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Diabetes Care Cardiovascular and Metabolic Risk



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Prevalence and Prognostic Impact of Diabetes in Takotsubo Syndrome: Insights From the International, Multicenter GEIST Registry

2018-04-20T12:00:23-07:00

OBJECTIVE

In view of low prevalence rates, diabetes is discussed as a protective factor for the occurrence of Takotsubo syndrome (TTS). Furthermore, it was associated with improved outcome in a small single-center analysis. Therefore, this study assessed the prevalence and prognostic relevance of concomitant diabetes in TTS.

RESEARCH DESIGN AND METHODS

A total of 826 patients with TTS were enrolled in an international, multicenter, registry-based study (eight centers in Italy and Germany). All-cause mortality was compared between patients with diabetes and patients without diabetes, and the independent predictive value of diabetes was evaluated in multivariate regression analysis.

RESULTS

The prevalence of diabetes was 21.1% (n = 174). TTS patients with diabetes were older (P < 0.001), were more frequently male (P = 0.003), had a higher prevalence of hypertension (P < 0.001), physical triggers (P = 0.041), and typical apical ballooning (P = 0.010), had a lower left ventricular ejection fraction (P = 0.008), had a higher rate of pulmonary edema (P = 0.032), and had a longer hospital stay (P = 0.009). However, 28-day all-cause mortality did not differ between patients with diabetes and patients without diabetes (6.4% vs. 5.7%; hazard ratio [HR] 1.11 [95% CI 0.55–2.25]; P = 0.772). Longer-term follow-up after a median of 2.5 years revealed a significantly higher mortality among TTS patients with diabetes (31.4% vs. 16.5%; P < 0.001), and multivariate regression analysis identified diabetes as an independent predictor of adverse outcome (HR 1.66 [95% CI 1.16–2.39]; P = 0.006).

CONCLUSIONS

Diabetes is not uncommon in patients with TTS, is associated with increased longer-term mortality rates, and is an independent predictor of adverse outcome irrespective of additional risk factors.




Childhood BMI and Adult Type 2 Diabetes, Coronary Artery Diseases, Chronic Kidney Disease, and Cardiometabolic Traits: A Mendelian Randomization Analysis

2018-04-20T12:00:23-07:00

OBJECTIVE

To test the causal effect of childhood BMI on adult cardiometabolic diseases using a Mendelian randomization analysis.

RESEARCH DESIGN AND METHODS

We used 15 single nucleotide polymorphisms 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 1-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 x 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 x 10–8) at the Bonferroni-adjusted level of significance (P < 0.017) in adults. In addition, a 1-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-transformed HOMA of ß-cell function (%), a 0.126 increase in log-transformed HOMA of insulin resistance (%), and a 0.109-SD increase in triglyceride (mg/dL) 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 higher 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.




Plasma Connective Tissue Growth Factor (CTGF/CCN2) Levels Predict Myocardial Infarction in the Veterans Affairs Diabetes Trial (VADT) Cohort

2018-03-20T12:04:33-07:00

OBJECTIVE

Connective tissue growth factor (CTGF), also known as CCN2, is a potent chemotactic and extracellular matrix-inducing matricellular protein that has been implicated in progression of inflammatory and fibroproliferative disorders. An emerging role of CTGF/CCN2 is that of a prosclerotic factor implicated in the development of cardiac disease. Our objective was to determine the role of CTGF/CCN2 as a predictor of cardiovascular events in type 2 diabetes in the Veterans Affairs Diabetes Trial (VADT) cohort.

RESEARCH DESIGN AND METHODS

Levels of CTGF/CCN2 were measured in 952 VADT patients a median of 1.9 years after entry into the study. Participants were followed for an average of 3.3 years for vascular outcomes. CTGF/CCN2 categories were defined as below the detectable limit (referent, 54.5%), lower half of detectable values (22.8%), and upper half of detectable values (22.7%). Hazard ratios (HRs) for cardiovascular end points in relation to CTGF/CCN2 categories were calculated by Cox proportional hazards models.

RESULTS

During follow-up, 4.8% had a myocardial infarction (MI), 6.9% had an MI or cardiovascular death, and 6.9% died. After adjustments by conventional risk factors, individuals in the highest category of CTGF/CCN2 were at higher risk of MI (HR 2.43 [95% CI 1.15, 5.14]), MI or cardiovascular death (HR 2.71 [95% CI 1.44, 5.08]), and all-cause mortality (HR 2.70 [95% CI 1.43, 5.08]) relative to individuals with CTGF below the detectable limit.

CONCLUSIONS

Our study indicates that high levels of CTGF/CCN2 predict future MI and cardiovascular death in patients with type 2 diabetes.




Prognostic Value of the Acute-to-Chronic Glycemic Ratio at Admission in Acute Myocardial Infarction: A Prospective Study

2018-03-20T12:04:33-07:00

OBJECTIVE

Acute hyperglycemia is a powerful predictor of poor prognosis in acute myocardial infarction (AMI), particularly in patients without diabetes. This emphasizes the importance of an acute glycemic rise rather than glycemia level at admission alone. We investigated in AMI whether the combined evaluation of acute and chronic glycemic levels, as compared with admission glycemia alone, may have a better prognostic value.

RESEARCH DESIGN AND METHODS

We prospectively measured admission glycemia and estimated average chronic glucose levels (mg/dL) by the following formula: [(28.7 x glycosylated hemoglobin %) – 46.7], and calculated the acute-to-chronic (A/C) glycemic ratio in 1,553 consecutive AMI patients (mean ± SD age 67 ± 13 years). The primary end point was the combination of in-hospital mortality, acute pulmonary edema, and cardiogenic shock.

RESULTS

The primary end point rate increased in parallel with A/C glycemic ratio tertiles (5%, 8%, and 20%, respectively; P for trend <0.0001). A parallel increase was observed in troponin I peak value (15 ± 34 ng/mL, 34 ± 66 ng/mL, and 68 ± 131 ng/mL; P < 0.0001). At multivariable analysis, A/C glycemic ratio remained an independent predictor of the primary end point and of troponin I peak value, even after adjustment for major confounders. At reclassification analyses, A/C glycemic ratio showed the best prognostic power in predicting the primary end point as compared with glycemia at admission in the entire population (net reclassification improvement 12% [95% CI 4–20]; P = 0.003) and, particularly, in patients with diabetes (27% [95% CI 14–40]; P < 0.0001).

CONCLUSIONS

In AMI patients with diabetes, A/C glycemic ratio is a better predictor of in-hospital morbidity and mortality than glycemia at admission.




Diagnosis and Significance of Pulmonary Microvascular Disease in Diabetes

2018-03-20T12:04:33-07:00

OBJECTIVE

To determine whether pulmonary microvascular disease is detectable in subjects with diabetes and associated with diminished exercise capacity using a novel echocardiographic marker quantifying the pulmonary transit of agitated contrast bubbles (PTAC).

RESEARCH DESIGN AND METHODS

Sixty participants (40 with diabetes and 20 control subjects) performed cardiopulmonary (maximal oxygen consumption [VO2peak]) and semisupine bicycle echocardiography exercise tests within a 1-week period. Pulmonary microvascular disease was assessed using PTAC (the number of bubbles traversing the pulmonary circulation to reach the left ventricle, categorized as low PTAC or high PTAC). Echocardiographic measures of cardiac output, pulmonary artery pressures, and biventricular function were obtained during exercise.

RESULTS

Subjects with diabetes and control subjects were of similar age (44 ± 13 vs. 43 ± 13 years, P = 0.87) and sex composition (70% vs. 65% male, P = 0.7). At peak exercise, low PTAC was present in more participants with diabetes than control subjects (41% vs. 12.5%, 2 P = 0.041) and, in particular, in more subjects with diabetes with microvascular complications compared with both those without complications and control subjects (55% vs. 26% vs. 13%, 2 P = 0.02). When compared with high PTAC, low PTAC was associated with a 24% lower VO2peak (P = 0.006), reduced right ventricular function (P = 0.015), and greater pulmonary artery pressures during exercise (P = 0.02).

CONCLUSIONS

PTAC is reduced in diabetes, particularly in the presence of microvascular pathology in other vascular beds, suggesting that it may be a meaningful indicator of pulmonary microvascular disease with important consequences for cardiovascular function and exercise capacity.




Low-grade Inflammatory Marker Profile May Help to Differentiate Patients With LADA, Classic Adult-Onset Type 1 Diabetes, and Type 2 Diabetes

2018-03-20T12:04:33-07:00

OBJECTIVE

To test whether differences in serum concentrations of adiposity-related low-grade inflammatory mediators could help to differentiate patients with latent autoimmune diabetes in adults (LADA), classic adult-onset type 1 diabetes, and type 2 diabetes.

RESEARCH DESIGN AND METHODS

This cross-sectional study involved 75 patients with LADA, 67 with classic adult-onset type 1 diabetes, and 390 with type 2 diabetes. Serum concentrations of adiponectin, soluble tumor necrosis factor-α receptor 2 (sTNFRII), interleukin-6, hs-CRP, and total leukocyte number were measured. To evaluate the differences of these markers among diabetes types, we performed logistic regression models and evaluated area under the receiver-operating characteristic curve (AUCROC) values.

RESULTS

The profile of innate immunity-related inflammatory markers correlated with metabolic syndrome components. LADA versus classic adult-onset type 1 diabetes was independently related to sTNFRII (odds ratio [OR] 1.9 [95% CI 1.01–3.97]; P = 0.047) and hs-CRP levels (OR 0.78 [95% CI 0.62–0.96]; P = 0.019), and a higher number of total leukocytes lowered the risk of LADA compared with type 2 diabetes (OR 0.98 [95% CI 0.97–0.99]; P = 0.036). The logistic regression model including explanatory biomarkers explained 35% of the variation for LADA versus classic adult-onset type 1 diabetes (AUCROC 0.83 [95% CI 0.74–0.92]; P < 0.001) and 15% of the variation for LADA versus type 2 diabetes (AUCROC 0.73 [95% CI 0.70–0.80]; P < 0.001).

CONCLUSIONS

Inflammatory, adiposity, and immune-related markers could help to differentiate a LADA diagnosis from that of classic adult-onset type 1 diabetes, and also LADA from that of type 2 diabetes, along with islet autoantibody positivity.




Disordered Eating Behaviors Are Not Increased by an Intervention to Improve Diet Quality but Are Associated With Poorer Glycemic Control Among Youth With Type 1 Diabetes

2018-03-20T12:04:33-07:00

OBJECTIVE

This study examines whether participation in an 18-month behavioral intervention shown previously to improve overall diet quality inadvertently increases disordered eating behaviors (DEBs) in youth with type 1 diabetes and investigates the association of DEB with multiple measures of glycemic control and variability.

RESEARCH DESIGN AND METHODS

Participants reported DEB and diabetes management at baseline and 6, 12, and 18 months; masked continuous glucose monitoring, HbA1c, and 1,5-anhydroglucitol (1,5-AG) were obtained concurrently. Linear mixed models estimated the intervention effect on DEB, the association of DEB with diabetes adherence and measures of glycemic control and variability, and whether DEB modified glycemic trajectories.

RESULTS

There was no intervention effect on DEB (P = 0.84). DEB was associated with higher HbA1c (P = 0.001), mean sensor glucose (P = 0.001), and percent sensor glucose values >180 mg/dL (P = <0.001); with lower 1,5-AG (P = 0.01); and with worse diabetes adherence (P = 0.03). DEB was not associated with percent sensor glucose values <70 mg/dL or any measures of glycemic variability. There was a significant DEB x time interaction effect for mean sensor glucose (P = 0.05) and percent sensor glucose values >180 mg/dL (P = 0.04). Participants reporting less DEB had a developmentally expected deterioration in glycemic control throughout the study. Participants reporting more DEB had poor glycemic control at baseline that remained poor throughout the study.

CONCLUSIONS

Findings show a potential to improve diet quality without increasing DEB and indicate an association of DEB with persistent hyperglycemia but not hypoglycemia or glycemic variability.




Characteristics and Prognosis in Women and Men With Type 1 Diabetes Undergoing Coronary Angiography: A Nationwide Registry Report

2018-03-20T12:04:33-07:00

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, one-vessel disease, two-vessel disease, three-vessel disease, and left main stem 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 hazard ratio 1.03 [95% CI 0.88–1.20]; P = 0.754). The standard mortality ratio for women the first year was 7.49 (5.73–9.62) and for men was 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.




Elevated Serum Xanthine Oxidase Activity Is Associated With the Development of Type 2 Diabetes: A Prospective Cohort Study

2018-03-20T12:04:34-07:00

OBJECTIVE

We aimed to evaluate whether xanthine oxidase (XO), a key enzyme in uric acid (UA) metabolism and a major source of reactive oxygen species, plays a causal and important role in the development of type 2 diabetes mellitus (T2DM) in a large prospective cohort study.

RESEARCH DESIGN AND METHODS

A total of 4,412 diabetes-free adults (2,071 women and 2,341 men) aged 30–65 years at baseline in 2008 were involved. Participants were followed for incident change of glucose metabolism during an average of 4.7 years. At baseline, serum XO and UA, serum lipids, and glucose homeostasis indexes including fasting blood glucose (FBG), 2-h blood glucose (PBG), glycosylated hemoglobin A1c (HbA1c), and fasting insulin were tested for analysis.

RESULTS

During an average follow-up period of 4.7 years, 249 women and 360 men developed new-onset T2DM. Serum XO activity was positively associated with UA concentration (all P values <0.001). When XO activity and UA concentration were considered in the same model of the sex-specific analysis, only XO activity was significantly associated with the incidence of T2DM, with the hazard ratios from the bottom to the top quartile of XO activity being 1.00, 1.67 (95% CI 1.00–2.79), 1.86 (1.11–3.13), and 2.36 (1.43–3.90) in women and 1.00, 1.01 (0.68–1.52), 1.41 (0.98–2.03), and 1.90 (1.30–2.78) in men.

CONCLUSIONS

Elevated serum XO activity, but not UA concentration, was associated with an increased risk of developing T2DM in women and men with mutual adjustment for XO and UA. Further studies are needed to examine the underlying mechanisms.




Limb- and Person-Level Risk Factors for Lower-Limb Amputation in the Prospective Seattle Diabetic Foot Study

2018-03-20T12:04:34-07:00

OBJECTIVE

Diabetes is the leading cause of nontraumatic lower-limb amputations in the U.S., but no research has prospectively examined associations between limb-specific measurements and amputation risk among patients without foot ulcer. We investigated amputation risk by limb in relation to the same limb- and person-level factors.

RESEARCH DESIGN AND METHODS

We conducted a 22-year prospective study among 1,461 male patients with diabetes without foot ulcer (mean age 62.4 years), with 2,893 lower limbs among subjects recruited between 1990 and 2002 from one Department of Veterans Affairs general internal medicine clinic. The following information was collected: demographic, lifestyle, and diabetes characteristics; visual acuity; kidney function (estimated glomerular filtration rate [eGFR]); and lower-limb measurements including presence of Charcot deformity, sensory neuropathy by 10-g monofilament, dorsal foot transcutaneous oximetry (TcPO2) at 44°C, and ankle-brachial index (ABI).

RESULTS

Over 25,735 limb-years, 136 amputations occurred. A multivariable Cox model identified multiple independent risk factors: sensory neuropathy (hazard ratio 3.09 [95% CI 2.02–4.74]), ABI ≤0.5 vs. >0.9 to <1.3 (3.98 [2.31–6.85]), ABI ≥1.3 vs. >0.9 to <1.3 (2.20 [1.18–4.09]), 1-SD decrease in eGFR (1.18 [1.00–1.38]), poor vision (1.70 [1.05–2.73]), body weight in 21.4-kg increments (0.78 [0.61–0.98]), and age >70 years vs. <57 years (0.13 [0.04–0.38]). Although TcPO2 was not significantly associated with amputation overall, TcPO2 <26 mmHg significantly predicted a higher risk in the ABI ≥1.3 category.

CONCLUSIONS

Arterial disease and neuropathy emerged as the only limb-specific risk factors for amputation, but these and several person-level factors may be amenable to prevention or treatment interventions to potentially reduce diabetic amputation risk.




Risk of Cardiovascular Disease and Death in Individuals With Prediabetes Defined by Different Criteria: The Whitehall II Study

2018-03-20T12:04:34-07:00

OBJECTIVE

We compared the risk of cardiovascular disease (CVD) and all-cause mortality in subgroups of prediabetes defined by fasting plasma glucose (FPG), 2-h plasma glucose (2hPG), or HbA1c.

RESEARCH DESIGN AND METHODS

In the Whitehall II cohort, 5,427 participants aged 50–79 years and without diabetes were followed for a median of 11.5 years. A total of 628 (11.6%) had prediabetes by the World Health Organization (WHO)/International Expert Committee (IEC) criteria (FPG 6.1–6.9 mmol/L and/or HbA1c 6.0–6.4%), and 1,996 (36.8%) by the American Diabetes Association (ADA) criteria (FPG 5.6–6.9 mmol/L and/or HbA1c 5.7–6.4%). In a subset of 4,730 individuals with additional measures of 2hPG, 663 (14.0%) had prediabetes by 2hPG. Incidence rates of a major event (nonfatal/fatal CVD or all-cause mortality) were compared for different definitions of prediabetes, with adjustment for relevant confounders.

RESULTS

Compared with that for normoglycemia, incidence rate in the context of prediabetes was 54% higher with the WHO/IEC definition and 37% higher with the ADA definition (P < 0.001) but declining to 17% and 12% after confounder adjustment (P ≥ 0.111). Prediabetes by HbA1c was associated with a doubling in incidence rate for both the IEC and ADA criteria. However, upon adjustment, excess risk was reduced to 13% and 17% (P ≥ 0.055), respectively. Prediabetes by FPG or 2hPG was not associated with an excess risk in the adjusted analysis.

CONCLUSIONS

Prediabetes defined by HbA1c was associated with a worse prognosis than prediabetes defined by FPG or 2hPG. However, the excess risk among individuals with prediabetes is mainly explained by the clustering of other cardiometabolic risk factors associated with hyperglycemia.




Objectively Measured Physical Activity and Sedentary Time Are Associated With Cardiometabolic Risk Factors in Adults With Prediabetes: The PREVIEW Study

2018-02-20T12:00:41-08:00

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

2018-02-20T12:00:41-08:00

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

2018-02-20T12:00:41-08:00

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.

2018-02-20T12:00:41-08:00

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

2018-02-20T12:00:41-08:00

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

2018-02-20T12:00:41-08:00

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

2018-02-20T12:00:41-08:00

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%.




Efficacy and Safety of ITCA 650, a Novel Drug-Device GLP-1 Receptor Agonist, in Type 2 Diabetes Uncontrolled With Oral Antidiabetes Drugs: The FREEDOM-1 Trial

2018-01-22T12:00:29-08:00

OBJECTIVE

ITCA 650 (exenatide in osmotic mini-pump) continuously delivers exenatide subcutaneously for 3–6 months. Two doses of ITCA 650 were compared with placebo in patients with uncontrolled type 2 diabetes.

RESEARCH DESIGN AND METHODS

This 39-week, phase 3, double-blind, placebo-controlled trial randomized 460 patients aged 18–80 years with glycated hemoglobin (HbA1c) 7.5–10% [58–86 mmol/mol] 1:1:1 to placebo, ITCA 650 40 μg/day, or ITCA 650 60 μg/day. Primary end point was change in HbA1c at 39 weeks.

RESULTS

Least squares (LS) mean change from baseline HbA1c was –1.1% [–12.2 mmol/mol] and –1.2% [–13.2 mmol/mol] for ITCA 650 40 and 60 μg/day, respectively (P < 0.001 vs. placebo –0.1% [–1.3 mmol/mol]). In a prespecified analysis, greater HbA1c reductions occurred in patients not receiving sulfonylureas (SUs) versus those receiving SUs (–1.7% vs. –1.2% [–18.6 and –13.1 mmol/mol]). At week 39, HbA1c <7% [53 mmol/mol] was attained in 37%, 44%, and 9% of ITCA 650 40 μg/day, ITCA 650 60 μg/day, and placebo groups, respectively (P < 0.001 each dose vs. placebo). LS mean change from baseline body weight was –2.3 kg and –3.0 kg for ITCA 650 40 and 60 μg/day, respectively (P ≤ 0.015 vs. placebo –1.0 kg). Nausea was the most common adverse event (AE) and subsided over time. Discontinuation for gastrointestinal AEs occurred in 7.2% with ITCA and 1.3% with placebo. Most AEs associated with procedures to place and remove ITCA 650 were mild and transient.

CONCLUSIONS

ITCA 650 significantly reduced HbA1c and weight compared with placebo and was well tolerated in patients with uncontrolled type 2 diabetes on oral antidiabetes medications.




Cardiovascular Disease, Cancer, and Mortality Among People With Type 2 Diabetes and Alcoholic or Nonalcoholic Fatty Liver Disease Hospital Admission

2018-01-22T12:00:29-08:00

OBJECTIVE

To describe associations between alcoholic liver disease (ALD) or nonalcoholic fatty liver disease (NAFLD) hospital admission and cardiovascular disease (CVD), cancer, and mortality in people with type 2 diabetes mellitus (T2DM).

RESEARCH DESIGN AND METHODS

We performed a retrospective cohort study by using linked population-based routine data from diabetes registry, hospital, cancer, and death records for people aged 40–89 years diagnosed with T2DM in Scotland between 2004 and 2013 who had one or more hospital admission records. Liver disease and outcomes were identified by using ICD-9 and ICD-10 codes. We estimated hazard ratios (HRs) from Cox proportional hazards regression models, adjusting for key risk factors.

RESULTS

A total of 134,368 people with T2DM (1,707 with ALD and 1,452 with NAFLD) were studied, with a mean follow-up of 4.3 years for CVD and 4.7 years for mortality. Among those with ALD, NAFLD, or without liver disease hospital records 378, 320, and 21,873 CVD events; 268, 176, and 15,101 cancers; and 724, 221, and 16,203 deaths were reported, respectively. For ALD and NAFLD, respectively, adjusted HRs (95% CIs) compared with the group with no record of liver disease were 1.59 (1.43, 1.76) and 1.70 (1.52, 1.90) for CVD, 40.3 (28.8, 56.5) and 19.12 (11.71, 31.2) for hepatocellular carcinoma (HCC), 1.28 (1.12, 1.47) and 1.10 (0.94, 1.29) for non-HCC cancer, and 4.86 (4.50, 5.24) and 1.60 (1.40, 1.83) for all-cause mortality.

CONCLUSIONS

Hospital records of ALD or NAFLD are associated to varying degrees with an increased risk of CVD, cancer, and mortality among people with T2DM.




Modulation of GLP-1 Levels by a Genetic Variant That Regulates the Cardiovascular Effects of Intensive Glycemic Control in ACCORD

2018-01-22T12:00:29-08:00

OBJECTIVE

A genome-wide association study in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial identified two markers (rs57922 and rs9299870) that were significantly associated with cardiovascular mortality during intensive glycemic control and could potentially be used, when combined into a genetic risk score (GRS), to identify patients with diabetes likely to derive benefit from intensive control rather than harm. The aim of this study was to gain insights into the pathways involved in the modulatory effect of these variants.

RESEARCH DESIGN AND METHODS

Fasting levels of 65 biomarkers were measured at baseline and at 12 months of follow-up in the ACCORD-Memory in Diabetes (ACCORD-MIND) MRI substudy (n = 562). Using linear regression models, we tested the association of the GRS with baseline and 12-month biomarker levels, and with their difference (), among white subjects, with genotype data (n = 351) stratified by intervention arm.

RESULTS

A significant association was observed between GRS and GLP-1 (glucagon-like peptide 1, active) in the intensive arm (P = 3 x 10–4). This effect was driven by rs57922 (P = 5 x 10–4). C/C homozygotes, who had been found to derive cardiovascular benefits from intensive treatment, showed a 22% increase in GLP-1 levels during follow-up. By contrast, T/T homozygotes, who had been found to experience increased cardiac mortality with intensive treatment, showed a 28% reduction in GLP-1 levels. No association between GLP-1 and GRS or rs57922 was observed in the standard treatment arm.

CONCLUSIONS

Differences in GLP-1 axis activation may mediate the modulatory effect of variant rs57922 on the cardiovascular response to intensive glycemic control. These findings highlight the importance of GLP-1 as a cardioprotective factor.




How Does Empagliflozin Reduce Cardiovascular Mortality? Insights From a Mediation Analysis of the EMPA-REG OUTCOME Trial

2018-01-22T12:00:29-08:00

OBJECTIVE

In the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial involving 7,020 patients with type 2 diabetes and established cardiovascular (CV) disease, empagliflozin given in addition to standard of care reduced the risk of CV death by 38% versus placebo (hazard ratio [HR] 0.62 [95% CI 0.49, 0.77]). This exploratory mediation analysis assesses the extent to which treatment group differences in covariates during the trial contributed to CV death risk reduction with empagliflozin.

RESEARCH DESIGN AND METHODS

Effects of potential mediators, identified post hoc, on the HR for CV death with empagliflozin versus placebo were analyzed by Cox regression models, with treatment group adjusted for the baseline value of the variable and its change from baseline or updated mean (i.e., considering all prior values), each as a time-dependent covariate. HRs were compared with a model without adjustment for covariates. Multivariable analyses also were performed.

RESULTS

Changes in hematocrit and hemoglobin mediated 51.8% and 48.9%, respectively, of the effect of empagliflozin versus placebo on the risk of CV death on the basis of changes from baseline, with similar results in analyses on the basis of updated means. Smaller mediation effects (maximum 29.3%) were observed for uric acid, fasting plasma glucose, and HbA1c. In multivariable models, which incorporated effects of empagliflozin on hematocrit, fasting glucose, uric acid, and urine albumin:creatinine ratio, the combined changes from baseline provided 85.2% mediation, whereas updated mean analyses provided 94.6% mediation of the effect of empagliflozin on CV death.

CONCLUSIONS

In this exploratory analysis from the EMPA-REG OUTCOME trial, changes in markers of plasma volume were the most important mediators of the reduction in risk of CV death with empagliflozin versus placebo.