2024-27488. Supplemental Evidence and Data Request on Dietary Saturated Fat Replacement and Plasma Lipid and Cardiovascular Events

PICOTS (Populations, Interventions, Comparators, Outcomes, Timing, and Setting)

[Study eligibility criteria based on Population, Intervention, Comparator, Outcome (PICO), and other elements]

Element	Inclusion criteria	Exclusion criteria
Population	Both Key Questions	Both Key Questions
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	General population, without CVD, with or without modifiable CV risk factors, including ○ Dyslipidemia (including if taking lipid lowering medications) ○ Overweight/obese ○ Hyperglycemia and related conditions, including type 2 diabetes ○ Hypertension/high blood pressure Key Question 1 Children and adults Key Question 2 Adults (≥18 years old)	• Participants with a health-related condition or taking medications that impact fat absorption, fat metabolism. • Participants taking weight loss medications, including glucagon-like peptide-1 agonists. • Undernourished, underweight, stunted, or wasted participants. • Participants who are pre- or post-bariatric surgery. • Participants with other chronic diseases ( e.g., cancer, gastrointestinal disease, rheumatic disease, chronic kidney disease, neurologic diseases), including type 1 diabetes. • Participants with clinical CVD ( e.g., history of myocardial infarction, angina, stroke, arrhythmia), including congenital heart diseases, or familial hypercholesterolemia.
Interventions	Both Key Questions	Both Key Questions
	• Diets with a lower intake of total saturated fatty acids • Diets with a lower intake of individual saturated fatty acids • Diets with a lower intake of a combination of saturated fatty acids other than stearic acid (ranging from C8 to C16; i.e., caprylic, caproic, lauric, myristic, palmitic) • Saturated fatty acid intake is exchanged for: ○ Carbohydrates, including different types (complex including fiber, refined, sugars) ○ Protein ○ Unsaturated fatty acids, any ○ Mono-unsaturated fatty acids (MUFA) ○ Polyunsaturated fatty acids (PUFA) ○ Combination of the above • Dietary intake must be defined or described prospectively (in real time) • Must specify daily quantity of dietary saturated fat intake	• Studies that do not quantify fatty acid intake as either g/day or % of total energy intake from saturated fat. • Analyses with fat intake as a continuous variable. • Fatty acid intake during a single meal or eating occasion. • Fatty acid intake via infusion (not orally). • Food products or dietary supplements not widely available to U.S. consumers. • Multi-component interventions ( e.g., diet + exercise vs. exercise or plant sterols + diet vs. plant sterols) (adult studies). • Multi-component interventions of statins + diet where statins are being initiated. Dietary interventions among existing statin users will be included. • Interventions designed to induce weight loss or treat overweight and obesity through energy restriction or hypocaloric diets. • Interventions designed for the purposes of treating medical conditions other than modifiable CV risk factors. • Enteral feeding.
	Key Question 1 For studies in children, ○ Include multicomponent interventions ( e.g., diet + exercise vs. exercise) ○ Infant formula
Comparators	Both Key Questions	Both Key Questions
	• Diets with no exchange and, thus, a higher intake of total saturated fatty acids, individual saturated fatty acids, or combination of saturated fatty acids • Well defined conventional or usual diet • Diets with same reduction in saturated fat intake but different replacement ( e.g., 6% saturated fatty acids in all arms, replaced with protein vs. replaced with carbohydrates)	Diets with a caloric intake that are significantly higher or lower than the intervention/exposure diet. Diets or interventions that vary substantially in intake of macronutrients (or other factors) other than the intervention and comparator of interest. Different dietary fat exposure ( e.g., comparison of undefined quantiles).
Outcomes	Key Question 1	Key Question 1
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	• Plasma lipoprotein concentrations ○ LDL cholesterol (LDL-c) ○ HDL cholesterol (HDL-c) ○ Non-HDL-cholesterol ○ Triglycerides (triacylglycerol) (Tg) ○ Lipoprotein(a) ○ Apolipoprotein B (ApoB)	• Total cholesterol (TC). • TC:HDL ratio. • LDL:HDL ratio. • Chylomicrons. • VLDL-c. • IDL-c. • Other apolipoproteins. • Lipoprotein profiles. • Evaluations of fatty acid biomarker levels.
	Key Question 2 • Cardiovascular events ○ Atherosclerotic cardiovascular disease (total) ○ Major adverse cardiac (or cerebral) events (MAC[C]E) ○ Specific cardiovascular events Myocardial infarction Coronary heart/artery disease Peripheral vascular/artery disease ○ Revascularization (for studies published after 1995) ○ Cardiovascular disease-related mortality ○ Stroke ○ Incident atrial fibrillation	Key Question 2 • Other cardiac or vascular related outcomes. • Participant reported events.
Subgroups/effect modifiers of interest	Both Key Questions	None.
	○ Specific life stages ○ Infants (for Key Question 1 only) ○ Children and adolescents (for Key Question 1 only) ○ Adults (19-64) ○ Older adults (≥65) ○ Pregnant or postpartum ○ Menopausal status
	• Other characteristics ○ Sex (male, female) ○ Socioeconomic status ○ Social determinants of health ○ Race/ethnicity ○ Physical activity level ○ Anthropometry ○ Health status, including type 2 diabetes ○ Percent of total energy intake replaced ○ Dietary trans fatty acid intake ○ Baseline lipid concentrations ○ Dietary cholesterol intake
Design	Key Question 1	Both Key Questions
	• Studies of adults ○ Parallel or cross-over randomized controlled trials (RCTs) n ≥25/group * • Studies of children ○ Parallel or cross-over RCTs n ≥25/group * ○ Nonrandomized comparative studies Must account for potential confounders Dietary intake must be defined or described prospectively n ≥50/group *	• Observational studies that do not account for confounders. • Analyses of dietary fat as a continuous variable ( e.g., RR per g/day intake) without an analysis at a threshold ( e.g., RR for > vs < threshold). • All other study designs.
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	Key Question 2 • Studies of adults ○ Parallel or cross-over RCTs n ≥25/group * ○ Nonrandomized comparative studies Must account for potential confounders Dietary intake must be defined or described prospectively We will aim for a minimum of about 10 observational studies for each specific intervention—CV event pair ( e.g., reduced saturated fat and stroke). We will thus select the largest observational studies within each category.† n ≥100/group
Timing	Key Question 1	None.
	• Minimum intervention length: 4 weeks • In cross-over studies, any change in outcome measure must exclude data from the first week after end of any prior treatments Key Question 2 • Minimum follow-up ○ If population has no CV risk factors: 10 years ○ If population has one or more CV risk factors (or unselected general population): 5 years
Setting	• General community settings, including nursing homes, assisted living facilities, etc	• Hospital or other acute care settings. • Institutionalized, confined settings ( e.g., prisons)
Publication	• English language • Published in peer-reviewed journals
* Minimum sample size may be altered depending on the number of eligible studies found.
† Applying this approach for the 2016 AHRQ report n-3 fatty acids and cardiovascular disease ( https://doi.org/​10.23970/​AHRQEPCERTA223), we included: for cardiac event outcomes, observational studies with at least 10,000 participants; for stroke outcomes, at least 3000 participants; for arrhythmia outcomes, at least 2000 participants; congestive heart failure outcomes, at least 700 participants; and for peripheral vascular disease events and MACE outcomes, at least 500 participants. In all instances, if a study meets eligibility criteria for any outcome, we will extract all outcomes of interest from that study; therefore, there will be multiple instances of studies being included for an outcome even though the study might not have met study size criteria for that specific outcome.
CV = cardiovascular; CVD = cardiovascular disease; MUFA = mono-unsaturated fatty acids; PUFA = polyunsaturated fatty acids; c = cholesterol; LDL = low-density lipoprotein; IDL = intermediate-density lipoprotein; HDL high-density lipoprotein; TC—total cholesterol; Tg = Triglycerides/Triacylglycerols; apoA = apolipoprotein; MAC[C]E = Major adverse cardiac (or cerebro) events; BMI = body mass index; KQ = key question; N = number of participants.