Safety of metformin in Type 2 diabetes mellitus.
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Biomedical subjects
Publications and source records attributed to R Peto.
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OBJECTIVE: To assess the hazards at an early phase of the growing epidemic of deaths from tobacco in China. DESIGN: Smoking habits before 1980 (obtained from family or other informants) of 0.7 million adults who had died of neoplastic, respiratory, or vascular causes were compared with those of a reference group of 0.2 million who had died of other causes. SETTING: 24 urban and 74 rural areas of China. SUBJECTS: One million people who had died during 1986-8 and whose families could be interviewed. MAIN OUTCOME MEASURES: Tobacco attributable mortality in middle or old age from neoplastic, respiratory, or vascular disease. RESULTS: Among male smokers aged 35-69 there was a 51% (SE 2) excess of neoplastic deaths, a 31% (2) excess of respiratory deaths, and a 15% (2) excess of vascular deaths. All three excesses were significant (P<0.0001). Among male smokers aged >/70 there was a 39% (3) excess of neoplastic deaths, a 54% (2) excess of respiratory deaths, and a 6% (2) excess of vascular deaths. Fewer women smoked, but those who did had tobacco attributable risks of lung cancer and respiratory disease about the same as men. For both sexes, the lung cancer rates at ages 35-69 were about three times as great in smokers as in non-smokers, but because the rates among non-smokers in different parts of China varied widely the absolute excesses of lung cancer in smokers also varied. Of all deaths attributed to tobacco, 45% were due to chronic obstructive pulmonary disease and 15% to lung cancer; oesophageal cancer, stomach cancer, liver cancer, tuberculosis, stroke, and ischaemic heart disease each caused 5-8%. Tobacco caused about 0.6 million Chinese deaths in 1990 (0.5 million men). This will rise to 0.8 million in 2000 (0.4 million at ages 35-69) or to more if the tobacco attributed fractions increase. CONCLUSIONS: At current age specific death rates in smokers and non-smokers one in four smokers would be killed by tobacco, but as the epidemic grows this proportion will roughly double. If current smoking uptake rates persist in China (where about two thirds of men but few women become smokers) tobacco will kill about 100 million of the 0.3 billion males now aged 0-29, with half these deaths in middle age and half in old age.
OBJECTIVE: To monitor the evolving epidemic of mortality from tobacco in China following the large increase in male cigarette use in recent decades. DESIGN: Prospective study of smoking and mortality starting with 224 500 interviewees who should eventually be followed for some decades. SETTING: 45 nationally representative small urban or rural areas distributed across China. SUBJECTS: Male population aged 40 or over in 1991, of whom about 80% were interviewed about smoking, drinking, and medical history. MAIN OUTCOME MEASURE: Cause specific mortality, initially to 1995 but later to continue, with smoker versus non-smoker risk ratios standardised for area, age, and use of alcohol. RESULTS: 74% were smokers (73% current, only 1% former), but few of this generation would have smoked substantial numbers of cigarettes since early adult life. Overall mortality is increased among smokers (risk ratio 1.19; 95% confidence interval 1.13 to 1.25, P<0.0001). Almost all the increased mortality involved neoplastic, respiratory, or vascular disease. The overall risk ratios currently associated with smoking are less extreme in rural areas (1.26, 1.12, or 1.02 respectively for smokers who started before age 20, at 20-24, or at older ages) than in urban areas (1.73, 1.40, or 1.16 respectively). CONCLUSION: This prospective study and the accompanying retrospective study show that by 1990 smoking was already causing about 12% of Chinese male mortality in middle age. This proportion is predicted to rise to about 33% by 2030. Long term continuation of the prospective study (with periodic resurveys) can monitor the evolution of this epidemic.
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The relation between dietary vitamin C intake and pulmonary function was investigated in a cross-sectional study carried out in 69 counties in rural China in 1989. Within each of the 69 counties, 120 subjects aged 35-64 years were identified using a three-stage random clustering procedure. Each subject underwent pulmonary function testing, completed a detailed questionnaire, and provided a blood sample. Dietary vitamin C intakes were estimated among half of the subjects using a 3-day weighed record of household food intake. Plasma vitamin C was measured in sex-specific blood pools created from individual samples in each geographic area. Among the 3,085 subjects for whom there were complete data, dietary intake of vitamin C (151 mg/day (standard deviation, 111)) was significantly related to forced expiratory volume in the first second (FEV1) and forced vital capacity after adjustment for sex, age, height, weight, total caloric intake, tobacco smoking, and education. An increase of 100 mg/day in vitamin C intake was associated with an increase of 21.6 ml (95% confidence interval -0.4 to 43.5) in FEV1 and an increase of 24.9 ml (95% confidence interval 0.2 to 49.6) in forced vital capacity. No significant interaction with smoking status was observed. A significant positive association was also observed at the geographic level, between county-pooled plasma vitamin C and mean FEV1. These data support the hypothesis that dietary vitamin C may protect against the loss of pulmonary function.
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CONTEXT: A large number of epidemiologic studies have reported on associations between various "inflammatory" factors and coronary heart disease (CHD). OBJECTIVE: To assess the associations of blood levels of fibrinogen, C-reactive protein (CRP), and albumin and leukocyte count with the subsequent risk of CHD. DATA SOURCES: Meta-analyses of any long-term prospective studies of CHD published before 1998 on any of these 4 factors. Studies were identified by MEDLINE searches, scanning of relevant reference lists, hand searching of cardiology, epidemiology, and other relevant journals, and discussions with authors of relevant reports. STUDY SELECTION: All relevant studies identified were included. DATA EXTRACTION: The following information was abstracted from published reports (supplemented, in several cases, by the authors): size and type of cohort, mean age, mean duration of follow-up, assay methods, degree of adjustment for confounders, and relationship of CHD risk to the baseline assay results. DATA SYNTHESIS: For fibrinogen, with 4018 CHD cases in 18 studies, comparison of individuals in the top third with those in the bottom third of the baseline measurements yielded a combined risk ratio of 1.8 (95% confidence interval [CI], 1.6-2.0) associated with a difference in long-term usual mean fibrinogen levels of 2.9 pmol/L (0.1 g/dL) between the top and bottom thirds (10.3 vs 7.4 pmol/L [0.35 vs 0.25 g/dL]). For CRP, with 1053 CHD cases in 7 studies, the combined risk ratio of 1.7 (95% CI, 1.4-2.1) was associated with a difference of 1.4 mg/L (2.4 vs 1.0 mg/L). For albumin, with 3770 CHD cases in 8 studies, the combined risk ratio of 1.5 (95% CI, 1.3-1.7) was associated with a difference of 4 g/L (38 vs 42 g/L, ie, an inverse association). For leukocyte count, with 5337 CHD cases in the 7 largest studies, the combined risk ratio of 1.4 (95% CI, 1.3-1.5) was associated with a difference of 2.8 x 10(9)/L (8.4 vs 5.6 x 10(9)/L). Each of these overall results was highly significant (P<.0001). CONCLUSIONS: The published results from these prospective studies are remarkably consistent for each factor, indicating moderate but highly statistically significant associations with CHD. Hence, even though mechanisms that might account for these associations are not clear, further study of the relevance of these factors to the causation of CHD is warranted.
OBJECTIVE: To assess effects of intravenous streptokinase, one month of oral aspirin, or both, on long term survival after suspected acute myocardial infarction. DESIGN: Randomised, "2 x 2 factorial," placebo controlled trial. SETTING: 417 hospitals in 16 countries. SUBJECTS: 17 187 patients with suspected acute myocardial infarction randomised between March 1985 and December 1987. Follow up of vital status complete to at least 1 January 1990 for 95% of all patients and to mid-1997 for the 6213 patients in United Kingdom. INTERVENTIONS: Intravenous streptokinase (1.5 MU in 1 hour) and oral aspirin (162 mg daily for 1 month) versus matching placebos. MAIN OUTCOME MEASURES: Mortality from all causes during up to 10 years' follow up, with subgroup analyses based on 4 year follow up. RESULTS: After randomisation, 1841 deaths were recorded in days 0-35, 991 from day 36 to end of year 1, 1478 in years 2-4, and 1230 in years 5-10. Allocation to streptokinase was associated with 29 (95% confidence interval 20 to 38) fewer deaths per 1000 patients during days 0-35. This early benefit persisted (death rate ratio 0.98 (0.92 to 1.04) for additional deaths between day 36 and end of year 10), so that there were 28 (14 to 42) and 23 (2 to 44) fewer deaths per 1000 patients treated with streptokinase after 4 years and 10 years respectively. There was no evidence that absolute survival benefit increased with prolonged follow up among any category of patient, including those presenting early after symptoms started or with anterior ST elevation. Nor did the early benefits seem to be lost in any category (including those aged over 70). Allocation to one month of aspirin was associated with 26 (16 to 35) fewer deaths per 1000 during first 35 days, with little further benefit or loss during subsequent years (death rate ratio 0.99 (0.93 to 1.06) between day 36 and end of year 10). The early benefit obtained with combination of streptokinase and one month of aspirin also seemed to persist long term. CONCLUSIONS: The early survival advantages produced by fibrinolytic therapy and one month of aspirin started in acute myocardial infarction seem to be maintained for at least 10 years.
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PURPOSE: To assess the effect of more extensive radiotherapy and of adjuvant combination chemotherapy on long-term outcome of early-stage Hodgkin's disease. METHODS: In a collaborative worldwide systematic overview, individual patient data were centrally reviewed on 1,974 patients in eight randomized trials of more versus less extensive radiotherapy and on 1,688 patients in 13 trials of radiotherapy plus chemotherapy versus radiotherapy alone. Crude mortality data on 226 patients in two other trials of chemotherapy were also reviewed. RESULTS: More extensive radiotherapy reduced the risk of treatment failure (resistant or recurrent disease) at 10 years by more than one third (31.3% v 43.4% failures; P < .00001), but there was no apparent improvement in overall 10-year survival (77.1 % v 77.0% alive). The addition of chemotherapy to radiotherapy halved the 10-year risk of failure (15.8% v 32.7%; P < .00001), with a small, nonsignificant improvement in survival (79.4% v 76.5% alive). This involved a reduction of borderline significance for deaths from Hodgkin's disease (12.3% v 15.4% dead at 10 years; P = .07), which was partly counterbalanced by a nonsignificant excess of deaths from other causes (12.4% v 10.0% 10-year risk). CONCLUSION: More extensive radiotherapy fields or the addition of chemotherapy to radiotherapy in the initial treatment of early-stage Hodgkin's disease had a large effect on disease control, but only a small effect on overall survival. Recurrences could be prevented by more extensive radiotherapy or by additional chemotherapy. However, if chemotherapy had not been given initially, recurrences were generally salvageable by re-treatment with chemotherapy. Hence, less intensive primary treatment--particularly a reduction in radiotherapy fields--appears to achieve similar survival rates as more intensive treatment, although more randomized evidence is needed to confirm this.
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BACKGROUND: Alcohol consumption has both adverse and beneficial effects on survival. We examined the balance of these in a large prospective study of mortality among U.S. adults. METHODS: Of 490,000 men and women (mean age, 56 years; range, 30 to 104) who reported their alcohol and tobacco use in 1982, 46,000 died during nine years of follow-up. We compared cause-specific and rates of death from all causes across categories of base-line alcohol consumption, adjusting for other risk factors, and related drinking and smoking habits to the cumulative probability of dying between the ages of 35 and 69 years. RESULTS: Causes of death associated with drinking were cirrhosis and alcoholism; cancers of the mouth, esophagus, pharynx, larynx, and liver combined; breast cancer in women; and injuries and other external causes in men. The mortality from breast cancer was 30 percent higher among women reporting at least one drink daily than among nondrinkers (relative risk, 1.3; 95 percent confidence interval, 1.1 to 1.6). The rates of death from all cardiovascular diseases were 30 to 40 percent lower among men (relative risk, 0.7; 95 percent confidence interval, 0.7 to 0.8) and women (relative risk, 0.6; 95 percent confidence interval, 0.6 to 0.7) reporting at least one drink daily than among nondrinkers, with little relation to the level of consumption. The overall death rates were lowest among men and women reporting about one drink daily. Mortality from all causes increased with heavier drinking, particularly among adults under age 60 with lower risk of cardiovascular disease. Alcohol consumption was associated with a small reduction in the overall risk of death in middle age (ages 35 to 69), whereas smoking approximately doubled this risk. CONCLUSIONS: In this middle-aged and elderly population, moderate alcohol consumption slightly reduced overall mortality. The benefit depended in part on age and background cardiovascular risk and was far smaller than the large increase in risk produced by tobacco.
CONTEXT: In recent decades, there has been a rapid and substantial increase in tobacco consumption in China, particularly by men, but little is known from local epidemiologic studies about the pattern of smoking-related deaths. OBJECTIVE: To assess the current health effects of cigarette smoking in Shanghai, China. DESIGN: Prospective observational study of mortality in relation to cigarette smoking. SETTING: Eleven factories in urban Shanghai. SUBJECTS: A total of 9351 adults (6494 men and 2857 women) aged 35 to 64 years at baseline survey during the 1970s. OUTCOME MEASURES: All-cause and cause-specific mortality. RESULTS: During an average follow-up of 16 years, 881 men and 207 women died. Among men, 61% had described themselves as current cigarette smokers at baseline, and their overall mortality was significantly greater than that of nonsmokers (relative risk [RR], 1.4; 95% confidence interval [CI], 1.2-1.7; P<.001). The excess was almost twice as great (RR, 1.8; 95% CI, 1.5-2.2 [corrected]; P<.001) among the men who had begun smoking before the age of 25 years and was significantly associated with the number of cigarettes smoked (P<.001 for trend) after adjustment for other major risk factors. The chief sources of the excess were lung cancer (RR, 3.8; 95% CI, 2.1-6.8; P<.001), esophageal cancer (RR, 3.6; 95% CI, 1.2-10.5; P=.02), liver cancer (RR, 2.0; 95% CI, 1.1-3.7; P=.03), coronary heart disease (RR, 1.8; 95% CI, 1.0-3.2; P=.04), and chronic obstructive pulmonary disease (RR, 2.5; 95% CI, 1.4-4.4; P<.01). Among the men in this Chinese population, about 20% (95% CI, 12%-29%) of all deaths during the study period could be attributed to cigarette smoking. Of these deaths, one third involved lung cancer, one third involved other cancers, and one third involved other diseases. Only 7% of women described themselves as current cigarette smokers at baseline, but among them there was also a statistically significant excess of overall mortality (RR, 1.7; 95% CI, 1.2-2.5; P<.01). CONCLUSIONS: Cigarette smoking is already a major cause of death in China, and among middle-aged Shanghai men, about 20% of all deaths during the 1980s were due to smoking. The excess was greatest among men who began smoking before the age of 25 years, about 47% of whom would, at 1987 mortality rates, die between the ages of 35 and 69 years (compared with only 29% of nonsmokers). These estimates reflect the consequences of past smoking patterns. The future health effects of current smoking patterns are likely to be greater because of the recent large increase in cigarette consumption, particularly at younger ages, in China.