The role of nutrition-related clinical trials in informing dietary recommendations for health and treatment of diseases.

Dietary guidance is based on a robust evidence base that includes high-quality clinical trials, of which some have been designed to establish causal relationships between dietary interventions and ASCVD risk reduction. However, the complexity associated with conducting these trials has resulted in criticism of nutrition and dietary recommendations because the strength and quality of evidence falls short of that for some pharmaceutical interventions. In this paper, we aim to promote greater awareness of the nutrition-related clinical trials that have been conducted showing ASCVD benefits and how this evidence has contributed to dietary recommendations.

ApoA-I Infusions and Burden of Ischemic Events After Acute Myocardial Infarction: Insights From the AEGIS-II Trial.

Background: Following an acute myocardial infarction (AMI), patients remain at risk for subsequent cardiovascular (CV) events. In the AEGIS-II trial, CSL112, a human apolipoprotein A-I derived from plasma that enhances cholesterol efflux, did not significantly reduce the first occurrence of CV death, myocardial infarction (MI), or stroke through 90 days compared with placebo. However, an analysis involving only the first event may not capture the totality of the clinical impact of an intervention because patients may experience multiple events.

Apolipoprotein A-I infusions and cardiovascular outcomes in acute myocardial infarction according to baseline LDL-cholesterol levels: the AEGIS-II trial.

Background And Aims: In the AEGIS-II trial (NCT03473223), CSL112, a human apolipoprotein A1 derived from plasma that increases cholesterol efflux capacity, did not significantly reduce the risk of the primary endpoint through 90 days vs. placebo after acute myocardial infarction (MI). Nevertheless, given the well-established relationship between higher low-density lipoprotein cholesterol (LDL-C) and plaque burden, as well as greater risk reductions seen with PCSK9 inhibitors in patients with baseline LDL-C ≥ 100 mg/dL on statin therapy, the efficacy of CSL112 may be influenced by baseline LDL-C.

Is There an Ideal Diet? Some Insights from the POUNDS Lost Study.

Diets for weight loss have a long history but an ideal one has not yet been clearly identified. To compare low-fat and lower carbohydrate diets, we designed The Preventing Overweight by Novel Dietary Strategies (POUNDS) Lost study. This is a 2 × 2 factorial study with diets of 20% or 40% fat and 15% or 25% protein with a graded carbohydrate intake of 35, 45, 55 and 65%.

Isocaloric replacement of ultraprocessed foods was associated with greater weight loss in the POUNDS Lost trial.

Objective: Higher intake of ultraprocessed foods (UPFs) is associated with obesity. We examined whether replacing UPFs (NOVA 4) with minimally processed foods and culinary ingredients (NOVA 1 + 2) was associated with differential weight change in this secondary prospective analysis of the Preventing Overweight Using Novel Dietary Strategies (POUNDS) Lost trial.

Methods: We estimated percent energy intake (%kcal) from the four NOVA groups using 24-h dietary recalls in a subset of 356 participants.

Apolipoprotein A1 Infusions and Cardiovascular Outcomes after Acute Myocardial Infarction.

Background: Cardiovascular events frequently recur after acute myocardial infarction, and low cholesterol efflux - a process mediated by apolipoprotein A1, which is the main protein in high-density lipoprotein - has been associated with an increased risk of cardiovascular events. CSL112 is human apolipoprotein A1 derived from plasma that increases cholesterol efflux capacity. Whether infusions of CSL112 can reduce the risk of recurrent cardiovascular events after acute myocardial infarction is unclear.

Changes in bile acid subtypes and improvements in lipid metabolism and atherosclerotic cardiovascular disease risk: the Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) trial.

Background: Distinct circulating bile acid (BA) subtypes may play roles in regulating lipid homeostasis and atherosclerosis.

Objectives: We investigated whether changes in circulating BA subtypes induced by weight-loss dietary interventions were associated with improved lipid profiles and atherosclerotic cardiovascular disease (ASCVD) risk estimates.

Methods: This study included adults with overweight or obesity (n = 536) who participated in a randomized weight-loss dietary intervention trial.

Circulating MicroRNA-19 and cardiovascular risk reduction in response to weight-loss diets.

Objective: MicroRNA-19 (miR-19) plays a critical role in cardiac development and cardiovascular disease (CVD). We examined whether change in circulating miR-19 was associated with change in CVD risk during weight loss.

Methods: This study included 509 participants with overweight or obesity from the 24-month weight-loss diet intervention study (the POUNDS Lost trial) and with available data on circulating miR-19a-3p and miR-19b-3p at baseline and 6 months.

Food Intake Suppresses ApoB Secretion and Fractional Catabolic Rates in Humans.

Background: Humans spend much of the day in the postprandial state. However, most research and clinical guidelines on plasma lipids pertain to blood drawn after a 12-hour fast. We aimed to study the metabolic differences of apoB lipoproteins between the fasting and postprandial states.

MTNR1B genotype and effects of carbohydrate quantity and dietary glycaemic index on glycaemic response to an oral glucose load: the OmniCarb trial.

Aims/hypothesis: A type 2 diabetes-risk-increasing variant, MTNR1B (melatonin receptor 1B) rs10830963, regulates the circadian function and may influence the variability in metabolic responses to dietary carbohydrates. We investigated whether the effects of carbohydrate quantity and dietary glycaemic index (GI) on glycaemic response during OGTTs varied by the risk G allele of MTNR1B-rs10830963.

Methods: This study included participants (n=150) of a randomised crossover-controlled feeding trial of four diets with high/low GI levels and high/low carbohydrate content for 5 weeks.

Red meat intake and risk of type 2 diabetes in a prospective cohort study of United States females and males.

Background: Studies with methodological advancements are warranted to confirm the relation of red meat consumption to the incidence of type 2 diabetes (T2D).

Objective: We aimed to assess the relationships of intakes of total, processed, and unprocessed red meat to risk of T2D and to estimate the effects of substituting different protein sources for red meats on T2D risk.

Methods: Our study included 216,695 participants (81% females) from the Nurses' Health Study (NHS), NHS II, and Health Professionals Follow-up Study (HPFS).

Understanding HDL Metabolism and Biology Through In Vivo Tracer Kinetics.

HDL (high-density lipoprotein), owing to its high protein content and small size, is the densest circulating lipoprotein. In contrast to lipid-laden VLDL (very-low-density lipoprotein) and LDL (low-density lipoprotein) that promote atherosclerosis, HDL is hypothesized to mitigate atherosclerosis via reverse cholesterol transport, a process that entails the uptake and clearance of excess cholesterol from peripheral tissues. This process is mediated by APOA1 (apolipoprotein A-I), the primary structural protein of HDL, as well as by the activities of additional HDL proteins.

Proteomic Determinants of Variation in Cholesterol Efflux: Observations from the Dallas Heart Study.

High-density lipoproteins (HDLs) are promising targets for predicting and treating atherosclerotic cardiovascular disease (ASCVD), as they mediate removal of excess cholesterol from lipid-laden macrophages that accumulate in the vasculature. This functional property of HDLs, termed cholesterol efflux capacity (CEC), is inversely associated with ASCVD. HDLs are compositionally diverse, associating with >250 different proteins, but their relative contribution to CEC remains poorly understood.

DNA Methylation at ABCG1 and Long-term Changes in Adiposity and Fat Distribution in Response to Dietary Interventions: The POUNDS Lost Trial.

Objective: To examine whether participants with different levels of diabetes-related DNA methylation at ABCG1 might respond differently to dietary weight loss interventions with long-term changes in adiposity and body fat distribution.

Research Design And Methods: The current study included overweight/obese participants from the POUNDS Lost trial. Blood levels of regional DNA methylation at ABCG1 were profiled by high-resolution methylC-capture sequencing at baseline among 673 participants, of whom 598 were followed up at 6 months and 543 at 2 years.

Toward Precision Weight-Loss Dietary Interventions: Findings from the POUNDS Lost Trial.

The POUNDS Lost trial is a 2-year clinical trial testing the effects of dietary interventions on weight loss. This study included 811 adults with overweight or obesity who were randomized to one of four diets that contained either 15% or 25% protein and 20% or 40% fat in a 2 × 2 factorial design. By 2 years, participants on average lost from 2.

Trial of the MIND Diet for Prevention of Cognitive Decline in Older Persons.

Background: Findings from observational studies suggest that dietary patterns may offer protective benefits against cognitive decline, but data from clinical trials are limited. The Mediterranean-DASH Intervention for Neurodegenerative Delay, known as the MIND diet, is a hybrid of the Mediterranean diet and the DASH (Dietary Approaches to Stop Hypertension) diet, with modifications to include foods that have been putatively associated with a decreased risk of dementia.

Methods: We performed a two-site, randomized, controlled trial involving older adults without cognitive impairment but with a family history of dementia, a body-mass index (the weight in kilograms divided by the square of the height in meters) greater than 25, and a suboptimal diet, as determined by means of a 14-item questionnaire, to test the cognitive effects of the MIND diet with mild caloric restriction as compared with a control diet with mild caloric restriction.

Dietary Effects on Monocyte Phenotypes in Subjects With Hypertriglyceridemia and Metabolic Syndrome.

In patients with hypertriglyceridemia, a short-term low-saturated fat vs high-saturated fat diet induced lower plasma lipids and improved monocyte phenotypes. These findings highlight the role of diet fat content and composition for monocyte phenotypes and possibly cardiovascular disease risk in these patients. (Effects of Dietary Interventions on Monocytes in Metabolic Syndrome; NCT03591588).

The distinct metabolism between large and small HDL indicates unique origins of human apolipoprotein A4.

Apolipoprotein A4's (APOA4's) functions on HDL in humans are not well understood. A unique feature of APOA4 is that it is an intestinal apolipoprotein secreted on HDL and chylomicrons. The goal of this study was to gain a better understanding of the origin and function of APOA4 on HDL by studying its metabolism across 6 HDL sizes.

DNA Methylation of Birthweight-Blood Pressure Genes and Changes of Blood Pressure in Response to Weight-Loss Diets in the POUNDS Lost Trial.

Background: DNA methylation (DNAm) may play a critical role in bridging prenatal adverse events and cardiometabolic disorders including hypertension in later life.

Methods: We included 672 adult participants with overweight or obesity, who participated in a 2-year randomized weight-loss dietary intervention study. We defined the regional DNAm levels as the average methylation level of 5'-cytosine-phosphate-guanine-3' within 500 bp of (cg01820192), (cg00508575), and (cg12593793), respectively.

DNA Methylation Near CPT1A and Changes in Triglyceride-rich Lipoproteins in Response to Weight-loss Diet Interventions.

Context: Carnitine palmitoyltransferase-1A, encoded by the CPT1A gene, plays a key role in the oxidation of long-chain fatty acids in the mitochondria and may be important in triglyceride metabolism. Previous work has shown that high fat intake was negatively associated with CPT1A methylation and positively associated with CPT1A expression.

Objective: We aim to investigate the association of DNA methylation (DNAm) at the CPT1A gene with reductions in triglycerides and triglyceride-rich lipoproteins (TRLs) in response to weight-loss diet interventions.

Circulating thrifty microRNA is related to insulin sensitivity, adiposity, and energy metabolism in adults with overweight and obesity: the POUNDS Lost trial.

Background: MicroRNA 128-1 (miR-128-1) was recently linked to the evolutionary adaptation to famine and identified as a thrifty microRNA that controls energy expenditure, contributing to obesity and impaired glucose metabolism.

Objectives: We investigated whether circulating miR-128-1-5p and its temporal changes in response to weight-loss diet interventions were related to regulating insulin resistance, adiposity, and energy expenditure in adults with overweight and obesity. We also examined whether habitual physical activity (PA) and different macronutrient intakes modified associations of changes in miR-128-1-5p with improved metabolic outcomes.

Effects of the Dietary Approaches to Stop Hypertension Diet on Change in Cardiac Biomarkers Over Time: Results From the DASH-Sodium Trial.

Background The Dietary Approaches to Stop Hypertension (DASH) diet has been shown to reduce biomarkers of cardiovascular disease. We aimed to characterize the time course of change in biomarkers of cardiac injury (high-sensitivity cardiac troponin I), cardiac strain (NT-proBNP [N-terminal pro-B-type natriuretic peptide]), and inflammation (hs-CRP [high-sensitivity C-reactive protein]) while consuming the DASH diet. Methods and Results The DASH-Sodium trial was a randomized controlled trial of 412 adults with elevated blood pressure or hypertension.

Genetically determined gut microbial abundance and 2-year changes in central adiposity and body composition: The POUNDS lost trial.

Background And Aim: Growing evidence has linked gut microbiota with regulation of adiposity. We aimed to examine whether the genetically determined relative abundance of gut microbial taxa was associated with long-term changes in adiposity and body composition among individuals who were overweight or obese in weight-loss diet interventions.

Methods: The study included 692 participants with overweight or obese from the POUNDS Lost trial.

Changes in circulating bile acid subtypes in response to weight-loss diets are associated with improvements in glycemic status and insulin resistance: The POUNDS Lost trial.

Objective: Various primary and secondary bile acids (BAs) may play pivotal roles in glucose/insulin metabolism. We investigated whether changes in specific BA subtypes were associated with long-term changes in glucose and insulin sensitivity.

Methods: This study included 515 adults with overweight or obesity who participated in a 2-year intervention study of weight-loss diets with different macronutrient intakes.