Substituting a Type-4 Resistant Starch for Available Carbohydrate Reduces Postprandial Glucose, Insulin and Hunger: An Acute, Randomized, Double-Blind, Controlled Study

Substituting a Type-4 Resistant Starch for Available Carbohydrate Reduces Postprandial Glucose, Insulin and Hunger:  An Acute, Randomized, Double-Blind, Controlled Study1

 By Kristen N Smith, PhD, RD, LD; Mary R Dicklin, PhD; Kevin C Maki, PhD

 Background:

Dietary fiber (including a wide variety of nondigestible carbohydrates) is a noted shortfall nutrient in Western diets, despite the fact that appropriate consumption is associated with a broad range of health benefits.2,3 One of the benefits that has received considerable attention is blunting of postprandial blood glucose control. Researchers have established a benefit between consumption of viscous fibers and blood glucose excursions.4 When certain fibers, such as resistant starch (RS), are used in place of available carbohydrate in foods, less glucose is liberated through digestion, thus lowering the rate and quantity of glucose entering the bloodstream after a meal.5

It is important to note that there are different types of RS receiving varying levels of attention in clinical trials. These differences are outlined in the table below.

Type of RS

Description

Amount of Research

Resistant starch type-2

Granular, native starch

Resistant to digestion

Majority of clinical research is in these 2 areas

Resistant starch type-3

Retrograded starch

Resistant to digestion

Resistant starch type-4 (RS4)

Chemically modified starch

Resists digestion by intestinal enzymes

Fewer clinical trials in this area

Among the types of RS4, phosphate distarch phosphate is the most frequently tested6-8, with fewer studies on hydroxypropyl distarch phosphate9,10 and only one study on acid hydrolyzed and heat treated RS4, to date.11

The primary aim of this study was to characterize the postprandial blood glucose response in healthy adults to a novel RS4 (acid hydrolyzed and heat treated maize-based RS) in a ready-to-eat baked good (scone), compared with the response to consumption of a scone made with a control starch. The secondary aims were to evaluate postprandial insulin response, satiety and gastrointestinal tolerance. It was hypothesized that the replacement of digestible carbohydrate from refined wheat flour with RS4 would reduce postprandial blood glucose.

 Methods:

This was a double-blind, randomized, controlled trial conducted at MB Clinical Research in Boca Raton, Florida, USA.

Main Entry Criteria:

  • Age 18-74 y
  • Men and women
  • Body mass index (BMI) 18.5-29.99 kg/m2
  • General good health
  • Fasting capillary glucose <100 mg/dL

The treatment fiber scone contained VERSAFIBE™ 2470 resistant starch (provided by Ingredion Incorporated, Bridgewater, NJ) as the primary fiber source. VERSAFIBE™ 2470 is a RS4 with 70% dietary fiber and is produced from food grade high-amylose maize starch. Acid hydrolysis and heat treatment both reduce the digestibility of this high-amylose maize starch resulting in increased RS4 and total dietary fiber in the finished product. There are no nonstarch polysaccharides present in VERSAFIBE™ 2470. The nutrition composition of the Fiber Scone and Control Scone are shown in the following table.

 

Per Serving, As-Eaten

Control Scone

Fiber

Scone

Weight (g)

83.9

84.1

Calories (kcal)

328

270

Fat (g)

16.0

14.4

Saturated fat (g)

5.0

4.7

Protein (g)

7.1

6.1

Total Carbohydrates (g)

42.8

46.4

Available Carbohydrates (g)

38.8

28.9

Dietary Fiber (g)*

4.0

17.5

Sugars (g)

14.8

14.9

*VERSAFIBE™ 2470 resistant starch provided 16.5 g dietary fiber in the Fiber Scone

The subjects attended 3 study visits, one for screening and two test visits. At the test visits, subjects consumed the Control Scone or Fiber Scone (randomly assigned sequence) with 240 mL water.  Capillary glucose, plasma glucose and plasma insulin were measured pre-consumption and at t = -15, 15, 30, 45, 60, 90, 120 and 180 min ± 2 min, where t = 0 was the start of the study product consumption. Satiety visual analog scale (VAS) ratings were assessed pre-consumption and at 3 min intervals.  Questionnaires were used to assess Gastrointestinal (GI) Tolerability and product palatability at each test visit.

 Results:

A total of 36 subjects were randomized in the study, and one was withdrawn due to non-compliance. Ultimately, 32 subjects were included in the glucose and insulin analyses and 35 were included in the satiety VAS, GI tolerability and palatability analyses.

Consumption of the Fiber Scone significantly reduced postprandial glucose and insulin incremental areas under the curve (43-45% reduction and 35-40% reduction, respectively, p<0.05 for both) as well as postprandial glucose and insulin maximum concentrations (8-10% and 22% reductions, respectively, p<0.05 for both).  Ratings of hunger and desire to eat were also significantly reduced following consumption of the Fiber Scone vs. the Control Scone during the 180 minutes after intake (p<0.05) and there were no GI side effects with the Fiber Scone compared with Control.

Comment:

This study shows significant reductions in postprandial glucose and insulin levels associated with the replacement of refined carbohydrate with RS4 in healthy subjects. In addition, ratings of hunger and desire to eat were reduced after consumption of the RS4-containing food product, a first for this specific RS ingredient. Incorporation of a fiber such as RS4 into the diet has potential clinical and practical relevance due to favorable impacts on markers of cardiometabolic health.12,13

References:

  1. Stewart ML, Wilcox ML, Bell M, Buggia MA, Maki KC. Type-4 resistant starch in substitution for available carbohydrate reduces postprandial glycemic response and hunger in acute, randomized, double-blind, controlled study. Nutrients. 2018;10(2).
  2. Dahl WJ, Stewart ML. Position of the Academy of Nutrition and Dietetics: Health implications of dietary fiber. J Acad Nutr Diet. 2015;115:1861-1870.
  3. Stephen AM, Champ MM, Cloran SJ, et al. Dietary fibre in Europe: current state of knowledge on definitions, sources, recommendations, intakes and relationships to health. Nutr Res Rev. 2017;30:149-190.
  4. Tosh SM. Review of human studies investigating the post-prandial blood-glucose lowering ability of oat and barley food products. European J Clin Nutr. 2013;67:310-317.
  5. Robertson MD. Dietary-resistant starch and glucose metabolism. Curr Opin Clin Nutr Metab Care. 2012;15:362-367.
  6. Haub MD, Hubach KL, Al-Tamimi EK, Ornelas S, Seib PA. Different types of resistant starch elicit different glucose reponses in humans. J Nutr Metab. 2010;2010.
  7. Al-Tamimi EK, Seib PA, Snyder BS, Haub MD. Consumption of cross-linked resistant starch (RS4(XL)) on glucose and insulin responses in humans. J Nutr Metab. 2010;2010.
  8. Martinez I, Kim J, Duffy PR, Schlegel VL, Walter J. Resistant starches types 2 and 4 have differential effects on the composition of the fecal microbiota in human subjects. PLoS One. 2010;5:e15046.
  9. Shimotoyodome A, Suzuki J, Kameo Y, Hase T. Dietary supplementation with hydroxypropyl-distarch phosphate from waxy maize starch increases resting energy expenditure by lowering the postprandial glucose-dependent insulinotropic polypeptide response in human subjects. Br J Nutr. 2011;106:96-104.
  10. Gentile CL, Ward E, Holst JJ, et al. Resistant starch and protein intake enhances fat oxidation and feelings of fullness in lean and overweight/obese women. Nutr J. 2015;14:113.
  11. Stewart ML, Zimmer JP. Post-prandial glucose and insulin response to high-fiber muffin top containing resistant starch type 4 in healthy adults: a double-blind, randomized, controlled trial. Nutrition. 2018 (in press).
  12. Maki KC, Pelkman CL, Finocchiaro ET, et al. Resistant starch from high-amylose maize increases insulin sensitivity in overweight and obese men. J Nutr. 2012;142:717-723.
  13. Marlatt KL, White UA, Beyl RA, et al. Role of resistant starch on diabetes risk factors in people with prediabetes: design, conduct, and baseline reuslts of the STARCH trial. Contemp Clin Trials. 2018;65:99-108.
tape measure

Breakfast Skippers Beware: Newly Published Data on Breakfast Patterns Identifies Association with Atherosclerosis, Independent of Cardiovascular Disease Risk Factors

Breakfast Skippers Beware: Newly Published Data on Breakfast Patterns Identifies Association with Atherosclerosis, Independent of Cardiovascular Disease Risk Factors

Insights from the Progression of Early Subclinical Atherosclerosis (PESA) Study

By Kristen N Smith, PhD, RD, LD; Mary R Dicklin, PhD; Kevin C Maki, PhD

 Background: It is well accepted that a person’s lifestyle may impact markers of overall health. Factors associated with lifestyle may be dependent on cultural, social and psychological practices as they fit into a daily routine. Researchers have paid particular attention to the lifestyle habit of breakfast consumption (or non-consumption) and how it may contribute to disease risk.

Whether or not a person consumes breakfast has correlations to such factors as:

  • Measures of satiety,
  • Daily energy intake,
  • Metabolic efficiency of the diet,
  • Appetite regulation.

The regular omission of breakfast has associations with increased cardiovascular health markers such as obesity, diabetes, and unfavorable lipid profiles. Although there have been studies investigating the impacts of breakfast skipping behaviors with heart disease risk, the current study may be the first to research an association between breakfast patterns and subclinical atherosclerosis. The aim of the Progression of Early Subclinical Atherosclerosis (PESA) study1 was to characterize the association between different breakfast patterns and cardiovascular disease (CVD) risk factors; especially focusing on whether the regular omission of breakfast is associated with subclinical atherosclerosis (noted by investigating the presence of atherosclerotic plaques in the carotid arteries, aorta, and iliofemoral arteries or coronary artery calcium in a population with no previous CVD history).

 Methods: The PESA study is an ongoing observational prospective cohort of 4,082 employees of the Bank Santander Headquarters in Madrid, Spain. Male and female volunteers, aged 40 to 54 years old, were included if they met the following criteria:

  • Free of any CVD or chronic kidney disease,
  • No previous transplant,
  • Did not exceed body mass index (BMI) of 40 kg/m2,
  • Did not have any disease that might affect life expectancy and decrease it to <6 years.

Estimates of usual diet were determined through the use of a computerized questionnaire, which was developed and validated in the Estudio de Nutrición y Riesgo Cardiovascular (ENRICA) study of a Spanish population and contains nutritional information on 861 food items including many typically consumed Spanish meals and dishes. Subjects reported the foods consumed in the past 15 days while also noting specific occasions throughout the day (waking up, breakfast, mid-morning, lunch, mid-afternoon, and dinner). To characterize breakfast patterns, the researchers first utilized the quantitative description of breakfast provided by Timlin and Pereira2: “the first meal of the day that breaks the fast after the longest period of sleep, eaten before the start of daily activities (e.g., errands, travel, work), within 2 h of waking, typically no later than 10:00 in the morning, and an energy level between 20 and 35% of total daily energy need.” Additional input was gathered by application of a qualitative definition of breakfast by O’Neill et al. where breakfast is defined as “a food or beverage from at least one food group, and may be consumed at any location. Coffee, water and nonalcoholic beverages are not included in a food group.”3 Mean energy intake of the subjects in the PESA study was 2,314 kcal/day; three major breakfast groups were identified:

  • <5% total energy intake (EI) = skipping breakfast (SBF)
  • 5 to 20% total EI from breakfast = low-energy breakfast (LBF)
  • >20% total EI from breakfast = high-energy breakfast (HBF)

Anthropometric data were collected and CVD risk factors and metabolic syndrome (MetS) were assessed. The European Society of Cardiology CVD risk assessment tool, the Systematic Coronary Risk Evaluation, was used to assess fatal cardiovascular risk. Additionally, researchers noted variables such as age, gender, marital status, highest educational level, smoking status, diet practices and physical activity. Specific ultrasound equipment was utilized to assess atherosclerotic plaque in multiple vascular areas: bilateral carotid, infrarenal abdominal aorta and iliofemoral arteries. Plaques were defined as “focal protrusion into the arterial lumen of thickness >0.5 mm or >50% of the surrounding intima-media thickness or a diffuse thickness >1.5 mm measured between the media-adventitia and intima-lumen interfaces.” Coronary artery calcium (CAC) was also assessed, and states of atherosclerosis were defined as follows:

 

State of Atherosclerosis Definition
Subclinical atherosclerosis The presence of plaque in the right carotid, left carotid, aorta, right iliofemoral, or left iliofemoral or as the presence of calcium (CAC score > 0) in the coronary arteries
Non-coronary atherosclerosis The presence of plaque in the above areas and excluding CAC
Generalized atherosclerosis Dependent on the number of sites affected with atherosclerosis; 4 to 6 sites affected

 

Results: Of the 4,052 participants, 2.9%, 69.4% and 27.7% fell into the SBF (breakfast skipping), LBF (low-energy breakfast) and HBF (high-energy breakfast) categories, respectively. Compared with HBF and LBF, the SBF group was made up mostly of men, current smokers, subjects who had reportedly changed their diet in the previous year to lose weight, and subjects who consumed their highest energy intake at lunch. Compared with HBF, the LBF subjects were more likely to be men with lower education level and to be current smokers with higher calorie intakes at lunch.

Regarding diet quality, the subjects in the SBF group were most likely to have higher energy, protein (from animal sources) and dietary cholesterol intakes while also having the lowest fiber and carbohydrate intakes and greatest consumption of alcoholic and sugar-sweetened beverages and red meat.  The LBF group (compared with HBF) had higher overall energy, animal protein and cholesterol intakes and lower intakes of sugar and polysaccharides while also having dietary patterns lower in fruits, vegetables, whole grains and olive oil and higher in refined grains, red meat, fast food and precooked meals (as well as lean meat and seafood). The HBF group had the greatest intakes of dietary fiber, fruits and vegetables, whole grains and high-fat dairy.

The cardiometabolic risk marker profile was less favorable in the LBF and SBF groups, including higher levels of waist circumference, BMI, blood pressure, blood lipids and fasting blood glucose. Participants in the SBF group had a greater likelihood of scoring high on the European Society of Cardiology Systematic Coronary Risk Evaluation risk scale. Probabilities of obesity, abdominal obesity, MetS, low high-density lipoprotein cholesterol, and hypertension were significantly greater for the SBF group compared with HBF.  The prevalence values for atherosclerosis (subclinical, non-coronary and generalized) across all PESA subjects were 62.5%, 60.3% and 13.4%, respectively.

The odds ratios (ORs) for subclinical atherosclerosis were significantly elevated in the SBF group compared with the HBF group:

  • Abdominal aorta - OR 1.79, 95% confidence interval (CI) 1.16 to 2.77,
  • Carotid atherosclerotic plaques - OR 1.76, 95% CI 1.17 to 2.65,
  • Iliofemoral plaques - OR 1.72, 95% CI 1.11 to 2.64,
  • Coronary atherosclerosis – OR 1.55, 95% CI 0.97 to 2.46,
  • Non-coronary and generalized atherosclerosis - OR 2.57, 95% CI 1.54 to 4.31.

The participants in the LBF group had greater risk of carotid or iliofemoral atherosclerotic plaques compared with the HBF group (OR 1.21; 95% CI 1.03 to 1.43 and OR 1.17; 95% CI 1.00 to 1.37, respectively).

Comment: The results from the PESA study indicate that regular skipping of breakfast was associated with 1.55- to 2.57-fold higher odds for subclinical atherosclerosis, even after adjustment for traditional CVD risk factors and diet quality. Breakfast skipping behavior was also linked to an overall unhealthy lifestyle (poor overall diet, higher consumption of alcohol and smoking).  Other researchers have also noted these same associations in that skipping breakfast is often associated with smoking4, greater total energy intake5, and noncompliance with “Healthy Eating” recommendations.6

Results from PESA confirm the association between breakfast skipping and an adverse cardiometabolic risk marker profile and further show that breakfast skipping is independently associated with subclinical measures of atherosclerosis.  However, the degree to which this association might be causal vs. reflective of residual confounding due to greater exposure to CVD risk markers over time is uncertain.

Several studies have demonstrated that insulin sensitivity shows diurnal variation.  For example, Saad et al. reported that mean values for an index of insulin sensitivity produced from postprandial responses to identical meals at breakfast, lunch and dinner were 11.2, 7.9 and 8.1 (units = 10-4 dL/kg/min/mU/mL).7  Thus, insulin sensitivity was ~40% higher in the morning compared with the afternoon or evening.  It is possible that consuming a lower percentage of daily energy during the times of day when insulin sensitivity is highest (consumption of a low-energy breakfast or breakfast skipping) has an adverse impact on the cardiometabolic risk profile, increasing risks for both type 2 diabetes mellitus and atherosclerotic CVD, although prospective trials will be needed to investigate this possibility.8

 References

  1. Uzhova I, Fuster V, Fernandez-Ortiz A, et al. The Importance of Breakfast in Atherosclerosis Disease: Insights From the PESA Study. J Am Coll Cardiol. 2017;70(15):1833-1842.
  2. Timlin MT, Pereira MA. Breakfast frequency and quality in the etiology of adult obesity and chronic diseases. Nutr Rev. 2007;65(6 Pt 1):268-281.
  3. O'Neil CE, Byrd-Bredbenner C, Hayes D, Jana L, Klinger SE, Stephenson-Martin S. The role of breakfast in health: definition and criteria for a quality breakfast. J Acad Nutr Diet. 2014;114(12 Suppl):S8-S26.
  4. Nishiyama M, Muto T, Minakawa T, Shibata T. The combined unhealthy behaviors of breakfast skipping and smoking are associated with the prevalence of diabetes mellitus. Tohoku J Exp Med. 2009;218(4):259-264.
  5. van der Heijden AA, Hu FB, Rimm EB, van Dam RM. A prospective study of breakfast consumption and weight gain among U.S. men. Obesity (Silver Spring, Md). 2007;15(10):2463-2469.
  6. Smith TJ, Dotson LE, Young AJ, et al. Eating patterns and leisure-time exercise among active duty military personnel: comparison to the Healthy People objectives. J Acad Nutr Diet. 2013;113(7):907-919.
  7. Saad A, Dalla Man C, et al. Diurnal pattern to insulin secretion and insulin action in healthy individuals. Diabetes. 2012;61(11):2691-2700.
  8. Maki KC, Phillips-Eakley AK, Smith KN. The effects of breakfast consumption and composition on metabolic wellness with a focus on carbohydrate metabolism. Adv Nutr. 2016;7 (Suppl 6):613S-621S.

 

Photo by Brooke Lark

Putting the FOURIER Findings in Perspective

FOURIER

Putting the FOURIER Findings in Perspective

By Kevin C Maki, PhD

Background and Methods
Earlier this year the results from the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial were published in the New England Journal of Medicine1 in conjunction with their presentation at the American College of Cardiology Scientific Sessions.  For the trial, 27,564 patients with atherosclerotic cardiovascular disease (ASCVD) and low-density lipoprotein cholesterol (LDL-C) at least 70 mg/dL while on statin therapy were randomly assigned to receive 140 mg of evolocumab or placebo by subcutaneous injection every 2 weeks.  Evolocumab is a proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor that lowers LDL-C and cholesterol carried by other apolipoprotein B-containing lipoproteins by reducing the rate at which hepatic LDL receptors are catabolized.

The primary and key secondary composite outcomes were:

  • Primary: cardiovascular (CV) death, myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization;
  • Key secondary: CV death, myocardial infarction, stroke.

 

Results
The median baseline LDL-C level was 92 mg/dL, which was reduced by an average of 59% compared to placebo at 48 weeks to a median value of 30 mg/dL. Levels of non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B, were also reduced by 52% and 49%, respectively. 

The primary outcome was reduced by 15% (95% confidence interval [CI] 8 to 21%) and the key secondary endpoint was reduced by 20% (95% CI 12 to 27%) with evolocumab vs. placebo over an average follow-up period of 2.2 years.  In the placebo group, the primary and key secondary outcomes occurred in 11.3% and 7.4% of subjects, respectively.  Efficacy results were consistent across subgroups, including men and women and quartiles of baseline LDL-C.  The effect appeared to grow over time.  Beyond 12 months, the reduction in the key secondary outcome with evolocumab was 25%, compared to 16% during the first 12 months.  Other than injection site reactions (2.1% vs. 1.6%), no significant differences in adverse events were present between treatment groups.

 

Comment
The results from FOURIER bolster the case for the view that “lower is better” when it comes to LDL-C and related atherogenic lipoprotein variables such as non-HDL-C and apolipoprotein B.  The trial had a shorter follow-up time (2.2 years) than most statin trials, which have averaged roughly 5 years of treatment.  The event rate in FOURIER was relatively high (about 3-5% per year in the placebo group).

The reduction in LDL-C from a median baseline level of 92 to an on-treatment level of 30 mg/dL is a reduction of about 62 mg/dL (1.6 mmol/L). The results from the Cholesterol Treatment Trialists’ (CTT) analysis of data from statin trials2,3 would predict a reduction in risk of roughly 33% over five years for major vascular events [1 – (0.78^1.6) = 0.328], assuming a hazard ratio of 0.78 per 1.0 mmol/L reduction in LDL-C.  However, the follow-up period was shorter than 5 years, so we have to look at the CTT analysis for shorter timeframes for comparison.  The definition of major vascular event in the CTT analysis included the combined outcome of major coronary event, non-fatal or fatal stroke, or coronary revascularization.  This outcome has elements of both the primary and key secondary outcomes in FOURIER.  For simplicity, I will focus on the key secondary outcome in FOURIER of CV death, myocardial infarction or stroke for comparison to the CTT results with statin therapy.

During years 0-1, the hazard ratio in the CTT analysis was 0.90 per mmol/L of LDL-C reduction.2 The corresponding hazard ratios for years 1-2 and 2-3 were 0.78 and 0.74, respectively.2  I will use 0.78 in my calculations for simplicity, since this corresponds to the overall result from the CTT analysis.  For the first year, the predicted risk reduction in FOURIER based on the CTT values would be 15.5% [1 – (0.90^1.6) = 0.155].  This corresponds very closely to the 16% reduction in the key secondary outcome during the first 12 months.  Beyond 12 months, the effect in FOURIER was a 25% reduction in risk.  This is slightly below the predicted 32.8% reduction predicted by the CTT relationship, but certainly not far enough below the predicted value to conclude that the relationship is not similar.

In his presentation at the American College of Cardiology meeting, the Principal Investigator, Dr. Marc Sabatine, compared the results from year 2 of follow-up in FOURIER and the CTT analysis for the outcomes of major coronary events and stroke.3 They were very similar, as you can see by examining the hazard ratios and 95% CIs, which are shown below:

  • Major coronary events
    • CTT: 0.78 (0.70 to 0.86)
    • FOURIER: 0.80 (0.71 to 0.90)
  • Stroke
    • CTT: 0.77 (0.66 to 0.91)
    • FOURIER: 0.77 (0.63 to 0.94)

Thus, once the relatively short follow-up period is taken into account, the results from FOURIER are consistent with those from the CTT analysis, and are generally supportive of a linear relationship between LDL-C reduction and lower CV event risk, extending to lower levels than had previously been studied in large CV outcomes trials.

The findings from FOURIER are consistent with those from a pooled analysis of 10 trials in the development program for another PCSK9 inhibitor, alirocumab.4 In that analysis, a 39 mg/dL reduction in LDL-C (roughly 1 mmol/L) was associated with a hazard ratio of 0.76 (95% CI 0.63 to 0.91) compared with control for major adverse CV events.  Similar results were obtained for non-HDL-C and apolipoprotein B reductions.  When expressed per 50% reduction from baseline, the relative risk reductions for LDL-C, non-HDL-C and apolipoprotein B were 29%, 29% and 32%, respectively.

The results from FOURIER have generated confusion because the risk reduction reported was less than some had expected.  The CV benefits of LDL-C reduction take some time to become fully apparent.  Thus, after taking into account the comparatively short follow-up period of 2.2 years, it is clear that the FOURIER results are aligned with previous results from statin trials, as represented by the CTT analysis, as well as the findings from the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), in which the small incremental reduction of about 0.4 mmol/L in LDL-C when ezetimibe was added to statin therapy translated into additional CV event risk reduction of 7-10%.5  Accordingly, the FOURIER results further strengthen the evidence that reducing LDL-C (and related variables such as non-HDL-C and apolipoprotein B) will reduce CV event risk in high-risk patients.

Additional evidence is expected to become available in 2018 from a trial with the other PCSK9 inhibitor currently cleared by the Food and Drug Administration, ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab.  Assuming that the results from that trial confirm those from FOURIER, the debate will continue to focus not on who might benefit from therapy, but rather for whom PCSK9 inhibitor therapy is justified, given the cost of approximately $14,000 per year.

References:
1.     Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713-1722.

2.     The Cholesterol Treatment Trialists’ Collaboration. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267-1278.

3.     The Cholesterol Treatment Trialists’ Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670-1681.

4.     Ray KK, Ginsberg HN, Davidson MH, et al. Reductions in atherogenic lipids and major cardiovascular events: a pooled analysis of 10 ODYSSEY trials comparing alirocumab with control. 2016;134:1931-1943.

5.     Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387-2397.

 

FOURIER

Changes in Diet Quality and Mortality

Changes in Diet Quality and Mortality

Changes in Diet Quality and Mortality

By Kevin C Maki, PhD

Background
Sotos-Prieto and colleagues from the Departments of Nutrition and Epidemiology at Harvard University published an analysis of the relationships between changes in diet quality scores and mortality [all-cause, cardiovascular (CV), and cancer] in a recent issue of the New England Journal of Medicine.1  These relationships were examined in two large cohorts of health professionals, the US Nurses’ Health Study (women) and the US Health Professionals Follow-up Study (men).

Previous studies have shown that higher diet quality scores are associated with lower mortality.  Of course, the potential problem with observational evidence is that it is difficult to know whether it is higher diet quality per se that is responsible for the relationship to lower mortality, or other differences between those with lower and higher diet quality scores.  People who consume diets that conform to recommendations from health authorities often have other characteristics that might contribute to better outcomes.  They tend to be more health conscious, have higher educational attainment, exercise more regularly, have lower body mass index, and be less likely to smoke, use illicit substances and consume alcohol to excess, just to name a few of the differences.

Epidemiologists attempt to adjust for these differences using statistical techniques to reduce the potential for bias and confounding by differences other than the exposure of interest; in this case diet quality score.  It is often impossible to identify and adjust for all of the variables that may be relevant.  The ultimate goal is to identify exposures that are causally related to disease status and modifiable, which can serve as the basis for public health actions, including recommendations for the characteristics of a healthy diet.

While far from perfect, it is useful to investigate the relationships between changes in exposure variables over time and disease risk.  For example, it bolstered the case for a causal relationship between cigarette smoking and risks for lung cancer and heart disease when it was shown that risks declined over time in those who quit smoking, but did not in those who continued to smoke.  Similarly, the Harvard group sought to assess whether changes in diet quality scores over time predicted risks for all-cause and cause-specific mortality.

Methods
In order to address this question, the researchers calculated changes over time in three scores:  the Alternative Healthy Eating Index (aHEI), the Alternative Mediterranean Diet (aMED) score, and the Dietary Approaches to Stop Hypertension (DASH) score.  Scores were calculated based on responses to the Willett Food Frequency Questionnaire that was administered every 4 years over long periods in both cohorts.  For the main analysis, changes in diet quality were calculated from 1986 to 1998 and follow-up was through 2010 (12 years).  The analysis included data from 73,739 participants (65% women).

The aHEI used scores from 0-10 for 11 food components selected on the basis of their relationships with chronic diseases.  Thus, the score could be from 0 to 110.  The aMED score included 9 components and were scored as 0 or 1 according to whether intake was above or below the cohort-specific median, allowing a score from 0 to 9.  The DASH score included 8 components, each scored 1-5, thus producing scores ranging from 8 to 40.  For all, a higher score indicated higher diet quality.

Results
Participants who increased their diet quality scores reported increased intakes of whole grains, vegetables and omega-3 fatty acids, as well as reduced intakes of sodium.  Compared to participants with relatively stable scores (middle quintile for change), those in the top 20% for increases (roughly 15-16 points for aHEI, 2-3 points for aMED, and 5-6 points for DASH), had 9-14% lower mortality risk, all p < 0.05 for the fifth vs. the third quintile in multivariable-adjusted models.  Similar results were obtained when a 20-percentile increase in score was modeled (8-17% lower risk for mortality).

Results were somewhat less consistent for deaths from CV causes and cancer.  A 20-percentile increase in aHEI was associated with 15% lower CV mortality (p < 0.05), while the same increase in aMED was associated with a 7% lower CV mortality (p < 0.05), and a 20-percentile increase in DASH score was associated with a non-significant 4% reduction in mortality.  For cancer mortality, a 20-percentile increase was associated with 6-9% lower mortality, which was only statistically significant (p < 0.05) for the DASH score (9%).

Having constant high diet quality score was associated with reductions of 9-14% in all-cause mortality over 12 years compared to those with constant low scores.  The investigators also looked at 8-year and 16-year changes.  In general, the effect became more pronounced with longer periods.  This was particularly evident for the aHEI, although that may be due to the greater range of values possible, which increases the variation in the populations studied.

Comment
This study adds support for the healthy eating patterns recommended in the Dietary Guidelines for Americans (2015-2020).2  Although confounding by unmeasured, or crudely measured, factors cannot be ruled out, the available data are consistent with a causal association between a healthy diet pattern and reduced risks for all-cause and CV mortality.  The evidence for a reduction in cancer mortality with a healthy dietary pattern is less convincing.  These results particularly support the recommendations for increased consumption of whole grains, fruits, vegetables, and fish/omega-3 fatty acids, compared with the average American diet, since these were the foods that were primarily responsible for changes in diet quality scores over time.

As I have stated repeatedly, public policy recommendations regarding diet often have to be based on evidence from observational studies assessing disease risk and intervention studies of biomarkers for disease risk, because few randomized, controlled dietary intervention studies have been completed to assess effects on disease incidence.  The strongest recommendations should be reserved for those areas where we have alignment between results from all three types of studies.

The results from the Prevención con Dieta Mediterránea (PREDIMED) study support health benefits, including reduced incidence of CV events (particularly stroke) and diabetes associated with advice to consume a Mediterranean diet pattern supplemented with nuts or olive oil, compared to low-fat diet advice.3 PREDIMED was not a perfect trial.  More randomized, controlled dietary intervention trials with outcomes of disease incidence are badly needed to answer questions about risks and benefits of various types of dietary advice.  PREDIMED demonstrates the feasibility of completing such studies.

For now, despite a number of caveats and uncertainties, the best available evidence suggests that the dietary patterns recommended in the Dietary Guidelines for Americans (healthy US diet, Mediterranean diet, DASH diet) are associated with a variety of favorable outcomes, including reduced total and CV mortality.

References:

  1. Sotos-Prieto M, Bhupathiraju SN, Mattei J, et al. Association of changes in diet quality with total and cause-specific mortality. N Engl J Med. 2017;377:143-153.
  2. US Department of Health and Human Services and US Department of Agriculture. Dietary Guidelines for Americans 2015-2020. 8th December 2016. Available at https://health.gov/dietaryguidelines/2015/resources/2015-2020_Dietary_Guidelines.pdf.
  3. Estruch R, Martínez-González MA, Corella D, et al.; PREDIMED Study Investigators. Effects of a Mediterranean-style diet on cardiovascular risk factors: a randomized trial. Ann Intern Med. 2006;145:1-11.

 

 

Changes in Diet Quality and Mortality

Another CETP Inhibitor Fails to Show Cardiovascular Benefit, Despite Reducing LDL Cholesterol and Raising HDL Cholesterol: Implications of the ACCELERATE Trial

CETP Inhibitor

Another CETP Inhibitor Fails to Show Cardiovascular Benefit, Despite Reducing LDL Cholesterol and Raising HDL Cholesterol: Implications of the ACCELERATE Trial

  By Kevin C Maki, PhD

Cholesteryl ester transfer protein (CETP) is an enzyme that modulates the transfer of cholesterol esters from high-density lipoprotein (HDL) particles to apolipoprotein (apo)-B containing particles, including very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) particles.  CETP inhibitor drugs, by blocking this action, raise the level of HDL cholesterol (HDL-C) and lower the level of LDL cholesterol (LDL-C).

Previous outcomes trials with two CETP inhibitors, torcetrapib and dalcetrapib, failed to show cardiovascular disease (CVD) event risk reduction.1 Torcetrapib use was associated with increased CVD event risk, which was believed to be secondary to off-target effects, including raising blood pressure and aldosterone levels and lowering serum potassium concentration.  Whereas torcetrapib raised HDL-C by 70% and lowered LDL-C by 25%, dalcetrapib was a weak CETP inhibitor and raised HDL-C by only 30%, while having no effect on LDL-C.  A CVD outcomes trial with dalcetrapib was stopped for futility, showing no evidence of benefit or harm regarding CVD event risk.

The ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes) trial evaluated the effects of evacetrapib 130 mg/d vs. placebo, when added to standard therapies in ~12,000 men and women with high CVD risk secondary to having clinical atherosclerotic CVD with a history of a recent acute coronary syndrome, cerebrovascular atherosclerosis, peripheral atherosclerosis, or diabetes mellitus with known coronary disease).2

After randomization, the effects of evacetrapib compared to placebo on mean or median changes from baseline to the 3-month timepoint in lipoprotein-related parameters were as follows (all p < 0.001):

  • HDL-C: +134.8%;
  • LDL-C: -37.1%;
  • Triglycerides (TG): -6.0%;
  • Apo B: -19.3%;
  • Lipoprotein (a): -22.3%.

There were also small changes (all p < 0.01), relative to placebo, in systolic/diastolic blood pressure (+1.2/+0.5 mm Hg) and C-reactive protein (8.6%).

Despite substantial changes in potentially favorable directions in lipoprotein-related variables, no difference was present for the primary efficacy outcome of the first occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina:  hazard ratio (HR) 1.01, 95% confidence interval (CI) 0.91 to 1.11, p = 0.91.  After an interim analysis with 82% of the final projected number of events, the trial was stopped early for futility.  No significant benefits were present for any of the individual components of the primary outcome, nor for a secondary composite that excluded hospitalization for unstable angina.

Comment.  The third failure of a CETP inhibitor to show CVD event risk reduction may sound the death knell for this class of lipid-altering agents.  The reasons for the lack of benefit in ACCELERATE are unclear.  Although HDL-C concentration is a strong inverse predictor for CVD event risk, the mechanisms responsible for this consistent finding are uncertain.   There are numerous ways that the HDL-C level can be raised, some of which could be beneficial, while others may be only cosmetic.

More disturbing than the lack of benefit associated with a rise in HDL-C, is the fact that LDL-C, TG, apo B and lipoprotein (a) were all lowered, yet this did not reduce CVD event risk.  Reduced CVD event risk has been observed with other agents that lower apo B-containing lipoproteins such statins, ezetimibe and proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors, so why did changes in these values with evacetrapib fail to lower risk?

Niacin lowers apo B-containing lipoproteins and lipoprotein (a), while also raising HDL-C, and it failed to demonstrate CVD event risk reduction in both the HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) study (co-administered with laropiprant) and in the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial .3  However, there were issues in both trials regarding whether the subjects enrolled were appropriate candidates for niacin therapy.3  For example, more than two-thirds of the subjects in HPS2-THRIVE had baseline non-HDL-C of less than 100 mg/dL.  Such individuals would not be likely to have been prescribed niacin in clinical practice.

Interventions that lower LDL-C and apo B-containing lipoproteins through mechanisms that involve inducing an upregulation in hepatic LDL receptor activity, including statins, ezetimibe and PCSK9 inhibitors have all been shown to reduce CVD event risk.  Lowering LDL-C and apo B-containing lipoproteins with evacetrapib had no effect on risk.  Should we infer from these results that lowering LDL-C and apo B-containing lipoproteins through mechanisms that do not upregulate hepatic LDL receptor activity will not reduce CVD risk?  Alternatively, is it the case that evacetrapib had some off-target effect(s) that offset the benefits of LDL-C and apo B-containing lipoprotein reduction, as has been hypothesized for torcetrapib?  Evacetrapib did produce modest increases in blood pressure and C-reactive protein.  These changes were small enough that they are unlikely to have been sufficient to directly offset the expected CVD benefits from reductions in LDL-C and apo B-containing lipoproteins.  However, they could be indicators of other adverse neuroendocrine and/or inflammatory effects.  At present, it is not possible to determine whether the explanation for the lack of benefit with evacetrapib was attributable to one of these, or perhaps some other explanation.

References:

  1. Barter PJ, Rye KA. Targeting high-density lipoproteins to reduce cardiovascular risk: what is the evidence? Clin Ther. 2015;37:2716-2731.
  2. Lincoff AM, Nicholls SJ, Riesmeyer JS, et al.; ACCELERATE Investigators. Evacetrapib and cardiovascular outcomes in high-risk vascular disease. N Engl J Med. 2017;376:1933-1942.
  3. Mani P, Rohatgi A. Niacin therapy, HDL cholesterol, and cardiovascular disease: is the HDL hypothesis defunct? Curr Atheroscler Rep. 2015;17:521.

 

 

CETP Inhibitor

MB Clinical Academy Releases its First Two Educational Programs

MB Clinical Academy

MB Clinical Academy Releases its First Two Educational Programs

MB Clinical Academy produces educational materials to help clinicians, clinical research professionals and students more effectively manage the cardiometabolic health of their patients/clients, and to understand the strengths and limitations of the available evidence, including gaps that can be filled with future studies.

We have just completed two new programs, which will be available for purchase and download during the week of July 10, 2017.

Short Course

Diet and Prevention of Type 2 Diabetes Mellitus:  Beyond Weight Loss and Exercise

This short course will review the evidence for dietary factors in the prevention of type 2 diabetes mellitus (T2D).  It contains three modules that will cover:

  • Module 1: Epidemiology and pathophysiology of T2D
  • Module 2: Predictors of T2D risk and effects of interventions on incidence
  • Module 3: Summary of the associations and mechanisms through which diet may affect T2D risk, with an emphasis on insulin sensitivity and glycemic load

Short Course

Interpreting Efficacy Results from Cardiovascular Outcomes Trials

Cardiovascular outcomes trials are integral to evidence-based medicine, and they are the most effective means for demonstrating that an intervention reduces major adverse cardiovascular events.  A sound understanding of the fundamentals of clinical study design and statistical methodology is essential for the interpretation of efficacy results from cardiovascular outcomes trials.  However, most clinicians have not had extensive training on how to interpret measures of association and statistical procedures used to assess the efficacy of interventions intended to reduce cardiovascular event risk.  This course will review of the following concepts and their use in cardiovascular outcomes studies:

  • Measures of cardiovascular event incidence
    1. Relative risk
    2. Hazard ratio
    3. Odds ratio
  • Comparing event rates and treatment effects
    1. Relative risk reduction
    2. Absolute risk reduction
    3. Number needed to treat (or harm)
  • Pitfalls when making comparisons between cardiovascular outcomes trials, including the three most important questions
    1. Who was studied (risk profile)?
    2. What outcomes were assessed?
    3. Over what time period?
  • Additional factors to consider in the interpretation of findings from cardiovascular outcomes trials
    1. Evaluating the roles of chance, bias and confounding
    2. Factors affecting validity and generalizability
    3. Assessing the potential for type I and type II statistical errors

We expect that those who purchase these programs will find them informative and practical.  If you have suggestions for future programs, don’t hesitate to send us an email:  info@mbclinicalresearch.com.

 

MB Clinical Academy

Replacing Refined Carbohydrates with Egg Protein and Unsaturated Fatty Acids Improves Insulin Sensitivity and the Cardiometabolic Profile

Replacing Refined Carbohydrates with Egg Protein

Replacing Refined Carbohydrates with Egg Protein and Unsaturated Fatty Acids Improves Insulin Sensitivity and the Cardiometabolic Profile

Replacing Refined Carbohydrates with Egg Protein and Unsaturated Fatty Acids Improves Insulin Sensitivity and the Cardiometabolic Profile

Consuming a healthful diet and participating in an adequate amount of physical activity are key tools for managing metabolic abnormalities that can increase risk for both cardiovascular disease and type 2 diabetes mellitus.  A growing body of evidence supports the view that a diet high in refined starches and added sugars exacerbates disturbances in carbohydrate (CHO) metabolism.  Replacement of these macronutrients with protein and/or unsaturated fatty acids (UFA) may help to improve the cardiometabolic risk factor profile.  The MB Clinical Research team conducted a trial to evaluate the effects of a combination of egg protein (Epro) and UFA, substituted for refined starches and added sugars, on insulin sensitivity and other cardiometabolic health markers in adults with elevated (≥150 mg/dL) triglycerides (TG).

Participants (11 men, 14 women) with elevated TG were randomly assigned to consume test foods prepared using Epro (~8% of energy) and UFA (~8% of energy) for the Epro/UFA condition, or using refined starch and sugar (~16% of energy) for the CHO condition.  Each diet was low in saturated fat and consumed for 3 weeks in a controlled feeding (all food provided) crossover trial, with a 2-week washout between diets.  Insulin sensitivity, assessed by the Matsuda insulin sensitivity index (MISI), increased 18.1 ± 8.7% from baseline during the Epro/UFA condition, compared to a change of -5.7 ± 6.2% during the CHO condition (p < 0.001). The disposition index, a measure of pancreatic beta-cell function, increased during the Epro/UFA condition compared to the CHO condition (net difference 40%, p = 0.042), and low-density lipoprotein (LDL) peak particle size increased during the Epro/UFA condition compared to the CHO condition (net difference 0.27 nm, p = 0.019).  TG and very low-density lipoprotein cholesterol (VLDL-C) levels were lowered more following the Epro/UFA (~16% differences, p < 0.002) versus the CHO diet condition.  LDL-C was lowered by 9-10% with both diets, compared with baseline, but the response did not differ between diets.

Comment:

Consumption of a low-saturated fat diet, where ~16% of energy from refined starches and added sugars was replaced with Epro and UFA, increased indices of insulin sensitivity and pancreatic beta-cell function, increased LDL peak particle size, and lowered fasting TG and VLDL-C levels in men and women with elevated TG.  The results of this study are consistent with a previous study by our group, where daily consumption of three servings of sugar-sweetened products reduced insulin sensitivity by 18% as assessed by HOMA2-%S compared to a habitual diet baseline, and three daily servings of dairy products produced no change.  Reductions in TG and VLDL-C may benefit cardiometabolic health, and are often accompanied by a shift toward larger, more buoyant LDL particles.  This shift, as observed in the current trial, may result in a less atherogenic LDL particle.  The findings from this trial support the Dietary Guidelines for Americans’ recommendations to limit intake of refined starches and added sugars, and to emphasize UFA intake as replacements for both dietary saturated fatty acids and refined CHO.

References:

Maki KC, Palacios OM, Lindner E, Nieman KM, Bell M, Sorce J. Replacement of refined starches and added sugars with egg protein and unsaturated fats increases insulin sensitivity and lowers triglycerides in overweight or obese adults with elevated triglycerides. J Nutr. 2017;May 17 [Epub ahead of print]

Maki KC, Nieman KM, Schild AL, Kaden VN, Lawless AL, Kelley KM, Rains TM. Sugar-sweetened product consumption alters glucose homeostasis compared with dairy product consumption in men and women at risk of type 2 diabetes mellitus. J Nutr. 2015; 145:459-466. Available at http://jn.nutrition.org/content/145/3/459.full.pdf+html.

U.S. Department of Health and Human Services and U.S. Department of Agriculture. 2015-2020 Dietary Guidelines for Americans 2015-2020. Eighth Edition. December 2015. Available at http://health.gov/dietaryguidelines/2015/guidelines/.

 

Replacing Refined Carbohydrates with Egg Protein