Long-Term Outcomes of Medical Management vs Bariatric Surgery in Type 2 Diabetes.

Importance: Randomized clinical trials of bariatric surgery have been limited in size, type of surgical procedure, and follow-up duration. Objective: To determine long-term glycemic control and safety of bariatric surgery compared with medical/lifestyle management of type 2 diabetes. Design, Setting, and Participants: ARMMS-T2D (Alliance of Randomized Trials of Medicine vs Metabolic Surgery in Type 2 Diabetes) is a pooled analysis from 4 US single-center randomized trials conducted between May 2007 and August 2013, with observational follow-up through July 2022. Intervention: Participants were originally randomized to undergo either medical/lifestyle management or 1 of the following 3 bariatric surgical procedures: Roux-en-Y gastric bypass, sleeve gastrectomy, or adjustable gastric banding. Main Outcome and Measures: The primary outcome was change in hemoglobin A1c (HbA1c) from baseline to 7 years for all participants. Data are reported for up to 12 years. Results: A total of 262 of 305 eligible participants (86%) enrolled in long-term follow-up for this pooled analysis. The mean (SD) age of participants was 49.9 (8.3) years, mean (SD) body mass index was 36.4 (3.5), 68.3% were women, 31% were Black, and 67.2% were White. During follow-up, 25% of participants randomized to undergo medical/lifestyle management underwent bariatric surgery. The median follow-up was 11 years. At 7 years, HbA1c decreased by 0.2% (95% CI, -0.5% to 0.2%), from a baseline of 8.2%, in the medical/lifestyle group and by 1.6% (95% CI, -1.8% to -1.3%), from a baseline of 8.7%, in the bariatric surgery group. The between-group difference was -1.4% (95% CI, -1.8% to -1.0%; P < .001) at 7 years and -1.1% (95% CI, -1.7% to -0.5%; P = .002) at 12 years. Fewer antidiabetes medications were used in the bariatric surgery group. Diabetes remission was greater after bariatric surgery (6.2% in the medical/lifestyle group vs 18.2% in the bariatric surgery group; P = .02) at 7 years and at 12 years (0.0% in the medical/lifestyle group vs 12.7% in the bariatric surgery group; P < .001). There were 4 deaths (2.2%), 2 in each group, and no differences in major cardiovascular adverse events. Anemia, fractures, and gastrointestinal adverse events were more common after bariatric surgery. Conclusion and Relevance: After 7 to 12 years of follow-up, individuals originally randomized to undergo bariatric surgery compared with medical/lifestyle intervention had superior glycemic control with less diabetes medication use and higher rates of diabetes remission. Trial Registration: ClinicalTrials.gov Identifier: NCT02328599.

Metabolic labeling unveils alterations in the turnover of HDL-associated proteins during diabetes progression in mice.

Several aspects of diabetes pathophysiology and complications result from hyperglycemia-induced alterations in the structure and function of plasma proteins. Furthermore, insulin has a significant influence on protein metabolism by affecting both the synthesis and degradation of proteins in various tissues. To understand the role of progressive hyperglycemia on plasma proteins, in this study, we measured the turnover rates of high-density lipoprotein (HDL)-associated proteins in control (chow diet), prediabetic [a high-fat diet (HFD) for 8 wk] or diabetic [HFD for 8 wk with low-dose streptozotocin (HFD + STZ) in weeks 5-8 of HFD] C57BL/6J mice using heavy water (2H2O)-based metabolic labeling approach. Compared with control mice, HFD and HFD + STZ mice showed elevations of fasting plasma glucose levels in the prediabetic and diabetic range, respectively. Furthermore, the HFD and HFD + STZ mice showed increased hepatic triglyceride (TG) levels, total plasma cholesterol, and plasma TGs. The kinetics of 40 proteins were quantified using the proteome dynamics method, which revealed an increase in the fractional synthesis rate (FSR) of HDL-associated proteins in the prediabetic mice compared with control mice, and a decrease in FSR in the diabetic mice. The pathway analysis revealed that proteins with altered turnover rates were involved in acute-phase response, lipid metabolism, and coagulation. In conclusion, prediabetes and diabetes have distinct effects on the turnover rates of HDL proteins. These findings suggest that an early dysregulation of the HDL proteome dynamics can provide mechanistic insights into the changes in protein levels in these conditions.NEW & NOTEWORTHY This study is the first to examine the role of gradual hyperglycemia during diabetes disease progression on HDL-associated protein dynamics in the prediabetes and diabetic mice. Our results show that the fractional synthesis rate of HDL-associated proteins increased in the prediabetic mice whereas it decreased in the diabetic mice compared with control mice. These kinetic changes can help to elucidate the mechanism of altered protein levels and HDL dysfunction during diabetes disease progression.

Vitamin D Supplementation and Prevention of Type 2 Diabetes.

BACKGROUND: Observational studies support an association between a low blood 25-hydroxyvitamin D level and the risk of type 2 diabetes. However, whether vitamin D supplementation lowers the risk of diabetes is unknown. METHODS: We randomly assigned adults who met at least two of three glycemic criteria for prediabetes (fasting plasma glucose level, 100 to 125 mg per deciliter; plasma glucose level 2 hours after a 75-g oral glucose load, 140 to 199 mg per deciliter; and glycated hemoglobin level, 5.7 to 6.4%) and no diagnostic criteria for diabetes to receive 4000 IU per day of vitamin D3 or placebo, regardless of the baseline serum 25-hydroxyvitamin D level. The primary outcome in this time-to-event analysis was new-onset diabetes, and the trial design was event-driven, with a target number of diabetes events of 508. RESULTS: A total of 2423 participants underwent randomization (1211 to the vitamin D group and 1212 to the placebo group). By month 24, the mean serum 25-hydroxyvitamin D level in the vitamin D group was 54.3 ng per milliliter (from 27.7 ng per milliliter at baseline), as compared with 28.8 ng per milliliter in the placebo group (from 28.2 ng per milliliter at baseline). After a median follow-up of 2.5 years, the primary outcome of diabetes occurred in 293 participants in the vitamin D group and 323 in the placebo group (9.39 and 10.66 events per 100 person-years, respectively). The hazard ratio for vitamin D as compared with placebo was 0.88 (95% confidence interval, 0.75 to 1.04; P = 0.12). The incidence of adverse events did not differ significantly between the two groups. CONCLUSIONS: Among persons at high risk for type 2 diabetes not selected for vitamin D insufficiency, vitamin D3 supplementation at a dose of 4000 IU per day did not result in a significantly lower risk of diabetes than placebo. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; D2d ClinicalTrials.gov number, NCT01942694.).

Alliance of Randomized Trials of Medicine vs Metabolic Surgery in Type 2 Diabetes (ARMMS-T2D): Study rationale, design, and methods.

AIMS: Long-term data from randomized clinical trials comparing metabolic (bariatric) surgery versus a medical/lifestyle intervention for treatment of patients with obesity/overweight and type 2 diabetes (T2D) are lacking. The Alliance of Randomized Trials of Medicine vs Metabolic Surgery in Type 2 Diabetes (ARMMS-T2D) is a consortium of four randomized trials designed to compare long-term efficacy and safety of surgery versus medical/lifestyle therapy on diabetes control and clinical outcomes. MATERIALS AND METHODS: Patients with T2D and body mass index (BMI) of 27-45 kg/m2 who were previously randomized to metabolic surgery (Roux-en-Y gastric bypass, adjustable gastric band, or sleeve gastrectomy) versus medical/lifestyle intervention in the STAMPEDE, SLIMM-T2D, TRIABETES, or CROSSROADS trials have been enrolled in ARMMS-T2D for observational follow-up. The primary outcome is change in glycated haemoglobin after a minimum 7 years of follow-up, with additional analyses to determine rates of diabetes remission and relapse, as well as cardiovascular and renal endpoints. RESULTS: In total, 302 patients (192 surgical, 110 medical/lifestyle) previously randomized in the four parent studies were eligible for participation in the ARMMS-T2D observational study. Participant demographics were 71% white, 27% African-American and 68% female. At baseline: age, 50 ± 8 years; BMI, 36.5 ± 3.5 kg/m2 ; duration of diabetes, 8.8 ± 5.6 years; glycated haemoglobin, 8.6% ± 1.6%; and fasting glucose, 168 ± 64 mg/dl. More than 35% of patients had a BMI <35 kg/m2 . CONCLUSIONS: ARMMS-T2D will provide the largest body of long-term, level 1 evidence to inform clinical decision-making regarding the comparative durability, efficacy and safety of metabolic surgery relative to a medical/lifestyle intervention among patients with T2D, including those with milder class I obesity or mere overweight.

Prevalence and Clinical Determinants of Obesity in Adults With Type 1 Diabetes Mellitus: A Single-Center Retrospective Observational Study.

OBJECTIVE: To determine the prevalence of obesity and assess the cardiometabolic risk profile and treatments associated with obesity management in the type 1 diabetes mellitus adult population. METHODS: We reviewed the records of all patients with type 1 diabetes mellitus seen in our institution's outpatient endocrinology clinic between 2015 and 2018. We stratified the patients into 4 weight categories on the basis of body mass index (BMI) (normal, overweight, obesity class I, and combined obesity class II and III) and evaluated their associated clinical characteristics and relevant medications. RESULTS: Of 451 patients, 64% had a BMI of >25 kg/m2, and 25% had a BMI of ≥30 kg/m2. Over 40% of patients with a BMI of >30 kg/m2 had a history of cardiovascular disease. The off-label use of the glucagon-like peptide 1 receptor agonist was 12% and the sodium glucose cotransporter 2 inhibitor use was 5% in those with obesity. Only 2 patients were prescribed phentermine and 3 had undergone bariatric surgery. Hemoglobin A1C and low-density lipoprotein did not significantly differ between the normal weight and obesity groups. The obesity groups had significantly higher levels of median triglycerides and lower high-density lipoprotein than the normal weight group. CONCLUSION: Obesity was prevalent in a population of patients with type 1 diabetes mellitus seen in a specialty clinic. Those with obesity had a higher prevalence of cardiovascular disease than their normal weight counterparts. The use of weight loss medications was scarce. Studies exploring the safety and efficacy of obesity-targeted therapy in the type 1 diabetes mellitus population are needed.

American Association of Clinical Endocrinology Clinical Practice Guideline for the Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Primary Care and Endocrinology Clinical Settings: Co-Sponsored by the American Association for the Study of Liver Diseases (AASLD).

OBJECTIVE: To provide evidence-based recommendations regarding the diagnosis and management of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) to endocrinologists, primary care clinicians, health care professionals, and other stakeholders. METHODS: The American Association of Clinical Endocrinology conducted literature searches for relevant articles published from January 1, 2010, to November 15, 2021. A task force of medical experts developed evidence-based guideline recommendations based on a review of clinical evidence, expertise, and informal consensus, according to established American Association of Clinical Endocrinology protocol for guideline development. RECOMMENDATION SUMMARY: This guideline includes 34 evidence-based clinical practice recommendations for the diagnosis and management of persons with NAFLD and/or NASH and contains 385 citations that inform the evidence base. CONCLUSION: NAFLD is a major public health problem that will only worsen in the future, as it is closely linked to the epidemics of obesity and type 2 diabetes mellitus. Given this link, endocrinologists and primary care physicians are in an ideal position to identify persons at risk on to prevent the development of cirrhosis and comorbidities. While no U.S. Food and Drug Administration-approved medications to treat NAFLD are currently available, management can include lifestyle changes that promote an energy deficit leading to weight loss; consideration of weight loss medications, particularly glucagon-like peptide-1 receptor agonists; and bariatric surgery, for persons who have obesity, as well as some diabetes medications, such as pioglitazone and glucagon-like peptide-1 receptor agonists, for those with type 2 diabetes mellitus and NASH. Management should also promote cardiometabolic health and reduce the increased cardiovascular risk associated with this complex disease.

Patient-reported Outcomes After Metabolic Surgery Versus Medical Therapy for Diabetes: Insights From the STAMPEDE Randomized Trial.

OBJECTIVE: The aim of this study was to investigate the long-term effects of medical and surgical treatments of type 2 diabetes mellitus (T2DM) on patient-reported outcomes (PROs). BACKGROUND: Robust data on PROs from randomized trials comparing medical and surgical treatments for T2DM are lacking. METHODS: The Surgical Treatment And Medications Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial showed that 5 years after randomization, Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) were superior to intensive medical therapy (IMT) alone in achieving glycemic control in patients with T2DM and obesity. A subset of 104 patients participating in the STAMPEDE trial were administered two generic health-related quality of life (QoL) questionnaires (RAND-36 and EQ-5D-3L) and a diabetes-specific instrument at baseline, and then on an annual basis up to 5 years after randomization. RESULTS: On longitudinal analysis, RYGB and SG significantly improved the domains of physical functioning, general health perception, energy/fatigue, and diabetes-related QoL compared with IMT group. In the IMT group, none of the QoL components in the generic questionnaires improved significantly from baseline. No significant long-term differences were observed among the study groups in measures of psychological and social aspects of QoL. On multivariable analysis, independent factors associated with improved general health perception at long-term included baseline general health (P < 0.001), insulin independence at 5 years (P = 0.005), RYGB versus IMT (P = 0.005), and SG versus IMT (P = 0.034). Favorable changes following RYGB and SG were comparable. CONCLUSIONS: In patients with T2DM, metabolic surgery is associated with long-term favorable changes in certain PROs compared with IMT, mainly on physical health and diabetes-related domains. Psychosocial well-being warrants greater attention after metabolic surgery.

Bariatric Surgery versus Intensive Medical Therapy for Diabetes - 5-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 .).

A Review of the Current Evidence: Impact of Metabolic Surgery on Diabetes Outcomes and Obesity-Associated Macrovascular Complications.

PURPOSE OF REVIEW: Type 2 diabetes (T2D) and obesity are comorbidities that generally progress with time even when non-invasive therapies are prescribed. Indeed, weight loss that is achieved with behavioral modification alone is generally inconsistent and often short-lived. In contrast, although patients do experience weight regain with metabolic surgery, they still benefit from a significant net decrease in weight. As a result, T2D remission can be achieved in up to 60% of patients within 2 years after surgery. However, it is unknown if the positive effects of metabolic surgery extend to macrovascular disease risk reduction. RECENT FINDINGS: As noted in four randomized controlled trials (RCTs), Roux-en-Y gastric bypass (RYGB) facilitates partial remission of T2D in about 30% of volunteers 5 years after surgery. Of the four RCTs, only one investigated the effects of sleeve gastrectomy (SG) at 5 years; that study found that the rate of partial relapse was slightly lower with SG (23%). However, observational studies indicate that the gap between RYGB and SG may be larger than that observed in RCTs. In contrast, the rate of full remission is noted infrequently 5 years after SG or RYGB. Metabolic surgery also mitigates macrovascular disease risk as indicated by multiple observational studies. The effects of metabolic surgery on cardiometabolic parameters are clinically meaningful. The weight loss that is facilitated by metabolic surgery reduces the metabolic and inflammatory stress caused by T2D and obesity. In turn, metabolic surgery likely mitigates macrovascular disease risk. Additional evidence from RCTs is needed to substantiate the effects of metabolic surgery on macrovascular disease risk.

IMPACT OF WEIGHT LOSS TRAJECTORY FOLLOWING RANDOMIZATION TO BARIATRIC SURGERY ON LONG-TERM DIABETES GLYCEMIC AND CARDIOMETABOLIC PARAMETERS.

Objective: It is unclear whether acute weight loss or the chronic trajectory of weight loss after bariatric surgery is associated with long-term type 2 diabetes mellitus (T2DM) glycemic improvement. This ancillary study of the Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial aimed to answer this question. Methods: In STAMPEDE, 150 patients with T2DM were randomized to bariatric surgery, and 96 had 5-year follow-up. Data post-Roux-en-Y gastric bypass (RYGB, n = 49) and sleeve gastrectomy (SG, n = 47) were analyzed. We defined percent weight loss in the first year as negative percent decrease from baseline weight to lowest weight in the first year. Percent weight regain was positive percent change from lowest weight in the first year to fifth year. Weight change was then correlated with cardiometabolic (CM) and glycemic outcomes at 5 years using Spearman rank correlations and multivariate analysis. Results: In both RYGB and SG, less weight loss in the first year positively correlated with higher 5-year glycated hemoglobin (HbA1c) (RYGB, ß = +0.13; P<.001 and SG, ß = 0.14; P<.001). In SG, greater weight regain from nadir positively correlated with higher HbA1c (ß = 0.06; P = .02), but not in RYGB. Reduced first-year weight loss was also correlated with increased 5-year triglycerides (ß = 1.81; P = .01), but not systolic blood pressure. Weight regain did not correlate with CM outcomes. Conclusion: Acute weight loss may be more important for T2DM glycemic control following both RYGB and SG as compared with weight regain. Clinicians should aim to assist patients with achieving maximal weight loss in the first year post-op to maximize long-term health of patients. Abbreviations: BMI = body mass index; HbA1c = glycated hemoglobin; RYGB = Roux-en-Y gastric bypass; SBP = systolic blood pressure; SG = sleeve gastrectomy; STAMPEDE = Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently; T2DM = type 2 diabetes mellitus; TG = triglyceride.

INCREASED BONE TURNOVER IN TYPE 2 DIABETES PATIENTS RANDOMIZED TO BARIATRIC SURGERY VERSUS MEDICAL THERAPY AT 5 YEARS.

OBJECTIVE: The aim of our study was to determine the 5-year outcomes of bariatric surgery versus intensive medical therapy on bone turnover in patients with type 2 diabetes mellitus (T2DM) from the STAMPEDE trial. METHODS: This was an ancillary investigation of a 5-year randomized control trial at a single tertiary care center involving 95 patients aged 48.5 ± 8 years with obesity (body mass index [BMI], 36.5 ± 3.6 kg/m2) and uncontrolled T2DM (glycated hemoglobin 9.3 ± 1.6% [78 mmol/mol]). Patients were randomized to intensive medical therapy (IMT; n = 25), Roux-en-Y gastric bypass (RYGB; n = 37), or sleeve gastrectomy (SG; n = 33) for diabetes treatment. Bone formation marker osteocalcin (OC), bone resorption marker serum C-telopeptide of type 1 collagen (CTX), and intact parathyroid hormone (PTH) were assessed at baseline and 5 years postintervention. Analysis with key clinical parameters and outcomes (i.e., age, menopausal status, gender, weight loss) was performed. RESULTS: Percent change in CTX at 5 years increased in both surgical groups, by 137 ± 108% in RYGB ( P<.001) and 61.1 ± 90% in SG ( P<.001) compared to 29.8 ± 93% in IMT ( P = .12). OC also increased from baseline in the surgical cohorts, by 138 ± 19% in RYGB ( P<.001) and 71 ± 69% in SG ( P<.001) compared to 43.8 ± 121.1% in IMT ( P = .83). Increases in both CTX and OC correlated linearly with increases in PTH levels in RYGB patients ( P<.001). Increase in CTX correlated with decreased BMI in SG patients ( P = .039). CONCLUSION: In patients with T2DM, bone turnover remains chronically elevated at 5 years following RYGB, and to a lesser extent in SG patients. ABBREVIATIONS: BMI = body mass index; BTM = bone turnover marker; CTX = C-telopeptide of type 1 collagen; HbA1c = glycated hemoglobin; IMT = intensive medical therapy; OC = osteocalcin; PPI = proton-pump inhibitor; PTH = parathyroid hormone; RYGB = Roux-en-Y gastric bypass; SG = sleeve gastrectomy; T2DM = type 2 diabetes mellitus; TZD = thiazolidinedione.

Cardiovascular and Renal Outcomes of Newer Anti-Diabetic Medications in High-Risk Patients.

PURPOSE OF REVIEW: We review the cardiovascular and renal outcomes and safety of newer anti-diabetic medications in high-risk patients. We examine the outcomes of the IRIS, EMPA-REG OUTCOME, CANVAS, LEADER, SAVOR-TIMI 53, and EXAMINE trials demonstrating the cardiovascular and renal benefits of thiazolidinediones, SGLT2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors. RECENT FINDINGS: Diabetes mellitus is a leading risk factor for cardiovascular disease with rising prevalence and disease burden. The microvascular and macrovascular complications of diabetes are well-recognized and include increased risk of cardiovascular disease, myocardial infarction, and stroke. Newer diabetes medications have demonstrated significant cerebrovascular, cardiovascular, renal, and mortality benefits in high risk patients with diabetes. In addition to their glucose-lowering effects, the thiazolidinedione pioglitazone, SGLT2 inhibitors, GLP-1 agonist, and DPP-4 inhibitors have demonstrated significant cerebrovascular, cardiovascular, renal, and mortality effects. The outcomes and safety data of newer diabetes medications from recent trials demonstrate cardiovascular and mortality effects with significant implications for clinical practice.

Circulating soluble RAGE isoforms are attenuated in obese, impaired-glucose-tolerant individuals and are associated with the development of type 2 diabetes.

The soluble receptor for advanced glycation end products (sRAGE) may be protective against inflammation associated with obesity and type 2 diabetes (T2DM). The aim of this study was to determine the distribution of sRAGE isoforms and whether sRAGE isoforms are associated with risk of T2DM development in subjects spanning the glucose tolerance continuum. In this retrospective analysis, circulating total sRAGE and endogenous secretory RAGE (esRAGE) were quantified via ELISA, and cleaved RAGE (cRAGE) was calculated in 274 individuals stratified by glucose tolerance status (GTS) and obesity. Group differences were probed by ANOVA, and multivariate ordinal logistic regression was used to test the association between sRAGE isoform concentrations and the proportional odds of developing diabetes, vs. normal glucose tolerance (NGT) or impaired glucose tolerance (IGT). When stratified by GTS, total sRAGE, cRAGE, and esRAGE were all lower with IGT and T2DM, while the ratio of cRAGE to esRAGE (cRAGE:esRAGE) was only lower (P < 0.01) with T2DM compared with NGT. When stratified by GTS and obesity, cRAGE:esRAGE was higher with obesity and lower with IGT (P < 0.0001) compared with lean, NGT. In ordinal logistic regression models, greater total sRAGE (odds ratio, 0.91; P < 0.01) and cRAGE (odds ratio, 0.84; P < 0.01) were associated with lower proportional odds of developing T2DM. Reduced values of sRAGE isoforms observed with both obesity and IGT are independently associated with greater proportional odds of developing T2DM. The mechanisms by which each respective isoform contributes to obesity and insulin resistance may reveal novel treatment strategies for diabetes.

Individualized Metabolic Surgery Score: Procedure Selection Based on Diabetes Severity.

OBJECTIVE: To construct and validate a scoring system for evidence-based selection of bariatric and metabolic surgery procedures according to severity of type 2 diabetes (T2DM). BACKGROUND: Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) account for >95% of bariatric procedures in United States in patients with T2DM. To date, there is no validated model to guide procedure selection based on long-term glucose control in patients with T2DM. METHODS: A total of 659 patients with T2DM who underwent RYGB and SG at an academic center in the United States and had a minimum 5-year follow-up (2005-2011) were analyzed to generate the model. The validation dataset consisted of 241 patients from an academic center in Spain where similar criteria were applied. RESULTS: At median postoperative follow-up of 7 years (range 5-12), diabetes remission (HbA1C <6.5% off medications) was observed in 49% after RYGB and 28% after SG (P < 0.001). Four independent predictors of long-term remission including preoperative duration of T2DM (P < 0.0001), preoperative number of diabetes medications (P < 0.0001), insulin use (P = 0.002), and glycemic control (HbA1C < 7%) (P = 0.002) were used to develop the Individualized Metabolic Surgery (IMS) score using a nomogram. Patients were then categorized into 3 stages of diabetes severity. In mild T2DM (IMS score ≤25), both procedures significantly improved T2DM. In severe T2DM (IMS score >95), when clinical features suggest limited functional ß-cell reserve, both procedures had similarly low efficacy for diabetes remission. There was an intermediate group, however, in which RYGB was significantly more effective than SG, likely related to its more pronounced neurohormonal effects. Findings were externally validated and procedure recommendations for each severity stage were provided. CONCLUSIONS: This is the largest reported cohort (n = 900) with long-term postoperative glycemic follow-up, which, for the first time, categorizes T2DM into 3 validated severity stages for evidence-based procedure selection.

Bariatric surgery versus intensive medical therapy for diabetes--3-year outcomes.

BACKGROUND: In short-term randomized trials (duration, 1 to 2 years), bariatric surgery has been associated with improvement in type 2 diabetes mellitus. METHODS: We assessed outcomes 3 years after the randomization of 150 obese patients with uncontrolled type 2 diabetes to receive either intensive medical therapy alone or intensive medical therapy plus Roux-en-Y gastric bypass or sleeve gastrectomy. The primary end point was a glycated hemoglobin level of 6.0% or less. RESULTS: The mean (±SD) age of the patients at baseline was 48±8 years, 68% were women, the mean baseline glycated hemoglobin level was 9.3±1.5%, and the mean baseline body-mass index (the weight in kilograms divided by the square of the height in meters) was 36.0±3.5. A total of 91% of the patients completed 36 months of follow-up. At 3 years, the criterion for the primary end point was met by 5% of the patients in the medical-therapy group, as compared with 38% of those in the gastric-bypass group (P<0.001) and 24% of those in the sleeve-gastrectomy group (P=0.01). The use of glucose-lowering medications, including insulin, was lower in the surgical groups than in the medical-therapy group. Patients in the surgical groups had greater mean percentage reductions in weight from baseline, with reductions of 24.5±9.1% in the gastric-bypass group and 21.1±8.9% in the sleeve-gastrectomy group, as compared with a reduction of 4.2±8.3% in the medical-therapy group (P<0.001 for both comparisons). Quality-of-life measures were significantly better in the two surgical groups than in the medical-therapy group. There were no major late surgical complications. CONCLUSIONS: Among obese patients with uncontrolled type 2 diabetes, 3 years of intensive medical therapy plus bariatric surgery resulted in glycemic control in significantly more patients than did medical therapy alone. Analyses of secondary end points, including body weight, use of glucose-lowering medications, and quality of life, also showed favorable results at 3 years in the surgical groups, as compared with the group receiving medical therapy alone. (Funded by Ethicon and others; STAMPEDE ClinicalTrials.gov number, NCT00432809.).

Assessing the real-world effect of laparoscopic bariatric surgery on the management of obesity-related comorbidities: A retrospective matched cohort study using a US Claims Database.

AIMS: To evaluate the real-world effect of laparoscopic bariatric surgery, comprising adjustable gastric banding (LAGB), laparoscopic Roux-en-Y gastric bypass (LRYGB) and laparoscopic sleeve gastrectomy (LSG), on the management of obesity-related comorbidities. METHODS: Patients who underwent laparoscopic bariatric surgeries between 2006 and 2013 were identified from the Optum Clinformatics administrative claims database. Those surgical patients were matched to medically managed patients (controls) on selected patient characteristics. Comorbidity management was assessed every 6 months up to 5 years after the surgery or an assigned index date for control subjects (follow-up), by evaluating the number of medication classes used to treat type 2 diabetes, hypertension and dyslipidaemia, as well as by evaluating the percentages of patients free of medications for these comorbidities. RESULTS: Patients who underwent LAGB (n = 4208, mean age 46.3 years), LRYGB (n = 4308, mean age 46.4 years) or LSG (n = 545, mean age 45.1 years) and patients in the control cohort (n = 9061, mean age 46.4 years) were similar in age, and the majority of patients in each study cohort were female (69.4%-75.8%). Compared with control subjects, patients who had laparoscopic bariatric surgery had significantly lower medication usage for obesity-related comorbidities, a trend that was evident at 6 months and that continued for up to 5 years of follow-up. Sub-analyses of changes in selected laboratory test values over follow-up corroborated the primary analyses. CONCLUSIONS: Patients who had laparoscopic bariatric surgery used fewer medications for type 2 diabetes, hypertension and dyslipidaemia and had significant improvement in cardiometabolic risk factors for up to 5 years of follow-up compared with matched control subjects.

LIMITED CARBOHYDRATE REFEEDING INSTRUCTION FOR LONG-TERM WEIGHT MAINTENANCE FOLLOWING A KETOGENIC, VERY-LOW-CALORIE MEAL PLAN.

OBJECTIVE: Weight-loss maintenance following very-low-calorie meal plans is poorly studied. This report describes weight-loss efficacy and predictors of weight-loss maintenance of a ketogenic, very-low-calorie meal plan (protein-sparing modified fast, PSMF) in people with obesity. METHODS: A total of 127 consecutive adults in the PSMF meal plan (27.2 ± 19.5 weeks) and 48 adults on a conventional, hypocaloric meal plan (23.6 ± 20.8 weeks) were retrospectively studied for percent weight change from baseline to end of intervention and at 6, 12, and 24 months postintervention. Baseline factors were analyzed for correlations with weight-loss maintenance. RESULTS: At end of intervention, weight loss from baseline was greater for the PSMF group compared to the conventional intervention group (-12.4% vs. -2.6%; P<.001) but was similar between groups by 12 months postintervention. PSMF subjects who attended follow-up visits to receive instruction on gradual and limited carbohydrate refeeding after ketosis saw significant weight loss at the end of PSMF compared to those who did not follow-up to receive instruction (-17.5% vs. -8.0%; P<.001) and maintained greater weight loss through 12 months post-PSMF (-9.8% vs. -1.5%; P<.001). Higher baseline body mass index correlated with less weight loss at 12 months post-PSMF (P = .035). CONCLUSION: PSMF results in effective short-term weight loss of more than 5% from baseline weight. Follow-up for limited carbohydrate refeeding instruction is important for weight-loss maintenance up to 2 years after initial weight loss. ABBREVIATIONS: BMI = body mass index; PSMF = protein-sparing modified fast.

The therapeutic efficacy of intensive medical therapy in ameliorating high-density lipoprotein dysfunction in subjects with type two diabetes.

BACKGROUND: To determine whether 12 months of intensive medical therapy (IMT) improves HDL functionality parameters in subjects with type II diabetes (T2D). METHODS: Retrospective, randomized, and controlled 12-month IMT intervention trial that enrolled 13-subjects with T2D (age 51- years, fasting glucose 147 mg/dL, body mass index [BMI] 36.5 kg/m(2)) and nine healthy control (46-years, fasting glucose 90 mg/dL, BMI 26.5 kg/m2). Subjects with T2D underwent IMT and HDL functionality measures (pro-inflammatory index of high-density lipoprotein (pHDL)), paraoxonase one (PON1), ceruloplasmin (Cp), and myeloperoxidase (MPO) activity were performed on samples at baseline and at 12-months following IMT. RESULTS: At baseline, pHDL index was significantly higher in subjects with T2D (p < 0.001) and apolipoprotein A-1 levels were significantly lower (p = 0.013) vs. CONTROLS: After 12-months, there was a trend for improved pHDL activity (p = 0.083), as indicated by intent-to-treat analysis, but when the non-adherent subject was omitted (per-protocol), significant attenuations in pHDL activity (p = 0.040) were noted; Δ pHDL activity at 12-months was associated with Δ weight (r = 0.62, p = 0.032) and Δ fasting glucose (r = 0.65, p = 0.022). Moreover, PON1 activity significantly improved (p < 0.001). The aforementioned occurred in association with improvements in inflammatory markers (i.e., C-reactive protein & tumor necrosis factor), hemoglobin A1C, fasting glucose, triglycerides, high-density lipoprotein levels and adipokines. CONCLUSION: IMT ameliorates pHDL index and significantly improves anti-oxidative function, as measured by PON1. Improvements in weight and fasting glucose mediated the decrease in pHDL index. Pharmacological aids and lifestyle modification are required to improve cardiovascular risk factors, subsequent mortality risk, and promote T2D remission. Application of either form of therapy alone may only have relatively miniscule effects on the aforementioned factors, in relation to the aggregate.

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.).