Effect of alpha-tocopherol and beta-carotene supplementation on macrovascular complications and total mortality from diabetes: Results of the ATBC Study

Figures & data

Table I. Base-line characteristics of diabetic participants by intervention group in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study.

Characteristics^a	Alpha-tocopherol	Beta-carotene	Alpha-tocopherol and beta-carotene	Placebo
Number of subject	417	434	443	406
Age (years)	57.8	58.1	57.8	57.9
Number of cigarettes/day	20	20	20	20
Smoking (years)	38	39	38	37
Total cholesterol (mmol/L)	6.13	5.93	5.97	6.11
HDL cholesterol (mmol/L)	0.98	0.99	1.00	1.01
Body mass index (kg/m^2)	28.2	28.2	28.8	29.0
Systolic blood pressure (mmHg)	146	146	148	146
Diastolic blood pressure (mmHg)	90	90	88	90
Alcohol consumption (g/day)	10	11	12	10
Physical activity, moderate or heavy (%)	50	53	53	52

^aData are medians or proportions.

Table II. Crude relative risk (RR) with 95% confidence intervals (CIs) for macrovascular outcomes and total mortality by intervention group among diabetic participants of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study during the intervention period and the extended 19-year follow-up (n for macrovascular outcomes = 1238 and for total mortality = 1700).

		Intervention period				19-year follow-up
		Placebo	Alpha-tocopherol	Beta-carotene	Alpha-tocopherol and beta-carotene	Placebo	Alpha-tocopherol	Beta-carotene	Alpha-tocopherol and beta-carotene
Total macrovascular outcomes	Number	52	51	74	54	158	159	184	161
	Rate^a	31.8	31.8	42.2	31.1	47.5	52.1	53.0	48.1
	RR	1.00	1.00	1.34	0.98	1.00	1.12	1.14	1.03
	95% CI		0.68–1.49	0.93–1.92	0.66–1.44		0.90–1.41	0.91–1.41	0.82–1.29
Major coronary event	Number	30	21	41	28	85	66	85	66
	Rate^a	18.3	13.1	23.4	16.1	25.5	21.6	24.5	19.7
	RR	1.00	0.71	1.27	0.88	1.00	0.86	0.97	0.78
	95% CI		0.40–1.26	0.79–2.06	0.52–1.48		0.62–1.20	0.71–1.32	0.56–1.08
Total stroke	Number	13	16	25	18	42	50	54	58
	Rate^a	7.9	10.0	14.2	10.4	12.6	16.4	15.6	17.3
	RR	1.00	1.27	1.82	1.31	1.00	1.33	1.25	1.39
	95% CI		0.60–2.68	0.92–3.61	0.63–2.71		0.88–2.03	0.83–1.89	0.93–2.09
Peripheral arterial disease	Number	9	14	8	8	31	43	45	37
	Rate^a	5.5	8.7	4.6	4.6	9.3	14.1	13.0	11.0
	RR	1.00	1.59	0.84	0.83	1.00	1.56	1.43	1.22
	95% CI		0.67–3.73	0.32–2.21	0.31–2.20		0.98–2.50	0.89–2.27	0.75–1.99
Total mortality	Number	72	78	84	84	255	292	296	299
	Rate^a	31.1	32.6	34.5	33.3	49.8	57.4	56.6	55.4
	RR	1.00	1.04	1.11	1.06	1.00	1.17	1.16	1.13
	95% CI		0.75–1.45	0.81–1.53	0.77–1.47		0.99–1.39	0.98–1.37	0.95–1.34

^aRate per 1000 person-years.

RR = relative risk; CI = confidence interval.

Table III. Crude relative risk (RR) with 95% confidence intervals (CIs) for macrovascular outcomes and total mortality by alpha-tocopherol and beta-carotene supplementation among diabetic participants of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study during the intervention period and the extended 19-year follow-up (n for macrovascular outcomes = 1238 and for total mortality = 1700).

		Intervention period				19-year follow-up
		Alpha-tocopherol	No alpha-tocopherol	Beta-carotene	No beta-carotene	Alpha-tocopherol	No alpha-tocopherol	Beta-carotene	No beta-carotene
Macrovascular outcomes, total	Number	105	126	128	103	320	342	345	317
	Rate^a	31.4	37.2	36.7	31.8	50.0	50.3	50.6	49.7
	RR	0.84	1.00	1.15	1.00	1.00	1.00	1.02	1.00
	95% CI	0.65–1.10		0.89–1.50		0.86–1.17		0.88–1.19
Major coronary event	Number	49	71	69	51	132	170	151	151
	Rate^a	14.7	20.9	19.8	15.7	20.6	25.0	22.1	23.7
	RR	0.70	1.00	1.26	1.00	0.83	1.00	0.94	1.00
	95% CI	0.48–1.01		0.87–1.82		0.66–1.05		0.74–1.18
Total stroke	Number	34	38	43	29	108	96	112	92
	Rate^a	10.2	11.2	12.3	9.0	16.9	14.1	16.4	14.4
	RR	0.91	1.00	1.38	1.00	1.21	1.00	1.14	1.00
	95% CI	0.57–1.45		0.85–2.23		0.91–1.60		0.86–1.51
Peripheral arterial disease	Number	22	17	16	23	80	76	82	74
	Rate^a	6.6	5.0	4.6	7.1	12.5	11.2	12.0	11.6
	RR	1.30	1.00	0.65	1.00	1.14	1.00	1.05	1.00
	95% CI	0.68–2.49		0.34–1.24		0.83–1.57		0.76–1.44
Total mortality	Number	162	156	168	150	591	551	595	547
	Rate^a	32.9	32.8	33.9	31.8	56.3	53.2	56.0	53.5
	RR	1.00	1.00	1.06	1.00	1.06	1.00	1.05
	95% CI	0.80–1.25		0.85–1.33		0.95–1.20		0.93–1.18	1.00

^aRate per 1000 person-years.

RR = relative risk; CI = confidence interval.

Table IV. Intervention trials that reported the effects of antioxidant supplementation on cardiovascular complications in individuals with diabetes.

Study	Country	Study type	Study population	Duration of treatment	Daily dose	Results
The Heart Outcomes Prevention Evaluation (HOPE) Study (9)	19 countries from Europe, North and South America	Randomized, double-blind, placebo-controlled	3654 men and women, aged ≥ 55 years	Mean 4.5 years	400 IU vitamin E	No effect
MRC/BHF Heart Protection Study (11)	United Kingdom	Randomized, double-blind, placebo-controlled	3982 men and women, aged 40–80 years	Mean 5 years	20 mg beta-carotene, 600 mg alphatocopherol, 250 mg vitamin C	No significant differences in outcome
Primary Prevention Project Trial (10)	Italy	Randomized, open trial	1031 men and women, aged ≥ 50 years	Median 3.7 years	300 mg vitamin E	No effect
Women's Health Study (13)	United States	Randomized, double-blind, placebo-controlled	1027 women aged ≥ 45 years	Average 10.1 years	600 IU alpha-tocopherol every other day	No effect
Women's Antioxidant Cardiovascular Study (12)	United States	Randomized, double-blind, placebo-controlled, factorial	1564 women aged ≥ 40 years	Mean 9.4 years	500 mg vitamin C, or 600 IU alphatocopherol every other day, or 50 mg beta-carotene every other day	No benefit of any of the antioxidants
Physicians Health Study II (14)	United States	Randomized, double-blind, placebo-controlled, factorial	905 men, aged ≥50 years	Mean 8 years	400 IU alpha-tocopherol (alternate days), or 500 mg vitamin C	No effect

Lonn E, Yusuf S, Hoogwerf B, Poque J, Yi Q, Zinman B, . Effects of vitamin E on cardiovascular and microvascular outcomes in high-risk patients with diabetes: results of the HOPE study and MICRO-HOPE substudy. Diabetes Care. 2002;25:1919–27.

 PubMed Web of Science ®Google Scholar

Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:23–33.

 PubMed Web of Science ®Google Scholar

Sacco M, Pellegrini F, Roncaglioni MC, Avanzini FM, Tognoni G, Nicolucci A. Primary prevention of cardiovascular events with low-dose aspirin and vitamin E in type 2 diabetic patients: results of the Primary Prevention Project (PPP) trial. Diabetes Care. 2003;26:3264–72.

 PubMed Web of Science ®Google Scholar

Lee IM, Cook NR, Gaziano JM, Gordon D, Ridker PM, Manson JE, . Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women’s Health Study: a randomized controlled trial. JAMA. 2005;294:56–65.

 PubMed Web of Science ®Google Scholar

Cook NR, Albert CM, Gaziano JM, Zaharris E, MacFayden J, Danielson E, . A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: results from the Women’s Antioxidant Cardiovascular Study. Arch Intern Med. 2007;167:1610–8.

 PubMed Web of Science ®Google Scholar

Sesso HD, Buring JE, Christen WG, Kurth T, Belanger C, MacFayden J, . Vitamins E and C in the Prevention of Cardiovascular Disease in Men, The Physicians’ Health Study II Randomized Controlled Trial. JAMA. 2008;300: 2123–33.

 PubMed Web of Science ®Google Scholar