Gestational Diabetes Mellitus: Does One Size Fit All? A Challenge to Uniform Worldwide Diagnostic Thresholds Diabetes Care (IF 11.857) Pub Date : 2018-03-20 H. David McIntyre; Dorte M. Jensen; Richard C. Jensen; Henriette B. Kyhl; Tina K. Jensen; Dorte Glintborg; Marianne Andersen
OBJECTIVE To define the prevalence and pregnancy outcomes related to elevated fasting venous plasma glucose (FVPG) in a Danish pregnancy cohort. RESEARCH DESIGN AND METHODS This was an observational cohort study including 1,516 women without gestational diabetes mellitus (GDM) by Danish criteria. FVPG measured at 28 weeks’ gestation was related to pregnancy outcomes. RESULTS With use of the World Health Organization 2013 threshold of FVPG ≥5.1 mmol/L, 40.1% of the cohort qualified as having GDM. There was no evidence of excess fetal growth, hypertension in pregnancy, or caesarean delivery in women with FVPG <5.6 mmol/L. CONCLUSIONS The WHO 2013 FVPG threshold for GDM is unsuitable for Denmark. It inappropriately labels as having GDM an unmanageably large number of women who are at low absolute risk of pregnancy complications.
Food Insecurity, Food “Deserts,” and Glycemic Control in Patients With Diabetes: A Longitudinal Analysis Diabetes Care (IF 11.857) Pub Date : 2018-03-19 Seth A. Berkowitz; Andrew J. Karter; Giselle Corbie-Smith; Hilary K. Seligman; Sarah A. Ackroyd; Lily S. Barnard; Steven J. Atlas; Deborah J. Wexler
OBJECTIVE Both food insecurity (limited food access owing to cost) and living in areas with low physical access to nutritious foods are public health concerns, but their relative contribution to diabetes management is poorly understood. RESEARCH DESIGN AND METHODS This was a prospective cohort study. A random sample of patients with diabetes in a primary care network completed food insecurity assessment in 2013. Low physical food access at the census tract level was defined as no supermarket within 1 mile in urban areas and 10 miles in rural areas. HbA1c measurements were obtained from electronic health records through November 2016. The relationship among food insecurity, low physical food access, and glycemic control (as defined by HbA1c) was analyzed using hierarchical linear mixed models. RESULTS Three hundred and ninety-one participants were followed for a mean of 37 months. Twenty percent of respondents reported food insecurity, and 31% resided in an area of low physical food access. In adjusted models, food insecurity was associated with higher HbA1c (difference of 0.6% [6.6 mmol/mol], 95% CI 0.4–0.8 [4.4–8.7], P < 0.0001), which did not improve over time (P = 0.50). Living in an area with low physical food access was not associated with a difference in HbA1c (difference 0.2% [2.2 mmol/mol], 95% CI −0.2 to 0.5 [−2.2 to 5.6], P = 0.33) or with change over time (P = 0.07). CONCLUSIONS Food insecurity is associated with higher HbA1c, but living in an area with low physical food access is not. Food insecurity screening and interventions may help improve glycemic control for vulnerable patients.
Patient Characteristics Associated With Severe Hypoglycemia in a Type 2 Diabetes Cohort in a Large, Integrated Health Care System From 2006 to 2015 Diabetes Care (IF 11.857) Pub Date : 2018-03-16 Anita D. Misra-Hebert; Kevin M. Pantalone; Xinge Ji; Alex Milinovich; Tanujit Dey; Kevin M. Chagin; Janine M. Bauman; Michael W. Kattan; Robert S. Zimmerman
OBJECTIVE To identify severe hypoglycemia events, defined as emergency department visits or hospitalizations for hypoglycemia, in patients with type 2 diabetes receiving care in a large health system and to identify patient characteristics associated with severe hypoglycemia events. RESEARCH DESIGN AND METHODS This was a retrospective cohort study from January 2006 to December 2015 using the electronic medical record in the Cleveland Clinic Health System (CCHS). Participants included 50,439 patients with type 2 diabetes receiving care in the CCHS. Number of severe hypoglycemia events and associated patient characteristics were identified. RESULTS The incidence proportion of severe hypoglycemia increased from 0.12% in 2006 to 0.31% in 2015 (P = 0.01). Compared with patients who did not experience severe hypoglycemia, those with severe hypoglycemia had similar median glycosylated hemoglobin (HbA1c) levels. More patients with severe hypoglycemia versus those without had a prior diagnosis of nonsevere hypoglycemia (9% vs. 2%, P < 0.001). Logistic regression confirmed an increased odds for severe hypoglycemia with insulin, sulfonylureas, increased number of diabetes medications, history of nonsevere hypoglycemia (odds ratio [OR] 3.01, P < 0.001), HbA1c <6% (42 mmol/mol) (OR 1.95, P < 0.001), black race, and increased Charlson comorbidity index. Lower odds of severe hypoglycemia were noted with higher BMI and use of metformin, dipeptidyl peptidase-4 inhibitor inhibitors, and glucagon-like peptide 1 agonists. CONCLUSIONS In this retrospective study of patients with type 2 diabetes with severe hypoglycemia, patient characteristics were identified. Patients with severe hypoglycemia had previous nonsevere hypoglycemia diagnoses more frequently than those without. Identifying patients at high risk at the point of care can allow for change in modifiable risk factors and prevention of severe hypoglycemia events.
Impact of Intensive Lifestyle Intervention on Disability-Free Life Expectancy: The Look AHEAD Study Diabetes Care (IF 11.857) Pub Date : 2018-03-15 Edward W. Gregg; Ji Lin; Barbara Bardenheier; Haiying Chen; W. Jack Rejeski; Xiaohui Zhuo; Andrea L. Hergenroeder; Stephen B. Kritchevsky; Anne L. Peters; Lynne E. Wagenknecht; Edward H. Ip; Mark A. Espeland; for the Look AHEAD Study Group
OBJECTIVE The impact of weight loss intervention on disability-free life expectancy in adults with diabetes is unknown. We examined the impact of a long-term weight loss intervention on years spent with and without physical disability. RESEARCH DESIGN AND METHODS Overweight or obese adults with type 2 diabetes age 45–76 years (n = 5,145) were randomly assigned to a 10-year intensive lifestyle intervention (ILI) or diabetes support and education (DSE). Physical function was assessed annually for 12 years using the SF-36. Annual incidence of physical disability, mortality, and disability remission were incorporated into a Markov model to quantify years of life spent active and physically disabled. RESULTS Physical disability incidence was lower in the ILI group (6.0% per year) than in the DSE group (6.8% per year) (incidence rate ratio 0.88 [95% CI 0.81–0.96]), whereas rates of disability remission and mortality did not differ between groups. ILI participants had a significant delay in moderate or severe disability onset and an increase in number of nondisabled years (P < 0.05) compared with DSE participants. For a 60-year-old, this effect translates to 0.9 more disability-free years (12.0 years [95% CI 11.5–12.4] vs. 11.1 years [95% CI 10.6–11.7]) but no difference in total years of life. In stratified analyses, ILI increased disability-free years of life in women and participants without cardiovascular disease (CVD) but not in men or participants with CVD. CONCLUSIONS Long-term lifestyle interventions among overweight or obese adults with type 2 diabetes may reduce long-term disability, leading to an effect on disability-free life expectancy but not on total life expectancy.
Accelerated Progression to Type 1 Diabetes in the Presence of HLA-A*24 and -B*18 Is Restricted to Multiple-Islet Autoantibody-Positive Individuals With Distinct HLA-DQ- and Autoantibody Risk Profiles Diabetes Care (IF 11.857) Pub Date : 2018-03-15 Else M. Balke; Eric V. Balti; Bart Van der Auwera; Ilse Weets; Olivier Costa; Simke Demeester; Pascale Abrams; Kristina Casteels; Marina Coeckelberghs; Sylvie Tenoutasse; Bart Keymeulen; Daniel G. Pipeleers; Frans K. Gorus; the Belgian Diabetes Registry
OBJECTIVE We investigated the effect of HLA class I risk alleles on disease progression in various phases of subclinical islet autoimmunity in first-degree relatives of patients with type 1 diabetes. RESEARCH DESIGN AND METHODS A registry-based group of siblings/offspring (aged 0–39 years) was monitored from single- to multiple-autoantibody positivity (n = 267) and from multiple-autoantibody positivity to clinical onset (n = 252) according to HLA-DQ, -A*24, -B*18 and -B*39 status. Genetic markers were determined by PCR sequence-specific oligotyping. RESULTS Unlike HLA-B*18 or -B*39, HLA-A*24 associated with delayed progression from single- to multiple-autoantibody positivity (P = 0.009) but not to type 1 diabetes. This occurred independently from older age (P < 0.001) and absence of HLA-DQ2/DQ8 or -DQ8 (P < 0.001 and P = 0.003, respectively), and only in the presence of GAD autoantibodies. In contrast, HLA-A*24 associated with accelerated progression from multiple-autoantibody positivity to clinical onset (P = 0.006), but its effects were restricted to HLA-DQ8+ relatives with IA-2- or zinc transporter 8 autoantibodies (P = 0.002). HLA-B*18, but not -B*39, was also associated with more rapid progression, but only in HLA-DQ2 carriers with double positivity for GAD and insulin autoantibodies (P = 0.004). CONCLUSIONS HLA-A*24 predisposes to a delayed antigen spreading of humoral autoimmunity, whereas HLA-A*24 and -B*18 associate with accelerated progression of advanced subclinical autoimmunity in distinct risk groups. The relation of these alleles to the underlying disease process requires further investigation. Their typing should be relevant for the preparation and interpretation of observational and interventional studies in asymptomatic type 1 diabetes.
Impact of Body Weight Loss From Maximum Weight on Fragility Bone Fractures in Japanese Patients With type 2 Diabetes: the Fukuoka Diabetes Registry Diabetes Care (IF 11.857) Pub Date : 2018-03-14 Yuji Komorita; Masanori Iwase; Hiroki Fujii; Toshiaki Ohkuma; Hitoshi Ide; Tamaki Jodai-Kitamura; Akiko Sumi; Masahito Yoshinari; Udai Nakamura; Dongchon Kang; Takanari Kitazono
OBJECTIVE There is growing evidence that weight loss is associated with increased fracture risk in the general population. As patients with diabetes often lose weight intentionally or unintentionally, we aimed to investigate prospectively the relationship between weight loss from maximum body weight and fracture risk. RESEARCH DESIGN AND METHODS A total of 4,706 Japanese participants with type 2 diabetes (mean age 66 years), including 2,755 men and 1,951 postmenopausal women, were followed for a median of 5.3 years and were divided according to weight loss from maximum weight: <10%, 10% to <20%, 20% to <30%, and ≥30%. The primary outcomes were fragility fractures defined as fractures at sites of hip and spine. RESULTS During the follow-up period, fragility fractures occurred in 198 participants. The age- and sex-adjusted incidence rates per 1,000 person-years in all participants were 6.4 (<10% weight loss from maximum body weight), 7.8 (10% to <20%), 11.7 (20% to <30%), and 19.2 (≥30%) (P for trend <0.001). Multivariate-adjusted hazard ratios for fragility fractures compared with reference (<10% weight loss) were 1.48 ([95% CI] 0.79–2.77) in the 10% to <20% group, 2.23 (1.08–4.64) in 20% to <30%, and 5.20 (2.15–12.57) in ≥30% in men, and 1.19 (0.78–1.82) in 10% to <20%, 1.62 (0.96–2.73) in 20% to <30%, and 1.97 (0.84–4.62) in ≥30% in postmenopausal women. CONCLUSIONS The current study demonstrates that ≥20% body weight loss from maximum weight is a significant risk factor for fragility fractures in patients with type 2 diabetes, especially in men.
Day-and-Night Closed-Loop Insulin Delivery in a Broad Population of Pregnant Women With Type 1 Diabetes: A Randomized Controlled Crossover Trial Diabetes Care (IF 11.857) Pub Date : 2018-03-13 Zoe A. Stewart; Malgorzata E. Wilinska; Sara Hartnell; Leanne K. O’Neil; Gerry Rayman; Eleanor M. Scott; Katharine Barnard; Conor Farrington; Roman Hovorka; Helen R. Murphy
OBJECTIVE Despite advances in technology, optimal glucose control remains elusive and neonatal complications ubiquitous in type 1 diabetes (T1D) pregnancy. Our aim was to examine the safety, efficacy, and longer-term feasibility of day-and-night closed-loop insulin delivery. RESEARCH DESIGN AND METHODS We recruited 16 pregnant women (mean [SD]: age 32.8 [5.0] years, T1D duration 19.4 [10.2] years, HbA1c 8.0% [1.1%], BMI 26.6 [4.4] kg/m2) to an open-label, randomized, crossover trial. Participants completed 28 days of closed-loop and sensor-augmented pump (SAP) insulin delivery separated by a washout period. Afterward, participants could continue to use the closed-loop system up to 6 weeks postpartum. The primary end point was the proportion of time with glucose levels within the target range (63–140 mg/dL). RESULTS The proportion of time with glucose levels within target was comparable during closed-loop and SAP insulin delivery (62.3 vs. 60.1% [95% CI −4.1 to 8.3%]; P = 0.47). Mean glucose and time spent hyperglycemic >140 mg/dL also did not differ (131.4 vs. 131.4 mg/dL [P = 0.85] and 36.6 vs. 36.1% [P = 0.86], respectively). During closed-loop, fewer hypoglycemic episodes occurred (median [range] 8 [1–17] vs. 12.5 [1–53] over 28 days; P = 0.04) and less time at <63 mg/dL (1.6 vs. 2.7%; P = 0.02). Hypoglycemia <50 mg/dL (0.24 vs. 0.47%; P = 0.03) and low blood glucose index (1.0 vs. 1.4; P = 0.01) were lower. Less nocturnal hypoglycemia (2300–0700 h) during closed-loop therapy (1.1 vs. 2.7%; P = 0.008) and a trend toward higher overnight time in target (67.7 vs. 60.6%; P = 0.06) were found. CONCLUSIONS Closed-loop insulin delivery was associated with comparable glucose control and significantly less hypoglycemia than SAP therapy. Larger, longer duration multicenter trials are now indicated to determine clinical efficacy of closed-loop insulin delivery in T1D pregnancy and the impact on neonatal outcomes.
Meat Cooking Methods and Risk of Type 2 Diabetes: Results From Three Prospective Cohort Studies Diabetes Care (IF 11.857) Pub Date : 2018-03-12 Gang Liu; Geng Zong; Kana Wu; Yang Hu; Yanping Li; Walter C. Willett; David M. Eisenberg; Frank B. Hu; Qi Sun
OBJECTIVE To examine open-flame and/or high-temperature cooking (grilling/barbecuing, broiling, or roasting) and doneness preferences (rare, medium, or well done) for red meat, chicken, and fish in relation to type 2 diabetes (T2D) risk among U.S. adults who consumed animal flesh regularly (≥2 servings/week). RESEARCH DESIGN AND METHODS The prospective studies included 52,752 women from the Nurses’ Health Study (NHS, followed during 1996–2012), 60,809 women from NHS II (followed during 2001–2013), and 24,679 men from the Health Professionals Follow-up Study (HPFS, followed during 1996–2012) who were free of diabetes, cardiovascular disease, and cancer at baseline. Incident cases of T2D were confirmed by validated supplementary questionnaires. RESULTS We documented 7,895 incident cases of T2D during 1.74 million person-years of follow-up. After multivariate adjustments including baseline BMI and total consumption of red meat, chicken, and fish, higher frequency of open-flame and/or high-temperature cooking was independently associated with an elevated T2D risk. When comparing open-flame and/or high-temperature cooking >15 times/month with <4 times/month, the pooled hazard ratio (HR) (95% CI) of T2D was 1.28 (1.18, 1.39; Ptrend <0.001). When comparing the extreme quartiles of doneness-weighted frequency of high-temperature cooking, the pooled HR (95% CI) of T2D was 1.20 (1.12, 1.28; Ptrend <0.001). These associations remained significant when red meat and chicken were examined separately. In addition, estimated intake of heterocyclic aromatic amines was also associated with an increased T2D risk. CONCLUSIONS Independent of consumption amount, open-flame and/or high-temperature cooking for both red meat and chicken is associated with an increased T2D risk among adults who consume animal flesh regularly.
Obesity Progression Between Young Adulthood and Midlife and Incident Diabetes: A Retrospective Cohort Study of U.S. Adults Diabetes Care (IF 11.857) Pub Date : 2018-03-05 Andrew Stokes; Jason M. Collins; Bethany F. Grant; Robin F. Scamuffa; Chia-Wen Hsiao; Stephen S. Johnston; Eric M. Ammann; JoAnn E. Manson; Samuel H. Preston
OBJECTIVE Understanding how changes in weight over the life course shape risk for diabetes is critical for the prevention of diabetes. Using data from the National Health and Nutrition Examination Survey (NHANES), we investigated the association between self-reported weight change from young adulthood to midlife and incident diabetes. RESEARCH DESIGN AND METHODS We categorized individuals into four weight-change groups: those who remained nonobese (stable nonobese), those who moved from an obese BMI to a nonobese BMI (losing), those who moved from a nonobese BMI to an obese BMI (gaining), and those who remained obese (stable obese). Diabetes status was determined by self-report of a prior diagnosis, and age at diagnosis was used to establish time of diabetes onset. Hazard ratios (HRs) relating weight change to incident diabetes over 10 years of follow-up were calculated using Cox models adjusting for covariates. RESULTS Those who were obese and lost weight exhibited a significantly lower risk (HR 0.33; 95% CI 0.14, 0.76) of diabetes compared with those with stable obesity. We also observed lower risk among those who were stable nonobese (HR 0.22; 95% CI 0.18, 0.28) and those in the gaining category (HR 0.70; 95% CI 0.57, 0.87). Further, there was evidence of an increased incidence of diabetes among obese individuals who lost weight compared with individuals who were stable nonobese; however, weight loss was rare, and the association was not statistically significant. If those who were obese had become nonobese during the 10-year period, we estimate that 9.1% (95% CI 5.3, 12.8) of observed diabetes cases could have been averted, and if the population had maintained a normal BMI during the period, 64.2% (95% CI 59.4, 68.3) of cases could have been averted. CONCLUSIONS The findings from this study underscore the importance of population-level approaches to the prevention and treatment of obesity across the life course of individuals.
Long-Acting Glucagon-Like Peptide 1 Receptor Agonists Diabetes Care (IF 11.857) Pub Date : 2011-05-01 Alan J. Garber
Targeting the incretin system has become an important therapeutic approach for treating type 2 diabetes. Two drug classes have been developed: glucagon-like peptide (GLP)-1 receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors. Clinical data have revealed that these therapies improve glycemic control while reducing body weight (GLP-1 receptor agonists, specifically) and systolic blood pressure (SBP) in patients with type 2 diabetes. Furthermore, incidence of hypoglycemia is relatively low with these treatments (except when used in combination with a sulfonylurea) because of their glucose-dependent mechanism of action. There are currently two GLP-1 receptor agonists available (exenatide and liraglutide), with several more currently being developed. This review considers the efficacy and safety of both the short- and long-acting GLP-1 receptor agonists. Head-to-head clinical trial data suggest that long-acting GLP-1 receptor agonists produce superior glycemic control when compared with their short-acting counterparts. Furthermore, these long-acting GLP-1 receptor agonists were generally well tolerated, with transient nausea being the most frequently reported adverse effect.
Prevalence of Major Behavioral Risk Factors for Type 2 Diabetes Diabetes Care (IF 11.857) Pub Date : 2018-03-02 Karen R. Siegel; Kai McKeever Bullard; Giuseppina Imperatore; Mohammed K. Ali; Ann Albright; Carla I. Mercado; Rui Li; Edward W. Gregg
OBJECTIVE We examined the proportion of American adults without type 2 diabetes that engages in lifestyle behaviors known to reduce type 2 diabetes risk. RESEARCH DESIGN AND METHODS We conducted a cross-sectional analysis of 3,679 nonpregnant, nonlactating individuals aged ≥20 years without diabetes (self-reported diagnosis or glycated hemoglobin ≥6.5% [8 mmol/mol] or fasting plasma glucose ≥126 mg/dL) and who provided 2 days of reliable dietary data in the 2007–2012 National Health and Nutrition Examination Surveys (NHANES). We used the average of 2 days of dietary recall and self-reported leisure-time physical activity to assess whether participants met type 2 diabetes risk reduction goals (meeting four or more MyPlate recommendations [adequate consumption of fruits, vegetables, dairy, grains, meat, beans, and eggs]; not exceeding three maximum allowances for alcoholic beverages, added sugars, fat, and cholesterol; and meeting physical activity recommendations [≥150 min/week]). RESULTS Approximately 21%, 29%, and 13% of individuals met fruit, vegetable, and dairy goals, respectively. Half (51.6%) met the goal for total grains, compared with 18% for whole grains, and 54.2% met the meat/beans goal and 40.6% met the oils goal. About one-third (37.8%) met the physical activity goal, and 58.6% met the weight loss/maintenance goal. Overall, 3.1% (95% CI 2.4–4.0) of individuals met the majority of type 2 diabetes risk reduction goals. Younger age and lower educational attainment were associated with lower probability of meeting goals. CONCLUSIONS A small proportion of U.S. adults engages in risk reduction behaviors. Research and interventions targeted at young and less-educated segments of the population may help close gaps in risk reduction behaviors.
Racial/Ethnic Minority Youth With Recent-Onset Type 1 Diabetes Have Poor Prognostic Factors Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Maria Jose Redondo; Ingrid Libman; Peiyao Cheng; Craig Kollman; Mustafa Tosur; Robin L. Gal; Fida Bacha; Georgeanna J. Klingensmith; Mark Clements; for the Pediatric Diabetes Consortium
OBJECTIVE To compare races/ethnicities for characteristics, at type 1 diabetes diagnosis and during the first 3 years postdiagnosis, known to influence long-term health outcomes. RESEARCH DESIGN AND METHODS We analyzed 927 Pediatric Diabetes Consortium (PDC) participants <19 years old (631 non-Hispanic white [NHW], 216 Hispanic, and 80 African American [AA]) diagnosed with type 1 diabetes and followed for a median of 3.0 years (interquartile range 2.2–3.6). Demographic and clinical data were collected from medical records and patient/parent interviews. Partial remission period or “honeymoon” was defined as insulin dose–adjusted hemoglobin A1c (IDAA1c) ≤9.0%. We used logistic, linear, and multinomial regression models, as well as repeated measures logistic and linear regression models. Models were adjusted for known confounders. RESULTS AA subjects, compared with NHW, at diagnosis, were in a higher age- and sex-adjusted BMI percentile (BMI%), had more advanced pubertal development, and had higher frequency of presentation in diabetic ketoacidosis, largely explained by socioeconomic factors. During the first 3 years, AA subjects were more likely to have hypertension and severe hypoglycemia events; had trajectories with higher hemoglobin A1c, BMI%, insulin doses, and IDAA1c; and were less likely to enter partial remission period. Hispanics, compared with NHWs, had higher BMI% at diagnosis and over the three subsequent years. During the 3 years postdiagnosis, Hispanics had higher prevalence of dyslipidemia and maintained trajectories of higher insulin doses and IDAA1c. CONCLUSIONS Youth of minority race/ethnicity have increased markers of poor prognosis of type 1 diabetes at diagnosis and 3 years postdiagnosis, possibly contributing to higher risk of long-term diabetes complications compared with NHWs.
The Productivity Burden of Diabetes at a Population Level Diabetes Care (IF 11.857) Pub Date : 2018-02-28 Dianna J. Magliano; Valencia J. Martin; Alice J. Owen; Ella Zomer; Danny Liew
OBJECTIVE Recent studies suggest that diabetes may impact work productivity. In the current study, we sought to estimate the lifetime and population impact of diabetes on productivity using the novel measure of “productivity-adjusted life years” (PALYs). RESEARCH DESIGN AND METHODS Using age-specific mortality rates and a productivity index attributable to diabetes (akin to the quality of life index, but which adjusts for reduction in productivity) and life table modeling, we estimated years of life and PALYs lost to diabetes among Australians with diabetes currently aged 20–65 years, with follow-up until 69 years. Life tables were first constructed for the cohort with diabetes and then repeated for the same cohort but with the assumption that they no longer had diabetes. The “nondiabetic” cohort had lower mortality rates and improved productivity. The differences in total years of life lived and PALYs lived between the two cohorts reflected the impact of diabetes. RESULTS Overall, diabetes reduced 190,219 years of life lived by the cohort, or by 3%. Diabetes reduced PALYs by 11.6% and 10.5% among men and women, respectively. For both sexes, the impact of diabetes on productivity was lowest in those aged 65–69 years and highest in those 20–24 years. Among the latter, PALYs were reduced by 12.2% and 11.0% for men and women, respectively. CONCLUSIONS Elimination of diabetes can prolong life years lived by the whole population and increase the amount of productive years lived. Employers and government should be aware that having diabetes affects work force productivity and implement prevention programs to reduce the impact of diabetes on the workforce.
Risk Factors for Incident Diabetic Polyneuropathy in a Cohort With Screen-Detected Type 2 Diabetes Followed for 13 Years: ADDITION-Denmark Diabetes Care (IF 11.857) Pub Date : 2018-02-27 Signe T. Andersen; Daniel R. Witte; Else-Marie Dalsgaard; Henning Andersen; Peter Nawroth; Thomas Fleming; Troels M. Jensen; Nanna B. Finnerup; Troels S. Jensen; Torsten Lauritzen; Eva L. Feldman; Brian C. Callaghan; Morten Charles
OBJECTIVE To study incident diabetic polyneuropathy (DPN) prospectively during the first 13 years after a screening-based diagnosis of type 2 diabetes and determine the associated risk factors for the development of DPN. RESEARCH DESIGN AND METHODS We assessed DPN longitudinally in the Danish arm of the Anglo-Danish-Dutch study of Intensive Treatment of Diabetes in Primary Care (ADDITION) using the Michigan Neuropathy Screening Instrument questionnaire (MNSIQ), defining DPN with scores ≥4. Risk factors present at the diabetes diagnosis associated with the risk of incident DPN were estimated using Cox proportional hazard models adjusted for trial randomization group, sex, and age. RESULTS Of the total cohort of 1,533 people, 1,445 completed the MNSIQ at baseline and 189 (13.1%) had DPN at baseline. The remaining 1,256 without DPN entered this study (median age 60.8 years [interquartile range 55.6; 65.6], 59% of whom were men). The cumulative incidence of DPN was 10% during 13 years of diabetes. Age (hazard ratio [HR] 1.03 [95% CI 1.00; 1.07]) (unit = 1 year), weight (HR 1.09 [95% CI 1.03; 1.16]) (unit = 5 kg), waist circumference (HR 1.14 [95% CI 1.05; 1.24]) (unit = 5 cm), BMI (HR 1.14 [95% CI 1.06; 1.23]) (unit = 2 kg/m2), log2 methylglyoxal (HR 1.45 [95% CI 1.12; 1.89]) (unit = doubling), HDL cholesterol (HR 0.82 [95% CI 0.69; 0.99]) (unit = 0.25 mmol/L), and LDL cholesterol (HR 0.92 [95% CI 0.86; 0.98]) (unit = 0.25 mmol/L) at baseline were significantly associated with the risk of incident DPN. CONCLUSIONS This study provides further epidemiological evidence for obesity as a risk factor for DPN. Moreover, low HDL cholesterol levels and higher levels of methylglyoxal, a marker of dicarbonyl stress, are identified as risk factors for the development of DPN.
Childhood BMI and Adult Type 2 Diabetes, Coronary Artery Diseases, Chronic Kidney Disease, and Cardiometabolic Traits: A Mendelian Randomization Analysis Diabetes Care (IF 11.857) Pub Date : 2018-02-26 Tingting Geng; Caren E. Smith; Changwei Li; Tao Huang
OBJECTIVE To test the causal effect of childhood BMI on adult cardiometabolic diseases using a Mendelian randomization (MR) analysis. RESEARCH DESIGN AND METHODS We used 15 single nucleotide polymorphisms (SNPs) as instrumental variables for childhood BMI to test the causal effect of childhood BMI on cardiometabolic diseases using summary-level data from consortia. RESULTS We found that a one-SD increase in childhood BMI (kg/m2) was associated with an 83% increase in risk of type 2 diabetes (odds ratio [OR] 1.83 [95% CI 1.46, 2.30]; P = 2.5 × 10−7) and a 28% increase in risk of coronary artery disease (CAD) (OR 1.28 [95% CI 1.17, 1.39]; P = 2.1 × 10−8) at the Bonferroni-adjusted level of significance (P < 0.017) in adults. In addition, a one-SD increase in childhood BMI was associated with a 0.587-SD increase in adulthood BMI (kg/m2), a 0.062-SD increase in hip circumference (cm), a 0.602-SD increase in waist circumference (cm), a 0.111 pmol/L increase in log fasting insulin, a 0.068 increase in log HOMA β (log HOMA-B) (%), a 0.126 increase in log HOMA of insulin resistance (log HOMA-IR) (%), and a 0.109-SD increase in triglyceride (TG) (mg/dL), respectively, but a 0.138-SD decrease in HDL (mg/dL) in adults at the Bonferroni-adjusted level of significance (P < 0.0026). CONCLUSIONS A genetic predisposition to childhood BMI was associated with increased risk of type 2 diabetes and CAD in adult life. These results provide evidence supportive of a causal association between childhood BMI and these outcomes.
Efficacy and Safety of IDegLira Versus Basal-Bolus Insulin Therapy in Patients With Type 2 Diabetes Uncontrolled on Metformin and Basal Insulin; DUAL VII Randomized Clinical Trial Diabetes Care (IF 11.857) Pub Date : 2018-02-26 Liana K. Billings; Ankur Doshi; Didier Gouet; Alejandra Oviedo; Helena W. Rodbard; Nikolaos Tentolouris; Randi Grøn; Natalie Halladin; Esteban Jodar
OBJECTIVE In patients with uncontrolled type 2 diabetes on basal insulin, prandial insulin may be initiated. We assessed the efficacy and safety of initiating insulin degludec/liraglutide fixed-ratio combination (IDegLira) versus basal-bolus insulin. RESEARCH DESIGN AND METHODS A phase 3b trial examined patients with uncontrolled type 2 diabetes on insulin glargine (IGlar U100) 20–50 units/day and metformin, randomized to IDegLira or IGlar U100 and insulin aspart four or fewer times per day. RESULTS Glycated hemoglobin (HbA1c) decreased from 8.2% (66 mmol/mol) to 6.7% (50 mmol/mol) with IDegLira, and from 8.2% (67 mmol/mol) to 6.7% (50 mmol/mol) with basal-bolus (estimated treatment difference [ETD] −0.02% [95% CI −0.16, 0.12]; −0.2 mmol/mol [95% CI −1.7, 1.3]), confirming IDegLira noninferiority versus basal-bolus (P < 0.0001). The number of severe or blood glucose–confirmed symptomatic hypoglycemia events was lower with IDegLira versus basal-bolus (risk ratio 0.39 [95% CI 0.29, 0.51]; rate ratio 0.11 [95% CI 0.08, 0.17]). Body weight decreased with IDegLira and increased with basal-bolus (ETD −3.6 kg [95% CI −4.2, −2.9]). Fasting plasma glucose reductions were similar; lunch, dinner, and bedtime self-monitored plasma glucose measurements were significantly lower with basal-bolus. Sixty-six percent of patients on IDegLira versus 67.0% on basal-bolus achieved HbA1c <7.0% (53 mmol/mol). Total daily insulin dose was lower with IDegLira (40 units) than basal-bolus (84 units total; 52 units basal). CONCLUSIONS In patients with uncontrolled type 2 diabetes on IGlar U100 and metformin, IDegLira treatment elicited HbA1c reductions comparable to basal-bolus, with statistically superior lower hypoglycemia rates and weight loss versus weight gain.
Changes in Health Insurance Coverage Under the Affordable Care Act: A National Sample of U.S. Adults With Diabetes, 2009 and 2016 Diabetes Care (IF 11.857) Pub Date : 2018-02-23 Sarah S. Casagrande; Laura N. McEwen; William H. Herman
OBJECTIVE To assess national changes in health insurance coverage and related costs before and after implementation of the Affordable Care Act (ACA) among U.S. adults with diabetes. RESEARCH DESIGN AND METHODS Data were cross-sectional from the 2009 and 2016 National Health Interview Surveys. Participants were adults age ≥18 years with a previous diagnosis of diabetes who self-reported on their health insurance coverage, demographic information, diabetes-related factors, and amount spent on medical expenses and insurance premiums (N = 6,220). RESULTS Among adults with diabetes age 18–64 years, health insurance coverage increased from 84.7% in 2009 to 90.1% in 2016 (P < 0.001). Coverage remained near universal for those age ≥65 years (99.5%). For adults age 18–64 years, coverage increased for almost all subgroups and significantly for men; non-Hispanic whites, non-Hispanic blacks, and Hispanics; those who were married; those with less than or more than a high school education; family income <$35,000; diabetes duration <5 or >15 years; and those taking oral agents (P < 0.05 for all). Among adults age 18–64 years, Medicaid coverage significantly increased between 2009 and 2016 (19.4% vs. 24.3%, P = 0.006), and for those with private insurance, 7.8% acquired their plan through HealthCare.gov. For adults age ≥65 years, private insurance decreased and Medicare Part D increased (P < 0.007 for both). Among those age 18–64 years with an income <$35,000, the proportion of income spent on family medical costs decreased (6.3% vs. 4.8% for 2009 vs. 2016, respectively; P = 0.004). CONCLUSIONS Health insurance coverage among adults with diabetes age 18–64 years increased significantly after implementation of the ACA, and medical costs to families decreased among those with lower incomes.
Global Economic Burden of Diabetes in Adults: Projections From 2015 to 2030 Diabetes Care (IF 11.857) Pub Date : 2018-02-23 Christian Bommer; Vera Sagalova; Esther Heesemann; Jennifer Manne-Goehler; Rifat Atun; Till Bärnighausen; Justine Davies; Sebastian Vollmer
OBJECTIVE Despite the importance of diabetes for global health, the future economic consequences of the disease remain opaque. We forecast the full global costs of diabetes in adults through the year 2030 and predict the economic consequences of diabetes if global targets under the Sustainable Development Goals (SDG) and World Health Organization Global Action Plan for the Prevention and Control of Noncommunicable Diseases 2013–2020 are met. RESEARCH DESIGN AND METHODS We modeled the absolute and gross domestic product (GDP)-relative economic burden of diabetes in individuals aged 20–79 years using epidemiological and demographic data, as well as recent GDP forecasts for 180 countries. We assumed three scenarios: prevalence and mortality 1) increased only with urbanization and population aging (baseline scenario), 2) increased in line with previous trends (past trends scenario), and 3) achieved global targets (target scenario). RESULTS The absolute global economic burden will increase from U.S. $1.3 trillion (95% CI 1.3–1.4) in 2015 to $2.2 trillion (2.2–2.3) in the baseline, $2.5 trillion (2.4–2.6) in the past trends, and $2.1 trillion (2.1–2.2) in the target scenarios by 2030. This translates to an increase in costs as a share of global GDP from 1.8% (1.7–1.9) in 2015 to a maximum of 2.2% (2.1–2.2). CONCLUSIONS The global costs of diabetes and its consequences are large and will substantially increase by 2030. Even if countries meet international targets, the global economic burden will not decrease. Policy makers need to take urgent action to prepare health and social security systems to mitigate the effects of diabetes.
Predicting the Effect of Fenofibrate on Cardiovascular Risk for Individual Patients With Type 2 Diabetes Mellitus Diabetes Care (IF 11.857) Pub Date : 2018-02-22 Charlotte Koopal; Frank L.J. Visseren; Jan Westerink; Yolanda van der Graaf; Henry N. Ginsberg; Anthony C. Keech
OBJECTIVE In clinical trials, treatment with fenofibrate did not reduce the incidence of major cardiovascular events (MCVE) in patients with type 2 diabetes mellitus (T2DM). However, treatment effects reported by trials comprise patients who respond poorly and patients who respond well to fenofibrate. Our aim was to use statistical modeling to estimate the expected treatment effect of fenofibrate for individual patients with T2DM. RESEARCH DESIGN AND METHODS To estimate individual risk, the FIELD risk model, with 5-year MCVE as primary outcome, was externally validated in T2DM patients from ACCORD and the SMART observational cohort. Fenofibrate treatment effect was estimated in 17,142 T2DM patients from FIELD, ACCORD, and SMART. Individual treatment effect, expressed as absolute risk reduction (ARR), is the difference between treated and untreated MCVE risk. Results were stratified for patients with and without dyslipidemia (i.e., high triglycerides and low LDL cholesterol). RESULTS External validation of the FIELD risk model showed good calibration and moderate discrimination in ACCORD (C-statistic 0.67 [95% CI 0.65–0.69]) and SMART (C-statistic 0.66 [95% CI 0.63–0.69]). Median 5-year MCVE risk in all three studies combined was 6.7% (interquartile range [IQR] 4.0–11.7) in patients without (N = 13,224), and 9.4% (IQR 5.4–16.1%) in patients with (N = 3,918), dyslipidemia. The median ARR was 2.15% (IQR 1.23–3.68) in patients with dyslipidemia, corresponding with a number needed to treat (NNT) of 47, and 0.22% (IQR 0.13–0.38) in patients without dyslipidemia (NNT 455). CONCLUSIONS In individual patients with T2DM, there is a wide range of absolute treatment effect of fenofibrate, and overall the fenofibrate treatment effect was larger in patients with dyslipidemia. The method of individualized treatment effect prediction of fenofibrate on MCVE risk reduction in T2DM can be used to guide clinical decision-making.
Characteristics and Prognosis in Women and Men With Type 1 Diabetes Undergoing Coronary Angiography: A Nationwide Registry Report Diabetes Care (IF 11.857) Pub Date : 2018-02-20 Viveca Ritsinger; Christel Hero; Ann-Marie Svensson; Nawzad Saleh; Bo Lagerqvist; Katarina Eeg-Olofsson; Anna Norhammar
OBJECTIVE To describe sex aspects on extent of coronary artery disease (CAD) and prognosis in a contemporary population with type 1 diabetes. RESEARCH DESIGN AND METHODS All patients undergoing coronary angiography, 2001–2013, included in the Swedish Coronary Angiography and Angioplasty Registry and the Swedish National Diabetes Register as type 1 diabetes were followed for mortality until 31 December 2013. The coronary angiogram was classified into normal and one-, two-, three-, and left main vessel disease. RESULTS In all, 2,776 patients (42% women) with mean age 58 years (SD 11) were followed for 7.2 years (SD 2.2). Diabetes duration was longer in women (37 ± 14 vs. 34 ± 14 years in men; P < 0.001) who also had more retinopathy (68% vs. 65%; P = 0.050) whereas microalbuminuria was less common (41% vs. 51%; P < 0.001). Indications for coronary angiography did not substantially differ in women and men. The extent of CAD was somewhat less severe in women (normal angiogram 23.5% vs. 19.1%, three-vessel and left main stem disease 34.5% vs. 40.4%; P = 0.002) whereas mortality did not differ (adjusted HR 1.03 [95% CI 0.88–1.20]; P = 0.754). The standard mortality ratio for women the 1st year was 7.49 (5.73–9.62) and for men 4.58 (3.60–5.74). CONCLUSIONS In patients with type 1 diabetes admitted for coronary angiography, the extent of CAD was almost similar in women and men, and total long-term mortality did not differ. Type 1 diabetes was associated with higher mortality risk in women than in men when compared with the general population. These data support that type 1 diabetes attenuates the cardiovascular risk difference seen in men and women in the general population.
Impact of the 2013 National Rollout of CMS Competitive Bidding Program: the Disruption Continues Diabetes Care (IF 11.857) Pub Date : 2017-11-17 Gary A. Puckrein; Irl B. Hirsch; Christopher G. Parkin; Bruce T. Taylor; Liou Xu; David G. Marrero
OBJECTIVE Use of glucose monitoring is essential to the safety of individuals with insulin-treated diabetes. In 2011, the Centers for Medicare & Medicaid Services (CMS) implemented the Medicare Competitive Bidding Program (CBP) in nine test markets. This resulted in a substantial disruption of beneficiary access to self-monitoring of blood glucose (SMBG) supplies and significant increases in the percentage of beneficiaries with either reduced or no acquisition of supplies. These reductions were significantly associated with increased mortality, hospitalizations, and costs. The CBP was implemented nationally in July 2013. We evaluated the impact of this rollout to determine if the adverse outcomes seen in 2011 persisted. RESEARCH DESIGN AND METHODS This longitudinal study followed 529,627 insulin-treated beneficiaries from 2009 through 2013 to assess changes in beneficiary acquisition of testing supplies in the initial nine test markets (TEST, n = 43,939) and beneficiaries not affected by the 2011 rollout (NONTEST, n = 485,688). All Medicare beneficiary records for analysis were obtained from CMS. RESULTS The percentages of beneficiaries with partial/no SMBG acquisition were significantly higher in both the TEST (37.4%) and NONTEST (37.6%) groups after the first 6 months of the national CBP rollout, showing increases of 48.1% and 60.0%, respectively (both P < 0.0001). The percentage of beneficiaries with no record for SMBG acquisition increased from 54.1% in January 2013 to 62.5% by December 2013. CONCLUSIONS Disruption of beneficiary access to their prescribed SMBG supplies has persisted and worsened. Diabetes testing supplies should be excluded from the CBP until transparent, science-based methodologies for safety monitoring are adopted and implemented.
In This Issue of Diabetes Care Diabetes Care (IF 11.857) Pub Date : 2018-03-01 American Diabetes Association
By Max Bingham, PhD Microencapsulated niacin targeted to the ileocolonic region of the gut appears to result in improved measures of insulin sensitivity, according to Fangmann et al. ( p. 398 ). As a result, they suggest the approach might represent a potential therapy for prediabetes—a claim that will need substantiation in future trials. According to the authors, obese individuals without type 2 diabetes had a lower dietary intake of niacin than nonobese individuals. At the same time, based on DNA sequencing of stool samples, they found that obesity was also associated with reduced gut microbiota α-diversity and Bacteroidetes abundance. Reportedly, a correlation between niacin intake and the bacterial measures did exist. Together with previous evidence, this led them to hypothesize that niacin delivered directly to the ileocolonic region might result in improved metabolic outcomes and that they were somehow mediated by the bacterial phylum Bacteroidetes . Using delayed-release microcapsules with varying doses of either nicotinic acid or nicotinamide, the authors go on to show in a small study of 10 healthy humans that nicotinic acid but not nicotinamide resulted in significant decreases in myostatin, fetuin-A, and osteopontin, which they say are markers for skeletal muscle, liver insulin resistance, and metabolic inflammation, respectively. Concurrently, Bacteroidetes abundance in stool samples reportedly also increased over a 6-week period. Commenting more widely on the research, author Matthias Laudes told Diabetes Care : “We feel that this type of intervention will be a promising approach for the prevention of the progression of prediabetes into type 2 diabetes. The reason is that despite prediabetes prevalence increasing worldwide, and the conversion rate into type 2 diabetes is 5–10%, in most …
American Diabetes Association’s Standards of Care: A Paradigm Shift in the Dissemination of Information Diabetes Care (IF 11.857) Pub Date : 2018-03-01 William T. Cefalu; Erika Gebel Berg; Matthew P. Petersen; Tamara Darsow
It is well understood that diabetes is a complex, chronic illness in which glycemic control reduces the development and progression of macrovascular and microvascular complications. Achieving risk reduction requires continuous medical care and self-management, with multifactorial risk-management strategies beyond just glycemic control, including lifestyle changes and cardiovascular risk reduction. Given the current knowledge of what is required to reduce complications, improve quality of life, and prevent progression to overt disease states, it is important that providers caring for people with diabetes have the latest and most updated clinical translation of the evidence as they consider the day-to-day management of their patients. In this regard, the American Diabetes Association (ADA) has been actively involved in the development and dissemination of diabetes care standards, guidelines, and related documents to support and improve patient care for over 25 years. Specifically, the ADA’s “Standards of Medical Care in Diabetes,” referred to as the Standards of Care, has always been intended to provide clinicians, patients, researchers, payers, and other interested individuals with evidence-based information on all aspects of diabetes care, general treatment goals, and tools to evaluate the quality of care (1). The recent acceleration of the pace of new information being released regarding diabetes care and research has been startling. To put this in perspective, the first ADA Standards of Care, published in 1989, provided recommendations based on the available evidence at that time and filled only four pages in Diabetes Care (2). In the most recent update, 28 years later, the document is well over 170 pages! Over 40 new type 2 diabetes treatment options have been approved since 2005 (3), not even counting advances in technology, such as continuous glucose monitoring. In the last year alone, there have been many significant changes to the Standards of Care, and the 2018 version …
Are All Patients With Type 1 Diabetes Destined for Dialysis if They Live Long Enough? Probably Not Diabetes Care (IF 11.857) Pub Date : 2018-03-01 George L. Bakris; Mark Molitch
Over the past three decades there have been numerous innovations, supported by large outcome trials that have resulted in improved blood glucose and blood pressure control, ultimately reducing cardiovascular (CV) risk and progression to nephropathy in type 1 diabetes (T1D) (1,2). The epidemiological data also support the concept that 25–30% of people with T1D will progress to end-stage renal disease (ESRD). Thus, not everyone develops progressive nephropathy that ultimately requires dialysis or transplantation. This is a result of numerous factors, including the competing CV risk of death as well as blood glucose and pressure control. Good glycemic and blood pressure control have been documented in long-term trials to markedly slow nephropathy progression, with effects of blood pressure control seen as early as 2.5 years and of glucose control at 5–7 years (3,4). It is well documented that the presence of diabetic kidney disease increases the risk of CV events and death in persons with diabetes (5,6). Moreover, this is independent of hypertension. Data from two recent studies reported in this issue of Diabetes Care examine the long-term incidence of chronic kidney disease (CKD) in T1D. Costacou and Orchard (7) examined a cohort of 932 people evaluated for 50-year cumulative kidney complication risk in the Pittsburgh Epidemiology of Diabetes Complications study. They used both albuminuria levels and ESRD/transplant data for assessment. By 30 years’ duration of diabetes, ESRD affected 14.5% and by 40 years it affected 26.5% of the group with onset of T1D between 1965 and 1980. For those who developed diabetes between 1950 and 1964, the proportions developing ESRD were …
Assessing Health-Related Quality of Life in Patients With Diabetic Foot Disease: Why Is It Important and How Can We Improve? The 2017 Roger E. Pecoraro Award Lecture Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Dane K. Wukich; Katherine M. Raspovic
Patient-reported outcomes (PROs) have become an important subject in the area of diabetes-related foot complications. Self-reported health-related quality of life (HRQOL) surveys can provide a generic measure of overall health (global) and can be disease specific (i.e., diabetes) or even region specific (i.e., lower-extremity function). Analysis of PRO measures utilizing validated instruments allows health care providers to determine whether medical and surgical treatments are providing patients with the highest level of outcome possible and are actually improving HRQOL. The 36-item Short Form (SF-36), EuroQol five-dimension questionnaire (EQ-5D-5L), and Foot and Ankle Ability Measure (FAAM) are examples of commonly used HRQOL surveys. Low HRQOL has been associated with higher rates of hospital admission and mortality in patients with diabetes. Previous studies have demonstrated that patients with diabetes-related foot disease have low self-reported physical quality of life but do not typically report low mental quality of life. The impact of mental quality of life may be underestimated in these patients using the SF-36. In this article, we will discuss several widely used outcome instruments used to measure patient HRQOL and the impact of diabetic foot disease on HRQOL. As health care providers, we must continue to adjust and modify our treatments to achieve the best patient outcomes and associated high quality of life. Assessing PROs will become increasingly important as health care systems transition from a volume-based reimbursement model to a value-based model.
Targeted Microbiome Intervention by Microencapsulated Delayed-Release Niacin Beneficially Affects Insulin Sensitivity in Humans Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Daniela Fangmann; Eva-Maria Theismann; Kathrin Türk; Dominik M. Schulte; Isabelle Relling; Katharina Hartmann; Julia K. Keppler; Jörg-Rainer Knipp; Ateequr Rehman; Femke-Anouska Heinsen; Andre Franke; Lennart Lenk; Sandra Freitag-Wolf; Esther Appel; Stanislav Gorb; Charles Brenner; Dirk Seegert; Georg H. Waetzig; Philip Rosenstiel; Stefan Schreiber; Karin Schwarz; Matthias Laudes
OBJECTIVE Gut microbiota represent a potential novel target for future prediabetes and type 2 diabetes therapies. In that respect, niacin has been shown to beneficially affect the host-microbiome interaction in rodent models. RESEARCH DESIGN AND METHODS We characterized more than 500 human subjects with different metabolic phenotypes regarding their niacin (nicotinic acid [NA] and nicotinamide [NAM]) status and their gut microbiome. In addition, NA and NAM delayed-release microcapsules were engineered and examined in vitro and in vivo in two human intervention studies (bioavailability study and proof-of-concept/safety study). RESULTS We found a reduced α-diversity and Bacteroidetes abundance in the microbiome of obese human subjects associated with a low dietary niacin intake. We therefore developed delayed-release microcapsules targeting the ileocolonic region to deliver increasing amounts of NA and NAM to the microbiome while preventing systemic resorption to avoid negative side effects (e.g., facial flushing). In vitro studies on these delayed-release microcapsules revealed stable conditions at pH 1.4, 4.5, and 6.8, followed by release of the compounds at pH 7.4, simulating the ileocolonic region. In humans in vivo, gut-targeted delayed-release NA but not NAM produced a significant increase in the abundance of Bacteroidetes . In the absence of systemic side effects, these favorable microbiome changes induced by microencapsulated delayed-release NA were associated with an improvement of biomarkers for systemic insulin sensitivity and metabolic inflammation. CONCLUSION Targeted microbiome intervention by delayed-release NA might represent a future therapeutic option for prediabetes and type 2 diabetes.
Prospective, Cluster-Randomized Trial to Implement the Ottawa Model for Smoking Cessation in Diabetes Education Programs in Ontario, Canada Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Robert D. Reid; Janine Malcolm; Evyanne Wooding; Amy Geertsma; Debbie Aitken; David Arbeau; Chris Blanchard; Jo-Anne Gagnier; Anil Gupta; Kerri-Anne Mullen; Paul Oh; Sophia Papadakis; Heather Tulloch; Allana G. LeBlanc; George A. Wells; Andrew L. Pipe
OBJECTIVE To test whether a practice-level intervention to promote the systematic identification, treatment, and follow-up of smokers (the Ottawa Model for Smoking Cessation [OMSC]) would improve long-term abstinence rates among smoker-patients with type 2 diabetes or prediabetes receiving care from diabetes education programs in Ontario, Canada. RESEARCH DESIGN AND METHODS The Tobacco Intervention in Diabetes Education study was a matched-pair, cluster-randomized clinical trial. Within each pair, sites were randomly allocated to either an OMSC intervention (n = 7) or a wait-list control (WLC) condition (n = 7). Diabetes education programs in the OMSC group introduced standardized processes to identify smokers and routinely provided smoking cessation interventions and follow-up. Smokers in the OMSC group received counseling, a discount card to partially cover the cost of smoking cessation medication, and follow-up telephone calls over a 6-month period. Diabetes education programs in the WLC condition were offered the OMSC intervention after a 1-year waiting period. Smokers in the WLC group received usual care for smoking cessation from their diabetes educator. The primary end point was carbon monoxide (CO)–confirmed 7-day point prevalence abstinence from smoking at 6-month follow-up. RESULTS A total of 313 smokers (OMSC group n = 199, WLC group n = 114) with diabetes or prediabetes were enrolled. The CO-confirmed abstinence rate at 6 months was 11.1% in the OMSC group versus 2.6% in the WLC group (odds ratio 3.73 [95% CI 1.20, 11.58]; P = 0.02). CONCLUSIONS Implementation of the OMSC in diabetes education programs resulted in clinically and statistically significant improvements in long-term abstinence among smokers with diabetes or prediabetes.
Changes in Gut Microbiota–Related Metabolites and Long-term Successful Weight Loss in Response to Weight-Loss Diets: The POUNDS Lost Trial Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Yoriko Heianza; Dianjianyi Sun; Steven R. Smith; George A. Bray; Frank M. Sacks; Lu Qi
OBJECTIVE Adiposity and the gut microbiota are both related to the risk of type 2 diabetes. We aimed to comprehensively examine how changes induced by a weight-loss diet intervention in gut microbiota–related metabolites, such as trimethylamine N-oxide (TMAO) and its precursors (choline and l-carnitine), were associated with improvements in adiposity and regional fat deposition. RESEARCH DESIGN AND METHODS This study included 510 overweight and obese individuals who were randomly assigned one of four diets varying in macronutrient intake. We examined associations of 6-month changes in blood metabolites (TMAO, choline, and l-carnitine) with improvements in body weight (BW), waist circumference (WC), body fat composition, fat distribution, and resting energy expenditure (REE). RESULTS Individuals with a greater reduction of choline (P < 0.0001) and l-carnitine (P < 0.01) rather than TMAO showed significant losses of BW and WC at 6 months. The reduction of choline was significantly predictive of decreases in body fat composition, fat distribution, and REE. Results of sensitivity analysis showed that the baseline diabetes risk status, such as the presence of hyperglycemia (31% of the total participants) and fasting glucose levels, did not modify the associations. Early changes in choline and l-carnitine were significantly predictive of weight loss over 2 years (P < 0.05 for all). Individuals with increases in choline or l-carnitine were 2.35-times (95% CI 1.38, 4.00) or 1.77-times (1.06, 2.95) more likely to fail to lose weight (–5% or more loss) at 2 years. CONCLUSIONS Overweight and obese individuals who showed decreases in circulating choline or l-carnitine levels achieved greater improvements of adiposity and energy metabolism by eating a low-calorie weight-loss diet, suggesting that such metabolites are predictive of individuals’ response to the treatment. Further investigations are necessary to confirm our findings, particularly in a population with prediabetes that is more representative of the U.S. population with obesity.
Low Incidence of End-Stage Renal Disease in Childhood-Onset Type 1 Diabetes Followed for Up to 42 Years Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Vibeke Gagnum; Maryam Saeed; Lars C. Stene; Torbjørn Leivestad; Geir Joner; Torild Skrivarhaug
OBJECTIVE End-stage renal disease (ESRD) is one of the most severe complications in type 1 diabetes. We aimed to estimate the cumulative incidence of ESRD in individuals with childhood-onset type 1 diabetes followed for up to 42 years. RESEARCH DESIGN AND METHODS Data were based on the nationwide, population-based Norwegian Childhood Diabetes Registry and included case patients with new-onset type 1 diabetes (age <15 years) who had received a diagnosis during the periods 1973–1982 and 1989–2012. Follow-up took place until the development of ESRD, death, emigration, or 30 November 2015. We estimated the cumulative incidence of ESRD by linking to the Norwegian Renal Registry. RESULTS Among the 7,871 patients, representing 147,714 person-years of follow-up, ESRD developed in 103 individuals (1.3%). The mean time from the diagnosis of diabetes to the development of ESRD was 25.9 years (range 12.7–39.1). The cumulative incidence of ESRD was 0.7% (95% CI 0.4–1.0) at 20 years’ diabetes duration, 2.9% (2.3–3.7) at 30 years’ duration, and 5.3% (4.3–6.5) at 40 years’ duration. The risk of the development of ESRD was lower in women than in men (hazard ratio [HR] 0.61; 95% CI 0.41–0.91) and higher in individuals in whom diabetes had been diagnosed at 10–14 years of age compared with those in whom it was diagnosed before 10 years of age (HR 1.29; 1.06–1.56). We did not identify any significant difference in the risk of the development of ESRD between those in whom diabetes was diagnosed in 1973–1982 and in 1989–2012 (HR 0.80; 0.45–1.45). CONCLUSIONS We report a very low incidence of ESRD among patients with childhood-onset diabetes in Norway. The risk was lower in women compared with men and in individuals in whom diabetes was diagnosed at a younger age.
Cumulative Kidney Complication Risk by 50 Years of Type 1 Diabetes: The Effects of Sex, Age, and Calendar Year at Onset Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Tina Costacou; Trevor J. Orchard
OBJECTIVE A common belief is that only a minority of patients with type 1 diabetes (T1D) develop advanced kidney disease and that incidence is higher among men and lower in those diagnosed at a younger age. However, because few patients with T1D survived to older ages until recently, long-term risks have been unclear. RESEARCH DESIGN AND METHODS We examined the 50-year cumulative kidney complication risk in a childhood-onset T1D cohort diagnosed during 1950–80 (n = 932; mean baseline age 29 years, duration 19 years). Participants comprised 144 who died prior to baseline, 130 followed with periodic surveys, and 658 followed with biennial surveys and a maximum of nine examinations for 25 years. Micro- and macroalbuminuria were defined as an albumin excretion rate of 20–199 and ≥200 μg/min, respectively, and end-stage renal disease (ESRD) was defined as dialysis or kidney transplantation. Cumulative incidence was estimated at 10-year intervals between 20 and 50 years, duration and compared by calendar year of diabetes onset. RESULTS By 50 years, T1D duration, ESRD affected 60% of the cohort; macroalbuminuria, 72%; and microalbuminuria, 88%. Little evidence existed for declines in cumulative incidence in recent cohorts, except for ESRD (microalbuminuria 3% increase, macroalbuminuria no change; ESRD 45% decrease by 40 years of T1D duration). Onset before age 6 years was associated with the lowest risk; incidence generally did not differ by sex. CONCLUSIONS Some degree of kidney disease in T1D is virtually universal at long durations and not declining, which has major implications for formulating health care and research strategies. ESRD has declined, but continues to affect >25% of the population by 40 years, duration.
Incidence of End-Stage Renal Disease in Patients With Type 1 Diabetes Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Jaakko Helve; Reijo Sund; Martti Arffman; Valma Harjutsalo; Per-Henrik Groop; Carola Grönhagen-Riska; Patrik Finne
OBJECTIVE To investigate how risk of end-stage renal disease (ESRD) among patients with type 1 diabetes has changed over time and further how the risk is affected by age, sex, and time period of diagnosis of diabetes. RESEARCH DESIGN AND METHODS A cohort including all patients <30 years old diagnosed with type 1 diabetes in Finland in 1965–2011 was followed until start of renal replacement therapy, death, or end of follow-up at the end of 2013. Altogether, 29,906 patients were included. The main outcome was cumulative risk of ESRD, accounting for death as a competing risk. RESULTS The patients were followed up for a median of 20 years. During 616,403 patient-years, 1,543 ESRD cases and 4,185 deaths were recorded. The cumulative risk of ESRD was 2.2% after 20 years and 7.0% after 30 years from the diabetes diagnosis. The relative risk of ESRD was 0.13 (95% CI 0.08–0.22) among patients diagnosed in 1995–2011 compared with those diagnosed in 1965–1979. Patients <5 years old at the time of diagnosis had the lowest risk of ESRD after diagnosis. With the cumulative risk of ESRD estimated from time of birth, the patients aged 5–9 years at diabetes diagnosis were at highest risk. CONCLUSIONS The cumulative risk of ESRD has decreased markedly during the past five decades. This highlights the importance of modern treatment of diabetes and diabetic nephropathy.
Plasma Alkylresorcinol Metabolite, a Biomarker of Whole-Grain Wheat and Rye Intake, and Risk of Type 2 Diabetes and Impaired Glucose Regulation in a Chinese Population Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Taoping Sun; Ying Rong; Xiaoli Hu; Yalun Zhu; Hao Huang; Liangkai Chen; Peiyun Li; Shuzhen Li; Wei Yang; Jinquan Cheng; Xuefeng Yang; Ping Yao; Frank B. Hu; Liegang Liu
OBJECTIVE To examine the association of plasma alkylresorcinol metabolite 3-(3,5-dihydroxyphenyl)-1-propanoic acid (DHPPA), a biomarker of whole-grain wheat and rye intake, with type 2 diabetes (T2D) and impaired glucose regulation (IGR) in a Chinese population. RESEARCH DESIGN AND METHODS A total of 1,060 newly diagnosed T2D patients, 736 newly diagnosed IGR patients, and 1,443 control subjects with normal glucose tolerance were recruited in the case-control study. Plasma DHPPA concentrations were determined by high-performance liquid chromatography–tandem mass spectroscopy. Multivariate logistic regression analysis was used to evaluate the independent association of plasma DHPPA concentrations with the likelihood of T2D and IGR. RESULTS After adjustment for age, sex, BMI, and family history of diabetes, the odds ratios (95% CI) of T2D and IGR were 0.57 (0.45, 0.73) and 0.66 (0.50, 0.85), respectively, comparing the lowest with the highest quartile of plasma DHPPA concentrations. Further adjustment for current smoking status, current alcohol consumption, physical activity, history of hypertension, and educational level did not change the observed association materially. Similar results were also obtained in T2D and IGR groups combined. The inverse association of plasma DHPPA with T2D persisted in stratified analyses according to age, sex, BMI, current smoking status, current alcohol consumption, physical activity, family history of diabetes, and history of hypertension. CONCLUSIONS These findings suggested that higher plasma DHPPA concentrations were associated with lower odds of T2D and IGR. Further studies are warranted to confirm these findings in prospective cohorts.
The Bidirectional Association Between Depression and Severe Hypoglycemic and Hyperglycemic Events in Type 1 Diabetes Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Paola Gilsanz; Andrew J. Karter; Michal Schnaider Beeri; Charles P. Quesenberry; Rachel A. Whitmer
OBJECTIVE Severe hyperglycemia and hypoglycemia (“severe dysglycemia”) are serious complications of type 1 diabetes (T1D). Depression has been associated with severe dysglycemia in type 2 diabetes but has not been thoroughly examined specifically in T1D. We evaluated bidirectional associations between depression and severe dysglycemia among older people with T1D. RESEARCH DESIGN AND METHODS We abstracted depression and severe dysglycemia requiring emergency room visit or hospitalization from medical health records in 3,742 patients with T1D during the study period (1996–2015). Cox proportional hazards models estimated the associations between depression and severe dysglycemia in both directions, adjusting for demographics, micro- and macrovascular complications, and HbA1c. RESULTS During the study period, 41% had depression and 376 (11%) and 641 (20%) had hyperglycemia and hypoglycemia, respectively. Depression was strongly associated with a 2.5-fold increased risk of severe hyperglycemic events (hazard ratio [HR] 2.47 [95% CI 2.00, 3.05]) and 89% increased risk of severe hypoglycemic events (HR 1.89 [95% CI 1.61, 2.22]). The association was strongest within the first 6 months (HRhyperglycemia 7.14 [95% CI 5.29, 9.63]; HRhypoglycemia 5.58 [95% CI 4.46, 6.99]) to 1 year (HRhyperglycemia 5.16 [95% CI 3.88, 6.88]; HRhypoglycemia 4.05 [95% CI 3.26, 5.04]) after depression diagnosis. In models specifying severe dysglycemia as the exposure, hyperglycemic and hypoglycemic events were associated with 143% (HR 2.43 [95% CI 2.03, 2.91]) and 74% (HR 1.75 [95% CI 1.49, 2.05]) increased risk of depression, respectively. CONCLUSIONS Depression and severe dysglycemia are associated bidirectionally among patients with T1D. Depression greatly increases the risk of severe hypoglycemic and hyperglycemic events, particularly in the first 6 months to 1 year after diagnosis, and depression risk increases after severe dysglycemia episodes.
Effect of Changing Work Stressors and Coping Resources on the Risk of Type 2 Diabetes: The OHSPIW Cohort Study Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Yulong Lian; Qing Sun; Suzhen Guan; Hua Ge; Ning Tao; Yu Jiang; YanXia Zhang; Li Ning; Jing Xiao; Jiwen Liu
OBJECTIVE Little is known about the relationship between changing psychosocial work conditions and type 2 diabetes. We determined whether changing work stressors and coping resources affect the risk of type 2 diabetes. RESEARCH DESIGN AND METHODS In this prospective cohort (2003–2014) of 3,740 workers without diabetes (OHSPIW [Occupational Health Study of Petroleum Industry Workers]), participants completed an evaluation of work-related stress and coping resources and type 2 diabetes diagnosis at baseline and 12 years follow-up (two waves). The changes in work stressors and coping resources were measured with the Occupation Stress Inventory–Revised and the Instrument for Stress-Related Job Analysis (Version 6.0). Type 2 diabetes was diagnosed on the basis of an oral glucose tolerance test supplemented by physician report. RESULTS Increased task stressors (relative risk [RR] 1.57 [95% CI 1.03–2.63]) and decreased coping resources (RR 1.68 [95% CI 1.02–2.83]) were associated with risk of type 2 diabetes. The main risk factors were increased role overload, increased role insufficiency, increased physical environment stressors, decreased self-care, and decreased rational coping. Increased coping resources also had a buffering effect on increased task stressors and type 2 diabetes. CONCLUSIONS Changes in work stressors and coping resources have an influence on the risk for type 2 diabetes, highlighting the importance of preventive measures against adverse psychosocial work conditions and reduced coping resources for diabetes prevention in the workplace.
Associations of Four Community Factors With Longitudinal Change in Hemoglobin A1c Levels in Patients With Type 2 Diabetes Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Annemarie G. Hirsch; T. Elizabeth Durden; Cara Nordberg; Andrea Berger; Brian S. Schwartz
OBJECTIVE To evaluate associations of community factors with glycated hemoglobin (HbA1c). RESEARCH DESIGN AND METHODS We identified patients with type 2 diabetes who had an HbA1c ≥7.5% (58 mmol/mol) and subsequent HbA1c testing within 90–270 days. We used mixed-effect models to assess whether treatment intensification (TI) and community domains (community socioeconomic deprivation [CSD], food availability, fitness assets, and utilitarian physical activity favorability [quartiled]) were associated with HbA1c change over 6 and 24 months, controlling for demographics, HbA1c, BMI, and time with evidence of type 2 diabetes. We evaluated whether community domains modified associations of TI with HbA1c change using cross product terms. RESULTS There were 15,308 patients with 69,818 elevated HbA1c measures. The average reduction in HbA1c over 6 months was 0.07% less in townships with a high level of CSD (third quartile versus the first). Reductions were 0.10% greater for HbA1c in townships with the best food availability (versus worst). HbA1c reductions were 0.17–0.19% greater in census tracts in the second and third quartiles of utilitarian physical activity favorability versus the first. The association of TI with 6-month HbA1c change was weaker in townships and boroughs with the worst CSD (versus best) and in boroughs with the best fitness assets (versus worst). The association of TI with 24-month HbA1c change was weaker in census tracts with the worst CSD (versus third quartile) and strongest in census tracts most favorable for utilitarian physical activity (versus worst). CONCLUSIONS Community domains were associated with HbA1c change and blunted TI effectiveness.
Diabetes Is Associated With Reduced Stress Hyperlactatemia in Cardiac Surgery Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Giampaolo Greco; Katherine A. Kirkwood; Annetine C. Gelijns; Alan J. Moskowitz; David W. Lam
OBJECTIVE Hyperglycemia and hyperlactatemia are associated with increased morbidity and mortality in critical illness. We evaluated the relationship among hyperlactatemia, glycemic control, and diabetes mellitus (DM) after cardiac surgery. RESEARCH DESIGN AND METHODS This was a retrospective cohort study of 4,098 cardiac surgery patients treated between 2011 and 2015. Patients were stratified by DM and glucose-lowering medication history. Hyperglycemia (glucose >180 mg/dL), hypoglycemia (<70 mg/dL), and the hyperglycemic index were assessed postoperatively (48 h). The relationship between lactate and glucose levels was modeled using generalized linear regression. Mortality was analyzed using an extended Cox regression model. RESULTS Hyperglycemia occurred in 26.0% of patients without DM (NODM), 46.5% with DM without prior drug treatment (DMNT), 62.8% on oral medication (DMOM), and 73.8% on insulin therapy (DMIT) (P < 0.0001). Hypoglycemia occurred in 6.3%, 9.1%, 8.8%, and 10.8% of NODM, DMNT, DMOM, and DMIT, respectively (P = 0.0012). The lactate levels of all patients were temporarily increased with surgery. This increase was greater in patients who also had hyperglycemia or hypoglycemia and was markedly attenuated in patients with DM. Peak lactate was 5.8 mmol/L (95% CI 5.6, 6.0) in NODM with hyperglycemia vs. 3.3 (95% CI 3.2, 3.4) without hyperglycemia; in DMNT: 4.8 (95% CI 4.4, 5.2) vs. 3.4 (95% CI 3.1, 3.6); in DMOM: 3.8 (95% CI 3.5, 4.1) vs. 2.9 (95% CI 2.7, 3.1); and in DMIT: 3.3 (95% CI 3.0, 3.5) vs. 2.7 (95% CI 2.3, 3.0). Increasing lactate levels were associated with increasing mortality; increasing glucose reduced this effect in DM but not in NODM (P = 0.0069 for three-way interaction). CONCLUSIONS Stress hyperlactatemia is markedly attenuated in patients with DM. There is a three-way interaction among DM, stress hyperlactatemia, and stress hyperglycemia associated with mortality after cardiac surgery.
Markedly Decreasing Incidence of Blindness in People With and Without Diabetes in Southern Germany Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Heiner Claessen; Tatjana Kvitkina; Maria Narres; Christoph Trautner; Iris Zöllner; Bernd Bertram; Andrea Icks
OBJECTIVE Studies comparing the incidence of blindness in persons with and without diabetes are scarce worldwide. In Germany, a decline in the incidence of blindness was found during the 1990s. The aim of this study was to analyze the recent time trend. RESEARCH DESIGN AND METHODS Data were based on administrative files in southern Germany to assess recipients of blindness allowance newly registered between 1 January 2008 and 31 December 2012. We estimated age- and sex-standardized incidence of blindness in people with and people without diabetes and the corresponding relative risk. Poisson regression was used to examine age- and sex-adjusted time trends. RESULTS We identified 1,897 new cases of blindness (23.7% of which were associated with diabetes). We observed a strong decrease in incidence in both the population with diabetes (2008, 17.3 per 100,000 person-years [95% CI 13.6–21.1], and 2012, 8.9 per 100,000 person-years [6.3–11.6]: 16% decrease [10–22] per year) and that without diabetes (2008, 9.3 per 100,000 person-years [8.3–10.3], and 2012, 6.6 [5.8–7.4]: 9% decrease [5–13] per year). The relative risk comparing those incidences was 1.70 (95% CI 1.32–2.16) and remained constant in the observation period. Regarding time trend, we found similar results for both sexes. CONCLUSIONS We found a significant reduction in incidence of blindness in the populations with and without diabetes, which was more prominent among individuals with diabetes compared with the 1990s. Our findings may be explained by effective secondary prevention therapies and improved ophthalmologic care beyond diabetic retinopathy, particularly regarding macular degeneration, which means earlier detection and earlier and better treatment.
BMI and Mortality in Patients With New-Onset Type 2 Diabetes: A Comparison With Age- and Sex-Matched Control Subjects From the General Population Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Jon Edqvist; Araz Rawshani; Martin Adiels; Lena Björck; Marcus Lind; Ann-Marie Svensson; Sofia Gudbjörnsdottir; Naveed Sattar; Annika Rosengren
OBJECTIVE Type 2 diabetes is strongly associated with obesity, but the mortality risk related to elevated body weight in people with type 2 diabetes compared with people without diabetes has not been established. RESEARCH DESIGN AND METHODS We prospectively assessed short- and long-term mortality in people with type 2 diabetes with a recorded diabetes duration ≤5 years identified from the Swedish National Diabetes Register (NDR) between 1998 and 2012 and five age- and sex-matched control subjects per study participant from the general population. RESULTS Over a median follow-up of 5.5 years, there were 17,546 deaths among 149,345 patients with type 2 diabetes (mean age 59.6 years [40% women]) and 68,429 deaths among 743,907 matched control subjects. Short-term all-cause mortality risk (≤5 years) displayed a U-shaped relationship with BMI, with hazard ratios (HRs) ranging from 0.81 (95% CI 0.75–0.88) among patients with diabetes and BMI 30 to <35 kg/m2 to 1.37 (95% CI 1.11–1.71) with BMI ≥40 kg/m2 compared with control subjects after multiple adjustments. Long-term, all weight categories showed increased mortality, with a nadir at BMI 25 to <30 kg/m2 and a stepwise increase up to HR 2.00 (95% CI 1.58–2.54) among patients with BMI ≥40 kg/m2, that was more pronounced in patients <65 years old. CONCLUSIONS Our findings suggest that the apparent paradoxical findings in other studies in this area may have been affected by reverse causality. Long-term, overweight (BMI 25 to <30 kg/m2) patients with type 2 diabetes had low excess mortality risk compared with control subjects, whereas risk in those with BMI ≥40 kg/m2 was substantially increased.
Associations of General and Central Adiposity With Incident Diabetes in Chinese Men and Women Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Fiona Bragg; Kun Tang; Yu Guo; Andri Iona; Huaidong Du; Michael V. Holmes; Zheng Bian; Christiana Kartsonaki; Yiping Chen; Ling Yang; Qiang Sun; Caixia Dong; Junshi Chen; Rory Collins; Richard Peto; Liming Li; Zhengming Chen
OBJECTIVE We assess associations of general and central adiposity in middle age and of young adulthood adiposity with incident diabetes in adult Chinese and estimate the associated population burden of diabetes. RESEARCH DESIGN AND METHODS The prospective China Kadoorie Biobank enrolled 512,891 adults 30–79 years of age from 10 localities across China during 2004–2008. During 9.2 years of follow-up, 13,416 cases of diabetes were recorded among 482,589 participants without diabetes at baseline. Cox regression yielded adjusted hazard ratios (HRs) for incident diabetes associated with measures of general (e.g., BMI and BMI at 25 years) and central (e.g., waist circumference [WC]) adiposity. RESULTS The mean (SD) BMI was 23.6 kg/m2 (3.4 kg/m2), and 3.8% had a BMI ≥30 kg/m2. Throughout the range examined (19–32 kg/m2), BMI showed a positive log-linear relationship with diabetes, with adjusted HRs per SD higher usual BMI greater in men (1.98; 95% CI 1.93–2.04) than in women (1.77; 1.73–1.81) (P for heterogeneity <0.001). For WC, HRs per SD were 2.13 (95% CI 2.07–2.19) in men and 1.91 (1.87–1.95) in women (P for heterogeneity <0.001). Mutual adjustment attenuated these associations, especially those of BMI. BMI at age 25 years was weakly positively associated with diabetes (men HR 1.09 [95% CI 1.05–1.12]; women 1.04 [1.02–1.07] per SD), which was reversed after adjustment for baseline BMI. In China, the increase in adiposity accounted for ∼50% of the increase in diabetes burden since 1980. CONCLUSIONS Among relatively lean Chinese adults, higher adiposity—general and central—was strongly positively associated with the risk of incident diabetes. The predicted continuing increase in adiposity in China foreshadows escalating rates of diabetes.
Risk of Hypoglycemia Following Hospital Discharge in Patients With Diabetes and Acute Kidney Injury Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Adriana M. Hung; Edward D. Siew; Otis D. Wilson; Amy M. Perkins; Robert A. Greevy; Jeffrey Horner; Khaled Abdel-Kader; Sharidan K. Parr; Christianne L. Roumie; Marie R. Griffin; T. Alp Ikizler; Theodore Speroff; Michael E. Matheny
OBJECTIVE Hypoglycemia is common in patients with diabetes. The risk of hypoglycemia after acute kidney injury (AKI) is not well defined. The purpose of this study was to compare the risk for postdischarge hypoglycemia among hospitalized patients with diabetes who do and do not experience AKI. RESEARCH DESIGN AND METHODS We performed a propensity-matched analysis of patients with diabetes, with and without AKI, using a retrospective national cohort of veterans hospitalized between 2004 and 2012. AKI was defined as a 0.3 mg/dL or 50% increase in serum creatinine from baseline to peak serum creatinine during hospitalization. Hypoglycemia was defined as hospital admission or an emergency department visit for hypoglycemia or as an outpatient blood glucose <60 mg/dL. Time to incident hypoglycemia within 90 days postdischarge was examined using Cox proportional hazards models. Prespecified subgroup analyses by renal recovery, baseline chronic kidney disease, preadmission drug regimen, and HbA1c were performed. RESULTS We identified 65,151 propensity score–matched pairs with and without AKI. The incidence of hypoglycemia was 29.6 (95% CI 28.9–30.4) and 23.5 (95% CI 22.9–24.2) per 100 person-years for patients with and without AKI, respectively. After adjustment, AKI was associated with a 27% increased risk of hypoglycemia (hazard ratio [HR] 1.27 [95% CI 1.22–1.33]). For patients with full recovery, the HR was 1.18 (95% CI 1.12–1.25); for partial recovery, the HR was 1.30 (95% CI 1.23–1.37); and for no recovery, the HR was 1.48 (95% CI 1.36–1.60) compared with patients without AKI. Across all antidiabetes drug regimens, patients with AKI experienced hypoglycemia more frequently than patients without AKI, though the incidence of hypoglycemia was highest among insulin users, followed by glyburide and glipizide users, respectively. CONCLUSIONS AKI is a risk factor for hypoglycemia in the postdischarge period. Studies to identify risk-reduction strategies in this population are warranted.
Risk of Infection in Type 1 and Type 2 Diabetes Compared With the General Population: A Matched Cohort Study Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Iain M. Carey; Julia A. Critchley; Stephen DeWilde; Tess Harris; Fay J. Hosking; Derek G. Cook
OBJECTIVE We describe in detail the burden of infections in adults with diabetes within a large national population cohort. We also compare infection rates between patients with type 1 and type 2 diabetes mellitus (T1DM and T2DM). RESEARCH DESIGN AND METHODS A retrospective cohort study compared 102,493 English primary care patients aged 40–89 years with a diabetes diagnosis by 2008 (n = 5,863 T1DM and n = 96,630 T2DM) with 203,518 age-sex-practice–matched control subjects without diabetes. Infection rates during 2008–2015, compiled from primary care and linked hospital and mortality records, were compared across 19 individual infection categories. These were further summarized as any requiring a prescription or hospitalization or as cause of death. Poisson regression was used to estimate incidence rate ratios (IRRs) between 1) people with diabetes and control subjects and 2) T1DM and T2DM adjusted for age, sex, smoking, BMI, and deprivation. RESULTS Compared with control subjects without diabetes, patients with diabetes had higher rates for all infections, with the highest IRRs seen for bone and joint infections, sepsis, and cellulitis. IRRs for infection-related hospitalizations were 3.71 (95% CI 3.27–4.21) for T1DM and 1.88 (95% CI 1.83–1.92) for T2DM. A direct comparison of types confirmed higher adjusted risks for T1DM versus T2DM (death from infection IRR 2.19 [95% CI 1.75–2.74]). We estimate that 6% of infection-related hospitalizations and 12% of infection-related deaths were attributable to diabetes. CONCLUSIONS People with diabetes, particularly T1DM, are at increased risk of serious infection, representing an important population burden. Strategies that reduce the risk of developing severe infections and poor treatment outcomes are under-researched and should be explored.
Early Infant Diet and Islet Autoimmunity in the TEDDY Study Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Ulla Uusitalo; Hye-Seung Lee; Carin Andrén Aronsson; Kendra Vehik; Jimin Yang; Sandra Hummel; Katherine Silvis; Åke Lernmark; Marian Rewers; William Hagopian; Jin-Xiong She; Olli Simell; Jorma Toppari; Anette-G. Ziegler; Beena Akolkar; Jeffrey Krischer; Suvi M. Virtanen; Jill M. Norris; the TEDDY Study Group
OBJECTIVE To examine duration of breastfeeding and timing of complementary foods and risk of islet autoimmunity (IA). RESEARCH DESIGN AND METHODS The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively follows 8,676 children with increased genetic risk of type 1 diabetes (T1D) in the U.S., Finland, Germany, and Sweden. This study included 7,563 children with at least 9 months of follow-up. Blood samples were collected every 3 months from birth to evaluate IA, defined as persistent, confirmed positive antibodies to insulin (IAAs), GAD, or insulinoma antigen-2. We examined the associations between diet and the risk of IA using Cox regression models adjusted for country, T1D family history, HLA genotype, sex, and early probiotic exposure. Additionally, we investigated martingale residuals and log-rank statistics to determine cut points for ages of dietary exposures. RESULTS Later introduction of gluten was associated with increased risk of any IA and IAA. The hazard ratios (HRs) for every 1-month delay in gluten introduction were 1.05 (95% CI 1.01, 1.10; P = 0.02) and 1.08 (95% CI 1.00, 1.16; P = 0.04), respectively. Martingale residual analysis suggested that the age at gluten introduction could be grouped as <4, 4–9, and >9 months. The risk of IA associated with introducing gluten before 4 months of age was lower (HR 0.68; 95% CI 0.47, 0.99), and the risk of IA associated with introducing it later than the age of 9 months was higher (HR 1.57; 95% CI 1.07, 2.31) than introduction between 4 and 9 months of age. CONCLUSIONS The timing of gluten-containing cereals and IA should be studied further.
Pharmacokinetic and Pharmacodynamic Characteristics of Dasiglucagon, a Novel Soluble and Stable Glucagon Analog Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Ulrike Hövelmann; Britta Væver Bysted; Ulrik Mouritzen; Francesca Macchi; Daniela Lamers; Birgit Kronshage; Daniél Vega Møller; Tim Heise
OBJECTIVE Treatment of severe hypoglycemia outside of the hospital setting is limited to glucagon formulations requiring reconstitution before use, which may lead to erroneous or delayed glucagon administration. We compared the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics and safety and tolerability of different doses of dasiglucagon, a novel soluble glucagon analog, with approved pediatric and full doses of GlucaGen in insulin-induced hypoglycemia in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS In this single-center, randomized, double-blind trial, 58 patients with type 1 diabetes received single subcutaneous injections of 0.1, 0.3, 0.6, or 1.0 mg dasiglucagon or 0.5 or 1.0 mg GlucaGen in a state of hypoglycemia (blood glucose target 55 mg/dL) induced by an intravenous insulin infusion. RESULTS Dasiglucagon demonstrated a dose-dependent and rapid increase in plasma concentrations, reaching a maximum at ∼35 min with a half-life of ∼0.5 h. Dasiglucagon rapidly increased plasma glucose (PG) by ≥20 mg/dL (9–14 min) to PG ≥70 mg/dL (within 6–10 min), similar to GlucaGen, but with a longer-lasting and greater effect on PG. All patients on both treatments reached these end points within 30 min (predefined success criteria). Both treatments were well tolerated. Nausea was the most frequent adverse event, occurring at a similar rate (44–56%). CONCLUSIONS Dasiglucagon was well tolerated and showed an early PD response similar to that of GlucaGen at corresponding doses, suggesting comparable clinical effects of the two glucagon formulations. Dasiglucagon has the potential to become an effective and reliable rescue treatment for severe hypoglycemia in a ready-to-use pen.
Effects of Pemafibrate, a Novel Selective PPARα Modulator, on Lipid and Glucose Metabolism in Patients With Type 2 Diabetes and Hypertriglyceridemia: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Eiichi Araki; Shizuya Yamashita; Hidenori Arai; Koutaro Yokote; Jo Satoh; Toyoshi Inoguchi; Jiro Nakamura; Hiroshi Maegawa; Narihito Yoshioka; Yukio Tanizawa; Hirotaka Watada; Hideki Suganami; Shun Ishibashi
OBJECTIVE Type 2 diabetes is frequently complicated with atherogenic dyslipidemia. This study aimed to evaluate the efficacy and safety of pemafibrate (K-877) in patients with type 2 diabetes comorbid with hypertriglyceridemia. RESEARCH DESIGN AND METHODS Patients were randomly assigned to three groups and received placebo (n = 57), 0.2 mg/day pemafibrate (n = 54), or 0.4 mg/day pemafibrate (n = 55) for 24 weeks (treatment period 1). Subsequently, the patients received follow-up treatment for another 28 weeks (treatment period 2), in which the placebo was switched to 0.2 mg/day pemafibrate. This article presents the results of treatment period 1, which were the primary objectives. RESULTS The pemafibrate groups showed significantly reduced fasting serum triglyceride levels by ∼45% compared with the placebo group (P < 0.001). Additionally, the pemafibrate groups displayed significant decreases in non-HDL and remnant lipoprotein cholesterol, apolipoprotein (Apo) B100, ApoB48, and ApoCIII levels and significant increases in HDL cholesterol and ApoA-I levels. LDL cholesterol levels were not considerably altered in the pemafibrate groups. Furthermore, the 0.2 mg/day pemafibrate group showed a significantly reduced HOMA–insulin resistance score compared with the placebo group; however, no significant changes compared with placebo were found in fasting plasma glucose, fasting insulin, glycoalbumin, or HbA1c levels. The pemafibrate groups also showed significantly increased fibroblast growth factor 21 levels compared with the placebo group. All groups displayed comparable rates of adverse events and drug reactions. CONCLUSIONS Pemafibrate significantly ameliorated lipid abnormalities and was well tolerated in patients with type 2 diabetes comorbid with hypertriglyceridemia.
Metformin Treatment in Patients With Type 2 Diabetes and Chronic Kidney Disease Stages 3A, 3B, or 4 Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Jean-Daniel Lalau; Farshad Kajbaf; Youssef Bennis; Anne-Sophie Hurtel-Lemaire; Frans Belpaire; Marc E. De Broe
OBJECTIVE This study was conducted to define a safe, effective dose regimen for metformin in moderate and severe chronic kidney disease (CKD; stages 3A/3B and 4, respectively), after the lifting of restrictions on metformin use in patients with diabetes with moderate-to-severe CKD in the absence of prospective safety and efficacy studies. RESEARCH DESIGN AND METHODS Three complementary studies were performed: 1) a dose-finding study in CKD stages 1–5, in which blood metformin concentrations were evaluated during a 1-week period after each dose increase; 2) a 4-month metformin treatment study for validating the optimal metformin dose as a function of the CKD stage (3A, 3B, and 4), with blood metformin, lactate, and HbA1c concentrations monitored monthly; and 3) an assessment of pharmacokinetic parameters after the administration of a single dose of metformin in steady-state CKD stages 3A, 3B, and 4. RESULTS First, in the dose-finding study, the appropriate daily dosing schedules were 1,500 mg (0.5 g in the morning [qam] +1 g in the evening [qpm]) in CKD stage 3A, 1,000 mg (0.5 g qam + 0.5 g qpm) in CKD stage 3B, and 500 mg (qam) in CKD stage 4. Second, after 4 months on these regimens, patients displayed stable metformin concentrations that never exceeded the generally accepted safe upper limit of 5.0 mg/L. Hyperlactatemia (>5 mmol/L) was absent (except in a patient with myocardial infarction), and HbA1c levels did not change. Third, there were no significant differences in pharmacokinetic parameters among the CKD stage groups. CONCLUSIONS Provided that the dose is adjusted for renal function, metformin treatment appears to be safe and still pharmacologically efficacious in moderate-to-severe CKD.
TCF7L2 Genetic Variation Augments Incretin Resistance and Influences Response to a Sulfonylurea and Metformin: The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH) Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Shylaja Srinivasan; Varinderpal Kaur; Bindu Chamarthi; Katherine R. Littleton; Ling Chen; Alisa K. Manning; Jordi Merino; Melissa K. Thomas; Margo Hudson; Allison Goldfine; Jose C. Florez
OBJECTIVE The rs7903146 T allele in transcription factor 7 like 2 (TCF7L2) is strongly associated with type 2 diabetes (T2D), but the mechanisms for increased risk remain unclear. We evaluated the physiologic and hormonal effects of TCF7L2 genotype before and after interventions that influence glucose physiology. RESEARCH DESIGN AND METHODS We genotyped rs7903146 in 608 individuals without diabetes and recorded biochemical data before and after 1) one dose of glipizide (5 mg) on visit 1 and 2) a 75-g oral glucose tolerance test (OGTT) performed after administration of metformin 500 mg twice daily over 2 days. Incretin levels were measured in 150 of the 608 participants. RESULTS TT risk-allele homozygotes had 1.6 mg/dL higher baseline fasting glucose levels and 2.5 pg/mL lower glucagon levels per T allele than carriers of other genotypes at baseline. In a subset of participants, the T allele was associated with higher basal glucagon-like peptide 1 (GLP-1) levels at visit 1 (β = 1.52, P = 0.02 and β = 0.96, P = 0.002 for total and active GLP-1, respectively), and across all points of the OGTT after metformin administration. Regarding drug response, the T allele was associated with a shorter time (β = −7.00, P = 0.03) and a steeper slope (β = 0.23, P = 0.04) to trough glucose levels after glipizide administration, and lower visit 2 fasting glucose level adjusted for visit 1 fasting glucose level (β = −1.02, P = 0.04) and a greater decline in glucose level between visits (β = −1.61, P = 0.047) after metformin administration. CONCLUSIONS Our findings demonstrate that common variation at TCF7L2 influences acute responses to both glipizide and metformin in people without diabetes and highlight altered incretin signaling as a potential mechanism by which TCF7L2 variation increases T2D risk.
Objectively Measured Physical Activity and Sedentary Time Are Associated With Cardiometabolic Risk Factors in Adults With Prediabetes: The PREVIEW Study Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Nils Swindell; Kelly Mackintosh; Melitta McNarry; Jeffrey W. Stephens; Diewertje Sluik; Mikael Fogelholm; Mathijs Drummen; Ian MacDonald; J. Alfredo Martinez; Teodora Handjieva-Darlenska; Sally D. Poppitt; Jennie Brand-Miller; Thomas M. Larsen; Anne Raben; Gareth Stratton
OBJECTIVE The aim of the present cross-sectional study was to examine the association among physical activity (PA), sedentary time (ST), and cardiometabolic risk in adults with prediabetes. RESEARCH DESIGN AND METHODS Participants ( n = 2,326; 25–70 years old, 67% female) from eight countries, with a BMI >25 kg ⋅ m−2 and impaired fasting glucose (5.6–6.9 mmol ⋅ L−1) or impaired glucose tolerance (7.8–11.0 mmol ⋅ L−1 at 2 h), participated. Seven-day accelerometry objectively assessed PA levels and ST. RESULTS Multiple linear regression revealed that moderate-to-vigorous PA (MVPA) was negatively associated with HOMA of insulin resistance (HOMA-IR) (standardized β = −0.078 [95% CI −0.128, −0.027]), waist circumference (WC) (β = −0.177 [−0.122, −0.134]), fasting insulin (β = −0.115 [−0.158, −0.072]), 2-h glucose (β = −0.069 [−0.112, −0.025]), triglycerides (β = −0.091 [−0.138, −0.044]), and CRP (β = −0.086 [−0.127, −0.045]). ST was positively associated with HOMA-IR (β = 0.175 [0.114, 0.236]), WC (β = 0.215 [0.026, 0.131]), fasting insulin (β = 0.155 [0.092, 0.219]), triglycerides (β = 0.106 [0.052, 0.16]), CRP (β = 0.106 [0.39, 0.172]), systolic blood pressure (BP) (β = 0.078 [0.026, 0.131]), and diastolic BP (β = 0.106 [0.39, −0.172]). Associations reported between total PA (counts ⋅ min−1), and all risk factors were comparable or stronger than for MVPA: HOMA-IR (β = −0.151 [−0.194, −0.107]), WC (β = −0.179 [−0.224, −0.134]), fasting insulin (β = −0.139 [−0.183, −0.096]), 2-h glucose (β = −0.088 [−0.131, −0.045]), triglycerides (β = −0.117 [−0.162, −0.071]), and CRP (β = −0.104 [−0.146, −0.062]). CONCLUSIONS In adults with prediabetes, objectively measured PA and ST were associated with cardiometabolic risk markers. Total PA was at least as strongly associated with cardiometabolic risk markers as MVPA, which may imply that the accumulation of total PA over the day is as important as achieving the intensity of MVPA.
Advanced Glycation End Products, Oxidation Products, and Incident Cardiovascular Events in Patients With Type 2 Diabetes Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Juraj Koska; Aramesh Saremi; Scott Howell; Gideon Bahn; Barbora De Courten; Henry Ginsberg; Paul J. Beisswenger; Peter D. Reaven
OBJECTIVE The goal of this study was to determine whether plasma levels of advanced glycation end products (AGE) and oxidation products (OP) predict the incidence of cardiovascular disease (CVD) in type 2 diabetes. RESEARCH DESIGN AND METHODS Five specific AGE (methylglyoxal hydroimidazolone, carboxymethyl lysine, carboxyethyl lysine, 3-deoxyglucosone hydroimidazolone, and glyoxal hydroimidazolone) and two OP (2-aminoadipic acid and methionine sulfoxide [MetSO]) were measured at baseline in two intensive glucose-lowering studies: 1) a subcohort of the Veterans Affairs Diabetes Trial (VADT) (n = 445) and 2) a nested case-control subgroup from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study (n = 271). RESULTS Increased levels of several AGE and OP were associated with older age, decreased kidney function, previous CVD, and longer diabetes duration, but not with hemoglobin A1c. In the VADT, increased risk of incident CVD events (n = 107) was associated with lower MetSO after adjusting for age, race/ethnicity, sex, prior CVD event, kidney function, treatment assignment, and diabetes duration (hazard ratio [HR] 0.53; 95% CI 0.28–0.99; P = 0.047). Individuals with both low MetSO and high 3-deoxyglucosone hydroimidazolone concentrations were at highest risk for CVD (HR 1.70; P = 0.01). In the ACCORD study, those with incident CVD events (n = 136) had lower MetSO (by 14%; P = 0.007) and higher glyoxal hydroimidazolone and carboxymethyl lysine (by 18% and 15%, respectively; P = 0.04 for both); however, only the difference in MetSO remained significant after adjustment for prior CVD event (P = 0.002). CONCLUSIONS Lower levels of MetSO and higher levels of select AGE are associated with increased incident CVD and may help account for the limited benefit of intensive glucose lowering in type 2 diabetes.
Risk Assessment in Patients With Diabetes With the TIMI Risk Score for Atherothrombotic Disease Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Brian A. Bergmark; Deepak L. Bhatt; Eugene Braunwald; David A. Morrow; Ph. Gabriel Steg; Yared Gurmu; Avivit Cahn; Ofri Mosenzon; Itamar Raz; Erin Bohula; Benjamin M. Scirica
OBJECTIVE Improved risk assessment for patients with type 2 diabetes and elevated cardiovascular (CV) risk is needed. The Thrombolysis in Myocardial Infarction (TIMI) Risk Score for Secondary Prevention (TRS 2°P) predicts a gradient of risk in patients with prior myocardial infarction (MI) but has not been evaluated in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS CV event rates were compared by baseline TRS 2°P in 16,488 patients enrolled in SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53) with type 2 diabetes and high CV risk or established CV disease. Calibration was tested in the diabetes cohort from the REACH (REduction of Atherothrombosis for Continued Health) Registry. RESULTS TRS 2°P revealed a robust risk gradient for the composite of CV death, MI, and ischemic stroke in the full trial population, with 2-year event rates of 0.9% in the lowest- and 19.8% in the highest-risk groups (Ptrend < 0.001). A clear risk gradient was present within the subgroups of all coronary artery disease (CAD), CAD without prior MI, CAD with prior MI, peripheral artery disease, and prior stroke (Ptrend < 0.001 for each), with consistent risk relationships across subgroups. The C-statistic (0.71 for CV death and 0.66 for the composite end point) was consistent in each subgroup. There was close calibration with the type 2 diabetes cohort from the REACH Registry (goodness-of-fit P = 0.78). CONCLUSIONS The expanded TRS 2°P provides a practical and well-calibrated risk prediction tool for patients with type 2 diabetes.
Validation of Risk Equations for Complications of Type 2 Diabetes (RECODe) Using Individual Participant Data From Diverse Longitudinal Cohorts in the U.S. Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Sanjay Basu; Jeremy B. Sussman; Seth A. Berkowitz; Rodney A. Hayward; Alain G. Bertoni; Adolfo Correa; Stanford Mwasongwe; John S. Yudkin
OBJECTIVE We sought to validate Risk Equations for Complications of Type 2 Diabetes (RECODe) among diverse populations. RESEARCH DESIGN AND METHODS We compared risk predictions from RECODe equations and from two alternative risk models (UK Prospective Diabetes Study Outcomes Model 2 [UKPDS OM2] and American College of Cardiology/American Heart Association Pooled Cohort Equations) to observed outcomes in two studies: the Multi-Ethnic Study of Atherosclerosis (MESA, n = 1,555 adults with type 2 diabetes, median follow-up 9.1 years) and the Jackson Heart Study (JHS, n = 1,746 adults with type 2 diabetes, median follow-up 8.0 years). Outcomes included nephropathy by multiple measures (microalbuminuria, macroalbuminuria, renal failure, end-stage renal disease, and reduction in glomerular filtration rate), moderate to severe diabetic retinopathy by Airlie House classification, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, congestive heart failure, and all-cause mortality. RESULTS RECODe equations for microvascular and cardiovascular outcomes had C-statistics for discrimination ranging from 0.71 to 0.85 in MESA and 0.64 to 0.91 in JHS for alternative outcomes. Calibration slopes in MESA ranged from 0.62 for a composite nephropathy outcome, 0.83–1.04 for individual nephropathy outcomes, 1.07 for retinopathy, 1.00–1.05 for cardiovascular outcomes, and 1.03 for all-cause mortality. Slopes in JHS ranged from 0.47 for retinopathy, 0.97–1.16 for nephropathy, 0.72–1.05 for cardiovascular outcomes, and 1.01 for all-cause mortality. The alternative models had C-statistics 0.50–0.72 and calibration slopes 0.07–0.60. CONCLUSIONS RECODe equations improved risk estimation for diverse patients with type 2 diabetes, as compared with two commonly used alternatives.
Increased Risk of Severe Hypoglycemic Events Before and After Cardiovascular Outcomes in TECOS Suggests an At-Risk Type 2 Diabetes Frail Patient Phenotype Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Eberhard Standl; Susanna R. Stevens; Paul W. Armstrong; John B. Buse; Juliana C.N. Chan; Jennifer B. Green; John M. Lachin; Andre Scheen; Florence Travert; Frans Van de Werf; Eric D. Peterson; Rury R. Holman
OBJECTIVE Severe hypoglycemic events (SHEs) in type 2 diabetes are associated with subsequent cardiovascular (CV) event risk. We examined whether CV events were associated with subsequent SHE risk. RESEARCH DESIGN AND METHODS Time-dependent associations between SHEs and a composite CV end point (fatal/nonfatal myocardial infarction or stroke, hospitalization for unstable angina, hospitalization for heart failure [hHF]) were examined post hoc in 14,671 TECOS (Trial Evaluating Cardiovascular Outcomes With Sitagliptin) participants with type 2 diabetes and CV disease followed for a median of 3.0 years. RESULTS SHEs were uncommon and unassociated with sitagliptin therapy (N = 160 [2.2%], 0.78/100 patient-years vs. N = 143 [1.9%], 0.70/100 patient-years for placebo; hazard ratio [HR] 1.12 [95% CI 0.89, 1.40], P = 0.33). Patients with (versus without) SHEs were older with longer diabetes duration, lower body weight, and lower estimated glomerular filtration rate; were more frequently women, nonwhite, and insulin treated; and more often had microalbuminuria or macroalbuminuria. Analyses adjusted for clinical factors showed SHEs were associated with increased risk of the primary composite CV end point (1.55 [1.06, 2.28], P = 0.025), all-cause death (1.83 [1.22, 2.75], P = 0.004), and CV death (1.72 [1.02, 2.87], P = 0.040). Conversely, nonfatal myocardial infarction (3.02 [1.83, 4.96], P < 0.001), nonfatal stroke (2.77 [1.36, 5.63], P = 0.005), and hHF (3.68 [2.13, 6.36], P < 0.001) were associated with increased risk of SHEs. Fully adjusted models showed no association between SHEs and subsequent CV or hHF events, but the association between CV events and subsequent SHEs remained robust. CONCLUSIONS These findings, showing greater risk of SHEs after CV events and greater risk of CV events after SHEs, suggest a common at-risk type 2 diabetes frail patient phenotype.
Characteristics Associated With Decreased or Increased Mortality Risk From Glycemic Therapy Among Patients With Type 2 Diabetes and High Cardiovascular Risk: Machine Learning Analysis of the ACCORD Trial Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Sanjay Basu; Sridharan Raghavan; Deborah J. Wexler; Seth A. Berkowitz
OBJECTIVE Identifying patients who may experience decreased or increased mortality risk from intensive glycemic therapy for type 2 diabetes remains an important clinical challenge. We sought to identify characteristics of patients at high cardiovascular risk with decreased or increased mortality risk from glycemic therapy for type 2 diabetes using new methods to identify complex combinations of treatment effect modifiers. RESEARCH DESIGN AND METHODS The machine learning method of gradient forest analysis was applied to understand the variation in all-cause mortality within the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial (N = 10,251), whose participants were 40–79 years old with type 2 diabetes, hemoglobin A1c (HbA1c) ≥7.5% (58 mmol/mol), cardiovascular disease (CVD) or multiple CVD risk factors, and randomized to target HbA1c <6.0% (42 mmol/mol; intensive) or 7.0–7.9% (53–63 mmol/mol; standard). Covariates included demographics, BMI, hemoglobin glycosylation index (HGI; observed minus expected HbA1c derived from prerandomization fasting plasma glucose), other biomarkers, history, and medications. RESULTS The analysis identified four groups defined by age, BMI, and HGI with varied risk for mortality under intensive glycemic therapy. The lowest risk group (HGI <0.44, BMI <30 kg/m2, age <61 years) had an absolute mortality risk decrease of 2.3% attributable to intensive therapy (95% CI 0.2 to 4.5, P = 0.038; number needed to treat: 43), whereas the highest risk group (HGI ≥0.44) had an absolute mortality risk increase of 3.7% attributable to intensive therapy (95% CI 1.5 to 6.0; P < 0.001; number needed to harm: 27). CONCLUSIONS Age, BMI, and HGI may help individualize prediction of the benefit and harm from intensive glycemic therapy.
Clinical Impact of ITCA 650, a Novel Drug-Device GLP-1 Receptor Agonist, in Uncontrolled Type 2 Diabetes and Very High Baseline HbA1c: The FREEDOM-1 HBL (High Baseline) Study Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Robert R. Henry; Julio Rosenstock; Douglas S. Denham; Prakash Prabhakar; Lise Kjems; Michelle A. Baron
OBJECTIVE ITCA 650 is a subdermal osmotic mini-pump that continuously delivers exenatide subcutaneously for 3–6 months. The efficacy, safety, and tolerability of ITCA 650 added to diet and exercise alone or combined with metformin, sulfonylurea, or thiazolidinedione monotherapy or a combination of these drugs was evaluated in poorly controlled patients with type 2 diabetes (T2D) who were ineligible for participation in a placebo-controlled study (FREEDOM-1) because of severe hyperglycemia (HbA1c >10% [86 mmol/mol]). RESEARCH DESIGN AND METHODS This 39-week, open-label, phase 3 trial enrolled patients aged 18–80 years with HbA1c >10% to ≤12% (86–108 mmol/mol) and BMI 25–45 kg/m2. Patients received ITCA 650 20 μg/day for 13 weeks, then 60 μg/day for 26 weeks. The primary end point was change in HbA1c at week 39. RESULTS Sixty patients were enrolled. At baseline, mean HbA1c was 10.8% (94.7 mmol/mol) and mean (± SD) duration of diabetes was 8.6 (± 5.3) years. At week 39, there was a mean reduction in HbA1c of −2.8% (−30.3 mmol/mol; P < 0.001 vs. baseline) and in body weight of −1.2 kg ( P = 0.105), and 25% of patients achieved HbA1c <7% (53 mmol/mol). A reduction in HbA1c of ≥1% (≥10.9 mmol/mol) occurred in 90% of patients. The most common adverse events were nausea, vomiting, diarrhea, and headache. Gastrointestinal adverse events were generally transient and subsided over time; only 4 patients (6.7%) discontinued for gastrointestinal events. CONCLUSIONS Treatment with ITCA 650, the first injection-free glucagon-like peptide 1 receptor agonist, resulted in significant improvements in glycemic control in poorly controlled long-standing T2D patients with a high baseline HbA1c >10%.
No Evidence of Increase in Calcitonin Concentrations or Development of C-Cell Malignancy in Response to Liraglutide for Up to 5 Years in the LEADER Trial Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Laszlo Hegedüs; Steven I. Sherman; R. Michael Tuttle; Bernt J. von Scholten; Søren Rasmussen; Julie D. Karsbøl; Gilbert H. Daniels
OBJECTIVE To describe the changes in serum levels of calcitonin in liraglutide- and placebo-treated patients in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results—A Long Term Evaluation (LEADER) trial over a 3.5–5-year period. RESEARCH DESIGN AND METHODS Patients (n = 9,340) with type 2 diabetes and high risk for cardiovascular events were randomized 1:1 to liraglutide or placebo. We analyzed calcitonin levels, thyroid and C-cell adverse events, and neoplasms. RESULTS At 36 months, patients randomized to liraglutide versus placebo showed no evidence of increase in calcitonin concentrations in male (estimated treatment ratio [ETR] 1.03 [95% CI 1.00, 1.06]; P = 0.068) and female (ETR 1.00 [95% CI 0.97, 1.02]; P = 0.671) subgroups. There were no episodes of C-cell hyperplasia or medullary thyroid carcinoma in liraglutide-treated patients. CONCLUSIONS There was no evidence of a difference in calcitonin concentrations between the liraglutide and placebo groups, and no C-cell malignancies occurred in the liraglutide group.
Fasting Glucose and All-Cause Mortality by Age in Diabetes: A Prospective Cohort Study Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Sang-Wook Yi; Sangkyu Park; Yong-ho Lee; Beverley Balkau; Jee-Jeon Yi
OBJECTIVE To examine associations between fasting glucose and mortality and to identify the levels associated with lowest mortality by age in diabetes. RESEARCH DESIGN AND METHODS A total of 359,645 Korean adults with known prevalent diabetes participated in health screening during 2001–2004 and were followed up until 2013. RESULTS U-curve associations were found. Fasting glucose levels associated with the lowest mortality were ∼90–130 mg/dL, except for in those aged 18–44 years (∼80–95 mg/dL). Multivariable-adjusted hazard ratios of fasting glucose <65, 65–74, 75–84, 140–169, 170–199, and ≥200 mg/dL were 1.46, 1.12, 1.09, 1.12, 1.31, and 1.78, respectively, compared with 85–99 mg/dL. CONCLUSIONS Optimal fasting glucose range for survival is higher in adults with than without known prevalent diabetes, except, perhaps, younger adults. Tight glucose control may lessen premature death in younger adults with diabetes. Hypoglycemia (<65 mg/dL) was associated with higher mortality than was fasting glucose 170–199 mg/dL, while fasting glucose 65–84 mg/dL had risks comparable with those at levels 140–169 mg/dL in diabetes.
Gastrointestinal Symptoms in Diabetes: Prevalence, Assessment, Pathogenesis, and Management Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Yang T. Du; Christopher K. Rayner; Karen L. Jones; Nicholas J. Talley; Michael Horowitz
If you haven’t measured something, you really don’t know much about it.—Karl Pearson (attributed) Gastrointestinal (GI) symptoms represent an important and often unappreciated cause of morbidity in diabetes, although the significance of this burden across the spectrum of patients and the underlying pathophysiology, including the relationship of symptoms with glycemic control, remain poorly defined. The relevance of GI symptoms and the necessity for their accurate assessment have increased with the greater focus on the gut as a therapeutic target for glucose lowering. This review addresses the prevalence, assessment, pathogenesis, and management of GI symptoms in diabetes, beginning with broad principles and then focusing on specific segments of the GI tract. We initially performed a literature search of PubMed by using synonyms and combinations of the following search terms: “gastrointestinal symptoms”, “diabetes”, “prevalence”, “pathogenesis”, “diagnosis”, and “management”. We restricted the search results to English only. Review papers and meta-analyses are presented as the highest level of evidence where possible followed by randomized controlled trials, uncontrolled trials, retrospective and observational data, and expert opinion.
Anti–Programmed Death 1 (PD-1) Antibodies and the Pancreas: A Diabetic Storm Ahead? Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Lucien Marchand; Arnaud Thivolet; Pierre Saintigny; Nicole Fabien; Julien Vouillarmet; Charles Thivolet
Nivolumab, a human IgG4 programmed death 1 (PD-1) immune checkpoint–inhibitor antibody, disrupts PD-1–mediated signaling and restores antitumor immunity (1). Many recent studies have emphasized the importance of anti–PD-1 antibodies to improve survival outcomes among patients with advanced melanoma or lung cancer. Several endocrinological side effects have been reported and a few patients developed insulin-requiring diabetes (2). Some …
Erratum. Factors Associated With Diabetes-Specific Health-Related Quality of Life in Youth With Type 1 Diabetes: The Global TEENs Study. Diabetes Care 2017;40:1002—1009 Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Barbara J. Anderson; Lori M. Laffel; Catherine Domenger; Thomas Danne; Moshe Phillip; Carmen Mazza; Ragnar Hanas; Sheridan Waldron; Roy W. Beck; Francoise Calvi-Gries; Chantal Mathieu
In the article cited above, the Supplementary Data file for the “TEENs—List of Contributors” was …
Erratum. Mitigating Cardiovascular Risk in Type 2 Diabetes With Antidiabetes Drugs: A Review of Principal Cardiovascular Outcome Results of EMPA-REG OUTCOME, LEADER, and SUSTAIN-6 Trials. Diabetes Care 2017;40:821–831 Diabetes Care (IF 11.857) Pub Date : 2018-03-01 Sanjay Kaul
In the article cited above, there are typographical errors in Table 3 with regard to the values for hospitalization for heart …
Erratum. Maternal BMI and Glycemia Impact the Fetal Metabolome. Diabetes Care 2017;40:902–910 Diabetes Care (IF 11.857) Pub Date : 2018-03-01 William L. Lowe; James R. Bain; Michael Nodzenski; Anna C. Reisetter; Michael J. Muehlbauer; Robert D. Stevens; Olga R. Ilkayeva; Lynn P. Lowe; Boyd E. Metzger; Christopher B. Newgard; Denise M. Scholtens
In the article cited above, the authors have requested that three sentences be corrected: 1. In the research design and methods section of the abstract, the sentence was corrected to read: “Targeted metabolic assays were performed on cord blood plasma samples from European ancestry, Afro-Caribbean, Thai, and …
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