Association of low fasting C-peptide levels with cardiovascular risk, visit-to-visit glucose variation and severe hypoglycemia in the Veterans Affairs Diabetes Trial (VADT).

AIMS: Low C-peptide levels, indicating beta-cell dysfunction, are associated with increased within-day glucose variation and hypoglycemia. In advanced type 2 diabetes, severe hypoglycemia and increased glucose variation predict cardiovascular (CVD) risk. The present study examined the association between C-peptide levels and CVD risk and whether it can be explained by visit-to-visit glucose variation and severe hypoglycemia. MATERIALS AND METHODS: Fasting C-peptide levels at baseline, composite CVD outcome, severe hypoglycemia, and visit-to-visit fasting glucose coefficient of variation (CV) and average real variability (ARV) were assessed in 1565 Veterans Affairs Diabetes Trial participants. RESULTS: There was a U-shaped relationship between C-peptide and CVD risk with increased risk with declining levels in the low range (< 0.50 nmol/l, HR 1.30 [95%CI 1.05-1.60], p = 0.02) and with rising levels in the high range (> 1.23 nmol/l, 1.27 [1.00-1.63], p = 0.05). C-peptide levels were inversely associated with the risk of severe hypoglycemia (OR 0.68 [0.60-0.77]) and visit-to-visit glucose variation (CV, standardized beta-estimate - 0.12 [SE 0.01]; ARV, - 0.10 [0.01]) (p < 0.0001 all). The association of low C-peptide levels with CVD risk was independent of cardiometabolic risk factors (1.48 [1.17-1.87, p = 0.001) and remained associated with CVD when tested in the same model with severe hypoglycemia and glucose CV. CONCLUSIONS: Low C-peptide levels were associated with increased CVD risk in advanced type 2 diabetes. The association was independent of increases in glucose variation or severe hypoglycemia. C-peptide levels may predict future glucose control patterns and CVD risk, and identify phenotypes influencing clinical decision making in advanced type 2 diabetes.

New Insights into the Role of Visit-to-Visit Glycemic Variability and Blood Pressure Variability in Cardiovascular Disease Risk.

PURPOSE OF REVIEW: There is evidence from epidemiologic studies that variability in cardiovascular risk factors influences risk of cardiovascular disease. We review new studies and novel findings in the relationship between visit-to-visit glycemic variability and blood pressure variability and risk of adverse outcomes. RECENT FINDINGS: Visit-to-visit glycemic variability is consistently linked to macrovascular disease. This relationship has been observed in both clinical trials and retrospective studies of electronic health records. Long-term blood pressure variability also predicts cardiovascular outcomes, and the association appears stronger in those with lower levels of systolic and diastolic function. As epidemiologic evidence increases in support of a role for metabolic risk factor variability in cardiovascular risk, there is a corresponding rise in interest in applying this information toward improving risk factor prediction and treatment. Future investigation of underlying mechanisms for these associations as well as implications for therapy is also warranted. The potential additive contribution of variability of multiple parameters also merits additional scrutiny. As our technology for capturing risk factor variability continues to improve, this will only enhance our understanding of its links with vascular disease and how to best utilize this information to reduce cardiovascular outcomes.

Medication use and multiple myeloma risk in Los Angeles County.

BACKGROUND: The role of medication use in multiple myeloma (MM) risk remains unclear. METHODS: The Los Angeles County Multiple Myeloma Case-Control Study, comprising 278 MM cases and individually matched neighborhood controls, provided data to assess associations between medication use and MM risk. Odds ratios (OR) and 95 % confidence intervals (CI) were estimated using conditional logistic regression. RESULTS: Erythromycin (ever) use was associated with increased MM risk (OR 1.85, 95 % CI 1.13-3.03). This association was restricted to men (OR 3.77, 95 % CI 1.72-8.29) and was especially apparent among men who took two or more courses of erythromycin (OR 4.68, 95 % CI 1.70-12.87). CONCLUSIONS: Compared to females, males have lower levels of cytochrome P450 3A4 (CYP3A4), for which erythromycin is both a substrate and inhibitor. Use of CYP3A4-inhibiting drugs such as erythromycin in men may thus result in even lower levels of CYP3A4 and, consequently, higher levels of CYP3A4-metabolized substances. These results could potentially provide clues to explain discrepancies in MM incidence by sex. Consortial efforts to confirm these associations are warranted.

Refining determinants of associations of visit-to-visit blood pressure variability with cardiovascular risk: results from the Action to Control Cardiovascular Risk in Diabetes Trial.

OBJECTIVES: As there is uncertainty about the extent to which baseline blood pressure level or cardiovascular risk modifies the relationship between blood pressure variability (BPv) and cardiovascular disease, we comprehensively examined the role of BPv in cardiovascular disease risk in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial. METHODS: Using data from ACCORD, we examined the relationship of BPv with development of the primary CVD outcome, major coronary heart disease (CHD), and total stroke using time-dependent Cox proportional hazards models. RESULTS: BPv was associated with the primary CVD outcome and major CHD but not stroke. The positive association with the primary CVD outcome and major CHD was more pronounced in low and high strata of baseline SBP (<120 and >140 mmHg) and DBP (<70 and >80 mmHg). The effect of BPv on CVD and CHD was more pronounced in those with both prior CVD history and low blood pressure. Dips, not elevations, in blood pressure appeared to drive these associations. The relationships were generally not attenuated by adjustment for mean blood pressure, medication adherence, or baseline comorbidities. A sensitivity analysis using CVD events from the long-term posttrial follow-up (ACCORDION) was consistent with the results from ACCORD. CONCLUSION: In ACCORD, the effect of BPv on adverse cardiovascular (but not cerebrovascular) outcomes is modified by baseline blood pressure and prior CVD. Recognizing these more nuanced relationships may help improve risk stratification and blood pressure management decisions as well as provide insight into potential underlying mechanisms.

Blood Pressure Variability and Risk of Heart Failure in ACCORD and the VADT.

OBJECTIVE: Although blood pressure variability is increasingly appreciated as a risk factor for cardiovascular disease, its relationship with heart failure (HF) is less clear. We examined the relationship between blood pressure variability and risk of HF in two cohorts of type 2 diabetes participating in trials of glucose and/or other risk factor management. RESEARCH DESIGN AND METHODS: Data were drawn from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and the Veterans Affairs Diabetes Trial (VADT). Coefficient of variation (CV) and average real variability (ARV) were calculated for systolic (SBP) and diastolic blood pressure (DBP) along with maximum and cumulative mean SBP and DBP during both trials. RESULTS: In ACCORD, CV and ARV of SBP and DBP were associated with increased risk of HF, even after adjusting for other risk factors and mean blood pressure (e.g., CV-SBP: hazard ratio [HR] 1.15, P = 0.01; CV-DBP: HR 1.18, P = 0.003). In the VADT, DBP variability was associated with increased risk of HF (ARV-DBP: HR 1.16, P = 0.001; CV-DBP: HR 1.09, P = 0.04). Further, in ACCORD, those with progressively lower baseline blood pressure demonstrated a stepwise increase in risk of HF with higher CV-SBP, ARV-SBP, and CV-DBP. Effects of blood pressure variability were related to dips, not elevations, in blood pressure. CONCLUSIONS: Blood pressure variability is associated with HF risk in individuals with type 2 diabetes, possibly a consequence of periods of ischemia during diastole. These results may have implications for optimizing blood pressure treatment strategies in those with type 2 diabetes.

Associations of sleep duration with cardiometabolic outcomes in American Indians and Alaska Natives and other race/ethnicities: results from the BRFSS.

OBJECTIVES: This study assessed the associations between short and long sleep duration and prevalence of cardiometabolic outcomes in American Indians and Alaska Natives (AI/ANs) and compared these associations to those evident among other race/ethnicities. METHODS: We analyzed data from the 2013-2014 Behavioral Risk Factor Surveillance System. In total, 14,536 AI/ANs, 729,962 non-Hispanic whites, 71,765 blacks, and 59,472 Hispanics were included. Logistic regressions were conducted to compute unadjusted and adjusted odds ratios (OR) for the associations of interest. RESULTS: Among AI/ANs, 38.6% reported sleeping <7 hours per night (short sleepers) while 39.3% reported 8+ hours of sleep (long sleepers). After adjusting for age and gender, both short and long sleep durations were associated with higher odds of reporting diabetes, stroke, coronary heart disease and heart attack in almost all race/ethnic groups. After multiple adjustments, the sleep-diabetes association was more pronounced (OR = 1.71 and OR = 1.56 for short and long sleepers, respectively) among AI/ANs than other race/ethnicities. CONCLUSIONS: Future studies are warranted to examine race/ethnic variability in the association between sleep duration and cardiometabolic outcomes.

Sleep Duration and Diabetes Risk in American Indian and Alaska Native Participants of a Lifestyle Intervention Project.

STUDY OBJECTIVES: We examine the association between self-reported sleep duration and diabetes incidence in a national sample of American Indians/ Alaska Natives (AI/ANs) with prediabetes. METHODS: Data were derived from the Special Diabetes Program for Indians Diabetes Prevention demonstration project. This longitudinal analysis included 1,899 participants with prediabetes recruited between January 1, 2006 and July 31, 2009 who reported sleep duration and completed all 16 classes of the lifestyle intervention consisting of diet, exercise, and behavior modification sessions to promote weight loss. Three years of follow-up data were included to fit Cox regression models to compute hazard ratios (HRs) for diabetes incidence across sleep duration categories. RESULTS: The crude diabetes incidence rate was 4.6 per 100 person-years among short sleepers (≤ 6 h per night) compared to 3.2 among those sleeping 7 h and 3.3 among those sleeping 8 h or more. After adjustment for age and sex, short sleep (≤ 6 h vs. others) was associated with increased diabetes risk (HR 1.55 [95% confidence interval 1.11-2.17]); risk remained significantly elevated after controlling for socioeconomic characteristics, health behaviors, and health status. When adjusting for body mass index and percent weight loss, the short sleep-diabetes relationship was attenuated (HR 1.32 [95% confidence interval 0.92-1.89]). No significant long sleep-diabetes association was found. Further, short sleepers lost significantly less weight than others (3.7% vs. 4.3%, P = 0.003). CONCLUSIONS: Short sleep duration, but not long duration, was significantly associated with increased diabetes risk and less weight loss among AI/ANs in a lifestyle intervention. Further exploration of the complex factors underlying short sleep duration is warranted.