MD Conference Express ADA 2011 - (Page 23)

• • • • They are not essential for life (as shown by glucosegalactose-malabsorption and familial renal glucosuria) Selective SGLT2 inhibitors have been developed SGLT2 inhibitors improve glucose homeostasis in diabetic rats SGLT2 inhibitors in Phase 3 trials have had promising results and no remarkable adverse events could be achieved while minimizing unwanted side effects [Higgins LS, Mantzoros CM. PPAR Res 2008]. Dual PPARα/PPARγ agonists have been designed to treat patients with insulin resistance and dyslipidemia. Known as glitazars, they combine the insulin-sensitizing effects of PPARγ activation with the lipid-lowering effects PPARα agonists, lowering triglycerides, increasing high-density lipoprotein cholesterol levels and insulin sensitivity, and reducing cardiovascular risk [Lalloyer F, Staels B. Arterioscler Thromb Vasc Biol 2010]. The SYNCHRONY study (NCT00388518), for example, aimed to establish the glucose-lowering and lipidmodifying effects and safety profile of the dual PPARα and PPARγ agonist aleglitazar. In a double-blind study, patients with T2DM (either drug-naive or pretreated with ≤two oral agents) were enrolled from 47 sites in 7 countries. After a single-blind, 4- to 5-week placebo runin period, 332 patients were randomized (double-blind) via an interactive voice-response system to 16 weeks of treatment with aleglitazar at once-daily doses of 50 mug, 150 mug, 300 mug, or 600 mug; matching placebo (n=55 in each group); or open-label pioglitazone 45 mg once daily (n=57) as a reference. The primary efficacy endpoint was the change in glycosylated HbA1C concentration from baseline to the end of treatment. Patients who received at least one dose of study drug and had at least one evaluable postbaseline HbA1C measurement were included in the efficacy analysis [Henry RR et al. Lancet 2009]. Findings showed that aleglitazar significantly reduced baseline HbA1C versus placebo in a dose-dependent manner, from -0.36% (95% CI, 0.00 to -0.70; p=0.048) with 50 mug to -1.35% (-0.99 to -1.70; p<0.0001) with 600 mug. The trend of changes over time suggested that the maximum effect of aleglitazar on HbA1C concentration was not yet reached after 16 weeks of treatment. Edema, hemodilution, and weight gain occurred in a dosedependent manner. However, at aleglitazar doses less than 300 mug, no patients had congestive heart failure, frequency of edema was similar to placebo and less than with pioglitazone, and body weight gain was less than with pioglitazone (0.52 kg at 150 mug vs 1.06 kg) [Henry RR et al. Lancet 2009]. The favorable balance in the safety and efficacy profile of aleglitazar represents encouraging short-term clinical data for this agent and provides good evidence to enter Phase 3 investigation. New insights into fundamental aspects of PPAR and RXR biology and their actions in the vasculature continue to be discovered. Although RXRs are obligate heterodimeric 23 Figure 1. Time Course of Change in HbA1C in Dapagliflozin-Treated Diabetic Subjects. 8.4 Placebo 8.0 HbA1C (%) 7.6 Dapa 5 mg Dapa 2 mg Dapa 10 mg 7.2 6.8 0 0 4 8 12 Week 16 20 24 Reproduced with permission from from the Lancet, from “Management of type 2 diabetes: new and future developments in treatment"; Tahrani A et al, vol. 378, no. 9786, 182, 2010; permission conveyed through Copyright Clearance Center, Inc. Drugs Targeting the Metabolic Syndrome: Selective PPAR Agonists The peroxisome proliferator-activated receptors (PPARs) and the retinoid X receptors (RXRs) are ligand-activated transcription factors that coordinate and regulate gene expression. This PPAR-RXR transcriptional complex plays a critical role in energy balance, including triglyceride metabolism, fatty acid handling and storage, and glucose homeostasis—processes in which dysregulation is characterized by obesity, diabetes, and atherosclerosis. PPARs and RXRs are also involved directly in inflammatory and vascular responses in endothelial and vascular smooth muscle cells [Plutzky J. Circ Res 2011]. The uncoupling of dose-response relations for different effects is the defining characteristic of a selective modulator. Thus, the pharmacological definition of a selective modulator is a ligand that, compared with a full agonist, differentially induces specific receptor effects [Higgins LS, DePaoli AM. Am J Clin Nutr 2010]. An ideal selective PPAR modulator (SPPARM) would be a potent and highly efficacious inducer of insulin sensitization, with low potency and/or low maximal activity for effects on adipose generation, loss of bone mineral density, fluid retention, and congestive heart failure. In such an ideal case, a therapeutic dose could be selected for a SPPARM at which antidiabetic benefits Peer-Reviewed Highlights from the American Diabetes Association 71st Annual Scientific Sessions  http://www.mdconferencexpress.com

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MD Conference Express ADA 2011

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