Postgraduate Medicine
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Raisins Compared with Other Snack Effects on Glycemia and Blood Pressure: A Randomized, Controlled Trial James W. Anderson MD, Kathy M. Weiter RD, LD, RN, BSN, Amber L. Christian RD, LD, Michelle B. Ritchey APRN & Harold E. Bays MD, FTOS, FACE, FNLA To cite this article: James W. Anderson MD, Kathy M. Weiter RD, LD, RN, BSN, Amber L. Christian RD, LD, Michelle B. Ritchey APRN & Harold E. Bays MD, FTOS, FACE, FNLA (2014) Raisins Compared with Other Snack Effects on Glycemia and Blood Pressure: A Randomized, Controlled Trial, Postgraduate Medicine, 126:1, 37-43 To link to this article: http://dx.doi.org/10.3810/pgm.2014.01.2723
Published online: 13 Mar 2015.
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Date: 13 September 2015, At: 00:00
C L I N I C A L F O C U S : C A R D I O V A S C U L A R E V E N T S , U R O L O G Y, F O R T H E P R I M A RY C A R E D O C T O R
Raisins Compared With Other Snack Effects on Glycemia and Blood Pressure: A Randomized, Controlled Trial
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DOI: 10.3810/pgm.2014.01.2723
James W. Anderson, MD 1 Kathy M. Weiter, RD, LD, RN, BSN 2 Amber L. Christian, RD, LD 2 Michelle B. Ritchey, APRN 3 Harold E. Bays, MD, FTOS, FACE, FNLA 4 Professor Emeritus, Medicine and Clinical Nutrition, University of Kentucky, Lexington, KY; 2 Research Coordinator/Dietitian; 3 Subinvestigator/Nurse Practitioner; 4 Medical Director/President, Louisville Metabolic and Atherosclerosis Research Center, Louisville, KY 1
Abstract Objective: To compare effects of raisin snacks with conventional snacks on glycemia and cardiovascular risk factors. Materials and Methods: A 12-week, randomized, controlled trial compared 3-times-a-day consumption of raisins with intake of processed snacks on glycemia and cardiovascular risk factors. Men and women were randomized to snacks (n = 15) or raisins (n = 31). Outcome measures were performed at baseline, 4, 8, and 12 weeks. Results: Fasting plasma glucose levels were not significantly affected by intake of raisins or snacks. Mean subject post prandial glucose levels were significantly reduced by raisin intake at 12 weeks; changes with raisin intake were −13.1 mg/dL (P = 0.003 vs baseline; P = 0.03 vs snacks). E ating raisins significantly decreased glycated hemoglobin (HbA1c) level (−0.12%; P = 0.004), a significantly greater level decrease than seen with snack intake (P = 0.036). Snack intake did not significantly affect subject systolic or diastolic blood pressure (BP). Raisin intake was associated with reductions in systolic blood pressure (SBP) at 4, 8, and 12 weeks with mean changes of −6.0 to 10.2 mmHg; all these changes were statistically significant (P = 0.015 to 0.001). Raisins were associated with significantly greater changes in diastolic blood pressure (DBP) at 4, 8, and 12 weeks than snacks (P , 0.05). Body weight did not significantly change within or between groups. Conclusions: Regular consumption of raisins may reduce glycemia and cardiovascular risk factors, including BP rate. Keywords: blood pressure; fruits; glycemia; hypertension; lipids; raisins
Introduction
Correspondence: James W. Anderson, MD, 506 Knapp Farm Drive, Hermitage, TN 37076. Tel: 615-457-2441 E-mail: [email protected]
Like most fruits, raisins are low in sodium and devoid of fat, saturated fat, and cholesterol. However, raisins are high in dietary fiber content and contain potassium, antioxidants, and phytochemicals, which might improve glycemia and cardiovascular disease (CVD) risk factors, such as blood pressure (BP) and lipid parameters, which may make raisins a healthier food choice compared with processed snacks.1,2 It is often recommended that total daily caloric intake be spread out throughout the day. Individuals who consume snacks regularly may experience healthier outcomes, such as lower body weight and less abdominal obesity, than those who do not snack.3 These outcomes would presumably promote more favorable adipose tissue functionality,4 a more favorable metabolic profile,5 and an improvement in CVD risk factors.6 Individuals with higher dried fruit consumption, such as raisins, may have lower body weight, lower body mass index (BMI), and reduced waist circumference than non-consumers of dried fruit.7 One might conclude that a reasonable nutritional measure to improve metabolic health is to recommend individuals frequently snack with healthy food choices.
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Anderson et al
Raisins are of particular interest because of clinical studies indicating that they have low glycemic and insulinogenic indices8–11; these properties suggest that regular consumption of raisins may lower the risk for developing diabetes for persons with prediabetes.12–15 Preliminary evidence suggests that raisins may have favorable effects on blood pressure (BP).16 Thus, our study was designed to assess the effects of raisin intake on fasting and postprandial plasma glucose levels, serum insulin levels, and BP rate. We constructed our study to evaluate a “real-life” comparison of raisin intake, a natural dried fruit, compared with processed snack-food consumption, the hypothesis being that routine raisin snacks consumed 3 times a day over 12 weeks might be more beneficial in terms of associated improvements in glycemic and CVD risk factors compared with equicaloric alternative processed-food snacks.
Materials and Methods
The objective of our pilot study was to compare the effects of eating raisins 3 times per day with eating alternative processed-food snacks 3 times per day on CVD risk factors. The primary endpoints were changes at week 12 in subject fasting plasma glucose level, plasma glucose level 2 hours post-administration of 75 g oral glucose, and body weight, in raisin-eating versus control-snack consuming groups. Secondary endpoints were changes at weeks 4, 8, and 12 for raisin versus control snack groups regarding glycated hemoglobin (HbA1c) levels, BP (systolic [SBP] and diastolic [DBP]) rates, body mass index (BMI), waist circumference, and serum lipid levels—total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDLC), and high-density lipoprotein cholesterol (HDL-C). Endpoints of special interest included serum potassium, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels. The active, or raisin group, consumed a 1-ounce, prepackaged serving of dark raisins (90 kcal/serving), 3 times daily. The control, or snack comparator group, consumed prepackaged processed snacks (100 kcal/serving), 3 times daily. The use of commonly available prepackaged raisins and snacks was chosen for the purpose of commercial availability, and to obtain study outcome data through real-life food consumption. Control subjects could choose from the following snacks: Fudge Shoppe or Grasshopper cookies; Fudge Shoppe mini fudge stripes cookies; Honey Maid cinnamon roll thin crisps; Keebler Cheez-It crackers; Lorna Doone baked shortbread cookie crisps; Nabisco Chips Ahoy! baked chocolate chip snacks; Oreo baked chocolate wafer snacks; 38
Pepperidge Farm Goldfish baked snacks. The prepackaged commercial snacks provided 100 kcal/serving and did not contain raisins, or solely fruits, or solely vegetables. The nutrition summary for raisins and snacks is provided in Table 1. Both raisins and snacks were to be eaten 3 times daily and consumed before breakfast, lunch, or dinner with 8 ounces of a non-caloric beverage (preferably water but non-caloric soft drinks or a hot beverage were acceptable). Study participants were educated by a registered dietitian on therapeutic lifestyle changes17 at the randomization visit. Fasting blood samples for analyses were obtained after a 12-hour fast. Blood pressure measurements were obtained after study subjects had been seated quietly for $ 5 minutes, with 3 readings taken, and then averaged. Body weight was obtained on calibrated scales, with study participants placed in gowns. Two body weights were recorded, with the average of the weights recorded. The design was a randomized, un-blinded, single research site, active-controlled pilot study. Expected participation for each study subject was 14 to 16 weeks, including 2 to 4 weeks of screening, and 12 weeks of randomized intake of assigned snack. The protocol was approved by a central Institutional Review Board, and the study registered on http://clinicaltrials.gov (Identifier: NCT01260272). Prior to initiation of the study, and prior to protocol-directed procedures, study participants underwent the informed consent process, including review of an Institutional Review Boardapproved informed consent document/agreement explaining the procedures of the study and the potential risks. Inclusion criteria was men and women, aged . 18 years, with a body mass index (BMI) from 25.0 to 34.9 kg/m² and with $ 1 fasting plasma or serum glucose levels of 90 to 150 mg/dL documented within 4 weeks of the initial study visit. Baseline BP was required to be . 120 mm Hg s ystolic or . 80 mm Hg diastolic. Exclusion criteTable 1. Nutrition Values per Servinga Nutritive Measure
Raisins
Representative Snackb
Range
Calories (kcal) Total fat, g Cholesterol, mg Sodium, mg Potassium, mg Total Carbohydrate, g Dietary fiber, g Sugars, g Protein, g
90 0 0 5 220 22 2 20 ,1
100 3.0 0.5 134 23 16 0.5 5.3 1.5
100 2.0–3.5 0–4.0 65–170 15–30 14–19 0–1 0–8 0.8–3
Subjects consumed 3 snacks/d. Values are average of the 8 representative snacks listed in article text (Materials and Methods section).
a
b
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Raisins Versus Snack Effects on Cardiovascular Risk
ria included: intolerance, dislike, or unwillingness to consume raisins or any of the comparator snacks; weight loss of . 5 pounds in the 2 months prior to study entry; previous diagnosis of diabetes mellitus; and currently taking diabetes mellitus treatment (including drugs such as metformin or colesevelam HCl, even if not being taken for diabetes mellitus). Exclusionary BP was . 160 mm Hg systolic or . 100 mm Hg diastolic. Exclusionary laboratory values included: fasting serum lipoprotein levels of LDL-C . 160 mg/dL, or triglycerides . 500 mg/dL, creatinine level . 1.5 times the upper range of normal (0.6–1.2 mg/dL), and potassium level above the upper range of normal (3.5–5.5 mEq/L). In addition to anti-diabetes mellitus medications, other exclusionary therapeutic criteria included initiation or change of any antihypertensive medication or lipid-altering medication within 2 months prior to initial study entry (subjects were eligible if on a stable dose of 1 or 2 antihypertensive or lipid-altering medications that were maintained at constant dose throughout the study). Compliance was assessed by counting the number of snacks returned at each clinic visit; subjects were issued about 21 snacks more than required during the preceding 4 weeks.18 Safety was assessed in all subjects who received $ 1 snacks by monitoring for the occurrence of adverse experiences and by clinical evaluation, including medical history, physical examination, and laboratory evaluations. The investigator assessed whether each adverse experience was definitely not, probably not, possibly, probably, or definitely due to study therapy, based upon clinical judgment. The randomized population was defined as all subjects who underwent the informed consent process, who signed the informed consent document, and who were assigned a randomization number. The intent-to-treat (ITT) population consisted of all randomized subjects who had a baseline efficacy measurement, consumed $ 1 snack, and had $ 1 post-randomization efficacy measurement. The safety population was defined as all randomized subjects who consumed $ 1 snack and assessed by treatment-emergent adverse experiences, clinical laboratory test results, and physical examinations in the safety sample. For the ITT analysis, the last observation carry forward (LOCF) method was used to impute missing data points for subjects who discontinued without completing the entire treatment period. The sample size was determined by an estimate of what might represent clinically meaningful differences between the raisin and commercially available snacks groups. Thirtytwo subjects (assuming 27 completing subjects) administered raisins were estimated to be sufficient in detecting a
s ignificant (5 mg/dL) reduction in fasting plasma glucose HbA1c level (P , 0.05), assuming a baseline fasting plasma glucose level of 110 + 9.5 mg/dL (mean + SD). Comparative efficacy within paired groups (raisin or snack) was determined by study variables at study visits described as absolute change from baseline; these are termed “within raisin” or “within snack” comparisons. Comparative efficacy between unpaired groups was determined by comparing raisin versus snack on absolute change from baseline to the same study visit; these are termed “raisin vs snack” comparisons. For efficacy endpoint datasets of parametric distribution, same within-group paired comparisons over all study visit assessment time periods (weeks 0, 4, 8, and 12) were performed by repeated measure of 1-way ANOVA. If $ 1 of the post-baseline measures within group datasets were of non-parametric distribution, then repeated measures were performed with the Friedman test. For comparative datasets of parametric (normal) distribution, a paired t test was utilized for within-treatment group comparisons (eg, raisins at baseline and weeks 4, 8, and 12, and snacks at baseline and weeks 4, 8, and 12); an unpaired t test was used for raisin vs snack group comparisons. For comparative datasets of nonparametric (not normal) distribution, paired Wilcoxon tests were used for within-treatment group comparisons (eg, within-raisin comparisons; unpaired MannWhitney test was utilized for raisin vs snack comparisons). Fisher exact test was utilized for categorical comparisons. The α level for statistical testing was P # 0.05, 2-sided, with a CI at 95%. Software used for our analyses included Analyse-it for Microsoft Excel (version 2.20), Microsoft Excel 2010, and Minitab version 16.0.
Results
The baseline ITT study population included 46 study participants (15 in the snack group; 31 in the raisin group) (Figure 1). Most subjects were white, and mean subject age was approximately 60 years for both groups (Table 2). By chance, slightly more men were randomized to snacks (60%), whereas more women were randomized to raisins (61%). Only 3 randomized subjects (2 in snacks and 1 in raisins) failed to be included in the ITT. Of the ITT population, 100% of snack participants and 97% of raisin participants completed the study. Study compliance with study intervention was very good to excellent,18 with average snack administration compliance at 97% and average raisin administration compliance at 94%. The baseline values for outcome variables did not differ significantly (Tables 3 and 4).
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Figure 1. Flow diagram of screening, randomization, enrollment, and completion of subjects in our study.
Antihypertensive medications were maintained at baseline doses for all subjects. The number of subjects taking antihypertensive medications was 5 of 15 (33%) subjects in the snack group and 12 of 31 (40%) subjects in the raisins group. As seen in Table 3, mean baseline fasting plasma glucose levels were within the 90- to 100- mg/dL range, which is at the upper range of normal. Neither snack nor raisin intake significantly affected fasting plasma glucose levels. Significant differences in changes for 2-hour post prandial glucose levels were seen at 12 weeks. For within-snack intake comparisons, there was a nonsignificant +0.4 mg/dL change in 2-hour post-prandial levels; for within-raisin intake comparisons, there was a 13.1 mg/dL change (P = 0.003). The raisin vs snack comparisons showed a significant difference (P = 0.03) for 2-hour postprandial glucose level changes. Within-snack comparisons for HbA1c levels were not significantly changed, whereas within-raisin comparisons were associated with a change of −0.12% (P = 0.004); the raisin vs snack comparisons indicated that raisins produced a significantly greater reduction in subject HbA1c levels (P = 0.036). Table 2. Subject Baseline Demographic Data: ITT Population Factor
Snack
Raisins
Number of subjects Mean age Gender, n (%)
15 61.1 6 (40) 9 (60) 13 (87) 2 (13) 29.2 + 0.6
31 60.3 19 (61) 12 (39) 25 (81) 6 (19) 30.0 + 0.5
Race, n (%) BMI, kg/m2 + SEM
Women Men White Black
Abbreviations: BMI, body mass index; ITT, intent to treat; SEM, standard error of the mean.
40
As anticipated by protocol design, there were no significant changes in body weight. Waist circumference decreased 1.6 cm (P = 0.009) for within-snack comparisons, and 2.0 cm (P = 0.008) for within raisin comparisons but the difference for the snack vs raison comparison was not significant. Within-snack comparisons were associated with a nonsignificant increase in both SBP and DBP (Table 4). Within-raisin comparisons were accompanied by significant decreases in both SBP and DBP. For SBP within-raisin comparisons, these changes, ranging from −6.0 to −10.2 mm Hg (−4.8% to −7.2%) were: 4 weeks, P = 0.001; 8 weeks, P = 0.001; and 12 weeks, P = 0.015. The raisin vs snack comparisons were: 4 weeks, P = 0.002; 8 weeks, P = 0.004; and 12 weeks, P = 0.047. Raisin intake decreased DBP significantly, with changes ranging from −2.6 to −5.0 mm Hg or by −2.5% to –6.4%. Within-raisin comparisons, decreases in DBP were significant at 4 weeks (P = 0.045) and 12 weeks (P = 0.002). Raisin vs snack comparisons indicated that raisin intake was associated with significantly greater decreases in DBP at all weeks (P , 0.05). Overall, raisin intake was associated with mean BP changes of −5.4 mm Hg for SBP and −4.5 mm Hg in DBP. Serum total cholesterol, triglycerides, and LDL-C levels did not change significantly with either snacks or raisins intake. Subject HDL-C level for within-raisins comparisons significantly decreased by 3.6 mg/dL (P = 0.005) from baseline to 12 weeks; the raisin vs snack difference was significant (P = 0.002). Snack intake did not significantly affect HDL-C levels. Liver function tests—serum potassium, alanine transaminase, aspartate aminotransferase, and
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Raisins Versus Snack Effects on Cardiovascular Risk
Table 3. Changes in Major Risk Factors Measure
Units
Fasting plasma glucose level 2-hour postprandial glucose level
Group
Baseline
SEM
12-Wk Within-Group Change
SEM
P Value, Within-Group Change
Mg/dL or P value Snack
92.2
1.9
0.5
0.5
0.196
Raisins Mg/dL or P value Snack
96.2 101.7
2.2 9.5
2.4 0.4
1.9 7.8
0.360 0.200
0.830
Raisins Snack Raisins Snack Raisins Snack Raisins
102.0 5.75 5.88 85.2 86.3 100.8 100.5
7.7 0.12 0.07 3.2 2.2 3.0 1.7
-13.1 -0.04 -0.12 -0.5 0.1 -1.6 -2.0
4.0 0.13 0.20 0.4 0.4 0.5 0.7
0.003 0.336 0.004 0.576 0.378 0.009 0.008
0.030
HbA1c level
% or P value
Body weight
Kg or P value
Waist circumference
Cm or P value
P Value, Difference Between-Group Changes
0.036 0.320 0.692
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Abbreviations: HbA1c, glycated hemoglobin; SEM, standard error of the mean.
alkaline phosphatase levels—were not significantly altered by either intervention. Regarding safety, no deaths or serious adverse experiences occurred during the study. Subjects in the raisins group had numerically more adverse experiences than subjects in the snack group; however, the raisin group had almost twice as many subjects as the snack group. There were no significant differences in adverse experiences between raisins and snacks. Three subjects in the raisin group had intervention-related adverse experiences compared with zero in the snack group. The 5 adverse experiences in the 3 raisins-group subjects thought to be possibly, probably, or definitely due to raisins were all gastrointestinal in nature (excess gas, decreased hunger, increased frequency of stools, indigestion, and constipation). The adverse experiences were not reported as serious, did not result in withholding or discontinuation of raisins, and were all resolved with continued raisin administration. Only 1 subject was discontinued due to
an adverse experience; a subject in the raisin group developed elevated liver enzymes and experienced abdominal pain. She had had a recent exposure to a sick child and the subject had a history of a hepatic hemangioma; the subject was evaluated by a gastroenterologist after exiting the study.
Discussion
Compared to common non-fruit snacks, our study demonstrated that raisins, administered 3 times per day, significantly decreased mean postprandial glucose levels by 13.1 mg/dL. The reduction in postprandial glucose levels with raisins was associated with a significant reduction of HbA1c levels of 0.12%; snacks did not significantly reduce mean HbA1c levels from baseline. The relatively low glycemic index of raisins10,11 is likely influenced by their fiber content1,2,13 and potassium content.19 Other possible but uncertain glycemic (and possible BP) lowering contributions of raisins are their polyphenols, phenolic acid, tannins, antioxidants, flavonoids
Table 4. Blood Pressure Changes Measure
Group
Value
Baseline
4 wks
8 wks
12 wks
Systolic Blood Pressure
Snack
Mean value, mm HG SEM P value for change from baseline Mean value, mm HG SEM P value for change from baseline P value for difference in change between groups Mean value, mm HG SEM P value for change from baseline Mean value, mm HG SEM P value for change from baseline P value for difference in change between groups
129.2 1.6
131.3 2.6 NS 127.7 1.8 0.001 0.002 79.0 2.7 NS 82.0 2.0 0.045 , 0.05
133.3 2.7 NS 126.7 2.5 0.001 0.004 80.3 2.1 NS 80.4 2.0 0.31 , 0.05
130.1 2.8 NS 129.6 2.6 0.015 0.047 77.0 1.9 NS 78.9 1.9 0.002 , 0.05
Raisins
Diastolic Blood Pressure
Snack
Raisins
135.0 2.3
78.9 1.9 84.4 2.0
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Anderson et al
(such as quercetin), and resveratrol constituents.20,21 Clinically, a general consensus is that elevated HbA1c level (for patients with diabetes mellitus) increases the risk of microvascular disease, and a reduction in HbA1c level reduces the risk of microvascular disease.22 Additional evidence suggests that postprandial glucose levels may have a more deleterious effect on the vasculature than fasting glucose levels.22 Thus, strategies that improve postprandial glucose levels in patients with impaired glucose tolerance hold promise in reducing CVD risk. Perhaps the most striking finding in our study was the favorable effects of raisins on the secondary endpoints of SBP and DBP. Depending on the study visit, when compared with snacks, raisins significantly reduced SBP with changes ranging from −6.0 to 10.2 mm Hg. In contrast, snacks did not significantly affect mean SBP. Similarly, compared with snacks, raisins reduced mean DBP (P , 0.05, at all visits) with changes ranging from −2.6 to −5.0 mm Hg. Previous studies in hypertensive rats indicate that grape juice, red wine, or grape extracts decreased BP.23 Dohadwala et al24 reported that grape juice consumption did not reduce modestly elevated BP in relatively healthy individuals. However, Banini et al,25 in a study of diabetic subjects (using 9 or 10 subjects per group), reported important but not significant reductions in fasting blood glucose and insulin levels and BP with either grape juice or red wine intake.25 Raisins, as used in our study, have a wide range of bioactive compounds. Because of the sun processing, the phytochemical content of raisins probably differ significantly from grapes, grape juice, or wine.26 These differences may contribute to the decreases seen in blood glucose and insulin levels, as well as BP to those reported for other studies using grape products. However, in our study, specifically utilizing raisins consumption (not just grape juice), subject BP was significantly improved. In addition, the increased intake of dietary fiber2 or potassium27,28 may have contributed to the decrease in BP seen in our study. It is noteworthy that snacks provided about 400 mg per day of sodium compared with about 15 mg per day with raisins. However, snacks did not significantly increase either SBP or DBP. Conversely, raisin administration increased the intake of potassium to approximately 660 mg per day compared with approximately 70 mg per day with snacks. Clinically, increased pharmacologic intake of potassium is known to reduce BP.27–30 Cardiovascular outcome studies support the substantial potential clinical benefits of modest BP reduction, even in patients with CVD who have “normal” BP. In the Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis (CAMELOT) study, the cardiovascular effects 42
of amlodipine or enalapril were compared with placebo in a 2-year trial.31 In the CAMELOT study, overall baseline BP was 129/78 mm Hg, similar to mean baseline BP for the raisin group—134/84 mm Hg. At the end of the CAMELOT study, amlodipine and enalapril were associated with BP reductions of approximately 4.8/2.5 mm Hg. In our raisins trial, raisins significantly decreased both SBP and DBP with mean reductions of 5.4/4.5 mm Hg at 12 weeks. Compared with placebo, the CAMELOT study demonstrated that amlodipine significantly reduced cardiovascular events. It is intriguing to speculate that the simple and routine consumption of raisins might not only produce similar BP-lowering effects as common antihypertensive drugs but also produce similar favorable cardiovascular outcomes. Our study is limited by being unblinded, single-site pilot study of modest size. Another limitation is that metabolic efficacy of therapeutic interventions is often highly dependent upon baseline values. Our study selected subjects based upon an inclusion criterion of modestly elevated blood glucose levels and excluded subjects with low-normal BP. Thus, as expected, many of our study subjects were mildly hyperglycemic or hypertensive at baseline. Raisin consumption had the greatest effect upon these abnormal metabolic parameters. Subjects were not selected based upon obesity, increased waist circumference, abnormal lipid levels, or other out-of-range laboratory values. Raisins had the least differential effects upon these “other” metabolic parameters. Finally, as with other exploratory studies, our observations require confirmation by other clinical trials.
Conclusion
Using a real-life study design, the intake of raisins 3 times daily significantly decreased postprandial plasma glucose levels, SBP, and DPB. These observations support the emerging research suggesting that raisin or grape product intake may have a favorable effect on patient risks for diabetes mellitus and CVD.
Conflict of Interest Statement
James W. Anderson, MD, is a member of the Scientific Nutrition Research Panel for the California Raisin Marketing Board and serves as a consultant for the California Marketing Board; Kathy M. Weiter, RD, LD, RN, BSN, Amber L. Christian, RD, LD, Michelle B. Ritchey, APRN, and Harold E. Bays, MD, FTOS, FACE, FNLA, are employees of the Louisville Metabolic and Atherosclerosis Research Center (L-MARC), which received research grants from the California Raisin Marketing Board to perform this trial.
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either L-MARC, nor its employees received specific payN ment or ancillary assistance in writing this submission.
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References 1. Bell SJ. A review of dietary fiber and health: focus on raisins. J Med Food. 2011;14(9):877–883. 2. Anderson JW, Baird P, Davis RH Jr, et al. Health benefits of dietary fiber. Nutr Rev. 2009;67(4):188–205. 3. Keast DR, Nicklas TA, O’Neil CE. Snacking is associated with reduced risk of overweight and reduced abdominal obesity in adolescents: National Health and Nutrition Examination Survey (NHANES) 1999–2004. Am J Clin Nutr. 2010;92(2):428–435. 4. Bays HE. “Sick fat,” metabolic disease, and atherosclerosis. Am J Med. 2009;122(1 Suppl):S26–S37. 5. Bays HE, Gonzalez-Campoy JM, Bray GA, et al. Pathogenic potential of adipose tissue and metabolic consequences of adipocyte hypertrophy and increased visceral adiposity. Expert Rev Cardiovasc Ther. 2008;6(3):343–368. 6. Bays HE. Adiposopathy is “sick fat” a cardiovascular disease? J Am Coll Cardiol. 2011;57(25):2461–2473. 7. Keast DR, O’Neil CE, Jones JM. Dried fruit consumption is associated with improved diet quality and reduced obesity in US adults: National Health and Nutrition Examination Survey, 1999–2004. Nutr Res. 2011;31(6):460–467. 8. Jenkins DJ, Wolever TM, Taylor RH, et al. Glycemic index of foods: a physiological basis for carbohydrate exchanges. Am J Clin Nutr. 1981;34(3):362–366. 9. Byrne HK, Kim Y, Hertzler SR, Watt CA, Mattern CO. Glycemic and insulinemic responses to different preexercise snacks in participants with impaired fasting glucose. Int J Sport Nutr Exerc Metab. 2011;21(1):1–10. 10. Kim Y, Hertzler SR, Byrne HK, Mattern CO. Raisins are a low to moderate glycemic index food with a correspondingly low insulin index. Nutr Res. 2008;28(5):304–308. 11. Kanellos PT, Kaliora AC, Liaskos C, Tentolouris NK, Perrea D, Karanthanos VT. A study of glycemic response to Corinthian raisins in healthy subjects and in type 2 diabetes mellitus patients. Plant Foods Hum Nutr. 2013;68(2):145–148. 12. Brand-Miller JC. Postprandial glycemia, glycemic index, and the prevention of type 2 diabetes. Am J Clin Nutr. 2004;80(2):243–244. 13. Bajorek SA, Morello CM. Effects of dietary fiber and low glycemic index diet on glucose control in subjects with type 2 diabetes mellitus. Ann Pharmacother. 2010;44(11):1786–1792. 14. Salmeron J, Manson JE, Stampfer MJ, Colditz GA, Wing AL, Willett WC. Dietary fiber, glucemic load, and risk of non-insulindependent diabetes mellitus in women. JAMA. 1997;277(6):472–477. 15. Rankin JW, Andreae MC, Oliver Chen CY, O’Keefe SF. Effects of raisin consumption on oxidative stress and inflammation in obesity. Diabetes Obes Metab. 2008;10(11):1086–1096.
16. Puglisi MJ, Vaishnav U, Shrestha S, et al. Raisins and additional walking have distinct effects on plasma lipids and inflammatory cytokines. Lipids Health Dis. 2008;7:14–22. 17. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001;285(19):2486–2497. 18. Anderson JW, Reynolds LR, Bush HM, Rinsky JL, Washnock C. Effect of a behavioral/nutritional intervention program on weight loss in obese adults: a randomized controlled trial. Postgrad Med. 2011;123(5):205–213. 19. Chatterjee R, Yeh HC, Edelman, D, Brancati F. Potassium and risk for Type 2 diabetes. Expert Rev Endocrinol Metab. 2011;6(5):665–672. 20. Williamson G, Carughi A. Polyphenol content and health benefits of raisins. Nutr Res. 2010;30(8):511–519. 21. Suwannaphet W, Meeprom A, Yibchok-Anun S, Adisakwattana S. Preventive effect of grape seed extract against high-fructose diet-induced insulin resistance and oxidative stress in rats. Food Chem Toxicol. 2010;48(7):1853–1857. 22. Rendell MS, Jovanovic L. Targeting postprandial hyperglycemia. Metabolism. 2006;55(9):1263–1281. 23. Dohadwala MM, Vita JA. Grapes and cardiovascular disease. J Nutr. 2009;139(9):1788S–1793S. 24. Dohadwala MM, Hamburg NM, Holbrook M, et al. Effects of Concord grape juice on ambulatory blood pressure in prehypertension and stage 1 hypertension. Am J Clin Nutr. 2010;92(5):1052–1059. 25. Banini AE, Boyd LC, Allen JC, Allen HG, Sauls DL. Muscadine grape products intake, diet and blood constitutients of non-diabetic and type 2 diabetes subjects. Nutrition. 2006;22(11–12):1137–1145. 26. Kardeniz F, Durst RW, Wrolsted RE. Polyphenolic composition of raisins. J Agric Food Chem. 2000;48(11):5343–5350. 27. Brancati FL, Appel LJ, Seidler AJ, Whelton PK. Effect of potassium supplementation on blood pressure in African Americans on a lowpotassium diet. A randomized, double-blind, placebo-controlled trial. Arch Intern Med. 1996;156(1):61–67. 28. Cappuccio FP, MacGregor GA. Does potassium supplementation lower blood pressure? A meta-analysis of published trials. J Hypertens. 1991;9(5):465–473. 29. O’Shaughnessy KM. Role of diet in hypertension management. Curr Hypertens Rep. 2006;8(4):292–297. 30. Haddy FJ, Vanhoutte PM, Feletou M. Role of potassium in regulating blood flow and blood pressure. Am J Physiol Regul Integr Comp Physiol. 2006;290(3):R546–R552. 31. Nissen SE, Tuzcu EM, Libby P, et al; CAMELOT Investigators. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. JAMA. 2004;292(18):2217–2225.
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Raisins Compared with Other Snack Effects on Glycemia and Blood Pressure: A Randomized, Controlled Trial James W. Anderson MD, Kathy M. Weiter RD, LD, RN, BSN, Amber L. Christian RD, LD, Michelle B. Ritchey APRN & Harold E. Bays MD, FTOS, FACE, FNLA To cite this article: James W. Anderson MD, Kathy M. Weiter RD, LD, RN, BSN, Amber L. Christian RD, LD, Michelle B. Ritchey APRN & Harold E. Bays MD, FTOS, FACE, FNLA (2014) Raisins Compared with Other Snack Effects on Glycemia and Blood Pressure: A Randomized, Controlled Trial, Postgraduate Medicine, 126:1, 37-43 To link to this article: http://dx.doi.org/10.3810/pgm.2014.01.2723
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Date: 13 September 2015, At: 00:00
C L I N I C A L F O C U S : C A R D I O V A S C U L A R E V E N T S , U R O L O G Y, F O R T H E P R I M A RY C A R E D O C T O R
Raisins Compared With Other Snack Effects on Glycemia and Blood Pressure: A Randomized, Controlled Trial
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DOI: 10.3810/pgm.2014.01.2723
James W. Anderson, MD 1 Kathy M. Weiter, RD, LD, RN, BSN 2 Amber L. Christian, RD, LD 2 Michelle B. Ritchey, APRN 3 Harold E. Bays, MD, FTOS, FACE, FNLA 4 Professor Emeritus, Medicine and Clinical Nutrition, University of Kentucky, Lexington, KY; 2 Research Coordinator/Dietitian; 3 Subinvestigator/Nurse Practitioner; 4 Medical Director/President, Louisville Metabolic and Atherosclerosis Research Center, Louisville, KY 1
Abstract Objective: To compare effects of raisin snacks with conventional snacks on glycemia and cardiovascular risk factors. Materials and Methods: A 12-week, randomized, controlled trial compared 3-times-a-day consumption of raisins with intake of processed snacks on glycemia and cardiovascular risk factors. Men and women were randomized to snacks (n = 15) or raisins (n = 31). Outcome measures were performed at baseline, 4, 8, and 12 weeks. Results: Fasting plasma glucose levels were not significantly affected by intake of raisins or snacks. Mean subject post prandial glucose levels were significantly reduced by raisin intake at 12 weeks; changes with raisin intake were −13.1 mg/dL (P = 0.003 vs baseline; P = 0.03 vs snacks). E ating raisins significantly decreased glycated hemoglobin (HbA1c) level (−0.12%; P = 0.004), a significantly greater level decrease than seen with snack intake (P = 0.036). Snack intake did not significantly affect subject systolic or diastolic blood pressure (BP). Raisin intake was associated with reductions in systolic blood pressure (SBP) at 4, 8, and 12 weeks with mean changes of −6.0 to 10.2 mmHg; all these changes were statistically significant (P = 0.015 to 0.001). Raisins were associated with significantly greater changes in diastolic blood pressure (DBP) at 4, 8, and 12 weeks than snacks (P , 0.05). Body weight did not significantly change within or between groups. Conclusions: Regular consumption of raisins may reduce glycemia and cardiovascular risk factors, including BP rate. Keywords: blood pressure; fruits; glycemia; hypertension; lipids; raisins
Introduction
Correspondence: James W. Anderson, MD, 506 Knapp Farm Drive, Hermitage, TN 37076. Tel: 615-457-2441 E-mail: [email protected]
Like most fruits, raisins are low in sodium and devoid of fat, saturated fat, and cholesterol. However, raisins are high in dietary fiber content and contain potassium, antioxidants, and phytochemicals, which might improve glycemia and cardiovascular disease (CVD) risk factors, such as blood pressure (BP) and lipid parameters, which may make raisins a healthier food choice compared with processed snacks.1,2 It is often recommended that total daily caloric intake be spread out throughout the day. Individuals who consume snacks regularly may experience healthier outcomes, such as lower body weight and less abdominal obesity, than those who do not snack.3 These outcomes would presumably promote more favorable adipose tissue functionality,4 a more favorable metabolic profile,5 and an improvement in CVD risk factors.6 Individuals with higher dried fruit consumption, such as raisins, may have lower body weight, lower body mass index (BMI), and reduced waist circumference than non-consumers of dried fruit.7 One might conclude that a reasonable nutritional measure to improve metabolic health is to recommend individuals frequently snack with healthy food choices.
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Anderson et al
Raisins are of particular interest because of clinical studies indicating that they have low glycemic and insulinogenic indices8–11; these properties suggest that regular consumption of raisins may lower the risk for developing diabetes for persons with prediabetes.12–15 Preliminary evidence suggests that raisins may have favorable effects on blood pressure (BP).16 Thus, our study was designed to assess the effects of raisin intake on fasting and postprandial plasma glucose levels, serum insulin levels, and BP rate. We constructed our study to evaluate a “real-life” comparison of raisin intake, a natural dried fruit, compared with processed snack-food consumption, the hypothesis being that routine raisin snacks consumed 3 times a day over 12 weeks might be more beneficial in terms of associated improvements in glycemic and CVD risk factors compared with equicaloric alternative processed-food snacks.
Materials and Methods
The objective of our pilot study was to compare the effects of eating raisins 3 times per day with eating alternative processed-food snacks 3 times per day on CVD risk factors. The primary endpoints were changes at week 12 in subject fasting plasma glucose level, plasma glucose level 2 hours post-administration of 75 g oral glucose, and body weight, in raisin-eating versus control-snack consuming groups. Secondary endpoints were changes at weeks 4, 8, and 12 for raisin versus control snack groups regarding glycated hemoglobin (HbA1c) levels, BP (systolic [SBP] and diastolic [DBP]) rates, body mass index (BMI), waist circumference, and serum lipid levels—total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDLC), and high-density lipoprotein cholesterol (HDL-C). Endpoints of special interest included serum potassium, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels. The active, or raisin group, consumed a 1-ounce, prepackaged serving of dark raisins (90 kcal/serving), 3 times daily. The control, or snack comparator group, consumed prepackaged processed snacks (100 kcal/serving), 3 times daily. The use of commonly available prepackaged raisins and snacks was chosen for the purpose of commercial availability, and to obtain study outcome data through real-life food consumption. Control subjects could choose from the following snacks: Fudge Shoppe or Grasshopper cookies; Fudge Shoppe mini fudge stripes cookies; Honey Maid cinnamon roll thin crisps; Keebler Cheez-It crackers; Lorna Doone baked shortbread cookie crisps; Nabisco Chips Ahoy! baked chocolate chip snacks; Oreo baked chocolate wafer snacks; 38
Pepperidge Farm Goldfish baked snacks. The prepackaged commercial snacks provided 100 kcal/serving and did not contain raisins, or solely fruits, or solely vegetables. The nutrition summary for raisins and snacks is provided in Table 1. Both raisins and snacks were to be eaten 3 times daily and consumed before breakfast, lunch, or dinner with 8 ounces of a non-caloric beverage (preferably water but non-caloric soft drinks or a hot beverage were acceptable). Study participants were educated by a registered dietitian on therapeutic lifestyle changes17 at the randomization visit. Fasting blood samples for analyses were obtained after a 12-hour fast. Blood pressure measurements were obtained after study subjects had been seated quietly for $ 5 minutes, with 3 readings taken, and then averaged. Body weight was obtained on calibrated scales, with study participants placed in gowns. Two body weights were recorded, with the average of the weights recorded. The design was a randomized, un-blinded, single research site, active-controlled pilot study. Expected participation for each study subject was 14 to 16 weeks, including 2 to 4 weeks of screening, and 12 weeks of randomized intake of assigned snack. The protocol was approved by a central Institutional Review Board, and the study registered on http://clinicaltrials.gov (Identifier: NCT01260272). Prior to initiation of the study, and prior to protocol-directed procedures, study participants underwent the informed consent process, including review of an Institutional Review Boardapproved informed consent document/agreement explaining the procedures of the study and the potential risks. Inclusion criteria was men and women, aged . 18 years, with a body mass index (BMI) from 25.0 to 34.9 kg/m² and with $ 1 fasting plasma or serum glucose levels of 90 to 150 mg/dL documented within 4 weeks of the initial study visit. Baseline BP was required to be . 120 mm Hg s ystolic or . 80 mm Hg diastolic. Exclusion criteTable 1. Nutrition Values per Servinga Nutritive Measure
Raisins
Representative Snackb
Range
Calories (kcal) Total fat, g Cholesterol, mg Sodium, mg Potassium, mg Total Carbohydrate, g Dietary fiber, g Sugars, g Protein, g
90 0 0 5 220 22 2 20 ,1
100 3.0 0.5 134 23 16 0.5 5.3 1.5
100 2.0–3.5 0–4.0 65–170 15–30 14–19 0–1 0–8 0.8–3
Subjects consumed 3 snacks/d. Values are average of the 8 representative snacks listed in article text (Materials and Methods section).
a
b
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Raisins Versus Snack Effects on Cardiovascular Risk
ria included: intolerance, dislike, or unwillingness to consume raisins or any of the comparator snacks; weight loss of . 5 pounds in the 2 months prior to study entry; previous diagnosis of diabetes mellitus; and currently taking diabetes mellitus treatment (including drugs such as metformin or colesevelam HCl, even if not being taken for diabetes mellitus). Exclusionary BP was . 160 mm Hg systolic or . 100 mm Hg diastolic. Exclusionary laboratory values included: fasting serum lipoprotein levels of LDL-C . 160 mg/dL, or triglycerides . 500 mg/dL, creatinine level . 1.5 times the upper range of normal (0.6–1.2 mg/dL), and potassium level above the upper range of normal (3.5–5.5 mEq/L). In addition to anti-diabetes mellitus medications, other exclusionary therapeutic criteria included initiation or change of any antihypertensive medication or lipid-altering medication within 2 months prior to initial study entry (subjects were eligible if on a stable dose of 1 or 2 antihypertensive or lipid-altering medications that were maintained at constant dose throughout the study). Compliance was assessed by counting the number of snacks returned at each clinic visit; subjects were issued about 21 snacks more than required during the preceding 4 weeks.18 Safety was assessed in all subjects who received $ 1 snacks by monitoring for the occurrence of adverse experiences and by clinical evaluation, including medical history, physical examination, and laboratory evaluations. The investigator assessed whether each adverse experience was definitely not, probably not, possibly, probably, or definitely due to study therapy, based upon clinical judgment. The randomized population was defined as all subjects who underwent the informed consent process, who signed the informed consent document, and who were assigned a randomization number. The intent-to-treat (ITT) population consisted of all randomized subjects who had a baseline efficacy measurement, consumed $ 1 snack, and had $ 1 post-randomization efficacy measurement. The safety population was defined as all randomized subjects who consumed $ 1 snack and assessed by treatment-emergent adverse experiences, clinical laboratory test results, and physical examinations in the safety sample. For the ITT analysis, the last observation carry forward (LOCF) method was used to impute missing data points for subjects who discontinued without completing the entire treatment period. The sample size was determined by an estimate of what might represent clinically meaningful differences between the raisin and commercially available snacks groups. Thirtytwo subjects (assuming 27 completing subjects) administered raisins were estimated to be sufficient in detecting a
s ignificant (5 mg/dL) reduction in fasting plasma glucose HbA1c level (P , 0.05), assuming a baseline fasting plasma glucose level of 110 + 9.5 mg/dL (mean + SD). Comparative efficacy within paired groups (raisin or snack) was determined by study variables at study visits described as absolute change from baseline; these are termed “within raisin” or “within snack” comparisons. Comparative efficacy between unpaired groups was determined by comparing raisin versus snack on absolute change from baseline to the same study visit; these are termed “raisin vs snack” comparisons. For efficacy endpoint datasets of parametric distribution, same within-group paired comparisons over all study visit assessment time periods (weeks 0, 4, 8, and 12) were performed by repeated measure of 1-way ANOVA. If $ 1 of the post-baseline measures within group datasets were of non-parametric distribution, then repeated measures were performed with the Friedman test. For comparative datasets of parametric (normal) distribution, a paired t test was utilized for within-treatment group comparisons (eg, raisins at baseline and weeks 4, 8, and 12, and snacks at baseline and weeks 4, 8, and 12); an unpaired t test was used for raisin vs snack group comparisons. For comparative datasets of nonparametric (not normal) distribution, paired Wilcoxon tests were used for within-treatment group comparisons (eg, within-raisin comparisons; unpaired MannWhitney test was utilized for raisin vs snack comparisons). Fisher exact test was utilized for categorical comparisons. The α level for statistical testing was P # 0.05, 2-sided, with a CI at 95%. Software used for our analyses included Analyse-it for Microsoft Excel (version 2.20), Microsoft Excel 2010, and Minitab version 16.0.
Results
The baseline ITT study population included 46 study participants (15 in the snack group; 31 in the raisin group) (Figure 1). Most subjects were white, and mean subject age was approximately 60 years for both groups (Table 2). By chance, slightly more men were randomized to snacks (60%), whereas more women were randomized to raisins (61%). Only 3 randomized subjects (2 in snacks and 1 in raisins) failed to be included in the ITT. Of the ITT population, 100% of snack participants and 97% of raisin participants completed the study. Study compliance with study intervention was very good to excellent,18 with average snack administration compliance at 97% and average raisin administration compliance at 94%. The baseline values for outcome variables did not differ significantly (Tables 3 and 4).
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Figure 1. Flow diagram of screening, randomization, enrollment, and completion of subjects in our study.
Antihypertensive medications were maintained at baseline doses for all subjects. The number of subjects taking antihypertensive medications was 5 of 15 (33%) subjects in the snack group and 12 of 31 (40%) subjects in the raisins group. As seen in Table 3, mean baseline fasting plasma glucose levels were within the 90- to 100- mg/dL range, which is at the upper range of normal. Neither snack nor raisin intake significantly affected fasting plasma glucose levels. Significant differences in changes for 2-hour post prandial glucose levels were seen at 12 weeks. For within-snack intake comparisons, there was a nonsignificant +0.4 mg/dL change in 2-hour post-prandial levels; for within-raisin intake comparisons, there was a 13.1 mg/dL change (P = 0.003). The raisin vs snack comparisons showed a significant difference (P = 0.03) for 2-hour postprandial glucose level changes. Within-snack comparisons for HbA1c levels were not significantly changed, whereas within-raisin comparisons were associated with a change of −0.12% (P = 0.004); the raisin vs snack comparisons indicated that raisins produced a significantly greater reduction in subject HbA1c levels (P = 0.036). Table 2. Subject Baseline Demographic Data: ITT Population Factor
Snack
Raisins
Number of subjects Mean age Gender, n (%)
15 61.1 6 (40) 9 (60) 13 (87) 2 (13) 29.2 + 0.6
31 60.3 19 (61) 12 (39) 25 (81) 6 (19) 30.0 + 0.5
Race, n (%) BMI, kg/m2 + SEM
Women Men White Black
Abbreviations: BMI, body mass index; ITT, intent to treat; SEM, standard error of the mean.
40
As anticipated by protocol design, there were no significant changes in body weight. Waist circumference decreased 1.6 cm (P = 0.009) for within-snack comparisons, and 2.0 cm (P = 0.008) for within raisin comparisons but the difference for the snack vs raison comparison was not significant. Within-snack comparisons were associated with a nonsignificant increase in both SBP and DBP (Table 4). Within-raisin comparisons were accompanied by significant decreases in both SBP and DBP. For SBP within-raisin comparisons, these changes, ranging from −6.0 to −10.2 mm Hg (−4.8% to −7.2%) were: 4 weeks, P = 0.001; 8 weeks, P = 0.001; and 12 weeks, P = 0.015. The raisin vs snack comparisons were: 4 weeks, P = 0.002; 8 weeks, P = 0.004; and 12 weeks, P = 0.047. Raisin intake decreased DBP significantly, with changes ranging from −2.6 to −5.0 mm Hg or by −2.5% to –6.4%. Within-raisin comparisons, decreases in DBP were significant at 4 weeks (P = 0.045) and 12 weeks (P = 0.002). Raisin vs snack comparisons indicated that raisin intake was associated with significantly greater decreases in DBP at all weeks (P , 0.05). Overall, raisin intake was associated with mean BP changes of −5.4 mm Hg for SBP and −4.5 mm Hg in DBP. Serum total cholesterol, triglycerides, and LDL-C levels did not change significantly with either snacks or raisins intake. Subject HDL-C level for within-raisins comparisons significantly decreased by 3.6 mg/dL (P = 0.005) from baseline to 12 weeks; the raisin vs snack difference was significant (P = 0.002). Snack intake did not significantly affect HDL-C levels. Liver function tests—serum potassium, alanine transaminase, aspartate aminotransferase, and
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Raisins Versus Snack Effects on Cardiovascular Risk
Table 3. Changes in Major Risk Factors Measure
Units
Fasting plasma glucose level 2-hour postprandial glucose level
Group
Baseline
SEM
12-Wk Within-Group Change
SEM
P Value, Within-Group Change
Mg/dL or P value Snack
92.2
1.9
0.5
0.5
0.196
Raisins Mg/dL or P value Snack
96.2 101.7
2.2 9.5
2.4 0.4
1.9 7.8
0.360 0.200
0.830
Raisins Snack Raisins Snack Raisins Snack Raisins
102.0 5.75 5.88 85.2 86.3 100.8 100.5
7.7 0.12 0.07 3.2 2.2 3.0 1.7
-13.1 -0.04 -0.12 -0.5 0.1 -1.6 -2.0
4.0 0.13 0.20 0.4 0.4 0.5 0.7
0.003 0.336 0.004 0.576 0.378 0.009 0.008
0.030
HbA1c level
% or P value
Body weight
Kg or P value
Waist circumference
Cm or P value
P Value, Difference Between-Group Changes
0.036 0.320 0.692
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Abbreviations: HbA1c, glycated hemoglobin; SEM, standard error of the mean.
alkaline phosphatase levels—were not significantly altered by either intervention. Regarding safety, no deaths or serious adverse experiences occurred during the study. Subjects in the raisins group had numerically more adverse experiences than subjects in the snack group; however, the raisin group had almost twice as many subjects as the snack group. There were no significant differences in adverse experiences between raisins and snacks. Three subjects in the raisin group had intervention-related adverse experiences compared with zero in the snack group. The 5 adverse experiences in the 3 raisins-group subjects thought to be possibly, probably, or definitely due to raisins were all gastrointestinal in nature (excess gas, decreased hunger, increased frequency of stools, indigestion, and constipation). The adverse experiences were not reported as serious, did not result in withholding or discontinuation of raisins, and were all resolved with continued raisin administration. Only 1 subject was discontinued due to
an adverse experience; a subject in the raisin group developed elevated liver enzymes and experienced abdominal pain. She had had a recent exposure to a sick child and the subject had a history of a hepatic hemangioma; the subject was evaluated by a gastroenterologist after exiting the study.
Discussion
Compared to common non-fruit snacks, our study demonstrated that raisins, administered 3 times per day, significantly decreased mean postprandial glucose levels by 13.1 mg/dL. The reduction in postprandial glucose levels with raisins was associated with a significant reduction of HbA1c levels of 0.12%; snacks did not significantly reduce mean HbA1c levels from baseline. The relatively low glycemic index of raisins10,11 is likely influenced by their fiber content1,2,13 and potassium content.19 Other possible but uncertain glycemic (and possible BP) lowering contributions of raisins are their polyphenols, phenolic acid, tannins, antioxidants, flavonoids
Table 4. Blood Pressure Changes Measure
Group
Value
Baseline
4 wks
8 wks
12 wks
Systolic Blood Pressure
Snack
Mean value, mm HG SEM P value for change from baseline Mean value, mm HG SEM P value for change from baseline P value for difference in change between groups Mean value, mm HG SEM P value for change from baseline Mean value, mm HG SEM P value for change from baseline P value for difference in change between groups
129.2 1.6
131.3 2.6 NS 127.7 1.8 0.001 0.002 79.0 2.7 NS 82.0 2.0 0.045 , 0.05
133.3 2.7 NS 126.7 2.5 0.001 0.004 80.3 2.1 NS 80.4 2.0 0.31 , 0.05
130.1 2.8 NS 129.6 2.6 0.015 0.047 77.0 1.9 NS 78.9 1.9 0.002 , 0.05
Raisins
Diastolic Blood Pressure
Snack
Raisins
135.0 2.3
78.9 1.9 84.4 2.0
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Anderson et al
(such as quercetin), and resveratrol constituents.20,21 Clinically, a general consensus is that elevated HbA1c level (for patients with diabetes mellitus) increases the risk of microvascular disease, and a reduction in HbA1c level reduces the risk of microvascular disease.22 Additional evidence suggests that postprandial glucose levels may have a more deleterious effect on the vasculature than fasting glucose levels.22 Thus, strategies that improve postprandial glucose levels in patients with impaired glucose tolerance hold promise in reducing CVD risk. Perhaps the most striking finding in our study was the favorable effects of raisins on the secondary endpoints of SBP and DBP. Depending on the study visit, when compared with snacks, raisins significantly reduced SBP with changes ranging from −6.0 to 10.2 mm Hg. In contrast, snacks did not significantly affect mean SBP. Similarly, compared with snacks, raisins reduced mean DBP (P , 0.05, at all visits) with changes ranging from −2.6 to −5.0 mm Hg. Previous studies in hypertensive rats indicate that grape juice, red wine, or grape extracts decreased BP.23 Dohadwala et al24 reported that grape juice consumption did not reduce modestly elevated BP in relatively healthy individuals. However, Banini et al,25 in a study of diabetic subjects (using 9 or 10 subjects per group), reported important but not significant reductions in fasting blood glucose and insulin levels and BP with either grape juice or red wine intake.25 Raisins, as used in our study, have a wide range of bioactive compounds. Because of the sun processing, the phytochemical content of raisins probably differ significantly from grapes, grape juice, or wine.26 These differences may contribute to the decreases seen in blood glucose and insulin levels, as well as BP to those reported for other studies using grape products. However, in our study, specifically utilizing raisins consumption (not just grape juice), subject BP was significantly improved. In addition, the increased intake of dietary fiber2 or potassium27,28 may have contributed to the decrease in BP seen in our study. It is noteworthy that snacks provided about 400 mg per day of sodium compared with about 15 mg per day with raisins. However, snacks did not significantly increase either SBP or DBP. Conversely, raisin administration increased the intake of potassium to approximately 660 mg per day compared with approximately 70 mg per day with snacks. Clinically, increased pharmacologic intake of potassium is known to reduce BP.27–30 Cardiovascular outcome studies support the substantial potential clinical benefits of modest BP reduction, even in patients with CVD who have “normal” BP. In the Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis (CAMELOT) study, the cardiovascular effects 42
of amlodipine or enalapril were compared with placebo in a 2-year trial.31 In the CAMELOT study, overall baseline BP was 129/78 mm Hg, similar to mean baseline BP for the raisin group—134/84 mm Hg. At the end of the CAMELOT study, amlodipine and enalapril were associated with BP reductions of approximately 4.8/2.5 mm Hg. In our raisins trial, raisins significantly decreased both SBP and DBP with mean reductions of 5.4/4.5 mm Hg at 12 weeks. Compared with placebo, the CAMELOT study demonstrated that amlodipine significantly reduced cardiovascular events. It is intriguing to speculate that the simple and routine consumption of raisins might not only produce similar BP-lowering effects as common antihypertensive drugs but also produce similar favorable cardiovascular outcomes. Our study is limited by being unblinded, single-site pilot study of modest size. Another limitation is that metabolic efficacy of therapeutic interventions is often highly dependent upon baseline values. Our study selected subjects based upon an inclusion criterion of modestly elevated blood glucose levels and excluded subjects with low-normal BP. Thus, as expected, many of our study subjects were mildly hyperglycemic or hypertensive at baseline. Raisin consumption had the greatest effect upon these abnormal metabolic parameters. Subjects were not selected based upon obesity, increased waist circumference, abnormal lipid levels, or other out-of-range laboratory values. Raisins had the least differential effects upon these “other” metabolic parameters. Finally, as with other exploratory studies, our observations require confirmation by other clinical trials.
Conclusion
Using a real-life study design, the intake of raisins 3 times daily significantly decreased postprandial plasma glucose levels, SBP, and DPB. These observations support the emerging research suggesting that raisin or grape product intake may have a favorable effect on patient risks for diabetes mellitus and CVD.
Conflict of Interest Statement
James W. Anderson, MD, is a member of the Scientific Nutrition Research Panel for the California Raisin Marketing Board and serves as a consultant for the California Marketing Board; Kathy M. Weiter, RD, LD, RN, BSN, Amber L. Christian, RD, LD, Michelle B. Ritchey, APRN, and Harold E. Bays, MD, FTOS, FACE, FNLA, are employees of the Louisville Metabolic and Atherosclerosis Research Center (L-MARC), which received research grants from the California Raisin Marketing Board to perform this trial.
© Postgraduate Medicine Volume 126, Issue 1, January 2014, e-ISSN – 1941-9260 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.
Raisins Versus Snack Effects on Cardiovascular Risk
either L-MARC, nor its employees received specific payN ment or ancillary assistance in writing this submission.
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References 1. Bell SJ. A review of dietary fiber and health: focus on raisins. J Med Food. 2011;14(9):877–883. 2. Anderson JW, Baird P, Davis RH Jr, et al. Health benefits of dietary fiber. Nutr Rev. 2009;67(4):188–205. 3. Keast DR, Nicklas TA, O’Neil CE. Snacking is associated with reduced risk of overweight and reduced abdominal obesity in adolescents: National Health and Nutrition Examination Survey (NHANES) 1999–2004. Am J Clin Nutr. 2010;92(2):428–435. 4. Bays HE. “Sick fat,” metabolic disease, and atherosclerosis. Am J Med. 2009;122(1 Suppl):S26–S37. 5. Bays HE, Gonzalez-Campoy JM, Bray GA, et al. Pathogenic potential of adipose tissue and metabolic consequences of adipocyte hypertrophy and increased visceral adiposity. Expert Rev Cardiovasc Ther. 2008;6(3):343–368. 6. Bays HE. Adiposopathy is “sick fat” a cardiovascular disease? J Am Coll Cardiol. 2011;57(25):2461–2473. 7. Keast DR, O’Neil CE, Jones JM. Dried fruit consumption is associated with improved diet quality and reduced obesity in US adults: National Health and Nutrition Examination Survey, 1999–2004. Nutr Res. 2011;31(6):460–467. 8. Jenkins DJ, Wolever TM, Taylor RH, et al. Glycemic index of foods: a physiological basis for carbohydrate exchanges. Am J Clin Nutr. 1981;34(3):362–366. 9. Byrne HK, Kim Y, Hertzler SR, Watt CA, Mattern CO. Glycemic and insulinemic responses to different preexercise snacks in participants with impaired fasting glucose. Int J Sport Nutr Exerc Metab. 2011;21(1):1–10. 10. Kim Y, Hertzler SR, Byrne HK, Mattern CO. Raisins are a low to moderate glycemic index food with a correspondingly low insulin index. Nutr Res. 2008;28(5):304–308. 11. Kanellos PT, Kaliora AC, Liaskos C, Tentolouris NK, Perrea D, Karanthanos VT. A study of glycemic response to Corinthian raisins in healthy subjects and in type 2 diabetes mellitus patients. Plant Foods Hum Nutr. 2013;68(2):145–148. 12. Brand-Miller JC. Postprandial glycemia, glycemic index, and the prevention of type 2 diabetes. Am J Clin Nutr. 2004;80(2):243–244. 13. Bajorek SA, Morello CM. Effects of dietary fiber and low glycemic index diet on glucose control in subjects with type 2 diabetes mellitus. Ann Pharmacother. 2010;44(11):1786–1792. 14. Salmeron J, Manson JE, Stampfer MJ, Colditz GA, Wing AL, Willett WC. Dietary fiber, glucemic load, and risk of non-insulindependent diabetes mellitus in women. JAMA. 1997;277(6):472–477. 15. Rankin JW, Andreae MC, Oliver Chen CY, O’Keefe SF. Effects of raisin consumption on oxidative stress and inflammation in obesity. Diabetes Obes Metab. 2008;10(11):1086–1096.
16. Puglisi MJ, Vaishnav U, Shrestha S, et al. Raisins and additional walking have distinct effects on plasma lipids and inflammatory cytokines. Lipids Health Dis. 2008;7:14–22. 17. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001;285(19):2486–2497. 18. Anderson JW, Reynolds LR, Bush HM, Rinsky JL, Washnock C. Effect of a behavioral/nutritional intervention program on weight loss in obese adults: a randomized controlled trial. Postgrad Med. 2011;123(5):205–213. 19. Chatterjee R, Yeh HC, Edelman, D, Brancati F. Potassium and risk for Type 2 diabetes. Expert Rev Endocrinol Metab. 2011;6(5):665–672. 20. Williamson G, Carughi A. Polyphenol content and health benefits of raisins. Nutr Res. 2010;30(8):511–519. 21. Suwannaphet W, Meeprom A, Yibchok-Anun S, Adisakwattana S. Preventive effect of grape seed extract against high-fructose diet-induced insulin resistance and oxidative stress in rats. Food Chem Toxicol. 2010;48(7):1853–1857. 22. Rendell MS, Jovanovic L. Targeting postprandial hyperglycemia. Metabolism. 2006;55(9):1263–1281. 23. Dohadwala MM, Vita JA. Grapes and cardiovascular disease. J Nutr. 2009;139(9):1788S–1793S. 24. Dohadwala MM, Hamburg NM, Holbrook M, et al. Effects of Concord grape juice on ambulatory blood pressure in prehypertension and stage 1 hypertension. Am J Clin Nutr. 2010;92(5):1052–1059. 25. Banini AE, Boyd LC, Allen JC, Allen HG, Sauls DL. Muscadine grape products intake, diet and blood constitutients of non-diabetic and type 2 diabetes subjects. Nutrition. 2006;22(11–12):1137–1145. 26. Kardeniz F, Durst RW, Wrolsted RE. Polyphenolic composition of raisins. J Agric Food Chem. 2000;48(11):5343–5350. 27. Brancati FL, Appel LJ, Seidler AJ, Whelton PK. Effect of potassium supplementation on blood pressure in African Americans on a lowpotassium diet. A randomized, double-blind, placebo-controlled trial. Arch Intern Med. 1996;156(1):61–67. 28. Cappuccio FP, MacGregor GA. Does potassium supplementation lower blood pressure? A meta-analysis of published trials. J Hypertens. 1991;9(5):465–473. 29. O’Shaughnessy KM. Role of diet in hypertension management. Curr Hypertens Rep. 2006;8(4):292–297. 30. Haddy FJ, Vanhoutte PM, Feletou M. Role of potassium in regulating blood flow and blood pressure. Am J Physiol Regul Integr Comp Physiol. 2006;290(3):R546–R552. 31. Nissen SE, Tuzcu EM, Libby P, et al; CAMELOT Investigators. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. JAMA. 2004;292(18):2217–2225.
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