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Targets of therapy for NIDDM
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ELSEVIER
Diabetes Research and Clinical Practice 28 Suppl. (1995) S49-S55
Targets of therapy for NIDDM Robert Tattersall Diabetes Unit, University Hospital. Nottingham NG7 2UH. UK
Abstract Non-insulin-dependent diabetes (NIDDM) is a common multimetabolic disorder with potential (and potentially severe) long-term complications affecting large and small blood vessels. Where microvascular complications (retinopathy, nephropathy and neuropathy) are concerned, the Diabetes Control and Complications Trial (DCCT), as well as much circumstantial evidence, suggests that hyperglycaemia is the main aetiological factor and this is likely to apply in NIDDM as well as IDDM. Unfortunately, achieving normoglycaemia in NIDDM is not easy and it is unclear whether insulin has advantages over oral hypoglycaemic agents or vice versa. Turning to macrovascular disease, it is unclear which of the many potentially atherogenic abnormalities - hypertension, hyperinsulinaemia, hyperlipidaemia, etc - are most important. A further problem is that macrovascular disease is already well developed in many patients when NIDDM is diagnosed and we do not know whether secondary prevention is effective. Nevertheless, it is sensible to try to reverse the atherogenic milieu and this should be done in the first instance by lifestyle modification rather than drugs. Even if we cannot manipulate the biochemistry to prevent small or large vessel complications, much can still be done; proactive foot care can prevent ulceration, timely laser treatment can prevent visual loss and thrombolytic therapy is relatively more effective in diabetic patients with myocardial infarction than in their non-diabetic peers. Finally, patients with NIDDM need intensive education and each needs an individualised treatment plan and goals.
Keywords:
Non-insulin-dependent diabetes; Microvascular complications; Hyperglycaemia; Thrombolytic therapy
1. Introduction
Non-insulin-dependent diabetes (NIDDM) is one of the commonest chronic disorders in the world, attacks rich and poor alike and, in some countries, affects up to a third of the population. The health care costs of NIDDM are staggering; in a recent analysis based on data from the 1987
National Medical Expenditure Survey, Rubin et al. (1) estimated that in the USA in 1992, 14.6% of total health care expenditure was used by the 4.5% of the population with diabetes. Two-thirds of this money ($65.2 billion) was incurred by hospital inpatients compared to only 9% ($9.9 billion) on drugs and accessories such as urine or blood glucose testing strips. Rubin et al. make the
0168-8227/95/$09.50 © 1995 Elsevier Science Ireland Ltd. All rights reserved. SSDI 0168-8227(95) 0 I 086-S
S50
R. Tattersall / Diabetes Research and Clinical Practice 28 Suppl. (1995) S49~S55
obvious comment that 'significant savings to the health care system could be realised if even a fraction of these costs could be avoided through prevention or effective management of the disease and its complications'. Simplistically, the main causes of morbidity and mortality in NIDDM are macrovascular or microvascular disease. Macrovascular disease or accelerated atherosclerosis of major arteries is characteristic, and confers an excess risk of between 2 and 4-fold for heart attack, stroke or gangrene of the leg [2]. Microvascular disease affects the eyes, kidneys and nerves, leading to blindness, renal failure and foot ulcers. In the United States, diabetes is the commonest cause of new cases of blindness [3], end-stage renal disease [4], and leg amputation [5]. Apart from making the patient feel better in the short term, treatment of NIDDM must aim to prevent or delay macro and microvascular disease (secondary prevention) or, if we cannot do this, treat established complications to prevent the worst outcomes (tertiary prevention). 2. Is it too late to wait for the patient to come to the doctor? Population surveys always find as many previously undiagnosed diabetics as previously known cases. Maureen Harris [6] argues persuasively that NIDDM probably starts up to 12 years before clinical diagnosis and estimates that 10-20% of the US population over age 50 years have undiagnosed NIDDM, with even higher rates in Blacks and Mexican Americans. This long subclinical phase means that many patients already have complications when they first come to the doctor. If examined carefully through dilated pupils, up to 29% of 'new' patients have retinopathy and the same is true for other microvascular complications. One very characteristic group, mostly middle-aged men, present with retinopathy and neuropathic foot ulcers and most die within 5 years [8]. Patients with newly diagnosed NIDDM also have a high prevalence of large vessel disease. Uusitupa et al. [9] found a previous myocardial infarction twice as often in newly diagnosed dia-
betic men and four times as often in women as in the general population. Hypertension was present in 51% of patients (18% previously diagnosed and 33% not treated) in the UK Prospective Diabetes Study (UKPDS, [10]). An index of the poor general health of people with newly diagnosed NIDDM is that relative mortality is already increased in the first year after diagnosis and 44% have died after 10 years of follow up [11], leading Panzram to comment that 'at present we are doing too little too late, if anything can be done at all'. Harris [6] makes the persuasive case that 'If we believe that undiagnosed diabetes is highly prevalent, that it is associated with a high frequency of risk factors for complications, that a high prevalence of micro and macrovascular complications exists, and that treatments are available, then we must be drawn to the conclusion that these subjects should not remain undiagnosed'. I agree with this argument, although it is a condition of screening that effective treatment should be available for those identified as being ill. Whether or not we agree that the primary abnormality in NIDDM is insulin resistance [12], it is obvious that we are dealing with a multimetabolic disorder involving variable combinations of hyperglycaemia, hyperinsulinaemia, hyperlipidaemia, hypertension, obesity and platelet abnormalities (Table 1). The difficulty facing the clinician is to know whether it is more important to attack one or other of these targets selectively Table I Syndrome X (Reaven)
Syndrome X plus (Zimmet)
Insulin resistance Glucose intolerance Hyperinsulinaemia Increased VLDL triglyceride Decreased HDL cholesterol Hypertension
Insulin resistance Glucose intolerance Hyperinsulinaemia Increased VLDL triglyceride Decreased HDL cholesterol Hypertension Upper body obesity Hyperuricaemia Physical inactivity Ageing
Reproduced with permission from Zimmet P Diabetes Care 1992 15: 247.
R. Tattersall / Diabetes Research and Clinical Practice 28 SuppJ. (J995) S49-S55
or whether we should attempt to attack them all on a broad front. The history of the First World War suggests that the blunderbuss approach is likely to fail and simply lead to stalemate, confusion and ignorance among the combatants. The degree of biochemical abnormality in newly diagnosed patients in the UKPDS is shown in Table 2, and I will discuss each of these targets individually. 2.1. Education and general care There is an enormous literature on patient non-compliance in general and non-compliance in diabetes in particular [14] and I agree that one reason for this is that physicians often make the paternalistic assumption that they are entitled to make treatment decisions without consulting their patients [15]. In fact, most patients with NIDDM are looked after by primary care physicians rather than endocrinologists or diabetologists and it is likely that the providers themselves are confused when faced with a complex, and perhaps ambiguous, set of treatment alternatives. Obvious reasons why patients might not comply is that they do not believe the disease to be serious, have not understood the instructions of the nurse, doctor or dietitian or are simply overwhelmed by the number of targets they are being set. One patient of mine summarised what he had been told by the diabetes educator as 'Don't eat, smoke, rest or drink alcohol', while another asked 'If I do what you say, will I really live longer or will it just seem longer?'. Mason [16] tape recorded consultations
of 91 newly diagnosed diabetics with physician and dietitian and then went back to find out what the patients had understood. She showed clearly that many were confused by the language (too technical) and the exhortations (contradictory). Patients were also uncertain how much authority was being delegated to them in practice rather than in theory. The way in which patients can contribute productively to therapeutic decisions has been well shown by Greenfield and colleagues (17), who showed that a 20-min 'coaching session' enabled the patient to have a more productive encounter with the physician and also improved diabetic control. Patients with NIDDM need as much, if not more, education than those with IDDM and, although much of this will have to be done in groups, each patient needs an individualised plan and goals. I think that this should be written down [18) and given to the patient, general practitioner and anyone else with whom the patient is likely to come in contact. It is essential to get across to the patient that they have a potentially serious disorder, and a useful way of empowering them is a statement of expectations and responsibilities such as the British Diabetic Association leaflet 'What Diabetic Care to Expect' [19]. 2.2. Diet, exercise and (non) smoking Broad aims of diet are to abolish symptoms, achieve ideal body weight, attain normoglycaemia and reduce the risk of macrovascular disease. Whether it is possible to devise a single diet to
Table 2 Biochemical risk factors at diagnosis in newly diagnosed NIDDM - - - - - - - - - - _... _ -
---------
Age BMI (kgyrrr') HbA le (%) Total cholesterol mmoljl HDL cholesterol mmoljl Triglyceride mmoljl Hypertension
---
Normal subjects (25-65 years) - - _ .._ - _ . _ - 52 26.2 5.4 5.5 1.34
UK Prospective Diabetes Study Group [13].
2.9
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NIDDM at diagnosis (25-65 years) 52 30.1 9.3 5.7 1.05 6.5 51%
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R. Tattersall / Diabetes Research and Clinical Practice 28 Suppl. (1995) 549-555
Table 3 Possible targets in NIDDM Cigarette smoking Insulin resistance Hyperglycaemia Obesity Physical inactivity Hyperinsulinaemia Hypertension Increased VLDL triglyceride Decreased HDL cholesterol Hyperuricaemia Platelet abnormalities
meet all these objectives is doubtful, and it is wrong to give the impression that diet is the panacea with the implication that if it fails it is the patient's fault. In the UKPDS, patients with a fasting plasma glucose of 10-12 mmoljl at diagnosis had to lose 18 kg to achieve a fasting plasma glucose below 6 mmoljl, and the mean fasting plasma glucose after 1 year in 56 patients randornised to diet alone was 9.3 mmoljl [20]. The theoretical benefit of exercise is that it will reduce weight and insulin resistance. In practice, it is unsuccessful in the average patient with NIDDM. In a prospective population study of 60-year-old men with NIDDM, 39 of 48 were unsuitable because of circulatory and other disorders. Of eight who started the programme, six dropped out and after a year only, two of the 48 originally eligible were still exercising, and they were not improved metabolically [21]. In a lO-year study of an exercise-based lifestyle modification programme reported by Schneider et al. [22], half the participants had dropped out after 3 months and 90% after 1 year. In the 10% who stuck it out, benefits such as reduction in blood glucose, triglycerides and blood pressure were modest. At the moment, there is no satisfactory drug for the treatment of obesity [23], but it is an area of active research by pharmaceutical companies, as is the quest to find a drug which will reduce peripheral insulin resistance. Like Gill [24], I am familiar with the overweight, sedentary hyperlipidaernic, 50-year-old man with newly diagnosed NIDDM who smokes 20 cigarettes per day. I also agree that the great-
est service we can do him, after explaining the problem, is to concentrate on his weight and smoking rather than immediately confuse him with what Gill calls 'the tricks of the diabetic trade'. 2.3. Blood glucose control The Diabetes Control and Complications Trial (DCCT) has shown conclusively that nearnormoglycaemia is effective in both primary and secondary prevention of microvascular complications in insulin dependent diabetes (lDDM) [25], and I agree with Steinberg [26] that this is likely to be true in NIDDM, even though it has not been formally tested. The blood glucose levels which need to be achieved to prevent or delay the progression of complications are presumably the same as those in IDDM, although the strictness of the target will be modified on an individual basis, taking into account age, other diseases, macrovascular complications and living circumstances. We do not know which is the best hypoglycaemic agent to use in NIDDM; conventionally (but not logically), patients progress from diet to either sulphonylureas or biguanides, a combination of sulphonylureas and biguanides and, finally, to insulin. There remains a lingering concern that sulphonylureas may 'wear out the pancreas' and there are theoretical reasons why insulin might be a better initial treatment in some patients. Animal work suggests that hyperglycaemia per se impairs !,-cell function Cglucotoxicity') and one advantage of exogenous insulin might be to break the vicious circle and preserve pancreatic function. At least three published studies (reviewed in Ref. 27) suggest that insulin treatment does restore sulphonylurea sensitivity, although the duration of the effect is disappointingly short. A potential disadvantage of insulin is that it might be atherogenic; the idea that excessive concentrations of circulating insulin might cause or exacerbate atherosclerosis appeared in the mid-1960s [28] and has been much discussed but never resolved. In the real world, it is a matter of opinion whether hyperglycaemia or hyperinsulinaemia is likely to be more damaging in the long term.
R. Tattersall / Diabetes Research and Clinical Practice 28 Suppl. (1995) 549-555
2.4. Hypertension Hypertension is common in NIDDM and substantially increases cardiovascular mortality. In the Rancho Bernardo study [29], the relative risk of cardiovascular death for men and women with hypertension but not diabetes was 2.1 and 1.9. whereas if both risk factors were present, the relative mortalities were 3.0 and 9.9. In addition, hypertension is associated with and contributes to the progression of diabetic nephropathy. We assume that lowering blood pressure will benefit diabetic patients but, unfortunately, they have been excluded from most studies of antihypertensive treatment. Nevertheless, consensus groups recommend similar treatment strategies as in non-diabetics [30] although, like others [31], I worry that uncritical 'aggressive' antihypertensive treatment may in some cases do more harm than good. If we are to treat, what drugs should be used? Both thiazides and ,B-blockers have undesirable effects on glucose and lipids, and this may be why they do not reduce the death rate from myocardial infarction in trials. Also, many patients with NIDDM have peripheral vascular disease and should probably not be treated with ,B-blockers. Both calcium channel blockers and angiotensinconverting enzyme (ACE) inhibitors are metabolically neutral and theoretically more suitable. In patients with IDDM and nephropathy, ACE inhibitors appear to prevent the decline in renal function more than would be expected from their antihypertensive effect alone, probably because they reduce intraglomerular pressure [32]. On the other hand, they may cause an irreversible decline in renal function in patients with bilateral renal artery stenosis, something which may be relatively common but unsuspected in the NIDDM patient with generalised atherosclerosis [33]. 2.5. Lipids There is much evidence that raised levels of cholesterol and triglycerides are together and independently associated with an increased risk of cardiovascular disease in the non-diabetic population. It is also clear that dyslipidaemia is common in patients with NIDDM with the characteristic
553
abnormalities being low levels of HDL cholesterol and high triglycerides. The literature is full of clarion calls such as 'Lipids, diabetes, and vascular disease: The time to act' [34]. The European Atherosclerosis Study Group [35] suggests that the targets should be to reduce total plasma cholesterol below 5.2 mmol z'l, LDL cholesterol below 3.5 mmolyl, plasma triglyercide below 2.3 mmoly l, and raise HDL cholesterol above 0.9 mmolyl. As with blood pressure, so with lipids, enthusiasts recommend 'aggressive' treatment. I would urge caution; while I agree with the scientific evidence that hyperlipidaemia is involved in causing coronary heart disease, trials of lipidlowering drugs in the non-diabetic population have generally not shown a reduction in total death rate. Also, there has never been a proper long-term study of lipid lowering in patients with diabetes. The problem is essentially the same as that in treating hypertension - for every 100 patients, only three or four will benefit while one may have his or her life ruined by side effects. All authors recommend that the first line of treatment for diabetic dyslipoproteinaemia should be diet, and one recent article [36] suggests that drugs should be introduced if cholesterol is persistently over 6.5 mmol /l, triglycerides over 2.2 rnmoly l or HDL cholesterol under 1 mmol /I, A fibric acid derivative is recommended as first line treatment, with acipimox (a nicotinic acid derivative) being added if necessary. 2.6. Blood flow and platelet abnormalities Blood viscosity is increased in patients with NIDDM, due mainly to increased plasma proteins [37]. It is likely that the rheological abnormalities are worst in the patients with worst blood glucose control. but their contribution to vascular disease has not been quantitated and, short of avoiding very high haematocrits, no therapy is known. A large number of platelet abnormalities have been described in diabetes, although it is unclear whether these are the cause or the consequence of vascular disease [38]. Many, if not all, are normalised by achieving normoglycaemia. Studies in non-diabetic patients suggest that antiplatelet drugs, particularly aspirin, are useful in the sec-
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ondary prevention of vascular disease [39] but the situation in diabetes is unclear because few large-scale multicentre trials have been done. Nevertheless, I would agree with Colwell [38] that diabetic patients who have had a previous stroke, myocardial infarction and/or have clinically apparent peripheral vascular disease should be treated with aspirin as secondary prevention. A dose of 150 mg daily is probably adequate. There is a temptation to use aspirin for primary prevention of vascular disease but no evidence to support its use in this way. 3. Quality of life and therapeutic realism
NIDDM is, to those whose wards are filled with patients with horrible complications, such an unpleasant disease that it is easy to go over the top and adopt what I called earlier in this paper a blunderbuss approach. What I have in mind is the following admonition: 'People with diabetes should be encouraged to view themselves as a population with a disproportionate number of risk factors for adverse health outcomes. and should be encouraged to adopt healthy lifestyles, to control obesity, to control hypertension, to stop smoking, and to control cholesterol and blood glucose levels, Efforts to achieve these ends should be redoubled in populations at high risk for the complications of diabetes' [40].
Even if we cannot manipulate the biochemistry sufficiently to prevent small and large vessel complications, there is still much which can be done. Proactive foot care can prevent ulceration and limit its effects [41], timely photocoagulation can prevent blindness in patients with maculopathy [42] and thrombolytic therapy is relatively more effective in diabetic patients with myocardial infarction than in their non-diabetic peers [43]. References [1] Rubin, R.J., Altman, W.M. and Mendelson, D.N. (1994) Health care expenditures for people with diabetes mellitus, 1992. J. Clin. Endocrinol. Metab. 78, 809A-809F. [2] Panzram, G. (1987) Mortality and survival in Type 11 (non-insulin-dependent) diabetes mellitus. Diabetologia 30, 123-131.
[3] Klein, R, Klein, BEK and Moss, SE. (1984) Visual impairment in diabetes. Ophthalmology 91, 1-9. [4] US Renal Data System USRDS (1991) Annual Data Report. Bethesda, MD, National Institutes of Health. [5] Bild, D.E., Selby, W., Sinnock, P., Browner, W.S., Braverman, P. and Showstack, J.A (1989) Lower extremity amputation in people with diabetes: epidemiology and prevention. Diabetes Care 12,24-31. [6] Harris, M.I. (1993) Undiagnosed NIDDM: clinical and public health issues. Diabetes Care, 16, 642-652. [7] Harris, M.I., Klein, R., Welborn, T.A, Knviman, M.W. (1992) Onset of NIDDM occurs at least 4-7 years before clinical diagnosis. Diabetes Care 15, 815-819. [8] Walsh, C.H., Soler, N.G., Fitzgerald, M.G. and Malins, J.M. (1975) Association of foot lesions with retinopathy in patients with newly diagnosed diabetes. Lancet I, 878-880. [9] Uusitupa, M., Siltonen, 0., Ard, A, Pyorala K. (1985) Prevalence of coronary heart disease, left ventricular failure and hypertension in middle aged, newly diagnosed Type 11 (non-insulin-dependent) diabetic subjects. Diabetologia 28, 22-27. [10] UK Prospective Diabetes Study Group. (1993) UK Prospective Diabetes Study (UKPDS) IX: Relationships of urinary albumin and N-acetylglucosaminidase to glycaemia and hypertension at diagnosis of Type II (noninsulin-dependent) diabetes mellitus and after 3 months diet therapy. Diabetologia 36, 835-842. [11] Panzram, G., Zabel-Langhennig (1981) Prognosis of diabetes mellitus in a geographically defined population. Diabetologia 20, 587 [12] Reaven, G.M. (1985) Role of insulin resistance in human disease. Diabetes 37, 1595-1607. [13] UK Prospective Diabetes Study Group. (1994) UK Prospective Diabetes Study (UKPDS) XI: Biochemical risk factors in Type 11 diabetic patients at diagnosis compared with age matched normal subjects. Diabetic Med. 11, 534-544. [14] Dunn, S.M. (1986) Reactions to educational techniques: coping strategies for diabetes and learning. Diabetic Med. 3, 419-429. [15] Kaplan, R.M. and Ganiats, T.G. (1989) Trade-offs in treatment alternatives for non-insulin-dependent diabetes mellitus. J. Gen. Intern. Med. 4, 167-171. [16] Mason, C. (1985) The production and effects of uncertainty with special reference to diabetes mellitus. Soc. Sci. Med. 21, 1329-1344. [17] Greenfield, S., Kaplan, S.H., Ware, J.E. et al. (1988) Patients' participation in medical care: effects on blood sugar and quality of life in diabetes. J. Gen. Intern. Med. 3, 448-457. [18] Tattersall, R.B. (1990) Writing to patients. Diabetic Med. 7, 917-919. [19] Redmond, S. (1990) What diabetic care to expect. Diabetic Med. 7, 554-556.
R. Tattersall / Diabetes Research and Clinical Practice 28 Suppl. (J995) 549-555
[20] UK Prospective Diabetes Study II: (1985) Reduction in HbA l e with basal insulin supplement, sulphonylurea or bignanide therapy in maturity-onset diabetes. Diabetes 34, 793-798. [21] Skarfors, E.T., Wegener, TA., Lithell, H. and Selenius I. (1987) Physical training as a treatment for Type II (non-insulin-dependent) diabetes in elderly men: a feasibility study over 2 years. Diabetologia 30, 930-3. [22) Schneider, S.H., Katchadurian, AX., Amorosa, L.F.. Vlemow, L. and Ruderman, N.B. (1992) Ten-year experience with an exercise-based outpatient lifestyle modification program in the treatment of diabetes mellitus. Diabetes Care 15, suppl 4, 1800-1810. [23] Carpenter, M.A. and Bodansky, H.J. (1990) Drug treatment of obesity in Type II diabetes mellitus. Diabetic Med. 7, 99-104. [24] Gill, G.V. (1986) Type II diabetes - is it 'mild diabetes'? Pract. Diabetes (UK) 3,280-282. [25) The Diabetes Control and Complications Research Group. (1993) The effect of intensive treatment on the development of microvascular complications of diabetes mellitus. N. Eng. J. Med. 320, 977-986. [26] Steinberg, C. (1993) Tight for Type II too? What do the results of the DCCT say to people with Type II diabetes? Diabetes Forecast 46, 61-62. [27] Tattersall, RB. (1990) Combined insulin and tablet treatment in sulphonylurea failures. Diabetes Nutr. Metab. 3, Suppl 1, 35-42. [28] Stout, RW. (Ed.) (1992) Insulin and Atherosclerosis. Kinwer Academic Publishers, Dordrccht. Boston. London, pp. 165-204. [29) Barrett-Connor, E. (1989) Non-insulin-dependent diabetes and hypertension. In: KG.M.M. Alberti and R. Mazze (Eds.), Frontiers of Diabetes Research: Current trends in non-insulin-dependent diabetes mellitus, chapter 13. Elsevier Science Publishers. [30] American Diabetes Association: Consensus Statement. (1991) Role of cardiovascular risk factors in prevention and treatment of microvascular disease in diabetes. Diabetes Care 14, Suppl 2, 69-75.
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[31] Fuller, J.H. and Stevens, L.K (1991) Epidemiology of hypertension in diabetic patients and implications for treatment. Diabetes Care 14, Suppl 4, 8-12. [32] Lewis, E.J., Hunsicker, L.G., Bain, RP., Rhode RD. (] 993) The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy. N. Eng. J. Med. 329, 1456-1462. [33] Kerr. D. and Tattersall, R.B. (I 99]) Renal artery stenosis. Br. Med. J. 302, 115 [34] Betteridge, D.J. (1989) Lipids, diabetes and vascular disease: the time to act. Diabetic Med. 6, 195-218. [35] Study Group of the European Atherosclerosis Society. (1987) Strategies for the prevention of coronary heart disease, a policy statement of the European Atherosclerosis Society. Eur. Heart J. 8, 77-88. [36) Winocour, P.H. and Laker, M.F. (1990) Drug therapy for diabetic dyslipoproteinaemia: a practical approach. Diabetic Med. 7, 292-298. [37] MacRury, S.M. and Lowe, G.D.D. (1990) Blood rheology in diabetes mellitus. Diabetic Med. 7, 285-291. [38] Colwell, J.A. (1988) Macroangiopathy. In: KG.M.M. Alberti and L.P. Krall (Eds.), Diabetes Annual 4. Amsterdam Elsevier Science Publishers, pp. 355-383. [39] Antiplatelet Trialists' Collaboration. (1988) Secondary prevention of vascular disease by prolonged antiplatelet treatment. Br. Med. J. 296,310-331. [40] The Carter Center of Emory University. (1985) Closing the gap: The problem of diabetes mellitus in the United States. Diabetes Care 8, 391-406. [41] Edmonds, M.E., Blundell, M.P., Morris, H.E, Thomas, EM., Cotton, L.T. and Watkins, P.J. (1986) Improved survival of the diabetic foot: the role of a specialised foot clinic. Q. 1. Med. 60, 763-771. [42] Kohner, EM. and Barry, P.J. (1984) Prevention of blindness in diabetic retinopathy. Diabetologia 26, 173-179. [43] Lynch, M., Gammage, M.D., Lamb, P., Nattrass, M. and Pentecost, B.L. (1994) Acute myocardial infarction in diabetic patients in the thrombolytic era. Diabetic Med. 11, 162-165.
C.uHJCAl IPJlAC']ITCIR
ELSEVIER
Diabetes Research and Clinical Practice 28 Suppl. (1995) S49-S55
Targets of therapy for NIDDM Robert Tattersall Diabetes Unit, University Hospital. Nottingham NG7 2UH. UK
Abstract Non-insulin-dependent diabetes (NIDDM) is a common multimetabolic disorder with potential (and potentially severe) long-term complications affecting large and small blood vessels. Where microvascular complications (retinopathy, nephropathy and neuropathy) are concerned, the Diabetes Control and Complications Trial (DCCT), as well as much circumstantial evidence, suggests that hyperglycaemia is the main aetiological factor and this is likely to apply in NIDDM as well as IDDM. Unfortunately, achieving normoglycaemia in NIDDM is not easy and it is unclear whether insulin has advantages over oral hypoglycaemic agents or vice versa. Turning to macrovascular disease, it is unclear which of the many potentially atherogenic abnormalities - hypertension, hyperinsulinaemia, hyperlipidaemia, etc - are most important. A further problem is that macrovascular disease is already well developed in many patients when NIDDM is diagnosed and we do not know whether secondary prevention is effective. Nevertheless, it is sensible to try to reverse the atherogenic milieu and this should be done in the first instance by lifestyle modification rather than drugs. Even if we cannot manipulate the biochemistry to prevent small or large vessel complications, much can still be done; proactive foot care can prevent ulceration, timely laser treatment can prevent visual loss and thrombolytic therapy is relatively more effective in diabetic patients with myocardial infarction than in their non-diabetic peers. Finally, patients with NIDDM need intensive education and each needs an individualised treatment plan and goals.
Keywords:
Non-insulin-dependent diabetes; Microvascular complications; Hyperglycaemia; Thrombolytic therapy
1. Introduction
Non-insulin-dependent diabetes (NIDDM) is one of the commonest chronic disorders in the world, attacks rich and poor alike and, in some countries, affects up to a third of the population. The health care costs of NIDDM are staggering; in a recent analysis based on data from the 1987
National Medical Expenditure Survey, Rubin et al. (1) estimated that in the USA in 1992, 14.6% of total health care expenditure was used by the 4.5% of the population with diabetes. Two-thirds of this money ($65.2 billion) was incurred by hospital inpatients compared to only 9% ($9.9 billion) on drugs and accessories such as urine or blood glucose testing strips. Rubin et al. make the
0168-8227/95/$09.50 © 1995 Elsevier Science Ireland Ltd. All rights reserved. SSDI 0168-8227(95) 0 I 086-S
S50
R. Tattersall / Diabetes Research and Clinical Practice 28 Suppl. (1995) S49~S55
obvious comment that 'significant savings to the health care system could be realised if even a fraction of these costs could be avoided through prevention or effective management of the disease and its complications'. Simplistically, the main causes of morbidity and mortality in NIDDM are macrovascular or microvascular disease. Macrovascular disease or accelerated atherosclerosis of major arteries is characteristic, and confers an excess risk of between 2 and 4-fold for heart attack, stroke or gangrene of the leg [2]. Microvascular disease affects the eyes, kidneys and nerves, leading to blindness, renal failure and foot ulcers. In the United States, diabetes is the commonest cause of new cases of blindness [3], end-stage renal disease [4], and leg amputation [5]. Apart from making the patient feel better in the short term, treatment of NIDDM must aim to prevent or delay macro and microvascular disease (secondary prevention) or, if we cannot do this, treat established complications to prevent the worst outcomes (tertiary prevention). 2. Is it too late to wait for the patient to come to the doctor? Population surveys always find as many previously undiagnosed diabetics as previously known cases. Maureen Harris [6] argues persuasively that NIDDM probably starts up to 12 years before clinical diagnosis and estimates that 10-20% of the US population over age 50 years have undiagnosed NIDDM, with even higher rates in Blacks and Mexican Americans. This long subclinical phase means that many patients already have complications when they first come to the doctor. If examined carefully through dilated pupils, up to 29% of 'new' patients have retinopathy and the same is true for other microvascular complications. One very characteristic group, mostly middle-aged men, present with retinopathy and neuropathic foot ulcers and most die within 5 years [8]. Patients with newly diagnosed NIDDM also have a high prevalence of large vessel disease. Uusitupa et al. [9] found a previous myocardial infarction twice as often in newly diagnosed dia-
betic men and four times as often in women as in the general population. Hypertension was present in 51% of patients (18% previously diagnosed and 33% not treated) in the UK Prospective Diabetes Study (UKPDS, [10]). An index of the poor general health of people with newly diagnosed NIDDM is that relative mortality is already increased in the first year after diagnosis and 44% have died after 10 years of follow up [11], leading Panzram to comment that 'at present we are doing too little too late, if anything can be done at all'. Harris [6] makes the persuasive case that 'If we believe that undiagnosed diabetes is highly prevalent, that it is associated with a high frequency of risk factors for complications, that a high prevalence of micro and macrovascular complications exists, and that treatments are available, then we must be drawn to the conclusion that these subjects should not remain undiagnosed'. I agree with this argument, although it is a condition of screening that effective treatment should be available for those identified as being ill. Whether or not we agree that the primary abnormality in NIDDM is insulin resistance [12], it is obvious that we are dealing with a multimetabolic disorder involving variable combinations of hyperglycaemia, hyperinsulinaemia, hyperlipidaemia, hypertension, obesity and platelet abnormalities (Table 1). The difficulty facing the clinician is to know whether it is more important to attack one or other of these targets selectively Table I Syndrome X (Reaven)
Syndrome X plus (Zimmet)
Insulin resistance Glucose intolerance Hyperinsulinaemia Increased VLDL triglyceride Decreased HDL cholesterol Hypertension
Insulin resistance Glucose intolerance Hyperinsulinaemia Increased VLDL triglyceride Decreased HDL cholesterol Hypertension Upper body obesity Hyperuricaemia Physical inactivity Ageing
Reproduced with permission from Zimmet P Diabetes Care 1992 15: 247.
R. Tattersall / Diabetes Research and Clinical Practice 28 SuppJ. (J995) S49-S55
or whether we should attempt to attack them all on a broad front. The history of the First World War suggests that the blunderbuss approach is likely to fail and simply lead to stalemate, confusion and ignorance among the combatants. The degree of biochemical abnormality in newly diagnosed patients in the UKPDS is shown in Table 2, and I will discuss each of these targets individually. 2.1. Education and general care There is an enormous literature on patient non-compliance in general and non-compliance in diabetes in particular [14] and I agree that one reason for this is that physicians often make the paternalistic assumption that they are entitled to make treatment decisions without consulting their patients [15]. In fact, most patients with NIDDM are looked after by primary care physicians rather than endocrinologists or diabetologists and it is likely that the providers themselves are confused when faced with a complex, and perhaps ambiguous, set of treatment alternatives. Obvious reasons why patients might not comply is that they do not believe the disease to be serious, have not understood the instructions of the nurse, doctor or dietitian or are simply overwhelmed by the number of targets they are being set. One patient of mine summarised what he had been told by the diabetes educator as 'Don't eat, smoke, rest or drink alcohol', while another asked 'If I do what you say, will I really live longer or will it just seem longer?'. Mason [16] tape recorded consultations
of 91 newly diagnosed diabetics with physician and dietitian and then went back to find out what the patients had understood. She showed clearly that many were confused by the language (too technical) and the exhortations (contradictory). Patients were also uncertain how much authority was being delegated to them in practice rather than in theory. The way in which patients can contribute productively to therapeutic decisions has been well shown by Greenfield and colleagues (17), who showed that a 20-min 'coaching session' enabled the patient to have a more productive encounter with the physician and also improved diabetic control. Patients with NIDDM need as much, if not more, education than those with IDDM and, although much of this will have to be done in groups, each patient needs an individualised plan and goals. I think that this should be written down [18) and given to the patient, general practitioner and anyone else with whom the patient is likely to come in contact. It is essential to get across to the patient that they have a potentially serious disorder, and a useful way of empowering them is a statement of expectations and responsibilities such as the British Diabetic Association leaflet 'What Diabetic Care to Expect' [19]. 2.2. Diet, exercise and (non) smoking Broad aims of diet are to abolish symptoms, achieve ideal body weight, attain normoglycaemia and reduce the risk of macrovascular disease. Whether it is possible to devise a single diet to
Table 2 Biochemical risk factors at diagnosis in newly diagnosed NIDDM - - - - - - - - - - _... _ -
---------
Age BMI (kgyrrr') HbA le (%) Total cholesterol mmoljl HDL cholesterol mmoljl Triglyceride mmoljl Hypertension
---
Normal subjects (25-65 years) - - _ .._ - _ . _ - 52 26.2 5.4 5.5 1.34
UK Prospective Diabetes Study Group [13].
2.9
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NIDDM at diagnosis (25-65 years) 52 30.1 9.3 5.7 1.05 6.5 51%
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Table 3 Possible targets in NIDDM Cigarette smoking Insulin resistance Hyperglycaemia Obesity Physical inactivity Hyperinsulinaemia Hypertension Increased VLDL triglyceride Decreased HDL cholesterol Hyperuricaemia Platelet abnormalities
meet all these objectives is doubtful, and it is wrong to give the impression that diet is the panacea with the implication that if it fails it is the patient's fault. In the UKPDS, patients with a fasting plasma glucose of 10-12 mmoljl at diagnosis had to lose 18 kg to achieve a fasting plasma glucose below 6 mmoljl, and the mean fasting plasma glucose after 1 year in 56 patients randornised to diet alone was 9.3 mmoljl [20]. The theoretical benefit of exercise is that it will reduce weight and insulin resistance. In practice, it is unsuccessful in the average patient with NIDDM. In a prospective population study of 60-year-old men with NIDDM, 39 of 48 were unsuitable because of circulatory and other disorders. Of eight who started the programme, six dropped out and after a year only, two of the 48 originally eligible were still exercising, and they were not improved metabolically [21]. In a lO-year study of an exercise-based lifestyle modification programme reported by Schneider et al. [22], half the participants had dropped out after 3 months and 90% after 1 year. In the 10% who stuck it out, benefits such as reduction in blood glucose, triglycerides and blood pressure were modest. At the moment, there is no satisfactory drug for the treatment of obesity [23], but it is an area of active research by pharmaceutical companies, as is the quest to find a drug which will reduce peripheral insulin resistance. Like Gill [24], I am familiar with the overweight, sedentary hyperlipidaernic, 50-year-old man with newly diagnosed NIDDM who smokes 20 cigarettes per day. I also agree that the great-
est service we can do him, after explaining the problem, is to concentrate on his weight and smoking rather than immediately confuse him with what Gill calls 'the tricks of the diabetic trade'. 2.3. Blood glucose control The Diabetes Control and Complications Trial (DCCT) has shown conclusively that nearnormoglycaemia is effective in both primary and secondary prevention of microvascular complications in insulin dependent diabetes (lDDM) [25], and I agree with Steinberg [26] that this is likely to be true in NIDDM, even though it has not been formally tested. The blood glucose levels which need to be achieved to prevent or delay the progression of complications are presumably the same as those in IDDM, although the strictness of the target will be modified on an individual basis, taking into account age, other diseases, macrovascular complications and living circumstances. We do not know which is the best hypoglycaemic agent to use in NIDDM; conventionally (but not logically), patients progress from diet to either sulphonylureas or biguanides, a combination of sulphonylureas and biguanides and, finally, to insulin. There remains a lingering concern that sulphonylureas may 'wear out the pancreas' and there are theoretical reasons why insulin might be a better initial treatment in some patients. Animal work suggests that hyperglycaemia per se impairs !,-cell function Cglucotoxicity') and one advantage of exogenous insulin might be to break the vicious circle and preserve pancreatic function. At least three published studies (reviewed in Ref. 27) suggest that insulin treatment does restore sulphonylurea sensitivity, although the duration of the effect is disappointingly short. A potential disadvantage of insulin is that it might be atherogenic; the idea that excessive concentrations of circulating insulin might cause or exacerbate atherosclerosis appeared in the mid-1960s [28] and has been much discussed but never resolved. In the real world, it is a matter of opinion whether hyperglycaemia or hyperinsulinaemia is likely to be more damaging in the long term.
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2.4. Hypertension Hypertension is common in NIDDM and substantially increases cardiovascular mortality. In the Rancho Bernardo study [29], the relative risk of cardiovascular death for men and women with hypertension but not diabetes was 2.1 and 1.9. whereas if both risk factors were present, the relative mortalities were 3.0 and 9.9. In addition, hypertension is associated with and contributes to the progression of diabetic nephropathy. We assume that lowering blood pressure will benefit diabetic patients but, unfortunately, they have been excluded from most studies of antihypertensive treatment. Nevertheless, consensus groups recommend similar treatment strategies as in non-diabetics [30] although, like others [31], I worry that uncritical 'aggressive' antihypertensive treatment may in some cases do more harm than good. If we are to treat, what drugs should be used? Both thiazides and ,B-blockers have undesirable effects on glucose and lipids, and this may be why they do not reduce the death rate from myocardial infarction in trials. Also, many patients with NIDDM have peripheral vascular disease and should probably not be treated with ,B-blockers. Both calcium channel blockers and angiotensinconverting enzyme (ACE) inhibitors are metabolically neutral and theoretically more suitable. In patients with IDDM and nephropathy, ACE inhibitors appear to prevent the decline in renal function more than would be expected from their antihypertensive effect alone, probably because they reduce intraglomerular pressure [32]. On the other hand, they may cause an irreversible decline in renal function in patients with bilateral renal artery stenosis, something which may be relatively common but unsuspected in the NIDDM patient with generalised atherosclerosis [33]. 2.5. Lipids There is much evidence that raised levels of cholesterol and triglycerides are together and independently associated with an increased risk of cardiovascular disease in the non-diabetic population. It is also clear that dyslipidaemia is common in patients with NIDDM with the characteristic
553
abnormalities being low levels of HDL cholesterol and high triglycerides. The literature is full of clarion calls such as 'Lipids, diabetes, and vascular disease: The time to act' [34]. The European Atherosclerosis Study Group [35] suggests that the targets should be to reduce total plasma cholesterol below 5.2 mmol z'l, LDL cholesterol below 3.5 mmolyl, plasma triglyercide below 2.3 mmoly l, and raise HDL cholesterol above 0.9 mmolyl. As with blood pressure, so with lipids, enthusiasts recommend 'aggressive' treatment. I would urge caution; while I agree with the scientific evidence that hyperlipidaemia is involved in causing coronary heart disease, trials of lipidlowering drugs in the non-diabetic population have generally not shown a reduction in total death rate. Also, there has never been a proper long-term study of lipid lowering in patients with diabetes. The problem is essentially the same as that in treating hypertension - for every 100 patients, only three or four will benefit while one may have his or her life ruined by side effects. All authors recommend that the first line of treatment for diabetic dyslipoproteinaemia should be diet, and one recent article [36] suggests that drugs should be introduced if cholesterol is persistently over 6.5 mmol /l, triglycerides over 2.2 rnmoly l or HDL cholesterol under 1 mmol /I, A fibric acid derivative is recommended as first line treatment, with acipimox (a nicotinic acid derivative) being added if necessary. 2.6. Blood flow and platelet abnormalities Blood viscosity is increased in patients with NIDDM, due mainly to increased plasma proteins [37]. It is likely that the rheological abnormalities are worst in the patients with worst blood glucose control. but their contribution to vascular disease has not been quantitated and, short of avoiding very high haematocrits, no therapy is known. A large number of platelet abnormalities have been described in diabetes, although it is unclear whether these are the cause or the consequence of vascular disease [38]. Many, if not all, are normalised by achieving normoglycaemia. Studies in non-diabetic patients suggest that antiplatelet drugs, particularly aspirin, are useful in the sec-
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ondary prevention of vascular disease [39] but the situation in diabetes is unclear because few large-scale multicentre trials have been done. Nevertheless, I would agree with Colwell [38] that diabetic patients who have had a previous stroke, myocardial infarction and/or have clinically apparent peripheral vascular disease should be treated with aspirin as secondary prevention. A dose of 150 mg daily is probably adequate. There is a temptation to use aspirin for primary prevention of vascular disease but no evidence to support its use in this way. 3. Quality of life and therapeutic realism
NIDDM is, to those whose wards are filled with patients with horrible complications, such an unpleasant disease that it is easy to go over the top and adopt what I called earlier in this paper a blunderbuss approach. What I have in mind is the following admonition: 'People with diabetes should be encouraged to view themselves as a population with a disproportionate number of risk factors for adverse health outcomes. and should be encouraged to adopt healthy lifestyles, to control obesity, to control hypertension, to stop smoking, and to control cholesterol and blood glucose levels, Efforts to achieve these ends should be redoubled in populations at high risk for the complications of diabetes' [40].
Even if we cannot manipulate the biochemistry sufficiently to prevent small and large vessel complications, there is still much which can be done. Proactive foot care can prevent ulceration and limit its effects [41], timely photocoagulation can prevent blindness in patients with maculopathy [42] and thrombolytic therapy is relatively more effective in diabetic patients with myocardial infarction than in their non-diabetic peers [43]. References [1] Rubin, R.J., Altman, W.M. and Mendelson, D.N. (1994) Health care expenditures for people with diabetes mellitus, 1992. J. Clin. Endocrinol. Metab. 78, 809A-809F. [2] Panzram, G. (1987) Mortality and survival in Type 11 (non-insulin-dependent) diabetes mellitus. Diabetologia 30, 123-131.
[3] Klein, R, Klein, BEK and Moss, SE. (1984) Visual impairment in diabetes. Ophthalmology 91, 1-9. [4] US Renal Data System USRDS (1991) Annual Data Report. Bethesda, MD, National Institutes of Health. [5] Bild, D.E., Selby, W., Sinnock, P., Browner, W.S., Braverman, P. and Showstack, J.A (1989) Lower extremity amputation in people with diabetes: epidemiology and prevention. Diabetes Care 12,24-31. [6] Harris, M.I. (1993) Undiagnosed NIDDM: clinical and public health issues. Diabetes Care, 16, 642-652. [7] Harris, M.I., Klein, R., Welborn, T.A, Knviman, M.W. (1992) Onset of NIDDM occurs at least 4-7 years before clinical diagnosis. Diabetes Care 15, 815-819. [8] Walsh, C.H., Soler, N.G., Fitzgerald, M.G. and Malins, J.M. (1975) Association of foot lesions with retinopathy in patients with newly diagnosed diabetes. Lancet I, 878-880. [9] Uusitupa, M., Siltonen, 0., Ard, A, Pyorala K. (1985) Prevalence of coronary heart disease, left ventricular failure and hypertension in middle aged, newly diagnosed Type 11 (non-insulin-dependent) diabetic subjects. Diabetologia 28, 22-27. [10] UK Prospective Diabetes Study Group. (1993) UK Prospective Diabetes Study (UKPDS) IX: Relationships of urinary albumin and N-acetylglucosaminidase to glycaemia and hypertension at diagnosis of Type II (noninsulin-dependent) diabetes mellitus and after 3 months diet therapy. Diabetologia 36, 835-842. [11] Panzram, G., Zabel-Langhennig (1981) Prognosis of diabetes mellitus in a geographically defined population. Diabetologia 20, 587 [12] Reaven, G.M. (1985) Role of insulin resistance in human disease. Diabetes 37, 1595-1607. [13] UK Prospective Diabetes Study Group. (1994) UK Prospective Diabetes Study (UKPDS) XI: Biochemical risk factors in Type 11 diabetic patients at diagnosis compared with age matched normal subjects. Diabetic Med. 11, 534-544. [14] Dunn, S.M. (1986) Reactions to educational techniques: coping strategies for diabetes and learning. Diabetic Med. 3, 419-429. [15] Kaplan, R.M. and Ganiats, T.G. (1989) Trade-offs in treatment alternatives for non-insulin-dependent diabetes mellitus. J. Gen. Intern. Med. 4, 167-171. [16] Mason, C. (1985) The production and effects of uncertainty with special reference to diabetes mellitus. Soc. Sci. Med. 21, 1329-1344. [17] Greenfield, S., Kaplan, S.H., Ware, J.E. et al. (1988) Patients' participation in medical care: effects on blood sugar and quality of life in diabetes. J. Gen. Intern. Med. 3, 448-457. [18] Tattersall, R.B. (1990) Writing to patients. Diabetic Med. 7, 917-919. [19] Redmond, S. (1990) What diabetic care to expect. Diabetic Med. 7, 554-556.
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[20] UK Prospective Diabetes Study II: (1985) Reduction in HbA l e with basal insulin supplement, sulphonylurea or bignanide therapy in maturity-onset diabetes. Diabetes 34, 793-798. [21] Skarfors, E.T., Wegener, TA., Lithell, H. and Selenius I. (1987) Physical training as a treatment for Type II (non-insulin-dependent) diabetes in elderly men: a feasibility study over 2 years. Diabetologia 30, 930-3. [22) Schneider, S.H., Katchadurian, AX., Amorosa, L.F.. Vlemow, L. and Ruderman, N.B. (1992) Ten-year experience with an exercise-based outpatient lifestyle modification program in the treatment of diabetes mellitus. Diabetes Care 15, suppl 4, 1800-1810. [23] Carpenter, M.A. and Bodansky, H.J. (1990) Drug treatment of obesity in Type II diabetes mellitus. Diabetic Med. 7, 99-104. [24] Gill, G.V. (1986) Type II diabetes - is it 'mild diabetes'? Pract. Diabetes (UK) 3,280-282. [25) The Diabetes Control and Complications Research Group. (1993) The effect of intensive treatment on the development of microvascular complications of diabetes mellitus. N. Eng. J. Med. 320, 977-986. [26] Steinberg, C. (1993) Tight for Type II too? What do the results of the DCCT say to people with Type II diabetes? Diabetes Forecast 46, 61-62. [27] Tattersall, RB. (1990) Combined insulin and tablet treatment in sulphonylurea failures. Diabetes Nutr. Metab. 3, Suppl 1, 35-42. [28] Stout, RW. (Ed.) (1992) Insulin and Atherosclerosis. Kinwer Academic Publishers, Dordrccht. Boston. London, pp. 165-204. [29) Barrett-Connor, E. (1989) Non-insulin-dependent diabetes and hypertension. In: KG.M.M. Alberti and R. Mazze (Eds.), Frontiers of Diabetes Research: Current trends in non-insulin-dependent diabetes mellitus, chapter 13. Elsevier Science Publishers. [30] American Diabetes Association: Consensus Statement. (1991) Role of cardiovascular risk factors in prevention and treatment of microvascular disease in diabetes. Diabetes Care 14, Suppl 2, 69-75.
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[31] Fuller, J.H. and Stevens, L.K (1991) Epidemiology of hypertension in diabetic patients and implications for treatment. Diabetes Care 14, Suppl 4, 8-12. [32] Lewis, E.J., Hunsicker, L.G., Bain, RP., Rhode RD. (] 993) The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy. N. Eng. J. Med. 329, 1456-1462. [33] Kerr. D. and Tattersall, R.B. (I 99]) Renal artery stenosis. Br. Med. J. 302, 115 [34] Betteridge, D.J. (1989) Lipids, diabetes and vascular disease: the time to act. Diabetic Med. 6, 195-218. [35] Study Group of the European Atherosclerosis Society. (1987) Strategies for the prevention of coronary heart disease, a policy statement of the European Atherosclerosis Society. Eur. Heart J. 8, 77-88. [36) Winocour, P.H. and Laker, M.F. (1990) Drug therapy for diabetic dyslipoproteinaemia: a practical approach. Diabetic Med. 7, 292-298. [37] MacRury, S.M. and Lowe, G.D.D. (1990) Blood rheology in diabetes mellitus. Diabetic Med. 7, 285-291. [38] Colwell, J.A. (1988) Macroangiopathy. In: KG.M.M. Alberti and L.P. Krall (Eds.), Diabetes Annual 4. Amsterdam Elsevier Science Publishers, pp. 355-383. [39] Antiplatelet Trialists' Collaboration. (1988) Secondary prevention of vascular disease by prolonged antiplatelet treatment. Br. Med. J. 296,310-331. [40] The Carter Center of Emory University. (1985) Closing the gap: The problem of diabetes mellitus in the United States. Diabetes Care 8, 391-406. [41] Edmonds, M.E., Blundell, M.P., Morris, H.E, Thomas, EM., Cotton, L.T. and Watkins, P.J. (1986) Improved survival of the diabetic foot: the role of a specialised foot clinic. Q. 1. Med. 60, 763-771. [42] Kohner, EM. and Barry, P.J. (1984) Prevention of blindness in diabetic retinopathy. Diabetologia 26, 173-179. [43] Lynch, M., Gammage, M.D., Lamb, P., Nattrass, M. and Pentecost, B.L. (1994) Acute myocardial infarction in diabetic patients in the thrombolytic era. Diabetic Med. 11, 162-165.