Kathy Wolski

Bariatric Surgery versus Intensive Medical Therapy in Obese Patients with Diabetes

BACKGROUND Observational studies have shown improvement in patients with type 2 diabetes mellitus after bariatric surgery. METHODS In this randomized, nonblinded, single-center trial, we evaluated the efficacy of intensive medical therapy alone versus medical therapy plus Roux-en-Y gastric bypass or sleeve gastrectomy in 150 obese patients with uncontrolled type 2 diabetes. The mean (±SD) age of the patients was 49±8 years, and 66% were women. The average glycated hemoglobin level was 9.2±1.5%. The primary end point was the proportion of patients with a glycated hemoglobin level of 6.0% or less 12 months after treatment. RESULTS Of the 150 patients, 93% completed 12 months of follow-up. The proportion of patients with the primary end point was 12% (5 of 41 patients) in the medical-therapy group versus 42% (21 of 50 patients) in the gastric-bypass group (P=0.002) and 37% (18 of 49 patients) in the sleeve-gastrectomy group (P=0.008). Glycemic control improved in all three groups, with a mean glycated hemoglobin level of 7.5±1.8% in the medical-therapy group, 6.4±0.9% in the gastric-bypass group (P<0.001), and 6.6±1.0% in the sleeve-gastrectomy group (P=0.003). Weight loss was greater in the gastric-bypass group and sleeve-gastrectomy group (-29.4±9.0 kg and -25.1±8.5 kg, respectively) than in the medical-therapy group (-5.4±8.0 kg) (P<0.001 for both comparisons). The use of drugs to lower glucose, lipid, and blood-pressure levels decreased significantly after both surgical procedures but increased in patients receiving medical therapy only. The index for homeostasis model assessment of insulin resistance (HOMA-IR) improved significantly after bariatric surgery. Four patients underwent reoperation. There were no deaths or life-threatening complications. CONCLUSIONS In obese patients with uncontrolled type 2 diabetes, 12 months of medical therapy plus bariatric surgery achieved glycemic control in significantly more patients than medical therapy alone. Further study will be necessary to assess the durability of these results. (Funded by Ethicon Endo-Surgery and others; ClinicalTrials.gov number, NCT00432809.).

Bariatric Surgery versus Intensive Medical Therapy for Diabetes — 3-Year Outcomes

BACKGROUND Long‐term results from randomized, controlled trials that compare medical therapy with surgical therapy in patients with type 2 diabetes are limited. METHODS We assessed outcomes 5 years after 150 patients who had type 2 diabetes and a body‐mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 27 to 43 were randomly assigned to receive intensive medical therapy alone or intensive medical therapy plus Roux‐en‐Y gastric bypass or sleeve gastrectomy. The primary outcome was a glycated hemoglobin level of 6.0% or less with or without the use of diabetes medications. RESULTS Of the 150 patients who underwent randomization, 1 patient died during the 5‐year follow‐up period; 134 of the remaining 149 patients (90%) completed 5 years of follow‐up. At baseline, the mean (±SD) age of the 134 patients was 49±8 years, 66% were women, the mean glycated hemoglobin level was 9.2±1.5%, and the mean BMI was 37±3.5. At 5 years, the criterion for the primary end point was met by 2 of 38 patients (5%) who received medical therapy alone, as compared with 14 of 49 patients (29%) who underwent gastric bypass (unadjusted P=0.01, adjusted P=0.03, P=0.08 in the intention‐to‐treat analysis) and 11 of 47 patients (23%) who underwent sleeve gastrectomy (unadjusted P=0.03, adjusted P=0.07, P=0.17 in the intention‐to‐treat analysis). Patients who underwent surgical procedures had a greater mean percentage reduction from baseline in glycated hemoglobin level than did patients who received medical therapy alone (2.1% vs. 0.3%, P=0.003). At 5 years, changes from baseline observed in the gastric‐bypass and sleeve‐gastrectomy groups were superior to the changes seen in the medical‐therapy group with respect to body weight (‐23%, ‐19%, and ‐5% in the gastric‐bypass, sleeve‐gastrectomy, and medical‐therapy groups, respectively), triglyceride level (‐40%, ‐29%, and ‐8%), high‐density lipoprotein cholesterol level (32%, 30%, and 7%), use of insulin (‐35%, ‐34%, and ‐13%), and quality‐of‐life measures (general health score increases of 17, 16, and 0.3; scores on the RAND 36‐Item Health Survey ranged from 0 to 100, with higher scores indicating better health) (P<0.05 for all comparisons). No major late surgical complications were reported except for one reoperation. CONCLUSIONS Five‐year outcome data showed that, among patients with type 2 diabetes and a BMI of 27 to 43, bariatric surgery plus intensive medical therapy was more effective than intensive medical therapy alone in decreasing, or in some cases resolving, hyperglycemia. (Funded by Ethicon Endo‐Surgery and others; STAMPEDE ClinicalTrials.gov number, NCT00432809.)

Comparison of Pioglitazone vs Glimepiride on Progression of Coronary Atherosclerosis in Patients With Type 2 Diabetes: The PERISCOPE Randomized Controlled Trial

CONTEXT No antidiabetic regimen has demonstrated the ability to reduce progression of coronary atherosclerosis. Commonly used oral glucose-lowering agents include sulfonylureas, which are insulin secretagogues, and thiazolidinediones, which are insulin sensitizers. OBJECTIVE To compare the effects of an insulin sensitizer, pioglitazone, with an insulin secretagogue, glimepiride, on the progression of coronary atherosclerosis in patients with type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS Double-blind, randomized, multicenter trial at 97 academic and community hospitals in North and South America (enrollment August 2003-March 2006) in 543 patients with coronary disease and type 2 diabetes. INTERVENTIONS A total of 543 patients underwent coronary intravascular ultrasonography and were randomized to receive glimepiride, 1 to 4 mg, or pioglitazone, 15 to 45 mg, for 18 months with titration to maximum dosage, if tolerated. Atherosclerosis progression was measured by repeat intravascular ultrasonography examination in 360 patients at study completion. MAIN OUTCOME MEASURE Change in percent atheroma volume (PAV) from baseline to study completion. RESULTS Least squares mean PAV increased 0.73% (95% CI, 0.33% to 1.12%) with glimepiride and decreased 0.16% (95% CI, -0.57% to 0.25%) with pioglitazone(P = .002). An alternative analysis imputing values for noncompleters based on baseline characteristics showed an increase in PAV of 0.64% (95% CI, 0.23% to 1.05%) for glimepiride and a decrease of 0.06% (-0.47% to 0.35%) for pioglitazone (between-group P = .02). Mean (SD) baseline HbA(1c) levels were 7.4% (1.0%) in both groups and declined during treatment an average 0.55% (95% CI, -0.68% to -0.42%) with pioglitazone and 0.36% (95% CI, -0.48% to -0.24%) with glimepiride (between-group P = .03). In the pioglitazone group, compared with glimepiride, high-density lipoprotein levels increased 5.7 mg/dL (95% CI, 4.4 to 7.0 mg/dL; 16.0%) vs 0.9 mg/dL (95% CI, -0.3 to 2.1 mg/dL; 4.1%), and median triglyceride levels decreased 16.3 mg/dL (95% CI, -27.7 to -11.0 mg/dL; 15.3%) vs an increase of 3.3 mg/dL (95% CI, -10.7 to 11.7 mg/dL; 0.6%) (P < .001 for both comparisons). Median fasting insulin levels decreased with pioglitazone and increased with glimepiride (P < .001). Hypoglycemia was more common in the glimepiride group and edema, fractures, and decreased hemoglobin levels occurred more frequently in the pioglitazone group. CONCLUSION In patients with type 2 diabetes and coronary artery disease, treatment with pioglitazone resulted in a significantly lower rate of progression of coronary atherosclerosis compared with glimepiride. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00225277.

Rosiglitazone Revisited: An Updated Meta-analysis of Risk for Myocardial Infarction and Cardiovascular Mortality

CONTEXT Controversy regarding the effects of rosiglitazone therapy on myocardial infarction (MI) and cardiovascular (CV) mortality persists 3 years after a meta-analysis initially raised concerns about the use of this drug. OBJECTIVE To systematically review the effects of rosiglitazone therapy on MI and mortality (CV and all-cause). DATA SOURCES We searched MEDLINE, the Web site of the Food and Drug Administration, and the GlaxoSmithKline clinical trials registry for trials published through February 2010. STUDY SELECTION The study included all randomized controlled trials of rosiglitazone at least 24 weeks in duration that reported CV adverse events. DATA EXTRACTION Odds ratios (ORs) for MI and mortality were estimated using a fixed-effects meta-analysis of 56 trials, which included 35 531 patients: 19 509 who received rosiglitazone and 16 022 who received control therapy. RESULTS Rosiglitazone therapy significantly increased the risk of MI (OR, 1.28; 95% confidence interval [CI], 1.02-1.63; P = .04) but not CV mortality (OR, 1.03; 95% CI, 0.78-1.36; P = .86). Exclusion of the RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes) trial yielded similar results but with more elevated estimates of the OR for MI (OR, 1.39; 95% CI, 1.02-1.89; P = .04) and CV mortality (OR, 1.46; 95% CI, 0.92-2.33; P = .11). An alternative analysis pooling trials according to allocation ratios allowed inclusion of studies with no events, yielding similar results for MI (OR, 1.28; 95% CI, 1.01-1.62; P = .04) and CV mortality (OR 0.99; 95% CI, 0.75-1.32; P = .96). CONCLUSIONS Eleven years after the introduction of rosiglitazone, the totality of randomized clinical trials continue to demonstrate increased risk for MI although not for CV or all-cause mortality. The current findings suggest an unfavorable benefit to risk ratio for rosiglitazone.

Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease : the STRADIVARIUS randomized controlled trial

CONTEXT Abdominal obesity is associated with metabolic abnormalities and increased risk of atherosclerotic cardiovascular disease. However, no obesity management strategy has demonstrated the ability to slow progression of coronary disease. OBJECTIVE To determine whether weight loss and metabolic effects of the selective cannabinoid type 1 receptor antagonist rimonabant reduces progression of coronary disease in patients with abdominal obesity and the metabolic syndrome. DESIGN, SETTING, AND PATIENTS Randomized, double-blinded, placebo-controlled, 2-group, parallel-group trial (enrollment December 2004-December 2005) comparing rimonabant with placebo in 839 patients at 112 centers in North America, Europe, and Australia. INTERVENTIONS Patients received dietary counseling, were randomized to receive rimonabant (20 mg daily) or matching placebo, and underwent coronary intravascular ultrasonography at baseline (n = 839) and study completion (n = 676). MAIN OUTCOME MEASURES The primary efficacy parameter was change in percent atheroma volume (PAV); the secondary efficacy parameter was change in normalized total atheroma volume (TAV). RESULTS In the rimonabant vs placebo groups, PAV (95% confidence interval [CI]) increased 0.25% (-0.04% to 0.54%) vs 0.51% (0.22% to 0.80%) (P = .22), respectively, and TAV decreased 2.2 mm3 (-4.09 to -0.24) vs an increase of 0.88 mm3 (-1.03 to 2.79) (P = .03). In the rimonabant vs placebo groups, imputing results based on baseline characteristics for patients not completing the trial, PAV increased 0.25% (-0.04% to 0.55%) vs 0.57% (0.29% to 0.84%) (P = .13), and TAV decreased 1.95 mm3 (-3.8 to -0.10) vs an increase of 1.19 mm3 (-0.73 to 3.12) (P = .02). Rimonabant-treated patients had a larger reduction in body weight (4.3 kg [-5.1 to -3.5] vs 0.5 kg [-1.3 to 0.3]) and greater decrease in waist circumference (4.5 cm [-5.4 to -3.7] vs 1.0 cm [-1.9 to -0.2]) (P < .001 for both comparisons). In the rimonabant vs placebo groups, high-density lipoprotein cholesterol levels increased 5.8 mg/dL (4.9 to 6.8) (22.4%) vs 1.8 mg/dL (0.9 to 2.7) (6.9%) (P < .001), and median triglyceride levels decreased 24.8 mg/dL (-35.4 to -17.3) (20.5%) vs 8.9 mg/dL (-14.2 to -1.8) (6.2%) (P < .001). Rimonabant-treated patients had greater decreases in high-sensitivity C-reactive protein (1.3 mg/dL [-1.7 to -1.2] [50.3%] vs 0.9 mg/dL [-1.4 to -0.5] [30.9%]) and less increase in glycated hemoglobin levels (0.11% [0.02% to 0.20%] vs 0.40% [0.31% to 0.49%]) (P < .001 for both comparisons). Psychiatric adverse effects were more common in the rimonabant group (43.4% vs 28.4%, P < .001). CONCLUSIONS After 18 months of treatment, the study failed to show an effect for rimonabant on disease progression for the primary end point (PAV) but showed a favorable effect on the secondary end point (TAV). Determining whether rimonabant is useful in management of coronary disease will require additional imaging and outcomes trials, which are currently under way. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00124332.

Intravascular Ultrasound-Derived Measures of Coronary Atherosclerotic Plaque Burden and Clinical Outcome

OBJECTIVES The aim of this study was to investigate the relationship between intravascular ultrasound (IVUS)-derived measures of atherosclerosis and cardiovascular outcomes. BACKGROUND IVUS has been used in clinical trials to evaluate the effect of medical therapies on coronary atheroma progression. METHODS Coronary plaque progression was evaluated in 4,137 patients in 6 clinical trials that used serial IVUS. The relationship between baseline and change in percent atheroma volume (PAV) and total atheroma volume with incident major adverse cardiovascular events (MACE) was investigated. RESULTS PAV increased by 0.3% (p < 0.001), and 19.9% of subjects experienced MACE (0.9% death, 1.8% myocardial infarction, 18.9% coronary revascularization). Greater baseline PAVs were observed in patients who experienced myocardial infarctions (42.2 +/- 9.6% vs. 38.6 +/- 9.1%, p = 0.001), coronary revascularization (41.2 +/- 9.3% vs. 38.1 +/- 9.0%, p < 0.001), or MACE (41.3 +/- 9.2% vs. 38.0 +/- 9.0%, p < 0.001). Each standard deviation increase in PAV was associated with a 1.32-fold (95% confidence interval: 1.22 to 1.42; p < 0.001) greater likelihood of experiencing a MACE. During follow-up (21.1 +/- 3.7 months), greater increases in PAV, but not total atheroma volume, were observed in subjects who experienced MACE compared with those who did not (0.95 +/- 0.19% vs. 0.46 +/- 0.16%, p < 0.001). Each standard deviation increase in PAV was associated with a 1.20-fold (95% confidence interval: 1.10 to 1.31; p < 0.001) greater risk for MACE. Multivariate analysis revealed that factors associated with MACE included baseline PAV (p < 0.0001), change in PAV (p = 0.002), smoking (p = 0.0002) and hypertension (p = 0.01). CONCLUSIONS A direct relationship was observed between the burden of coronary atherosclerosis, its progression, and adverse cardiovascular events. The relationship between disease progression and outcomes largely reflected the need for coronary revascularization. These data support the use of atherosclerosis imaging with IVUS in the evaluation of novel antiatherosclerotic therapies.

Effect of Diabetes on Progression of Coronary Atherosclerosis and Arterial Remodeling A Pooled Analysis of 5 Intravascular Ultrasound Trials

OBJECTIVES Our goal was to characterize coronary atherosclerosis progression and arterial remodeling in diabetic patients. BACKGROUND The mechanisms that underlie adverse cardiovascular outcomes in diabetic patients have not been well characterized. METHODS A systematic analysis was performed in 2,237 subjects in randomized controlled studies of atherosclerosis progression. The pattern of arterial remodeling, extent of coronary atherosclerosis, and disease progression was compared in subjects with and without diabetes. RESULTS In association with more risk factors, diabetic patients demonstrated a greater percent atheroma volume (PAV) (40.2 +/- 0.9% vs. 37.5 +/- 0.8%, p < 0.0001) and total atheroma volume (TAV) (199.4 +/- 7.9 mm(3) vs. 189.4 +/- 7.1 mm(3), p = 0.03) on multivariate analysis. A stronger correlation was observed between PAV and glycated hemoglobin (r = 0.22, p = 0.0003) than fasting glucose (r = 0.09, p < 0.0001), although the difference just failed to meet statistical significance after controlling for study. Diabetic patients exhibited a smaller lumen (291.1 +/- 104.8 mm(3) vs. 306.5 +/- 108.2 mm(3), p = 0.005) but no difference in external elastic membrane (494.9 +/- 166.9 mm(3) vs. 498.8 +/- 167.2 mm(3), p = 0.61) volumes. More rapid progression of PAV (0.6 +/- 0.4% vs. 0.05 +/- 0.3%, p = 0.0001) and TAV (-0.6 +/- 2.5 mm(3) vs. -2.7 +/- 2.4 mm(3), p = 0.03) was observed in diabetic patients on multivariate analysis. Smaller external elastic membrane (482.5 +/- 160.7 mm(3) vs. 519.9 +/- 166.9 mm(3), p = 0.03) and lumen (276.0 +/- 100.3 mm(3) vs. 310.1 +/- 105.6 mm(3), p = 0.001) volumes were observed in diabetic patients treated with insulin despite the presence of a similar TAV (206.5 +/- 88.6 mm(3) vs. 209.9 +/- 90.2 mm(3), p = 0.84). Intensive low-density lipoprotein cholesterol lowering in patients improved the rate of plaque progression, but only to the level observed in nondiabetic patients with suboptimal lipid control. CONCLUSIONS Diabetes is accompanied by more extensive atherosclerosis and inadequate compensatory remodeling. Accelerated plaque progression, despite use of medical therapies, supports the need to develop new antiatherosclerotic strategies in diabetic patients.

Metabolic Effects of Bariatric Surgery in Patients With Moderate Obesity and Type 2 Diabetes: Analysis of a randomized control trial comparing surgery with intensive medical treatment

OBJECTIVE To evaluate the effects of two bariatric procedures versus intensive medical therapy (IMT) on β-cell function and body composition. RESEARCH DESIGN AND METHODS This was a prospective, randomized, controlled trial of 60 subjects with uncontrolled type 2 diabetes (HbA1c 9.7 ± 1%) and moderate obesity (BMI 36 ± 2 kg/m2) randomized to IMT alone, IMT plus Roux-en-Y gastric bypass, or IMT plus sleeve gastrectomy. Assessment of β-cell function (mixed-meal tolerance testing) and body composition was performed at baseline and 12 and 24 months. RESULTS Glycemic control improved in all three groups at 24 months (N = 54), with a mean HbA1c of 6.7 ± 1.2% for gastric bypass, 7.1 ± 0.8% for sleeve gastrectomy, and 8.4 ± 2.3% for IMT (P < 0.05 for each surgical group versus IMT). Reduction in body fat was similar for both surgery groups, with greater absolute reduction in truncal fat in gastric bypass versus sleeve gastrectomy (−16 vs. −10%; P = 0.04). Insulin sensitivity increased significantly from baseline in gastric bypass (2.7-fold; P = 0.004) and did not change in sleeve gastrectomy or IMT. β-Cell function (oral disposition index) increased 5.8-fold in gastric bypass from baseline, was markedly greater than IMT (P = 0.001), and was not different between sleeve gastrectomy versus IMT (P = 0.30). At 24 months, β-cell function inversely correlated with truncal fat and prandial free fatty acid levels. CONCLUSIONS Bariatric surgery provides durable glycemic control compared with intensive medical therapy at 2 years. Despite similar weight loss as sleeve gastrectomy, gastric bypass uniquely restores pancreatic β-cell function and reduces truncal fat, thus reversing the core defects in diabetes.

Relationship Between Activated Clotting Time and Ischemic or Hemorrhagic Complications Analysis of 4 Recent Randomized Clinical Trials of Percutaneous Coronary Intervention

Background—Unfractionated heparin (UFH) is the most widely used antithrombin during percutaneous coronary intervention (PCI). Despite significant pharmacological and mechanical advancements in PCI, uncertainty remains about the optimal activated clotting time (ACT) for prevention of ischemic or hemorrhagic complications. Methods and Results—We analyzed the outcome of all UFH-treated patients enrolled in 4 large, contemporary PCI trials with independent adjudication of ischemic and bleeding events. Of 9974 eligible patients, maximum ACT was available in 8369 (84%). The median ACT was 297 seconds (interquartile range 256 to 348 seconds). The incidence of death, myocardial infarction, or revascularization at 48 hours, by ACT quartile, was 6.2%, 6.8%, 6.0%, and 5.7%, respectively (P=0.40 for trend). Covariate-adjusted rate of ischemic complications was not correlated with maximal procedural ACT (continuous value, P=0.29). Higher doses of UFH (>5000 U, or up to 90 U/kg) were independently associated with higher rates of events. The incidence of major or minor bleeding at 48 hours, by ACT quartile, was 2.9%, 3.5%, 3.8%, and 4.0%, respectively (P=0.04 for trend). In a multivariable logistic model with a spline transformation for ACT, there was a linear increase in risk of bleeding as the ACT approached 365 seconds (P=0.01), which leveled off beyond that value. Increasing UFH weight-indexed dose was independently associated with higher bleeding rates (OR 1.04 [1.02 to 1.07] for each 10 U/kg, P=0.001). Conclusions—In patients undergoing PCI with frequent stent and potent platelet inhibition use, ACT does not correlate with ischemic complications and has a modest association with bleeding complications, driven mainly by minor bleeding. Lower values do not appear to compromise efficacy while increasing safety.

Determinants of arterial wall remodeling during lipid-lowering therapy : Serial intravascular ultrasound observations from the reversal of atherosclerosis with aggressive lipid lowering therapy (REVERSAL) trial

Background— Coronary plaque progression and instability are associated with expansive remodeling of the arterial wall. However, the remodeling response during plaque-stabilizing therapy and its relationship to markers of lipid metabolism and inflammation are incompletely understood. Methods and Results— Serial intravascular ultrasound (IVUS) data from the Reversal of Atherosclerosis with Aggressive Lipid Lowering Therapy (REVERSAL) trial were obtained during 18 months of intensive versus moderate lipid-lowering therapy. In a subgroup of 210 patients, focal coronary lesions with mild luminal narrowing were identified. Lumen area, external elastic membrane (EEM) area, and plaque area were determined at the lesion and proximal reference sites at baseline and during follow-up. The remodeling ratio (RR) was calculated by dividing the lesion EEM area by the reference EEM area. The relationship between the change in remodeling, change in plaque area, lipid profile, and inflammatory markers was examined. At the lesion site, a progression in plaque area (8.9±25.7%) and a decrease in the RR (−3.0±11.2%) occurred during follow-up. In multivariable analyses, the percentage change in plaque area (P<0.0001), baseline RR (P<0.0001), baseline lesion lumen area (0.019), logarithmic value of the change in high-sensitivity C-reactive protein (P=0.027), and hypertension at baseline (P=0.014) showed a significant, direct relation with the RR at follow-up. Lesion location in the right coronary artery (P=0.006), percentage change in triglyceride levels (P=0.049), and age (P=0.037) demonstrated a significant, inverse relation with the RR at follow-up. Changes in LDL cholesterol, HDL cholesterol, and treatment group demonstrated no significant associations. Conclusions— Constrictive remodeling of the arterial wall was observed during plaque-stabilizing therapy with statin medications and appears related to their antiinflammatory effects.