberg, S.E. et al., Abst 0973; Hayes, R.P. et al., Abst 0974]. A study in poorly controlled type 1 diabetes patients suggested improved glycemic control, quality of life and treatment satisfaction with intraperitoneal compared to subcutaneous insulin [van Ballegooie, E. et al., Abst 0223]. Other options demonstrated feasible include solid lipid insulin nanoparticles [Sarmento, B. et al., Abst 0967] and albumin-G, a fully recombinant fusion protein consisting of a single-chain mini-human insulin fused at the C-terminus to the N-terminus of human serum albumin [Bell, A.C. et al., Abst 0975]. On the other hand, the pharmacokinetic:pharmacodynamic profile of the insulin when injected is that of a very rapid-acting formulation, proving faster-acting than regular human insulin or insulin lispro and offering better glycemic control of type 2 diabetes than any of the two comparators [Steiner, S.S. et al., Abst 0047].
In the experimental arena, intravenous insulin was reported to inhibit hypothalamic appetite-stimulating neuropeptide release during euglycemia in animals [Bouman, S.D. et al., Abst 0038].
Regarding risks during insulin therapy, development of anti-insulin antibodies may hinder the efficacy of treatment, but at least one case successfully responding to plasmapheresis, rituximab and cyclophosphamide was reported [Franco, D.R. et al., Abst 0926].
INSULIN ANALOGS
While insulin lispro offered significant improvements in glycemic control in 438 type 1 diabetic patients switching from soluble regular human insulin or short-acting insulin analogs [Poole, C.D. et al., Abst 0330] and 374 patients switching from insulin glargine plus oral antidiabetic agents to either premixed prandial insulin lispro or basal bolus insulin glargine plus insulin lispro [Ahmann, A.J. et al., Abst 0991], the use of basal insulin lispro with insulin lispro protamine suspension offered better control of hemoglobin A1c levels than human insulin bolus with isophane insulin [Beattie, S.D. et al., Abst 0962] (Fig. 1). Levels of insulin lispro were blunted and delayed in obese compared to normal-weight subjects [Gagnon-Auger, M. et al., Abst 0048]. Continuous subcutaneous infusion of insulin lispro was feasible and resulted in pharmacokinetic and pharmacodynamic responses similar to those of standard insulin pumps in 27 healthy volunteers [Rave, K. et al., Abst 0954], opening new future treatment modalities. Furthermore, use of insulin lispro as baseline infusion for euglycemic glucose clamping improved pharmacokinetic evaluation, with reduced data variability and suppression of endogenous insulin [Cassidy, J. et al., Abst 0961].
Fig. 1. Hemoglobin A1c levels in patients treated with insulin lispro plus protamine insulin lispro or regular human insulin plus human isophane insulin [Beattie, S.D. et al., Abst 0962].
Another rapid-acting insulin analog, insulin aspart was as safe and effective as insulin lispro when infused continuously via the subcutaneous route to 298 children and adolescents with type 1 diabetes, with higher hemoglobin A1c goal attainment after treatment with insulin aspart [Ternand, C. et al., Abst 0188] (Fig. 2), and offered a very rapid onset of action in mechanistic studies in 32 further patients [Eckers, U. et al., Abst 0963]. The PRESENT and REFORM studies further demonstrated improvements in hemoglobin A1c and fasting and postprandial glucose levels with the use of biphasic insulin aspart 30 [Khutsoane, D. et al., Abst 0985; Lund, S.S. et al., Abst 0989], while in the INITIATE plus study, initiation of therapy with this particular insulin analog formulation combined with dietary counseling safely and effectively reached recommended hemoglobin A1c levels in the primary care setting [Oyer, D.S. et al., Abst 0987]. In that respect, a 24-week study in 321 Chinese patients suggested similar safety with twice- and thrice-daily biphasic insulin aspart 30, but greater efficacy with the thrice-daily administration [Yang, W. et al., Abst 0990]. However, biphasic insulin aspart 50 t.i.d. proved superior to biphasic insulin aspart 30 b.i.d. in providing glycemic control without increasing the risk of hypoglycemia, while biphasic insulin aspart 70 was noninferior regarding efficacy, but increased the rate of hypoglycemic episodes [Cucinotta, D. et al., Abst 0988]. Insulin aspart was as safe and effective as regular human insulin in 72 children with type 1 diabetes [Ludvigsson, J. et al., Abst 0921]; nevertheless, additional studies demonstrated a reduced risk of hypoglycemia compared to biphasic human insulin [Davidson, J. et al., Abst 0986]. Furthermore, insulin aspart was associated with reduced lipolysis and reduced pancreatic secretion of insulin, with an overall attenuation of the proatherogenic profile [DeCampo, A. et al., Abst 0996]. Used while planning pregnancy, insulin aspart reduced the incidence of severe hypoglycemia before and during pregnancy [Heller, S. et al., Abst 0247], and no increase in insulin antibodies was noted [Mathiesen, E. et al., Abst 0248]. On the other hand, weight gain is possible during treatment with insulin aspart, and data from the ADAPT trial suggested relationship between mealtime insulin aspart dose rather than basal insulin detemir bolus [Le Floch, J.P. et al., Abst 0964].
Fig. 2. Hemoglobin A1c goal attainment rates after continuous subcutaneous infusions of insulin aspart or insulin lispro [Ternand, C. et al., Abst 0188].
Pharmaceutical evaluations suggested less dissociation of insulin glulisine compared with insulin lispro or insulin aspart in solution, suggesting higher stability [Becker, R.H.A. et al., Abst 0959], and insulin glulisine was in fact reported to improve postprandial metabolism and microvascular blood flow more effectively than regular human insulin in 15 type 2 diabetic individuals treated with oral antidiabetic drugs [Hohberg, C. et al., Abst 0960]. Furthermore, single-dose insulin glulisine added to basal insulin and oral antidiabetic therapy improved hemoglobin A1c and glucose levels, with similar efficacy when administered at breakfast or during the main meal [Lankisch, M. et al., Abst 0980], while combining insulin glulisine to basal insulin glargine proved effective in 123 type 1 and 1,674 type 2 diabetic patients [Schreiber, S. et al., Abst 0992].
According to some studies insulin detemir and human insulin were confirmed equipotent in healthy nondiabetic individuals [Rossetti, P. et al., Abst 0044], while insulin detemir combined with insulin aspart safely reached hemoglobin A1c target levels in 373 previously uncontrolled patients with type 2 diabetes [Milek, K. et al., Abst 0994]. Other studies suggested superiority regarding glycemic control, diabetes complications and survival without weight gain for basal insulin detemir over human insulin [Larsen, J.J. et al., Abst 0956; Hermansen, K. et al., Abst 0995; Kotchie, R.W. et al., Abst 1043] (Fig. 3), and comparing insulin detemir to another long-acting insulin analog, insulin glargine, and NPH insulin, the three insulins were associated with similar exercise-induced glycemia decreases in 51 patients with type 1 diabetes, but the risk of hypoglycemia and carbohydrate snacking postexercise was less common with insulin detemir than insulin glargine [Arutchelvam, V. et al., Abst 0043] (Fig. 4). Insulin detemir also proved superior to NPH insulin, both combined with insulin aspart, regarding hemoglobin A1c reductions with lower risk for nocturnal hypoglycemia and weight gain [Bartley, P.C. et al., Abst 0222]. Furthermore, insulin detemir offered optimal efficacy with meaningful improvements in glycemic control and weight and reduced risk for hypoglycemia in type 2 diabetes as first-line therapy or after switching from insulin glargine or regular insulin, as demonstrated in the PREDICTIVE and other studies, with feasibility for patient self-titration [Meneghini, L. et al., Abst 0224; Koenen, C. et al., Abst 0976; Robinson, A. et al., Abst 0977; Fajardo Montanana, C. et al., Abst 0978; Philis-Tsimikas, A. et al., Abst 0979] and showed lower within-patient pharmacokinetic variability than insulin glargine [Danne, T. et al., Abst 0189]. Compared to NPH insulin, insulin detemir appeared as hepatoselective, with a greater impact on endogenous glucose output [Smeeton, F.J. et al., Abst 0045], and compared to insulin glargine, insulin detemir arose as equipotent on glucose metabolism with lower antilipolytic activity [Porcellati, F. et al., Abst 0046]. Pharmacoeconomic assessments suggested cost-effectiveness for insulin detemir basal-bolus therapy compared to human isophane insulin, with improvements in quality-adjusted life years and reductions in complications [Ray, J.A. et al., Abst 1033]. On the other hand, insulin glargine, but not insulin detemir, shared the activating intracellular signaling pathways and mitogenic activity of human insulin, while insulin detemir was less active [Sasaoka, T. et al., Abst 0560].
Fig. 3. Estimated quality-adjusted life year expectancy in patients with type 2 diabetes receiving insulin detemir- or NPH insulin-based basal-bolus therapy [Kotchie, R.W. et al., Abst 1043].
Fig. 4. Postexercise hypoglycemia rates in patients treated with insulin detemir, insulin glargine or NPH insulin [Arutchelvam, V. et al., Abst 0043].
However, insulin glargine remained active and effective, as suggested by observations in groups of 489 patients switching from basal-bolus regular insulin combined with human insulin or insulin lispro to once-daily insulin glargine plus regular insulin or insulin lispro, with superiority for the latter combination [Brunetti, P. et al., Abst 0957], as well as in a study in 643 type 2 diabetes patients in which the addition of insulin glargine to ongoing oral therapy with metformin, sulfonylureas or thiazolidinediones improved hemoglobin A1c levels and target attainment rates [Raskin, P. et al., Abst 0982]. Insulin glargine was also reported effective in the management of diabetic individuals on gastrostomy feeding [Tutuncu, N.B. et al., Abst 0998], and according to a post-hoc analysis of two randomized studies lowered hemoglobin A1c more effectively than pioglitazone, leading to greater reductions in free fatty acids in patients with higher hemoglobin A1c levels at baseline [Rosenberg, N. et al., Abst 1236], although pioglitazone more effectively increased HDL-cholesterol, and the two compounds had a similar overall impact on triglycerides when added to metformin or sulfonylurea [McGill, J.B. et al., Abst 1237]. In mechanistic studies, insulin glargine relieved fatty liver disease and high fat diet-induced insulin resistance [Li, M. et al., Abst 0574]; used during pregnancy, it had no negative impact on embryofetal development, according to data from 107 pregnant type 1 diabetic women [Torlone, E. et al., Abst 0246].
Being more resistant to proteolytic digestion than normal insulin and also orally bioavailable in experimental, animals, the novel insulin analog IN-105 proved safe in healthy volunteers and showed rapid onset of action [Suryanarayan, S. et al., Abst 0219].
BIGUANIDES
While a naturalistic registry demonstrated benefits of metformin and sulfonylureas, and especially of the two in combination, on survival after an acute myocardial infarction [Zeller, M. et al., Abst 0243], metformin was suggested not to improve glycemic control in poorly controlled patients with type 1 diabetes, but to show benefits on cardiovascular risk factors such as insulin dose, body weight and LDL-cholesterol levels [Jacobsen, P.K. et al., Abst 0242] and compared to glibenclamide offered more durable glycemic control with a lower risk of hypoglycemia and no weight gain [Herman, W.H. et al., Abst 0877] (Fig. 5). Observations in 2,039 patients with type 2 diabetes on baseline metformin therapy proved the usefulness of the compound as well as the feasibility of combining with sulfonylureas or thiazolidinediones as required for glycemic control [Krishnarajah, G. et al., Abst 0329]. In general oral antidiabetic therapies, including metformin, have been associated with higher adherence and compliance rates than insulin [Ucak, S. et al., Abst 0331].
Fig. 5. Time hemogloblin levels were maintained under 7% during treatment with metformin or glibenclamide in the ADOPT trial [Herman, W.H. et al., Abst 0877].
New mechanistic data was reported this year for metformin, which was reported to activate AMP-activated protein kinase activity in hepatocytes [Guigas, B. et al., Abst 0241] and to act as a glucagon-like polypeptide-1 secretagogue in vivo [Sinha Roy, R. et al., Abst 0688].
Experimental results were reported with phenformin, an alternative biguanide, which showed overstimulation of glucose uptake after exposure of cardiomyocytes to insulin through activation of AMP-dependent protein kinase [Bertrand, L. et al., Abst 0555], while similar studies using metformin demonstrated effects similar to 5’-phosphoribosyl-5-aminoimidzole-4-carboxamide (AICAR) on inhibition of lipolysis and stimulation of glucose transporter-4 expression through activation of AMP-dependent protein kinase-independent pathways [Radimerski, T. et al., Abst 0556].
SULFONYLUREAS
Sulfonylurea therapy was related to normalization of the insulinotropic effects of glucose-dependent insulinotropic peptide in type 2 diabetes [Aaboe, K. et al., Abst 0599] and improved survival [Danchin, N. et al., Abst 0874], but treatment with sulfonylureas and to a lesser extent insulin therapy were related with an increased risk for cancer death, according to a retrospective study of 3,002 patients with type 2 diabetes [Monami, M. et al., Abst 0244]. Initial therapy with glibenclamide or glipizide was associated with a higher risk of coronary artery disease compared to gliclazide or glimepiride in a case-control study involving 2,733 patients [Sadikot, S.M.., Abst 0341] (Fig. 6), while glimepiride combined with metformin was reported to improve endothelial dysfunction as a result of improved glycemic control [Alexanderson, E. et al., Abst 1177]. Moreover, glibenclamide was suggested as effective compared to insulin or diet only in the control of gestational diabetes, according to preliminary evidence in 144 women [Holt, R.I.G. et al., Abst 0935]. However, gliclazide is still a useful sulfonylurea that partly counteracted glucotoxicity and reduced oxidative DNA instability on human pancreatic islets [Del Guerra, S. et al., Abst 0875; Drzewoski, J. et al., Abst 0876], and mechanistic data in lymphocytes from patients with type 2 diabetes demonstrated significant increases in cellular glucose transport [Taton, J. et al., Abst 0766]. Further insights into the mechanism of glibenclamide demonstrated insulinotropic effects on human islets by the metabolite 4-trans-hydroxyglibenclamide and its nitrooxy derivative DK-315 [Torri, S. et al., Abst 0907].
Fig. 6. Odds ratio for coronary artery disease according to initial sulfonylurea use in patients with type 2 diabetes [Sadikot, S.M., Abst 0341].
Although not a sulfonylurea, the Kir6.2/sulfonylurea receptor-1 blocker and insulin secretagogue nateglinide offered antidiabetic activity that included an effect in augmenting glucagon-like polypeptide-1 activity at least in part through inhibition of dipeptidyl peptidase IV-mediated degradation [McKillop, A.M. et al., Abst 0882].
THIAZOLODINEDIONES
With direct and acute hypoglycemic effects on the liver through inhibition of gluconeogenesis [Sanchez, C. et al., Abst 0860] and favorable cost-effectiveness profile compared to insulin, both added to sulfonylurea or metformin monotherapy [Balu, S. et al., Abst 0868; Arondekar, B. et al., Abst 0869], thiazolidinediones such as pioglitazone and rosiglitazone have arisen as important therapies for type 2 diabetes, although a direct comparison in 735 patients, the GLAI study, suggested better control of hyperglycemia and dyslipidemia with pioglitazone 30 mg than rosiglitazone 4 mg [McCall, T. et al., Abst 0865] (Fig. 7).
Fig. 7. Change in hemoglobin A1c, triglyceride and non-HDL- and HDL-cholesterol levels after 3 months of treatment with pioglitazone or rosiglitazone [McCall, T. et al., Abst 0865].
Being a cost-effective treatment option for diabetes, according to analysis of the PROactive study [Brandle, M. et al., Abst 1034], pioglitazone therapy brought about improvements in insulin sensitivity and glucagon and adiponectin secretion in patients with impaired glucose tolerance or type 2 diabetes [Pauvaday, V. et al., Abst 0484] as well as in experimental animal studies [Pita, J. et al., Abst 0606], resulting in reduction in liver fat and necroinflammation in subjects with nonalcoholic hepatic steatosis [Gastaldelli, A. et al., Abst 0073]. Furthermore, addition of pioglitazone to atorvastatin in nondiabetic patients at high cardiovascular risk improved a number of metabolic parameters and inflammatory markers (insulin sensitivity and intact proinsulin, adiponectin, monocyte chemoattracting protein-1, P-selectin and tissue plasminogen activator levels), suggesting clinical benefits in special risk populations [Forst, T. et al., Abst 1256] that, in an additional retrospective, claims-based study, translated into a lowered risk for stroke and myocardial infarction [Xu, Y. et al., Abst 1257]. The effects of pioglitazone were related to regulation of peroxisome proliferator-activated receptor (PPAR)-y expression in β-cells [Kanda, Y. et al., Abst 0413] and the expression of genes related with lipid metabolism and cell death and cycle regulation [Lamounier, R.N. et al., Abst 0494], but depended upon the presence of the Pro12Ala variant of the PPAR-2 gene, with lower response compared to the Pro12Pro variant [Vestergaard, H. et al., Abst 0866]. Pioglitazone also offered benefits on inflammatory markers and abdominal and total fat mass in patients with polycystic ovary syndrome [Glintborg, D. et al., Abst 790], and compared to metformin improved hepatic insulin activity and suppressed glucose production, gluconeogenesis and free fatty acid release in response to insulin [Basu, R. et al., Abst 0861]. However, compared to glimepiride, pioglitazone increased body mass index and subcutaneous fat content, which may in fact be a mediator in the insulin-sensitizing effect of the drug [Davidson, M. et al., Abst 0864] (Fig. 8). In experimental diabetes-prone animals, pioglitazone prevented hyperglycemia and improved lipid profiles [Szöcs, Z. et al., Abst 0639]. Further mechanistic studies revealed inhibition of high glucose-induced umbilical vein endothelial cell apoptosis through interactions with ceramide signaling pathways [Huang, D. et al., Abst 0856].
Fig. 8. Change in total, visceral and subcutaneous fat volume after treatment with pioglitazone or glimepiride [Davidson, M. et al., Abst 0864].
With improvements in insulin sensitivity, glycemic control, endothelial function, galectin 3 expression and inflammatory status [Kadoglou, N.P. et al., Abst 0630; Ioannidis, G. et al., Abst 1178; Sun, Z. et al., Abst 1189], though with no immediate improvements in mitochondrial function [Mensink, M. et al., Abst 0180] or sodium/potassium-exchanging ATPase function during insulin resistance [Fraser, S.F. et al., Abst 0855], rosiglitazone was superior to glibenclamide and metformin in lowering C-reactive protein levels in the ADOPT trial, despite greater weight gain and an increased risk for bone fracture [Haffner, S.M. et al., Abst 0074; Kahn, S.E. et al., Abst 0077], which could be related to the fact that its use in 56 obese postmenopausal diabetic women brought about decreases in bone-specific alkaline phosphatase levels [Berberoglu, Z. et al., Abst 0078]. In fact, rosiglitazone showed broad antiinflammatory activity in type 2 diabetic patients [Harte, A.L. et al., Abst 0660], and was also associated with decreased circulating levels and adipose tissue expression of visfatin, an adipocytokine with insulin-mimetic effects [McGee, K.C. et al., Abst 0126]. Moreover, cardiovascular safety data from 39 type 2 diabetes patients revealed no major differences between rosiglitazone and metformin regarding plasma brain natriuretic peptide levels and myocardial performance [Kemal, Y.T. et al., Abst 0858], while rosiglitazone, but not glimepiride, improved myocardial diastolic function, oxidative stress and inflammation in 12 patients with type 2 diabetes [von Bibra, H. et al., Abst 1204]; the compound did not impair diuretic responses to furosemide or amiloride in insulin-resistant subjects [Rennings, A.J.M. et al., Abst 0859]. Furthermore, combination of rosiglitazone with ω3 fatty acids showed lipid benefits in experimental models of metabolic syndrome [Kuda, O. et al., Abst 0631], and rosiglitazone was also related to reduced thrombogenicity in human and experimental animal studies through suppression of plasminogen activator inhibitor-1 production [Chow, W.S. et al., Abst 0857]. Detailed analysis of predictors of monotherapy failure in the ADOPT trial identified low insulin resistance index in case of treatment with rosiglitazone and high level of hyperglycemia in case of treatment with metformin [Holman, R.R. et al., Abst 0862], but the combination of both drugs offered increased efficacy against hyperinsulinemia in 58 women with polycystic ovary syndrome [Lee, K.O. et al., Abst 0863]. Overall, first-line treatment with rosiglitazone was associated with reduced resource utilization and costs compared to sulfonylurea in 15,155 patients [Duh, M.S. et al., Abst 0867], but on the negative side, the presence of autonomic neuropathy was identified as predisposing towards rosiglitazone-induced vascular leakage in patients with type 2 diabetes on insulin [Tack, C.J.J. et al., Abst 0076].
A novel thiazolidinedione currently in advanced clinical research, rivoglitazone improved glucose and lipid metabolism in obese experimental animal models through enhancements of insulin sensitivity without an effect on PPARα target genes [Ohsumi, J. et al., Abst 0854].
Regarding concerns about the safety of thiazolidinediones, a meta-analysis of 25 randomized clinical trials that included 5,121 patients treated with pioglitazone demonstrated a 2.5- to 3-fold increase in the risk of edema, the risk being higher when the drug was used in a combination than in monotherapy but not when pioglitazone was used with insulin. However, this did not translate into a high rate of congestive heart failure, which developed in 21 out of 5,121 patients on pioglitazone compared to 5 out of 4,567 patients on other therapies or placebo, an excess, but very low, acceptable risk [De Flines, J. & Scheen, A.J., Abst 0075].
Although not a thiazolidinedione, the dual α/γ activator muraglitazar also showed efficacy, with significant improvements in muscle, liver and adipose tissue insulin sensitivity and decreases in hepatic and visceral fat content, but a moderate increase in body fat in type 2 diabetes patients [Fernandez, M. et al., Abst 0909]. Furthermore, the pan-PPAR agonist PPM-204 has also been developed and is currently under phase II studies for the treatment of type 2 diabetes. Results presented during the meeting demonstrated dose-dependent glucose-lowering activity with a favorable safety and tolerability profile in 87 patients [Katz, A. et al., Abst 0220] (Fig. 9).
Fig. 9. Change in time-adjusted glucose AUC after treatment with placebo or increasing doses of PPM-204 (in mg/day) or pioglitazone (30 mg/day) [Katz, A. et al., Abst 0220].
FRUCTOSE 1,6-BISPHOSPHATASE INHIBITORS
Though still in phase II clinical research, managlinat demonstrated significant benefits compared to metformin in experimental studies, with effective reduction of hepatic glucose production while metformin stimulated gastrointestinal glucose uptake [Okuno, A. et al., Abst 0218] (Fig. 10). In combination with thiazolidinediones or insulin, managlinat offered significant decreases in plasma glucose and improvements in lactate metabolism in further animal studies [Yoshida, T. et al., Abst 910].
Fig. 10. Change in hepatic glucose release and gastrointestinal glucose uptake after treatment with managlinat and metformin compared to control data [Okuno, A. et al., Abst 0218].
SODIUM-GLUCOSE REUPTAKE COTRANSPORTER-2 INHIBITORS
Although still in clinical research, data is accumulating on the safety and efficacy of dapagliflozin in the treatment of type 2 diabetes, with new results from a randomized trials suggesting safety, good tolerability, optimal pharmacokinetics with no dietary fat interactions and promise as a therapeutic approach regarding inhibition of glucose reabsorption and reduction in fasting glucose levels [Komoroski, B. et al., Abst 0763; Li, L. et al., Abst 0764; Brenner, E. et al., Abst 0765] (Fig. 11). Following in clinical research steps, sergliflozin proved effective in improving postprandial glucose levels and glucose and fatty acid metabolism in animal models of diabetes and preventing glucotoxicity; the drug regulated the expression of key genes involved in metabolic control [Harrington, W.W. et al., Abst 0767; Ghosh, S. et al., Abst 0913]. Human data with sergliflozin revealed good tolerability with pharmacodynamic changes consistent with inhibition of the renal sodium-glucose contransporter-2 [Kler, L. et al., Abst 0914].
Fig. 11. Percent change in fasting serum glucose levels and renal glucose reabsorption after 13 and 14 days of treatment with dapagliflozin or placebo, respectively [Komoroski, B. et al., Abst 0763].
INCRETIN MIMETICS
Intravenous infusions of glucagon-like polypeptide-1 (GLP-1) normalized glycemia in type 2 diabetes faster than insulin [Schmoelzer, I. et al., Abst 0848]. Oral formulations of GLP-1 and peptide YY3-36, were studied in healthy male volunteers, demonstrating feasibility of oral administration and activity on insulin release (the former) and ghrelin (the latter) [Arbit, E. et al., Abst 0112]. Detailed data demonstrated normalization of glucose metabolism after administration of GLP-1 in 20 patients with type 2 diabetes undergoing coronary artery bypass surgery [Gallwitz, B. et al., Abst 0252], while continuous administration for 48 hours resulted in no hypoglycemia in fasting volunteers [Lerche, S. et al., Abst 0581].
While improving β-cell function [Bunck, M.C. et al., Abst 0251] and hepatic function in type 2 diabetes [Okerson, T. et al., Abst O110], an effect of exenatide in rapidly increasing nitric oxide production and promoting proliferation of coronary artery endothelial cells was reported [Tütüncü, Ö, et al., Abst 0025], and the agent was superior to insulin itself in improving hemoglobin A1c levels in patients failing sulfonylurea and metformin therapy [Brodows, R. et al., Abst 0853]. Furthermore, like GLP-1, exenatide improved glucose transport in muscle and fat during insulin resistance [Moreno, P. et al., Abst 0583], while like pioglitazone, it regulated and normalized gene expression in pancreatic islets from diabetic animals exposed to palmitate [Ghanaat-pour, H. et al., Abst 0493], and an effect was specifically demonstrated on glucose transporter-4 expression in the adipose tissue [Tornero-Esteban, P. et al., Abst 0591]. A long-acting release formulation of exenatide was well tolerated and dose-dependently modified postprandial glucose and body weight, though not fasting plasma glucose levels [MacConell, L. et al., Abst 0849]. Mechanistic insights into the drug’s activity suggested profound benefits on hepatic glucose handling by exenatide through enhancement of insulin sensitivity and increase in glucose uptake [Cersosimo, E., Abst 0250], and also via portal GLP-1 receptors independently of islet function and intestinal motility [Ionut, V. et al., Abst 0590], while an antiapoptotic effect was described in insulin-secreting β-cells that was related to regulation of mitochondria [Tews, D. et al., Abst 0549]. In fact, GLP-1 mimetics were related to protection against tumor necrosis factor-α-induced apoptosis in β-cells in further experimental studies [Natalicchio, A. et al., Abst 0550]. Independently of its effects on glucose and insulin, treatment with exenatide was demonstrated to reverse hypertension in an experimental model of metabolic syndrome, although the acute effects on blood pressure were not maintained over the long term [Parkes, D. et al., Abst 0586]; similarly, both exenatide and GLP-1 showed an insulin-independent effect on bone remodeling in type 2 diabetic animals [Sancho, V. et al., Abst 0587; Nuche-Berenguer, B. et al., Abst 0588].
With a suitable pharmacokinetic profile for 24-hour coverage independent of renal function [Jonker, D.M. et al., Abst 0850; Jacobsen, L.V. et al., Abst 0852], another long-acting glucagon-like polypeptide-1 analog, liraglutide was reported to improve fasting and postprandial glucose levels in type 2 diabetes [Seino, Y. et al., Abst 0851], to regulate glucose-stimulated insulin release [Ma, L. et al., Abst 0504] and zinc transporter messenger RNA expression in β-cells over the long term [Magnusson, N. et al., Abst 0144] and to prevent or revert olanzapine-induced weight gain and glucose abnormalities [Lykkegaard, K. et al., Abst 0578]. Further insight into the activity of the compound resulted in observations of inhibition of tumor necrosis factor-α-mediated plasminogen activator inhibitor-1, vascular and intercellular cell adhesion molecule-1 and E-selectin expression during endothelial dysfunction [Dear, A.E. et al., Abst 0594].
A direct GLP-1 receptor agonist, AVE-0010 also improved postprandial glycemia with no effect on insulin levels, and delayed gastric emptying in experimental animals [Moore, M.C. et al., Abst 0584]. A GLP-1 mimetibody, CNTO-736, also proved feasible in controlling glucose homeostasis in experimental studies [Picha, K.M. et al., Abst 0592].
DIPEPTIDYL PEPTIDASE-IV INHIBITORS
Although reportedly less effective than exenatide in modulating glucoregulation [Gedulin, B. et al., Abst 0576], sitagliptin has been proved dose-dependently effective in a number of clinical trials regarding 24-hour improvements in glucose control in subjects with type 2 diabetes [Nonaka, K. et al., Abst 0886; Iwamoto, Y. et al., Abst 0888]. Complementary activity was reported for sitagliptin and metformin regarding their effects in rising glucagon-like polypeptide-1 levels in healthy adults [Migoya, E.M. et al., Abst 0111] (Fig. 12) and improving β-cell function in patients with type 2 diabetes [Xu, L. & Williams-Herman, D.E., Abst 0884]. First-line combination therapy with the two compounds provided durable glycemic improvements with favorable tolerability in a 54-week trial [Williams-Herman, D.E. et al., Abst 0113] (Fig. 13).
Fig. 12. Active and total glucagon-like polyeptide-1 levels after treatment with sitagliptin, metformin, the combination of both or placebo [Migoya, E.M. et al., Abst 0111].
Fig. 13. Change in hemoglobin A1c levels after 54 weeks of treatment with sitagliptin (S) and/or metformin (M) [doses in mg/day) [Williams-Herman, D.E. et al., Abst 0113].
A related compound, vildagliptin offered prolonged improvements in β-cell function for up to 52 weeks in patients with mild hyperglycemia [Foley, J.E. et al., Abst 0880], doubled the proportion of patients reaching hemoglobin A1c goals (<7.0%) compared to placebo when used as mono- or combination therapy with metformin or as initial combination therapy with pioglitazone [Dejager, S. et al., Abst 0885] (Fig. 14), and was safe and well tolerated in elderly patients or subjects with mild or moderate renal impairment [Thuren, T. et al., Abst 0881; Pratley, R.E. et al., Abst 0887]. Vildagliptin induced no acute effects on exocrine pancreatic secretion from isolated pancreas [Hjøllund, K.R. et al., Abst 0691].
Fig. 14. Proportion of patients reaching hemoglobin A1c levels <7.0% after treatment with vildagliptin or placebo alone or added to metformin [Dejager, S. et al., Abst 0885].
Currently in advanced clinical research and with phase I data suggesting rapid, potent and sustained inhibition of dipeptidyl peptidase IV activity and pharmacokinetics suggesting the feasibility of once-daily dosing [Christopher, R. et al., Abst 0891], new experimental data with alogliptin suggested potent, highly selective inhibition of dipeptidyl peptidase IV, resulting in improved glucose tolerance and β-cell function [Takeuchi, K. et al., Abst 0878]. Also in clinical research, saxagliptin improved glycemic control and β-cell function in treatment-naïve patients with inadequately controlled type 2 diabetes [List, J. et al., Abst 0889]. A further compound, BI-1356 exhibited a favorable safety and pharmacodynamic profile in healthy volunteers [Dugi, K.A. et al., Abst 0890] with superiority compared to sitagliptin and vildagliptin and longer-lasting inhibition of dipeptidyl peptidase IV at lower doses in experimental animal models [Thomas, L. et al., Abst 0879]. A novel dipeptidyl peptidase IV inhibitor, PHX-1149 was shown to improve postprandial glucose with very good tolerability in 174 patients with type 2 diabetes [Guler, H.P. et al., Abst 0114] (Fig. 15), while yet a further related compound, SK-0403 offered potent preclinical activity in in vitro and in vivo tests [Yasuda, Y. et al., Abst 0689].
Fig. 15. Change in postprandial glucose AUC after 28 days of treatment with placebo or increasing doses of PHX-1149 (in mg/d) [Guler, H.P., Abst 0114].
Regarding general mechanistic issues, dipeptidyl peptidase IV inhibitors were reported to enhance the antilipolytic effects of neuropeptide Y in lean subjects, while in obese individuals with reduced adipose tissue the lack of effect may explain the absence of weight loss during treatment for type 2 diabetes [Kos, K. et al., Abst 0109].
AMYLIN ANALOGS AND AGONISTS
Use of pramlintide in 211 patients with type 2 diabetes inadequately controlled with insulin glargine alone or combined with oral hypoglycemic agents proved superior to placebo in improving hemoglobin A1c levels, without weight gain or risk of hypoglycemia [Riddle, M. et al., Abst 0912; Lush, C. et al., Abst 1258] (Fig. 16). Furthermore, sustained weight loss was reported after one year of pramlintide therapy in obese subjects [Halseth, A. et al., Abst 0838] (Fig. 17).
Fig. 16. Change in hemoglobin A1c levels after 16 weeks of treatment with pramlintide or placebo [Riddle, M. et al., Abst 0912].
Fig. 17. Proportion of patients with over 10% reduction in body weight after one year of pramlintide or placebo [Halseth, A. et al., Abst 0838].
OTHER EXPERIMENTAL THERAPIES UNDER DEVELOPMENT
Experimental data to support the potential as antidiabetic therapies were presented for a number of drugs acting on novel targets, including reports on improvements in insulin secretion and metabolism with the fatty acid synthase inhibitor C-75 [Straub, S.G. & Sharp, G.W.G., Abst 0401], inhibition of glucagon-stimulated glucose production by hepatocytes and reductions in blood glucose by an undisclosed glucagon receptor blocker [van Poelje, P.D. et al., Abst 0911] and the role of the gene coregulator and insulin-sensitizing isosteviol [Jeppesen, P.B. et al., Abst 0217]. Although discontinued in its development, an experimental study was presented on the selective SUR1/Kir6.2 potassium channel opener tifenazoxide in preventing mitochondrial changes brought about by hyperglycemia in diabetic animal models [Björklund, A. et al., Abst 0516]. Additionally, m-NO-ASA increased glucose transport via activation of glucose transporters in adipocytes, suggesting potential in the treatment of hyperglycemia in type 2 diabetes [Cormont, M. et al., Abst 0740].
Regarding physiological insights that may result in potential new targets for intervention, observations were reported of an insulin secretion-stimulating effect of obestatin, a 23-amino acid peptide from preproghrelin [Egido, E.M. et al., Abst 0505], while the 5-HT2B receptor blocker BW-723C86 was reported to stimulate insulin and glucagons release from pancreas islets via increases in intracellular calcium through the phospholipase C pathway [Ando, A. et al., Abst 0507]. Further experimental results demonstrated inhibition of cytokine-induced apoptosis and inducible nitric oxide synthase expression in β-cells by St. Johns’ wort extract and hyperforin, effects that were related to downregulation of the transcription factors STAT-1 and NF-κB [Masiello, P. et al., Abst 0547].
On the other hand, prevention of type 1 diabetes in experimental animals was feasible with the immunomodulator fingolimod [Jörns, A. et al., Abst 0444], an effect mimicked by high-dose pravastatin [Zhang, S. et al., Abst 0445] and activation of adenosine receptors by NECA [Mabley, J.G. et al., Abst 0446].
DIET SUPPLEMENTS AND NATURAL THERAPIES
In the experimental arena, epigallocatechin 3-gallate, a component of green tea, preserved β-cell structure and restored insulin secretion in animal models of diabetes [Sjöholm, Å. et al., Abst 0420] and protected pancreatic insulin-secreting β-cells against dioxin acute toxicity [De Tata, V. et al., Abst 0361], and both epigallocatechin 3-gallate and quercetin protected insulin-secreting β-cells from hydrogen peroxide-induced oxidative stress, though quercetin acted through activation of antioxidant defenses while the green tea component exhibited antiapoptotic activity [Kim, M.K. et al., Abst 0424]. With a different approach, ergothioneine exposure offered protection against lipotoxic effects in cultured myoblasts exposed to palmitate [Laurenza, I. et al., Abst 0920]. In a not dissimilar way, ginkgo biloba extract restored palmitate-induced insulin resistance in in vitro assays through an inhibitory effect on stress kinases, nuclear factor κB and protein kinase Cθ [Jung, J. et al., Abst 0554]. Administration of diets containing high levels of soy isoflavone brought about improvements in glucose homeostasis and insulin sensitivity while lowering triglycerides and weight in diabetic animal models [Nordentoft, I. et al., Abst 0492]. A further supplement reportedly effective in improving insulin resistance and attenuating muscle atrophy, at least transiently, in experimental animals was astaxanthin, a potent carotenoid antioxidant [Kobayashi, H. et al., Abst 0640]. Additional studies with plant-derived products demonstrated stimulation of insulin secretion and action and inhibition of starch digestion with Acacia catechu aqueous bark extract [Abdel-Wahab, Y.H.A. et al., Abst 0915], hypoglycemic and antihyperglycemic activity in normal and diabetic animals with Murraya koenigii ethanolic leave extract [Sarma, S. et al., Abst 0916] and potent antidiabetic and hypolipidemic activity in models of diabetes and metabolic syndrome with DC-25018 and PE-053, two undisclosed Chinese herbal remedies [Leng, Y. et al., Abst 0917; Bandara, T. et al., Abst 0918]. On the contrary, compared to olive oil, lard oil impaired insulin-dependent muscular glucose uptake in experimental animals [Lee, J. et al., Abst 0798].
Human data was also reported on the benefits of a number of dietary supplements, including β-glucan-enriched oat-based bread, which significantly lowered total and LDL-cholesterol in type 2 diabetes patients [Tsapogas, P. et al., Abst 0796]. In a related way, use of fenugreek seed extract reduced fat intake over the short and long term in both healthy and overweight subjects [Chevassus, H. et al., Abst 0800] while cinnamon improved markers of glycemic control, insulin resistance, β-cell dysfunction and cardiovascular risk compared to placebo in a double-blind trial in 109 patients with type 2 diabetes [Weitgasser, R. et al., Abst 0919] (Fig. 18). On the other hand, vinegar was also reported to reduce postprandial glycemia in type 2 diabetic patients receiving a high glycemic index carbohydrate-rich meal [Liatis, S. et al., Abst 0797].
Fig. 18. Change in hemoglobin A1c levels in patients receiving cinnamon supplements or placebo for 3 months [Weitgasser, R. et al., Abst 0919].
Regarding prevention, whole grain intake was inversely related to the risk of developing type 2 diabetes, with the relationship being stronger for bran compared to germ grain [Van Dam, R.M. et al., Abst 0363].
LIFESTYLE INTERVENTIONS AND RECOMMENDATIONS
A wealth of information is currently available regarding the influence of different lifestyle factors on the risk of developing diabetes or on the course of the disease. These include confirmation of the benefits of regular exercise and diet control on visceral fat, insulin sensitivity, glucose tolerance, endothelial function and aortic stiffness [Koo, B. et al., Abst 0825; Roumen, C. et al., Abst 0827], with a favorable impact on the risk of developing diabetes and metabolic syndrome [Fuh, M.M. et al., Abst 0826], and may be complemented by new observations suggesting that unsaturated, but not saturated, fatty acids lower postprandial glycemia, though not insulin sensitivity [Koopmans, S.J. et al., Abst 0145], that reducing viscosity of oat fiber in liquid meals enhanced short-term postprandial gastrointestinal responses [Juvonen, K.R. et al., Abst 0146] or that resveratrol, a polyphenol from fruits, prolongs the lifespans of experimental animals with high fat diet-induced metabolic disease [Fröjdö, S. et al., Abst 0557].
On the subject of alcohol, the benefits of moderate alcohol consumption were extended to the diabetic population, with the results of a controlled trial suggesting benefits on fasting but not postprandial glucose after drinking one glass of wine a day [Shai, I. et al., Abst 0147].
TREATMENT OF DIABETIC COMPLICATIONS
Diabetic nephropathy
While human clinical trial data revealed an rapid effect in decreasing albuminuria when prostaglandin E1 was added to ongoing benazepril therapy [Liao, L. et al., Abst 1123], in the experimental arena, isotretinoin improved urinary albumin excretion and glucose and lipid profiles in diabetic animals, offering potential as a treatment for diabetic nephropathy [Kim, C. et al., Abst 0213]. Similarly, edavarone protected against endothelial renal barrier injuries in diabetic animals [Sarai, K. et al., Abst 0214], while as in other diabetic complications, the FIELD study suggested that fenofibrate reversed plasma and urinary creatinine changes during diabetic nephropathy [Hiukka, A. et al., Abst 0216]. Also with antioxidant activity, stobadine prevented protein nitrosylation and oxidative modification and protected the kidneys from diabetic nephropathy in experimental animals [Cumaoglu, A. et al., Abst 1108]. An experimental study suggested potential in improving insulin sensitivity and improving kidney function and histopathology for a polysaccharide fraction from Lycium barbarum fruits [Sun, G. et al., Abst 0211].
Improvements in anemia in diabetic patients with chronic kidney disease not on dialysis were feasible with monthly administration of methoxy polyethylene glycol-epoetin-beta, which maintained stable hemoglobin levels in 324 patients [Bexon, M.F. et al., Abst 0776].
Diabetic neuropathy
Data is accumulating on the effectiveness of pregabalin in the treatment of painful diabetic peripheral neuropathy, as further discussed during the meeting with a new meta-analysis of 1,510 patients [Freeman, R. et al., Abst 0137] (Fig. 19) as well as individual studies, in which significant pain relief was not accompanied by meaningful effects on nerve conduction [Arezzo, J. et al., Abst 1146]. A related compound, gabapentin facilitated impaired GABA-mediated inhibitory activity in the central nervous system in experimental animals and exhibited antioxidant activity that could be of interest for the treatment of diabetic neuropathy [Shymanskyy, I. et al., Abst 1147]. The aldose reductase inhibitor zopolrestat suppressed sorbitol but not fructose in sural nerves of patients with diabetic neuropathy, suggesting the need for higher doses in order to also block sorbitol [Oates, P.J. & Klioze, S.S., Abst 0136]. Benefits in 460 mild to moderate cases were documented with α-lipoid acid, albeit only regarding symptoms and not nerve conduction [Ziegler, D. et al., Abst 0138]; the compound combined with benfotiamine improved diabetic autonomic gastropathy in 64 patients with type 1 diabetes [Serhiyenko, A.A. et al., Abst 1149]. In the experimental arena, N-methylnicotinamide offered potential in preventing diabetes-associated brain disorders [Kuchmerovska, T. et al., Abst 1148].
Fig. 19. Self-rated improvement rates after treatment with pregabalin or placebo [Freeman, R. et al., Abst 0137].
Diabetic cardiomyopathy
While metformin induced reversion of fibrosis and triglyceride accumulation in experimental models of diabetic cardiomyopathy, fenofibrate had favorable effects on a number of parameters related to oxidative stress and inflammation [Beylot, M. et al., Abst 0207].
CARDIOVASCULAR MEDICATIONS IN DIABETES
Among the angiotensin receptor blockers, telmisartan was noted to significantly increase insulin-stimulated adiponectin, leptin and resistin and decrease tumor necrosis factor-α levels [Wohl, P. et al., Abst 0629] and inhibit advanced glycation endproduct-induced asymmetric dimethylarginine accumulation in subjects with end-stage diabetic nephropathy through an effect on oxygen species generation [Hayashida, A. et al., Abst 0028]. An effect of losartan in lowering homocysteine levels was reported in healthy subjects [Neskudla, T. et al., Abst 0726], while valsartan, but not amlodipine improved central arterial stiffness in type 2 diabetic individuals [Karalliedde, J. et al., Abst 1162]. Among the benefits of renin-angiotensin system blockers in diabetes, nephroprotection is one of the most widely recognized properties, and in a study in 330 hypertensive and nonhypertensive patients with type 2 diabetes and albuminuria discussed during the meeting reductions in urinary albumin excretion rate were reported for irbesartan compared to placebo [Shang, S. & Pan, C., Abst 1120]. Angiotensin-converting enzyme inhibitors have also shown nephroprotective activity in diabetes, further confirmed in a study involving 56 type 1 diabetes patients treated with lisinopril, with short-term benefits on urinary albumin excretion rates [Schjoedt, K.J. et al., Abst 1119]. Direct blockade of the renin-angiotensin system with the renin blocker aliskiren offered another option that improved blood pressure as well as urinary albumin excretion rate in patients with type 2 diabetes and micro- or macroalbuminuria [Persson, F. et al., Abst 1118].
On the other hand, in a study comparing candesartan and eplerenone in diabetic animal models, the aldosterone blocker proved as effective as the angiotensin receptor blocker in the treatment of diabetic neuropathy [Takeda, Y. et al., Abst 0133].
Aspirin is commonly used for cardiovascular prevention, including in patients with diabetes. New experimental results suggested an effect in inhibiting adhesion molecule expression and matrix metalloproteinase-2 activity in resistin-induced endothelial dysfunction [Sheu, W.H.H. et al., Abst 1169].
OBESITY AND DIABETES
Inhibition of lipase by orlistat blocked glucose-induced calcium mobilization and insulin secretion, an effect that was partly reverted by fatty acids [Deeney, J.T. et al., Abst 0168]. In patients with fatty liver, long-term treatment with orlistat significantly reduced endotoxinemia [da Silva, N.F. et al., Abst 0720]. Sibutramine is also available for the treatment of obesity, and results from the SCOUT trial revealed appreciable reductions in systolic and diastolic blood pressure after treatment in high-risk diabetic patients with elevated blood pressure regardless of body weight loss [Caterson, I. et al., Abst 0837].
Cannabinoid receptor agonism has been studied as an approach to the treatment of obesity, and new data with rimonabant discussed in Amsterdam suggested reduction of visceral fat [Shirai, K., Abst 0834] (Fig. 20), prevention of fat accumulation during hypercaloric high-fat diet conditions [Woolcott, O.O. et al., Abst 0662], improvements in circulating neutrophil and monocyte counts, reduction in platelet activation and lowered RANTES levels [Schäfer, A. et al., Abst 1193] and prevention of hyperglycemia, improvements in β-cell function and maintenance of insulin secretion in experimental animal models of diabetes with less impact on body weight compared to rosiglitazone [Chamiot-Clerc, P. et al., Abst 0830]. The compound was specifically shown to prevent large adipocyte accumulation in omental and subcutaneous fat [Hsu, I.R. et al., Abst 0664] and also increased insulin sensitivity in experimental animals independently of weight loss [Richey, J.M. et al., Abst 0663], and in the SERENADE trial an effect on hemoglobin A1c levels accompanied reductions in weight and improvements in the lipid profile in treatment-naïve type 2 diabetes patients [Rosenstock, J. et al., Abst 0835]. Furthermore, according to one-year result estimates based on the RIO studies, weight loss and improvements in lipid and glycemic control with rimonabant will likely translate into clinically meaningful improvements in overweight or obese individuals with diabetes [Getsios, D. et al., Abst 0836]. A further CB1 receptor ligand, the inverse agonist taranabant showed good tolerability and dose-dependent central nervous system receptor occupancy in a placebo-controlled study, and pharmacodynamic activity was demonstrated regarding decreased food intake and increased energy expenditure in overweight/moderate obesity conditions [De Lepeleire, I. et al., Abst 0831; Addy, C. et al., Abst 0832; Wright, D. et al., Abst 0833] (Fig. 21). An experimental compound within this family, GRC-10801 was shown to potentiate control of obesity by inducing weight loss and improving glucose homeostasis in experimental animals [Anupindi, R. et al., Abst 0661].
Fig. 20. Percent change in body weight, visceral fat area and wais circumference after 24 weeks of treatment with rimonabant or placebo [Shirai, K., Abst 0834].
Fig. 21. Placebo-controlled change in 24-hour energy intake after treatment with taranabant or sibutramine [Wright, D. et al., Abst 0833].
Inhibition of acetyl-CoA carboxylase also offered benefits as suggested by prevention of obesity and improvements in insulin sensitivity with CP-640186 in high fat diet-fed animals [Schreurs, M. et al., Abst 0658], while inhibition of 11β-hydroxysteroid dehydrogenase with carbenoxolone improved body weight and metabolic control in the same experimental animal model [Gault, V.A. et al., Abst 0659]. Prevention of obesity-induced acceleration of adipose tissue senescence was demonstrated with dehydroepiandrosterone in further experimental studies [Kajita, K. et al., Abst 0678]. Estradiol also induced body weight loss and improved insulin sensitivity in high fat diet-fed animals [Bryzgalova, G. et al., Abst 0679], but induced selective apoptosis of sulfonylurea type 1 receptor-expressing β-cells [Ackermann, S. et al., Abst 0422], while progesterone increased glucose tolerance in glucose-intolerant animals [Faas, M.M. et al., Abst 0680]. Further experimental insights into this area revealed improvements in lipid peroxidation and free radical-scavenging enzyme systems in ovariectomized animals after estrogen replacement therapy [Ceylan-Isik, A. et al., Abst 0681]. In that respect, epidemiological data from women with type 1 diabetes demonstrated no relationship between the use of oral contraceptives and coronary artery disease [Costacou, T. & Orchard, T.J., Abst 1226].
DYSLIPIDEMIA IN DIABETES
Statins are the most extensively used drugs for the treatment of dyslipidemia in diabetic and nondiabetic subjects, and new data with atorvastatin reported in Amsterdam demonstrated an effect on advanced glycation endproducts (AGE) and AGE-induced C-reactive protein expression in the liver [Jinnouchi, Y. et al., Abst 1109], and the fixed combination of amlodipine and atorvastatin safely helped patients from the GEMINI-AALA trial to reach blood pressure and lipid goals regardless of ethnic background [Aguilar-Salinas, C.A. et al., Abst 1163]. Improvements in the lipid profile, with additional benefits on the prostacyclin I2-thromboxane A2 system and oxidative stress, were similarly reported with simvastatin and ω3-polyunsaturated fatty acids in patients with type 2 diabetes and diabetic cardiomyopathy [Serhiyenko, V.A. et al., Abst 1201], but achieving very low LDL-cholesterol levels (<70 mg/dl) with either simvastatin or atorvastatin had no negative impact on adrenocortical and testicular steroidogenesis in 120 high-risk diabetic subjects [Demirag, N. et al., Abst 1234]. On the other hand, treatment with rosuvastatin favorably modified LDL-apolipoprotein and triglyceride-rich lipoprotein catabolism in type 2 diabetes, with positive effects on atherosclerosis prevention [Vergès, B. et al., Abst 1233].
A study in 13 subjects with type 2 diabetes demonstrated improvements in the lipid profile, but not insulin sensitivity, during treatment with fenofibrate [Black, N. et al., Abst 0778]. Despite improving liver steatosis more effectively than metformin in experimental models of diabetic hepatic steatosis, fenofibrate was still poorly active [Nar Demirer, A. & Gedik, O., Abst 0722].
Through a different approach, the liver-targeted thyroid receptor-β agonist MB-07344’s prodrug MB-07811 is being developed for the treatment of dyslipidemia, and experimental studies demonstrated effective cholesterol- and triglyceride-lowering activity at no risk of fasting hyperglycemia [Linemeyer, D.L. et al., Abst 1195].
DIETARY SUPPLEMENTS AND NATURAL MEDICINES
Eicosapentaenoic acid was noted to prevent palmitate-induced β-cell lipotoxicity through suppression of sterol regulatory element-binding protein-1c [Kato, T. et al., Abst 0092], while high dietary intake of fish oil was reported to induce uncoupling protein-3 expression and preserve cardiac contractile function in experimental animals, suggesting prevention of cardiac lipotoxicity [Ouwens, M. et al., Abst 0206] and increased lipolysis and fat oxidation in healthy volunteers with dexamethasone-induced insulin resistance [Delarue, J. et al., Abst 0782]. In the JELIS study, the ω3 fatty acid improved glucometabolic alterations in patients with coronary artery disease [Oikawa, S. et al., Abst 0102]. However, ω3 fatty acid supplementation in 50 patients with type 2 diabetes induced significant arterial stiffness [Gupta, A. et al., Abst 0799] (Fig. 22). Prevention of palmitate-induced endoplasmic reticulum stress and apoptosis in umbilical vein endothelial cells was demonstrated with 4-phenylbutyrate [Jang, H.-J. et al., Abst 0673].
Fig. 22. Change in the left brachial pulse wave velocity in type 2 diabetes patients treated or not with flaxseed or fish oil [Gupta, A. et al., Abst 0799].
In complex studies in models of fatty liver, the antioxidant ricetrienol reduced plasma adiponectin levels and triglyceride accumulation in the liver, while α-tocopherol prevented the increase in plasma resistin [Tatsumi, K. et al., Abst 0727]. An in vivo study in experimental animal models of diabetes suggested normalization of the altered respiratory chain and antioxidative defense activity after oral supplementation with an amino acid-, aminosaccharide-, sialic acid-, mucopolysaccharide- and micronutrient-containing mussel-derived complex [Poltorak, V.V. et al., Abst 0761].
Regarding natural medicine, the benefits of an undisclosed Chinese herbal formula on insulin sensitivity and postprandial dyslipidemia in centrally obese patients were demonstrated in a placebo-controlled study [He, C. et al., Abst 0784]. Traditional Chinese medicine was also reported to suppress superoxide anion production by endothelial cells in culture [Gao, X. & Zhang, B., Abst 1170], adding to the potential of such therapeutic approach.
ISLET TRANSPLANTATION IN DIABETES
The benefits of islet transplantation on the quality of life of type 1 diabetic patients were confirmed in a survey of 10 patients [Milliat-Guittard, L. et al., Abst 0478]. Among other news related to pancreas and islet transplantation discussed in Amsterdam this year, a report focused on prolongation of islet graft survival after treatment with donor antigen-specific CD4/CD25-positive regulatory T-cells [Zhang, M. et al., Abst 0470], while experimental studies revealed a role of 1,25-dihydroxyvitamin D3 in modulating dendritic cells and their T cell-stimulatory capacity [Van Etten, E. et al., Abst 0471].
MISCELLANEOUS
A role of dexamethasone in regulating translation of serine/threonine protein phosphatase PP5, with differences in normal and diabetic pancreatic islets, was described [Grankvist, N. et al., Abst 0512].
Addition of α-lipoic acid to conventional therapy for type 1 diabetes improved the parasympathetic cardiovascular balance and myocardial function and innervations in 30 patients [Najmutdinova, D. & Sadikova, N., Abst 1260].
A novel antioxidant, L-2501 improved metabolic alterations and attenuated weight gain in experimental models of fructose-induced diabetes [Gorbenko, N. et al., Abst 0908].
A topical product containing Ruscus aculeatus, tocopheryl nicotinate, olamine piroctone, urea, lactamid, petrolatum jelly and glycerin was reported effective in preventing infections and clearing bacterial flora from patients with diabetic foot [Roques, C. et al., Abst 1131].
Report prepared by: X. Rabasseda, Prous Science Medical Information Department