Time in Range in Relation to All-Cause and Cardiovascular Mortality in Patients With Type 2 Diabetes: A Prospective Cohort Study

OBJECTIVEThere is growing evidence linking time in range (TIR), an emerging metric for assessing glycemic control, to diabetes-related outcomes. We aimed to investigate the association between TIR and mortality in patients with type 2 diabetes.RESEARCH DESIGN AND METHODSA total of 6,225 adult patients with type 2 diabetes were included from January 2005 to December 2015 from a single center in Shanghai, China. TIR was measured with continuous glucose monitoring at baseline, and the participants were stratified into four groups by TIR: >85%, 71–85%, 51–70%, and ≤50%. Cox proportional hazards regression models were used to estimate the association between different levels of TIR and the risks of all-cause and cardiovascular disease (CVD) mortality.RESULTSThe mean age of the participants was 61.7 years at baseline. During a median follow-up of 6.9 years, 838 deaths were identified, 287 of which were due to CVD. The multivariable-adjusted hazard ratios associated with different levels of TIR (>85% [reference group], 71–85%, 51–70%, and ≤50%) were 1.00, 1.23 (95% CI 0.98–1.55), 1.30 (95% CI 1.04–1.63), and 1.83 (95% CI 1.48–2.28) for all-cause mortality (P for trend <0.001) and 1.00, 1.35 (95% CI 0.90–2.04), 1.47 (95% CI 0.99–2.19), and 1.85 (95% CI 1.25–2.72) for CVD mortality (P for trend = 0.015), respectively.CONCLUSIONSThe current study indicated an association of lower TIR with an increased risk of all-cause and CVD mortality among patients with type 2 diabetes, supporting the validity of TIR as a surrogate marker of long-term adverse clinical outcomes.     

Severe Hypoglycemia,Cardiac Structure and Function,and Risk of Cardiovascular Events Among Older Adults With Diabetes

OBJECTIVETo assess the association of severe hypoglycemia measured at baseline with cardiovascular disease (CVD) among community-dwelling older individuals with diabetes, a group particularly susceptible to hypoglycemia.RESEARCH DESIGN AND METHODSWe included older adults with diabetes from the Atherosclerosis Risk in Communities (ARIC) study who attended visit 5 (2011–2013, baseline). Severe hypoglycemia at baseline was defined with use of first position ICD-9 codes from hospitalizations, emergency department visits, and ambulance calls. We examined cross-sectional associations of severe hypoglycemia with echocardiographic indices of cardiac structure-function. We prospectively evaluated the risks of incident or recurrent CVD (coronary heart disease, stroke, or heart failure) and all-cause mortality, from baseline to 31 December 2018, using negative binomial and Cox regression models.RESULTSAmong 2,193 participants (mean [SD] age 76 [5] years, 57% female, 32% Blacks), 79 had a history of severe hypoglycemia at baseline. Severe hypoglycemia was associated with a lower left ventricular (LV) ejection fraction (adjusted β-coefficient −3.66% [95% CI −5.54, −1.78]), higher LV end diastolic volume (14.80 mL [95% CI 8.77, 20.84]), higher E-to-A ratio (0.11 [95% CI 0.03, 0.18]), and higher septal E/e′ (2.48 [95% CI 1.13, 3.82]). In adjusted models, severe hypoglycemia was associated with incident or recurrent CVD (incidence rate ratio 2.19 (95% CI 1.24, 3.88]) and all-cause mortality (hazard ratio 1.71 [95% CI 1.10, 2.67]) among those without prevalent CVD.CONCLUSIONSOur findings suggest that a history of severe hypoglycemia is associated with alterations in cardiac function and is an important marker of future cardiovascular risk in older adults.     

Heart Rate–Corrected QT Interval Is an Independent Predictor of All-Cause and Cardiovascular Mortality in Individuals With Type 2 Diabetes: The Diabetes Heart Study

OBJECTIVE

Heart rate–corrected QT (QTc) interval is associated with mortality in the general population, but this association is less clear in individuals with type 2 diabetes. We assessed the association of QTc interval with all-cause and cardiovascular disease (CVD) mortality in the Diabetes Heart Study.

RESEARCH DESIGN AND METHODS

We studied 1,020 participants with type 2 diabetes (83% European Americans; 55% women; mean age 61.4 years) who were free of atrial fibrillation, major ventricular conduction defects, and antiarrhythmic therapy at baseline. QT duration was automatically calculated from a standard 12-lead electrocardiogram (ECG). Following American Heart Association/American College of Cardiology Foundation recommendations, a linear scale was used to correct the QT for heart rate. Using Cox regression, risk was estimated per 1-SD increase in QTc interval as well as prolonged QTc interval (>450 ms) vs. normal QTc interval for mortality.

RESULTS

At baseline, the mean (SD) QTc duration was 414.9 ms (18.1), and 3.0% of participants had prolonged QTc. After a median follow-up time of 8.5 years (maximum follow-up time 13.9 years), 204 participants were deceased. In adjusted multivariate models, a 1-SD increase in QTc interval was associated with an 18% higher risk for all-cause mortality (hazard ratio 1.18 [95% CI 1.03–1.36]) and 29% increased risk for CVD mortality (1.29 [1.05–1.59]). Similar results were obtained when QTc interval was used as a categorical variable (prolonged vs. normal) (all-cause mortality 1.73 [0.95–3.15]; CVD mortality 2.86 [1.35–6.08]).

CONCLUSIONS

Heart rate QTc interval is an independent predictor of all-cause and CVD mortality in this population with type 2 diabetes, suggesting that additional prognostic information may be available from this simple ECG measure.     

Type 2 Diabetes and COVID-19–Related Mortality in the Critical Care Setting: A National Cohort Study in England,March–July 2020

OBJECTIVETo describe the relationship between type 2 diabetes and all-cause mortality among adults with coronavirus disease 2019 (COVID-19) in the critical care setting.RESEARCH DESIGN AND METHODSThis was a nationwide retrospective cohort study in people admitted to hospital in England with COVID-19 requiring admission to a high dependency unit (HDU) or intensive care unit (ICU) between 1 March 2020 and 27 July 2020. Cox proportional hazards models were used to estimate 30-day in-hospital all-cause mortality associated with type 2 diabetes, with adjustment for age, sex, ethnicity, obesity, and other major comorbidities (chronic respiratory disease, asthma, chronic heart disease, hypertension, immunosuppression, chronic neurological disease, chronic renal disease, and chronic liver disease).RESULTSA total of 19,256 COVID-19–related HDU and ICU admissions were included in the primary analysis, including 13,809 HDU (mean age 70 years) and 5,447 ICU (mean age 58 years) admissions. Of those admitted, 3,524 (18.3%) had type 2 diabetes and 5,077 (26.4%) died during the study period. Patients with type 2 diabetes were at increased risk of death (adjusted hazard ratio [aHR] 1.23 [95% CI 1.14, 1.32]), and this result was consistent in HDU and ICU subsets. The relative mortality risk associated with type 2 diabetes decreased with higher age (age 18–49 years aHR 1.50 [95% CI 1.05, 2.15], age 50–64 years 1.29 [1.10, 1.51], and age ≥65 years 1.18 [1.09, 1.29]; P value for age–type 2 diabetes interaction = 0.002).CONCLUSIONSType 2 diabetes may be an independent prognostic factor for survival in people with severe COVID-19 requiring critical care treatment, and in this setting the risk increase associated with type 2 diabetes is greatest in younger people.     

Heart Rate and Heart Rate Variability Changes Are Not Related to Future Cardiovascular Disease and Death in People With and Without Dysglycemia: A Downfall of Risk Markers? The Whitehall II Cohort Study

OBJECTIVEHigher resting heart rate (rHR) and lower heart rate variability (HRV) are associated with increased risk of cardiovascular disease (CVD) and all-cause mortality in people with and without diabetes. It is unknown whether temporal changes in rHR and HRV may contribute to this risk. We investigated associations between 5-year changes in rHR and HRV and risk of future CVD and death, taking into account participants’ baseline glycemic state.RESEARCH DESIGN AND METHODSIn this prospective, population-based cohort study we investigated 4,611 CVD-free civil servants (mean [SD] age, 60 [5.9] years; 70% men). We measured rHR and/or six indices of HRV. Associations of 5-year change in 5-min rHR and HRV with fatal and nonfatal CVD and all-cause mortality or the composite of the two were assessed, with adjustments made for relevant confounders. Effect modification by glycemic state was tested.RESULTSAt baseline, 63% of participants were normoglycemic, 29% had prediabetes, and 8% had diabetes. During a median (interquartile range) follow-up of 11.9 (11.4; 12.3) years, 298 participants (6.5%) experienced a CVD event and 279 (6.1%) died of non–CVD-related causes. We found no association between 5-year changes in rHR and HRV and future events. Only baseline rHR was associated with all-cause mortality. A 10 bpm–higher baseline HR level was associated with an 11.4% higher rate of all-cause mortality (95% CI 1.0–22.9%; P = 0.032). Glycemic state did not modify associations.CONCLUSIONSChanges in rHR and HRV and possibly also baseline values of these measures are not associated with future CVD or death in people with or without dysglycemia.     

Cobalamin Intake and Related Biomarkers: Examining Associations With Mortality Risk Among Adults With Type 2 Diabetes in NHANES

OBJECTIVEDespite that periodical monitoring of cobalamin (vitamin B12) in metformin-treated patients with diabetes is recommended, cobalamin-associated mortality benefits or risks remain unclear. We investigated the association between cobalamin intake and related biomarkers and mortality risk in adults with diabetes using metformin or not.RESEARCH DESIGN AND METHODSThis study included 3,277 adults with type 2 diabetes from the National Health and Nutrition Examination Survey (NHANES) and followed up until 31 December 2015. Weighted Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs for mortality risk.RESULTSAmong 3,277 participants, 865 all-cause deaths occurred during a median follow-up of 7.02 years. There was no robust relationship between all-cause mortality and serum cobalamin or intake of foods or cobalamin supplements, regardless of metformin treatment (each P ≥ 0.120). The doubling of methylmalonic acid (MMA), a cobalamin-deficiency marker, was significantly associated with higher all-cause (HR 1.31 [95% CI 1.18–1.45], P < 0.001) and cardiac (HR 1.38 [95% CI 1.14–1.67], P = 0.001) mortality. Cobalamin sensitivity was assessed by the combination of binary B12_low/high and MMA_low/high (cutoff values: cobalamin 400 pg/mL, MMA 250 nmol/L). Patients with decreased cobalamin sensitivity (MMA_highB12_high) had the highest mortality risk. The multivariable-adjusted HRs (95% CIs) of all-cause mortality in MMA_lowB12_low, MMA_lowB12_high, MMA_highB12_low, and MMA_highB12_high groups were 1.00 (reference), 0.98 (0.75–1.28), 1.49 (1.16–1.92), and 1.96 (1.38–2.78), respectively. That association was especially significant in metformin nonusers.CONCLUSIONSSerum and dietary cobalamin were not associated with reduced mortality. Decreased cobalamin sensitivity was significantly associated with all-cause and cardiac mortality, particularly among metformin nonusers.     

Association Between Insulin Resistance and Cardiovascular Disease Risk Varies According to Glucose Tolerance Status: A Nationwide Prospective Cohort Study

OBJECTIVETo investigate whether the association between insulin resistance and cardiovascular disease (CVD) differs by glucose tolerance status.RESEARCH DESIGN AND METHODSWe analyzed a nationwide sample of 111,576 adults without CVD at baseline, using data from the China Cardiometabolic Disease and Cancer Cohort Study. Insulin resistance was estimated by sex-specific HOMA of insulin resistance (HOMA-IR) quartiles for participants with normal glucose tolerance, prediabetes, or diabetes, separately, and by 1 SD of HOMA-IR for the overall study participants. We used Cox proportional hazards models to examine the association between insulin resistance and incident CVD according to glucose tolerance status and evaluate the CVD risk associated with the combined categories of insulin resistance and obesity in prediabetes and diabetes, as compared with normal glucose tolerance. Models were adjusted for age, sex, education attainment, alcohol drinking, smoking, physical activity, and diet quality.RESULTSIn participants with normal glucose tolerance, prediabetes, and diabetes defined by three glucose parameters, multivariable-adjusted hazard ratios (95% CIs) for incident CVD associated with the highest versus the lowest quartile of HOMA-IR were 1.03 (0.82–1.30), 1.23 (1.07–1.42), and 1.61 (1.30–2.00), respectively; the corresponding values for CVD per 1-SD increase in HOMA-IR were 1.04 (0.92–1.18), 1.12 (1.06–1.18), and 1.15 (1.09–1.21), respectively (P for interaction = 0.011). Compared with participants with normal glucose tolerance, in participants with prediabetes, the combination of the highest HOMA-IR quartile and obesity showed 17% (95% CI 2–34%) higher risk of CVD, while the combination of the lowest two HOMA-IR quartiles and nonobesity showed 15–17% lower risk of CVD. In participants with diabetes, the upper two HOMA-IR quartiles exhibited 44–77% higher risk of CVD, regardless of obesity status. Consistent findings were observed for glucose tolerance status defined by different combinations of glycemic parameters.CONCLUSIONSGlucose intolerance status exacerbated the association between insulin resistance and CVD risk. Compared with adults with normal glucose tolerance, adults with prediabetes who were both insulin resistant and obese exhibited higher risks of CVD, while in adults with diabetes, the CVD risk related to insulin resistance remained, regardless of obesity.     

Genetic Risk Score Associations With Cardiovascular Disease and Mortality in the Diabetes Heart Study

OBJECTIVE

Given the high rates of cardiovascular disease (CVD) and associated mortality in individuals with type 2 diabetes, identifying and understanding predictors of CVD events and mortality could help inform clinical management in this high-risk group. Recent large-scale genetic studies may provide additional tools in this regard.

RESEARCH DESIGN AND METHODS

Genetic risk scores (GRSs) were constructed in 1,175 self-identified European American (EA) individuals comprising the family-based Diabetes Heart Study based on 1) 13 single nucleotide polymorphisms (SNPs) and 2) 30 SNPs with previously documented associations with CVD in genome-wide association studies. Associations between each GRS and a self-reported history of CVD, coronary artery calcified plaque (CAC) determined by noncontrast computed tomography scan, all-cause mortality, and CVD mortality were examined using marginal models with generalized estimating equations and Cox proportional hazards models.

RESULTS

The weighted 13-SNP GRS was associated with prior CVD (odds ratio [OR] 1.51 [95% CI 1.22–1.86]; P = 0.0002), CAC (β-coefficient [β] 0.22 [0.02–0.43]; P = 0.04) and CVD mortality (hazard ratio [HR] 1.35 [1.10–1.81]; P = 0.04) when adjusting for the other known CVD risk factors: age, sex, type 2 diabetes affection status, BMI, current smoking status, hypertension, and dyslipidemia. The weighted 30-SNP GRS was also associated with prior CVD (OR 1.33 [1.08–1.65]; P = 0.008), CAC (β 0.29 [0.08–0.50]; P = 0.006), all-cause mortality (HR 1.28 [1.05–1.56]; P = 0.01), and CVD mortality (HR 1.46 [1.08–1.96]; P = 0.01).

CONCLUSIONS

These findings support the utility of two simple GRSs in examining genetic associations for adverse outcomes in EAs with type 2 diabetes.     

Historical HbA1c Values May Explain the Type 2 Diabetes Legacy Effect: UKPDS 88

OBJECTIVEType 2 diabetes all-cause mortality (ACM) and myocardial infarction (MI) glycemic legacy effects have not been explained. We examined their relationships with prior individual HbA_1c values and explored the potential impact of instituting earlier, compared with delayed, glucose-lowering therapy.RESEARCH DESIGN AND METHODSTwenty-year ACM and MI hazard functions were estimated from diagnosis of type 2 diabetes in 3,802 UK Prospective Diabetes Study participants. Impact of HbA_1c values over time was analyzed by weighting them according to their influence on downstream ACM and MI risks.RESULTSHazard ratios for a one percentage unit higher HbA_1c for ACM were 1.08 (95% CI 1.07–1.09), 1.18 (1.15–1.21), and 1.36 (1.30–1.42) at 5, 10, and 20 years, respectively, and for MI was 1.13 (1.11–1.15) at 5 years, increasing to 1.31 (1.25–1.36) at 20 years. Imposing a one percentage unit lower HbA_1c from diagnosis generated an 18.8% (95% CI 21.1–16.0) ACM risk reduction 10–15 years later, whereas delaying this reduction until 10 years after diagnosis showed a sevenfold lower 2.7% (3.1–2.3) risk reduction. Corresponding MI risk reductions were 19.7% (22.4–16.5) when lowering HbA_1c at diagnosis, and threefold lower 6.5% (7.4–5.3%) when imposed 10 years later.CONCLUSIONSThe glycemic legacy effects seen in type 2 diabetes are explained largely by historical HbA_1c values having a greater impact than recent values on clinical outcomes. Early detection of diabetes and intensive glucose control from the time of diagnosis is essential to maximize reduction of the long-term risk of glycemic complications.     

Androgens,Bilateral Oophorectomy,and Cardiovascular Disease Mortality in Postmenopausal Women With and Without Diabetes: The Study of Osteoporotic Fractures

OBJECTIVE

Diabetes elevates cardiovascular disease (CVD) risk more markedly in women than in men. Because the high risk of CVD among women with type 2 diabetes (DM2) may be partly due to increased ovarian androgen production, we investigated whether a history of bilateral salpingo oophorectomy (BSO) is inversely associated with CVD mortality among women with DM2.

RESEARCH DESIGN AND METHODS

Data were obtained from 7,977 women (a random subset of 564 had measurements of sex-steroid hormones) enrolled in the Study of Osteoporotic Fractures (SOF), a community-based, multicenter study that monitored women aged ≥65 years for a mean of 15.1 years. Adjusted hazard ratios (HRs) and 95% CIs were calculated using Cox proportional hazards regression.

RESULTS

The average age at baseline was 71.5 years, with 6.3% and 18% of participants reporting a history of diabetes or BSO, respectively. In the subset of the SOF cohort with sex-steroid hormone measurements, those with DM2 had 43.6% significantly higher levels of free testosterone that were partly explained by age and adiposity, whereas total and free testosterone levels were lower in women with BSO than in those with intact ovaries. CVD mortality was elevated in women with DM2 without BSO (HR 1.95, 95% CI 1.62–2.35) as well as in women with DM2 and BSO (HR 2.56, 95% CI 1.79–3.65; P = 0.190 for interaction). Overall, BSO was not associated with CVD mortality (HR 1.05, 95% CI 0.89–1.23).

CONCLUSIONS

The association of diabetes with CVD was not reduced by BSO, suggesting that ovarian hyperandrogenemia may not be a primary mechanism to explain the high risk for CVD among women with DM2.     

Association Between Personal Activity Intelligence and Mortality: Population-Based China Kadoorie Biobank Study

ObjectiveTo prospectively investigate the association between personal activity intelligence (PAI) — a novel metabolic metric which translates heart rate during physical activity into a simple weekly score — and mortality in relatively healthy participants in China whose levels and patterns of physical activity in addition to other lifestyle factors are different from those in high-income countries.Patients and MethodsFrom the population-based China Kadoorie Biobank study, 443,792 healthy adults were recruited between June 2004 and July 2008. Participant’s weekly PAI score was estimated and divided into four groups (PAI scores of 0, ≤50, 51–99, or ≥100). Using Cox proportional hazard analyses, we calculated adjusted hazard ratios (AHRs) for cardiovascular disease (CVD) and all-cause mortality related to PAI scores.ResultsDuring a median follow-up of 8.2 (interquartile range, 7.3 to 9.1) years, there were 21,901 deaths, including 9466 CVD deaths. Compared with the inactive group (0 PAI score), a baseline weekly PAI score greater than or equal to 100 was associated with a lower risk of CVD mortality, an AHR of 0.87 (95% CI, 0.81 to 0.94) in men, and an AHR of 0.84 (95% CI, 0.78 to 0.92) in women, after adjusting for multiple confounders. Participants with a weekly PAI score greater than or equal to 100 also had a lower risk of all-cause mortality (AHR, 0.93; 95% CI, 0.89 to 0.97 in men, and AHR, 0.93; 95%, 0.88 to 0.98 in women). Moreover, this subgroup gained 2.7 (95% CI, 2.4 to 3.0) years of life, compared with the inactive cohort.ConclusionAmong relatively healthy Chinese adults, the PAI metric was inversely associated with CVD and all-cause mortality, highlighting the generalizability of the score in different races, ethnicities, and socioeconomic strata.     

Type 1 Diabetes Is Associated With an Increased Risk of Fracture Across the Life Span: A Population-Based Cohort Study Using The Health Improvement Network (THIN)

OBJECTIVE

This study was conducted to determine if type 1 diabetes is associated with an increased risk of fracture across the life span.

RESEARCH DESIGN AND METHODS

This population-based cohort study used data from The Health Improvement Network (THIN) in the U.K. (data from 1994 to 2012), in which 30,394 participants aged 0–89 years with type 1 diabetes were compared with 303,872 randomly selected age-, sex-, and practice-matched participants without diabetes. Cox regression analysis was used to determine hazard ratios (HRs) for incident fracture in participants with type 1 diabetes.

RESULTS

A total of 334,266 participants, median age 34 years, were monitored for 1.9 million person-years. HR were lowest in males and females age <20 years, with HR 1.14 (95% CI 1.01–1.29) and 1.35 (95% CI 1.12–1.63), respectively. Risk was highest in men 60–69 years (HR 2.18 [95% CI 1.79–2.65]), and in women 40–49 years (HR 2.03 [95% CI 1.73–2.39]). Lower extremity fractures comprised a higher proportion of incident fractures in participants with versus those without type 1 diabetes (31.1% vs. 25.1% in males, 39.3% vs. 32% in females; P < 0.001). Secondary analyses for incident hip fractures identified the highest HR of 5.64 (95% CI 3.55–8.97) in men 60–69 years and the highest HR of 5.63 (95% CI 2.25–14.11) in women 30–39 years.

CONCLUSIONS

Type 1 diabetes was associated with increased risk of incident fracture that began in childhood and extended across the life span. Participants with type 1 diabetes sustained a disproportionately greater number of lower extremity fractures. These findings have important public health implications, given the increasing prevalence of type 1 diabetes and the morbidity and mortality associated with hip fractures.     

Cardiovascular and All-Cause Mortality Over a 23-Year Period Among Chinese With Newly Diagnosed Diabetes in the Da Qing IGT and Diabetes Study

OBJECTIVE

Despite its growing prevalence in China, the extent to which diabetes leads to excess cardiovascular disease (CVD) mortality and all-cause mortality is unclear.

RESEARCH DESIGN AND METHODS

We compared death rates and causes of death among 630 people with newly diagnosed diabetes (NDD) and 519 with normal glucose tolerance (NGT) who, in 1986, were identified as a result of screening 110,660 adults aged 25–74 years for diabetes in Da Qing, China.

RESULTS

During 23 years of follow-up, 338 (56.5%) participants with NDD and 100 (20.3%) with NGT died. CVD was the predominant cause of death in those with diabetes (47.5% in men and 49.7% in women), almost half of which was due to stroke (52.3% in men and 42.3% in women). The age-standardized incidence of all-cause death was three times as high in those with NDD as in those with NGT with incidences (per 1,000 person-years) of 36.9 (95% CI 31.5–42.3) vs. 13.3 (10.2–16.5) in men (P < 0.0001) and 27.1 (22.9–31.4) vs. 9.2 (7.8–10.6) in women (P < 0.0001). The incidence of CVD deaths in men and women with NDD (17.5 [13.8–21.2] vs. 13.5 [10.5–16.5]) did not differ significantly. Significantly higher death rates attributable to renal disease and infection were also found in the NDD group.

CONCLUSIONS

Diabetes is associated with a substantially increased risk of death in Chinese adults, especially from CVD, almost half of which is due to stroke.     

Adipose Tissue,Muscle, and Function: Potential Mediators of Associations Between Body Weight and Mortality in Older Adults With Type 2 Diabetes

OBJECTIVEStudies in type 2 diabetes report both increased mortality for normal weight and no evidence of an obesity paradox. We aimed to examine whether adipose tissue, muscle size, and physical function, which are known to vary by weight, mediate associations between BMI and mortality.RESULTSThe median follow-up was 6.66 years, and there were 85, 59, and 44 deaths among normal weight, overweight, and obese participants, respectively. There was no mortality risk for obese participants and an increased risk among normal weight compared with overweight participants (HR 1.72 [95% CI 1.12–2.64]). Associations remained with adjustment for adipose tissues and knee extensor strength; however, mortality risk for normal weight was attenuated following adjustment for thigh muscle (HR 1.36 [95% CI 0.87–2.11]) and gait speed (HR 1.44 [95% CI 0.91–2.27]). Linear regression confirmed with bootstrapping indicated that thigh muscle size mediated 46% of the relationship between normal weight and mortality.CONCLUSIONSNormal weight participants had elevated mortality risk compared with overweight participants. This paradoxical association was mediated in part by muscle size.     

Does the Association Between Hemoglobin A1c and Risk of Cardiovascular Events Vary by Residential Segregation? The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study

OBJECTIVETo examine if the association between higher A1C and risk of cardiovascular disease (CVD) among adults with and without diabetes is modified by racial residential segregation.RESEARCH DESIGN AND METHODSThe study used a case-cohort design, which included a random sample of 2,136 participants at baseline and 1,248 participants with incident CVD (i.e., stroke, coronary heart disease [CHD], and fatal CHD during 7-year follow-up) selected from 30,239 REasons for Geographic And Racial Differences in Stroke (REGARDS) study participants originally assessed between 2003 and 2007. The relationship of A1C with incident CVD, stratified by baseline diabetes status, was assessed using Cox proportional hazards models adjusting for demographics, CVD risk factors, and socioeconomic status. Effect modification by census tract-level residential segregation indices (dissimilarity, interaction, and isolation) was assessed using interaction terms.RESULTSThe mean age of participants in the random sample was 64.2 years, with 44% African American, 59% female, and 19% with diabetes. In multivariable models, A1C was not associated with CVD risk among those without diabetes (hazard ratio [HR] per 1% [11 mmol/mol] increase, 0.94 [95% CI 0.76–1.16]). However, A1C was associated with an increased risk of CVD (HR per 1% increase, 1.23 [95% CI 1.08–1.40]) among those with diabetes. This A1C-CVD association was modified by the dissimilarity (P < 0.001) and interaction (P = 0.001) indices. The risk of CVD was increased at A1C levels between 7 and 9% (53–75 mmol/mol) for those in areas with higher residential segregation (i.e., lower interaction index). In race-stratified analyses, there was a more pronounced modifying effect of residential segregation among African American participants with diabetes.CONCLUSIONSHigher A1C was associated with increased CVD risk among individuals with diabetes, and this relationship was more pronounced at higher levels of residential segregation among African American adults. Additional research on how structural determinants like segregation may modify health effects is needed.     

All-Cause and Cardiovascular Mortality in Middle-Aged People With Type 2 Diabetes Compared With People Without Diabetes in a Large U.K. Primary Care Database

OBJECTIVE

Middle-aged people with diabetes have been reported to have significantly higher risks of cardiovascular events than people without diabetes. However, recent falls in cardiovascular disease rates and more active management of risk factors may have abolished the increased risk. We aimed to provide an up-to-date assessment of the relative risks associated with type 2 diabetes of all-cause and cardiovascular mortality in middle-aged people in the U.K.

RESEARCH DESIGN AND METHODS

Using data from the General Practice Research Database, from 2004 to 2010, we conducted a cohort study of 87,098 people, 40–65 years of age at baseline, comparing 21,798 with type 2 diabetes and 65,300 without diabetes, matched on age, sex, and general practice. We produced hazard ratios (HRs) for mortality and compared rates of blood pressure testing, cholesterol monitoring, and use of aspirin, statins, and antihypertensive drugs.

RESULTS

People with type 2 diabetes, compared with people without diabetes, had a twofold increased risk of all-cause mortality (HR 2.07 [95% CI 1.95–2.20], adjusted for smoking) and a threefold increased risk of cardiovascular mortality (3.25 [2.87–3.68], adjusted for smoking). Women had a higher relative risk than men, and people <55 years of age had a higher relative risk than those >55 years of age. Monitoring and medication rates were higher in those with diabetes (all P < 0.001).

CONCLUSIONS

Despite efforts to manage risk factors, administer effective treatments, and develop new therapies, middle-aged people with type 2 diabetes remain at significantly increased risk of death.In the U.K., cardiovascular disease (CVD) mortality rates in adults have fallen dramatically in recent years (1), by >40% in those 35–69 years of age during 2000–2010 alone (2). The fall in the rates of CVD in the general adult U.K. population may be attributed in part to using aspirin, hydroxymethylglutaryl-CoA reductase inhibitors (statins), and antihypertensive drugs and successfully incorporating lifestyle interventions, in particular reducing smoking (3). In people with type 2 diabetes, who are at increased risk of death from CVD, evidence has shown that statins, antihypertensive drugs (4), and smoking cessation (3,5) reduce the incidence of CVD (6,7). Consequently, these interventions, in addition to weight management strategies to target obesity, a known risk factor for CVD events (3), have been incorporated into the various clinical guidelines, national standards, and incentives relating to managing diabetes (8–10) and implemented by general practitioners with the aim of reducing the risk of complications.The magnitude of the increase in risk of CVD and all-cause mortality in middle-aged people with diabetes, compared with those without diabetes, has been reported at two to four times higher, but these estimates are largely based on data from the 1990s or earlier (11–16). Given that the rates of CVD mortality in the general population have rapidly fallen in recent years (2), and since 2004, the remuneration for general practice actively rewards intensive management for cardiovascular risk factors in people with diabetes (10), the differences may have narrowed even in the past 8 years. Most studies with post-2000 data on relative risk have not distinguished type 1 from type 2 diabetes (17–20), or have been restricted to newly diagnosed type 2 diabetes (21,22). One exception, reporting relative risks for prevalent type 2 diabetes, was the National Diabetes Audit in England (23). Using follow-up data from 2008 to 2009, they presented standardized mortality ratios in the absence of a nondiabetic comparator group; the report’s authors proposed that their results need replicating using survival analysis methods. Using data from the General Practice Research Database (GPRD), we aimed to provide a more up-to-date assessment of the risk of mortality in middle-aged people with prevalent type 2 diabetes in England, overcoming the acknowledged limitation of the National Diabetes Audit study and additionally considering mortality from CVD.     

Glycated Hemoglobin and All-Cause and Cause-Specific Mortality in Singaporean Chinese Without Diagnosed Diabetes: The Singapore Chinese Health Study

OBJECTIVEGlycated hemoglobin (HbA_1c) is a robust biomarker of the preceding 2 to 3 months average blood glucose level. The aim of this study was to examine the association between HbA_1c and mortality in a cohort of Southeast Asians.RESULTSRelative to participants with an HbA_1c of 5.4–5.6% (36–38 mmol/mol), participants with HbA_1c ≥6.5% (≥48 mmol/mol) had an increased risk of all-cause, cardiovascular, and cancer mortality during an average of 10.1 years of follow-up; HRs (95% CIs) were 1.96 (1.56–2.46), 2.63 (1.77–3.90), and 1.51 (1.04–2.18), respectively. No level of HbA_1c was associated with increased risk of respiratory mortality. Levels <6.5% HbA_1c were not associated with mortality during follow-up. The results did not materially change after excluding observation of first 3 years post–blood draw.CONCLUSIONSHbA_1c levels consistent with undiagnosed type 2 diabetes (≥6.5%) are associated with an increased risk of all-cause and cause-specific mortality in Chinese men and women.     

Type 2 Diabetes Subgroups,Risk for Complications,and Differential Effects Due to an Intensive Lifestyle Intervention

OBJECTIVEWe reevaluated the Action for Health in Diabetes (Look AHEAD) intervention, incorporating diabetes subgroups, to identify whether intensive lifestyle intervention (ILI) is associated with differential risk for cardiovascular disease (CVD) by diabetes subgroup.RESEARCH DESIGN AND METHODSIn the Look AHEAD trial, 5,145 participants, aged 45–76 years, with type 2 diabetes (T2D) and overweight or obesity were randomly assigned to 10 years of ILI or a control condition of diabetes support and education. The ILI focused on weight loss through decreased caloric intake and increased physical activity. To characterize diabetes subgroups, we applied k-means clustering to data on age of diabetes diagnosis, BMI, waist circumference, and glycated hemoglobin. We examined whether relative intervention effects on the trial’s prespecified CVD outcomes varied among diabetes subgroups.RESULTSWe characterized four subgroups related to older age at diabetes onset (42% of sample), poor glucose control (14%), severe obesity (24%), and younger age at diabetes onset (20%). We observed interactions (all P < 0.05) between intervention and diabetes subgroups for three separate composite cardiovascular outcomes. Randomization to ILI was associated with increased risk for each cardiovascular outcome only among the poor-glucose-control subgroup (hazard ratio >1.32). Among the three other diabetes subgroups, ILI was not associated with increased risk for CVD.CONCLUSIONSAmong overweight and obese adults with T2D, a lifestyle intervention was associated with differential risk for CVD that was dependent on diabetes subgroup. Diabetes subgroups may be important to identify the patients who would achieve benefit and avoid harm from an ILI.     

Trends in Diabetes Incidence: The Framingham Heart Study

OBJECTIVEObesity and type 2 diabetes continue to increase in prevalence in the U.S. Whether diabetes incidence continues to increase in recent times is less well documented. We examined trends in diabetes incidence over the previous four decades.RESULTSThe annualized rates of diabetes per 1,000 individuals were 2.6, 3.8, 4.7, and 3.0 (women) and 3.4, 4.5, 7.4, and 7.3 (men) in the 1970s, 1980s, 1990s, and 2000s, respectively. Compared with the 1970s, the age- and sex-adjusted relative risks of diabetes were 1.37 (95% CI 0.87–2.16; P = 0.17), 1.99 (95% CI 1.30–3.03; P = 0.001), and 1.81 (95% CI 1.16–2.82; P = 0.01) in the 1980s, 1990s, and 2000s, respectively. Compared with the 1990s, the relative risk of diabetes in the 2000s was 0.85 (95% CI 0.61–1.20; P = 0.36).CONCLUSIONSIn our community-based sample, the risk of new-onset diabetes continued to be higher in the 2000s compared with the 1970s. In the past decade, diabetes incidence remained steady despite the ongoing trend of rising adiposity.     

New-onset diabetes and risk of all-cause and cardiovascular mortality: the Cardiovascular Health Study

OBJECTIVE: Cardiovascular risk associated with new-onset diabetes is not well characterized. We hypothesized that risk of all-cause and cardiovascular mortality would be similar among participants with and without new-onset diabetes in the first years of follow-up and rise over time for new-onset diabetes. RESEARCH DESIGN AND METHODS: The Cardiovascular Health Study (CHS) is a longitudinal study of cardiovascular risk factors in adults aged > or =65 years. We used CHS participants to define a cohort (n = 282) with new-onset diabetes during 11 years of follow-up. New-onset diabetes was defined by initiation of antidiabetes medication or by fasting plasma glucose >125 mg/dl among CHS participants without diabetes at study entry. Three CHS participants without diabetes were matched for age, sex, and race to each participant with new-onset diabetes at the time of diabetes identification (n = 837). Survival analysis provided adjusted hazard ratios (HRs) for all-cause and cardiovascular mortality. RESULTS: During a median of 5.9 years of follow-up, there were 352 deaths, of which 41% were cardiovascular. In adjusted analyses, new-onset diabetes was associated with an HR of 1.9 (95% CI 1.4-2.5) for all-cause and 2.2 (1.4-3.4) for cardiovascular mortality compared with no diabetes. Mortality risks were elevated within 2 years of onset, especially cardiovascular risk (4.3 [95% CI 1.7-10.8]), and did not increase over time. CONCLUSIONS: Our findings indicate that there may be a mortality differential soon after diabetes onset in older adults and suggest that long-term macrovascular damage from atherosclerosis may not be primarily responsible for increased risk.