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Introduction: Finerenone reduced risk of cardiorenal outcomes in patients with CKD and T2D in the FIDELIO-DKD and FIGARO-DKD studies. In FIDELIO-DKD the effects of finerenone on kidney and CV outcomes were consistent irrespective of glucagon-like peptide-1 receptor agonist (GLP-1RA) use, but analyses were better powered to evaluate change in urine albumin-to-creatinine ratio (UACR) . Here, we extend these analyses to patients in both studies (FIDELITY analysis) , thus encompassing a larger population with broader inclusion criteria. Methods: Patients with T2D and CKD (UACR ≥30- Results: Of 13026 patients, 944 (7.2%) received GLP-1RAs at baseline. Results were consistent irrespective of GLP-1RA use at baseline for the CV composite outcome (hazard ratio [HR] 0.76; 95% CI 0.52-1.with GLP-1RA; HR 0.87, 95% CI 0.79-0.96 without GLP-1RA; p-interaction 0.63) , and the kidney composite outcome (HR 0.82; 95% CI 0.45-1.48 with GLP-1RA; HR 0.77, 95% CI 0.67-0.89 without GLP-1RA; p-interaction 0.79) . A greater reduction in UACR was observed with finerenone in patients taking GLP-1RA at baseline (placebo-corrected change -38% with GLP-1RA and -31% without GLP-1RA use; p-interaction 0.03) . Incidence of hyperkalemia was similarly increased with finerenone irrespective of GLP-1RA use at baseline. Conclusion: The benefits of finerenone on composite CV and kidney outcomes in patients with CKD and T2D are not modified by GLP-1RA use at baseline, with an increased effect observed for UACR reduction, suggesting a different mechanism of reduction in albuminuria. Disclosure P.Rossing: Consultant; Astellas Pharma Inc., AstraZeneca, Bayer AG, Gilead Sciences, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Speaker's Bureau; Eli Lilly and Company. P.Viswanathan: Employee; Bayer AG. R.Lawatscheck: None. A.Joseph: Employee; Bayer AG. G.Bakris: Consultant; Alnylam Pharmaceuticals, Inc., AstraZeneca, DiaMedica Therapeutics, Inc., Horizon Therapeutics plc, Ionis Pharmaceuticals, Merck & Co., Inc., Other Relationship; Novo Nordisk. S.Anker: Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Novartis AG, Novo Nordisk, Vifor Pharma Management Ltd., Research Support; Abbott. G.Filippatos: Other Relationship; Amgen Inc., Amgen Inc., Bayer AG, Boehringer Ingelheim International GmbH, Medtronic, Novartis AG, Servier Laboratories, Vifor Pharma Management Ltd. B.Pitt: Advisory Panel; Merck & Co., Inc., Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Lexicon Pharmaceuticals, Inc., Vifor Pharma Management Ltd. L.M.Ruilope: Consultant; Bayer AG. V.Fonseca: Consultant; Abbott, Asahi Kasei Corporation, Bayer AG, Novo Nordisk, Sanofi, Research Support; Fractyl Health, Inc., Jaguar Gene Therapy, Stock/Shareholder; Abbott, Amgen Inc., BRAVO4Health, Mellitus Health. G.E.Umpierrez: Research Support; AstraZeneca, Dexcom, Inc., Novo Nordisk. L.Caramori: Advisory Panel; Bayer AG, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk, Research Support; Bayer AG, Novartis AG. M.Lambelet: Other Relationship; Bayer AG.

This double-blind, randomized, placebo- and active-controlled, parallel group trial evaluated the potential for multiple-dose fasiglifam to prolong the QT/QTc interval in healthy adults. A total of 280 men and women aged 18-50 years were randomized to receive 14 days of fasiglifam 50 mg (n = 69), fasiglifam 400 mg (n = 70), or placebo (n = 70), or 13 days of placebo followed by single-dose moxifloxacin 400 mg (positive control; n = 71). The primary endpoint was the least square mean difference between fasiglifam and placebo in time-matched change from baseline to last dosing day in QT interval corrected using the Fridericia method (QTcF, calculated as QT/RR(0) (.333) ). For both fasiglifam doses, differences from placebo in QTcF were between -4.9 and 3.0 milliseconds at all postdose time points; maximum upper bounds of the one-sided 95% confidence interval for the difference were 5.7 milliseconds for fasiglifam 50 mg and 2.3 milliseconds for fasiglifam 400 mg, meeting predefined criteria for absence of prolongation. Alternate correction methods (Bazett and Individual) showed similar results. Fasiglifam was well tolerated; no subject withdrew due to an adverse event after receiving fasiglifam. In summary, multiple-dose fasiglifam did not affect cardiac repolarization at therapeutic and supratherapeutic doses and was well tolerated in healthy subjects.

To describe the distribution of costs and to identify the drivers of high costs among adult patients with type 2 diabetes mellitus (T2DM) receiving oral hypoglycemic agents.T2DM patients using oral hypoglycemic agents and having HbA1c test data were identified from the Truven MarketScan databases of Commercial and Medicare Supplemental insurance claims (2004-2010). All-cause and diabetes-related annual direct healthcare costs were measured and reported by cost components. The 25% most costly patients in the study sample were defined as high-cost patients. Drivers of high costs were identified in multivariate logistic regressions.Total 1-year all-cause costs for the 4104 study patients were $55,599,311 (mean cost per patient = $13,548). Diabetes-related costs accounted for 33.8% of all-cause costs (mean cost per patient = $4583). Medical service costs accounted for the majority of all-cause and diabetes-related total costs (63.7% and 59.5%, respectively), with a minority of patients incurring80% of these costs (23.5% and 14.7%, respectively). Within the medical claims, inpatient admission for diabetes-complications was the strongest cost driver for both all-cause (OR = 13.5, 95% CI = 8.1-23.6) and diabetes-related costs (OR = 9.7, 95% CI = 6.3-15.1), with macrovascular complications accounting for most inpatient admissions. Other cost drivers included heavier hypoglycemic agent use, diabetes complications, and chronic diseases.The study reports a conservative estimate for the relative share of diabetes-related costs relative to total cost. The findings of this study apply mainly to T2DM patients under 65 years of age.Among the T2DM patients receiving oral hypoglycemic agents, 23.5% of patients incurred 80% of the all-cause healthcare costs, with these costs being driven by inpatient admissions, complications of diabetes, and chronic diseases. Interventions targeting inpatient admissions and/or complications of diabetes may contribute to the decrease of the diabetes economic burden.

TAK-875 is a selective G-protein-coupled receptor 40 agonist in development for the treatment of type 2 diabetes mellitus. This randomized, double-blind, placebo-controlled study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-875 following administration of a single oral dose of TAK-875 (25-800 mg) in 60 healthy volunteers. TAK-875 was eliminated slowly with a mean terminal elimination t(1/2) of approximately 28.1 to 36.6 hours. Systemic exposure of TAK-875 did not exhibit dose-proportional increases across the dose range evaluated due to a greater than proportional increase in exposure at doses greater than 200 mg. A preliminary food effect assessment indicated that coadministration of TAK-875 with a high-fat meal decreased C(max) of TAK-875 by 40% and AUC by 17%. Clinical adverse experiences were generally mild and transient. No dose-dependent pattern was observed. In healthy volunteers, no glucose-lowering effect and no increase in insulin or c-peptide secretion were evident following administration of TAK-875; the frequency of plasma glucose concentrations

Activation of free fatty acid receptor 1 (FFAR1; also known as G-protein-coupled receptor 40) by fatty acids stimulated glucose-dependent β-cell insulin secretion in preclinical models. We aimed to assess whether selective pharmacological activation of this receptor by TAK-875 in patients with type 2 diabetes mellitus improved glycaemic control without hypoglycaemia risk.We undertook a phase 2, randomised, double-blind, and placebo-controlled and active-comparator-controlled trial in outpatients with type 2 diabetes who had not responded to diet or metformin treatment. Patients were randomly assigned equally to receive placebo, TAK-875 (6·25, 25, 50, 100, or 200 mg), or glimepiride (4 mg) once daily for 12 weeks. Patients and investigators were masked to treatment assignment. The primary outcome was change in haemoglobin A(1c) (HbA(1c)) from baseline. Analysis included all patients randomly assigned to treatment groups who received at least one dose of double-blind study drug. The trial is registered at ClinicalTrials.gov, NCT01007097.426 patients were randomly assigned to TAK-875 (n=303), placebo (n=61), and glimepiride (n=62). At week 12, significant least-squares mean reductions in HbA(1c) from baseline occurred in all TAK-875 (ranging from -1·12% [SE 0·113] with 50 mg to -0·65% [0·114] with 6·25 mg) and glimepiride (-1·05% [SE 0·111]) groups versus placebo (-0·13% [SE 0·115]; p value range 0·001 to0·0001). Treatment-emergent hypoglycaemic events were similar in the TAK-875 and placebo groups (2% [n=7, all TAK-875 groups] vs 3% [n=2]); significantly higher rates were reported in the glimepiride group (19% [n=12]; p value range 0·010-0·002 vs all TAK-875 groups). Incidence of treatment-emergent adverse events was similar in the TAK-875 overall (49%; n=147, all TAK-875 groups) and placebo groups (48%, n=29) and was lower than in the glimepiride group (61%, n=38).TAK-875 significantly improved glycaemic control in patients with type 2 diabetes with minimum risk of hypoglycaemia. The results show that activation of FFAR1 is a viable therapeutic target for treatment of type 2 diabetes.Takeda Global Research and Development.

OBJECTIVE We have recently shown that a high-fat high-carbohydrate (HFHC) meal induces an increase in plasma concentrations of endotoxin (lipopolysaccharide [LPS]) and the expression of Toll-like receptor-4 (TLR-4) and suppresser of cytokine signaling-3 (SOCS3) in mononuclear cells (MNCs) in addition to oxidative stress and cellular inflammation. Saturated fat and carbohydrates, components of the HFHC meal, known to induce oxidative stress and inflammation, also induce an increase in LPS, TLR-4, and SOCS3. RESEARCH DESIGN AND METHODS Fasting normal subjects were given 300-calorie drinks of either glucose, saturated fat as cream, orange juice, or only water to ingest. Blood samples were obtained at 0, 1, 3, and 5 h for analysis. RESULTS Indexes of inflammation including nuclear factor-κB (NF-κB) binding, and the expression of SOCS3, tumor necrosis factor-α (TNF-α), and interleukin (IL)-1β in MNCs, increased significantly after glucose and cream intake, but TLR-4 expression and plasma LPS concentrations increased only after cream intake. The intake of orange juice or water did not induce any change in any of the indexes measured. CONCLUSIONS Although both glucose and cream induce NF-κB binding and an increase in the expression of SOCS3, TNF-α, and IL-1β in MNCs, only cream caused an increase in LPS concentration and TLR-4 expression. Equicaloric amounts of orange juice or water did not induce a change in any of these indexes. These changes are relevant to the pathogenesis of atherosclerosis and insulin resistance.

� Objective: To determine whether prostate-specific antigen (PSA) concentrations in type 2 diabetic men with hypogonadotrophic hypogonadism are lower than those in eugonadal men with type 2 diabetes and whether PSA concentrations are related to plasma testosterone concentrations. � Methods: In this cross-sectional study, we measured serum total testosterone, sex hormone–binding globulin, free testosterone, PSA, hematocrit, and hemoglobin A 1c in consecutive type 2 diabetic men who presented to 2 endocrinology referral centers between January 2006 and January 2007. We collected other clinical and demographic data including age, height, weight, and ethnicity. � Results:�Of 400 eligible patients, 280 men met inclusion criteria. Plasma PSA concentrations were lower in type 2 diabetic men with low free testosterone concentrations than in those with normal free testosterone concentrations (25.65 ± 2.02 ng/dL vs 31.70 ± 2.31 ng/dL, P = .011). PSA concentrations were positively related to age (r = 0.34, P

Background: Because obesity is associated with chronic oxidative and inflammatory stress, and high-fat, high-carbohydrate meals induce significant oxidative and inflammatory stress in normal subjects, we have now hypothesized that the intake of a high-fat, high-carbohydrate meal would result in a greater and more prolonged oxidative and inflammatory stress in the obese than in normal subjects. Methods: Ten normal-weight and eight obese subjects were given a high-fat, high-carbohydrate meal after an overnight fast. Blood samples were collected at baseline and hourly following the meal for 3 h. Results: Reactive oxygen species generation by mononuclear cells increased significantly by 2 h in both groups but continued to increase significantly at 3 h in the obese subjects, whereas in normal subjects it returned to baseline. Levels of p47phox increased significantly (by 81 ± 26%) at 3 h in obese individuals (P < 0.05), whereas there was no significant change in p47phox in normal subjects. Nuclear factor-κB DNA binding in mononuclear cells increased significantly (by 48 ± 58%, P < 0.036) at 2 h but not at 3 h in normal subjects, whereas in the obese, nuclear factor-κB increased significantly at both 2 and 3 h (by 36 ± 57 and 42 ± 63%, respectively, P < 0.004). Matrix metalloproteinase-9 concentrations were significantly higher in the obese at baseline (580 ± 103.9 vs. 373 ± 30.03 ng/ml, P < 0.05) and increased to significantly greater concentrations after the meal than in the lean subjects. Conclusions: High-fat, high-carbohydrate meals induced a significantly more prolonged and greater oxidative and inflammatory stress in the obese. This may contribute to the increased atherogenic risk in obesity.

This double-blind, randomized, placebo- and active-controlled, parallel group trial evaluated the potential for multiple-dose fasiglifam to prolong the QT/QTc interval in healthy adults. A total of 280 men and women aged 18-50 years were randomized to receive 14 days of fasiglifam 50 mg (n = 69), fasiglifam 400 mg (n = 70), or placebo (n = 70), or 13 days of placebo followed by single-dose moxifloxacin 400 mg (positive control; n = 71). The primary endpoint was the least square mean difference between fasiglifam and placebo in time-matched change from baseline to last dosing day in QT interval corrected using the Fridericia method (QTcF, calculated as QT/RR(0) (.333) ). For both fasiglifam doses, differences from placebo in QTcF were between -4.9 and 3.0 milliseconds at all postdose time points; maximum upper bounds of the one-sided 95% confidence interval for the difference were 5.7 milliseconds for fasiglifam 50 mg and 2.3 milliseconds for fasiglifam 400 mg, meeting predefined criteria for absence of prolongation. Alternate correction methods (Bazett and Individual) showed similar results. Fasiglifam was well tolerated; no subject withdrew due to an adverse event after receiving fasiglifam. In summary, multiple-dose fasiglifam did not affect cardiac repolarization at therapeutic and supratherapeutic doses and was well tolerated in healthy subjects.

G-protein-coupled receptor 40 (GPR40), highly expressed in pancreatic β-cells, mediates free fatty acid (FFA)-induced insulin secretion. This phase I, double-blind, randomized study investigated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of a novel, glucose-lowering GPR40 agonist, TAK-875 (q.d., orally × 14 days), in type 2 diabetics (placebo, n = 14; at 25, 50, 100, 200, or 400 mg, n = 45). Approximately dose-proportional increases in AUC(0-24) and C(max) occurred. TAK-875 showed good tolerability with no dose-limiting side effects. Two subjects (on TAK-875) had mild hypoglycemia, probably related to prolonged fasting after oral glucose tolerance tests (OGTTs). TAK-875 showed reductions from baseline in fasting (2 to -93 mg/dl) and post-OGTT glucose (26 to -172 mg/dl), with an apparent dose-dependent increase in post-OGTT C-peptide over 14 days. Consistent with preclinical data, TAK-875 apparently acts as a glucose-dependent insulinotropic agent with low hypoglycemic risk. Its PK is suitable for once-daily oral administration.

We assessed the effect of extending the range of cardiovascular (CV) end points to include hospitalization for unstable angina and hospitalization for coronary revascularization (Extended Major Adverse Cardiac Event criteria (MACE)) in addition to the standard ones, namely, CV-related death, nonfatal stroke, and nonfatal myocardial infarction (Core MACE). The trials selected for the analysis had a duration/follow-up period of ≥1 year and involved more than 1,000 subjects. Annual event rates (AERs) for Core MACE in patients with type 2 diabetes were estimated, and the duration of an event-driven CV outcome trial necessary to exclude ≥80% risk increase was modeled. All the studies revealed hazard ratios ≤1.0 for Core MACE end points whereas in 21% of the studies, the hazard ratio for hospitalization for unstable angina or coronary revascularization (Extended MACE) was >1 and was therefore discordant with Core MACE. The AERs for Core MACE ranged from 0.5% (recent clinical programs) to 6% (epidemiological studies); these low rates observed in recent programs would have the effect of increasing the duration required for a CV outcome trial. The addition of Extended MACE end points to the primary composite outcome in antidiabetic clinical trials is unlikely to obscure CV-related risk and may improve the feasibility of CV outcome trials. Clinical Pharmacology & Therapeutics (2012); 91 3, 514–520. doi:10.1038/clpt.2011.257

Background: The intake of glucose or a high-fat, high-carbohydrate (HFHC) meal, but not orange juice, induces an increase in inflammation and oxidative stress in circulating mononuclear cells (MNCs) of normal-weight subjects. Objective: We investigated the effect of orange juice on HFHC meal‐induced inflammation and oxidative stress and the expression of plasma endotoxin and Toll-like receptors (TLRs). Design: Three groups (10 subjects in each group) of normal, healthy subjects were asked to drink water or 300 kcal glucose or orange juice in combination with a 900-kcal HFHC meal. Blood samples were obtained before and 1, 3, and 5 h after the drinks and meal combinations were consumed. Results: Protein expression of the NADPH oxidase subunit p47 phox , phosphorylated and total p38 mitogen-activated protein kinase, and suppressor of cytokine signaling-3; TLR2 and TLR4 messenger RNA (mRNA) and protein expression; mRNA expression of matrix metalloproteinase (MMP)-9 in MNCs; and plasma concentrations of endotoxin and MMP-9 increased significantly after glucose or water were consumed with the meal but not when orange juice was consumed with the meal. The generation of reactive oxygen species by polymorphonuclear cells was significantly lower when orange juice was added to the meal than when water or glucose was added to the meal. Conclusions: The combination of glucose or water and the HFHC meal induced oxidative and inflammatory stress and an increase in TLR expression and plasma endotoxin concentrations. In contrast, orange juice intake with the HFHC meal prevented meal-induced oxidative and inflammatory stress, including the increase in endotoxin and TLR expression. These observations may help explain the mechanisms underlying postprandial oxidative stress and inflammation, pathogenesis of insulin resistance, and atherosclerosis. Am J Clin Nutr 2010;91:940‐9.

This study evaluated the effects of exenatide, a GLP-1 receptor agonist, and sitagliptin, a DPP-4 inhibitor, on 2-h postprandial glucose (PPG), insulin and glucagon secretion, gastric emptying, and caloric intake in T2D patients.This double-blind, randomized cross-over, multi-center study was conducted in metformin-treated T2D patients: 54% female; BMI: 33 +/- 5 kg/m(2); HbA(1c): 8.5 +/- 1.2%; 2-h PPG: 245 +/- 65 mg/dL. Patients received exenatide (5 microg BID for 1 week, then 10 microg BID for 1 week) or sitagliptin (100 mg QAM) for 2 weeks. After 2 weeks, patients crossed-over to the alternate therapy. Postprandial glycemic measures were assessed via standard meal test; caloric intake assessed by ad libitum dinner (subset of patients). Gastric emptying was assessed by acetaminophen absorption (Clinicaltrials.gov Registry Number: NCT00477581).After 2 weeks of therapy, 2-h PPG was lower with exenatide versus sitagliptin: 133 +/- 6 mg/dL versus 208 +/- 6 mg/dL, p0.0001 (evaluable, N = 61). Switching from exenatide to sitagliptin increased 2-h PPG by +73 +/- 11 mg/dL, while switching from sitagliptin to exenatide further reduced 2-h PPG by -76 +/- 10 mg/dL. Postprandial glucose parameters (AUC, C(ave), C(max)) were lower with exenatide than sitagliptin (p0.0001). Reduction in fasting glucose was similar with exenatide and sitagliptin (-15 +/- 4 mg/dL vs. -19 +/- 4 mg/dL, p = 0.3234). Compared to sitagliptin, exenatide improved the insulinogenic index of insulin secretion (ratio exenatide to sitagliptin: 1.50 +/- 0.26, p = 0.0239), reduced postprandial glucagon (AUC ratio exenatide to sitagliptin: 0.88 +/- 0.03, p = 0.0011), reduced postprandial triglycerides (AUC ratio exenatide to sitagliptin: 0.90 +/- 0.04, p = 0.0118), and slowed gastric emptying (acetaminophen AUC ratio exenatide to sitagliptin: 0.56 +/- 0.05, p0.0001). Exenatide reduced total caloric intake compared to sitagliptin (-134 +/- 97 kcal vs. +130 +/- 97 kcal, p = 0.0227, N = 25). Common adverse events with both treatments were mild to moderate in intensity and gastrointestinal in nature.Although this study was limited by a 2-week duration of exposure, these data demonstrate that, exenatide had: (i) a greater effect than sitagliptin to lower postprandial glucose and (ii) a more potent effect to increase insulin secretion and reduce postprandial glucagon secretion in T2D patients. In contrast to sitagliptin, exenatide slowed gastric emptying and reduced caloric intake. These key findings differentiate the therapeutic actions of the two incretin-based approaches, and may have meaningful clinical implications.

To evaluate the effect of exenatide on clinical parameters in obese patients with type 2 diabetes mellitus whose hyperglycemia is not adequately controlled despite treatment with oral hypoglycemic agents and insulin.In this retrospective analysis, clinical progress of 52 obese patients with type 2 diabetes treated with exenatide, 5 mcg twice daily, in an outpatient setting was reviewed. Treatment initiation was between September and December 2005. Mean follow-up period was 26 weeks. Thirty-eight patients took exenatide regularly (Group A); 14 patients discontinued exenatide because of insurance, personal, or economic reasons (Group B). Measurements at baseline and at follow-up included body weight; blood pressure; and levels of hemoglobin A1c (HbA1c), high-sensitivity C-reactive protein (CRP), and plasma lipids. Insulin dosage requirements were assessed.Mean body weight (+/- standard error of the mean) decreased by 6.46 +/- 0.8 kg (P.001) in Group A and increased by 2.4 +/- 0.6 kg in Group B (P001). In Group A, mean HbA1c decreased by 0.6 +/- 0.21% (P = .007), and the insulin dosage requirement decreased for rapid-acting and mixed insulins (P.02). In Group A, means of the following parameters decreased: serum total cholesterol by 8.5 +/- 3.3% (P = .03), triglycerides by 26 +/- 7.6% (P = .01), systolic blood pressure by 9.2 +/- 3.3 mm Hg (P = .02), and high-sensitivity CRP by 34 +/- 14.3% (P = .05). These indices did not change in Group B.Exenatide effectively treats obese patients with type 2 diabetes on insulin, leading to weight loss and reduction in levels of HbA1c, systolic blood pressure, triglycerides, and high-sensitivity CRP.

Drugs that reverse insulin resistance are of importance as insulin resistance is frequently associated with type 2 diabetes. The three peroxisome proliferator-activated receptors (PPARs) PPARalpha, PPAR90 and PPARgamma are essential for the actions of the many insulin sensitizers. PPARalpha activation enhances free fatty acid oxidation and potentiates anti-inflammatory effects, while PPARgamma is essential for normal adipocyte differentiation and proliferation, as well as fatty acid uptake and storage. Thiazolidinediones (TZDs) are selective ligands of PPARgamma and act as insulin sensitizers. TZDs also suppress free fatty acids via the inhibition of lipolysis in adipose tissue. Insulin sensitizers currently under development include partial PPARgamma agonists and antagonists, and dual PPARalpha/PPARgamma agonists. Given that TZDs show anti-inflammatory, anti-oxidant and antiprocoagulant properties in addition to their insulin sensitizing and antilipotoxic properties, a case may be made for initiating TZD therapy early in the treatment of type 2 diabetes, particularly in those patients at risk of cardiovascular disease. TZDs may also be an important therapeutic option in the treatment of metabolic syndrome.

Background: We have previously demonstrated an early and potent antiinflammatory effect of troglitazone and rosiglitazone. Hypothesis: Because inflammatory mediators interfere with insulin signal transduction, we have now hypothesized that rosiglitazone exerts an initial antiinflammatory effect independently of its metabolic actions including the suppression of the plasma concentration of free fatty acids (FFAs), insulin, and glucose after which insulin sensitization occurs. Patient and Methods: Fourteen patients with type 2 diabetes were included in the study. Eight patients were given 2 mg daily of rosiglitazone for 6 wk, whereas the other six patients were given a placebo for the same period. Results: After a 2-mg dose of rosiglitazone, plasma FFAs, insulin, and glucose concentrations and homeostasis model assessment of insulin resistance did not change. Plasma C-reactive protein, serum amyloid A, and matrix metalloproteinase concentrations fell significantly at wk 1 and continued to be significantly lower than the baseline levels by 25, 29, and 24%, respectively, at wk 6. Leukocyte count was significantly lower at wk 6 after rosiglitazone, whereas there was no change in the control group. Plasma adiponectin concentrations increased significantly at wk 2 and continued to increase during the treatment period with rosiglitazone. Resistin concentrations fell significantly by 10% at wk 6 only. There were no changes in any of these indices in the placebo group. Conclusions: A low dose of rosiglitazone exerts an early and potent antiinflammatory effect with an increase in adiponectin and a fall in resistin concentrations without causing any metabolic changes (fall in plasma glucose, FFAs, and insulin concentrations) over a 6-wk period. The increase in adiponectin and the decrease in resistin after rosiglitazone are thus related primarily to its antiinflammatory effects rather than its metabolic actions. These observations have implications in relation to the mode of action of this drug as an insulin-sensitizing agent and also its use as a potential antiinflammatory and antiatherogenic drug in the future.