Diabetes Prevention Program Outcomes Study Research Articles

SAT-102 Self-efficacy As A Predictor Of Weight Loss In Veterans With Obesity Participating In Medical Weight Management.

Background: Overweight and obesity are major health burdens in veterans, occurring at higher rates than the general population (78% vs 69%) and associate with chronic disease development. Self-efficacy is a person's ability to overcome the difficulties inherent in performing a specific task in a particular situation such as smoking cessation. We evaluated if a simple self-efficacy score may serve as a predictor of weight control in de-identified records of veterans with obesity undergoing a weight loss intervention consisting of lifestyle modification with pharmacotherapy through a VA weight management clinic. Methods We reviewed deidentified records for 22 obese (BMI ≥ 30) participants (17 males, 5 females, age range = 43–69, race/ethnicity 45% Black, 32% White, 18% Latino, and 5% Asian) in the VA weight management clinic. As part of the intake assessment, we used 2 validated questions to assess participants’ confidence in their ability to lose weight. Individuals were asked: “How ready are you to commit time, energy and resources to weight loss therapy?" and "How confident are you in your ability to lose weight?" Answers were rated from 1 (not ready or not confident) to 3 (ready or confident). Self-efficacy was scored as high (5-6), intermediate (3-4) or low (0-2). Results: Participants were on average 56 years old with weight of 275±49 lb at baseline. Eight records were classified as having high self-efficacy, 7 had moderate self-efficacy, and 3 had low self-efficacy. After 3 months of lifestyle plus pharmacotherapy intervention, weight loss in the high self-efficacy group was 8.8 ± 4.6 lb vs -0.4 ± 1.2 lb (mean±SE, p = 0.088) in the non-high self-efficacy group. Excess body weight in high vs non-high self-efficacy groups at 3 months was 3.08% ± 0.02% vs -0.26% ± 0.01 (p = 0.094). Conclusions: Our data suggests that veterans with obesity and high self-efficacy may lose more weight than those with lower self-efficacy. This simple tool may serve as an important first screen for weight management clinical practice. References -Diabetes Prevention Program Research, G., et al., 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet, 2009. 374(9702): p. 1677-86. -Tsai et al. Readiness Redefined: A Behavioral Task during Screening Predicted 1-Year Weight Loss in the Look AHEAD Study. Obesity (Silver Spring). 2014 April ; 22(4): 1016–1023. doi:10.1002/oby.20648.

SAT-148 Vitamin B12 Deficiency Among Patients with Metformin and Diabetic Neuropathy.

Introduction: Vitamin B12 deficiency due to metformin use has been demonstrated in multiple studies with variable prevalence. There are no studies in our population that demonstrate the prevalence of vitamin B12 deficiency in patients with metformin and diabetic neuropathy. The objective of this study is to describe its prevalence and the characteristics of the patients who present vitamin B12 deficiency. Methodology: Cross sectional study. 162 patients were included. The level of vitamin B12 was considered low, less than 200 pg / ml and borderline, 201 to 300 pg / ml. The level of vitamin B12 was analized according to age, sex, metformin dose, metformin time of use, time from the diagnosis of diabetes or prediabetes and the presence of diabetic neuropathy. A linear regression model was used to evaluate the variables that correlate with vitamin B12 levels. Results: 162 patients were collected. An altered level of vitamin B12 was found in 29% (CI95%: 22% to 36%) and a low level of vitamin B12 in 7.3% (CI 95%: 4.0% to 12%). In patients with diabetic neuropathy the prevalence of altered B12 levels was 64% (95% CI 47-78%), while in patients without diabetic neuropathy it was 17% (95% CI 10-26%). Patients with diabetic neuropathy had lower levels of vitamin B12 compared with patients without neuropathy (coefficient -110.8, CI 95%: -165.8 to -59.7). A higher dose of metformin showed correlation with lower levels of vitamin B12 (coef -0.061 CI 95%: - 0.09 to -0.024). Female patients had higher levels of vitamin B12 compared to men (coef 49.1 CI 95%: 2.3 to 95). Conclusions: Vitamin B12 deficiency is frequent in our population of patients treated with metformin, with prevalences higher than those described in other populations. Patients with diabetic neuropathy have much higher prevalence of vitamin B12 deficiency. Male patients with higher doses of metformin and patients with diabetic neuropathy have the lowest levels of vitamin B12. More studies are needed to establish an association between vitamin b12 deficiency and diabetic neuropathy. Bibliography Berchtold P, Bolli P, Arbenz U, Keiser G. Disturbance of intestinal absorption following metformin therapy (observations on the mode of action of biguanides) [in German]. Diabetologia. 1969;5:405- 412. Aroda VR, Edelstein SL, Goldberg RB. Diabetes Prevention Program Research Group. Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study. J ClinEndocrinolMetab. 2016 Apr; 101(4): 1754-1761. Reinstatler L, Qi YP, Williamson RS, et al. Association of biochemical B₁₂ deficiency with metformin therapy and vitamin B₁₂ supplements: the National Health and Nutrition Examination Survey, 1999-2006.Diabetes Care. 2012 Feb;35(2):327-33.1. Roy RP, Ghosh K, Ghosh M; et al. Study of vitamin B12 deficiency and peripheral neuropathy in metformin treated early Type 2 diabetes mellitus. Indian J EndocrinolMetab. 2016; 20(6): 895.

Long-term Effects of Metformin on Diabetes Prevention: Identification of Subgroups That Benefited Most in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study.

OBJECTIVEWe examined the effects of metformin on diabetes prevention and the subgroups that benefited most over 15 years in the Diabetes Prevention Program (DPP) and its follow-up, the Diabetes Prevention Program Outcomes Study (DPPOS).RESEARCH DESIGN AND METHODSDuring the DPP (1996–2001), adults at high risk of developing diabetes were randomly assigned to masked placebo (n = 1,082) or metformin 850 mg twice daily (n = 1,073). Participants originally assigned to metformin continued to receive metformin, unmasked, in the DPPOS (2002–present). Ascertainment of diabetes development was based on fasting or 2-h glucose levels after an oral glucose tolerance test or on HbA1c. Reduction in diabetes incidence with metformin was compared with placebo in subgroups by hazard ratio (HR) and rate differences (RDs).RESULTSDuring 15 years of postrandomization follow-up, metformin reduced the incidence (by HR) of diabetes compared to placebo by 17% or 36% based on glucose or HbA1c levels, respectively. Metformin’s effect on the development of glucose-defined diabetes was greater for women with a history of prior gestational diabetes mellitus (GDM) (HR 0.59, RD −4.57 cases/100 person-years) compared with parous women without GDM (HR 0.94, RD −0.38 cases/100 person-years [interaction P = 0.03 for HR, P = 0.01 for RD]). Metformin also had greater effects, by HR and RD, at higher baseline fasting glucose levels. With diabetes development based on HbA1c, metformin was more effective in subjects with higher baseline HbA1c by RD, with metformin RD −1.03 cases/100 person-years with baseline HbA1c <6.0% (42 mmol/mol) and −3.88 cases/100 person-years with 6.0–6.4% (P = 0.0001).CONCLUSIONSMetformin reduces the development of diabetes over 15 years. The subsets that benefitted the most include subjects with higher baseline fasting glucose or HbA1c and women with a history of GDM.

Sex Hormones and Measures of Kidney Function in the Diabetes Prevention Program Outcomes Study.

Despite sex differences in chronic kidney disease (CKD) onset and progression, it is unclear whether endogenous sex hormones are associated with kidney function in persons without CKD. We conducted a secondary analysis of the Diabetes Prevention Program (DPP) and its follow-up observational study, the DPP Outcomes Study, over 11 years. Participants included overweight and glucose-intolerant men (n = 889) and pre- and postmenopausal women (n = 1281) not using exogenous sex hormones and whose urine albumin-to-creatinine ratio (ACR) was <30 mg/g and normal estimated glomerular filtration ratio (eGFR) was ≥60 mL/min/1.73 m2 at randomization. We examined the association between sex hormone levels and incidence of low eGFR and/or ACR ≥30 mg/g on at least one measurement. At randomization, the mean (SD) eGFR was 94 (15) mL/min/1.73 m2; the median ACR (interquartile range) was 4.5 (3.3 to 7.6) mg/g. During follow-up, 187 men (24.6%) and 263 women (24.2%) had incident albuminuria and 136 men (17.9%) and 123 women (11.3%) had incident low eGFR. Among men, higher baseline sex hormone-binding globulin (SHBG) level was associated with reduced low eGFR risk (hazard ratio per SD, 0.80; 95% CI, 0.57 to 0.90) in adjusted analyses. No significant associations were observed among women. There were significant interactions between sex steroid levels and low eGFR by randomization arm. Sex steroids were not associated with development of low eGFR or albuminuria. Among men, higher SHBG level was associated with reduced risk of low eGFR on at least one measurement.

Association of Perfluoroalkyl and Polyfluoroalkyl Substances With Adiposity

ImportancePerfluoroalkyl and polyfluoroalkyl substances (PFASs) are ubiquitous synthetic chemicals that are suspected endocrine disruptors.ObjectivesTo determine the extent to which PFASs are associated with increases in weight and body size and evaluate whether a lifestyle intervention modifies this association.Design, Setting, and ParticipantsThis prospective cohort study included 957 individuals who participated in the Diabetes Prevention Program trial, conducted from July 1996 to May 2001, and the Diabetes Prevention Program Outcomes Study, conducted from September 2002 to January 2014. Statistical analysis was conducted from September 1, 2017, to May 25, 2018.Interventions and ExposuresThe initial lifestyle intervention consisted of training in diet, physical activity, and behavior modification, with the major goals of achieving 7% weight loss with subsequent maintenance and a minimum of 150 minutes per week of physical activity. Participants randomized to placebo received standard information about diet and exercise. A total of 6 plasma PFASs were quantified at baseline and 2 years after randomization, means were calculated from baseline and year 2 concentrations, and means were summed to assess total PFAS burden.Main Outcomes and MeasuresWeight, waist circumference, and hip girth were measured at baseline and at scheduled visits.ResultsOf the 957 participants, 625 (65.3%) were women and 731 participants (76.4%) were between 40 and 64 years of age; 481 participants were randomized to the lifestyle intervention and 476 participants were randomized to the placebo arm. The PFAS concentrations were not different by treatment arm and were similar to concentrations reported for the US population in 1999-2000. The association of PFAS and weight change differed by treatment. Each doubling in total PFAS concentration was associated with an increase of 1.80 kg (95% CI, 0.43-3.17 kg; P = .01) from baseline to 9 years after randomization for the placebo group but not the lifestyle intervention group (−0.59 kg; 95% CI, –1.80 to 0.62 kg; P = .34). Similarly, each doubling in PFAS was associated with a 1.03-cm increase in hip girth in the Diabetes Prevention Program trial for the placebo group (95% CI, 0.18-1.88 cm; P = .02) but not the lifestyle intervention group (−0.09 cm; 95% CI, −0.82 to 0.63 cm; P = .80). No associations were observed for changes in mean waist circumference.Conclusions and RelevanceAmong adults at high risk for diabetes, higher plasma PFAS concentration was associated with increases in weight and hip girth over time, but a lifestyle intervention attenuated these associations. Diet and exercise may mitigate the obesogenic effects of environmental chemicals.Trial RegistrationClinicalTrials.gov Identifier: NCT00004992 and NCT00038727

Association of Intensive Lifestyle Intervention and Metformin with Frailty in the Diabetes Prevention Program (DPP) Outcomes Study (DPPOS)

Objective: To examine whether odds of frailty differ by DPP intervention arms (intensive lifestyle intervention [ILS], metformin [MET], placebo [PLB] after long-term follow-up in the DPPOS. Methods: DPP, a randomized trial of individuals at high risk of diabetes, lasted 2.8 years, after which there was a 13-month bridge period in which 16 sessions of group ILS was offered to all participants. During DPPOS, ILS was offered lifestyle reinforcement semi-annually and MET received unmasked metformin. Frailty was measured initially in DPPOS Year 8 in 2385 participants and repeated in 2264 of these in Year 10 (12 and 14 years after randomization). Using Fried criteria, presence of 3 of 5 characteristics (slow walking speed, weak grip strength, unintentional weight loss, low physical activity, and exhaustion) was classified as frail, 1 or 2 pre-frail, and 0 non-frail.: GEE models adjusting for visit year were employed with repeated measures pooled from Years 8 and 10 to estimate pairwise odds ratios between ILS, MET and PLB for the outcomes of frail and pre-frail vs. non-frail. Results: Odds of frailty vs. non-frailty were 37% lower in ILS compared to PLB (Table) and MET (OR=0.629, CI= 0.420-0.942, p=0.024). There were no significant treatment group differences in odds of pre-frailty. Conclusion: ILS intervention in persons at high risk of diabetes may reduce frailty in later life.12 years Post-randomization14 years post-randomizationOdds of Frailty vs. Non-Frailty Pooled over both examsTreatment GroupPrevalencePrevalence OR (95% CI) compared with placeboP-valuePre-FrailtyFrailtyPre-FrailtyFrailtyPlacebo42.8%5.7%43.7%5.4%1 (referent)n/aMetformin45.8%5.4%42.5%5.3%0.994 (0.694-1.424)0.976Lifestyle46.8%3.0%46.3%3.6%0.625 (0.419-0.934)0.022 Disclosure H.P. Hazuda: None. Q. Pan: None. J.P. Crandall: None. H. Florez: Advisory Panel; Self; Sanofi. J.A. Luchsinger: None. E.M. Venditti: None. A. Kriska: None. S. Golden: None. G. Bray: Advisory Panel; Self; Herbalife International of America, Inc., Novo Nordisk A/S. D. Research Group: None.

Metformin and Lifestyle Interventions in DPP Do Not Have Long-Term Effects on Bone Density or Falls

Randomization to lifestyle intervention (ILS) or metformin (MET) in the Diabetes Prevention Program (DPP) resulted in weight loss and reduced progression to diabetes. The long term effects of these interventions on bone mineral density (BMD) and falls, both associated with weight loss, are not known. We determined if ILS or MET was associated with prevalence of osteoporosis, osteopenia or history of falls in the DPP Outcome Study (DPPOS). During DPP, 3234 participants at high risk for diabetes were randomized to ILS, MET or PLB; 2779 continued in DPPOS and were offered modified group ILS. During DPPOS, ILS was offered additional lifestyle reinforcement semi-annually and MET received unmasked metformin. This analysis includes 1384 DPPOS participants who had dual-energy X-ray absorptiometry hip scans at year 12 (Y12). Osteoporosis was defined as femoral neck BMD T-score ≤-2.5 and osteopenia as -2.5&amp;lt;T-score≤-1. Participants were asked at Y12 if they had a fall in the previous year. Outcomes were compared across the 3 treatment groups using Pearson’s chi- squared test. Associations between treatment and outcomes were assessed with logistic regression. Mean age at Y12 was 66.5 (±9.5) years. Mean time since DPP baseline was 15.6 (±0.7) years. Weight loss (DPP baseline to DPPOS Y12) did not differ across treatment groups (-4.4 kg ILS; -3.5 kg MET; -3.1 kg PLB; p=0.114). There were no differences across groups in the prevalence of osteoporosis in men (1.4% ILS, 1.3% MET, 0.7% PLB; p=0.836) or women (2.9% ILS, 2.9% MET, 3.1% PLB; p=0.983). Prevalence of osteopenia was also similar across groups. Prevalence of history of falls was similar across groups in men (16.0% ILS, 16.4% MET, 16.0% PLB; p=0.995) and women (25.7% ILS, 21.3% MET, 21.6% PLB; p=0.342). Prevalence of osteoporosis, osteopenia or history of falls did not differ between ILS or MET and PLB in men or women. In a cohort at high risk of diabetes, lifestyle intervention or metformin did not have long-term effects on bone density or falls. Disclosure A.V. Schwartz: None. Q. Pan: None. V. Aroda: Consultant; Self; Novo Nordisk Inc.. Research Support; Self; Novo Nordisk Inc., AstraZeneca, Calibra Medical, Eisai Inc., Sanofi. Consultant; Self; Sanofi. Research Support; Self; Theracos, Inc.. Employee; Spouse/Partner; Merck &amp; Co., Inc.. Other Relationship; Self; American Diabetes Association. Consultant; Self; ADOCIA. J.P. Crandall: None. A. Kriska: None. C.S. Piromalli: None. M. Temprosa: Other Relationship; Self; Merck KGaA. H. Florez: Advisory Panel; Self; Sanofi. D. Research Group: None.

Long-Term Effects of Lifestyle Intervention and Metformin during DPP on Appendicular Lean Mass

Weight loss prevents progression to diabetes but long term effects on lean mass are unknown. We determined if intensive lifestyle modification (ILS), metformin (MET) or placebo (PLB) treatment in the Diabetes Prevention Program (DPP) had differential effects on appendicular lean mass (ALM) and sarcopenic-obesity (SO) ∼16 years after DPP randomization in the DPP Outcome Study (DPPOS). During DPP, 3234 participants at high risk for diabetes were randomized to ILS, MET or PLB; 2779 continued in DPPOS and were offered modified group ILS. During DPPOS, ILS was offered additional lifestyle reinforcement semi-annually and MET received unmasked metformin. This analysis includes 1374 DPPOS participants who had dual-energy X-ray absorptiometry scans at year 12 for ALM (sum of lean mass in arms and legs). Low ALM was defined as ALM/BMI &amp;lt;0.789 for men or &amp;lt;0.512 for women. SO was defined as low ALM with BMI&amp;gt;30. Prevalence of low ALM and SO was compared across the 3 groups using Pearson’s chi-squared test. Logistic regression models determined the associations between treatment and low ALM or SO and between weight loss and low ALM or SO. Mean age at Y12 was 66.5 (±9.5) years. Mean time since DPP baseline was 15.6 (±0.7) years. Weight loss (DPP baseline to DPPOS Y12) did not differ by group (-4.4 kg ILS; -3.5 kg MET; -3.1 kg PLB; p=0.114). Prevalence of low ALM differed by group in men (35.7% ILS, 28.3% MET, 22.5% PLB; p=0.049) but not women (20.9% ILS, 24.8% MET, 24.1% PLB; p=0.482). In men, low ALM prevalence was higher in ILS compared with PLB (P=0.024) but not in MET vs. PLB. Prevalence of SO did not differ across groups in men (23.1% ISL, 22.0% MET, 14.1% PLB; p=0.112) or women (17.3% ILS, 20.9% MET, 20.3% PLB; p=0.492). SO prevalence was not different in ILS vs. PLB or in MET vs. PLB in men or women. More weight loss was associated with higher risk of low ALM and SO in women and men (p&amp;lt;0.001) independent of group. In men but not women at high risk of diabetes, lifestyle intervention to prevent diabetes may contribute to lower ALM. Disclosure A.V. Schwartz: None. Q. Pan: None. H.P. Hazuda: None. E. Horton: Advisory Panel; Self; PTS Diagnostics, Merck &amp; Co., Inc., Theracos, Inc.. M.A. Hoskin: None. R. Rastogi Kalyani: None. W.C. Knowler: None. A. Kriska: None. M. Schlögl: None. H. Florez: Advisory Panel; Self; Sanofi. D. Research Group: None.

Sex Hormones and Development of Chronic Kidney Disease in the Diabetes Prevention Program Outcomes Study (DPPOS)

Whether endogenous sex hormones are associated with chronic kidney disease (CKD) is not known. We conducted a secondary analysis of longitudinal data from the DPPOS, the follow-up study of the Diabetes Prevention Program (DPP), a randomized trial of diabetes prevention that assigned participants to placebo, metformin, or lifestyle intervention. This analysis included overweight and glucose-intolerant men (n=889) and women (n=1281) not using exogenous sex hormones who had urine albumin-to-creatinine ratio [ACR] &amp;lt; 30 mg/g and normal estimated glomerular filtration ratio [eGFR] ≥ 60 ml/min/1.73 m2. Sex hormones (dehydroepiandrosterone [DHEAS], dihydrotestosterone, testosterone, estradiol, estrone, and sex hormone binding globulin [SHBG]) were measured at baseline. CKD was defined as incident low eGFR and/or albuminuria ACR ≥ 30 mg/g. eGFR and ACR were measured annually over 11 years of DPPOS follow-up. Multivariable Cox regression models adjusted for eGFR and log-ACR, age, race/ethnicity, body mass index, blood pressure, insulin resistance, high-density lipoprotein, C-reactive protein, and use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers at baseline. At baseline, the mean (SD) of eGFR was 94 (15) ml/min/1.73 m2, and the median (IQR) of ACR was 4.5 (3.3-7.6) mg/g. During the follow-up period, 187 men (24.6%) and 263 women (24.2%) had incident albuminuria and 136 men (17.9%) and 123 women (11.3%) had incident low eGFR. Fifty-four (7.1%) of men and 43 (3.9%) of women had both abnormalities. Among men, higher SHBG was associated with lower risk of low eGFR (pooled hazard ratio [HR] per SD, 95% confidence interval [CI]: 0.73 [0.57, 0.9], p=0.01) and lower risk for CKD (pooled HR per SD 95% CI: 0.78 [0.64, 0.95], p=0.01). No significant associations were observed among women. We conclude that among overweight glucose-intolerant men, higher SHBG was associated with reduced risk of CKD. Disclosure C. Kim: None. A. Ricardo: None. E.J. Boyko: None. C.A. Christophi: None. M. Temprosa: Other Relationship; Self; Merck KGaA. K. Watson: None. X. Pi-Sunyer: None. R. Rastogi Kalyani: None. D. Research Group: None.

Reducing the Risk of Developing Diabetes.

Reducing the Risk of Developing Diabetes.

Androgens, Irregular Menses, and Risk of Diabetes and Coronary Artery Calcification in the Diabetes Prevention Program.

It is unclear whether relative elevations in androgens or irregular menses (IM) are associated with greater cardiometabolic risk among women who are already overweight and glucose intolerant. We conducted a secondary analysis of the Diabetes Prevention Program (DPP) and the Diabetes Prevention Program Outcomes Study (DPPOS). Participants included women with sex hormone measurements who did not use exogenous estrogen (n = 1422). We examined whether free androgen index (FAI) or IM was associated with diabetes risk during the DPP/DPPOS or with coronary artery calcification (CAC) at DPPOS year 10. Models were adjusted for menopausal status, age, race or ethnicity, randomization arm, body mass index (BMI), and hemoglobin A1c. Women had an average age of 48.2 ± 9.9 years. Elevations in FAI and IM were associated with greater BMI, waist circumference, and blood pressure and lower adiponectin. FAI was not associated with diabetes risk during the DPP/DPPOS [hazard ratio (HR) 0.97; 95% confidence interval (CI), 0.93 to 1.02] or increased odds of CAC [odds ratio (OR) 1.06; 95% CI, 0.92 to 1.23]. IM was also not associated with diabetes risk during the DPP/DPPOS (HR 1.07; 95% CI, 0.87 to 1.31) or increased odds of CAC (OR 0.89; 95% CI, 0.53 to 1.49). Women who had both relative elevations in FAI and IM had similar diabetes risk and odds of CAC as women without these conditions. Differences by treatment arm and menopausal status were not observed. Among midlife women who were already glucose intolerant and overweight, androgen concentrations and IM did not additionally contribute to increased risk for diabetes or CAC.

Statin use and risk of developing diabetes: results from the Diabetes Prevention Program

ObjectiveSeveral clinical trials of cardiovascular disease prevention with statins have reported increased risk of type 2 diabetes (T2DM) with statin therapy. However, participants in these studies were at relatively low...

Exploring residual risk for diabetes and microvascular disease in the Diabetes Prevention Program Outcomes Study (DPPOS).

Approximately half of the participants in the Diabetes Prevention Outcomes Study (DPPOS) had diabetes after 15years of follow-up, whereas nearly all the others remained with pre-diabetes. We examined whether formerly unexplored factors in the DPPOS coexisted with known risk factors that posed additional risk for, or protection from, diabetes as well as microvascular disease. Cox proportional hazard models were used to examine predictors of diabetes. Sequential modelling procedures considered known and formerly unexplored factors. We also constructed models to determine whether the same unexplored factors that associated with progression to diabetes also predicted the prevalence of microvascular disease. Hazard ratios (HR) are per standard deviation change in the variable. In models adjusted for demographics and known diabetes risk factors, two formerly unknown factors were associated with risk for both diabetes and microvascular disease: number of medications taken (HR=1.07, 95% confidence intervals (95% CI) 1.03 to 1.12 for diabetes; odds ratio (OR)=1.10, 95% CI 1.04 to 1.16 for microvascular disease) and variability in HbA1c (HR=1.02, 95% CI 1.01 to 1.03 for diabetes; OR=1.06, 95% CI 1.04 to 1.09 for microvascular disease per sd). Total comorbidities increased risk for diabetes (HR=1.10, 95% CI 1.04 to 1.16), whereas higher systolic (OR=1.22, 95% CI 1.13 to 1.31) and diastolic (OR=1.14, 95% CI 1.05 to 1.22) blood pressure, as well as the use of anti-hypertensives (OR=1.41, 95% CI 1.23 to 1.62), increased risk of microvascular disease. Several formerly unexplored factors in the DPPOS predicted additional risk for diabetes and/or microvascular disease - particularly hypertension and the use of anti-hypertensive medications - helping to explain some of the residual disease risk in participants of the DPPOS.

The changing cost to prevent diabetes: A retrospective analysis of the Diabetes Prevention Program

ObjectivesDiabetes prevention interventions are poorly implemented. While health care costs generally increase, 2 factors affect the relative cost of diabetes prevention interventions: the declining cost of metformin (even without insurance) and the new recommendation for vitamin B12 monitoring during metformin treatment. The study’s objective was to update the relative health system cost estimate of metformin for diabetes prevention by incorporating the current health system cost of metformin and the cost of addressing potential metformin-associated vitamin B12 deficiency. The study was designed to assess whether metformin with vitamin B12 supplementation is a cost-saving measure for diabetes prevention and for the updated cost estimate to be useful in assessing future implementation studies. MethodsIn 2012, the Diabetes Prevention Program Research Group published detailed per capita total direct health system costs for the Diabetes Prevention Program (DPP) and the Diabetes Prevention Program Outcomes Study (DPPOS). The present analysis incorporated the declining cost of metformin and the increasing cost of metformin monitoring into the detailed per capita health system costs found in the DPP and DPPOS. The updated costs were used to assess the total cost of metformin use for diabetes prevention relative to placebo and lifestyle intervention. ResultsThe current health system cost to acquire metformin ranges from $0 to $72 per year. The estimated health system cost to address potential metformin-associated vitamin B12 deficiency is $28 per metformin-treated patient per year. The 10-year total health system cost for metformin in diabetes prevention can decrease by $329 or increase by $21 depending on the cost to acquire metformin. Compared with placebo, the unadjusted cost savings of metformin is generally maintained, although it may double or quadruple depending on how metformin is acquired by patients. Metformin with vitamin B12 supplementation remained less costly and less effective than lifestyle intervention. ConclusionMetformin is generally more cost-saving for diabetes prevention than previously reported because of decreasing costs for patients to acquire metformin. The cost savings was increased despite increased management cost associated with addressing metformin-associated vitamin B12 deficiency.

Development and validation of Risk Equations for Complications Of type 2 Diabetes (RECODe) using individual participant data from randomised trials

In view of substantial mis-estimation of risks of diabetes complications using existing equations, we sought to develop updated Risk Equations for Complications Of type 2 Diabetes (RECODe). To develop and validate these risk equations, we used data from the Action to Control Cardiovascular Risk in Diabetes study (ACCORD, n=9635; 2001-09) and validated the equations for microvascular events using data from the Diabetes Prevention Program Outcomes Study (DPPOS, n=1018; 1996-2001), and for cardiovascular events using data from the Action for Health in Diabetes (Look AHEAD, n=4760; 2001-12). Microvascular outcomes were nephropathy, retinopathy, and neuropathy. Cardiovascular outcomes were myocardial infarction, stroke, congestive heart failure, and cardiovascular mortality. We also included all-cause mortality as an outcome. We used a cross-validating machine learning method to select predictor variables from demographic characteristics, clinical variables, comorbidities, medications, and biomarkers into Cox proportional hazards models for each outcome. The new equations were compared to older risk equations by assessing model discrimination, calibration, and the net reclassification index. All equations had moderate internal and external discrimination (C-statistics 0·55-0·84 internally, 0·57-0·79 externally) and high internal and external calibration (slopes 0·71-1·31 between observed and estimated risk). Our equations had better discrimination and calibration than the UK Prospective Diabetes Study Outcomes Model 2 (for microvascular and cardiovascular outcomes, C-statistics 0·54-0·62, slopes 0·06-1·12) and the American College of Cardiology/American Heart Association Pooled Cohort Equations (for fatal or non-fatal myocardial infarction or stroke, C-statistics 0·61-0·66, slopes 0·30-0·39). RECODe might improve estimation of risk of complications for patients with type 2 diabetes. National Institute for Diabetes and Digestive and Kidney Disease, National Heart, Lung and Blood Institute, and National Institute on Minority Health and Health Disparities, National Institutes of Health, and US Department of Veterans Affairs.

Metformin, Lifestyle Intervention, and Cognition in the Diabetes Prevention Program Outcomes Study.

OBJECTIVEWe examined the association of the Diabetes Prevention Program (DPP) intervention arms (lifestyle intervention, metformin, and placebo) with cognition in the Diabetes Prevention Program Outcomes Study (DPPOS). We also examined metformin use, incident type 2 diabetes, and glycemia as exposures.RESEARCH DESIGN AND METHODSThe DPP lasted 2.8 years, followed by a 13-month bridge to DPPOS. Cognition was assessed in DPPOS years 8 and 10 (12 and 14 years after randomization) with the Spanish English Verbal Learning Test (SEVLT), letter fluency and animal fluency tests, Digit Symbol Substitution Test (DSST), and a composite cognitive score.RESULTSA total of 2,280 participants (749 lifestyle, 776 metformin, and 755 placebo) aged 63.1 ± 10.7 years underwent cognitive assessments; 67.7% women, 54.6% non-Hispanic white, 20.7% non-Hispanic black, 14.6% Hispanic, 5.5% American Indian, and 4.6% Asian; 26.6% were homozygous or heterozygous for APOE-ε4. At the time of cognitive assessment, type 2 diabetes was higher in the placebo group (57.9%; P < 0.001) compared with lifestyle (47.0%) and metformin (50.4%). Metformin exposure was higher in the metformin group (8.72 years; P < 0.001) compared with placebo (1.43 years) and lifestyle (0.96 years). There were no differences in cognition across intervention arms. Type 2 diabetes was not related to cognition, but higher glycated hemoglobin at year 8 was related to worse cognition after confounder adjustment. Cumulative metformin exposure was not related to cognition.CONCLUSIONSExposure to intensive lifestyle intervention or metformin was not related to cognition among DPPOS participants. Higher glycemia was related to worse cognitive performance. Metformin seemed cognitively safe among DPPOS participants.

Effect of Long-Term Metformin and Lifestyle in the Diabetes Prevention Program and Its Outcome Study on Coronary Artery Calcium.

Despite the reduced incidence of coronary heart disease with intensive risk factor management, people with diabetes mellitus and prediabetes remain at increased coronary heart disease risk. Diabetes prevention interventions may be needed to reduce coronary heart disease risk. This approach was examined in the DPP (Diabetes Prevention Program) and the DPPOS (Diabetes Prevention Program Outcome Study), a long-term intervention study in 3234 subjects with prediabetes (mean±SD age, 64±10 years) that showed reduced diabetes risk with lifestyle and metformin compared with placebo over 3.2 years. The DPPOS offered periodic group lifestyle sessions to all participants and continued metformin in the originally randomized metformin group. Subclinical atherosclerosis was assessed in 2029 participants with coronary artery calcium (CAC) measurements after an average of 14 years of follow-up. The CAC scores were analyzed continuously as CAC severity and categorically as CAC presence (CAC score >0) and reported separately in men and women. There were no CAC differences between lifestyle and placebo intervention groups in either sex. CAC severity and presence were significantly lower among men in the metformin versus the placebo group (age-adjusted mean CAC severity, 39.5 versus 66.9 Agatston units, P=0.04; CAC presence, 75% versus 84%, P=0.02), but no metformin effect was seen in women. In multivariate analysis, the metformin effect in men was not influenced by demographic, anthropometric, or metabolic factors; by the development of diabetes mellitus; or by use/nonuse of statin therapy. Metformin may protect against coronary atherosclerosis in prediabetes and early diabetes mellitus among men. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00038727.

Activity and Sedentary Time 10 Years After a Successful Lifestyle Intervention: The Diabetes Prevention Program.

This study aims to determine if evidence exists for a lasting effect of the Diabetes Prevention Program (DPP) lifestyle intervention on activity levels by comparing objectively collected activity data between the DPP Outcome Study (DPPOS) cohort and adults from the National Health and Nutrition Examination Survey (NHANES; 2003-2006). Average minutes/day of light and moderate to vigorous physical activity (MVPA) and sedentary behavior from ActiGraph accelerometers (collected 2010-2012) were examined (2013-2014) for comparable DPPOS and NHANES subgroups by age, sex, and diabetes status. Longitudinal questionnaire data on leisure activity, collected yearly from DPP baseline to the time of accelerometer measurement (1996-2010; 11.9-year mean follow-up), were also examined to provide support for a long-term intervention effect. Average minutes/day of accelerometer-derived MVPA was higher in all DPPOS subgroups versus NHANES subgroups of similar age/sex/diabetes status; with values as much as twice as high in some DPPOS subgroups. Longitudinal questionnaire data from DPP/DPPOS showed a maintained increase of 1.24 MET hours/week (p=0.026) of leisure activity in DPPOS participants from all original study arms between DPP baseline and accelerometer recording. There were no consistent differences between comparable DPPOS and NHANES subgroups for accelerometer-derived sedentary or light-intensity activity minutes/day. More than 10 years after the start of DPP, DPPOS participants performed more accelerometer-measured MVPA than similar adults from NHANES. Longitudinal questionnaire data support the accelerometer-based findings by suggesting that leisure activity levels at the time of accelerometer recording remained higher than DPP baseline levels.

B12 deficiency linked to long-term metformin use

B12 deficiency linked to long-term metformin use

Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study.

Vitamin B12 deficiency may occur with metformin treatment, but few studies have assessed risk with long-term use. To assess the risk of B12 deficiency with metformin use in the Diabetes Prevention Program (DPP)/DPP Outcomes Study (DPPOS). Secondary analysis from the DPP/DPPOS. Participants were assigned to the placebo group (PLA) (n = 1082) or the metformin group (MET) (n = 1073) for 3.2 years; subjects in the metformin group received open-label metformin for an additional 9 years. Twenty-seven study centers in the United States. DPP eligibility criteria were: elevated fasting glucose, impaired glucose tolerance, and overweight/obesity. The analytic population comprised participants with available stored samples. B12 levels were assessed at 5 years (n = 857, n = 858) and 13 years (n = 756, n = 764) in PLA and MET, respectively. Metformin 850 mg twice daily vs placebo (DPP), and open-label metformin in the metformin group (DPPOS). B12 deficiency, anemia, and peripheral neuropathy. Low B12 (≤ 203 pg/mL) occurred more often in MET than PLA at 5 years (4.3 vs 2.3%; P = .02) but not at 13 years (7.4 vs 5.4%; P = .12). Combined low and borderline-low B12 (≤ 298 pg/mL) was more common in MET at 5 years (19.1 vs 9.5%; P < .01) and 13 years (20.3 vs 15.6%; P = .02). Years of metformin use were associated with increased risk of B12 deficiency (odds ratio, B12 deficiency/year metformin use, 1.13; 95% confidence interval, 1.06–1.20). Anemia prevalence was higher in MET, but did not differ by B12 status. Neuropathy prevalence was higher in MET with low B12 levels. Long-term use of metformin in DPPOS was associated with biochemical B12 deficiency and anemia. Routine testing of vitamin B12 levels in metformin-treated patients should be considered.