Cardiovascular Outcomes in GRADE (Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness Study).

BACKGROUND: Cardiovascular disease is a major cause of morbidity and mortality in patients with type 2 diabetes. The effects of glucose-lowering medications on cardiovascular outcomes in individuals with type 2 diabetes and low cardiovascular risk are unclear. We investigated cardiovascular outcomes by treatment group in participants randomly assigned to insulin glargine, glimepiride, liraglutide, or sitagliptin, added to baseline metformin, in GRADE (Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness Study). METHODS: A total of 5047 participants with a mean±SD age of 57.2±10.0 years, type 2 diabetes duration of 4.0±2.7 years, and low baseline prevalence of cardiovascular disease (myocardial infarction, 5.1%; cerebrovascular accident, 2.0%) were followed for a median of 5 years. Prespecified outcomes included between-group time-to-first event analyses of MACE-3 (composite of major adverse cardiovascular events: cardiovascular death, myocardial infarction, and stroke), MACE-4 (MACE-3+unstable angina requiring hospitalization or revascularization), MACE-5 (MACE-4+coronary revascularization), MACE-6 (MACE-5+hospitalization for heart failure), and the individual components. MACE outcomes and hospitalization for heart failure in the liraglutide-treated group were compared with the other groups combined using Cox proportional hazards models. MACE-6 was also analyzed as recurrent events using a proportional rate model to compare all treatment groups. RESULTS: We observed no statistically significant differences in the cumulative incidence of first MACE-3, MACE-4, MACE-5, or MACE-6, or their individual components, by randomized treatment group. However, when compared with the other treatment groups combined, the liraglutide-treated group had a significantly lower risk of MACE-5 (adjusted hazard ratio, 0.70 [95% CI, 0.54-0.91]; P=0.021), MACE-6 (adjusted hazard ratio, 0.70 [95% CI, 0.55-0.90]; P=0.021), and hospitalization for heart failure (adjusted hazard ratio, 0.49 [95% CI, 0.28-0.86]; P=0.022). Compared with the liraglutide group, significantly higher rates of recurrent MACE-6 events occurred in the groups treated with glimepiride (rate ratio, 1.61 [95% CI, 1.13-2.29]) or sitagliptin (rate ratio 1.75; [95% CI, 1.24-2.48]). CONCLUSIONS: This comparative effectiveness study of a contemporary cohort of adults with type 2 diabetes, largely without established cardiovascular disease, suggests that liraglutide treatment may reduce the risk of cardiovascular events in patients at relatively low risk compared with other commonly used glucose-lowering medications. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01794143.

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.

Comparative Effects of Glucose-Lowering Medications on Kidney Outcomes in Type 2 Diabetes: The GRADE Randomized Clinical Trial.

Importance: Type 2 diabetes (T2D) is the leading cause of kidney disease in the US. It is not known whether glucose-lowering medications differentially affect kidney function. Objective: To evaluate kidney outcomes in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) trial comparing 4 classes of glucose-lowering medications added to metformin for glycemic management in individuals with T2D. Design, Setting, and Participants: A randomized clinical trial was conducted at 36 sites across the US. Participants included adults with T2D for less than 10 years, a hemoglobin A1c level between 6.8% and 8.5%, and estimated glomerular filtration rate (eGFR) greater than or equal to 60 mL/min/1.73 m2 who were receiving metformin treatment. A total of 5047 participants were enrolled between July 8, 2013, and August 11, 2017, and followed up for a mean of 5.0 years (range, 0-7.6 years). Data were analyzed from February 21, 2022, to March 27, 2023. Interventions: Addition of insulin glargine, glimepiride, liraglutide, or sitagliptin to metformin, with the medication combination continued until the HbA1c was greater than 7.5%; thereafter, insulin was added to maintain glycemic control. Main Outcomes and Measures: Chronic eGFR slope (change in eGFR between year 1 and trial end) and a composite kidney disease progression outcome (albuminuria, dialysis, transplant, or death due to kidney disease). Secondary outcomes included incident eGFR less than 60 mL/min/1.73 m2, 40% decrease in eGFR to less than 60 mL/min/1.73 m2, doubling of urine albumin-to-creatinine ratio (UACR) to 30 mg/g or greater, and progression of Kidney Disease Improving Global Outcomes stage. Analyses were intention-to-treat. Results: Of the 5047 participants, 3210 (63.6%) were men. Baseline characteristics were mean (SD) age 57.2 (10.0) years; HbA1c 7.5% (0.5%); diabetes duration, 4.2 (2.7) years; body mass index, 34.3 (6.8); blood pressure 128.3/77.3 (14.7/9.9) mm Hg; eGFR 94.9 (16.8) mL/min/1.73 m2; and median UACR, 6.4 (IQR 3.1-16.9) mg/g; 2933 (58.1%) were treated with renin-angiotensin-aldosterone inhibitors. Mean chronic eGFR slope was -2.03 (95% CI, -2.20 to -1.86) mL/min/1.73 m2 per year for patients receiving sitagliptin; glimepiride, -1.92 (95% CI, -2.08 to -1.75) mL/min/1.73 m2 per year; liraglutide, -2.08 (95% CI, -2.26 to -1.90) mL/min/1.73 m2 per year; and insulin glargine, -2.02 (95% CI, -2.19 to -1.84) mL/min/1.73 m2 per year (P = .61). Mean composite kidney disease progression occurred in 135 (10.6%) patients receiving sitagliptin; glimepiride, 155 (12.4%); liraglutide, 152 (12.0%); and insulin glargine, 150 (11.9%) (P = .56). Most of the composite outcome was attributable to albuminuria progression (98.4%). There were no significant differences by treatment assignment in secondary outcomes. There were no adverse kidney events attributable to medication assignment. Conclusions and Relevance: In this randomized clinical trial, among people with T2D and predominantly free of kidney disease at baseline, no significant differences in kidney outcomes were observed during 5 years of follow-up when a dipeptidyl peptidase 4 inhibitor, sulfonylurea, glucagonlike peptide 1 receptor agonist, or basal insulin was added to metformin for glycemic control. Trial Registration: ClinicalTrials.gov Identifier: NCT01794143.

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.

An Observational Study of the Equivalence of Age and Duration of Diabetes to Glycemic Control Relative to the Risk of Complications in the Combined Cohorts of the DCCT/EDIC Study.

OBJECTIVE: This epidemiological analysis of the pooled Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort describes the equivalence of a 1-percentage point increase in HbA1c (such as from 7% to 8%) and years of additional age or duration of type 1 diabetes (T1D) relative to the risk of complications. RESEARCH DESIGN AND METHODS: Separate Cox proportional hazards models determined the number of additional years of age and/or duration of T1D that would result in the same increase in risk of microvascular (retinopathy, nephropathy, and neuropathy) and cardiovascular complications and mortality as a 1-percentage point increase in HbA1c. RESULTS: The risk of any cardiovascular disease associated with a 1-percentage point increase in HbA1c was equivalent to the risk associated with 4.3 (95% CI 2.7-5.9) additional years of age or 5.6 (95% CI 2.7-6.5) additional years' duration of T1D. The risk of estimated glomerular filtration rate <60 mL/min/1.73 m2 and/or end-stage renal disease associated with a 1-percentage point increase in HbA1c was equivalent to the risk associated with 12.1 (95% CI 8.3-15.9) additional years of age or 18.0 (95% CI 4.3-31.7) additional years' duration of T1D. The proliferative diabetic retinopathy risk associated with a 1-percentage point increase in HbA1c was equivalent to the risk associated with 6.4 (95% CI 5.3-7.4) additional years' duration of T1D, while for mortality risk, it was equivalent to the risk associated with 12.9 (95% CI 6.6-19.3) additional years of age. CONCLUSIONS: Our results help evaluate the impact of glycemia on advanced complications in a way that may be more interpretable to health care providers and individuals with T1D.

Risk Factors for First and Subsequent CVD Events in Type 1 Diabetes: The DCCT/EDIC Study.

OBJECTIVE: The Diabetes Control and Complications Trial (DCCT) and its observational follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) demonstrated the dominant role of glycemia, second only to age, as a risk factor for a first cardiovascular event in type 1 diabetes (T1D). We now investigate the association between established risk factors and the total cardiovascular disease (CVD) burden, including subsequent (i.e., recurrent) events. RESEARCH DESIGN AND METHODS: CVD events in the 1,441 DCCT/EDIC participants were analyzed separately by type (CVD death, acute myocardial infarction [MI], stroke, silent MI, angina, percutaneous transluminal coronary angioplasty/coronary artery bypass graft [PTCA/CABG], and congestive heart failure [CHF]) or as composite outcomes (CVD or major adverse cardiovascular events [MACE]). Proportional rate models and conditional models assessed associations between risk factors and CVD outcomes. RESULTS: Over a median follow-up of 29 years, 239 participants had 421 CVD events, and 120 individuals had 149 MACE. Age was the strongest risk factor for acute MI, silent MI, stroke, and PTCA/CABG, while glycemia was the strongest risk factor for CVD death, CHF, and angina, second strongest for acute MI and PTCA/CABG, third strongest for stroke, and not associated with silent MI. HbA1c was the strongest modifiable risk factor for a first CVD event (CVD: HR 1.38 [95% CI 1.21, 1.56] per 1% higher HbA1c; MACE: HR 1.54 [1.30, 1.82]) and also for subsequent CVD events (CVD: incidence ratio [IR] 1.28 [95% CI 1.09, 1.51]; MACE: IR 1.89 [1.36, 2.61]). CONCLUSIONS: Intensive glycemic management is recommended to lower the risk of initial CVD events in T1D. After a first event, optimal glycemic control may reduce the risk of recurrent CVD events and should be maintained.

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.