BEYOND 2 years: durability of metabolic benefits by simplification of complex insulin regimens in type 2 diabetes.

PURPOSE: To assess the magnitude and durability of the metabolic benefits by simplification of complex insulin treatments in patients with type 2 diabetes inadequately controlled by a full basal-bolus insulin regimen. Herein we report the results of the scheduled 2-year extension of the BEYOND trial. METHODS: Originally, 305 participants with inadequate glycemic control (HbA1c > 7.5%) were randomly assigned to intensification of basal-bolus insulin regimen (n = 101), to a fixed-ratio combination (basal insulin + GLP-1RA, n = 102), or to an association of basal insulin plus an SGLT-2 inhibitor (gliflo-combo, n = 102). The primary efficacy outcome was change from baseline in HbA1c at 24 months assessed by an intention-to-treat analysis. A per-protocol analysis was also performed. RESULTS: Fifty-five percent of patients completed the study in the two comparison arms. Compared with patients randomized to basal-bolus, patients of the other groups experienced non statistically different reductions in HbA1c level according to either an intention-to-treat analysis (-0.8 ± 1.1%, -0.7 ± 1.1%, and -1.3 ± 1.1%, mean ± SD, fixed-ratio, gliflo-combo and basal bolus, respectively) or per-protocol analysis (-1.2 ± 1.0%, -1.2 ± 1.1%, and -1.3 ± 1.0%, respectively). The final HbA1c level (per protocol) was 7.2 ± 0.8%, 7.3 ± 0.9%, and 7.5 ± 0.9%, respectively (P = NS). Treatment satisfaction (DTSQ) increased in both exchange groups, whereas the proportion of patients with hypoglycemia was lower. CONCLUSION: Simplification of complex insulin regimen may be a durable option in at least one-half of patients with type 2 diabetes. CLINICAL TRIAL REGISTRATION: Clinical trial registration no. NCT04196231, clinicaltrials.gov.

Glucose control during breakthrough SARS-CoV-2 infections in vaccinated patients with type 1 diabetes.

AIMS: This study aims at evaluating the trend of glycemic control metrics during the infection of SARS-CoV-2 in individuals with Type 1 Diabetes (T1D) using a Continuous Glucose Monitoring (CGM) system and vaccinated against COVID-19. MATERIALS AND METHODS: This is a retrospective study of T1D subjects who got a breakthrough SARS-CoV-2 infection between November 2021 and February 2022. Data of glycemic control of CGM-derived metrics were compared 14 days before COVID-19 (Time 1), 14 days during COVID-19 (Time 2) and 14 days after COVID-19 (Time 3). RESULTS: A total of 106 patients with T1D and breakthrough SARS-CoV-2 infection was included in the analysis. A significant reduction of GMI [%, 7.41 ± 1.60 vs 7.52 ± 1.63, P = 0.006)] and increase of TIR [%, 54.6 ± 20.4 vs 52.1 ± 19.7, P = 0.026] were observed at Time 3 as compared with Time 2. There was a significant reduction of SD (P < 0.001) and CV (P < 0.001) at Time 3 and Time 2 as compared with Time 1, associated with significant changes of mean glucose levels, TBR level 1 and total daily insulin doses. CONCLUSIONS: Breakthrough SARS-CoV-2 infection did not worsen glycemic control in vaccinated people with T1D.

Clinical Practice Experiences Using a Professional Diabetes Management Ecosystem During COVID.

BACKGROUND: Challenges of patient care in diabetes were exacerbated by COVID, undermining the ability of patients to engage in-person with health care professionals (HCPs). To combat this, there has been accelerated adoption of telemedicine to support patient and provider connectivity. METHODS: We collated survey information regarding telemedicine from 21 European clinical institutions. Health care professionals joined virtual meetings focusing on the OneTouch Reveal (OTR) ecosystem and its utility for conducting telemedicine. Selected HCPs provided clinical case studies to explain how the OTR ecosystem supported patient care. RESULTS: Remote consultations increased by nearly 50% in 21 European clinics during the pandemic (Belgium [24%], Iberia [65%], Germany [34%], Italy [54%]). In all, 52% of people with diabetes using OTR app to connect remotely with HCPs had type 1 diabetes and 48% had type 2 diabetes. Remote connection methods included telephone (60%), email (19%), video chat (10%), text only (3%), or a mix of these methods (8%). Health care professionals usually reviewed patient data during consultations (45%) rather than before consultations (25%). Fifty-five percent of HCPs indicated digital ecosystems like OTR ecosystem would become their standard of care for diabetes management. In-depth conversations with HCPs provided a deeper understanding of how a digital ecosystem integrated into clinical practice and population management. In addition, five patient case studies using OTR ecosystem were provided by a selection of our HCPs. CONCLUSION: Diabetes management solutions, such as OTR ecosystem, supported telemedicine during the pandemic and will continue to play a valuable role in patient care beyond the pandemic.

Maternal and Fetal Outcomes in Women with Diabetes in Pregnancy Treated before and after the Introduction of a Standardized Multidisciplinary Management Protocol.

BACKGROUND: Diabetes in pregnancy is associated with an increased risk to the woman and to the developing fetus. Currently, there is no consensus on the optimal management strategies for the follow-up and the timing of delivery of pregnancies affected by gestational and pregestational diabetes, with different international guidelines suggesting different management options. MATERIALS AND METHODS: We conducted a retrospective cohort study from January 2017 to January 2021, to compare maternal and neonatal outcomes of pregnancies complicated by gestational and pregestational diabetes, followed-up and delivered in a third level referral center before and after the introduction of a standardized multidisciplinary management protocol including diagnostic, screening, and management criteria. RESULTS: Of the 131 women included, 55 were managed before the introduction of the multidisciplinary management protocol and included in group 1 (preprotocol), while 76 were managed according to the newly introduced multidisciplinary protocol and included in group 2 (after protocol). We observed an increase in the rates of vaginal delivery, rising from 32.7% to 64.5% (<0.001), and the rate of successful induction of labor improved from 28.6% to 86.2% (P < 0.001). No differences were found in neonatal outcomes, and the only significant difference was demonstrated for the rates of fetal macrosomia (20% versus 5.3%, P: 0.012). Therefore, the improvements observed in the maternal outcomes did not impact negatively on fetal and neonatal outcomes. CONCLUSION: The introduction of a standardized multidisciplinary management protocol led to an improvement in the rates of vaginal delivery and in the rate of successful induction of labor in our center. A strong cooperation between obstetricians, diabetologists, and neonatologists is crucial to obtain a successful outcome in women with diabetes in pregnancy.

Feasibility of Simplification From a Basal-Bolus Insulin Regimen to a Fixed-Ratio Formulation of Basal Insulin Plus a GLP-1RA or to Basal Insulin Plus an SGLT2 Inhibitor: BEYOND, a Randomized, Pragmatic Trial.

OBJECTIVE: BEYOND trial evaluated the feasibility of either basal insulin plus glucagon-like peptide 1 receptor agonist (GLP-1RA) or basal insulin plus sodium-glucose cotransporter 2 inhibitor (SGLT2i) to replace a full basal-bolus insulin (BBI) regimen in participants with type 2 diabetes and inadequate glycemic control. RESEARCH DESIGN AND METHODS: Participants were randomized (1:1:1) to: 1) intensification of the BBI regimen (n = 101), 2) fixed ratio of basal insulin plus GLP-1RA (fixed-combo group; n = 102), and 3) combination of basal insulin plus SGLT2i (gliflo-combo group; n = 102). The primary efficacy outcome was change from baseline in HbA1c at 6 months. RESULTS: Baseline characteristics were similar among the three groups (mean HbA1c was 8.6% [70 mmol/mol]). At 6 months, patients experienced similar reduction in HbA1c level (-0.6 ± 0.8, -0.6 ± 0.8, and -0.7 ± 0.9%, mean ± SD, respectively; noninferiority P < 0.001 vs. BBI), and the proportion of patients with HbA1c ≤7.5% was also similar (34%, 28%, and 27%, respectively; P = 0.489). Total insulin dose increased in the BBI group (62 units/day) and decreased both in the fixed-combo and gliflo-combo groups (27 units/day and 21 units/day, respectively; P < 0.01). The proportion of patients with hypoglycemia was 17.8%, 7.8%, and 5.9%, respectively (P = 0.015). There were 12 dropouts in the fixed-combo group, 9 in the gliflo-combo group, and none in the BBI group. CONCLUSIONS: BEYOND provides evidence that it is possible and safe to switch from a BBI regimen to either a once-daily fixed-combo injection or once-daily gliflozin added to basal insulin, with similar glucose control, fewer insulin doses, fewer injections daily, and less hypoglycemia.

Glycemic control in people with type 1 diabetes using a hybrid closed loop system and followed by telemedicine during the COVID-19 pandemic in Italy.

AIMS: This study aims at evaluating the metrics of glycemic control in people with type 1 diabetes using the hybrid closed loop (HCL) system during the COVID-19 lockdown. METHODS: This is a retrospective study of thirty adults with type 1 diabetes using HCL and followed with telemedicine at an Italian University Hospital. Data on metrics of glucose control were collected at different times: two weeks before the lockdown (Time 0), first two weeks of lockdown (Time 1), last two weeks of lockdown (Time 2) and first two weeks after the lockdown (Time 3). The primary endpoint was the change in glucose management indicator (GMI) across the different time points. RESULTS: GMI did not worsen over time (Time 1 vs Time 3, 7% vs 6.9%, P < 0.05), whereas a reduction of mean glucose (P = 0.004) and indices of glucose variability was observed. Time in range (TIR) significantly increased (68.5% vs 73.5%, P = 0.012), and time above range (TAR) level 2 (251-400 mg/dL) significantly decreased (P = 0.002). The improvement of TIR and glucose variability was mainly observed in participants < 35 years. CONCLUSIONS: Adults with type 1 diabetes using HCL showed a significant improvement of most of the metrics of glucose control during the COVID-19 lockdown.

Metabolic effectiveness of gliflozins and gliptins in the routine clinical practice of patients with type 2 diabetes: preliminary results from GIOIA, a prospective multicentre study.

AIMS: GIOIA is an ongoing prospective multicentre study aiming to assess the vascular and metabolic effects of SGLT-2 inhibitors (gliflozins) and DPP-4 inhibitors (gliptins) in the routine clinical practice of patients with type 2 diabetes (T2D). Herein we describe the preliminary effectiveness data at 6 months. METHODS: SGLT-2i and DPP-4i-naïve adult patients with T2D (N = 301 and 260, respectively), with glycated haemoglobin A1c (A1C) >7%, an estimated glomerular filtration rate (eGFR) ≥60 ml/min/1.73 m2, on background therapy with metformin, insulin or both, are being followed to evaluate markers of vascular (carotid intima-media thickness), myocardial (myocardial diastolic function) and renal (urinary albumin/creatinine ratio) damage during treatment with SGLT-2i or DPP-4i for a period of 24 months. RESULT: At baseline, patients initiated on SGLT-2i are younger (about 6 years) and more heavy (about 7.5 kg), have higher A1C level (0.5% more), a longer diabetes duration and more CV events (20% more) than patients initiated on DPP-4i. At 6 months, patients on SGLT-2i (N = 298) and DPP-4i (N = 258) exhibit significant ameliorations in A1C (-1.% and -0.7%, respectively), which were greater (-1.2% and -0.81%) in those on a background metformin treatment only. The composite endpoint (A1C ≤ 7.0% + weight loss ≥ 3 kg) was achieved by 24% and 16% of patients receiving SGLT-2i or DPP-4i, respectively. No unexpected adverse events were reported. CONCLUSIONS: Both SGLT-2i and DPP-4i provide substantial improvements in metabolic parameters in the usual clinical practice of T2D, especially when used as second-line treatment.

Gender-differences in glycemic control and diabetes related factors in young adults with type 1 diabetes: results from the METRO study.

PURPOSE: To describe gender differences concerning glycemic control, cardiovascular risk factors, diabetic complications, concomitant pathologies, and circulating endothelial progenitor cells (EPCs), in a population of young adults with type 1 diabetes. METHODS: We collected data from 300 consecutively patients (168 males and 132 females), aged 18-30 years, among those admitted at Diabetes Unit of University of Campania "Luigi Vanvitelli" (Naples, Italy) from March 2012 to January 2017. Circulating levels of seven EPCs phenotypes were determined by flow cytometry. RESULTS: As compared to men, women with type 1 diabetes had a significantly higher HbA1c levels (%, 8.4 ± 1.3 vs. 8.1 ± 1.3, P = 0.020), body mass index (Kg/m2, 24.8 ± 4.2 vs. 23.9 ± 3.9, P = 0.034), HDL-cholesterol (mg/dL, 61.7 ± 13.7 vs. 54.7 ± 13.9, P < 0.001), and a lower count of both CD133+KDR+ and CD34+KDR+CD133+ EPCs (P = 0.022, P < 0.001, respectively). A higher proportion of women had overweight/obesity, and thyroiditis; smoking and sexual dysfunctions were more prevalent in men than in women. CONCLUSIONS: Young adults with type 1 diabetes present gender differences with regard to glycemic control, prevalence of some cardiovascular risk factors, sexual dysfunctions and circulating levels of EPCs, most often to the detriment of women.

The Effects of Subcutaneous Insulin Infusion Versus Multiple Insulin Injections on Glucose Variability in Young Adults with Type 1 Diabetes: The 2-Year Follow-Up of the Observational METRO Study.

BACKGROUND: Type 1 diabetic patients have high instability of daily glucose levels. The aim of this study was to evaluate the long-term effects of continuous subcutaneous insulin infusion (CSII) therapy, compared with multiple daily injections of insulin (MDI), on glucose variability, in young type 1 diabetic patients transitioned to the adult diabetes care. METHODS: Patients aged 18-30 years and considered eligible for insulin pump therapy were included in the study. Ninety-eight patients who started CSII therapy and 125 who remained in MDI completed a 2-year follow-up. Glucose variability was assessed with continuous glucose monitoring using blood glucose standard deviation (BGSD), mean amplitude of glycemic excursion (MAGE), continuous overall net glycemic action (CONGA-2 h), low blood glucose index, high blood glucose index, and average daily risk range. RESULTS: MAGE and BGSD decreased in both groups, with adjusted differences at 2 years of -0.74 mM (95% confidence interval [CI] -1.22 to -0.26, P = 0.003) and -0.3 (CI -0.52 to -0.1, P = 0.005) favoring the pump-therapy group. No significant differences between groups in the other variability indexes were observed. HbA1c decreased in both groups without significant difference (0.05%, -0.26, 0.35, P = 0.77); fasting glucose, insulin dose, and overall hypoglycemia (daily, nocturnal, and severe) decreased more in patients with CSII, compared with those with MDI. CONCLUSIONS: Among young adults with type 1 diabetes transitioning from the pediatric care, the use of CSII is associated with lower glucose variability, fasting glycemia, and overall hypoglycemic events than MDI during a 2-year period of follow-up.

Continuous glucose monitoring for patients with type 1 diabetes on multiple daily injections of insulin: pros and cons.

Continuous glucose monitoring associated with intensive insulin regimens represents a useful tool to lower HbA1c in selected adults with type 1 diabetes. Recent randomized controlled trials demonstrated greater glycemic benefits in type 1 diabetic patients treated with multiple daily injections of insulin and continuous glucose monitoring over usual care. These positive outcomes, however, are counter-balanced by several limitations that restrict the use of continuous glucose monitoring in the real life, including the apparent lack of benefits in children and pregnant diabetic women, the high cost, the stringent patients' selection, and the presence of a multi-disciplinary team with specific expertise. Pros and Cons of using continuous glucose monitoring in type 1 diabetic patients with multiple daily injections of insulin are here discussed.

Effect of a Mediterranean diet on endothelial progenitor cells and carotid intima-media thickness in type 2 diabetes: Follow-up of a randomized trial.

Background We assessed the long-term effects of a Mediterranean diet on circulating levels of endothelial progenitor cells (EPCs) and the carotid intima-media thickness (CIMT) in patients with type 2 diabetes. Design This was a parallel, two-arm, single-centre trial. Methods Two hundred and fifteen men and women with newly diagnosed type 2 diabetes were randomized to a Mediterranean diet ( n = 108) or a low-fat diet ( n = 107). The primary outcome measures were changes in the EPC count and the CIMT of the common carotid artery after the treatment period defined as the end of trial (EOT). Results At the EOT, both the CD34+KDR+ and CD34+KDR+CD133+ counts had increased with the Mediterranean diet compared with the low-fat diet ( p < 0.05 for both). At the EOT evaluation, there was a significant ( p = 0.024) difference of -0.025 mm in the CIMT favouring the Mediterranean diet. Compared with the low-fat diet, the rate of regression in the CIMT was higher in the Mediterranean diet group (51 vs. 26%), whereas the rate of progression was lower (25 vs. 50%) ( p = 0.032 for both). Changes in the CIMT were inversely correlated with the changes in EPC levels (CD34+KDR+, r = -0.24, p = 0.020; CD34+KDR+CD133+, r = -0.28, p = 0.014). At the EOT, changes in levels of HbA1c, HOMA, total cholesterol, high-density lipoprotein cholesterol and systolic blood pressure were significantly greater with the Mediterranean diet than with the low-fat diet. Conclusion Compared with a low-fat diet, a long-term trial with Mediterranean diet was associated with an increase in circulating EPCs levels and prevention of the progression of subclinical atherosclerosis in patients with newly diagnosed type 2 diabetes.

Mediterranean diet cools down the inflammatory milieu in type 2 diabetes: the MÉDITA randomized controlled trial.

Mediterranean-style diets provide cardiovascular benefits and increase insulin sensitivity. There is little evidence that adherence to Mediterranean diet may influence the levels of the inflammatory milieu in type 2 diabetes. The aim of this study was to assess whether Mediterranean diet influences both C-reactive protein (CRP) and adiponectin in newly diagnosed type 2 diabetes, and whether adherence to Mediterranean diet affects their circulating levels. In a two-arm, single-center trial, 215 men and women with newly diagnosed type 2 diabetes were randomized to a Mediterranean diet (n = 108, 54 males and 54 females) or a low-fat diet (n = 107, 52 males and 55 females), with a total follow-up of 8.1 years. At baseline visit and at 1 year, body weight, HOMA index, CRP, and adiponectin and its fractions were assessed. Adherence to the diets was assessed by calculating the Mediterranean-diet score. At 1 year, CPR fell by 37 % and adiponectin rose by 43 % in the Mediterranean diet group, while remaining unchanged in the low-fat diet group. The pattern of adiponectin fractions (high and non-high molecular weight) showed a response similar to that of total adiponectin. Diabetic patients with the highest scores (6-9 points) of adherence to Mediterranean diet had lower circulating CRP level and higher circulating total adiponectin levels than the diabetic patients who scored <3 points on the scale (P = 0.001). The results of this randomized controlled trial demonstrate that Mediterranean diet cools down the inflammatory milieu of type 2 diabetes.

Particulate matter pollutants and risk of type 2 diabetes: a time for concern?

The World Health Organization estimates that worldwide in 2012 around 7 million deaths occurred prematurely due to air pollution, which is now the world's largest single environmental health risk. The higher premature mortality associated with air pollution is due to exposure to small particulate matter of 10 microns (PM10) or less in diameter. Exposure to air pollution has also been suggested as a contributing to diabetes incidence and progression. There are a number of possible biological pathways linking air pollutants to diabetes, including endothelial dysfunction, dysregulation of the visceral adipose tissue through inflammation, hepatic insulin resistance, elevated hemoglobin A1c level, elevated blood pressure, and alterations in autonomic tone, which may increase insulin resistance. The risk of future diabetes associated with exposure to 10 µg/m(3) increase of PM2.5 has been quantified in the range of 10 to 27%; the risk of diabetes mortality associated with PM2.5 appears to be quite lower, around 1% for each increment exposure of 10 µg/m(3) of both PM2.5 and PM10. Limitations of the current epidemiological evidence include the complex mixture of pollutants, the different design of the studies, the limited data available for non Western populations, and the lack of demonstration that improvement of air quality is associated with a decrease incidence of type 2 diabetes. Although the most sources of outdoor air pollution are well beyond the control of individuals, people should be informed that there are means to reduce the burden of air pollutants on diabetes risk, including avoidance of passive smoking, adoption of an healthy diet, and increasing leisure-time physical activity.

Setting the hemoglobin A1c target in type 2 diabetes: a priori, a posteriori, or neither?

Current guidelines specify hemoglobin A1c (HbA1c) targets around or less than 7.0 %, with more (<6.5 %) or less (<8 %) stringent goals being appropriate for selected patients. The difficulty in setting a precise HbA1c target depends, at least in part, on the physician perception of the relative importance of the parameters to be considered when determining the target. Using the "a priori" approach, physicians set the HbA1c target first, then prescribe the appropriate antidiabetic drug in order to cover the distance from the target, i.e., the difference between the current HbA1c value of the patient and the individualized HbA1c target: calculating the distance from the target may also be useful as a predictor of therapeutic success. In the "a posteriori" approach, physicians first prescribe, then decide if the achieved HbA1c is an appropriate level for that patient. Attainment of the HbA1c target ultimately depends on which target the physician set: both approaches ("a priori" and "a posteriori") may be useful for both physicians to make appropriate therapeutic decisions and patients to adhere to the best possible treatment. All this presumably will avoid unnecessary therapeutic inertia.

A nomogram to estimate the HbA1c response to different DPP-4 inhibitors in type 2 diabetes: a systematic review and meta-analysis of 98 trials with 24†163 patients.

OBJECTIVES: To develop a nomogram for estimating the glycated haemoglobin (HbA1c) response to different dipeptidyl peptidase-4 (DPP-4) inhibitors in type 2 diabetes. DESIGN: A systematic review and meta-analysis of randomised controlled trials (RCTs) of DPP-4 inhibitors (vildagliptin, sitagliptin, saxagliptin, linagliptin and alogliptin) on HbA1c were conducted. Electronic searches were carried out up to December 2013. Trials were included if they were carried out on participants with type 2 diabetes, lasted at least 12 weeks, included at least 30 participants and had a final assessment of HbA1c. A random effect model was used to pool data. A nomogram was used to represent results of the metaregression model. PARTICIPANTS: Adults with type 2 diabetes. INTERVENTIONS: Any DPP-4 inhibitor (vildagliptin, sitagliptin, saxagliptin, linagliptin or alogliptin). OUTCOME MEASURES: The HbA1c response to each DPP-4 inhibitor within 1 year of therapy. RESULTS: We screened 928 citations and reviewed 98 articles reporting 98 RCTs with 100 arms in 24 163 participants. There were 26 arms with vildagliptin, 37 with sitagliptin, 13 with saxagliptin, 13 with linagliptin and 11 with alogliptin. For all 100 arms, the mean baseline HbA1c value was 8.05% (64 mmol/mol); the decrease of HbA1c from baseline was -0.77% (95% CI -0.82 to -0.72%), with high heterogeneity (I(2)=96%). Multivariable metaregression model that included baseline HbA1c, type of DPP-4 inhibitor and fasting glucose explained 58% of variance between studies, with no significant interaction between them. Other factors, including age, previous diabetes drugs and duration of treatment added low predictive power (<1%). The nomogram estimates the absolute HbA1c reduction from baseline using the type of DPP-4 inhibitor, baseline values of HbA1c and fasting glucose. CONCLUSIONS: Baseline HbA1c level and fasting glucose explain most of the variance in HbA1c change in response to DPP-4 inhibitors: each increase of 1.0% units HbA1c provides a 0.4-0.5% units greater fall.

Remission of type 2 diabetes: is bariatric surgery ready for prime time?

There is mounting evidence that bariatric surgery leads to higher remission rates of type 2 diabetes than any conventional medical treatment, lifestyle intervention, or medically supervised weight loss program. Although remission rates of type 2 diabetes may be as high as 66.7 % after gastric bypass and 28.6 % after gastric band, very few bariatric surgery studies report long-term results with sufficient patient follow-up to minimize biased results. Hence, trials that directly compare bariatric surgery procedures with medical and lifestyle intervention for patients with type 2 diabetes are the best candidate for assessing the role of bariatric surgery in diabetes remission. Three randomized controlled trials and one prospective study have so far been published comparing the effect of Roux-en-Y gastric bypass (RYGB) procedure against optimal medical therapy, with a follow-up ranging from 1 to 6 years: the percentage of diabetic patients in remission (hemoglobin A1C < 6-6.5 % without medications) ranged from 38 to 75 % at the end of follow-up. Intensive lifestyle intervention is also superior to conventional treatment for inducing remission of type 2 diabetes, with remission rates of type 2 diabetes between 10 and 15 % at 1 year of follow-up. Bariatric surgical procedures, especially RYGB, are more effective at inducing initial type 2 diabetes remission in obese patients, but more information is needed about the long-term durability of comorbidity control and complications after bariatric procedures. In the meantime, all efforts should be directed toward primary prevention of type 2 diabetes, given the encouraging results of lifestyle intervention studies.