Nayyar Iqbal

An Inflammatory Cascade Leading to Hyperresistinemia in Humans

Background Obesity, the most common cause of insulin resistance, is increasingly recognized as a low-grade inflammatory state. Adipocyte-derived resistin is a circulating protein implicated in insulin resistance in rodents, but the role of human resistin is uncertain because it is produced largely by macrophages. Methods and Findings The effect of endotoxin and cytokines on resistin gene and protein expression was studied in human primary blood monocytes differentiated into macrophages and in healthy human participants. Inflammatory endotoxin induced resistin in primary human macrophages via a cascade involving the secretion of inflammatory cytokines that circulate at increased levels in individuals with obesity. Induction of resistin was attenuated by drugs with dual insulin-sensitizing and anti-inflammatory properties that converge on NF-κB. In human study participants, experimental endotoxemia, which produces an insulin-resistant state, causes a dramatic rise in circulating resistin levels. Moreover, in patients with type 2 diabetes, serum resistin levels are correlated with levels of soluble tumor necrosis factor α receptor, an inflammatory marker linked to obesity, insulin resistance, and atherosclerosis. Conclusions Inflammation is a hyperresistinemic state in humans, and cytokine induction of resistin may contribute to insulin resistance in endotoxemia, obesity, and other inflammatory states.

The effects of free fatty acids on gluconeogenesis and glycogenolysis in normal subjects

We have quantitatively determined gluconeogenesis (GNG) from all precursors, using a novel method employing 2H20 to address the question of whether changes in plasma free fatty acids (FFA) affect GNG in healthy, nonobese subjects. In the first study (n = 6), plasma FFA were lowered at 16 to 20 hours with nicotinic acid (NA) and were then allowed to rise at 20 to 24 hours (FFA rebound after administration of NA). FFA decreased from 387 microM at 16 hours to 43 microM at 20 hours, and then rebounded to 1,823 microM at 24 hours. GNG decreased from 58.1% at 16 hours to 38.6% of endogenous glucose production at 20 hours (P < 0.005) and then rebounded to 78. 9% at 24 hours (P < 0.05). Conversely, glycogenolysis (GL) increased from 41.9% at 16 hours to 61.4% at 20 hours (P < 0.05), and then decreased to 21.1% at 24 hours (P < 0.05). In the second study (controls; n = 6), volunteers were analyzed between 16 and 24 hours after the last meal. FFA rose from 423 to 681 microM (P < 0.05), and GNG from 50.3% to 61.7% (P < 0.02), whereas GL decreased from 49.7% to 38.3% (P < 0.05). Endogenous glucose production decreased at the same rate in both studies, from 10.7 to 8.6 micromol/kg/min (P < 0. 05). In study 3 (n = 6), in which the NA-mediated decrease of plasma FFA was prevented by infusion of lipid and heparin, neither FFA nor GNG changed significantly. In summary, our data suggest that (a) acute changes in plasma FFA produce acute changes in GNG and reciprocal changes in GL; (b) the decrease in EGP between 16 and 24 hours of fasting is due to a fall in GL; and (c) NA has no direct effect on GNG.

Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes

BACKGROUND The cardiovascular effects of adding once‐weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown. METHODS We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended‐release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy. RESULTS In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person‐years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person‐years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention‐to‐treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups. CONCLUSIONS Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number, NCT01144338.)

Narrative Review: Effect of Bariatric Surgery on Type 2 Diabetes Mellitus

Key Summary Points The rapid improvement in glycemic control after bariatric surgery results from caloric restriction and alterations in the gut hormones that control insulin secretion. The enteroinsular axis includes the incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), ghrelin, and peptide YY (PYY) and their subsequent effect on insulin secretion and sensitivity. Restrictive, malabsorptive, and combined bariatric surgery procedures have different effects on the enteroinsular axis. Intestinal bypass procedures increase GLP-1 and PYY levels. In contrast, restrictive procedures do not increase incretin or PYY levels. Familiarity with these changes can help physicians consider the various surgical approaches and develop postoperative treatment regimens for patients. Glycemic control in diabetic patients improves markedly within days of bariatric surgery, which suggests that the procedures alter the hormones that control insulin secretion (1). The enteroinsular axis includes the gut hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). These hormones, also known as incretins, are secreted by intestinal L and K cells, respectively, in response to nutrients and directly enhance insulin secretion (2). Restrictive, malabsorptive, and combined bariatric surgery procedures affect the enteroinsular axis differently. The various bariatric procedures also affect the secretion of other gut hormones that affect insulin sensitivity, including ghrelin and peptide YY (PYY). Thus, an altered pattern of gut hormone secretion after bariatric surgery may profoundly affect glucose tolerance. We focus on the short-term pathophysiologic changes in the enteroinsular axis and their subsequent effect on insulin secretion and sensitivity after bariatric surgery. Familiarity with these changes can help clinicians decide among the different surgical approaches and formulate treatment regimens that avoid severe postoperative hypoglycemia. Methods We searched English-language publications in PubMed and reference lists from relevant articles published between 1967 and 2008. Our main search terms were bariatric surgery, Roux-en-Y, gastric bypass, biliopancreatic diversion, gastric banding, laparoscopic adjustable gastric banding, diabetes, enteroinsular axis, incretins, GLP-1, GIP, ghrelin, PYY, insulin, and postoperative management. To determine the rates of diabetes resolution, we included studies that enrolled at least 10 diabetic patients (alone or along with nondiabetic patients) and reported diabetes-related outcomes. We retrieved randomized, controlled trials; cohort studies; and casecontrol studies that reported weight loss, diabetes resolution, and time to restoration of normoglycemia. Because we found few such studies, we also included large case series. We evaluated study quality by using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system (3). We used our judgment to identify high-quality studies that described gut hormone levels after bariatric surgery. Types of Bariatric Procedures and Effect on Weight Loss and Diabetes Since its inception in the 1950s, bariatric surgery has become increasingly refined. More recently, it has been touted as a cure for diabetes (4). Several procedures are now available (Figure 1). Bariatric procedures were initially classified as restrictive, malabsorptive, or combined, reflecting the purported mechanism of weight loss (1). Restrictive procedures, such as laparoscopic adjustable gastric banding (LAGB) and vertical banded gastroplasty (VBG), greatly reduce the volume of the stomach to decrease food intake and induce early satiety. Malabsorptive procedures, such as biliopancreatic diversion (BPD), shorten the small intestine to decrease nutrient absorption. Combined procedures, such as the Roux-en-Y gastric bypass (RYGB), incorporate both restrictive and malabsorptive elements. Roux-en-Y gastric bypass surgery is the current gold standard treatment for severe obesity. Both BPD and RYGB alter the secretion of orexigenic and anorexigenic gut peptides, which interact with appetitive centers in the arcuate nucleus of the hypothalamus to decrease appetite (5). Because both BPD and RYGB bypass similar segments of the small bowel, we use the term intestinal bypass procedure to refer to either. Figure 1. Surgical procedures. Reprinted with permission of the American Society for Metabolic and Bariatric Surgery, copyright 2008, all rights reserved. Weight Loss Two recent meta-analyses (6, 7) reported weight loss; operative mortality; and obesity-related comorbid conditions, including diabetes, after bariatric surgery. Buchwald and colleagues (7) reported mean excess weight loss (see Glossary) (710) of 61% across all procedures in 22094 patients; weight loss rates associated with each procedure varied (Table 1). On average, bariatric surgery reduces body mass index by 10 to 15 kg/m2 and weight by 30 to 50 kg (11). Table 1. Results of Different Types of Bariatric Surgery Several relatively poor-quality randomized, controlled trials that compared different bariatric surgery procedures (12) showed that weight loss was greater with gastric bypass than with VBG or LAGB. The SOS (Swedish Obese Subjects) study (13), a landmark observational study that followed more than 4000 obese participants, matched those who selected medical management with those undergoing various bariatric procedures, including RYGB, VBG, or LAGB. At 10 years, RYGB was associated with a 25% reduction in total body weight, whereas VBG and LAGB were associated with 16% and 14% weight loss, respectively. Diabetes Resolution and Improvement Observational evidence suggests that bariatric surgery is associated with a 60% to 80% rate of diabetes resolution (14). In 1 meta-analysis (7), approximately 15% of the patients were diabetic. In studies reporting complete resolution of diabetes (defined as normoglycemia with no diabetes medications), 1417 of 1846 patients (76.8%) met the criteria for resolution. Among studies reporting resolution or improvement of diabetes, 414 of 485 patients (mean, 86.0%) experienced either outcome. Table 1 shows rates of diabetes resolution for individual bariatric procedures. Conclusions about bariatric surgery and diabetes resolution come with an important qualifier: The studies had serious methodological weaknesses. Few are randomized, controlled trials; most surgical outcome studies are uncontrolled case series with considerable missing data (6, 10). In 1 meta-analysis (6), one quarter of the studies did not report enrolling consecutive patients and fewer than 50% reported how many enrolled patients provided follow-up data. Table 2 (4, 1422) includes selected studies that met the minimum GRADE criteria quality standards and reported follow-up rates of at least 80% (3). Paired comparisons of surgical procedures typically favored RYGB or BPD over the restrictive procedures (23). Table 2. Efficacy for Resolution of Diabetes Predictors of Diabetes Resolution Identifying preoperative predictors of diabetes resolution is critical for determining which diabetic patients will obtain the greatest benefit from surgery. In earlier studies of RYGB, longer duration of diabetes (>10 years), poor preoperative glycemic control, and preoperative insulin use reduced the probability of diabetes resolution (18, 19); however, these studies did not adjust for the effects of known confounding factors. More recently, Torquati and colleagues (24) adjusted for body mass index, sex, and preoperative hemoglobin A1c level and found that preoperative treatment with oral antidiabetic agents (as opposed to insulin) and smaller preoperative waist circumference predicted diabetes resolution (18). Shorter duration of diabetes was a weaker, statistically nonsignificant predictor, which supports earlier studies of RYGB (18). The same factors predict diabetes resolution after gastric banding. Dixon and colleagues (25) reported that diabetes for less than 3 years predicted diabetes resolution, after they controlled for age and excess weight loss. Less deterioration in -cell function at the time of surgery may maximize the effect of the surgery-altered secretion of gut peptides that enhance -cell insulin secretion. The Enteroinsular Axis Bayliss and Starling first described the connection between the gut and the pancreas in 1902, when they demonstrated that intestinal mucosa extracts contained a factor, which they called secretin, that acted through the bloodstream to stimulate exocrine secretion by the pancreas (26). Sixty-five years later, Perley and Kipnis (27) demonstrated that ingested nutrients stimulated greater insulin release than intravenously administered glucose. In 1979, Creutzfeldt (28) defined incretins as gastrointestinal hormones that stimulate insulin release after enteral nutrition. This connection between the gut and pancreatic islet cells is called the enteroinsular axis, a term first used by Unger and Eisentraut (29). The Incretins: GLP-1 and GIP By potentiating glucose-dependent insulin secretion, GLP-1 and GIP account for 50% to 60% of nutrient-stimulated insulin release (2). In animal models of diabetes, GLP-1 also increases -cell mass through regulation of proliferation, neogenesis, and apoptosis (30). Glucagon-like peptide-1 is a potent insulin secretatogue that is secreted by the L cells of the distal ileum in response to ingested nutrients and is inactivated by the enzyme dipeptidyl peptidase IV (DPP-IV) (31). By activating adenylate cyclase, GLP-1 acts on pancreatic islets to augment glucose-dependent insulin secretion. The subsequent increase in insulin levels within islets inhibits glucagon secretion, possibly through direct activation of GLP-1 receptors on cells (31). Glucagon-like peptide-1 also slows gastric emptying, which delays digestion and blunts postprandial glycemia (32), and acts on the central nervou

Dapagliflozin add-on to metformin in type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled 102-week trial

BackgroundManagement of type 2 diabetes with metformin often does not provide adequate glycemic control, thereby necessitating add-on treatment. In a 24-week clinical trial, dapagliflozin, an investigational sodium glucose cotransporter 2 inhibitor, improved glycemic control in patients inadequately controlled with metformin. The present study is an extension that was undertaken to evaluate dapagliflozin as long-term therapy in this population.MethodsThis was a long-term extension (total 102 weeks) of a 24-week phase 3, multicenter, randomized, placebo-controlled, double-blind, parallel-group trial. Patients were randomly assigned (1:1:1:1) to blinded daily treatment (placebo, or dapagliflozin 2.5 to 5, or 10 mg) plus open-label metformin (≥1,500 mg). The previously published primary endpoint was change from baseline in glycated hemoglobin (HbA1c) at 24 weeks. This paper reports the follow-up to week 102, with analysis of covariance model performed at 24 weeks with last observation carried forward; a repeated measures analysis was utilized to evaluate changes from baseline in HbA1c, fasting plasma glucose (FPG), and weight.ResultsA total of 546 patients were randomized to 1 of the 4 treatments. The completion rate for the 78-week double-blind extension period was lower for the placebo group (63.5%) than for the dapagliflozin groups (68.3% to 79.8%). At week 102, mean changes from baseline HbA1c (8.06%) were +0.02% for placebo compared with -0.48% (P = 0.0008), -0.58% (P <0.0001), and -0.78% (P <0.0001) for dapagliflozin 2.5 to 5, and 10 mg, respectively. In addition, all dapagliflozin groups had sustained reductions from baseline in FPG (-1.07 to -1.47 mmol/l) and body weight (-1.10 to -1.74 kg) at 102 weeks, whereas increases were noted in placebo-treated patients for both of these outcomes. Events of hypoglycemia were rare and were not severe. Evidence suggestive of genital infection was reported in 11.7% to 14.6% of dapagliflozin patients and 5.1% of placebo patients, with one related discontinuation (dapagliflozin 5 mg). Evidence suggestive of urinary tract infection was reported in 8.0% to 13.3% of dapagliflozin patients and 8.0% of placebo patients, with one related discontinuation (dapagliflozin 2.5 mg).ConclusionsDapagliflozin added to metformin for 102 weeks enabled sustained reductions in HbA1c, FPG, and weight without increased risk of hypoglycemia in patients with type 2 diabetes who were inadequately controlled on metformin alone.Trial registrationClinicalTrials.gov: NCT00528879

Dual Add-on Therapy in Type 2 Diabetes Poorly Controlled With Metformin Monotherapy: A Randomized Double-Blind Trial of Saxagliptin Plus Dapagliflozin Addition Versus Single Addition of Saxagliptin or Dapagliflozin to Metformin

OBJECTIVE This study compared the efficacy and safety of dual add-on of saxagliptin plus dapagliflozin versus saxagliptin and dapagliflozin added on alone in patients with type 2 diabetes poorly controlled with metformin. RESEARCH DESIGN AND METHODS This was a double-blind trial in adults with HbA1c ≥8.0% and ≤12.0% (64–108 mmol/mol), randomized to saxagliptin (SAXA) (5 mg/day) plus dapagliflozin (DAPA) (10 mg/day; n = 179), or SAXA (5 mg/day) and placebo (n = 176), or DAPA (10 mg/day) and placebo (n = 179) on background metformin extended release (MET) ≥1,500 mg/day. Primary objective compared changes from baseline in HbA1c with SAXA+DAPA+MET versus SAXA+MET and DAPA+MET. RESULTS Patients had a mean baseline HbA1c of 8.9% (74 mmol/mol), diabetes duration of 7.6 years, and a BMI of 32 kg/m2. At week 24, the adjusted mean change from the baseline HbA1c was –1.5% (–16.1 mmol/mol) with SAXA+DAPA+MET versus –0.9% (–9.6 mmol/mol) with SAXA+MET (difference −0.59% [–6.4 mmol/mol], P < 0.0001) and –1.2% (–13.1 mmol/mol) with DAPA+MET (difference −0.27% [3.0 mmol/mol], P < 0.02). The proportion of patients achieving HbA1c <7% (53 mmol/mol) was 41% with SAXA+DAPA+MET versus 18% with SAXA+MET and 22% with DAPA+MET. Urinary and genital infections occurred in ≤1% of patients receiving SAXA+DAPA+MET. Hypoglycemia was infrequent, with no episodes of major hypoglycemia. CONCLUSIONS In this first report of adding a well-tolerated combination of saxagliptin plus dapagliflozin to background metformin therapy in patients poorly controlled with metformin, greater improvements in glycemic control were obtained with triple therapy by the dual addition of saxagliptin and dapagliflozin than dual therapy with the addition of saxagliptin or dapagliflozin alone.

Effects of Rosiglitazone on Lipids, Adipokines, and Inflammatory Markers in Nondiabetic Patients With Low High-Density Lipoprotein Cholesterol and Metabolic Syndrome

Background—PPAR-γ agonists improve insulin sensitivity and glycemic control in type 2 diabetes and may reduce atherosclerosis progression. Thus, PPAR-γ agonists may be an effective therapy for metabolic syndrome. However, the full spectrum of potentially antiatherogenic mechanisms of PPAR-γ agonists have not been fully tested in nondiabetic patients with metabolic syndrome. Methods and Results—We performed a prospective, double-blinded, placebo-controlled study of 60 nondiabetic subjects with low high-density lipoprotein cholesterol (HDL-C) level and metabolic syndrome to rosiglitazone 8 mg daily or placebo for 12 weeks. We found no significant effect of rosiglitazone on HDL-C (+5.5% versus +5.8%, P=0.89), and an increase in total cholesterol (+8% versus −1%; P=0.03). Nevertheless, rosiglitazone significantly increased adiponectin (+168% versus +25%; P<0.001), and lowered resistin (−6% versus +4%; P=0.009), C-reactive protein (−32% versus +36%, P=0.002), interleukin (IL)-6 (−22% versus +4%, P<0.001), and soluble tumor-necrosis factor-α receptor-2 (−5% versus +7%, P<0.001). Conclusions—These findings suggest that rosiglitazone, presumably through its PPAR-γ agonist properties, has direct effects on inflammatory markers and adipokines in the absence of favorable lipid effects. These findings may help explain the mechanism underlying the possible antiatherosclerotic effects of rosiglitazone.

Exploring the Potential of the SGLT2 Inhibitor Dapagliflozin in Type 1 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Pilot Study

OBJECTIVE Insulin adjustments to maintain glycemic control in individuals with type 1 diabetes often lead to wide glucose fluctuations, hypoglycemia, and increased body weight. Dapagliflozin, an insulin-independent sodium–glucose cotransporter 2 (SGLT2) inhibitor, increases glucosuria and reduces hyperglycemia in individuals with type 2 diabetes. The primary objective of this study was to assess short-term safety of dapagliflozin in combination with insulin; secondary objectives included pharmacokinetic, pharmacodynamic, and efficacy parameters. RESEARCH DESIGN AND METHODS A 2-week, dose-ranging, randomized, double-blind, placebo-controlled proof-of-concept study randomly assigned 70 adults with type 1 diabetes (HbA1c 7–10%), who were receiving treatment with stable doses of insulin, to one of four dapagliflozin doses (1, 2.5, 5, or 10 mg) or placebo. The insulin dose was not proactively reduced at randomization but could be adjusted for safety reasons. RESULTS Sixty-two patients (88.6%) completed the study. Any hypoglycemia was common across all treatments (60.0–92.3%); one major event of hypoglycemia occurred with dapagliflozin 10 mg. No diabetic ketoacidosis occurred. Pharmacokinetic parameters were similar to those observed in patients with type 2 diabetes. Glucosuria increased by 88 g/24 h (95% CI 55 to 121) with dapagliflozin 10 mg and decreased by −21.5 g/24 h (95% CI −53.9 to 11.0) with placebo. Changes from baseline with dapagliflozin 10 mg by day 7 were as follows: −2.29 mmol/L (95% CI −3.71 to −0.87 [−41.3 mg/dL; 95% CI −66.9 to −15.7]) for 24-h daily average blood glucose; −3.77 mmol/L (95% CI −6.09 to −1.45 [−63.1 mg/dL; 95% CI −111.5 to −14.8]) for mean amplitude of glycemic excursion; and −16.2% (95% CI −29.4 to −0.5) for mean percent change in total daily insulin dose. Corresponding changes with placebo were as follows: −1.13 mmol/L (95% CI −3.63 to 1.37), −0.45 mmol/L (95% CI −4.98 to 4.08), and 1.7% (95% CI −22.8 to 33.9), respectively. However, for every efficacy parameter, the 95% CIs for all dapagliflozin doses overlapped those for placebo. CONCLUSIONS This exploratory study of dapagliflozin in adults with type 1 diabetes demonstrated acceptable short-term tolerability and expected pharmacokinetic profiles and increases in urinary glucose excretion. Within the dapagliflozin groups, dose-related reductions in 24-h glucose, glycemic variability, and insulin dose were suggested, which provide hope that SGLT2 inhibition may prove in larger randomized controlled trials to be efficacious in reducing hyperglycemia in type 1 diabetes.

Simvastatin vs Therapeutic Lifestyle Changes and Supplements: Randomized Primary Prevention Trial

OBJECTIVE To compare the lipid-lowering effects of an alternative regimen (lifestyle changes, red yeast rice, and fish oil) with a standard dose of a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin). PATIENTS AND METHODS This randomized trial enrolled 74 patients with hypercholesterolemia who met Adult Treatment Panel III criteria for primary prevention using statin therapy. All participants were randomized to an alternative treatment group (AG) or to receive simvastatin (40 mg/d) in this open-label trial conducted between April 1, 2006, and June 30, 2006. The alternative treatment included therapeutic lifestyle changes, ingestion of red yeast rice, and fish oil supplements for 12 weeks. The simvastatin group received medication and traditional counseling. The primary outcome measure was the percentage change in low-density lipoprotein cholesterol (LDL-C). Secondary measures were changes in other lipoproteins and weight loss. RESULTS There was a statistically significant reduction in LDL-C levels in both the AG (-42.4%+/-15%) (P<.001) and the simvastatin group (-39.6%+/-20%) (P<.001). No significant differences were noted between groups. The AG also demonstrated significant reductions in triglycerides (-29% vs -9.3%; 95% confidence interval, -61 to -11.7; P=.003) and weight (-5.5% vs -0.4%; 95% confidence interval, -5.5 to -3.4; P<.001) compared with the simvastatin group. CONCLUSION Lifestyle changes combined with ingestion of red yeast rice and fish oil reduced LDL-C in proportions similar to standard therapy with simvastatin. Pending confirmation in larger trials, this multifactorial, alternative approach to lipid lowering has promise for a subset of patients unwilling or unable to take statins.

Dapagliflozin as Monotherapy in Drug-Naive Asian Patients With Type 2 Diabetes Mellitus: A Randomized, Blinded, Prospective Phase III Study

OBJECTIVE Dapagliflozin is a highly selective, orally active inhibitor of renal sodium-glucose cotransporter 2 that reduces hyperglycemia by increasing urinary glucose excretion. The goal of this study was to evaluate dapagliflozin as monotherapy in drug-naive Asian patients with type 2 diabetes whose disease was inadequately controlled with diet and exercise. METHODS In this Phase III, multicenter, parallel-group, double-blind study, drug-naive patients with glycosylated hemoglobin (HbA1c) levels ≥7.0% to ≤10.5% (≥53-≤91 mmol/mol) were randomized (by using an interactive voice response system) to receive placebo (n = 132), dapagliflozin 5 mg (n = 128), or dapagliflozin 10 mg (n = 133). The primary end point was mean change from baseline in HbA1c level at week 24 (last-observation-carried-forward). Secondary end points included changes in fasting plasma glucose, 2-hour postprandial glucose, body weight, and other glycemic parameters. RESULTS Baseline characteristics were balanced across groups. Most patients (89%) were Chinese, median disease duration was 0.2 year, and mean HbA1c level was 8.26%. Most patients (87%) completed the study. At week 24, mean reductions in HbA1c were -0.29% for placebo versus -1.04% and -1.11% for dapagliflozin 5 and 10 mg, respectively (P < 0.0001 for both doses). Changes in fasting plasma glucose were 2.5, -25.1, and -31.6 mg/dL (0.14, -1.39, and -1.75 mmol/L) for placebo, dapagliflozin 5 mg, and dapagliflozin 10 mg. Changes in 2-hour postprandial glucose were 1.1, -46.8, and -54.9 mg/dL (0.06, -2.60, and -3.05 mmol/L). Reductions in body weight were -0.27, -1.64, and -2.25 kg. Proportions of patients achieving HbA1c levels <7.0% (53 mmol/mol) were 21.3%, 42.6%, and 49.8%. Adverse events (AEs) occurred in 63.6%, 61.7%, and 60.9% of patients, and serious AEs occurred in 1.5%, 3.9%, and 3.0% of patients. No deaths occurred. Hypoglycemia was uncommon (1.5%, 0.8%, and 0.8%); no hypoglycemic event led to discontinuation. Genital infections occurred in 0.8%, 3.1%, and 4.5% of patients and urinary tract infections in 3.0%, 3.9%, and 5.3% of patients. No AEs of renal infection or pyelonephritis were reported. No changes in renal function or AEs of renal failure occurred. CONCLUSIONS Compared with placebo, dapagliflozin 5 and 10 mg demonstrated clinically and statistically significant improvements in HbA1c levels after 24 weeks of treatment. Dose-dependent, statistically significant reductions in fasting plasma glucose, postprandial glucose, and weight were also observed for both doses compared with placebo. AEs and serious AEs were balanced across groups, with low rates of hypoglycemia and no increase in renal events. Genital infections and urinary tract infections were more common with dapagliflozin. Dapagliflozin as monotherapy in these drug-naive Asian patients was well tolerated, significantly improving glycemic control with the additional benefit of weight loss.