A Randomized Controlled Clinical Trial of Lifestyle Intervention and Pioglitazone for Normalization of Glucose Status in Chinese with Prediabetes

Aims. Prediabetes has been proved as an important risk factor of both diabetes and cardiovascular disease (CVD). Previous studies have shown that both lifestyle intervention and pioglitazone may delay the development of diabetes in patients with prediabetes. However, no study has ever explored whether these interventions could revert prediabetes to normal glycemic status as the primary outcome. Interventions that may revert prediabetes back to normal glucose status would be of great clinical importance. Materials and Methods. We conducted a randomized, multicenter, 2 × 2 factorial designed study to examine whether intensive lifestyle intervention and/or pioglitazone could revert prediabetes to normal glucose tolerance. The participants were followed up for three years unless they reverted to normal glucose state or developed diabetes at the annual oral glucose tolerance test (OGTT). Reversion to normal glucose tolerance was confirmed on the basis of the results of OGTT. Results. In our study, 1945 eligible patients were ultimately randomized into four groups. In this three-year follow-up study, overall, 60.0%, 50.3%, 56.6% and 65.1% reverted back to normoglycemic state over 3 years of follow-up in the conventional lifestyle intervention plus placebo, intensive lifestyle intervention plus placebo, conventional lifestyle intervention plus pioglitazone, and intensive lifestyle intervention plus pioglitazone groups, respectively. Compared to the conventional lifestyle intervention plus placebo group, all the other three groups did not show any significant benefit in terms of reverting back to normoglycemic state. Conclusion. In our study, for patients with prediabetes, neither intensive lifestyle intervention nor pioglitazone had led to a higher reversion rate to normal glucose state. Trail registration.http://www.chictr.org.cn: ChiCTR-PRC-06000005.

The Association of Prior Intensive Lifestyle Intervention and Diabetes Support and Education with Frailty Prevalence at Long-Term Follow-up in the Action for Health in Diabetes Extension Study

Background Frailty is common in older adults with obesity and diabetes. We compared prevalence of the frailty phenotype between intervention groups in long-term follow-up of Look AHEAD, a randomized trial comparing a multidomain intensive lifestyle intervention (ILI) that promoted weight loss and physical activity with a diabetes support and education (DSE) control group in adults with type 2 diabetes and overweight or obesity. Methods Participants included 2,979 individuals randomized to ILI or DSE in 2001-04 who completed frailty assessment in Look AHEAD - Extension Wave 1 (2016-2018) at average age of 72.1 ± 6.2 years. Frailty was assessed using a modified frailty phenotype (excluding weight loss) defined as the presence of 3 or more of: weakness, slow gait speed, low physical activity, and exhaustion. Frailty odds by intervention assignment (DSE vs. ILI) were estimated using multivariable logistic regression, adjusting for sex, clinic site, and time since randomization. Results At median follow-up of 14.0 years [IQR: 13.8-14.1], frailty prevalence was 10.9% in ILI compared with 11.6% in DSE (odds ratio for frailty in ILI vs. DSE =0.94, 95% confidence interval = 0.75-1.18, P =0.60). Frailty was more prevalent in participants who were older, female, non-white, of lower socioeconomic status, and at baseline had a higher BMI and waist circumference, longer duration of diabetes, history of CVD, and metabolic syndrome. Conclusions Prior randomization to ILI compared with DSE was not associated with a lower prevalence of frailty after a median follow-up of 14.0 years in adults with diabetes and overweight or obesity.

Intervention-specific association of weight variability with major adverse cardiovascular events in overweight or obese adults with type 2 diabetes mellitus

Background Weight variability is associated with cardiovascular outcomes in diabetic patients. However, the effect of higher weight variability caused by intensive lifestyle intervention (ILI) on cardiovascular outcomes in diabetic patients is not well established. We aimed to evaluate the intervention-specific association between weight variability with major adverse cardiovascular event (MACE) among overweight or obese adults with diabetes. Methods In 3,859 participants from the Action for Health in Diabetes (Look AHEAD) trial, multivariate-adjusted Cox regression models were used to evaluate the associations of weight variability measured by variability independent of the mean (VIM) with MACE and secondary outcomes in intensive lifestyle intervention (ILI) and diabetes support & education (DSE) arm, respectively. Results During a median follow-up of 9.6 years, 255 (12.9%) participants in the ILI arm and 247 (13.2%) participants in the DSE arm developed MACE. Participants with the highest quartile of weight variability (VIM Q4) experienced a 2.23-fold higher risk of MACE compared with the lowest quartile (VIM Q1) in the DSE arm (hazard ratio [HR] 2.23; 95% CI 1.51–3.30), but not the ILI arm (HR 1.05; 95% CI 0.73–1.50). Moreover, compared with the lowest weight variability (VIM Q1), participants with the highest weight variability (VIM Q4) were not associated with all secondary outcomes in the ILI arm (all P>0.05) but were associated with the higher risks of secondary cardiovascular composite outcome (HR 1.88; 95% CI 1.20–2.95), all-cause mortality (HR 3.19; 95% CI 1.75–5.82), and myocardial infarction (HR 1.95; 95% CI 1.12–3.37) in the DSE arm. Conclusions Among the overweight or obese individuals with type 2 diabetes mellitus, rising weight variability was independently associated with increased MACE risks in the DSE arm but not the ILI arm. Therefore, a guideline-recommended ILI strategy for weight loss should be adopted to improve cardiovascular outcomes without considering the effect of high weight variability. FUNDunding Acknowledgement Type of funding sources: None.

Intensive Lifestyle Intervention Increases Plasma Midregional Proatrial Natriuretic Peptide Concentrations in Overweight Children

Background Overweight adults have low circulating concentrations of ANP (atrial natriuretic peptide) and proANP fragments. We tested the hypothesis that an intensive lifestyle intervention with an intended weight loss would increase plasma concentrations of a proANP fragment in overweight children. Methods and Results We measured MR‐proANP (midregional proANP) concentrations in plasma from overweight children who participated in the OOIS (Odense Overweight Intervention Study). OOIS randomized 115 overweight children (11–13 years, 55% girls) to an intensive day‐camp intervention arm with increased physical activity and healthy diet or to a less intensive standard intervention arm for 6 weeks. We used linear mixed‐effects modeling for repeated measures to estimate the difference in the mean change with 95% CIs in fasting plasma MR‐proANP concentrations between the 2 arms, and we used partial least squares regression analysis to identify candidate mediators. Differences in weight, fitness, and metabolic factors were also analyzed. At baseline, fasting plasma MR‐proANP concentrations were (median [interquartile range]) 35.0 pmol/L (26.8–42.0) in the day‐camp intervention arm and 37.2 pmol/L (31.7–44.7) in standard intervention arm participants, respectively. After 6 weeks intervention, children in the day‐camp intervention arm had increased their MR‐proANP (5.4 pmol/L [0.8–10.0], P =0.022) and their fitness (2.33 mL O 2 /min per kg [0.52–4.14], P =0.012) and they had deceased their body mass index (−2.12 kg/m 2 [−2.59 to −1.65], P <0.001) as compared with children in standard intervention arm. In the partial least squares analysis, decreases in fasting insulin and in estimated insulin resistance were associated with the observed increase in MR‐proANP concentrations. Conclusions An intensive lifestyle intervention increases plasma MR‐proANP among overweight children. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01574352.

A clinical diabetes risk prediction model for prediabetic women with prior gestational diabetes

Introduction Without treatment, prediabetic women with a history of gestational diabetes mellitus (GDM) are at greater risk for developing type 2 diabetes compared with women without a history of GDM. Both intensive lifestyle intervention and metformin can reduce risk. To predict risk and treatment response, we developed a risk prediction model specifically for women with prior GDM. Methods The Diabetes Prevention Program was a randomized controlled trial to evaluate the effectiveness of intensive lifestyle intervention, metformin (850mg twice daily), and placebo in preventing diabetes. Data from the Diabetes Prevention Program (DPP) was used to conduct a secondary analysis to evaluate 11 baseline clinical variables of 317 women with prediabetes and a self-reported history of GDM to develop a 3-year diabetes risk prediction model using Cox proportional hazards regression. Reduced models were explored and compared with the main model. Results Within three years, 82 (25.9%) women developed diabetes. In our parsimonious model using 4 of 11 clinical variables, higher fasting glucose and hemoglobin A1C were each associated with greater risk for diabetes (each hazard ratio approximately 1.4), and there was an interaction between treatment arm and BMI suggesting that metformin was more effective relative to no treatment for BMI ≥ 35kg/m2 than BMI < 30kg/m2. The model had fair discrimination (bias corrected C index = 0.68) and was not significantly different from our main model using 11 clinical variables. The estimated incidence of diabetes without treatment was 37.4%, compared to 20.0% with intensive lifestyle intervention or metformin treatment for women with a prior GDM. Conclusions A clinical prediction model was developed for individualized decision making for prediabetes treatment in women with prior GDM.