Primary and Tertiary Prevention of type 2 diabetes

National Institute Of Diabetes And Digestive And Kidney Diseases

Investigators

Linked publications, trials & patents

Abstract

DPPOS -02DKN304 The Phoenix Epidemiology and Clinical Research Branch operated three clinical centers for the Diabetes Prevention Program (DPP) and Diabetes Prevention Program Outcomes Study (DPPOS) that recruited primarily an American Indian population in the nationwide multicenter clinical trial. Recruitment of the 3,234 volunteers nationwide began in 1996. Eighty-eight percent of the surviving DPP participants joined the DPPOS. The Diabetes Epidemiology and Clinical Research Section clinics enrolled 155 of these participants. Twenty-two years after initial enrollment and randomization in the DPP, participants are on average 72 years old and those in the original lifestyle intervention or metformin group were 25% and 18% less likely to have developed diabetes, respectively. Additionally, participants who did not develop diabetes had significantly lower rates of eye (57%), kidney (37%), and major cardiovascular disease (39%). Lifestyle intervention and metformin have been shown to prevent diabetes; however, their efficacy in preventing cardiovascular disease associated with the development of diabetes is unclear. We examined whether these interventions reduced the incidence of major cardiovascular events over a 21-year median follow-up of participants in DPP and DPPOS. During the next 18-year average follow-up in DPPOS, all participants were offered a less intensive group lifestyle intervention, and unmasked metformin was continued in the metformin group. The primary outcome was the first occurrence of nonfatal myocardial infarction, stroke, or cardiovascular death adjudicated by standard criteria. An extended cardiovascular outcome included the primary outcome or hospitalization for heart failure or unstable angina, coronary or peripheral revascularization, coronary heart disease diagnosed by angiography, or silent myocardial infarction by ECG. ECGs and cardiovascular risk factors were measured annually. Neither metformin nor lifestyle intervention reduced the primary outcome: metformin versus placebo hazard ratio 1.03 (95% CI, 0.78-1.37; P = 0.81) and lifestyle versus placebo hazard ratio 1.14 (95% CI, 0.87-1.50; P = 0.34). Risk factor adjustment did not change these results. No effect of either intervention was seen on the extended cardiovascular outcome. Provision of group lifestyle intervention to all, out-of-study use of statin and antihypertensive agents, and reduction in the use of study metformin together with out-of-study metformin use over time may have diluted the effects of the interventions. We determined whether metformin or lifestyle modification can lower rates of all-cause and cause-specific mortality in the DPP and DPPOS. Placebo and lifestyle interventions stopped in 2001, and a modified lifestyle program was offered to everyone, but unmasked study metformin continued in those originally randomized. Causes of deaths through 31 December 2018 were adjudicated by blinded reviews. All-cause and cause-specific mortality hazard ratios (HRs) were estimated from Cox proportional hazards regression models and Fine-Gray models, respectively. Over a median of 21 years, 453 participants died. Cancer was the leading cause of death (n = 170), followed by cardiovascular disease (n = 131). Compared with placebo, metformin did not influence mortality from all causes (HR 0.99 95% CI 0.79, 1.25), cancer (HR 1.04 95% CI 0.72, 1.52), or cardiovascular disease (HR 1.08 95% CI 0.70, 1.66). Similarly, lifestyle modification did not impact all-cause (HR 1.02 95% CI 0.81, 1.28), cancer (HR 1.07 95% CI 0.74, 1.55), or cardiovascular disease (HR 1.18 95% CI 0.77, 1.81) mortality. Analyses adjusted for diabetes status and duration, BMI, cumulative glycemic exposure, and cardiovascular risks yielded results similar to those for all-cause mortality. We also examined the role of insulin secretion and insulin resistance using an orthogonal technique that partitions the relationship into a component due to -cell compensation for insulin resistance and a component due to insulin secretory demand from uncompensated insulin resistance. Both components associated with diabetes incidence and mediated some of the effects of the treatments. We continue to analyze the role of weight loss and remission of dysglycemia during the intervention period as potential determinants of developing diabetes. The complex genetic architecture of type-2-diabetes (T2D) includes gene-by-environment (GE) and gene-by-gene (GG) interactions. To identify GE and GG, we screened markers for patterns indicative of interactions (relationship loci rQTL and variance heterogeneity loci vQTL). rQTL exist when the correlation between multiple traits varies by genotype and vQTL occur when the variance of a trait differs by genotype (potentially flagging GG and GE). Several loci of interest were identified. Some loci are directly associated with incident diabetes, and others are rQTL and modify a trait's relationship with diabetes (2 diabetes/glucose, 2 diabetes/insulin, 1 diabetes/IGI). GxG and GxE interaction in the development of T2D is complex and context dependent. Several putative loci that may influence metformin response were recently identified in GWAS. Look AHEAD -01DKN250 Look AHEAD was designed as a multicenter randomized clinical trial of weight loss for prevention of complications of type 2 diabetes. The Phoenix Epidemiology and Clinical Research Branch operates two clinical centers that work primarily with enrolled Native American participants. Since the clinical trial began in 2002, 5,145 volunteers with type 2 diabetes who were 45-76 years of age with overweight or obesity were enrolled and randomized to either the intensive lifestyle intervention (ILI) program or the diabetes support and education (DSE) program. The Diabetes Epidemiology and Clinical Research Section clinics enrolled 244 of these participants. The study has reported success in achieving and maintaining weight loss in the ILI group, while there was little weight loss on average in the DSE group. Data collection was completed in June of 2021. Effects of the weight loss on several health outcomes were reported in previous years. Several more health outcomes were reported during the current fiscal year. Look AHEAD compared effects of an ILI with DSE on cardiovascular disease events in 5145 adults aged 45-76 yr with overweight/obesity and type 2 diabetes. In 4773 participants, we performed a secondary analysis of the association of baseline CRF during maximal treadmill test mortality and cardiovascular disease events during a mean follow-up of 9.2 yr. Effects of METs were homogeneous on the HR scale for most baseline variables and outcomes but heterogeneous for many on the RD scale, with greater RD in subgroups at greater risk of the outcomes. For example, all-cause mortality was lower by 7.6 deaths/1000 person-years per SD greater METs in those with a history of cardiovascular disease at baseline but lower by only 1.6 in those without such history. BMI adjusted for CRF had little or no effect on these outcomes. Greater CRF is associated with reduced risks of mortality and cardiovascular disease events. Life-MOMS – 13DKN055 Lifestyle Intervention for Expectant Moms (LIFE-Moms) Phoenix center clinic is a randomized clinical trial that recruited overweight and obese pregnant women to test the effects of an intensive lifestyle intervention on gestational weight gain, control of maternal hyperglycemia, and post-partum return to pre-pregnancy weight. The Phoenix center was conducted in collaboration with the Phoenix Indian Medical Center (PIMC) nurse midwifery and obstetrics services and the Phoenix Epidemiology and Clinical Research Branch (PECRB) of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). It is part of the LIFE-Moms Consortium consisting of six other clinical centers that followed similar protocols and a research coordination unit. In the Phoenix site, the Institute of Medicine (IOM) guidelines were used for assessing weight gain targets that were based on estimated pre-pregnancy weight. Recruitment was stopped early in April of 2014 due to poor recruitment; participants were followed through the end of their planned study period. A total of 1616 individuals were screened during recruitment (Mar 2013-Mar 2014) and 43 mother/infant dyads were enrolled. Retention was excellent. The LIFE-Moms Consortium found that varied lifestyle interventions initiated between 9 and 16 weeks of pregnancy and designed to control GWG conducted in racially and socioeconomically diverse populations of pregnant women with overweight or obesity resulted in modestly but significantly less GWG and fewer women exceeding IOM weight gain recommendations. The primary outcome, incidence of excess GWG per week, was significantly lower in the intervention group compared with the standard care group (61.8% vs. 75.0%). Despite this difference, lifestyle intervention was not effective in preventing GDM defined using two different metrics and relative to standard care. GDM occurred in those who were significantly heavier and had early evidence of dysglycemia prior to 16-weeks.The two groups were balanced at baseline for key factors that may impact GWG, including baseline BMI category (overweight vs. obesity), race/ethnicity, education, family income, and marital status. The difference in GWG between the groups did not result in differences in pregnancy outcomes or infant birth weight.