SHORT COMMUNICATION. E Philippou 1, BMC McGowan 2, AE Brynes 1, A Dornhorst 2, AR Leeds 3 and GS Frost 4

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1 (2008) 62, & 2008 Nature Publishing Group All rights reserved /08 $ SHORT COMMUNICATION The effect of a 12-week low glycaemic index diet on heart disease risk factors and 24 h glycaemic response in healthy middle-aged volunteers at risk of heart disease: a pilot study E Philippou 1, BMC McGowan 2, AE Brynes 1, A Dornhorst 2, AR Leeds 3 and GS Frost 4 1 Department of Nutrition and Dietetics, Imperial College London, Hammersmith Hospital Campus, London, UK; 2 Department of Metabolic Medicine, Imperial College London, London, UK; 3 Department of Nutrition and Dietetics, King s College London, London, UK and 4 School of Biomedical and Molecular Sciences, University of Surrey, Guildford, Surrey, UK Objective: To compare the effects of two energy-restricted healthy diets, one with a low GI and one with a high GI, on heart disease risk factors and weight loss in subjects at risk of heart disease. Design: A 12-week randomized parallel study of low and high GI, healthy eating diets was carried out. Setting: The study was carried out at the Hammersmith Hospital. Subjects: Eighteen subjects were recruited by advertisement and randomized to one of the two diets. Fourteen completed the study but one was excluded from the final analysis. Methods: At randomization, subjects were advised to follow the intervention diet for 12 weeks. Before randomization and on completion of the study, anthropometrics, fasting cholesterol and glucose blood tests and 24-h glucose measurements were taken using a continuous glucose monitoring system (CGMS). Statistical analysis was carried out using non-parametric tests. Median (IQR) are presented. Results: A significantly different dietary GI was achieved in the low GI (median: 51.3 (IQR: ) compared to the high GI (59.3 ( ) (P ¼ 0.032) group. By week 12, both groups reduced their energy intake by: low GI group: 167 ( ) kcal/day (P ¼ 0018) vs high GI group: 596 ( ) (P ¼ 0.018) kcal/day, the difference between the groups being significant (P ¼ 0.010). However, only the low GI group lost weight ( 4.0 ( ) kg (P ¼ 0.018) whereas the high GI group did not significantly change in weight ( 1.5 ( ) kg (P ¼ 0.463). By week 12, the low GI group also had a significantly lower 24-h area under the curve (AUC) (7556 ( ) vs 8841 ( ) mmol-h/l (P ¼ 0.045) and overnight AUC (2429 ( ) vs 3000 ( ) mmol-h/l (P ¼ 0.006) glucose as measured by CGMS. There were no differences in the other heart disease risk factors assessed. Conclusions: This pilot study provides some evidence that consuming a low GI diet in addition to weight loss and healthy eating may reduce cardiovascular risk. Other potential benefits of GI might have been masked by weight loss in the low GI group. Larger-scale studies need to follow. Sponsorship: The study was funded by the British Heart Foundation. (2008) 62, ; doi: /sj.ejcn ; published online 21 February 2007 Keywords: glycaemic index; glycaemic load; glycaemic response; weight loss; coronary heart disease Correspondence: Professor GS Frost, School of Biomedical and Molecular Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK. g.frost@surrey.ac.uk Guarantor: GS Frost. Contributors: EP participated in study design, enrolled volunteers, did the study, analysed the data and wrote the manuscript. BMCMcG medically screened volunteers and reviewed the manuscript. AEB participated in study design, analysis of data and manuscript preparation and overviewed the project. AD participated in study design and reviewed the manuscript. ARL conceived the study and participated in study design. GSF conceived the study, participated in study design, analysis of data and manuscript preparation and overviewed the project. Received 12 May 2006; revised 7 December 2006; accepted 10 January 2007; published online 21 February 2007

2 146 Introduction Coronary heart disease (CHD) is the leading cause of death in the Western world (Murray and Lopez, 1997). The risk of CHD is determined by a complex interplay between synergistic metabolic abnormalities (Reaven, 1988) usually characterized by visceral adiposity and insulin resistance. The glycaemic index (GI) ranks carbohydrate-containing foods according to their postprandial blood glucose response compared to a glucose standard (Jenkins et al., 1981). The glycaemic load (GL) is a measure of the overall glycaemic impact of the diet and is the product of the GI and carbohydrate intake. Raised postprandial glycaemia, but not necessarily raised fasting glucose, increases heart disease risk, however, this may be confounded by other traditional heart disease risks (Coutinho et al., 1999; The DECODE Study Group, 2001). Low GI diets may improve cardiovascular risk in different population groups, however, the evidence is weak and further longer-term studies are required (Kelly et al., 2004). The present pilot study aimed to compare the effects of low and high GI, healthy eating diets on heart disease risks in subjects at risk of heart disease. Methods A randomized parallel group trial was carried out comparing the effects of low and high GI, healthy eating diets on heart disease risks over 12-weeks in free-living subjects. Inclusion criteria were age between 35 and 65 years and at least one recognized heart disease risk factor (BMI: kg/m 2, waist X88 cm for female subjects and X94 cm for male subjects, total cholesterol:hdl ratio X5.0 mmol/l, blood pressure systolic BP4130 mm Hg or diastolic BP485 mm Hg). Potential subjects were medically and dietetically screened before enrolment and all major illnesses, lipid lowering and weight loss medication were excluded. A MiniMed continuous glucose monitor (CGMS) was fitted before randomization and at the end of the study. It recorded a 24-h glucose profile by automatically detecting the subcutaneous interstitial fluid every 5 min. This has been previously validated (Sachedina and Pickup, 2003). The area under the glucose curve (AUC) was calculated for the 24 h period and for the 8 h overnight period ( ) using the trapezoid rule. At randomization, all subjects were advised individually on healthy eating for heart disease prevention aiming for 50 55% of energy intake from carbohydrates, o30% energy from total fat, of which o10% saturated fat, replacing saturated fats by monounsaturated fats, consuming oily fish twice a week and limiting alcohol and salt intake (Wood et al., 2005). Overweight subjects were advised on weight loss by achieving a 500 kcal/day deficit. In addition, subjects were advised to have one high or low GI food with meals and snacks from a list of food choices. Low GI foods (mean GI value in brackets, GI of glucose ¼ 100) included seeded bread (54), porridge oats (58), basmati rice (58), pasta (47) and lentils (30) and high GI foods included wholemeal bread (71), weetabix (70), jasmine rice (109), baked potato (85) and cous cous (65) (Foster-Powell et al., 2002). A fasting blood sample was taken at randomization, week 6 and week 12 to assess glucose, total cholesterol, HDL and LDL cholesterol and triglyceride levels. Dietary compliance was assessed through regular visits, telephone calls and 7-day food diaries. Diet diaries were analysed using DietPlan 5 (Forrest Hill Software Ltd, Sussex, UK) and a list of carbohydrate containing (contributing 0.5% or more carbohydrate to the diet) foods was reported for calculation of diet GI and GL. GI was calculated using published values (Foster-Powell et al., 2002) or if not available, an estimation was made based on a similar food s GI. Diet GL was calculated by multiplying the GI by the diet s carbohydrate content. The protocol was ethically approved by the Hammersmith, Queen Charlotte s and Chelsea Hospitals Research Ethics Committee and written informed consent was obtained from each subject. Statistical analysis Data was analysed using SPSS 12.0 for Windows. Nonparametric tests were performed as the data was not normally distributed. Comparison between groups at baseline, week 12 and changes from baseline was done by Mann Whitney tests. Comparison within groups was also done by Wilcoxon tests because of the small sample size. Median (IQR) are presented. Results Eighteen subjects were randomly allocated to a low GI or high GI diet for 12 weeks. Fourteen subjects completed the study, and one subject in the high GI group was excluded from analysis due to his high alcohol intake (24.5% of energy intake) and triglyceride levels (4.57 mmol/l) (4mean þ 2 SDs). Dietary intake and outcome data are shown in Table 1. The low GI (n ¼ 7, female subjects: four, BMI: 28.6 ( ) kg/m 2, age: 54.0 ( ) years and high GI group (n ¼ 6, female subjects: four, BMI: 33.2 ( ) kg/m 2, age: 45.0 ( ) years, P ¼ NS) did not differ at baseline. There were no differences in macronutrient or fibre intake between the groups at baseline or week 12. By week 12, the energy intake was significantly lower in the high GI group (1308 ( ) vs 1773 ( ) kcal/day (Po0.05); change from baseline of 596 ( ) vs 167 ( ) kcal/day (Po0.01). However, only the low GI group lost weight ( 4.0 ( ) vs 1.5 ( ) kg (Po0.05). By week 12 there was a significant difference in diet GI (low GI: 51.3 ( ) vs high GI: 59.3 ( ) (Po0.05). The diet GL did not differ between the groups (105.6 ( ) vs ( ) (P ¼ NS) for the low and high GI groups, respectively) since the carbohydrate intake reduced non-significantly over the study period in the high GI group by 48.8 ( ) g/day compared

3 Table 1 Comparison of dietary intake data, anthropometric data, heart disease risk factors and glucose profile data assessed by continuous glucose monitoring system in the high and low GI groups over the study period (Median (IQR) High GI Low GI Baseline Week 12 Change from baseline Baseline Week 12 Change from baseline Energy intake (kcal/day) 2052 ( ) 1308 a ( ) 596 ( ) 2034 ( ) 1773 a ( ) 167 c ( ) Protein (%) 16.0 ( ) 19.6 ( ) 0.9 ( ) 15.7 ( ) 17.1 ( ) 1.2 ( ) CHO (%) 38.7 ( ) 49.4 ( ) 1.6 ( ) 41.7 ( ) 46.0 ( ) 1.9 ( ) Total fat (%) 35.5 ( ) 29.2 ( ) 2.3 ( ) 36.2 ( ) 32.8 ( ) 2.7 ( ) Saturated fat (%) 9.9 ( ) 7.8 ( ) 1.4 ( ) 11.1 ( ) 10.1 ( ) 1.2 ( ) Alcohol (%) 3.6 ( ) 1.0 ( ) 0.0 ( ) 5.0 ( ) 5.7 ( ) 0.8 ( ) Fibre Englyst (g/day) 12.1 ( ) 10.0 a ( ) 1.8 ( ) 10.2 ( ) 8.0 ( ) 1.8 ( ) Diet GI 54.5 ( ) 59.3 ( ) 6.6 ( ) 53.6 ( ) 51.3 b ( ) 4.4 ( ) Diet GL ( ) ( ) 17.0 ( ) ( ) ( ) 13.3 ( ) CHO intake (g/day) 242 ( ) 181 ( ) 48.8 ( ) 211 ( ) 203 ( ) 7.1 ( ) Weight (kg) 96.2 ( ) 87.8 ( ) 1.5 ( ) 82.6 ( ) 79.6 ( ) 4.0 a ( ) BMI (kg/m 2 ) 33.2 ( ) 31.1 ( ) 0.5 ( ) 28.6 ( ) 27.6 a ( ) 1.4 ( ) Waist (cm) ( ) ( ) 4.0 ( ) 99.0 ( ) 93.0 a ( ) 6.5 ( ) % Body fat 38.4 ( ) 35.8 ( ) 0.9 ( ) 35.3 ( ) 36.6 ( ) 0.1 ( ) T-cholesterol (mmol/l) 5.3 ( ) 5.2 ( ) 0.1 ( ) 5.7 ( ) 5.5 ( ) 0.0 ( ) LDL cholesterol (mmol/l) 3.4 ( ) 3.5 ( ) 0.2 ( ) 3.7 ( ) 3.7 ( ) 0.2 ( ) HDL cholesterol (mmol/l) 1.3 ( ) 1.3 ( ) 0.0 ( ) 1.5 ( ) 1.4 ( ) 0.1 ( ) Total:HDL cholesterol 4.4 ( ) 4.0 ( ) 0.2 ( ) 3.9 ( ) 4.0 ( ) 0.1 ( ) Triglyceride (mmol/l) 1.5 ( ) 1.2 ( ) 0.4 ( ) 1.0 ( ) 1.0 ( ) 0.1 ( ) Glucose (mmol/l) 5.1 ( ) 5.3 ( ) 0.3 ( ) 5.2 ( ) 5.3 ( ) -0.1 ( ) Mean 24-h glucose (mmol/l) 6.3 ( ) 6.2 ( ) 0.1 ( ) 5.5 ( ) 5.3 b ( ) 0.2 ( ) 24 h AUC (mmol-h/l) 8985 ( ) 8841 ( ) 145 ( ) 7806 ( ) 7556 b ( ) 366 ( ) Overnight (8 h) glucose (mmol/l) 7.1 ( ) 6.3 ( ) 0.3 ( ) 5.5 ( ) 5.1 c ( ) 0.1 ( ) Overnight (8 h) AUC (mmol-h/l) 3386 ( ) 3000 ( ) 155 ( ) 2569 ( ) 2429 c ( ) 55 ( ) Abbreviations: AUC, area under the curve; BMI, body mass index; GI, glycaemic index. a Po0.05 between baseline and week 12 within group. b Po0.05 between groups. c Po0.01 between groups. 147

4 148 glucose (mmol/l) to 7.1 ( ) g/day (P ¼ NS) for the low GI group. There were no differences between the groups in the fasting glucose and lipid profiles neither at baseline nor at week 12. Completed CGMS results for baseline and week 12 were collected for 11 volunteers as the sensor failed in two volunteers. There were no differences between the two groups in the CGMS measurements at baseline (Figure 1). By week 12, the low GI group had a significantly lower 24-h AUC (7556 ( ) vs 8841 ( ) mmol-h/l (Po0.05) and overnight 8 h AUC (2429 ( ) vs 3000 ( ) mmol-h/l (Po0.01) glucose profile as measured by CGMS. However, there were no differences between the groups when changes from baseline in the glucose profiles were compared. Discussion Low GI (bs) Low GI (w12) High GI (bs) High GI (w12) P=NS for AUC at baseline, P<0.05 for AUC at week 12 between groups 5:00 6:00 7:00 8:00 9:00 10:00 11:00 12:00 13:00 14:00 15:00 16:00 17:00 18:00 19:00 20:00 21:00 22:00 23:00 0:00 1:00 2:00 3:00 4:00 time Figure 1 Mean 24-h glucose measurements taken by the continuous glucose monitoring system of the high and low glycaemic index groups at baseline and week 12. This pilot study aimed to assess the effect of changing the diet GI on heart disease risk factors and the 24-h glucose profile in subjects at risk of heart disease. Since it is a pilot study, results should be assessed with caution. Consumption of a low GI diet led to a lower 24-h and overnight glucose profile confirming a previous finding (Frost et al., 2005). This might suggest an improvement in hepatic insulin sensitivity resulting in a decrease in hepatic glucose output following meals (Thorburn et al., 1993). Whole body glucose utilization has been shown to improve on a low GI diet as assessed by euglycaemic-hyperinsulinaemic clamp (Rizkalla et al., 2004). This is clinically relevant as raised postprandial glycaemia would increase cardiovascular risk even in the normal glucose tolerance range, although this may be confounded by other heart disease risk factors (Coutinho et al., 1999; The DECODE Study Group, 2001). Glucose may lead to atherosclerosis through oxidative stress (Giugliano et al., 1996) and non-enzymatic glycation of LDL cholesterol and clotting factors (Vlassara et al., 1994). Damage may result from advanced glycation end-products deposited in the vessel wall and matrix and activating inflammation (Brownlee, 1994). Furthermore, large epidemiological studies showed that postprandial glucose levels are even better predictors of CHD risk than fasting glucose alone (The DECODE Study Group, 2001). It is of note that both groups reduced their carbohydrate intake by week 12 and thus the diet GL was not significantly different. Nevertheless only the low GI group had an improvement in blood glucose levels supporting Wolever s observation (Wolever, 2003) that the metabolic advantage of a slowly absorbed diet (low GI diet) is greater than its glycaemic impact. Reducing the glycaemic load via reduction in carbohydrate intake increases postprandial free fatty acids (FFAs) possibly via reduced insulin secretion and sensitivity (Wolever and Mehling, 2003) whereas a low GI diet suppresses FFAs (Rizkalla et al., 2004). A high plasma FFA concentration is associated with dyslipidaemia and an increased risk of cardiovascular disease (Carlsson et al., 2000). None of the other heart disease risk factors measured differed between the groups and we recognize that weight loss in the low GI group might have masked any further effects of changing diet GI. This has also been shown in a comparison between low GI and low fat weight loss diets where the low GI diet did not have any added benefit on glucose or triglyceride levels or insulin sensitivity (Raatz et al., 2005). In the present study, only the low GI group lost weight although both groups reduced their energy intake. It has been suggested that low GI foods promote satiety by preventing marked postprandial hyperglycaemia and hypoglycaemia (Brand-Miller et al., 2002) and weight loss by improving access to stored metabolic fuels (Ludwig, 2002). However, results have not been consistent (Alfenas and Mattes, 2005) and further research is necessary. In this pilot study, the results from the CGMS provided preliminary evidence that a low GI diet may be more efficacious in reducing heart disease risk. Longer-term and larger-scale studies comparing the effects of low and high GI healthy eating diets on heart disease risk need to be conducted. References Alfenas RCG, Mattes RD (2005). 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