Objectives

To evaluate the effects of dietary fat and carbohydrate modifications on lipids, lipoproteins, and hemostatic factors in several demographic/population groups, including those at high risk of cardiovascular diseases.

Background

Cardiovascular diseases (CVDs) are a leading cause of death globally. The American Heart Association recommends a diet that, among other characteristics, is low in saturated fatty acid (SFA), trans fat, and sodium to decrease atherosclerotic CVD risk factors. In addition, several hemostatic factors that affect CVD risk, notably fibrinogen, factor VIIc, and plasminogen activator inhibitor 1 (PAI-1), may also be modifiable, in part, by type and amount of dietary fat. The Dietary Effects on Lipoproteins and Thrombogenic Activity (DELTA) Study was conducted to evaluate the effects of diet modifications, particularly substituting carbohydrates and unsaturated fats for SFA, on lipids, lipoproteins, and hemostatic factors in various population groups, including those at high risk of CVD.

Participants

Eligible participants for the DELTA-1 trial were healthy individuals 22-67 years old that were not taking medications known to affect cholesterol or hemostatic factors. Eligible participants had mean fasting total cholesterol concentrations between the 25th and 90th percentile, and plasma triglycerides and HDL cholesterol between the 10th and 90th percentiles. 118 participants were enrolled in DELTA-1, with 103 completing the study.

Eligible participants for the DELTA-2 trial were individuals 21–68 years old with average screening measurements that met any of the following: HDL cholesterol ≤30th percentile, triglycerides ≥70th percentile, or insulin ≥70th percentile. Participants were ineligible if their average screening total cholesterol was <25th percentile or >90th percentile, LDL cholesterol was >190 mg/dL, fasting triglyceride concentrations were <30th percentile or >500 mg/dL, or HDL cholesterol was >70th percentile. 110 participants were enrolled in DELTA-2, with 85 completing the study.

Design

The DELTA Study comprised two multicenter nutrition intervention trials in which tightly controlled diets were fed to study participants using a randomized double-blind crossover design with 3 feeding periods and 6 diet sequences. Diet validation and quality control were achieved by sampling study foods across all clinical sites and assaying for composition during preliminary study design activities and also throughout the trial periods. Following a brief run-in period to assess protocol compliance, each participant was randomly assigned to 1 of 6 diet sequences. Randomization was stratified by center. All food was provided to participants during the feeding periods for both studies. Study participants were required to eat 2 meals on-site each weekday. Other meals and snacks were packed and distributed to participants for consumption at a time and place of convenience. Each period was followed by a 4-to-6-week washout interval during which time participants resumed their habitual dietary patterns.

The DELTA-1 trial evaluated the effects of a stepwise reduction in dietary total fat and SFA. Participants were provided with an average American diet (AAD; 37% of energy as total fat, 16% SFA, 14% MUFA), a Step 1 diet (Step 1; 30% of energy as total fat, 9% SFA, 14% MUFA), and a diet low in SFA (Low-Sat; 26% of energy as total fat, 5% SFA, 14% MUFA. DELTA-1 fasting blood samples were obtained once weekly during weeks 5, 6, 7, and 8 of each feeding period.

The DELTA-2 trial evaluated the effect of replacing SFA with either monounsaturated fatty acid (MUFA) or carbohydrate in participants with an accentuated metabolic and cardiovascular risk profile. Participants were provided with an AAD 37% of energy as total fat, 16% SFA, and 14% MUFA, a Step 1 diet (30% of energy as total fat, 8% SFA, and 15% MUFA, and a diet high in MUFA (High-MUFA; 37% energy as total fat, 8% SFA, 22% MUFA). Participants consumed each of the 3 diets for a period of 7 weeks. DELTA-2 fasting blood samples were obtained once weekly during weeks 5, 6, and 7 of each feeding period.

Primary endpoints for both trials included plasma lipids (total cholesterol and triglycerides), lipoproteins (VLDL, LDL, HDL, and Lp(a)), apoproteins A1 and B, and hemostatic factors/thrombogenic parameters (Factor VIIc, fibrinogen, and plasminogen activator inhibitor 1 (PAI-1)).

Secondary endpoints included, for DELTA-1: prothrombin fragment 1.2, plasmin-antiplasmin, D-dimer, DHEA, DHEA sulphate and, for premenopausal participants, menstrual cycle phase and hormone levels; and for DELTA-2: prothrombin fragment 1.2, plasmin-antiplasmin, D-dimer, glucose, uric acid, C-reactive protein, beta-thromboglobulin, Apo A-1, Apo B, microalbumin, and retinyl ester.

The four DELTA clinical sites were located at Columbia University (New York, NY), Pennsylvania State University (University Park, PA), University of Minnesota (Minneapolis, MN), and Pennington Biomedical Research Center (Baton Rouge, LA). The Collaborative Studies Coordinating Center, University of North Carolina (Chapel Hill, NC) served as both the clinical coordinating center and data coordinating center.

All Clinical sites analyzed lipids and lipoproteins; measurements of apo B, apo A-I, and Lp(a) were performed at the Mary Imogene Bassett Research Institute (Cooperstown, NY); experimental diets were chemically analyzed at Virginia Tech (Blacksburg, VA); and hemostatic factors/thrombogenic parameters were assayed at the University of Vermont (Burlington, VT). In the postprandial studies conducted for DELTA-2, insulin, glucose, and triacylglycerol concentrations were measured centrally at Columbia University.

Conclusions

In DELTA-1, stepwise reductions in SFA resulted in parallel reductions in plasma total and LDL cholesterol levels. Diet effects were remarkably similar in several age-related subgroups of men and women and in age-related Whites and African Americans. The reductions in total and LDL cholesterol achieved in these different subgroups indicate that diet likely can have a significant impact on risk for atherosclerotic cardiovascular disease in the general U.S. population. In DELTA-2, where participants were at increased risk of coronary artery disease, MUFA provided a greater reduction in risk factors than did carbohydrate as a replacement for saturated fat. An evaluation of menstrual cycle and menopausal status effects conducted in DELTA-1 participants found that, under conditions of tight dietary control, the variability in hemostatic factors in premenopausal women was no greater than for postmenopausal women or men. Consequently, premenopausal women can be included in studies investigating hemostatic factor responses without controlling for stage of menstrual cycle.

For hemostatic/thrombogenic factors, a combined analysis of DELTA-1 and DELTA-2 results showed that reducing SFA modestly lowers factor VIIc in healthy individuals and those at-risk for CVD. A diet low in total fat and SFA (i.e., higher in carbohydrate) elicited a greater mean increase in fibrinogen than a moderate fat diet that was low in SFA and high in MUFA. These results indicate that, as a substitute for SFA, MUFA compared with carbohydrate results in a lesser degree of increase in fibrinogen. The results regarding the diet effects on PAI-1 were inconclusive.

A combined CONSORT diagram for the DELTA-1 and DELTA-2 studies can be found in Kris-Etherton et al, 2020.

Publications

Kris-Etherton PM, Stewart PW, Ginsberg HN, Tracy RP, Lefevre M, Elmer PJ, Berglund L, Ershow AG, Pearson TA, Ramakrishnan R, Holleran SF, Dennis BH, Champagne CM, Karmally W; DELTA Investigators. The Type and Amount of Dietary Fat Affect Plasma Factor VIIc, Fibrinogen, and PAI-1 in Healthy Individuals and Individuals at High Cardiovascular Disease Risk: 2 Randomized Controlled Trials. J Nutr. (2020) Aug 1;150(8):2089-2100. doi: 10.1093/jn/nxaa137. PMID: 32492148.

Hill AM, Stewart PW, Fung MK, Kris-Etherton PM, Ginsberg HN, Tracy RP, Pearson TA, Lefevre M, Reed RG, Elmer PJ, Holleran S, Ershow AG; Dietary Effects on Lipoproteins and Thrombogenic Activity Investigators. Monthly hemostatic factor variability in women and men. Eur J Clin Invest. (2014) 44(3):309-18. doi: 10.1111/eci.12235. PMID: 24382103.

Berglund L, Lefevre M, Ginsberg HN, Kris-Etherton PM, Elmer PJ, Stewart PW, Ershow A, Pearson TA, Dennis BH, Roheim PS, Ramakrishnan R, Reed R, Stewart K, Phillips KM; DELTA Investigators. Comparison of monounsaturated fat with carbohydrates as a replacement for saturated fat in subjects with a high metabolic risk profile: studies in the fasting and postprandial states. Am J Clin Nutr. (2007) Dec;86(6):1611-20. doi: 10.1093/ajcn/86.5.1611. PMID: 18065577.

Ginsberg HN, Kris-Etherton P, Dennis B, Elmer PJ, Ershow A, Lefevre M, Pearson T, Roheim P, Ramakrishnan R, Reed R, Stewart K, Stewart P, Phillips K, Anderson N; Effects of reducing dietary saturated fatty acids on plasma lipids and lipoproteins in healthy subjects: the DELTA Study, protocol 1. Arterioscler Thromb Vasc Biol. (1998) Mar;18(3):441-9. doi: 10.1161/01.atv.18.3.441. PMID: 9514413.

Dennis B, Ershow A, Obarzanek E, Clevidence B. 1999. Well-Controlled Diet Studies in Humans, A Practical Guide to Design and Management, American Dietetic Association. ISBN 13: 9780880911580

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