Reducing Cardiovascular Disease-An Alternative Approach.

PURPOSE: Statin drugs are effective at reducing cardiovascular events, but adherence to statin therapy remains a problem for patients and their physicians. We review a paper estimating the economic costs of poor adherence to statin drugs. METHODS: The authors examined two large databases (Medicare and Market Scan databases) including 230,000 patients with hospitalization for myocardial infarction between 2018 and 2019 to determine how many patients were not adhering to guideline-recommended anti-hyperlipidemic medications. They have also calculated the potential consequences of patients who are not adhering to the recommended therapy. RESULTS: The authors estimate that if all patients were receiving guideline-directed medical therapy, then a 22% relative risk reduction would occur in the 3-year period following discharge from the initial cardiovascular event. These findings are consistent with prior reports. This editorial discusses rationale and strategies clinicians can use to improve patients' compliance with recommendations for lipid-lowering therapy. CONCLUSION: The authors conclude that better compliance with guideline-directed lipid therapy after a cardiovascular event would lead to a large reduction in second events. Increased efforts by clinicians to improve adherence to statin therapy are warranted.

Potential for repurposing oral hypertension/diabetes drugs to decrease asthma risk in obesity.

OBJECTIVE: Risk for asthma in the overweight/obese may be mediated by adiponectin and peroxisome proliferator activated receptor pathways and may be reduced by the use of oral drugs impacting these pathways, such as angiotensin converting enzyme inhibitors (ACE-I), thiazolidinediones (TZD), and angiotensin receptor blockers (ARB). Our study objective was to determine whether ACE-I, TZD, and/or ARB use in overweight/obese adults with diabetes mellitus and/or hypertension is associated with a lower risk for incident asthma. METHODS: Using an existing cohort of American veterans, we performed a longitudinal data analysis over 15 years. Exposure was defined by the prescription pickup of ACE-I, TZD, and/or ARB for at least 4 weeks. The outcome, time until new-onset of clinician-diagnosed asthma, was studied using survival analysis. The propensity scoring method controlled for treatment selection bias. RESULTS: 2.83 million eligible veterans, including 77,278 with incident asthma, were studied. As compared to those unexposed, the use of ACE-I alone, TZD alone, or their combinations were each associated with decreased risk for incident asthma (hazard ratios of 0.88, 0.74, and 0.20, respectively; p < 0.001 for all analyses in the fully adjusted statistical models). TZD lowered the risk among racial/ethnic minority subjects more than among White participants (p < 0.001). On the other hand, ARB use alone or in combination with TZD was associated with a higher risk for incident asthma. CONCLUSIONS: Use of ACE-I and/or TZD was associated with a lower risk for incident asthma in overweight/obese patients with diabetes mellitus and/or hypertension.

Resolving the Egg and Cholesterol Intake Controversy: New Clinical Insights Into Cholesterol Regulation by the Liver and Intestine.

OBJECTIVE: Cardiovascular disease is the number one cause of death. Achieving American Heart Association low-density lipoprotein (LDL) cholesterol treatment goals is very difficult for many patients. The importance of a low cholesterol diet is controversial and not emphasized by most physicians. Of critical importance is determining whether each individual is a "hyper- or hypo-absorber" of dietary cholesterol. Furthermore, the quantity of each individual's baseline daily dietary cholesterol and saturated fat intake is important in assessing the effect of added egg yolk cholesterol and saturated fat on blood LDL cholesterol. METHODS: Gut cholesterol is absorbed via a specific enteric receptor (the Niemann- Pick-like receptor). Dietary cholesterol contributes one fourth of the absorbed cholesterol, while the remaining gut cholesterol is derived from secreted bile cholesterol. This dietary quantity of cholesterol is significant when other determinants are constant. For some individuals, dietary cholesterol has no adverse effects and in others, a significant elevation in blood LDL cholesterol may occur. RESULTS: There are no readily available blood tests to determine the effect of egg yolk cholesterol and saturated fat on an individual's plasma LDL cholesterol. However, a one month trial of a low cholesterol and saturated fat diet will provide the needed information to make clinical decisions. CONCLUSION: This article delineates the mechanisms that are altered by genetic and environmental factors that determine the net effects of dietary cholesterol and saturated fat on circulating LDL cholesterol. It then makes a practical clinical recommendation based on these mechanisms.

A Pathophysiologic Primary Prevention Review of Aspirin Administration to Prevent Cardiovascular Thrombosis.

OBJECTIVE: Cardiovascular disease is the leading metabolic cause of mortality in the United States. Among current therapies, low-dose aspirin has been shown to reduce cardiovascular thrombosis. However, aspirin also causes major complications (hemorrhagic stroke and gastrointestinal bleeding). The American Heart Association recommends that aspirin only be prescribed for "high-risk" individuals. No guidelines are available as to the duration of aspirin therapy. METHODS: A reasonable approach to aspirin administration is to determine the appropriateness of aspirin therapy based on the pathophysiology of coronary artery thrombosis. It suggests that the coronary artery calcium (CAC) score be used as the basis for determining "high risk." This score was shown to accurately predict future cardiovascular events. The greater the CAC score, the greater the extent of coronary artery atherosclerotic plaque and future cardiovascular risk. RESULTS: A CAC score >400 places an individual at very-high 10-year risk for an atherosclerotic event. Since aggressive medical therapy initiates stabilization of unstable atherosclerotic plaques within 1 month and reversal within 2 years, this treatment significantly reduces the risk of the individual for a cardiovascular event. Thus, most individuals aged <75 years with a CAC score of >400 should receive aspirin therapy for a maximum of 2 years. CONCLUSION: Utilization of a CAC score greatly simplifies the decision of whom to treat with aspirin and for what duration. Importantly, focusing on two factors (hemorrhage and plaque stabilization) is easily understood by both the physician and the patient. ABBREVIATIONS: CAC = coronary artery calcium; CVD = cardiovascular disease; LDL = low-density lipoprotein; OCT = optical coherence tomography.

Cholesterol Review: A Metabolically Important Molecule.

OBJECTIVE: Cholesterol is an important molecule in humans and both its excess and its deficiency cause disease. Most clinicians appreciate its role in stabilizing cellular plasma membranes but are unaware of its myriad other functions. METHODS: This review highlights cholesterol's newly recognized important roles in human physiology and pathophysiology. RESULTS: The basis for cholesterol's ubiquitous presence in eukaryote organisms is its three part structure involving hydrophilic, hydrophobic, and rigid domains. This structure permits cholesterol to regulate multiple cellular processes ranging from membrane fluidity and permeability to gene transcription. Cholesterol not only serves as a molecule of regulation itself, but also forms the backbone of all steroid hormones and vitamin D analogs. Cholesterol is responsible for growth and development throughout life and may be useful as an anticancer facilitator. Because humans have a limited ability to catabolize cholesterol, it readily accumulates in the body when an excess from the diet or a genetic abnormality occurs. This accumulation results in the foremost cause of death and disease (atherosclerosis) in the Western world. Identification of cholesterol's disease-producing capabilities dates back 5,000 years to the Tyrolean iceman and more recently to ancient mummies from many cultures throughout the world. In contrast, a deficiency of cholesterol in the circulation may result in an inability to distribute vitamins K and E to vital organs with serious consequences. CONCLUSION: Understanding the benefits and hazards of cholesterol in the clinical setting will improve the endocrinologist's ability to control diseases associated with this unique molecule. ABBREVIATIONS: CVD = cardiovascular disease; HDL = high-density lipoprotein; LDL = low-density lipoprotein; NPC1L1 = Niemann-Pick C-1-like-1 protein; U.S. = United States; USDA = U.S. Department of Agriculture.

RISK FACTORS FOR HEARING IMPAIRMENT IN TYPE 1 DIABETES.

Objective: Studies have demonstrated that glycated hemoglobin (HbA1c) is a significant predictor of hearing impairment in type 1 diabetes. We identified additional factors associated with hearing impairment in participants with type 1 diabetes from the Diabetes Control and Complications Trial and its observational follow-up, the Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. Methods: A total of 1,150 DCCT/EDIC participants were recruited for the Hearing Study. A medical history, physical measurements, and a self-administered hearing questionnaire were obtained. Audiometry was performed by study-certified personnel and assessed centrally. Logistic regression models assessed the association of risk factors and comorbidities with speech- and high-frequency hearing impairment. Results: Mean age was 55 ± 7 years, duration of diabetes 34 ± 5 years, and DCCT/EDIC HbA1c 7.9 ± 0.9% (63 mmol/mol). In multivariable models, higher odds of speech-frequency impairment were significantly associated with older age, higher HbA1c, history of noise exposure, male sex, and higher triglycerides. Higher odds of high-frequency impairment were associated with older age, male sex, history of noise exposure, higher skin intrinsic florescence (SIF) as a marker of tissue glycation, higher HbA1c, nonprofessional/nontechnical occupations, sedentary activity, and lower low-density-lipoprotein cholesterol. Among participants who previously completed computed tomography and carotid ultrasonography, coronary artery calcification (CAC) >0 and carotid intima-medial thickness were significantly associated with high-but not speech-frequency impairment. Conclusion: Consistent with previous reports, male sex, age, several metabolic factors, and noise exposure are independently associated with hearing impairment. The association with SIF further emphasizes the importance of glycemia-as a modifiable risk factor-over time. In addition, the macrovascular contribution of CAC is novel and important. Abbreviations: AER = albumin excretion rate; CAC = coronary artery calcification; CVD = cardiovascular disease; DCCT/EDIC = Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications; eGFR = estimated glomerular filtration rate; ETDRS = Early Treatment Diabetic Retinopathy Study; HbA1c = glycated hemoglobin; HDL = high-density lipoprotein; IMT = intima-media thickness; LDL = low-density lipoprotein; NHANES = National Health and Nutrition Examination Survey; OR = odds ratio; SIF = skin intrinsic fluorescence; T1D = type 1 diabetes.

Apolipoprotein-defined lipoprotein subclasses, serum apolipoproteins, and carotid intima-media thickness in T1D.

Circulating apolipoprotein-defined lipoprotein subclasses (ADLS) and apolipoproteins predict vascular events in the general and type 2 diabetes populations, but data in T1D are limited. We examined associations of ADLS, serum apolipoproteins, and conventional lipids with carotid intima-media thickness (IMT) measured contemporaneously and 6 years later in 417 T1D participants [men: n = 269, age 42 ± 6 y (mean ± SD); women: n = 148, age 39 ± 8 y] in the Epidemiology of Diabetes Interventions and Complications study, the follow-up of the Diabetes Control and Complications Trial (DCCT). Date were analyzed by multiple linear regression stratified by sex, and adjusted for time-averaged hemoglobin A1C, diabetes duration, hypertension, BMI, albuminuria, DCCT randomization, smoking, statin treatment, and ultrasound devices. In cross-sectional analyses, lipoprotein B (Lp-B), Lp-B:C, Lp-B:E+Lp-B:C:E, Apo-A-II, Apo-B, Apo-C-III-HP (heparin precipitate; i.e., Apo-C-III in Apo-B-containing lipoproteins), and Apo-E were positively associated with common and/or internal carotid IMT in men, but only Apo-C-III (total) was (positively) associated with internal carotid IMT in women. In prospective analyses, Lp-B, Apo-B, and Apo-C-III-HP were positively associated with common and/or internal carotid IMT in men, while Lp-A1:AII and Apo-A1 were inversely associated with internal carotid IMT in women. The only significant prospective association between conventional lipids and IMT was between triacylglycerols and internal carotid IMT in men. ADLS and apolipoprotein concentrations may provide sex-specific biomarkers and suggest mechanisms for IMT in people with T1D.

INSULIN TIMING: A PATIENT-CENTERED APPROACH TO IMPROVE CONTROL IN TYPE 1 DIABETES.

OBJECTIVE: The goal of insulin therapy in type 1 diabetes (T1D) is to reduce hemoglobin A1C (A1C) to ≤7.0% (53 mmol/mol) with minimal hypoglycemia. We investigated the possibility that "insulin timing" would improve A1C without incurring severe hypoglycemia in volunteers with T1D over a 6-month observation period. METHODS: Forty healthy adult volunteers with T1D were randomly assigned for 6 months to either a control group or an insulin timing group. The primary endpoint was the difference in A1C between the two groups. As a secondary endpoint, both groups were further divided to assess the importance of the baseline A1C in determining the response to timing. The insulin timing algorithm altered the time when the meal dose of insulin was injected or infused from 30 minutes before the meal to 15 minutes after the meal, depending upon the premeal blood glucose concentration. RESULTS: An improvement in mean A1C was observed in the timing group compared with no change in the control group, but this improvement did not reach statistical significance (P>.05). In contrast, when the two groups were analyzed according to baseline A1C, the timing volunteers with baseline A1C values in the upper half (separated by the A1C median of 7.45% [57.9 mmol/mol]) of the timing group had a more robust response to timing (decline in A1C) than the upper half of the control group (P<.05). CONCLUSION: Insulin timing is a patient-centered translational approach that is safe and effective in improving A1C in individuals with T1D with an elevated A1C. ABBREVIATIONS: A1C = hemoglobin A1C ANOVA = analysis of variance CGM = continuous glucose monitoring CSII = continuous subcutaneous insulin infusion MDI = multiple daily injection T1D = type 1 diabetes.

Interpreting the Coronary Artery Calcium Score - Critical Information for the Practicing Physician.

Coronary artery calcium scanning is a routine test for assessing the severity of atherosclerosis in asymptomatic individuals. This inexpensive, noninvasive test quantifies the calcium deposition in the 4 principal coronary arteries. Correct interpretation is important to the physician (for recommending therapy) and to the patient (for determining his or her lifetime risk of a cardiovascular event). A score of 0 indicates that a cardiovascular event is extremely unlikely in the next 5 years. In contrast, a score greater than 0 portends a coronary event. The higher the score, the greater the risk. Both the arterial location of the calcium and the number of coronary arteries involved alter the interpretation of the calcium score. At any given age, females have significantly lower scores than males. One-third of individuals with scores greater than 1000 will have a cardiovascular event within 3 years. For all elevated calcium scores, aggressive treatment is warranted, including significant lifestyle changes and medications to reduce low-density lipoprotein cholesterol. Understanding the importance of the coronary artery calcium score will result in improved therapy and patient compliance.

Effect of intensive glycemic therapy on erectile function in men with type 1 diabetes.

PURPOSE: We determined whether intensive glycemic therapy reduces the risk of erectile dysfunction in men with type 1 diabetes enrolled in the Diabetes Control and Complications Trial. MATERIALS AND METHODS: The Diabetes Control and Complications Trial randomized 761 men with type 1 diabetes to intensive or conventional glycemic therapy at 28 sites between 1983 and 1989, of whom 366 had diabetes for 1 to 5 years and no microvascular complications (primary prevention cohort), and 395 had diabetes for 1 to 15 years with nonproliferative retinopathy or microalbuminuria (secondary intervention cohort). Subjects were treated until 1993, and followed in the Epidemiology of Diabetes Interventions and Complications study. In 2003 we conducted an ancillary study using a validated assessment of erectile dysfunction in 571 men (80% participation rate), 291 in the primary cohort and 280 in the secondary cohort. RESULTS: Of the participants 23% reported erectile dysfunction. The prevalence was significantly lower in the intensive vs conventional treatment group in the secondary cohort (12.8% vs 30.8%, p = 0.001) but not in the primary cohort (17% vs 20.3%, p = 0.49). The risk of erectile dysfunction in primary and secondary cohorts was directly associated with mean HbA1c during the Diabetes Control and Complications Trial, and Epidemiology of Diabetes Interventions and Complications combined. Age, peripheral neuropathy and lower urinary tract symptoms were other risk factors. CONCLUSIONS: A period of intensive therapy significantly reduced the prevalence of erectile dysfunction 10 years later among those men in the secondary intervention cohort but not in the primary prevention cohort. Higher HbA1c was significantly associated with risk in both cohorts. These findings provide further support for early implementation of intensive insulin therapy in young men with type 1 diabetes.

A Simplified Approach to Reducing Cardiovascular Risk.

CONTEXT: Cardiovascular disease remains the number one cause of morbidity and mortality in the United States, despite major advances in our understanding of its pathogenesis and prevention. One reason for this continued epidemic is the poor adherence to treatment guidelines by caregivers and the lack of understanding by patients relative to its reversibility with treatment. Current guidelines are complex and often contradictory; there are at least 21 organizations publishing guidelines. OBJECTIVE: This article proposes a simplified approach that is based on the low-density lipoprotein (LDL) hypothesis stating that the lower the LDL cholesterol (LDL-C), the less the cardiovascular disease. This goal focuses on obtaining a plasma LDL-C <50 mg/dL. DESIGN: A positive coronary artery calcium scan in conjunction with an intermediate online cardiovascular risk score will identify individuals with substantial cardiovascular disease risk. With lifestyle improvements (including a low cholesterol diet) and low-dose hypolipemic generic oral medications, this LDL-C concentration is readily achievable in the majority of asymptomatic patients at risk for atherosclerosis. CONCLUSION: Controlling the cardiovascular epidemic will require participation of both the patient and the physician caregiver. By simplifying the therapeutic regimen, patient compliance will increase, and an important reduction in cardiovascular morbidity and mortality will follow.

Hearing Impairment and Type 1 Diabetes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Cohort.

OBJECTIVE: To evaluate the prevalence of hearing impairment in participants with type 1 diabetes enrolled in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study and compare with that of a spousal control group without diabetes. Among participants with type 1 diabetes, to evaluate the association of hearing impairment with prior DCCT therapy and overall glycemia. RESEARCH DESIGN AND METHODS: DCCT/EDIC participants (n = 1,150) and 288 spouses without diabetes were recruited for the DCCT/EDIC Hearing Study. All subjects completed a self-administered questionnaire, medical history, and physical measurements. Audiometry was performed by study-certified personnel; audiograms were assessed centrally. Speech-frequency (pure-tone average [PTA] thresholds at 500, 1,000, 2,000, and 4,000 Hz) and high-frequency impairment (PTA thresholds at 3,000, 4,000, 6,000, and 8,000 Hz) were defined as PTA >25 dB hearing loss. Logistic regression models were adjusted for age and sex. RESULTS: DCCT/EDIC participants and spousal control subjects were similar in age, race, education, smoking, and systolic blood pressure. There were no statistically significant differences between groups in the prevalence or adjusted odds of speech- or high-frequency impairment in either ear. Among participants with type 1 diabetes, for every 10% increase in the time-weighted mean HbA1c, there was a 32% (95% CI 1.15-1.50) and 19% (95% CI 1.07-1.33) increase in speech- and high-frequency hearing impairment, respectively. CONCLUSIONS: We found no significant difference in the prevalence of hearing impairment between the group with type 1 diabetes and the spousal control group. Among those with type 1 diabetes, higher mean HbA1c over time was associated with hearing impairment.