Df=D
ORIGINAL ARTICLES
Obesity, Weight Loss and Prognosis in Type 2 Diabetes M.E.J. Lean”, J.K. Powrie”, A.S. Anderson”, P.H. Garthwaiteb ’Diabetic Clfnic, Aberdeen Royal Inffrrnary and bDepartrnent of Mathematical Soences, Kings College, Universfty of Aberdeen, UK
Medical records were reviewed of all 263 Type 2 diabetic patients from the Aberdeen diabetic clinic who were known to have died in 1985 or 1986. Mean age was 65 years (interquartile range 57-75 years) at diagnosis and 72 (66-80) years for men, 75 (72-83) years for women, at death. Life expectancy at age 65 was 35 % less than published figures for the general population. Analysis of survival in 233 patients who lived more than 1 year (1 89 overweight) using stepwise multiple regression indicated as significant ( p < 0.05) adverse independent variables: age at diagnosis, presence of clinical ischaemic heart disease at diagnosis, plasma glucose at diagnosis; and as significant favourable variables: oral hypoglycaemic drug therapy, weight loss in the first year, and an interaction between weight loss and BMI for patients with BMI > 25 kg m-2. Changes in fashions over the years are likely to have biased these results towards including oral hypoglycaemic therapy and excluding the expected adverse effect of smoking. Mean weight loss at 1 year was 2.6 kg for those with BMI 25-30 kg mP2, 6.8 kg with BMI > 30 kg m-’, following standard dietetic advice. For the average patient each 1 kg weight loss was associated with 3 - 4 months prolonged survival. KEY WORDS
Diet Slimming Oral hypoglycaemic agents Survival analysis Clinical audif
Introduction
Methods
Type 2 diabetes is strongly associated with obesity, causally or perhaps sharing common aetiological factors in susceptible individuals. It is commonly suggested that obesity contributes to the accelerated ischaemic vascular disease and mortality of patients with Type 2 diabetes. Large actuarial studies have been able to confirm that obesity increases vascular mortality in the general population,’ and it is probable from life assurance data that weight loss will improve outlook in terms of reduced m ~ r t a l i t y . There ~ , ~ i s no published evidence that, within a diabetic population, either the degree of obesity or success in slimming have any bearing on prognosis. Weight loss is advocated for obese diabetic patients, firstly, for the rather rapid metabolic improvement which results from negative energy balance but, secondly, in the belief that long-term vascular complications may be reduced. Symptoms regress and metabolic control often improves to approach normality with only very minor weight loss (supported by hypoglycaemic agents when necessary). Further weight loss can be achieved only by sustained dietary modification, and the gains from prolonged efforts are seldom obvious to patients or health professionals. The present study examines the hypothesis that weight loss improves survival in obese Type 2 diabetic patients.
Data were collected from the diabetic and general hospital files of the 312 patients (263 Type 2) from the Aberdeen Diabetic Clinic who were known to have died in 1985 or 1986. All deaths in the region are notified automatically to the hospital Records Department by the central Registrar of Deaths. From these lists the diabetic clinic staff compile lists and collect the records of diabetic patient deaths which were used for the present study. A separate clinic filing system has been in use since 1960, supplemented since 1984 by problem-oriented computer files, and records are not permitted to leave the clinic. Diabetes records of deceased patients are transferred from the current or non-attender clinic files and united with the general Aberdeen hospital records in an adjoining ‘death files‘ store room. The years 1985 and 1986 were selected for study since in 1987 a review of all 6000 sets of diabetic clinic records was conducted to ensure that all the records of deceased patients had been removed from the current and non-attender files to the death files, in order to identify missed deaths, or those who had died outside the area. Criteria for the diagnosis of diabetes have changed over the years. Cases originally labelled ‘diabetic’ on the basis of intravenous testing were excluded if elevated random plasma glucose (> 9.0 mmol I-’) was never recorded. Others, included in the present study, might have fallen into the new category of ‘impaired glucose t ~ l e r a n c e ’had ~ current diagnostic tests been applied. The diagnosis of impaired glucose tolerance also carries increased vascular m ~ r t a l i t y and , ~ thus cannot meaning-
Correspondence to: Dr M.E.J.Lean, Department of Human Nutrition, University of Clasgow, Queen Elizabeth Building, Glasgow Royal Infirmary, Glasgow, UK.
22 8
0742-307 1 1901030228-06$05.00 0 1990 by John Wiley & Sons, Ltd.
Accepted 1 Decmber 1989 DIABETIC IMEDICINE, 1990; 7: 228-233
DTT7
ORIGINAL ARTICLES
fully be differentiated from Type 2 diabetes within the context of the present study. Random plasma glucose was recorded at each clinic visit, measured by various methods over the years but mostly (since 1970) using a glucose oxidase method (Beckman glucose analyser II, Fullerton, CA, USA). Body weight was measured using an Avery (Birmingham, UK) Type 3205 COE weighing machine, height using a wall-mounted stadiometer, and blood pressure using a wall-mounted mercury sphygmomanometer. lnsu I i n-treated diabetic patients were excluded from the present analyses, except in cases where insulin was used for a limited period for therapeutic studies or in cases thought initially to be insulindependent but where the true diagnosis of Type 2 diabetes was proved by subsequent withdrawal of insulin therapy. The diagnosis of ischaemic heart disease (IHD) was accepted on the basis of angina or myocardial infarction, or for heart failure only in cases where it was documented in hospital as resulting from ischaemic heart disease.
were not available in sufficient numbers for analysis. O n a priori grounds it was believed that sex would affect survival, so this fixed variable was forced into the regression equation and other variables were entered sequentially according to which most improved the predictive model, with a cut-off at p = 0.10. It was also anticipated that BMI would be likely to affect survival, and that it might interact with weight loss (WL). To examine this tsossibilitv. an interaction term (BMI.WLI was constructid: BMI.WL = (BMI (weight loss where BMI and are the average BMI and weight loss for the group being considered. Subtracting averages in this way reduced the correlation between the interaction term and weight loss. Results are expressed as mean (SD) or median, with 95 % confidence interval (CI) estimated as ? SE x 1.98.
m)
, I
m),
ResuIts Clinical variables at the time of diagnosis of Type 2 diabetes which relate to degree of obesity and to weight change are described in Tables 1 and 2. BMI at diagnosis ranged from 19.7 to 43.9 kg m-]. The prognoses for different groups are shown in Table 3, but there are many interactions between variables which make simple comparisons misleading. The length of survival ranged from 0.8 to 35 years. The presence of clinically apparent ischaemic heart disease before diagnosis of diabetes, however, was clearly a powerful adverse prognostic factor, although this effect could also reflect greater age at diagnosis of diabetes in a subgroup whose diabetes was revealed at myocardial infarction (Table 3). Those with pre-existing ischaemic heart disease were no more obese than other cases of Type 2 diabetes.
Analysis of Survival Analysis used the SPSS-X program,6 with the primary aim of examining whether weight loss affected survival rates for the overweight. Survival time (in years) was measured from the date of diagnosis of diabetes, and only those who survived more than 12 months ( n = 233) were included in the analysis for effect of weight loss. The term ‘v‘survival time’ was selected as the appropriate dependent variable since residual errors appeared to follow a normal distribution most closely. Multiple stepwise regression equations based on the following variables were examined: sex, age, IHD at the time of diagnosis of diabetes, BMI, systolic and diastolic blood pressure, plasma glucose at time of diagnosis and after 12 months, weight change 12 months after diagnosis, smoking, treatment selected at diagnosis (1 for oral hypoglycaemic agents, 0 for diet alone). Plasma lipids
Life Expectancy with Type 2 Diabetes Those who reached the age of 65 years were 32 men and 37 women. Their mean future life expectancy was
Table 1. Clinical details of the Type 2 diabetic population Patient group
n
Sex (MIF)
CitylRegion Srnoki nginon-srnoking Clinical IHD Before diabetes After diabetes Never Blood pressure (mmHg) Systolic (SD) Diastolic (SD)
< 25
25-30
> 30
263 14611 17 1561107 941147
66 32134 5411 2 22137
115 72/43 63152 46/62
71 38133 34/37 34137
81 52 116
17 13 32
39 22 46
20 16 35
158(27) 90(13)
158(32) 88(12)
156(26) 90(13)
162(23) 93(14)
Number, or mean (SD) for blood pressure at diagnosis WEIGHT LOSS AND PROGNOSIS
229
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ORIGINAL ARTICLES Table 2. Body weight, BMI, and weight change in relation to major clinical factors for patients with Type 2 diabetes Weight at diagnosis (kg)
M F
(13.6) (15.0) (14.6) (16.2)
BMI
(kg m - 9
Weight change at 1 year (kg)
Smokers Non-smokers
80.4 67.3 77.7 72.8
Therapy from diagnosis Diet only Drug therapy
78.6 (14.5) 70.2 (15.7)
29.1 (4.2) 26.7 (5.2)
-4.1 (6.0) -1.5 (6.7)
Clinical IHD Before diabetes After diabetes Never
74.9 (14.9) 76.7 (17.3) 73.4 (15.9)
27.9 (4.1) 28.8 (5.8) 27.7 (4.9)
-2.7 (5.4) -3.8 (5.4) -2.4 (6.6)
BMI (kg m-2) < 25 25-30 > 30
60.3 (10.1) 73.1 (9.6) 90.8 (12.5)
22.6 (1.9) 27.3 (1.4) 34.0 (3.9)
+1.3 (4.3) -2.6 (5.6) -6.8 (7.1)
28.1 27.8 28.1 29.0
(4.0) (5.7) (4.2) (5.3)
-3.5 -2.3 -2.5 -2.8
(6.7) (6.2) (7.0) (6.4)
Mean (SD).
Table 3. Prognosis, in terms of mean age at death and survival after the diagnosis of Type 2 diabetes
(yr) All patients
64.9 (57.0, 73.1) 64.3 (55.9, 72.8) M F 65.6 (57.9, 73.9) 62.5 (54.7, 71.2) Smokers 66.0 (59.6, 74.3) Non-smokers City 66.0 (57.9, 74.0) Region 63.1 (56.0, 71.5) Therapy from diagnosis Diet only 65.8 (58.5, 73.1) Drug therapy 63.7 (54.5, 73.2) Clinical IHD at diagnosis of diabetes Present 67.9 (59.7, 74.8) Absent 63.5 (55.7, 71.8) BMl (kg m-2) < 25 64.8 (55.3, 73.9) 25-30 66.5 (59.9, 73.8) > 30 62.7 (56.0, 71.4)
Survival after diagnosis
Age at death (yr)
Age at diagnosis
(yr) 81 .O) 80.0) 82.9) 78.0) 82.0) 81.1) 80.8)
8.8 (2.5, 12.8) 7.8 (2.0, 10.7) 10.1 (3.4, 16.3) 7.9 (2.3, 10.3) 9.2 (2.8, 13.3) 8.1 (2.3, 11.2) 9.9 (2.6, 15.3)
72.5 (66.9, 79.4) 75.0 (70.8, 82.7)
6.6 (2.0, 8.7) 1 1 . 1 (3.6, 17.4)
74.1 (68.6, 80.6) 73.6 (68.8, 81.2)
5.9 (2.0, 8.3) 10.1 (3.1, 15.5)
73.9 (70.6, 82.2) 74.9 (70.7, 81.2) 71.5 (64.3, 78.8)
9.1 (2.5, 13.0) 8.5 (2.5, 12.0) 8.8 (2.6, 15.1)
73.7 72.1 75.8 70.4 75.1 74.1 73.2
(69.0, (65.5, (72.1, (63.2, (72.1, (69.7, (68.0,
Mean (interquartile range).
then 7.6 (95 % CI 5.7-9.5) years for men, 11.4 (95 % CI 9.4-13.3) years for women. Average expectation of life at age 65 years for the general population of Scotland was greater than these upper 95 % CIS, at 11.6 years for men, 15.4 years for women in 1980-82.’
Analysis of Survival Stepwise multiple regression analysis was used to identify the independent prognostic factors in all Type 2 diabetic patients (n = 233) and in those with BMI > 25 kg m-* 230
(n = 189) who lived more than 1 year from diagnosis (Table 4). Sex was forced into the model in case other variables covaried with it, although it did not itself relate significantly to survival. Age at diagnosis was the first variable to be selected by the regression analysis, accounting for 11.9 % of variance. Pre-existing clinical ischaemic heart disease (IHD) also had a clear adverse influence. Plasma glucose at diagnosis was inversely related to survival time, but there was no evidence that survival was affected by blood pressure or smoking (NS for all patients and M.E.J. LEAN ET AL.
Drn
ORIGINAL ARTICLES
Table 4. Independent variables for predicting the dependent variable Vsurvival time in years from diagnosis of Type 2 diabetes. Regression coefficients with their 95 % CI and the significance levels at which the coefficients differ from zero BMI
All patients
k
5.01 (4.10, 5.92)
Variables present at diagnosis of diabetes Sex" (rn=O, f = l ) Age (years)
IHD (yes=l)
kg m-'
P
Estimate (95 % CI)
P
Estimate (95 % CI)
> 25
5.79 (4.04, 7.54)
0.16 (-0.11, 0.42) -0.035 (-0.048, -0.022) -0.47 (-0.76, -0.19)
> 0.10 < 0.001 < 0.001
0.25 (-0.06, 0.56) -0.035 (-0.051, -0.01 8) -0.60 (-0.92, -0.26)
> 0.10 < 0.001 < 0.001
-0.023 (-0.044, -0.003) -
< 0.05
-0.027 (-0.052, -0.003) -0.026 (-0.065, -0.014)
< 0.05 > 0.10
Plasma glucose
(mmol I-') BMlb (kg m-')
-
Variable decided at diagnosis of diabetes Drug therapy (diet=(), drugs= 1 )
0.74 (0.47, 1.01)
< 0.001
Variables available 1 year after diagnosis Weight loss (kg) BMI.WLb (kg' m-2)
0.036 (0.016, 0.056) -
< 0.001
< 0.001
0.85 (0.54, 1 . 1 7) 0.053 (0.028, 0.079) -0.004 (-0.007, -0.001)
-
< 0.001 < 0.025
Variance accounted for
r2
0.42
0.35
"Sex was forced into the regression analysis, although not itself significant, in case other independent variables covaried with it (see text) bNeither BMI nor BMI.WL were significantly predictive of survival for patients of all BMI, so were not selected by the stepwise regression analysis. BMI appears in the model for patients with BMI > 25 kg m since the interaction term BMI.WL was significant, and both components of the interaction must then be included in the model
for those with BMI > 25 kg mP2). Plasma glucose at 1 year did not predict survival time, but there was evidence that patients treated with oral hypoglycaemic agents had survived longer ( p < 0.001). This applied to all patients and to the overweight. Weight loss was associated with improved survival ( p < O.OOl), but the evidence for BMI was inconclusive. Analysis was performed for all patients, as well as those with BMI > 25 kg mP2 at diagnosis, since weight loss may still be desirable even for patients with BMI < 25 kg mP2 who would not conventionally be considered overweight, and advice is routinely offered to approach ideal body weight for the general population (BMI 22 kg mP2). Results were similar for these two groups. BMI alone appeared not to affect survival ( p > 0.10). However, combined with BMI in the model (with BMI set equal to 29.86 and WL to - 4.2851, the interaction term BMI.WL was predictive for obese patients with BMI > 25 kg m-2 ( p < 0.025). (BMI appears in this model, although non-significant, since if an interaction term is included then both the variables forming the interaction should also be included). Weight loss did not appear to correlate with other independent variables considered: in particular, an anticipated relationship with change in plasma glucose over the first year was not apparent ( r = 0.1 1, NS). Figure 1 illustrates the life expectancy with different degrees of weight loss over the first year for an 'average' overweight Type 2 diabetic patient. The graph assumes an average BMI so that there is no BMI.WL interaction, and a life expectancy without weight loss of 8 years, just WEIGHT LOSS AND PROGNOSIS
n
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14
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13
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-
11
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c ([f
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9 -
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Weight loss in first 12 months (kg) Figure 1 . Life expectancy in Type 2 diabetic patients with BMI > 25 kg mP2 i n relation to weight loss i n the first year of treatment, based on an expected survival time without weight loss of 8 years. The shaded area represents the 95 % confidence intervals
below the median (with some weight loss) in the present study of 8.5 years for BMI 25-30 kg mPz. The regression equation implies that Vsurvival time will increase by 231
DTT7
ORIGINAL ARTICLES 0.0534 yro.S for each 1 kg weight loss, and life expectancy is estimated as ( 0 . 0 5 3 4 ~+ YO-^)^, where y years is the life expectancy without weight loss and the patient actually loses x kg. The 95 % CIS shown reflect the uncertainty in the figure of 0.0534 yr0.5 per kg weight loss.
Discussion Retrospective analysis i s appropriate to this study of obesity management since over the years there has been no change in the policy of urging weight loss by dietary energy restriction, most commonly with a standard 1000 kcal diet. Individual dietetic counselling from trained dietitians has been used since the clinic was established in 1927. The results presented here reflect advice mainly to restrict carbohydrate, since liberalcarbohydrate reducing diets were not introduced in any numbers until 1984-85. Although it is virtually impossible to ascertain the true compositions of the diets of obese subjects,” the amount of weight loss indicates very poor dietary compl iance.’O The 263 Type 2 diabetic patients studied are considered to be all those who died during the 2-year period. With a mean survival of 8.8 years this figure, taken as equal to incidence rate, indicates a total prevalence of 11 57, about 0.3 % of the population served by the clinic, and a high proportion of total (diagnosed) mortality. Rates of referral have risen over the years, so the current files of about 4000 Type 2 diabetic patients indicate a population prevalence of 1 %, with a referral rate of about 300 per annum. This increasing rate could reflect earlier diagnosis. It would not invalidate the conclusion that weight loss improves prognosis but would lead to underestimation of life expectancy. The mean age of death for the total study was 72 and 76 years for men and women, almost identical with the figures quoted for the subgroup who had diabetes at 65 years. They did not reach the expected age at death in the local general population of 77 years Hadden for men, 81 years for women, aged 65 et a/.” reported a small number of deaths in a younger sample with no apparent difference in expectation of life from the normal Northern Ireland population. O n the basis of the present data, however, Type 2 diabetes reduces life expectancy by about 35 % at the average age of diagnosis, agreeing with the findings of jarrett and Shipley.’O Causes of death could not be assessed since death certification is notoriously unreliable and very few cases underwent autopsy. Survival analysis of cohorts is weakened when some of the cohort is still alive and logistic analysis i s then necessary. It is most powerful when all subjects are dead. Any tendency of younger patients to leave the area and die elsewhere unrecorded would introduce errors. From the clinic review in 1987 a few ‘non-attenders’ were discovered who might fall into this category. Similarly, 6 patients included had moved into the area having been diagnosed elsewhere. The population of the north-east 232
of Scotland, particularly the older group with Type 2 diabetes, i s extremely stable, and it is estimated that < 5 % of cases originally diagnosed in the region could have died elsewhere. Provided that selection bias is not introduced by systematic loss of particular types of subject between diagnosis and death, and that factors which change with time are unrelated to the variables of primary interest, a cohort may be selected ‘antegradely’ from the time of diagnosis, or ’retrogradely’ from time of death. For practical reasons it was simpler to study this Aberdeen population ‘retrogradely’ as a cohort of 263 subjects who all died in the same 2 years. Given the stability of the population under study, this approach is a reasonable alternative to the more familiar ‘antegrade’ approach (as used in prospective studies) which might take a cohort of 263 patients who were all diagnosed at about the same time. Published prospective information about the influence of obesity and weight loss in Type 2 diabetes is not yet available but should emerge from other studies. The variables of interest which are likely to have been subject to non-random changes over the period studied, thus introducing bias, are prescribing practice for hypoglycaemic drugs and smoking habits. It has become more common to manage even the most severely hyperglycaemic with diet alone initially, so that patients with longer survivals in the present study are more likely to have been treated with drugs, according to the fashion at the time of diagnosis. Similarly, a decline in smoking prevalence over recent decades is likely to have biased the sample, to explain the failure of the present analysis to detect an expected effect of smoking. Hence, estimates of the effect of drug treatment and of smoking may be badly biased. However these biases will have limited influence on the assessment of other variables. The favourable variables, drug therapy and weight loss, were very weakly and negatively correlated (r = -0.138), so improved prognosis from weight loss i s not linked with drug therapy. For the 75 % of diabetic patients who are overweight, the clear conclusion can be drawn that weight loss is beneficial. This study did not indicate benefit from reduction of random clinic plasma glucose, and published evidence for any such relationship with life expectancy is very limited.l4 Obesity is a critical risk factor for the development of Type 2 diabetes but the present study provides little support for the widely held belief that obesity is an extra risk factor for arterial disease in the diabetic patient.12,15 Urging greater weight loss should not be based on obesity per se, and there was only a weak indication (from the BMI.WL interaction term) that greater weight loss is required for the more severely obese. O n average, each 1 kg weight loss over the first year from diagnosis was associated with about 3 - 4 months increased survival. A 10 kg weight loss, which should be attainable by most patients, would predict the restoration of about 35 % in life expectancy (Figure 1). Whether weight loss itself improves prognosis, or i s a
’
M.E.J. LEAN E l AL.
DCTl marker for other factors such as increased physical activity or diet composition, remains an open question, but weight loss over the first year after diagnosis probably represented intentional response t o advice. The conclusions were unaltered when subjects who died in the second year after diagnosis, perhaps losing weight through malignancy, were excluded. Most studies agree that those who are going t o lose weight under advice will do so i n the first few months.’j Weight loss was less than most dietitians would wish but similar to that achieved in other centre^,'^,'" and sufficient t o prevent primary diabetic symptoms. More sophisticated approaches are required for overweight diabetic patients,l0 b ut the present study provides for the first time evidence that weight loss improves life expectancy.
ORIGINAL ARTICLES 4. 5.
6.
7. 8.
9.
10.
Acknowledgements The coordinated w o r k of all staff at the Aberdeen Diabetic Clinic over many years was necessary t o make it possible to carry out this study. The help of the hospital records staff in tracing apparently untraceable records is particularly acknowledged.
References 1. James WPT. Treatment of obesity: the constraints on success. Clin Endocrinol Metab 1984; 13: 635-659. 2. Dublin LI, Marks HH. Mortality among insured overweights in recent years. New York: Recording and Statistical Corporation Press, 1951: 3-31. 3 . Dublin LI. Relation of obesity to longevity. N Engl 1 Med 1953; 248: 971-974.
WEIGHT LOSS AND PROGNOSIS
11.
12. 13.
14.
15.
16.
W H O Study Group. Diabetes Mellitus. W H O Technical Reports Series, 724. Geneva: WHO, 1985. Jarrett RJ, McCartney P, Keen H. The Bedford survey: ten year mortality rates in newly diagnosed diabetics, borderline diabetics and normoglycaemic controls and risk factors for coronary heart disease in borderline diabetics. Diabetologia 1982; 22: 79-84. Nye N, Hull C, Jenkins J, Steinbrenner K, Bent D. SPSSX Statistical Package for the Social Sciences. New York: McGraw-Hill, 1983. Registrar General, Scotland. Annual Report, 1987. Edinburgh: HMSO, 1988. Information and Statistics Division. Health For All by Year 2000-Targets for Scotland. Edinburgh: Information and Statistics Division, Common Services Agency, 1989: 23. Prentice AM, Black AE, Coward WA, et a / . High levels of energy expenditure in obese women. Br Med 1 1986; 292: 983-987. Lean MEJ, Anderson AS. Clinic strategies for management of obesity. Diabetic Med 1988; 5: 515-518. Hadden DR, Blair ALT, Wilson EA, et a / . Natural history of diabetes presenting age 40-49 years: a prospective study of the influence of intensive dietary therapy. Q 1 Med 1986; 59: 579-598. Jarrett RJ, Shipley MJ.Mortality and associated risk factors. Acta Endocrinol 1985; 110 (suppl 272): 21-26. UK Prospective Study of Therapies of Maturity Onset Diabetes. I. Effect of diet, sulphonylurea, insulin, or biguanide therapy on fasting plasma glucose and body weight over one year. Diabetologia 1983; 24: 404-41 1 . Dhar H, Hockaday TDR, Hurnphreys S, et a / . Mortal factors in type 2 (NIDDM) diabetes. Diabetes Res 1985; 2: 23-28. Jarrett RJ, Keen H, Chakrabarti R. Diabetes, hyperglycaemia and arterial disease. In: Keen H, Jarrett RJ, eds. Complications of Diabetes. 2nd edn. London: Edward Arnold, 1982: 190-1 92. Heller SR, Clarke P, Daly H, et a / . Group education for obese patients with type I1 diabetes: Greater success at greater cost. Diabetic Med 1988; 5: 552-556.
233
ORIGINAL ARTICLES
Obesity, Weight Loss and Prognosis in Type 2 Diabetes M.E.J. Lean”, J.K. Powrie”, A.S. Anderson”, P.H. Garthwaiteb ’Diabetic Clfnic, Aberdeen Royal Inffrrnary and bDepartrnent of Mathematical Soences, Kings College, Universfty of Aberdeen, UK
Medical records were reviewed of all 263 Type 2 diabetic patients from the Aberdeen diabetic clinic who were known to have died in 1985 or 1986. Mean age was 65 years (interquartile range 57-75 years) at diagnosis and 72 (66-80) years for men, 75 (72-83) years for women, at death. Life expectancy at age 65 was 35 % less than published figures for the general population. Analysis of survival in 233 patients who lived more than 1 year (1 89 overweight) using stepwise multiple regression indicated as significant ( p < 0.05) adverse independent variables: age at diagnosis, presence of clinical ischaemic heart disease at diagnosis, plasma glucose at diagnosis; and as significant favourable variables: oral hypoglycaemic drug therapy, weight loss in the first year, and an interaction between weight loss and BMI for patients with BMI > 25 kg m-2. Changes in fashions over the years are likely to have biased these results towards including oral hypoglycaemic therapy and excluding the expected adverse effect of smoking. Mean weight loss at 1 year was 2.6 kg for those with BMI 25-30 kg mP2, 6.8 kg with BMI > 30 kg m-’, following standard dietetic advice. For the average patient each 1 kg weight loss was associated with 3 - 4 months prolonged survival. KEY WORDS
Diet Slimming Oral hypoglycaemic agents Survival analysis Clinical audif
Introduction
Methods
Type 2 diabetes is strongly associated with obesity, causally or perhaps sharing common aetiological factors in susceptible individuals. It is commonly suggested that obesity contributes to the accelerated ischaemic vascular disease and mortality of patients with Type 2 diabetes. Large actuarial studies have been able to confirm that obesity increases vascular mortality in the general population,’ and it is probable from life assurance data that weight loss will improve outlook in terms of reduced m ~ r t a l i t y . There ~ , ~ i s no published evidence that, within a diabetic population, either the degree of obesity or success in slimming have any bearing on prognosis. Weight loss is advocated for obese diabetic patients, firstly, for the rather rapid metabolic improvement which results from negative energy balance but, secondly, in the belief that long-term vascular complications may be reduced. Symptoms regress and metabolic control often improves to approach normality with only very minor weight loss (supported by hypoglycaemic agents when necessary). Further weight loss can be achieved only by sustained dietary modification, and the gains from prolonged efforts are seldom obvious to patients or health professionals. The present study examines the hypothesis that weight loss improves survival in obese Type 2 diabetic patients.
Data were collected from the diabetic and general hospital files of the 312 patients (263 Type 2) from the Aberdeen Diabetic Clinic who were known to have died in 1985 or 1986. All deaths in the region are notified automatically to the hospital Records Department by the central Registrar of Deaths. From these lists the diabetic clinic staff compile lists and collect the records of diabetic patient deaths which were used for the present study. A separate clinic filing system has been in use since 1960, supplemented since 1984 by problem-oriented computer files, and records are not permitted to leave the clinic. Diabetes records of deceased patients are transferred from the current or non-attender clinic files and united with the general Aberdeen hospital records in an adjoining ‘death files‘ store room. The years 1985 and 1986 were selected for study since in 1987 a review of all 6000 sets of diabetic clinic records was conducted to ensure that all the records of deceased patients had been removed from the current and non-attender files to the death files, in order to identify missed deaths, or those who had died outside the area. Criteria for the diagnosis of diabetes have changed over the years. Cases originally labelled ‘diabetic’ on the basis of intravenous testing were excluded if elevated random plasma glucose (> 9.0 mmol I-’) was never recorded. Others, included in the present study, might have fallen into the new category of ‘impaired glucose t ~ l e r a n c e ’had ~ current diagnostic tests been applied. The diagnosis of impaired glucose tolerance also carries increased vascular m ~ r t a l i t y and , ~ thus cannot meaning-
Correspondence to: Dr M.E.J.Lean, Department of Human Nutrition, University of Clasgow, Queen Elizabeth Building, Glasgow Royal Infirmary, Glasgow, UK.
22 8
0742-307 1 1901030228-06$05.00 0 1990 by John Wiley & Sons, Ltd.
Accepted 1 Decmber 1989 DIABETIC IMEDICINE, 1990; 7: 228-233
DTT7
ORIGINAL ARTICLES
fully be differentiated from Type 2 diabetes within the context of the present study. Random plasma glucose was recorded at each clinic visit, measured by various methods over the years but mostly (since 1970) using a glucose oxidase method (Beckman glucose analyser II, Fullerton, CA, USA). Body weight was measured using an Avery (Birmingham, UK) Type 3205 COE weighing machine, height using a wall-mounted stadiometer, and blood pressure using a wall-mounted mercury sphygmomanometer. lnsu I i n-treated diabetic patients were excluded from the present analyses, except in cases where insulin was used for a limited period for therapeutic studies or in cases thought initially to be insulindependent but where the true diagnosis of Type 2 diabetes was proved by subsequent withdrawal of insulin therapy. The diagnosis of ischaemic heart disease (IHD) was accepted on the basis of angina or myocardial infarction, or for heart failure only in cases where it was documented in hospital as resulting from ischaemic heart disease.
were not available in sufficient numbers for analysis. O n a priori grounds it was believed that sex would affect survival, so this fixed variable was forced into the regression equation and other variables were entered sequentially according to which most improved the predictive model, with a cut-off at p = 0.10. It was also anticipated that BMI would be likely to affect survival, and that it might interact with weight loss (WL). To examine this tsossibilitv. an interaction term (BMI.WLI was constructid: BMI.WL = (BMI (weight loss where BMI and are the average BMI and weight loss for the group being considered. Subtracting averages in this way reduced the correlation between the interaction term and weight loss. Results are expressed as mean (SD) or median, with 95 % confidence interval (CI) estimated as ? SE x 1.98.
m)
, I
m),
ResuIts Clinical variables at the time of diagnosis of Type 2 diabetes which relate to degree of obesity and to weight change are described in Tables 1 and 2. BMI at diagnosis ranged from 19.7 to 43.9 kg m-]. The prognoses for different groups are shown in Table 3, but there are many interactions between variables which make simple comparisons misleading. The length of survival ranged from 0.8 to 35 years. The presence of clinically apparent ischaemic heart disease before diagnosis of diabetes, however, was clearly a powerful adverse prognostic factor, although this effect could also reflect greater age at diagnosis of diabetes in a subgroup whose diabetes was revealed at myocardial infarction (Table 3). Those with pre-existing ischaemic heart disease were no more obese than other cases of Type 2 diabetes.
Analysis of Survival Analysis used the SPSS-X program,6 with the primary aim of examining whether weight loss affected survival rates for the overweight. Survival time (in years) was measured from the date of diagnosis of diabetes, and only those who survived more than 12 months ( n = 233) were included in the analysis for effect of weight loss. The term ‘v‘survival time’ was selected as the appropriate dependent variable since residual errors appeared to follow a normal distribution most closely. Multiple stepwise regression equations based on the following variables were examined: sex, age, IHD at the time of diagnosis of diabetes, BMI, systolic and diastolic blood pressure, plasma glucose at time of diagnosis and after 12 months, weight change 12 months after diagnosis, smoking, treatment selected at diagnosis (1 for oral hypoglycaemic agents, 0 for diet alone). Plasma lipids
Life Expectancy with Type 2 Diabetes Those who reached the age of 65 years were 32 men and 37 women. Their mean future life expectancy was
Table 1. Clinical details of the Type 2 diabetic population Patient group
n
Sex (MIF)
CitylRegion Srnoki nginon-srnoking Clinical IHD Before diabetes After diabetes Never Blood pressure (mmHg) Systolic (SD) Diastolic (SD)
< 25
25-30
> 30
263 14611 17 1561107 941147
66 32134 5411 2 22137
115 72/43 63152 46/62
71 38133 34/37 34137
81 52 116
17 13 32
39 22 46
20 16 35
158(27) 90(13)
158(32) 88(12)
156(26) 90(13)
162(23) 93(14)
Number, or mean (SD) for blood pressure at diagnosis WEIGHT LOSS AND PROGNOSIS
229
DTT7
ORIGINAL ARTICLES Table 2. Body weight, BMI, and weight change in relation to major clinical factors for patients with Type 2 diabetes Weight at diagnosis (kg)
M F
(13.6) (15.0) (14.6) (16.2)
BMI
(kg m - 9
Weight change at 1 year (kg)
Smokers Non-smokers
80.4 67.3 77.7 72.8
Therapy from diagnosis Diet only Drug therapy
78.6 (14.5) 70.2 (15.7)
29.1 (4.2) 26.7 (5.2)
-4.1 (6.0) -1.5 (6.7)
Clinical IHD Before diabetes After diabetes Never
74.9 (14.9) 76.7 (17.3) 73.4 (15.9)
27.9 (4.1) 28.8 (5.8) 27.7 (4.9)
-2.7 (5.4) -3.8 (5.4) -2.4 (6.6)
BMI (kg m-2) < 25 25-30 > 30
60.3 (10.1) 73.1 (9.6) 90.8 (12.5)
22.6 (1.9) 27.3 (1.4) 34.0 (3.9)
+1.3 (4.3) -2.6 (5.6) -6.8 (7.1)
28.1 27.8 28.1 29.0
(4.0) (5.7) (4.2) (5.3)
-3.5 -2.3 -2.5 -2.8
(6.7) (6.2) (7.0) (6.4)
Mean (SD).
Table 3. Prognosis, in terms of mean age at death and survival after the diagnosis of Type 2 diabetes
(yr) All patients
64.9 (57.0, 73.1) 64.3 (55.9, 72.8) M F 65.6 (57.9, 73.9) 62.5 (54.7, 71.2) Smokers 66.0 (59.6, 74.3) Non-smokers City 66.0 (57.9, 74.0) Region 63.1 (56.0, 71.5) Therapy from diagnosis Diet only 65.8 (58.5, 73.1) Drug therapy 63.7 (54.5, 73.2) Clinical IHD at diagnosis of diabetes Present 67.9 (59.7, 74.8) Absent 63.5 (55.7, 71.8) BMl (kg m-2) < 25 64.8 (55.3, 73.9) 25-30 66.5 (59.9, 73.8) > 30 62.7 (56.0, 71.4)
Survival after diagnosis
Age at death (yr)
Age at diagnosis
(yr) 81 .O) 80.0) 82.9) 78.0) 82.0) 81.1) 80.8)
8.8 (2.5, 12.8) 7.8 (2.0, 10.7) 10.1 (3.4, 16.3) 7.9 (2.3, 10.3) 9.2 (2.8, 13.3) 8.1 (2.3, 11.2) 9.9 (2.6, 15.3)
72.5 (66.9, 79.4) 75.0 (70.8, 82.7)
6.6 (2.0, 8.7) 1 1 . 1 (3.6, 17.4)
74.1 (68.6, 80.6) 73.6 (68.8, 81.2)
5.9 (2.0, 8.3) 10.1 (3.1, 15.5)
73.9 (70.6, 82.2) 74.9 (70.7, 81.2) 71.5 (64.3, 78.8)
9.1 (2.5, 13.0) 8.5 (2.5, 12.0) 8.8 (2.6, 15.1)
73.7 72.1 75.8 70.4 75.1 74.1 73.2
(69.0, (65.5, (72.1, (63.2, (72.1, (69.7, (68.0,
Mean (interquartile range).
then 7.6 (95 % CI 5.7-9.5) years for men, 11.4 (95 % CI 9.4-13.3) years for women. Average expectation of life at age 65 years for the general population of Scotland was greater than these upper 95 % CIS, at 11.6 years for men, 15.4 years for women in 1980-82.’
Analysis of Survival Stepwise multiple regression analysis was used to identify the independent prognostic factors in all Type 2 diabetic patients (n = 233) and in those with BMI > 25 kg m-* 230
(n = 189) who lived more than 1 year from diagnosis (Table 4). Sex was forced into the model in case other variables covaried with it, although it did not itself relate significantly to survival. Age at diagnosis was the first variable to be selected by the regression analysis, accounting for 11.9 % of variance. Pre-existing clinical ischaemic heart disease (IHD) also had a clear adverse influence. Plasma glucose at diagnosis was inversely related to survival time, but there was no evidence that survival was affected by blood pressure or smoking (NS for all patients and M.E.J. LEAN ET AL.
Drn
ORIGINAL ARTICLES
Table 4. Independent variables for predicting the dependent variable Vsurvival time in years from diagnosis of Type 2 diabetes. Regression coefficients with their 95 % CI and the significance levels at which the coefficients differ from zero BMI
All patients
k
5.01 (4.10, 5.92)
Variables present at diagnosis of diabetes Sex" (rn=O, f = l ) Age (years)
IHD (yes=l)
kg m-'
P
Estimate (95 % CI)
P
Estimate (95 % CI)
> 25
5.79 (4.04, 7.54)
0.16 (-0.11, 0.42) -0.035 (-0.048, -0.022) -0.47 (-0.76, -0.19)
> 0.10 < 0.001 < 0.001
0.25 (-0.06, 0.56) -0.035 (-0.051, -0.01 8) -0.60 (-0.92, -0.26)
> 0.10 < 0.001 < 0.001
-0.023 (-0.044, -0.003) -
< 0.05
-0.027 (-0.052, -0.003) -0.026 (-0.065, -0.014)
< 0.05 > 0.10
Plasma glucose
(mmol I-') BMlb (kg m-')
-
Variable decided at diagnosis of diabetes Drug therapy (diet=(), drugs= 1 )
0.74 (0.47, 1.01)
< 0.001
Variables available 1 year after diagnosis Weight loss (kg) BMI.WLb (kg' m-2)
0.036 (0.016, 0.056) -
< 0.001
< 0.001
0.85 (0.54, 1 . 1 7) 0.053 (0.028, 0.079) -0.004 (-0.007, -0.001)
-
< 0.001 < 0.025
Variance accounted for
r2
0.42
0.35
"Sex was forced into the regression analysis, although not itself significant, in case other independent variables covaried with it (see text) bNeither BMI nor BMI.WL were significantly predictive of survival for patients of all BMI, so were not selected by the stepwise regression analysis. BMI appears in the model for patients with BMI > 25 kg m since the interaction term BMI.WL was significant, and both components of the interaction must then be included in the model
for those with BMI > 25 kg mP2). Plasma glucose at 1 year did not predict survival time, but there was evidence that patients treated with oral hypoglycaemic agents had survived longer ( p < 0.001). This applied to all patients and to the overweight. Weight loss was associated with improved survival ( p < O.OOl), but the evidence for BMI was inconclusive. Analysis was performed for all patients, as well as those with BMI > 25 kg mP2 at diagnosis, since weight loss may still be desirable even for patients with BMI < 25 kg mP2 who would not conventionally be considered overweight, and advice is routinely offered to approach ideal body weight for the general population (BMI 22 kg mP2). Results were similar for these two groups. BMI alone appeared not to affect survival ( p > 0.10). However, combined with BMI in the model (with BMI set equal to 29.86 and WL to - 4.2851, the interaction term BMI.WL was predictive for obese patients with BMI > 25 kg m-2 ( p < 0.025). (BMI appears in this model, although non-significant, since if an interaction term is included then both the variables forming the interaction should also be included). Weight loss did not appear to correlate with other independent variables considered: in particular, an anticipated relationship with change in plasma glucose over the first year was not apparent ( r = 0.1 1, NS). Figure 1 illustrates the life expectancy with different degrees of weight loss over the first year for an 'average' overweight Type 2 diabetic patient. The graph assumes an average BMI so that there is no BMI.WL interaction, and a life expectancy without weight loss of 8 years, just WEIGHT LOSS AND PROGNOSIS
n
15
8x
14
2
v
.-v) c
13
-
cn ([f
a 12 E
-
11
0
c ([f
0
10
a,
Q
%
9 -
a,
c
J
8 . 7 L
0
2
4
6
8
10
12 14
16
Weight loss in first 12 months (kg) Figure 1 . Life expectancy in Type 2 diabetic patients with BMI > 25 kg mP2 i n relation to weight loss i n the first year of treatment, based on an expected survival time without weight loss of 8 years. The shaded area represents the 95 % confidence intervals
below the median (with some weight loss) in the present study of 8.5 years for BMI 25-30 kg mPz. The regression equation implies that Vsurvival time will increase by 231
DTT7
ORIGINAL ARTICLES 0.0534 yro.S for each 1 kg weight loss, and life expectancy is estimated as ( 0 . 0 5 3 4 ~+ YO-^)^, where y years is the life expectancy without weight loss and the patient actually loses x kg. The 95 % CIS shown reflect the uncertainty in the figure of 0.0534 yr0.5 per kg weight loss.
Discussion Retrospective analysis i s appropriate to this study of obesity management since over the years there has been no change in the policy of urging weight loss by dietary energy restriction, most commonly with a standard 1000 kcal diet. Individual dietetic counselling from trained dietitians has been used since the clinic was established in 1927. The results presented here reflect advice mainly to restrict carbohydrate, since liberalcarbohydrate reducing diets were not introduced in any numbers until 1984-85. Although it is virtually impossible to ascertain the true compositions of the diets of obese subjects,” the amount of weight loss indicates very poor dietary compl iance.’O The 263 Type 2 diabetic patients studied are considered to be all those who died during the 2-year period. With a mean survival of 8.8 years this figure, taken as equal to incidence rate, indicates a total prevalence of 11 57, about 0.3 % of the population served by the clinic, and a high proportion of total (diagnosed) mortality. Rates of referral have risen over the years, so the current files of about 4000 Type 2 diabetic patients indicate a population prevalence of 1 %, with a referral rate of about 300 per annum. This increasing rate could reflect earlier diagnosis. It would not invalidate the conclusion that weight loss improves prognosis but would lead to underestimation of life expectancy. The mean age of death for the total study was 72 and 76 years for men and women, almost identical with the figures quoted for the subgroup who had diabetes at 65 years. They did not reach the expected age at death in the local general population of 77 years Hadden for men, 81 years for women, aged 65 et a/.” reported a small number of deaths in a younger sample with no apparent difference in expectation of life from the normal Northern Ireland population. O n the basis of the present data, however, Type 2 diabetes reduces life expectancy by about 35 % at the average age of diagnosis, agreeing with the findings of jarrett and Shipley.’O Causes of death could not be assessed since death certification is notoriously unreliable and very few cases underwent autopsy. Survival analysis of cohorts is weakened when some of the cohort is still alive and logistic analysis i s then necessary. It is most powerful when all subjects are dead. Any tendency of younger patients to leave the area and die elsewhere unrecorded would introduce errors. From the clinic review in 1987 a few ‘non-attenders’ were discovered who might fall into this category. Similarly, 6 patients included had moved into the area having been diagnosed elsewhere. The population of the north-east 232
of Scotland, particularly the older group with Type 2 diabetes, i s extremely stable, and it is estimated that < 5 % of cases originally diagnosed in the region could have died elsewhere. Provided that selection bias is not introduced by systematic loss of particular types of subject between diagnosis and death, and that factors which change with time are unrelated to the variables of primary interest, a cohort may be selected ‘antegradely’ from the time of diagnosis, or ’retrogradely’ from time of death. For practical reasons it was simpler to study this Aberdeen population ‘retrogradely’ as a cohort of 263 subjects who all died in the same 2 years. Given the stability of the population under study, this approach is a reasonable alternative to the more familiar ‘antegrade’ approach (as used in prospective studies) which might take a cohort of 263 patients who were all diagnosed at about the same time. Published prospective information about the influence of obesity and weight loss in Type 2 diabetes is not yet available but should emerge from other studies. The variables of interest which are likely to have been subject to non-random changes over the period studied, thus introducing bias, are prescribing practice for hypoglycaemic drugs and smoking habits. It has become more common to manage even the most severely hyperglycaemic with diet alone initially, so that patients with longer survivals in the present study are more likely to have been treated with drugs, according to the fashion at the time of diagnosis. Similarly, a decline in smoking prevalence over recent decades is likely to have biased the sample, to explain the failure of the present analysis to detect an expected effect of smoking. Hence, estimates of the effect of drug treatment and of smoking may be badly biased. However these biases will have limited influence on the assessment of other variables. The favourable variables, drug therapy and weight loss, were very weakly and negatively correlated (r = -0.138), so improved prognosis from weight loss i s not linked with drug therapy. For the 75 % of diabetic patients who are overweight, the clear conclusion can be drawn that weight loss is beneficial. This study did not indicate benefit from reduction of random clinic plasma glucose, and published evidence for any such relationship with life expectancy is very limited.l4 Obesity is a critical risk factor for the development of Type 2 diabetes but the present study provides little support for the widely held belief that obesity is an extra risk factor for arterial disease in the diabetic patient.12,15 Urging greater weight loss should not be based on obesity per se, and there was only a weak indication (from the BMI.WL interaction term) that greater weight loss is required for the more severely obese. O n average, each 1 kg weight loss over the first year from diagnosis was associated with about 3 - 4 months increased survival. A 10 kg weight loss, which should be attainable by most patients, would predict the restoration of about 35 % in life expectancy (Figure 1). Whether weight loss itself improves prognosis, or i s a
’
M.E.J. LEAN E l AL.
DCTl marker for other factors such as increased physical activity or diet composition, remains an open question, but weight loss over the first year after diagnosis probably represented intentional response t o advice. The conclusions were unaltered when subjects who died in the second year after diagnosis, perhaps losing weight through malignancy, were excluded. Most studies agree that those who are going t o lose weight under advice will do so i n the first few months.’j Weight loss was less than most dietitians would wish but similar to that achieved in other centre^,'^,'" and sufficient t o prevent primary diabetic symptoms. More sophisticated approaches are required for overweight diabetic patients,l0 b ut the present study provides for the first time evidence that weight loss improves life expectancy.
ORIGINAL ARTICLES 4. 5.
6.
7. 8.
9.
10.
Acknowledgements The coordinated w o r k of all staff at the Aberdeen Diabetic Clinic over many years was necessary t o make it possible to carry out this study. The help of the hospital records staff in tracing apparently untraceable records is particularly acknowledged.
References 1. James WPT. Treatment of obesity: the constraints on success. Clin Endocrinol Metab 1984; 13: 635-659. 2. Dublin LI, Marks HH. Mortality among insured overweights in recent years. New York: Recording and Statistical Corporation Press, 1951: 3-31. 3 . Dublin LI. Relation of obesity to longevity. N Engl 1 Med 1953; 248: 971-974.
WEIGHT LOSS AND PROGNOSIS
11.
12. 13.
14.
15.
16.
W H O Study Group. Diabetes Mellitus. W H O Technical Reports Series, 724. Geneva: WHO, 1985. Jarrett RJ, McCartney P, Keen H. The Bedford survey: ten year mortality rates in newly diagnosed diabetics, borderline diabetics and normoglycaemic controls and risk factors for coronary heart disease in borderline diabetics. Diabetologia 1982; 22: 79-84. Nye N, Hull C, Jenkins J, Steinbrenner K, Bent D. SPSSX Statistical Package for the Social Sciences. New York: McGraw-Hill, 1983. Registrar General, Scotland. Annual Report, 1987. Edinburgh: HMSO, 1988. Information and Statistics Division. Health For All by Year 2000-Targets for Scotland. Edinburgh: Information and Statistics Division, Common Services Agency, 1989: 23. Prentice AM, Black AE, Coward WA, et a / . High levels of energy expenditure in obese women. Br Med 1 1986; 292: 983-987. Lean MEJ, Anderson AS. Clinic strategies for management of obesity. Diabetic Med 1988; 5: 515-518. Hadden DR, Blair ALT, Wilson EA, et a / . Natural history of diabetes presenting age 40-49 years: a prospective study of the influence of intensive dietary therapy. Q 1 Med 1986; 59: 579-598. Jarrett RJ, Shipley MJ.Mortality and associated risk factors. Acta Endocrinol 1985; 110 (suppl 272): 21-26. UK Prospective Study of Therapies of Maturity Onset Diabetes. I. Effect of diet, sulphonylurea, insulin, or biguanide therapy on fasting plasma glucose and body weight over one year. Diabetologia 1983; 24: 404-41 1 . Dhar H, Hockaday TDR, Hurnphreys S, et a / . Mortal factors in type 2 (NIDDM) diabetes. Diabetes Res 1985; 2: 23-28. Jarrett RJ, Keen H, Chakrabarti R. Diabetes, hyperglycaemia and arterial disease. In: Keen H, Jarrett RJ, eds. Complications of Diabetes. 2nd edn. London: Edward Arnold, 1982: 190-1 92. Heller SR, Clarke P, Daly H, et a / . Group education for obese patients with type I1 diabetes: Greater success at greater cost. Diabetic Med 1988; 5: 552-556.
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