To investigate whether liraglutide added to treat-to-target insulin improves glycemic control and reduces insulin requirements and body weight in subjects with type 1 diabetes.
A 52-week, ...double-blind, treat-to-target trial involving 1,398 adults randomized 3:1 to receive once-daily subcutaneous injections of liraglutide (1.8, 1.2, or 0.6 mg) or placebo added to insulin.
HbA1c level was reduced 0.34-0.54% (3.7-5.9 mmol/mol) from a mean baseline of 8.2% (66 mmol/mol), and significantly more for liraglutide 1.8 and 1.2 mg compared with placebo (estimated treatment differences ETDs: 1.8 mg liraglutide -0.20% 95% CI -0.32; -0.07; 1.2 mg liraglutide -0.15% 95% CI -0.27; -0.03; 0.6 mg liraglutide -0.09% 95% CI -0.21; 0.03). Insulin doses were reduced by the addition of liraglutide 1.8 and 1.2 mg versus placebo (estimated treatment ratios: 1.8 mg liraglutide 0.92 95% CI 0.88; 0.96; 1.2 mg liraglutide 0.95 95% CI 0.91; 0.99; 0.6 mg liraglutide 1.00 95% CI 0.96; 1.04). Mean body weight was significantly reduced in all liraglutide groups compared with placebo ETDs (1.8 mg liraglutide -4.9 kg 95% CI -5.7; -4.2; 1.2 mg liraglutide -3.6 kg 95% CI -4.3; -2.8; 0.6 mg liraglutide -2.2 kg 95% CI -2.9; -1.5). The rate of symptomatic hypoglycemia increased in all liraglutide groups (estimated rate ratios: 1.8 mg liraglutide 1.31 95% CI 1.07; 1.59; 1.2 mg liraglutide 1.27 95% CI 1.03; 1.55; 0.6 mg liraglutide 1.17 95% CI 0.97; 1.43), and hyperglycemia with ketosis increased significantly for liraglutide 1.8 mg only (event rate ratio 2.22 95% CI 1.13; 4.34).
Liraglutide added to insulin therapy reduced HbA1c levels, total insulin dose, and body weight in a population that was generally representative of subjects with type 1 diabetes, accompanied by increased rates of symptomatic hypoglycemia and hyperglycemia with ketosis, thereby limiting clinical use in this group.
IntroductionRecurrent hypoglycemia due to postbariatric hypoglycemia (PBH) is a postoperative complication after Roux-en-Y gastric bypass (RYGBP). The historic term is late dumping syndrome or ...reactive hypoglycemia. The aim of this study was to assess clinically applicable tools, in order to diagnose these patients, for the purpose of preventing hypoglycemic complications.Research design and methodsTen patients with PBS and nine controls were recruited. Continuous glucose monitoring (CGM) and food intake were registered for 7 days, together with metabolic parameters at baseline.ResultsThere was a significant difference (p<0.05) in Dumping Syndrome Rating Scale (DSRS) between the groups. There was no difference between p-glucose or HbA1c between the groups, but a highly significant difference in C peptide p<0.01 was observed. Using the Dexcom Studio system, the PBH group had significantly (p<0.05) more time during the day in very low blood sugar (5.9±4.2% vs 1.8%±2.3%) compared with the controls. Counting hyperglycemic and hypoglycemic episodes showed that the quantity of hypoglycemic episodes was significantly higher, p<0.01, in the PBH group compared with controls (16.6±11.0 vs 8.1±8.6 hypoglycemic events). C peptide was positively correlated with the late dumping group, p<0.01 (CI 95% 0.353 to 0.814) and very low blood sugar (<3.2 mmol/L) in all subjects with p<0.01 (CI 95% 0.194 to 0.763).ConclusionsFinding patients with recurrent hypoglycemic episodes after bariatric surgery is important to prevent future health problems. To diagnose recurrent hypoglycemia (PBH) after RYGBP, we used blood sugar analyzing tools that are commonly available in clinical settings. Interestingly, patients with few or no symptoms of PHB still had recurrent hyperglycemic and hypoglycemic events. We recommend an active approach with dumping syndrome questionnaires, assessment of metabolic parameters and CGM with food registration. Assessment of PBH using this method can potentially lead to reduced blood glucose variability due to behavioral changes.
Objective: To compare estimates of total and truncal fatness from eight‐electrode bioelectrical impedance analysis equipment (BIA8) with those from DXA in centrally obese women. The secondary aim was ...to examine BMI and waist circumference (WC) as proxy measures for percentage total body fat (%TBF) and truncal body fat percentage (tr%BF).
Research Methods and Procedures: This was a cross‐sectional study of 136 women (age, 48.1 ± 7.7 years; BMI, 30.4 ± 2.9 kg/m2; %TBFDXA, 46.0 ± 3.7%; WC, 104 ± 8 cm). Fatness was measured by DXA and Tanita BC‐418 equipment (Tanita Corp., Tokyo, Japan). Agreement among methods was assessed by Bland‐Altman plots, and regression analysis was used to evaluate anthropometric measures as proxies for total and abdominal fatness.
Results: The percentage of overweight subjects was 41.9%, whereas 55.9% of the subjects were obese, as defined by BMI, and all subjects had a WC exceeding the World Health Organization cut‐off point for abdominal obesity. Compared with DXA, the BIA8 equipment significantly underestimated total %BF (−5.0; −3.6 to −8.5 mean; 95% confidence interval), fat mass (−3.6; −3.9 to −3.2), and tr%BF (−8.5; −9.1 to −7.9). The discrepancies between the methods increased with increasing adiposity for both %TBF and tr%BF (both p < 0.001). Variation in BMI explained 28% of the variation in %TBFDXA and 51% of %TBFBIA8. Using WC as a proxy for truncal adiposity, it explained only 18% of tr%BFDXA variance and 27% of tr%BFBIA8 variance. The corresponding figures for truncal fat mass were 49% and 35%, respectively. No significant age effects were observed in any of the regressions.
Discussion: BIA8 underestimated both total and truncal fatness, compared with DXA, with higher dispersion for tr%BF than %TBF. The discrepancies increased with degree of adiposity, suggesting that the accuracy of BIA is negatively affected by obesity.
Bioelectrical impedance (BIA) is quick, easy, and safe when quantifying fat and lean tissue. New BIA models (Tanita BC‐418 MA, abbreviated BIA8) can perform segmental body composition analysis, e.g., ...estimate %trunkal fatness (%TF). It is not known, however, whether new BIA models can detect metabolic risk factors (MRFs) better than older models (Tanita TBF‐300, abbreviated BIA4). We therefore tested the correlation between MRF and percentage whole‐body fat (%BF) from BIA4 and BIA8 and compared these with the correlation between MRF and dual‐energy X‐ray absorptiometry (DXA, used as gold standard), BMI and waist circumference (WC). The sample consisted of 136 abdominally obese (WC ≥ 88 cm), middle‐aged (30–60 years) women. MRF included fasting blood glucose and insulin; high‐density lipoprotein cholesterol, low‐density lipoprotein cholesterol, and triglycerides; high sensitive C‐reactive protein, plasminogen activator inhibitor‐1 (PAI‐1), and fibrinogen; and alanine transaminase (ALT) liver enzyme. We found that similar to DXA, but in contrast to BMI, neither %BF BIA4 nor %BF BIA8 correlated with blood lipids or ALT. In the segmental analysis of %TF, BIA8 only correlated with inflammatory markers, but not insulin, blood lipids, or ALT liver enzyme (in contrast to WC and %TF DXA). %TF DXA was associated with homeostatic model assessment insulin resistance (HOMA‐IR) independently of WC (P = 0.03), whereas %TF BIA8 was not (P = 0.53). Receiver‐operating characteristic (ROC) curves confirmed that %TF BIA8 did not differ from chance in the detection of insulin resistance (P = 0.26). BIA estimates of fatness were, at best, weakly correlated with obesity‐related risk factors in abdominally obese women, even the new eight‐electrode model. Our data support the continued use of WC and BMI.
To compare estimates of change in percent body fat (Delta%BF) between DXA and BIA8 in abdominally obese women.
Six-month longitudinal study of 106 women (baseline: age 48.2 +/- 7.6 yr; BMI 30.4 +/- ...2.9 kg.m; %BFDXA 45.8 +/- 3.6%) participating in an exercise-oriented behavior-change program (walking and bicycling). Fatness was measured by DXA and Tanita BC-418 (BIA8). Agreement between methods was assessed, and regression analysis was used to find predictors of the deviation between methods for estimating changes in fat mass percentage.
The methods differed significantly, both at baseline and follow-up (-5.0 and -4.4%BF, respectively; both P < 0.001). The mean Delta%BF was -1.1 +/- 2.5%BFDXA and -0.5 +/- 2.2%BFBIA8 (mean difference between methods 0.6 +/- 1.8%BF; P < 0.001; 95% limits of agreement -3.0 to 4.2%BF), with a range of -14.8 to 3.3%BFDXA and -9.4 to 3.5%BFBIA8. Approximately 49% of the variation in the difference between methods was explained by variations in age (beta = -0.05; P = 0.006), DeltaBMI (beta = 0.98; P < 0.001), and Delta%BFDXA (beta = -0.71; P < 0.001), indicating that the larger the change, the greater the discrepancy between methods.
The difference between methods regarding Delta%BF was statistically significant, but it was of small magnitude. However, with increasing Delta%BF, increasing discrepancies were observed, implying that the BIA equipment may have limited validity for detecting larger fat losses. Both clinicians and researchers may benefit from awareness of this potential limitation.
As an adjunct to a reduced-calorie diet and increased physical activity, treatment with liraglutide 3.0 mg for weight management provides a statistically significant and clinically meaningful weight ...loss of 5.7%-8.0% compared to 1.6%-2.6% with placebo. The objective of this post hoc analysis was to quantify the relative contribution of weight loss to the treatment effects of liraglutide 3.0 mg on key efficacy endpoints.
The analysis utilized data from 4725 participants across three randomized, placebo-controlled, double-blind trials that evaluated the efficacy and safety of liraglutide 3.0 mg versus placebo, as an adjunct to a reduced-calorie diet and increased physical activity (ClinicalTrials.gov identifiers: NCT01272219, NCT01272232 and NCT01557166). The duration of two of the trials was 56 weeks; one trial was of 32 weeks' duration. A mediation analysis was performed, which ranked the relative contribution of weight loss to the treatment effects of liraglutide 3.0 mg on key cardiometabolic efficacy endpoints, Apnea-Hypopnea Index (AHI) and health-related quality of life (QoL). A limitation of this type of analysis is that it cannot conclusively prove a causal relationship.
In individuals without type 2 diabetes mellitus (T2DM), endpoints predominantly driven by liraglutide-induced weight loss included waist circumference, diastolic blood pressure, triglycerides, high density lipoprotein cholesterol, AHI, and Impact of Weight on Quality of Life-Lite total and physical function scores. Endpoints predominantly independent of weight loss included the glycemic endpoints hemoglobin A1c and fasting plasma glucose in individuals with and without T2DM. Regardless of the degree of dependence on weight loss according to the mediation analysis, greater weight loss was associated with greater improvement in all endpoints.
Treatment with liraglutide 3.0 mg contributes to improved cardiometabolic parameters, AHI and health-related QoL through both weight-loss dependent and weight-loss independent mechanisms.
IMPORTANCE: Weight loss of 5% to 10% can improve type 2 diabetes and related comorbidities. Few safe, effective weight-management drugs are currently available. OBJECTIVE: To investigate efficacy and ...safety of liraglutide vs placebo for weight management in adults with overweight or obesity and type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS: Fifty-six–week randomized (2:1:1), double-blind, placebo-controlled, parallel-group trial with 12-week observational off-drug follow-up period. The study was conducted at 126 sites in 9 countries between June 2011 and January 2013. Of 1361 participants assessed for eligibility, 846 were randomized. Inclusion criteria were body mass index of 27.0 or greater, age 18 years or older, taking 0 to 3 oral hypoglycemic agents (metformin, thiazolidinedione, sulfonylurea) with stable body weight, and glycated hemoglobin level 7.0% to 10.0%. INTERVENTIONS: Once-daily, subcutaneous liraglutide (3.0 mg) (n = 423), liraglutide (1.8 mg) (n = 211), or placebo (n = 212), all as adjunct to 500 kcal/d dietary deficit and increased physical activity (≥150 min/wk). MAIN OUTCOMES AND MEASURES: Three coprimary end points: relative change in weight, proportion of participants losing 5% or more, or more than 10%, of baseline weight at week 56. RESULTS: Baseline weight was 105.7 kg with liraglutide (3.0-mg dose), 105.8 kg with liraglutide (1.8-mg dose), and 106.5 kg with placebo. Weight loss was 6.0% (6.4 kg) with liraglutide (3.0-mg dose), 4.7% (5.0 kg) with liraglutide (1.8-mg dose), and 2.0% (2.2 kg) with placebo (estimated difference for liraglutide 3.0 mg vs placebo, −4.00% 95% CI, −5.10% to −2.90%; liraglutide 1.8 mg vs placebo, −2.71% 95% CI, −4.00% to −1.42%; P < .001 for both). Weight loss of 5% or greater occurred in 54.3% with liraglutide (3.0 mg) and 40.4% with liraglutide (1.8 mg) vs 21.4% with placebo (estimated difference for liraglutide 3.0 mg vs placebo, 32.9% 95% CI, 24.6% to 41.2%; for liraglutide 1.8 mg vs placebo, 19.0% 95% CI, 9.1% to 28.8%; P < .001 for both). Weight loss greater than 10% occurred in 25.2% with liraglutide (3.0 mg) and 15.9% with liraglutide (1.8 mg) vs 6.7% with placebo (estimated difference for liraglutide 3.0 mg vs placebo, 18.5% 95% CI, 12.7% to 24.4%, P < .001; for liraglutide 1.8 mg vs placebo, 9.3% 95% CI, 2.7% to 15.8%, P = .006). More gastrointestinal disorders were reported with liraglutide (3.0 mg) vs liraglutide (1.8 mg) and placebo. No pancreatitis was reported. CONCLUSIONS AND RELEVANCE: Among overweight and obese participants with type 2 diabetes, use of subcutaneous liraglutide (3.0 mg) daily, compared with placebo, resulted in weight loss over 56 weeks. Further studies are needed to evaluate longer-term efficacy and safety. TRIAL REGISTRATION: clinicaltrials.gov Identifier:NCT01272232
Summary
Several studies have shown training induced morphological changes in the heart. Our aim was to assess how frequent, low‐intensity exercise (walking and cycling) influences heart function and ...morphology in abdominally obese women. Fifty women with abdominal obesity (mean age 47·0 ± 7·5 years, waist circumference (WC) 103·2 ± 7·8 cm), free of cardiovascular problems were recruited. They were equipped with a bicycle and pedometers and instructed to start commuting in a physically active way for 6 months. Evaluation of cardiac function and morphology was performed using echocardiography (ECHO) before and after 6 months of training. The subjects increased significantly their daily physical activity. After 6 months, there was a significant decrease in WC (from 103·3 ± 7·9 to 100·8 ± 8·4 cm, P = 0·0003), in systolic and diastolic blood pressure (126·8 ± 15·2 to 120·4 ± 14·5 mmHg, P = 0·0001, and 79·8 ± 7·8 to 77·8 ± 8·4 mmHg, P = 0·0006, respectively). ECHO showed an increase in the right ventricular (RV) systolic longitudinal function expressed as tricuspid annular motion from 22·00 ± 3·30 to 23·05 ± 3·59 mm, P = 0·015; and a similar trend in left ventricular (LV) mitral annular motion, which increased from 13·09 ± 1·53 to 13·39 ± 1·47 mm, P = 0·070. Cycling was associated with reductions in LV systolic and RV diastolic dimensions, whereas walking was not associated with any changes in the ECHO‐variables. A reduction in WC by frequent, low‐intensity exercise in abdominally obese women is associated with decrease in blood pressure and improved longitudinal RV systolic function.
Hyperinsulinemic hypoglycemia (HH) is a post-operative complication after Roux-en-Y gastric bypass (RYGBP). The dietary intake affects the symptoms but is not well-studied. Therefore, the aim of this ...study was to assess the compliance to the dietary recommendations of patients with HH compared to healthy controls after RYGBP.
Food intake of ten patients with HH and nine controls was registered during seven days. Meals per day, energy distribution, carbohydrate quality and nutrient content were compared between the two groups and also to the dietary recommendations.
Meals per day and energy distribution complied with the dietary recommendations in both groups. The fiber intake was lower in both groups compared to the recommendations. The maximum dietary recommendation for added sugar (10% of total energy intake) was exceeded by both groups; those with HH (14.6% of total energy intake) and the control group (11.4% of total energy intake) but the difference was not statistically significant (p = 0.327). The group with HH had a lower intake of vitamin B12 (3.4 ± 1.5 μg vs 5.5 ± 2.3 μg, p < 0.05) and calcium (680 ± 193 mg vs 866 ± 184 mg, p < 0.05) compared to the control group. The proportion of subjects (with no difference between the two groups) that actually complied with the dietary recommendations was only 16% for vitamin D, 53% for vitamin A, and 26% for iron.
The study does not show significant differences in compliance to the dietary recommendations between the HH group compared to healthy controls apart from lower intake of B12 and calcium in the HH group. However, there are trends towards higher intake of sugar, i.e. poor carbohydrate quality and lower micronutrient content in the group with HH. Both groups also exceeded the recommended dietary intake of added sugar. The study also shows that the overall intake of dietary micronutrients after RYGBP is inadequate, whether the patients have HH or not.
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