Primary and Tertiary Prevention of type 2 diabetes

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

DPPOS -02DKN304 The Diabetes Epidemiology and Clinical Research Branch operated three clinical centers for the DPP and 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. 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). In the metformin and placebo arms of the DPP (n = 1762) we screened 280,965 exomic and intergenic SNPs, for rQTL and vQTL patterns in association with year one changes from baseline in glycemia and related traits (insulinogenic index IGI, insulin sensitivity index ISI, fasting glucose and fasting insulin). Significant (p < 1.8 10-7) rQTL and vQTL generated a priori hypotheses of individual GE tests for a SNP metformin treatment interaction and secondarily for GG screens. Several rQTL and vQTL identified led to 6 nominally significant (p < 0.05) metformin treatment SNP interactions (4 for IGI, one insulin, and one glucose) and 12GG interactions (all IGI) that exceeded experiment-wide significance (p < 4.1 10-9). 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). rs3197999, an ISI/insulin rQTL, is a possible gene damaging missense mutation in MST1, is associated with ulcerative colitis, sclerosing cholangitis, Crohn's disease, BMI and coronary artery disease. GxG and GxE interaction in the development of T2D is complex and context dependent. 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 Diabetes 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 and overweight or obesity were enrolled in 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.