Intensive Lifestyle Group Research Articles

Effects of metformin and intensive lifestyle interventions on the incidence of kidney disease in adults in the DPP/DPPOS

AimsWe analyzed the incidence of kidney disease in the Diabetes Prevention Program Outcomes Study (DPPOS) by originally randomized treatment group assignment: Intensive Lifestyle (ILS), Metformin (MET) or Placebo (PLB). MethodsThe current analyses used a time-to-event approach in which the primary outcome was kidney disease, ascertained as urine albumin-to-creatinine ratio (ACR) ≥ 3.39 mg/mmol (30 mg/g) or eGFR <45 mL/min/1.73m2, with confirmation required at the next visit, or adjudicated end-stage kidney disease (ESKD). ResultsAt a median of 21 years following randomization in DPP, diabetes development was reduced in both the ILS (HR 0.73 [95%CI = 0.62, 0.85]) and MET groups (HR 0.85 [0.73, 0.99]) compared to the PLB group. Although risk for developing the primary kidney disease outcome was higher among those with incident diabetes compared to those without (HR 1.81 [1.43, 2.30]), it did not differ by intervention groups (ILS vs. PLB 1.02 (0.81, 1.29); MET vs. PLB 1.08 (0.86, 1.35). There was a non-significant metformin by age interaction (p = 0.057), with metformin being beneficial for kidney disease in the younger but potentially harmful in the older participants. ConclusionsDevelopment of kidney disease was increased in participants who developed diabetes but did not differ by original treatment group assignment. Clinical trial registrationsDiabetes Prevention Program (DPP) Clinical trial reg. no. NCT00004992DPP Outcomes Study (DPPOS) Clinical trial reg. no. NCT0038727

1119-P: Persistent and Heterogeneous Long-Term Effects of the Diabetes Prevention Program (DPP) Intensive Lifestyle (ILS) Intervention on Diabetes Incidence

During the three years of the DPP, ILS reduced incidence of diabetes compared with placebo in high-risk adults. Diabetes was defined using ADA criteria based on 1) annual OGTT or semi-annual fasting glucose (the primary DPP outcome, diab-G, hazard ratio (HR) =0.42 and rate difference (RD) = -6.2 cases/100 person-years) or 2) annual HbA1c ≥ 6.5% (diab‑A1C, HR=0.51 and RD = -4.2) . After DPP ended, participants were unmasked, placebo was discontinued, and all participants were offered group-based ILS and followed in the DPP Outcomes Study. We now compare the original ILS and placebo groups over a mean of 21 years since randomization. We test heterogeneity across subgroups defined by demographics and baseline glucose, HbA1c, BMI, and history of gestational diabetes and express it by interaction p-values (P-het) . During the total follow-up, ILS, compared with placebo, significantly reduced incidence of diab‑G: HR=0.76 (95% CI=0.68, 0.85) , RD= -1.62 (-2.28, -0.97) and of diab-A1C: HR=0.80 (0.70, 0.92) , RD= -1.67 (‑2.24, -1.10) . Effects on diab-G were homogenous across subgroups except for fasting glucose (P-het &amp;lt;0.01) and HbA1c (P-het &amp;lt;0.02) with greater effects at higher baseline values. By contrast, ILS reduced incidence of diab-A1C more in older than younger persons (P-het &amp;lt;0.02) , and more in men than women (P-het &amp;lt;0.03) . Notably, ILS was highly effective in reducing incidence of diab‑A1C if baseline HbA1c was already elevated (HbA1c=6.0-6.4%: HR=0.62, RD= -3.27) but ineffective if baseline HbA1c was normal by ADA criteria (HbA1c &amp;lt;5.7%: HR=1.09, RD= +0.19; P-het &amp;lt;0.001) . In sum, ILS effects on reducing incidence of diab-G and diab-A1C persisted but decreased during total follow-up from that observed during DPP (i.e., HRs and RDs closer to 1 and 0) . ILS effects on diab-G were greater in those with higher baseline fasting glucose or HbA1c. Effects on diab-A1C were greater in men, older participants, and those with higher baseline HbA1c. Disclosure W.C. Knowler: None. S. Edelstein: None. P.H. Bennett: Stock/Shareholder; Baxter INTERNTN Health Care, Merck &amp; Co., Inc., UnitedHealth Group. D. Dabelea: None. M.A. Hoskin: None. S.E. Kahn: Advisory Panel; Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Inc., Merck &amp; Co., Inc., Novo Nordisk, Pfizer Inc. R. Kalyani: None. C. Kim: None. S. Raghavan: None. M. Temprosa: None. E.M. Venditti: Advisory Panel; PeopleOne Health. D.M. Nathan: None. D. Research Group: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (UDK048489, UDK048339, UDK048377, UDK048349, UDK048381, UDK048468, UDK048434, UDK048485, UDK048375, UDK048514, UDK048437, UDK048413, UDK048411, UDK048406, UDK048380, UDK048397, UDK048412, UDK048404, UDK048387, UDK048407, UDK048443, and UDK048400)

Effects of preconception lifestyle intervention in infertile women with obesity: The FIT-PLESE randomized controlled trial.

BackgroundWomen with obesity and infertility are counseled to lose weight prior to conception and infertility treatment to improve pregnancy rates and birth outcomes, although confirmatory evidence from randomized trials is lacking. We assessed whether a preconception intensive lifestyle intervention with acute weight loss is superior to a weight neutral intervention at achieving a healthy live birth.Methods and findingsIn this open-label, randomized controlled study (FIT-PLESE), 379 women with obesity (BMI ≥ 30 kg/m2) and unexplained infertility were randomly assigned in a 1:1 ratio to 2 preconception lifestyle modification groups lasting 16 weeks, between July 2015 and July 2018 (final follow-up September 2019) followed by infertility therapy. The primary outcome was the healthy live birth (term infant of normal weight without major anomalies) incidence. This was conducted at 9 academic health centers across the United States. The intensive group underwent increased physical activity and weight loss (target 7%) through meal replacements and medication (Orlistat) compared to a standard group with increased physical activity alone without weight loss. This was followed by standardized empiric infertility treatment consisting of 3 cycles of ovarian stimulation/intrauterine insemination. Outcomes of any resulting pregnancy were tracked. Among 191 women randomized to standard lifestyle group, 40 dropped out of the study before conception; among 188 women randomized to intensive lifestyle group, 31 dropped out of the study before conception. All the randomized women were included in the intent-to-treat analysis for primary outcome of a healthy live birth. There were no significant differences in the incidence of healthy live births [standard 29/191(15.2%), intensive 23/188(12.2%), rate ratio 0.81 (0.48 to 1.34), P = 0.40]. Intensive had significant weight loss compared to standard (−6.6 ± 5.4% versus −0.3 ± 3.2%, P < 0.001). There were improvements in metabolic health, including a marked decrease in incidence of the metabolic syndrome (baseline to 16 weeks: standard: 53.6% to 49.4%, intensive 52.8% to 32.2%, P = 0.003). Gastrointestinal side effects were significantly more common in intensive. There was a higher, but nonsignificant, first trimester pregnancy loss in the intensive group (33.3% versus 23.7% in standard, 95% rate ratio 1.40, 95% confidence interval [CI]: 0.79 to 2.50). The main limitations of the study are the limited power of the study to detect rare complications and the design difficulty in finding an adequate time matched control intervention, as the standard exercise intervention may have potentially been helpful or harmful.ConclusionsA preconception intensive lifestyle intervention for weight loss did not improve fertility or birth outcomes compared to an exercise intervention without targeted weight loss. Improvement in metabolic health may not translate into improved female fecundity.Trial registrationClinicalTrials.gov NCT02432209.

Weight Loss in Underserved Patients — A Cluster-Randomized Trial

BackgroundEvidence of the effectiveness of treatment for obesity delivered in primary care settings in underserved populations is lacking.MethodsWe conducted a cluster-randomized trial to test the effectiveness of a high-intensity, lifestyle-based program for obesity treatment delivered in primary care clinics in which a high percentage of the patients were from low-income populations. We randomly assigned 18 clinics to provide patients with either an intensive lifestyle intervention, which focused on reduced caloric intake and increased physical activity, or usual care. Patients in the intensive-lifestyle group participated in a high-intensity program delivered by health coaches embedded in the clinics. The program consisted of weekly sessions for the first 6 months, followed by monthly sessions for the remaining 18 months. Patients in the usual-care group received standard care from their primary care team. The primary outcome was the percent change from baseline in body weight at 24 months.ResultsAll 18 clinics (9 assigned to the intensive program and 9 assigned to usual care) completed 24 months of participation; a median of 40.5 patients were enrolled at each clinic. A total of 803 adults with obesity were enrolled: 452 were assigned to the intensive-lifestyle group, and 351 were assigned to the usual-care group; 67.2% of the patients were Black, and 65.5% had an annual household income of less than $40,000. Of the enrolled patients, 83.4% completed the 24-month trial. The percent weight loss at 24 months was significantly greater in the intensive-lifestyle group (change in body weight, −4.99%; 95% confidence interval [CI], −6.02 to −3.96) than in the usual-care group (−0.48%; 95% CI, −1.57 to 0.61), with a mean between-group difference of −4.51 percentage points (95% CI, −5.93 to −3.10) (P<0.001). There were no significant between-group differences in serious adverse events.ConclusionsA high-intensity, lifestyle-based treatment program for obesity delivered in an underserved primary care population resulted in clinically significant weight loss at 24 months. (Funded by the Patient-Centered Outcomes Research Institute and others; PROPEL ClinicalTrials.gov number, NCT02561221.)

Effects of an intensive lifestyle intervention on the underlying mechanisms of improved glycaemic control in individuals with type 2 diabetes: a secondary analysis of a randomised clinical trial.

The aim was to investigate whether an intensive lifestyle intervention, with high volumes of exercise, improves beta cell function and to explore the role of low-grade inflammation and body weight. This was a randomised, assessor-blinded, controlled trial. Ninety-eight individuals with type 2 diabetes (duration <10years), BMI of 25-40kg/m2, no use of insulin and taking fewer than three glucose-lowering medications were randomised (2:1) to either the standard care plus intensive lifestyle group or the standard care alone group. Standard care consisted of individual guidance on disease management, lifestyle advice and blinded regulation of medication following a pre-specified algorithm. The intensive lifestyle intervention consisted of aerobic exercise sessions that took place 5-6 times per week, combined with resistance exercise sessions 2-3 times per week, with a concomitant dietary intervention aiming for a BMI of 25kg/m2. In this secondary analysis beta cell function was assessed from the 2h OGTT-derived disposition index, which is defined as the product of the Matsuda and the insulinogenic indices. At baseline, individuals were 54.8years (SD 8.9), 47% women, type 2 diabetes duration 5years (IQR 3-8) and HbA1c was 49.3mmol/mol (SD 9.2); 6.7% (SD 0.8). The intensive lifestyle group showed 40% greater improvement in the disposition index compared with the standard care group (ratio of geometric mean change [RGM] 1.40 [95% CI 1.01, 1.94]) from baseline to 12months' follow-up. Plasma concentration of IL-1 receptor antagonist (IL-1ra) decreased 30% more in the intensive lifestyle group compared with the standard care group (RGM 0.70 [95% CI 0.58, 0.85]). Statistical single mediation analysis estimated that the intervention effect on the change in IL-1ra and the change in body weight explained to a similar extent (59%) the variance in the intervention effect on the disposition index. Our findings show that incorporating an intensive lifestyle intervention, with high volumes of exercise, in individuals with type 2 diabetes has the potential to improve beta cell function, associated with a decrease in low-grade inflammation and/or body weight. ClinicalTrials.gov NCT02417012 Graphical abstract.

Non-traditional biomarkers and incident diabetes in the Diabetes Prevention Program: comparative effects of lifestyle and metformin interventions.

We compared the associations of circulating biomarkers of inflammation, endothelial and adipocyte dysfunction and coagulation with incident diabetes in the placebo, lifestyle and metformin intervention arms of the Diabetes Prevention Program, a randomised clinical trial, to determine whether reported associations in general populations are reproduced in individuals with impaired glucose tolerance, and whether these associations are independent of traditional diabetes risk factors. We further investigated whether biomarker-incident diabetes associations are influenced by interventions that alter pathophysiology, biomarker concentrations and rates of incident diabetes. The Diabetes Prevention Program randomised 3234 individuals with impaired glucose tolerance into placebo, metformin (850mg twice daily) and intensive lifestyle groups and showed that metformin and lifestyle reduced incident diabetes by 31% and 58%, respectively compared with placebo over an average follow-up period of 3.2years. For this study, we measured adiponectin, leptin, tissue plasminogen activator (as a surrogate for plasminogen activator inhibitor 1), high-sensitivity C-reactive protein, IL-6, monocyte chemotactic protein 1, fibrinogen, E-selectin and intercellular adhesion molecule 1 at baseline and at 1year by specific immunoassays. Traditional diabetes risk factors were defined as family history, HDL-cholesterol, triacylglycerol, BMI, fasting and 2h glucose, HbA1c, systolic blood pressure, inverse of fasting insulin and insulinogenic index. Cox proportional hazard models were used to assess the effects of each biomarker on the development of diabetes assessed semi-annually and the effects of covariates on these. E-selectin, (HR 1.19 [95% CI 1.06, 1.34]), adiponectin (0.84 [0.71, 0.99]) and tissue plasminogen activator (1.13 [1.03, 1.24]) were associated with incident diabetes in the placebo group, independent of diabetes risk factors. Only the association between adiponectin and diabetes was maintained in the lifestyle (0.69 [0.52, 0.92]) and metformin groups (0.79 [0.66, 0.94]). E-selectin was not related to diabetes development in either lifestyle or metformin groups. A novel association appeared for change in IL-6 in the metformin group (1.09 [1.021, 1.173]) and for baseline leptin in the lifestyle groups (1.31 [1.06, 1.63]). These findings clarify associations between an extensive group of biomarkers and incident diabetes in a multi-ethnic cohort with impaired glucose tolerance, the effects of diabetes risk factors on these, and demonstrate differential modification of associations by interventions. They strengthen evidence linking adiponectin to diabetes development, and argue against a central role for endothelial dysfunction. The findings have implications for the pathophysiology of diabetes development and its prevention.

Risk of suicide and non-fatal self-harm after bariatric surgery: results from two matched cohort studies

SUMMARYBACKGROUNDBariatric surgery reduces mortality, but may have adverse effects on mental health. We assessed suicide risk after surgical compared to nonsurgical obesity treatment.METHODSSuicide and nonfatal self-harm events retrieved from nationwide Swedish registers were examined in two cohorts. The nonrandomised prospective Swedish Obese Subjects (SOS) study compares bariatric surgery (n=2010; 1369 vertical-banded gastroplasty, 376 gastric banding, 265 gastric bypass) with usual care (n=2037; recruitment 1987–2001). The second cohort comprises individuals from the Scandinavian Obesity Surgery Registry (SOReg; n=20,256 gastric bypass patients) matched to individuals treated with intensive lifestyle modification (n=16,162; intervention 2006–2013) on baseline BMI, age, sex, education level, diabetes, cardiovascular disease, history of self-harm, substance abuse, antidepressant use, anxiolytics use, and psychiatric healthcare contacts.FINDINGSDuring 68,528 person-years (median 18; interquartile range 14–21) in SOS, there were 87 versus 49 suicides or nonfatal self-harm events in the surgery and control groups (adjusted hazard ratio [aHR] 1.78 [95%CI 1.23–2.57]; P=0.0021), of which 9 and 3 were suicides (3.06 [0.79–11.9]; P=0.107). In analyses by primary procedure type, increased risk of suicide or nonfatal self-harm was observed for gastric bypass (aHR 3.48 *1.65–7.31+; P=0.0010), gastric banding (2.43 *1.23–4.82+; P=0.011) and vertical-banded gastroplasty compared to controls (2.25 *1.37–3.71+; P=0.0015). Out of 9 deaths by suicide in the SOS surgery group, 5 occurred after gastric bypass (2 primary and 3 converted procedures). During 149,582 person-years (median 3.9; interquartile range 2.8–5.2), there were 341 suicides or nonfatal self-harm events in the SOReg gastric bypass group and 84 in the intensive lifestyle group (aHR 3.16 [2.46–4.06]; P<0.0001), of which 33 and 5 were suicides (5.17 [1.86–14.4]; P=0.0017). In SOS, substance abuse was recorded in 48% (39/81) of surgery patients and 28% (13/47) of controls with nonfatal self-harm events (P=0.023). The corresponding percentages for SOReg gastric bypass and intensive lifestyle participants were 51% (162/316) versus 29% (23/80; P=0.0003).INTERPRETATIONBariatric surgery was associated with suicide and nonfatal self-harm. Although the absolute risks were low, the findings indicate a need for post-operative psychiatric surveillance and patient information before surgery regarding self-harm.FUNDINGUS National Institutes of Health and Swedish Research Council

The effect of dietary changes on distinct components of the metabolic syndrome in a young Sri Lankan population at high risk of CVD.

South Asian populations are predisposed to early onset of the metabolic syndrome. Lifestyle intervention programmes have demonstrated a reduction in the metabolic syndrome and CVD risk; however, the most effective components of the multi-faceted lifestyle interventions are unknown. We studied 2637 Sri Lankan males (n 1237) and females (n 1380), with a mean BMI of 23·9 (sd 4·2) kg/m2, aged 22·5 (sd 10·0) years, who had participated in a 5-year lifestyle-modification programme to examine the effect of dietary changes on distinct components of the metabolic syndrome. The dietary intervention comprised advice to replace polished starches with unpolished starches, high-fat meat and dairy products with low-fat products and high-sugar beverages and snacks with low-sugar varieties. For the purposes of this analysis, data from the control and intensive lifestyle groups were combined. Anthropometric and biochemical data were recorded, and a FFQ was completed annually. Multiple regression was used to determine the effect of the dietary changes on distinct components of the metabolic syndrome. The ratio unpolished:polished rice was inversely related to change in fasting glucose (β=-0·084, P=0·007) and TAG (β=-0·084, P=0·005) and positively associated with change in HDL-cholesterol (β=0·066, P=0·031) at the 5-year follow-up after controlling for relevant confounders. Red meat intake was positively associated with fasting glucose concentrations (β=0·05, P=0·017), whereas low-fat (β=-0·046, P=0·018) but not high-fat dairy products (β=0·003, P=0·853) was inversely related to glucose tolerance at the follow-up visit. Replacement of polished with unpolished rice may be a particularly effective dietary advice in this and similar populations.

Implications of Look AHEAD for clinical trials and clinical practice.

Look AHEAD (Action for Health in Diabetes) was a randomized clinical trial designed to examine the long-term health effects of weight loss in overweight and obese individuals with type 2 diabetes. The primary result was that the incidence of cardiovascular events over a median follow-up of 9.6 years was not reduced in the Intensive Lifestyle Group relative to the control group. This finding is discussed, with emphasis on its implications for design of trials and clinical treatment of obese persons with type 2 diabetes.

Prevention of Weight Gain in Adult Patients With Type 2 Diabetes Treated With Pioglitazone

Pioglitazone, a thiazolidinedione (TZD) commonly used to treat type 2 diabetes, is associated with weight gain. Our study was designed to examine the effectiveness of three lifestyle-treatment programs of varying intensity on prevention of pioglitazone-induced weight gain and to measure the composition of the change in body weight. Thirty-nine adult overweight and obese subjects with type 2 diabetes mellitus were all treated with pioglitazone and prospectively randomized to one of three lifestyle-treatment programs with increasing level of intensity for 24 weeks. Body composition was measured by dual-energy X-ray absorptiometry (DXA), computed tomography, and multifrequency bioimpedance analysis both before and after therapy. Subjects demonstrated a "dose-response" effectiveness to three levels of lifestyle intervention to mitigate pioglitazone-induced weight gain. Mean (s.d.) weight change (kg) for the usual, standard, and intensive lifestyle groups were 4.9 +/- 4.9 (P = 0.005), 1.8 +/- 3.4 (P = 0.02), and -0.2 +/- 4.4 (NS) respectively. Total body fat increased 2.6 +/- 3.4 kg (P = 0.04) for the usual group and decreased for the intensive group -0.4 +/- 3.5 (NS). Change in abdominal subcutaneous and visceral adipose tissue (VAT) did not differ between groups, although ratio of visceral/subcutaneous fat decreased for the standard and intensive groups (NS). Both usual (P < 0.05) and standard care (NS) groups gained total body water. This is the first prospective, randomized study that demonstrates the beneficial effect of participation in a comprehensive lifestyle-weight-management program on lessening of weight gain associated with pioglitazone.

Changes in Albumin Excretion in the Diabetes Prevention Program

OBJECTIVEIncreased urinary albumin excretion rates have been linked to nephropathy and macrovascular disease. We here describe the baseline prevalence and effect of Diabetes Prevention Program (DPP) interventions on the development and reversal of elevated albumin excretion.RESEARCH DESIGN AND METHODSUrine albumin-to-creatinine ratios (ACRs) were calculated from untimed urine collections. Analyses compared participants by treatment group, diabetes and hypertension status, and use of ACE inhibitors or angiotensin II receptor blockers (ARBs).RESULTSElevated ACR levels (≥30 mg/g creatinine) were present at baseline in 198 (6.2%) of 3,188 participants: placebo 5.3%, metformin 6.5%, and intensive lifestyle (ILS) 6.8%. Of the 2,802 with ACR measurements at baseline and at the end of the study, the percentage with elevated levels declined (incident and regression) from 6.2 to 6.1%, with no significant differences between the groups even with adjustment for ACE inhibitor and ARB use. The odds of developing an elevated ACR were 59% higher for a participant who developed diabetes compared with one who did not.CONCLUSIONSAt entry into the DPP, an elevated ACR was present in 6.2%. Despite the marked decrease in progression to diabetes and the improvement in insulin resistance and other cardiovascular risk markers in the ILS and metformin groups, there was no improvement in ACR, on average, in those two groups. However, the frequency of an elevated ACR was higher in participants who developed diabetes. An increased ACR may have multiple causes, thus obscuring the improvements that might have been expected with the reduction in insulin resistance seen in the DPP.

Impact of Intensive Lifestyle and Metformin Therapy on Cardiovascular Disease Risk Factors in the Diabetes Prevention Program

The Diabetes Prevention Program demonstrated the ability to delay or prevent type 2 diabetes in participants with impaired glucose tolerance (IGT). Participants with IGT are at high risk for cardiovascular disease (CVD), with a marked increase in the number and severity of CVD risk factors. We prospectively assessed the impact of our interventions on hypertension, dyslipidemia, and CVD events. The study group consisted of 3,234 individuals with IGT randomly assigned to receive intensive lifestyle intervention, metformin, or placebo. Annual assessment of blood pressure, lipids, electrocardiogram, and CVD events was undertaken. Hypertension was present in 30% of participants at study entry and then increased in the placebo and metformin groups, although it significantly decreased with intensive lifestyle intervention. Triglyceride levels fell in all treatment groups, but fell significantly more with intensive lifestyle intervention. Total cholesterol and LDL cholesterol levels were similar among treatment groups. Intensive lifestyle intervention significantly increased the HDL cholesterol level and reduced the cumulative incidence of the proatherogenic LDL phenotype B. At 3 years of follow-up, the use for pharmacologic therapy to achieve established goals in the intensive lifestyle group was 27-28% less for hypertension and 25% less for hyperlipidemia compared with placebo and metformin groups. Over an average of 3 years, 89 CVD events from 64 participants were positively adjudicated studywide, with no differences among treatment groups. Lifestyle intervention improves CVD risk factor status compared with placebo and metformin therapy. Although no differences in CVD events were noted after 3 years, achieved risk factor modifications suggest that longer intervention may reduce CVD event rates.