Early-Onset Type 2 Diabetes and Tirzepatide Treatment: A Post Hoc Analysis From the SURPASS Clinical Trial Program.

OBJECTIVE: We evaluated baseline characteristics of participants with early-onset type 2 diabetes (T2D) from the SURPASS program and tirzepatide's effects on glycemic control, body weight (BW), and cardiometabolic markers. RESEARCH DESIGN AND METHODS: This post hoc analysis compared baseline characteristics and changes in mean HbA1c, BW, waist circumference (WC), lipids, and blood pressure (BP) in 3,792 participants with early-onset versus later-onset T2D at week 40 (A Study of Tirzepatide [LY3298176] in Participants With Type 2 Diabetes Not Controlled With Diet and Exercise Alone [SURPASS-1] and A Study of Tirzepatide [LY3298176] Versus Semaglutide Once Weekly as Add-on Therapy to Metformin in Participants With Type 2 Diabetes [SURPASS-2]) or week 52 (A Study of Tirzepatide [LY3298176] Versus Insulin Degludec in Participants With Type 2 Diabetes [SURPASS-3]). Analyses were performed by study on data from participants while on assigned treatment without rescue medication in case of persistent hyperglycemia. RESULTS: At baseline in SURPASS-2, participants with early-onset versus later-onset T2D were younger with longer diabetes duration (9 vs. 7 years, P < 0.001) higher glycemic levels (8.5% vs. 8.2%, P < 0.001), higher BW (97 vs. 93 kg, P < 0.001) and BMI (35 vs. 34 kg/m2, P < 0.001), and a similarly abnormal lipid profile (e.g., triglycerides 167 vs. 156 mg/dL). At week 40, similar improvements in HbA1c (-2.6% vs. -2.4%), BW (-14 vs. -13 kg), WC (-10 vs. -10 cm), triglycerides (-26% vs. -24%), HDL (7% vs. 7%), and systolic BP (-6 vs. -7 mmHg) were observed in both subgroups with tirzepatide. CONCLUSIONS: Despite younger age, participants with early-onset T2D from the SURPASS program had higher glycemic levels and worse overall metabolic health at baseline versus those with later-onset T2D. In this post hoc analysis, similar improvements in HbA1c, BW, and cardiometabolic markers were observed with tirzepatide, irrespective of age at T2D diagnosis. Future studies are needed to determine long-term outcomes of tirzepatide in early-onset T2D.

Improved Glycaemic and Weight Management Are Associated with Better Quality of Life in People with Type 2 Diabetes Treated with Tirzepatide.

INTRODUCTION: Limited data are available on the relationship between quality of life (QoL) change and significant degrees of reduction in glycated haemoglobin (HbA1c) and/or weight loss in people with type 2 diabetes (T2D). We explored the associations between HbA1c targets and/or weight loss achieved and patient-reported outcomes (PROs) in adults with T2D treated with tirzepatide, a first-in-class once weekly glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, using pooled data from SURPASS-1 to -5 Phase 3 clinical trials. METHODS: PROs were assessed using five instruments at baseline and endpoint (Week 40 in SURPASS-1, -2 and -5; Week 52 in SURPASS-3 and -4): Impact of Weight on Quality of Life-Lite Clinical Trials Version; Impact of Weight on Self-Perception (IW-SP) questionnaire; Ability to Perform Physical Activities of Daily Living (APPADL); Diabetes Treatment Satisfaction Questionnaire change; and EQ-5D-5L. All PROs were assessed in participants receiving pooled doses of tirzepatide (5, 10 or 15 mg) and achieving HbA1c targets of < 5.7%, ≥ 5.7-≤ 6.5% and > 6.5% or achieving ≥ 0-< 5%, ≥ 5-< 10%, ≥ 10-< 15% and ≥ 15% weight loss from baseline at endpoint. The APPADL, IW-SP and EQ visual analogue scores were evaluated in participants achieving each combination of HbA1c target and weight loss. RESULTS: Achievement of lower HbA1c targets or higher body weight percentage losses were each associated with greater improvements in QoL than achievement of higher HbA1c targets or lower body weight percentage losses, respectively. Achievement of lower HbA1c targets in combination with greater weight loss was generally associated with the best QoL ratings. CONCLUSIONS: Our findings demonstrate that HbA1c targets and significant percentage body weight reduction thresholds need to be achieved for people with T2D to help substantially increase their overall health-related QoL. Tirzepatide treatment may allow a high proportion of people with T2D to achieve these targets, enabling improved QoL. CLINICAL TRIAL REGISTRATION: SURPASS-1: NCT03954834; SURPASS-2: NCT03987919; SURPASS-3: NCT03882970; SURPASS-4: NCT03730662; SURPASS-5: NCT04039503.

Limited data exist about the relationship between quality of life (QoL) and changes in clinical measures, for example management of blood sugar levels and weight, in people with type 2 diabetes. We explored the associations between glucose and weight loss targets achieved and QoL outcomes reported by adults treated with tirzepatide, the first glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved for the treatment of people with type 2 diabetes, using data from SURPASS-1 to -5 Phase 3 clinical trials.Five questionnaires, developed to evaluate patients' health-related QoL, were completed by patients at the beginning and end of the clinical trials, which was after 40 weeks for SURPASS-1, -2 and -5 and after 52 weeks for SURPASS-3 and -4, or when the person left the trial if this was before the official end. These questionnaires were: EQ-5D-5L (SURPASS-1 to -5); Impact of Weight on Self-Perception questionnaire (SURPASS-1 to -5); Ability to Perform Physical Activities of Daily Living (SURPASS-1 to -5); Diabetes Treatment Satisfaction Questionnaire change (SURPASS-2 to -5); and Impact of Weight on Quality of Life­Lite Clinical Trials Version (SURPASS-2 only).Overall, achievement of lower glucose targets or higher percentage of body weight losses were each associated with greater improvements in QoL. Achievement of lower glucose targets in combination with greater weight loss was generally associated with the highest health-related QoL ratings.Tirzepatide treatment may allow a high proportion of people with type 2 diabetes to achieve lower glucose levels and higher weight loss, enabling improved health-related QoL.

Patient-Reported Outcomes in People with Type 2 Diabetes Receiving Tirzepatide in the SURPASS Clinical Trial Programme.

INTRODUCTION: Tirzepatide, a novel glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 receptor agonist, is approved for glycaemic control for people with type 2 diabetes (T2D). The SURPASS-1 to -5 clinical trials assessed the efficacy of once weekly tirzepatide (5, 10 and 15 mg) versus placebo or active comparators (semaglutide 1 mg, insulin degludec and insulin glargine) in T2D. We evaluated patient-reported outcomes (PROs) that measured overall quality of life (QoL), treatment satisfaction and weight-related attributes across the five SURPASS studies. METHODS: PRO instruments utilised at baseline and primary timepoint (40 weeks for SURPASS-1, -2 and -5; 52 weeks for SURPASS-3 and -4) or early termination visit were EQ-5D-5L (SURPASS-1 to -5); Impact of Weight on Self-Perceptions (SURPASS-1 to -5); Ability to Perform Physical Activities of Daily Living (SURPASS-1 to -5); Diabetes Treatment Satisfaction Questionnaire (SURPASS-2 to -5); and Impact of Weight on Quality of Life-Lite Clinical Trials Version (SURPASS-2 only). RESULTS: Across all five studies at week 40/52, tirzepatide improved patients' QoL measured by general health and weight-related PROs over the comparator. Generally, higher doses of tirzepatide resulted in greater increases in PRO scores. CONCLUSION: Overall, tirzepatide produced significant health and weight-related QoL improvements versus comparators in the five SURPASS studies. CLINICAL TRIAL REGISTRATION: SURPASS-1: NCT03954834; SURPASS-2: NCT03987919; SURPASS-3: NCT03882970; SURPASS-4: NCT03730662; SURPASS-5: NCT04039503.

Tirzepatide is the first glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 receptor agonist approved for the treatment of people with type 2 diabetes. The SURPASS-1 to -5 clinical trials evaluated the efficacy and safety of tirzepatide (5, 10 and 15 mg) compared with placebo or active comparators (including semaglutide 1 mg and basal insulins) in people with type 2 diabetes. We evaluated other outcomes reported by patients that measured overall quality of life, treatment satisfaction and weight-related attributes across the five SURPASS studies.Five validated questionnaires were completed by patients at the beginning and end of the clinical trials, which was after 40 weeks for SURPASS-1, -2 and -5 and after 52 weeks for SURPASS-3 and -4, or when the person left the trial if this was before the official end. These questionnaires were EQ-5D-5L (SURPASS-1 to -5); Impact of Weight on Self-Perceptions (SURPASS-1 to -5); Ability to Perform Physical Activities of Daily Living (SURPASS-1 to -5); Diabetes Treatment Satisfaction Questionnaire (SURPASS-2 to -5); and Impact of Weight on Quality of Life-Lite Clinical Trials Version (SURPASS-2 only).Across all five studies, treatment with tirzepatide resulted in greater improvements in people's quality of life at the end of the study compared with placebo or treatment with the comparators. Generally, higher doses of tirzepatide resulted in greater increases in questionnaire scores than lower doses of tirzepatide.Overall, tirzepatide 5, 10 or 15 mg treatment resulted in significant health- and weight-related quality of life improvements versus comparators in the five SURPASS studies.

Tirzepatide as Monotherapy Improved Markers of Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes (SURPASS-1).

Context: Tirzepatide is a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved for treatment of type 2 diabetes (T2D). SURPASS-1, a phase 3 trial of tirzepatide monotherapy in people with early T2D, enables evaluating effects of tirzepatide on pancreatic beta-cell function and insulin sensitivity (IS) without other background antihyperglycemic medications. Objective: Explore changes in biomarkers of beta-cell function and IS with tirzepatide monotherapy. Design: Post hoc analyses of fasting biomarkers with analysis of variance and mixed model repeated measures. Setting: Forty-seven sites in 4 countries. Patients: Four hundred seventy-eight T2D participants. Intervention: Tirzepatide (5, 10, 15 mg), placebo. Main Outcome Measures: Analyze biomarkers of beta-cell function and IS at 40 weeks. Results: At 40 weeks, markers of beta-cell function improved with tirzepatide monotherapy vs placebo with reductions from baseline in fasting proinsulin levels (49-55% vs -0.6%) and in intact proinsulin/C-peptide ratios (47-49% vs -0.1%) (P < .001, all doses vs placebo). Increases from baseline in homeostatic model assessment for beta-cell function (computed with C-peptide) (77-92% vs -1.4%) and decreases in glucose-adjusted glucagon levels (37-44% vs +4.8%) were observed with tirzepatide vs placebo (P < .001, all doses vs placebo). IS improved as indicated by reductions from baseline in homeostatic model assessment for insulin resistance (9-23% vs +14.7%) and fasting insulin levels (2-12% vs +15%), and increases in total adiponectin (16-23% vs -0.2%) and insulin-like growth factor binding protein 2 (38-70% vs +4.1%) with tirzepatide vs placebo at 40 weeks (P ≤ .031, all doses vs placebo, except for fasting insulin levels with tirzepatide 10 mg). Conclusions: As monotherapy for early T2D, tirzepatide achieved significant improvements in biomarkers of both pancreatic beta-cell function and IS.

Comparison of Hormonal Response to a Mixed-Meal Challenge in Hypoglycemia After Sleeve Gastrectomy vs Gastric Bypass.

CONTEXT: Exaggerated postprandial incretin and insulin responses are well documented in postbariatric surgery hypoglycemia (PBH) after Roux-en-Y gastric bypass (RYGB). However, less is known about PBH after sleeve gastrectomy (SG). OBJECTIVE: We sought to compare meal-stimulated hormonal response in those with PBH after SG vs RYGB. METHODS: We enrolled 23 post-SG (12 with and 11 without PBH) and 20 post-RYGB (7 with and 13 without PBH) individuals who underwent bariatric surgery at our institution. PBH was defined as plasma glucose less than 60 mg/dL on 4-hour mixed-meal tolerance test (MTT). Islet and incretin hormones were compared across the 4 groups. RESULTS: Participants (N = 43) were on average 5 years post surgery, with a mean age of 48 years, mean preoperative body mass index of 48.4, 81% female, 61% White, and 53% post SG. Regardless of PBH, the SG group showed lower glucose, glucagon, and glucagon-like peptide 1 (GLP-1) responses to MTT and similar insulin and glucose-dependent insulinotropic polypeptide (GIP) responses compared to the RYGB group. Among those with PBH, the SG group following the MTT showed a lower peak glucose (P = .02), a similar peak insulin (90.3 mU/L vs 171mU/L; P = .18), lower glucagon (P < .01), early GLP-1 response (AUC0-60 min; P = .01), and slower time to peak GIP (P = .02) compared to PBH after RYGB. CONCLUSION: Among individuals with PBH, those who underwent SG were significantly different compared to RYGB in meal-stimulated hormonal responses, including lower glucagon and GLP-1 responses, but similar insulin and GIP responses. Future studies are needed to better understand the differential contribution of insulin and non-insulin-mediated mechanisms behind PBH after SG vs RYGB.

GDF15 and Cortisol Response to Meal Tolerance Test in Post-Sleeve Gastrectomy Patients with Weight Regain.

BACKGROUND: Hormonal factors behind weight regain (WR) after surgical weight loss remain inadequately understood. Growth/differentiation factor 15 (GDF15) has emerged as a potential therapeutic target in obesity treatment. Cortisol, another stress hormone, has also been associated with weight gain at both low and high circulating concentrations. We aimed to compare meal-stimulated GDF15 and cortisol response in adults with and without WR after sleeve gastrectomy (SG). We hypothesized that GDF15 and cortisol response to meal tolerance test (MTT) will be lower in those with versus without WR after SG. METHODS: Cross-sectional study comprised 21 adults without diabetes, who underwent SG. WR was defined as 100 × (current weight - nadir)/(preoperative weight - nadir) > 10%. GDF15, cortisol, insulin, glucose, and incretins (total glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) circulating concentrations) were measured during MTT (0-240 min) after 3-6 years post-bariatric surgery. RESULTS: All participants were 48% White, 85% female, with mean (SD) age: 43(10) years, and BMI: 36.2(7.6) kg/m2. Compared to the non-WR group (n = 6), the WR group (n = 15) had significantly higher BMI (WR: 38.6 ± 7.6 kg/m2, non-WR: 30.3 ± 3.5 kg/m2, p = 0.02) and showed lower GDF15 response (WR AUC vs non-WR AUC (116143 ± 13973 vs 185798 ± 38884 ng*min/L, p = 0.047)) and lower cortisol response (WR AUC vs non-WR AUC (3492 ± 210 vs 4880 ± 655 µg*min/dL, p = 0.015)). Incretin response did not differ between the groups. CONCLUSIONS: GDF15 and cortisol responses to MTT were lower in those who regained the weight after SG compared to those who did not, suggesting that dysregulation in GDF15 and cortisol response following bariatric surgery.

Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial.

BACKGROUND: Despite advancements in care, many people with type 2 diabetes do not meet treatment goals; thus, development of new therapies is needed. We aimed to assess efficacy, safety, and tolerability of novel dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist tirzepatide monotherapy versus placebo in people with type 2 diabetes inadequately controlled by diet and exercise alone. METHODS: We did a 40-week, double-blind, randomised, placebo-controlled, phase 3 trial (SURPASS-1), at 52 medical research centres and hospitals in India, Japan, Mexico, and the USA. Adult participants (≥18 years) were included if they had type 2 diabetes inadequately controlled by diet and exercise alone and if they were naive to injectable diabetes therapy. Participants were randomly assigned (1:1:1:1) via computer-generated random sequence to once a week tirzepatide (5, 10, or 15 mg), or placebo. All participants, investigators, and the sponsor were masked to treatment assignment. The primary endpoint was the mean change in glycated haemoglobin (HbA1c) from baseline at 40 weeks. This study is registered with ClinicalTrials.gov, NCT03954834. FINDINGS: From June 3, 2019, to Oct 28, 2020, of 705 individuals assessed for eligibility, 478 (mean baseline HbA1c 7·9% [63 mmol/mol], age 54·1 years [SD 11·9], 231 [48%] women, diabetes duration 4·7 years, and body-mass index 31·9 kg/m2) were randomly assigned to tirzepatide 5 mg (n=121 [25%]), tirzepatide 10 mg (n=121 [25%]), tirzepatide 15 mg (n=121 [25%]), or placebo (n=115 [24%]). 66 (14%) participants discontinued the study drug and 50 (10%) discontinued the study prematurely. At 40 weeks, all tirzepatide doses were superior to placebo for changes from baseline in HbA1c, fasting serum glucose, bodyweight, and HbA1c targets of less than 7·0% (<53 mmol/mol) and less than 5·7% (<39 mmol/mol). Mean HbA1c decreased from baseline by 1·87% (20 mmol/mol) with tirzepatide 5 mg, 1·89% (21 mmol/mol) with tirzepatide 10 mg, and 2·07% (23 mmol/mol) with tirzepatide 15 mg versus +0·04% with placebo (+0·4 mmol/mol), resulting in estimated treatment differences versus placebo of -1·91% (-21 mmol/mol) with tirzepatide 5 mg, -1·93% (-21 mmol/mol) with tirzepatide 10 mg, and -2·11% (-23 mmol/mol) with tirzepatide 15 mg (all p<0·0001). More participants on tirzepatide than on placebo met HbA1c targets of less than 7·0% (<53 mmol/mol; 87-92% vs 20%) and 6·5% or less (≤48 mmol/mol; 81-86% vs 10%) and 31-52% of patients on tirzepatide versus 1% on placebo reached an HbA1c of less than 5·7% (<39 mmol/mol). Tirzepatide induced a dose-dependent bodyweight loss ranging from 7·0 to 9·5 kg. The most frequent adverse events with tirzepatide were mild to moderate and transient gastrointestinal events, including nausea (12-18% vs 6%), diarrhoea (12-14% vs 8%), and vomiting (2-6% vs 2%). No clinically significant (<54 mg/dL [<3 mmol/L]) or severe hypoglycaemia were reported with tirzepatide. One death occurred in the placebo group. INTERPRETATION: Tirzepatide showed robust improvements in glycaemic control and bodyweight, without increased risk of hypoglycaemia. The safety profile was consistent with GLP-1 receptor agonists, indicating a potential monotherapy use of tirzepatide for type 2 diabetes treatment. FUNDING: Eli Lilly and Company.

Gut microbiome and its role in obesity and insulin resistance.

Obesity is a complex metabolic disease caused, in part, by the interaction between an individual's genetics, metabolism, and environment. Emerging evidence supports the role of gut microbiota in mediating the interaction between the host and environment by extracting energy from food otherwise indigestible by the host and producing metabolites and cytokines that affect host metabolism. Furthermore, gut microbial imbalance or dysbiosis has been shown in metabolic diseases including obesity, and recent studies are beginning to unravel the mechanisms involved. The gut microbiota affects host metabolism and obesity through several pathways involving gut barrier integrity, production of metabolites affecting satiety and insulin resistance, epigenetic factors, and metabolism of bile acids and subsequent changes in metabolic signaling. While the field of gut microbiome and its role in obesity is early in its stage of development, it holds a promising future in providing us with novel therapeutic targets that may restore the gut microbiome to a healthy state and help in the prevention and treatment of obesity.

Changes in Gut Microbiome after Bariatric Surgery Versus Medical Weight Loss in a Pilot Randomized Trial.

BACKGROUND: Gut microbiota likely impact obesity and metabolic diseases. We evaluated the changes in gut microbiota after surgical versus medical weight loss in adults with diabetes and obesity. METHODS: We performed 16S rRNA amplicon sequencing to identify the gut microbial composition at baseline and at 10% weight loss in adults with diabetes who were randomized to medical weight loss (MWL, n = 4), adjustable gastric banding (AGB, n = 4), or Roux-en-Y gastric bypass (RYGB, n = 4). RESULTS: All participants were female, 75% reported black race with mean age of 51 years. At similar weight loss amount and glycemic improvement, the RYGB group had the most number of bacterial species (10 increased, 1 decreased) that significantly changed (p < 0.05) in relative abundance. Alpha-diversity at follow-up was significantly lower in AGB group compared to MWL and RYGB (observed species for AGB vs. MWL, p = 0.0093; AGB vs. RYGB, p = 0.0093). The relative abundance of Faecalibacterium prausnitzii increased in 3 participants after RYGB, 1 after AGB, and 1 after MWL. CONCLUSIONS: At similar weight loss and glycemic improvement, the greatest alteration in gut microbiota occurred after RYGB with an increase in the potentially beneficial bacterium, F. prausnitzii. Gut microbial diversity tended to decrease after AGB and increase after RYGB and MWL. Future studies are needed to determine the impact and durability of gut microbial changes over time and their role in long-term metabolic improvement after bariatric surgery in adults with type 2 diabetes. CLINICAL TRIAL REGISTRATION: NCTDK089557- ClinicalTrials.gov.

Comparative Effects of Medical Versus Surgical Weight Loss on Body Composition: a Pilot Randomized Trial.

OBJECTIVE: Bariatric surgery leads to more rapid and greater weight loss (WL) compared to medical weight loss (MWL), but the differences in body composition (BC) changes for these modalities remain unclear. Due to the known health risks associated with central adiposity, we compared the changes in regional distribution of fat mass (FM) and lean mass (LM) after surgical versus MWL. METHODS: In this 1:1:1 randomized trial among 15 persons with type 2 diabetes and body mass index (BMI) 30-39.9 kg/m2, we compared changes in BC, by dual-energy X-ray absorptiometry and abdominal computerized tomography, at time of 10%WL or 9 months after intervention (whichever came first). Participants underwent MWL, adjustable gastric banding (AGB), or Roux-en-Y gastric bypass (RYGB). Non-parametric tests evaluated BC differences (FM, LM, and visceral adipose tissue [VAT]) within and across all three arms and between pair-wise comparisons. RESULTS: Twelve female participants (75% African American) completed the study. Patient age, BMI, and baseline anthropometric characteristics were similar across study arms. AGB lost more LM (MWL - 5.2%, AGB - 10.3%, p = 0.021) and VAT (MWL + 10.9%, AGB - 28.0%, p = 0.049) than MWL. RYGB tended to lose more VAT (MWL +10.9%, RYGB - 20.2%, p = 0.077) than MWL. AGB tended to lose more LM than RYGB (AGB - 12.38%, RYGB - 7.29%, p = 0.15). CONCLUSIONS: At similar WL, AGB lost more LM and VAT than MWL; RYGB similarly lost more VAT. Given the metabolic benefits of reducing VAT and retaining LM, larger studies should confirm the changes in BC after surgical versus medical WL. CLINICAL TRIAL REGISTRATION: NCTDK089557 - ClinicalTrials.gov.

Validation of the Use of Electronic Medical Records for Identification of Post-gastric Bypass Hypoglycemia Cases.

OBJECTIVE: We sought to validate an algorithm designed to identify patients with post-gastric bypass hypoglycemia (PGBH) using clinician chart review. METHODS: We conducted a chart review study of non-diabetic patients who underwent Roux-en-Y gastric bypass (RYGB) at our institution from 2004 to 2013. The electronic medical record (EMR) algorithm was based on any post-operative glucose <60 mg/dl, diagnosis of hypoglycemia, or medication use for treatment of PGBH and identified 158 charts as PGBH and 1048 charts without PGBH. Two clinicians independently reviewed a random selection of 80 cases and 80 control charts and determined the presence or absence of PGBH by searching the chart using keywords and reviewing laboratory results, medications, and clinic notes. RESULTS: Of the 160 charts reviewed, the EMR algorithm agreed with the chart review for 130 (accuracy = 80%, 95% CI = 75-87%) with sensitivity of 89% (95% CI = 83-96%) and specificity of 86% (95% CI = 78-93%). We improved the algorithm's accuracy to 90% by limiting the search to data obtained 3 months or more following RYGB. CONCLUSION: The EMR algorithm has high sensitivity, specificity, and accuracy to identify post-gastric bypass hypoglycemia within our patient cohort. The use EMR-based algorithms may be a useful tool for future research to improve our understanding of epidemiology and risk factors for post-bariatric surgery hypoglycemia.

The incidence and risk factors associated with developing symptoms of hypoglycemia after bariatric surgery.

BACKGROUND: Hypoglycemia after bariatric surgery is an increasingly recognized metabolic complication associated with exaggerated secretion of insulin and gut hormones. OBJECTIVE: We sought to determine the incidence of hypoglycemic symptoms (hypo-sx) after bariatric surgery and characteristics of those affected compared with those unaffected. SETTING: University hospital. METHODS: We collected retrospective survey data from the patients who underwent bariatric surgery at a single center. Based on number and severity of postprandial hypo-sx in Edinburgh hypoglycemia questionnaire postoperatively, patients without preoperative hypo-sx were grouped into high versus low suspicion for hypoglycemia. We used multivariable logistic regression to examine potential baseline and operative risk factors for the development of hypo-sx after surgery. RESULTS: Among the 1119 patients who had undergone bariatric surgery who received the questionnaire, 464 (40.6%) responded. Among the 341 respondents without preexisting hypo-sx, 29% (n = 99) had new-onset hypo-sx, and most were severe cases (n = 92) with neuroglycopenic symptoms. Compared with the low suspicion group, the high suspicion group consisted of more female patients, younger patients, patients without diabetes, and those who underwent Roux-en-Y gastric bypass with a longer time since surgery and more weight loss. In multivariate analysis, factors independently associated with incidence of hypo-sx after bariatric surgery were female sex (P = .003), Roux-en-Y gastric bypass (P = .001), and absence of preexisting diabetes (P = .011). CONCLUSIONS: New onset postprandial hypoglycemic symptoms after bariatric surgery are common, affecting up to a third of those who underwent bariatric surgery. Many affected individuals reported neuroglycopenic symptoms and were more likely to be female and nondiabetic and to have undergone Roux-en-Y gastric bypass.

The Role of Laboratory Testing in Differentiating Type 1 Diabetes from Type 2 Diabetes in Patients Undergoing Bariatric Surgery.

BACKGROUND: It may be difficult to distinguish between adults with type 1 diabetes and type 2 diabetes by clinical assessment. In patients undergoing bariatric surgery, it is critical to correctly classify diabetes subtype to prevent adverse perioperative outcomes including diabetic ketoacidosis. This study aimed to determine whether testing for C-peptide and islet cell antibodies during preoperative evaluation for bariatric surgery could improve the classification of type 1 versus type 2 diabetes compared to clinical assessment alone. METHODS: This is a retrospective analysis of the Improving Diabetes through Lifestyle and Surgery trial, which randomized patients with clinically diagnosed type 2 diabetes and BMI 30-40 kg/m2 to medical weight loss or bariatric surgery; one participant was discovered to have type 1 diabetes after experiencing postoperative diabetic ketoacidosis. Using blood samples collected prior to study interventions, we measured islet cell antibodies and fasting/meal-stimulated C-peptide in all participants. RESULTS: The participant with type 1 diabetes was similar to the 11 participants with type 2 diabetes in age at diagnosis, adiposity, and glycemic control but had the lowest C-peptide levels. Among insulin-treated participants, fasting and stimulated C-peptide correlated strongly with the C-peptide area-under-the-curve on mixed meal tolerance testing (R = 0.86 and 0.88, respectively). Three participants, including the one with type 1 diabetes, were islet cell antibody positive. CONCLUSIONS: Clinical characteristics did not correctly identify type 1 diabetes in this study. Preoperative C-peptide testing may improve diabetes classification in patients undergoing bariatric surgery; further research is needed to define the optimal C-peptide thresholds.

The Association of Severe Hypoglycemia With Incident Cardiovascular Events and Mortality in Adults With Type 2 Diabetes.

OBJECTIVE: There is suggestive evidence linking hypoglycemia with cardiovascular disease, but few data have been collected in a community-based setting. Information is lacking on individual cardiovascular outcomes and cause-specific mortality. RESEARCH DESIGN AND METHODS: We conducted a prospective cohort analysis of 1,209 participants with diagnosed diabetes from the Atherosclerosis Risk in Communities (ARIC) study (analytic baseline, 1996-1998). Severe hypoglycemic episodes were identified using first position ICD-9 codes from hospitalizations, emergency department visits, and ambulance calls through 2013. Cardiovascular events and deaths were captured through 2013. We used adjusted Cox regression models with hypoglycemia as a time-varying exposure. RESULTS: There were 195 participants with at least one severe hypoglycemic episode during a median fellow-up of 15.3 years. After severe hypoglycemia, the 3-year cumulative incidence of coronary heart disease was 10.8% and of mortality was 28.3%. After adjustment, severe hypoglycemia was associated with coronary heart disease (hazard ratio [HR] 2.02, 95% CI 1.27-3.20), all-cause mortality (HR 1.73, 95% CI 1.38-2.17), cardiovascular mortality (HR 1.64, 95% CI 1.15-2.34), and cancer mortality (HR 2.49, 95% CI 1.46-4.24). Hypoglycemia was not associated with stroke, heart failure, atrial fibrillation, or noncardiovascular and noncancer death. Results were robust within subgroups defined by age, sex, race, diabetes duration, and baseline cardiovascular risk. CONCLUSIONS: Severe hypoglycemia is clearly indicative of declining health and is a potent marker of high absolute risk of cardiovascular events and mortality.

Weight regain in patients with symptoms of post-bariatric surgery hypoglycemia.

BACKGROUND: Weight regain (WR) and symptoms of post-bariatric surgery hypoglycemia (PBSH) are metabolic complications observed in a subset of postbariatric patients. Whether hypoglycemic symptoms are an important driver of increased caloric intake and WR after bariatric surgery is unknown. OBJECTIVE: This study aims to determine whether patients with PBSH symptoms have greater odds for WR. SETTING: Tertiary academic hospital. METHODS: Patients who underwent Roux-en-Y gastric bypass or sleeve gastrectomy at our tertiary academic hospital from August 2008 to August 2012 were mailed a survey, from which weight trajectory and PBSH symptoms were assessed. Percent WR was calculated as 100×(current weight-nadir weight)/(preoperative weight-nadir weight) and was compared between dates of survey completion and bariatric surgery. The primary outcome was WR≥10%, as a reflection of the median WR among respondents. Multivariable logistic regression was used to determine clinical factors that indicate greater odds for WR≥10% at the P<.05 level. RESULTS: Of 1119 potential patients, 428 respondents (40.6%) were eligible for analysis. WR was observed in 79.2% (n = 339), while 20.8% (n = 89) experienced either weight loss or no WR at a mean of 40.6±14.5 months. Median WR was 10.8% (interquartile range, 5.6-19.4). Odds of WR≥10% was significantly increased in those who experienced PBSH symptoms (odds ratio [OR] = 1.66; 95% confidence interval [CI]: 1.04-2.65), reported less adherence to nutritional guideline (OR = 2.36; 95% CI: 1.52-3.67), and had a longer time since surgery (OR = 1.05; 95% CI: 1.03-1.07). CONCLUSIONS: We found evidence that the presence of PBSH symptoms was associated with WR. Future studies should elucidate the role of hypoglycemia among other factors in post-bariatric surgery WR.

Levothyroxine Dosing Following Bariatric Surgery.

BACKGROUND: Based on the mechanisms of drug absorption, increased levothyroxine requirements are expected after bariatric surgery. However, there are conflicting data on this topic. This review evaluates the effects of bariatric surgery on levothyroxine dosing. METHODS: Data were obtained from PubMed, Scopus, and review of published bibliographies. RESULTS: Six of 10 studies demonstrated decreased postoperative requirements. Most demonstrated correlations between weight loss and dose. Only 3 case reports and 1 case series demonstrated increased levothyroxine requirements, attributed to malabsorption. CONCLUSIONS: The loss of both fat and lean body mass may counteract malabsorptive effects from surgery, resulting in decreased postoperative levothyroxine requirements. In addition, the reversal of impaired levothyroxine pharmacokinetics and an altered set point of thyroid hormone homeostasis may also contribute to postoperative levothyroxine reductions.

Evaluation of the Association Between Preoperative Clinical Factors and Long-term Weight Loss After Roux-en-Y Gastric Bypass.

Importance: Weight loss after bariatric surgery varies, yet preoperative clinical factors associated with long-term suboptimal outcomes are not well understood. Objective: To evaluate the association between preoperative clinical factors and long-term weight loss after Roux-en-Y gastric bypass (RYGB). Design, Setting, and Participants: From June 2001 to September 2007, this retrospective cohort study followed up RYGB patients before surgery to 7 to 12 years after surgery. The setting was a large rural integrated health system. Of 1033 eligible RYGB patients who consented to participate in longitudinal research and completed surgery before October 2007, a total of 726 (70.3%) had a weight entered in the electronic medical record 7 or more years after surgery and were included in the analyses after exclusions for pregnancy and mortality. Date of the long-term weight measurement was recorded between August 2010 and January 2016. Main Outcomes and Measures: The primary outcome was percentage weight loss (%WL) at 7 to 12 years after surgery. Preoperative clinical factors (>200) extracted from the electronic medical record included medications, comorbidities, laboratory test results, and demographics, among others. Results: Among the 726 study participants, 83.1% (n = 603) were female and 97.4% (n = 707) were of white race, with a mean (SD) preoperative body mass index (calculated as weight in kilograms divided by height in meters squared) of 47.5 (7.4). From the time of surgery to long-term follow-up (median, 9.3 postoperative years), the mean (SD) %WL was 22.5% (13.1%). Preoperative insulin use, history of smoking, and use of 12 or more medications before surgery were associated with greater long-term postoperative %WL (6.8%, 2.8%, and 3.1%, respectively). Preoperative hyperlipidemia, older age, and higher body mass index were associated with poorer long-term postoperative %WL (-2.8%, -8.8%, and -4.1%, respectively). Conclusions and Relevance: Few preoperative clinical factors associated with long-term weight loss after RYGB were identified. Preoperative insulin use was strongly associated with better long-term %WL, while preoperative hyperlipidemia, higher body mass index, and older age were associated with poorer %WL. Our findings provide additional insight into preoperative identification of RYGB patients at higher risk for long-term suboptimal outcomes.