i The Fellowship of Postgraduate Medicine, 1991
Postgrad Med J (1991) 67, 931 - 937
Treatment of diabetes: the effect on serum lipids and lipoproteins Peter K. Merrin and Robert S. Elkeles Department of Metabolic Medicine, St. Mary's Hospital, Praed Street, London W2 INY, UK
Introduction In both insulin dependent diabetes (IDDM) and non-insulin dependent diabetes (NIDDM), morbidity and mortality from cardiovascular disease is greatly increased. The causes of the accelerated cardiovascular disease are probably different in the two types. As yet there is no evidence that control of hyperglycaemia has reduced the incidence of cardiovascular disease in either type.' There is a large body of evidence that hyperlipidaemia in the general population is associated with cardiovascular disease. Furthermore there is considerable evidence that control of serum lipids results in the reduction of the incidence of coronary heart disease2'3 and that in those with established coronary heart disease, the rate of progression is reduced.4 It is therefore important to understand the effects of the treatments used in diabetes on serum lipids and lipoproteins.
Non-insulin dependent diabetes Prevalence of serum lipoprotein abnormalities In NIDDM there is a two- to three-fold increase in cardiovascular mortality' which accounts for between 50 and 75% of deaths.6 Risk factors for cardiovascular disease in the general population, such as hypertension, smoking and raised serum cholesterol, appear important in NIDDM.5 Crosssectional studies have indicated that increased serum triglyceride, total and low density lipoprotein (LDL) cholesterol, low high density lipoprotein (HDL) cholesterol and apoprotein Al are associated with cardiovascular disease in NIDDM.7'-0 Data from prospective studies have shown that serum triglyceride is an important risk factor.""2 In women, low HDL cholesterol,'3 and in middle aged men, serum cholesterol,'4 have emerged as important predictors of cardiovascular
Correspondence: R.S. Elkeles, M.D., F.R.C.P.
disease. The most common metabolic abnormalities in NIDDM are hypertriglyceridaemia and low HDL cholesterol.'5 There are sex differences in the distribution of the lipoprotein abnormalities in NIDDM.'6 The increase in serum triglyceride is relatively greater and the decrease in HDL cholesterol relatively lower in women than in men.'6 Hypertriglyceridaemia and low HDL cholesterol, often referred to as dyslipidaemia, are metabolically closely related and may well be important in the aetiology of macrovascular disease in NIDDM (see also Winocour, this issue, pp. 917-921). Diet
In the overweight, weight reduction reduces serum triglycerides and raises HDL cholesterol.'7"18 In the non-obese, diet may lower serum triglyceride but has little effect on HDL cholesterol.'7"8 Current advice is to encourage a high fibre, high carbohydrate, low saturated fat diet. It has been shown that a simple increase in digestible carbohydrate without a parallel increase in dietary fibre does not help in improving metabolic control.'9 Indeed, some high carbohydrate diets have been shown to increase serum triglyceride, lower HDL cholesterol and worsen glucose control.20 The hypoglycaemic and hypolipidaemic effects of high carbohydrate, high fibre diets are due mainly to the fibre content. It is important to remember that there are two types of fibre, soluble or viscous fibre and insoluble or fibrous fibre, such as bran. It is only soluble fibre, such as that contained in legumes and green vegetables, which has the desired metabolic effects whereas insoluble fibre has barely any. The pharmacological addition of fibre in the form of guar has been shown to reduce total and LDL cholesterol,21'22 but the quantity of fibre recommended in some diets is not acceptable to many patients. The benefits and disadvantages of fibre in the management of diabetes have been recently well debated.2324 Controversy therefore exists as to which constituent should replace the reduced saturated fat intake which is considered desirable. There is some evidence that partial replacement of complex
932
P.K. MERRIN & R.S. ELKELES
carbohydrate with mono-unsaturated fat improves shown to reduce serum triglyceride in non-diabetic glucose control, improves serum triglyceride and subjects.'" These data therefore suggest that metHDL cholesterol without raising LDL choles- formin does have a small effect in improving the terol.25 The current enthusiasm for high carbohy- lipid profile in patients with NIDDM. drate diets in NIDDM may need slight modification. Longer term studies are needed to define the most Insulin suitable diet for people with NIDDM. The decision as to when to use insulin in patients with NIDDM can be difficult. Insulin has been Oral hypoglycaemic drugs shown to reduce serum triglyceride and cholesterol, Doubts were expressed about the long term safety but not affect HDL cholesterol in a small group of of the sulphonylureas when the American Univer- patients with NIDDM.4' Lindstrom et al.42 comsity Group Diabetes Program Study showed that in pared two different insulin regimes in a group of people with NIDDM who were randomized to patients with NIDDM who were secondary sulreceive either diet alone, diet and tolbutamide or phonylurea failures. Insulin was given as either a 2 diet and insulin, the tolbutamide group had a or 4 dose regime. Both insulin regimes resulted in greatly increased cardiovascular mortality com- similar improvements in blood glucose control. pared with the other groups.26 The findings of this They also resulted in a decrease in serum cholesstudy have been disputed.27'28 Nevertheless, the terol, triglyceride and increases in total HDL, effects of sulphonylureas on serum lipids were HDL2 and HDL3 cholesterol as well as apolipoproinvestigated. Early cross-sectional studies showed tein Al. Insulin therapy has its disadvantages, that those taking sulphonylureas had lower HDL particularly in the obese subject and, clearly it cholesterol than those on diet or insulin.29'30 cannot be used in the majority of patients with Another study showed that those on sulphonyl- NIDDM. ureas had both higher triglycerides and lower HDL cholesterol than those on diet or insulin.3' How- Lipid-modifying drugs ever, subsequent prospective studies have failed to confirm these findings. Neutral or even beneficial There remain a large number of subjects with effects of sulphonylureas have been found. Paisey NIDDM who have a modestly increased serum et al.32 found a reduction in serum and very low triglyceride and reduced HDL cholesterol, despite density lipoprotein (VLDL) triglyceride with a rise diet and oral hypoglycaemic drugs. The important in HDL cholesterol with chlorpropamide, while question, therefore, arises as to whether such Greenfield et al.33 found a reduction in serum patients should be given a lipid-modifying agent. In triglyceride with glipizide, but no change in HDL the Helsinki Heart Study,3 middle aged men with cholesterol. Taylor et al.'8 found no significant mild hyperlipidaemia similar to that seen in change in serum lipids with glibenclamide though NIDDM were randomized into those receiving there was a rise in apoprotein A1. Rains et al.,34 placebo or the fibrate gemfibrozil. There was a comparing glibenclamide with metformin, found significant reduction in coronary events in the no significant change in serum lipids and lipopro- actively treated group during the 5-year period of teins with glibenclamide. It is of interest that follow-up. Gemfibrozil therapy was associated Glyburide (glibenclamide) given to insulin treated with a persistent increase in HDL cholesterol and non-insulin dependent diabetics35 had no signi- reductions in serum total and LDL cholesterol and ficant effects on lipids and lipoproteins. Taking all in triglyceride. Another fibrate, bezafibrate has the evidence together, sulphonylureas probably been shown to reduce serum triglyceride and have little overall effect on serum lipids and do not cholesterol and increase HDL cholesterol in correct the low HDL cholesterol of NIDDM.37 NIDDM.8 One of the new class of HMG CoA Metformin is the only biguanide drug in com- reductase inhibitors, lovastatin, has been shown to mon use in the United Kingdom. It has been shown reduce total and LDL cholesterol and LDL apoto have a small effect in reducing total and LDL protein B and triglycerides in NIDDM.43 The effect cholesterol.34 Furthermore, this effect was found to on HDL cholesterol was variable. A recent study be maintained in the long term.38 In another study compared the effects of gemfibrozil and lovastatin metformin was found to reduce only VLDL choles- on lipids and glucose control in NIDDM.4 Lovasterol in NIDDM.2' However, in those with a tatin significantly reduced total and LDL cholescholesterol greater than 6.5 mmol/l, metformin terol and raised HDL cholesterol but did not significantly reduced serum triglyceride.22 Wu et al. reduce triglyceride, while gemfibrozil did not signihave shown that metformin lowered both fasting ficantly reduced LDL cholesterol. Neither drug and post-prandial serum triglyceride and even affected blood glucose control. It is difficult to increased HDL cholesterol in a group of patients predict which class of drug will be the most effective with NIDDM.39 In addition metformin has been in this situation. However, since the dyslipidaemia
DIABETES: TREATMENT AND SERUM LIPIDS
933
minuria have higher total and LDL cholesterol, higher triglycerides and apolipoprotein B levels together with lower HDL cholesterol concentrations compared to those without albuminuria.57 Similar findings were reported in a group of patients with microalbuminuria.58 The presence of proteinuria in IDDM is associated with an increased mortality.59 In an analysis of 2,890 patients with proteinuria,W the relative mortality from cardiovascular disease was 37 times that of the Insulin dependent diabetes general population. In those without proteinuria it Prevalence ofserum lipid abnormalities andfactors was 4.2 times that in the general population. The influence of proteinuria on vascular disease, blood influencing it pressure and lipoproteins in IDDM was studied by In the pre-insulin era, death for those with juvenile Winocour et al.6' Of 22 patients who had proonset diabetes was invariably due to ketoacidosis. teinuria (but not renal failure), 10 had evidence of However, as insulin treatment became available, macrovascular disease, whilst this was only present there was a large increase in the numbers of in three patients with normal albumin excretion diabetics dying from cardiovascular disease.5 This rates. The patients with proteinuria had higher was even more evident in the female diabetic blood pressures, lower serum HDL concentrations population.45 Much of this increase in cardiovas- (as measured by a precipitation technique), lower cular mortality is from coronary artery disease.46-4' HDL2 concentrations (as isolated by ultracentriThere is a paucity of information on the relation- fugation) and high HDL3 concentrations. ship between serum lipids and cardiovascular disease in IDDM. Furthermore, there needs to be a Insulin therapy clear distinction drawn between the insulin treated non-insulin dependent and insulin dependent Lipid and lipoprotein abnormalities in insulin population. However, studies have indicated that dependent diabetes depend on the degree of insurisk factors for coronary artery disease in the linization of the individual. In the totally insulin insulin dependent diabetic include elevated LDL deficient state, i.e. ketoacidosis, gross hypertriglycholesterol,9 antecedent nephropathy49 and hyper- ceridaemia with greatly elevated levels of VLDL tension.' It is of interest that no inverse relation- cholesterol can occur.62'63 Weidman et al. showed, ship between HDL cholesterol concentrations and in a group of 13 patients, that these abnormalities vascular disease was found in the male insulin can largely be corrected within the 24 hours after treated diabetic.9 An early study5" indicated that the initiation of insulin treatment.' Mean levels of middle-aged diabetic patients treated with insulin intermediate density lipoprotein (IDL) cholesterol for a minimum period of 10 years had serum and LDL cholesterol were low and did not vary cholesterol and triglyceride concentrations similar with therapy. Mean basal levels of HDL cholesto that of non-diabetic controls. However, the terol were also low and did not vary during the first concentration of HDL cholesterol was significantly 12 hours of insulin therapy. However, from 12 to 24 higher in male and female diabetics than the hours the levels rose significantly. Plasma apolipoprotein B levels fell with the therapy due to respective control groups. The prevalence of hyperlipidaemia in 205 insu- significant decreases in VLDL cholesterol. lin-dependent individuals was examined by Winocour et al.52 They found that 40% ofthe individuals Intensive insulin therapy tested had some type of hyperlipidaemia. While the prevalence of hypertriglyceridaemia and combined Intensive insulin therapy was found to improve hyperlipidaemia was greater in patients with insu- lipid profiles by reducing the concentrations of lin-dependent diabetes than non-diabetics, this was total, LDL and VLDL cholesterol.65 The effects on not the case for hypercholesterolaemia. In this HDL cholesterol in this study were not as prostudy, hypertriglyceridaemia was associated with a nounced, although there were rises, particularly in decrease in the HDL2 cholesterol compared to male patients with poor overall control. In a patients with normal serum lipids or hypercholes- comparison of multiple injection therapy and conterolaemia. Nikkila53 demonstrated low HDL con- tinuous subcutaneous insulin infusion (CSII) by centrations in untreated type I diabetics, but most Pietri et al.66 both treatment modalities reduced other studies in treated patients have demonstrated serum triglyceride levels but only CSII reduced normal or above normal levels of this lipopro- serum and LDL cholesterol. Longer periods of tein. 54-6 The development of nephropathy has an subcutaneous insulin infusion are additionally adverse effect on serum lipids. Patients with albu- associated with elevations in HDL cholesterol67,6
of NIDDM is mainly elevated triglyceride and low HDL cholesterol, the fibrate group of drugs would seem to be more appropriate. There is a need for long term prospective studies in NIDDM to ascertain whether, by improving the dyslipidaemia with drug therapy, the progress of cardiovascular disease can be slowed and its incidence reduced.
934
P.K. MERRIN & R.S. ELKELES
and a reduction in plasma levels of apolipoprotein B.77 In a study of 10 normolipidaemic patients before and after improvement in metabolic control,69 changes in VLDL and LDL cholesterol composition were noted. Subfractions from the IDDM patients were cholesteryl-ester poor and triglyceride rich (particularly in the LDL subfractions) and contained higher proportions of nonapolipoprotein B apoproteins compared to the control group. The apolipoprotein abnormality responded to improved control, but did not normalize, and, although LDL and VLDL concentrations improved, the compositional abnormalities persisted. Diet In a study of 270 children by Kaufmann et al.70 the effects of a usual and modified diabetic diet on glycaemic control and serum lipids was assessed. The usual diabetic diet contained 700-1500 mg of cholesterol daily with a polyunsaturated/saturated (P/S) fatty acid ratio of 0.1, while the modified diet limited cholesterol to 300 mg daily with a P/S ratio of 1.0. Both diets contained similar amounts of protein and carbohydrate as calories. On admission to the study 24% of the subjects had hyperlipoproteinaemia (mostly combined hyperlipidaemia or hypertriglyceridaemia). After following the usual diet, hypertriglyceridaemia was only present in 1% of individuals, whereas 21% of the subjects still had a type II electrophoretic pattern, despite overall lower glucose levels. After consumption of the modified diet, hyperlipoproteinaemia was reduced to 5% with only 4% of subjects having a type II pattern and 1% hypertriglyceridaemia. Hollenbeck et al. studied the effects of diet in IDDM.7' They showed that after 6 weeks of a diet containing 65% of the calories as carbohydrate, plasma triglycerides were significantly increased, although this may not apply in well controlled patients.72 Decreases in concentrations of apolipoproteins Al, B and CIII were also shown in a group of IDDM patients treated with a low fat, high carbohydrate, cholesterol restricted diet.7' There have been few studies on the prolonged effects of dietary fibre on serum lipids in IDDM. In one study of 8 insulin-treated patients who received 14-26 grammes of guar/day there was a 15% reduction in LDL cholesterol without change in the serum HDL cholesterol." This was accompanied by a mean reduction in the insulin dose required to maintain glycaemic control. General considerations concerning the diet for IDDM, including the fibre content, are similar to those for NIDDM (see above).
Glycaemic control and serum lipids A number of investigators have examined the relationship between glycaemic control, as manifested by glycosylated haemoglobin levels, and serum lipids. Improved glycaemic control reduces serum cholesterol and triglycerides.74'75 There does not appear to be a correlation between haemoglobin Al and HDL cholesterol,757" although Lopes-Virella et al.78 found an inverse relationship between haemoglobin AIc and HDL cholesterol in men and women with poor overall diabetic control (as defined by haemoglobin Alc and 24 hour glycosuria). In a study of 544 patients haemoglobin Al was negatively correlated with HDL cholesterol and positively correlated with the levels of total cholesterol, total triglycerides and LDL cholesterol.79 These relationships were not present in black women suggesting that race and gender may be independent determinants of serum lipids in insulin-dependent diabetics.
Lipid modifying drugs There have been few studies on the action of hypolipidaemic agents in insulin-dependent diabetes. Fibric acid derivatives have been advocated as the drug of choice for diabetic dyslipidaemia.80 In Type 1 diabetes, bezafibrate therapy caused a significant reduction in fasting blood glucose, VLDL cholesterol, serum triglycerides and apolipoprotein B.8' There was no overall change in HDL cholesterol, but in those patients who were initially hypertriglyceridaemic, there was a significant increase in the HDL2 subfraction. The use of fish oil containing omega 3 fatty acids has been reviewed recently82 and there is some evidence for a beneficial effect on vascular permeability,83 suggesting a possible prophylactic use of these agents in the prevention of atherogenesis. However, the results in other studies have not shown consistent benefits in lipid profiles. In a group of male patients84 therapy caused elevations of total cholesterol and apolipoprotein B. In a further study of female patients, a fall in plasma triglycerides and a rise in HDL cholesterol was noted.85 Additionally, the use of 3-omega fatty acids may be associated with a deterioration in glycaemic control.86 Further studies on these and other newer hypolipidaemic agents in insulin-dependent diabetes are needed. The aetiology of macrovascular disease in IDDM appears more complex than in NIDDM and its relationship to dyslipidaemia is less well defined, although this may not be the case for those IDDM patients with proteinuria. The use of lipid-modifying drugs in both NIDDM and IDDM is considered in detail in another article in this series by Paul
Durrington (this issue, pp. 947-952).
DIABETES: TREATMENT AND SERUM LIPIDS
935
References 1. Pyorala, K. & Laakso, M. Macrovascular disease in diabetes mellitus. In: Mann, JI., Pyorala, K. & Teuscher, A. (eds), Diabetes in Epidemiological Perspective. Churchili Livingstone: Edinburgh, 1983, pp. 183-247. 2. The Lipid Research Clinic Program. The Lipid Research Clinics Coronary Primary Prevention Study Trial Results II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA 1984, 251: 365-374. 3. Frick, M.H., Elo, O., Happa, K. et al. Helsinki Heart Study: primary prevention trial with Gemfibrozil in middle-aged men with dyslipidaemia. NEngl JMed 1987, 317:1237-1245. 4. Blankenhorn, D.H., Nessim, S.A., Johnson, R.L., Sanmarco, M.E., Azen, S.P. & Cashin-Hemphill, L. Beneficial effects of combined Colestipol-Niacin therapy on coronary atherosclerosis and coronary venous bypass grafts. JAMA 1987, 257: 3233-3240. 5. Krannel, W.B. & McGee, D.L. Diabetes and cardiovascular disease. The Framingham Study. JAMA 1979, 241: 20352038. 6. Panzram, G. Mortality and survival in Type 2 (non-insulin dependent) diabetes. Diabetologia 1987, 30: 123-131. 7. Santen, R.J., Willis, P.W., Fajans, S.S. & Arbor, A. Atherosclerosis in diabetes mellitus. Correlations with serum lipid levels, adiposity and serum insulin level. Arch Intern Med 1972, 130: 833-843. 8. Seviour, P.W., Teal, T.K., Richmond, W.R. & Elkeles, R.S. Serum lipids and macrovascular disease in non-insulin dependent diabetics: A possible new approach to prevention. Diabetic Med 1988, 5: 166-171. 9. Reckless, J.P.D., Betteridge, D.J., Wu, P., Payne, B. & Galton, D.J. High density and low density lipoproteins and prevalence of vascular disease in diabetes mellitus. Br Med J 1978, 1: 883-886. 10. Laakso, M., Ronnemaa, T., Pyorala, K., Kallio, V., Puukka, P. & Penttila, I. Atherosclerotic vascular disease and its risk factors in non-insulin dependent diabetic and non-diabetic subjects in Finland. Diabetes Care 1988, 11: 449-463. 11. Janka, H.U. Five year incidence of major macrovascular complications in diabetes mellitus. Horm Metab Res 1985, 15 (Suppl): 15-19. 12. Fontbonne, A., Eschwege, E., Cemblen, F. et al. Hypertriglyceridaemia as a risk factor for coronary heart disease mortality in patients with impaired glucose tolerance or diabetes. Results from the eleven year follow up of the Paris Prospective Study. Diabetologia 1989, 32: 300-304. 13. Gordon, E., Casteli, W.P., Hjortland, M.C., Kannel, W.B. & Dawber, T.R. Diabetes, blood lipids, and the role of obesity in coronary heart disease risk for women. Arch Intern Med 1977, 137: 393-397. 14. Rosengren, A., Welin, L., Tsipogianni, A. & Wilhelmsen, L. Impact of cardiovascular risk factors on coronary heart disease and mortality among middle aged diabetic men: a general population study. Br Med J 1989, 299: 1127-1131. 15. Reaven, G.M. Non-insulin dependent diabetes mellitus, abnormal lipoprotein metabolism and atherosclerosis. Metabolism 1987, 36 (Suppl 1): 1-8. 16. Walden, C.E., Knopp, R.H., Wahl, P.W., Beach, K.W. & Strandness, E. Sex differences in the effect ofdiabetes mellitus on lipoprotein triglyceride and cholesterol concentrations. N Engl J Med 1984, 311: 953-959. 17. Kennedy, L., Walshe, K., Hadden, D.R., Weaver, J.A. & Buchanan, K.D. The effect of intensive dietary therapy on serum high density lipoprotein cholesterol in patients with type 2 (non-insulin dependent) diabetes mellitus, A prospective study. Diabetologia 1982, 23: 24-27. 18. Taylor, K.G., John, W.G., Matthews, K.A. & Wright, A.D. A prospective study of 12 months treatment on serum lipids and apolipoproteins A-1 and B in type 2 (non-insulin dependent) diabetes. Diabetologia 1982, 23: 507-510.
19. Riccardi, G., Rivellese, A., Pacioni, D., Genovese, S., Mastranzo, P. & Mancini, M. Separate influence of dietary carbohydrate and fibre on the metabolic control in diabetes. Diabetologia 1984, 26: 116-121. 20. Coulston, A.M., Hollenbeck, C.H., Swislocki, A.L.M. & Reaven, G.M. Deleterious metabolic effects of high carbohydrate, sucrose containing diets in patients with non-insulin dependent diabetes mellitus. Am J Med 1987, 82: 213-220. 21. Lalor, B.C., Bhatnager, D., Winocour, P.H. et al. Placebocontrolled trial of the effects on guar gum and Metformin on fasting blood glucose and serum lipids in obese, type 2 diabetic patients. Diabetic Med 1990, 7: 242-245. 22. Fuessl, H.S., Williams, G., Adrian, T.E. & Bloom, S.R. Guar sprinkled on food: effect on glycaemic control, plasma lipids and gut hormones in non-insulin dependent diabetic patients. Diabetic Med 1987, 4: 463-468. 23. Hockaday, T.D.R. Controversies in Therapeutics. Fibre in management of diabetes. 1. Natural fibre useful as a part of total dietary prescription. Br Med J 1990, 300: 1334-1336. 24. Tattersall, R. & Mansell, P. Controversies in Therapeutics. Fibre in the management ofdiabetes. 2. Benefits of fibre itself are uncertain. Br Med J 1990, 300: 1336-1337. 25. Garg, A., Bonanome, A., Grundy, S., Zhang, Z. & Ungar, R.H. Comparison of a high carbohydrate diet with a high mono-unsaturated fat diet in patients with non-insulin dependent diabetes mellitus. N Engl J Med 1988, 319: 629-634. 26. University Group Diabetes Program. A study of the effects of hypoglycaemic agents on vascular complications in patients with adult-onset diabetes. Diabetes 1970, 19 (Suppl 2). 27. Kilo, C., Miller P & Williamson, J.R The crux of the UGDP: spurious results and biologically inappropriate data analysis. Diabetologia 1980, 18: 179-185. 28. Fuller, J.H. Clinical trials in diabetes mellitus. In: Mann, J.I. et al. (eds) Diabetes in Epidemiological Perspective. Churchill Livingstone: Edinburgh, 1983, pp. 265-285. 29. Berry, E.M. & Bar-On, H. Comparison of sulphonylurea and insulin treatment on lipid levels in maturity-onset diabetic men and women. Isr J Med Sci 1981, 17: 384-387. 30. Calvert, G.D., Graham, J.J., Mannik, T., Wise, P.H. & Yeates, R.A. Effects of therapy on plasma- high-densitylipoprotein-cholesterol concentration in diabetes mellitus. Lancet 1978, if: 66-68. 31. Lisch, H.-J. & Sailer, S. Lipoprotein patterns in diet, sulphonylurea and insulin treated diabetics. Diabetologia 1981, 20: 118-122. 32. Paisey, R., Elkeles, R.S., Hambley, J. & Magill, P. The effects of chlorpropamide and insulin on serum lipids, lipoproteins and fractional triglyceride removal. Diabetologia 1978, 15: 81-85. 33. Greenfield, M.S., Doberne, L., Rosenthal, M., Vreman, H.J. & Reaven, G.M. Lipid metabolism in non-insulin diabetes mellitus. Effect of glipizide therapy. Arch Intern Med 1982, 142: 1498-1500. 34. Rains, S.G.H., Wilson, G.A., Richmond, W. & Elkeles, R.S. The effect of glibenclamide and metformin on serum lipoproteins in type 2 diabetes. Diabetic Med 1988, 5: 653-658. 35. Falko, J.M. & Ossei, K. Combination insulin/Glyburide therapy in type II diabetes mellitus. Am J Med 1985, 79 (Suppl 3B): 92- 101. 36. Seviour, P.W., Teal, T.K., Richmond, W. & Elkeles, R.S. Chlorpropamide lowers serum and lipoprotein cholesterol in insulin-dependent diabetes. Diabetic Med 1986, 3: 152-154. 37. Baynes, C., Feher, M. & Elkeles, R.S. The effect of treatment of non-insulin dependent diabetes mellitus on serum lipids and lipoproteins. Q J Med 1989, 72: 579-587. 38. Rains, S.G.H., Wilson, G.A., Richmond, W. & Elkeles, R.S. The reduction of low density lipoprotein cholesterol by metformin is maintained with long-term therapy. J R Soc Med 1989, 82: 93-94.
936
P.K. MERRIN & R.S. ELKELES
39. Wu, M.-S., Johnston, P., Sheu, W.H.-H. et al. Effect of metformin on carbohydrate and lipoprotein metabolism in NIDDM patients. Diabetes Care 1990, 13: 1-8. 40. Sirtori, C.R., Tremoli, E., Sirtori, M., Conti, F. & Paoletti, R. Treatment of hypertriglyceridaemia with metformin. Effectiveness and analysis of results. Atherosclerosis 1977, 26: 583-592. 41. Hollenbeck, C.H., Chen, Y.I., Greenfield, M.S., Lardinois, C.K. & Reaven, G.M. Reduced high density lipoprotein cholesterol concentrations need not increase when hyperglycaemia is controlled with insulin in non-insulin dependent diabetes mellitus. J Clin Endocrinol Metab 1986, 62: 605-608. 42. Lindstrom, T., Arnqvist, H.J. & Olsson, A.G. Effect of different insulin regimes on plasma lipoprotein and apolipoprotein concentrations in patients with non-insulin dependent diabetes mellitus. Atherosclerosis 1990, 81: 137-144. 43. Garg, A. & Grundy, S. Lovastatin for lowering cholesterol levels in non-insulin dependent diabetes mellitus. N Engl J Med 1988, 318: 81-86. 44. Goldberg, R., La Belle, P., Zupkis, R. & Ronca, P. Comparison of the effects of Lovastatin and Gemfibrozil on lipids and glucose control in non-insulin dependent diabetes mellitus. Am J Cardiol 1990, 66: 16B-21B. 45. Entmacher, P.S., Rout, H.F. & Marks, H.H. Longevity of diabetic patients in recent years. Diabetes 1964, 13: 373-377. 46. Jarrett, R.J. Risk factors of macrovascular disease in diabetes mellitus. Horm Metab Res 1985, 15 (Suppl): 1-3. 47. Dupree, E.A. & Meyer, M.B. Role of risk factors in complications ofdiabetes mellitus. Am JEpidemiol 1980, 112: 100-112. 48. Krolewski, A.S., Kosinski, E.J., Warram, J.H. et al. Magnitude and determinants of coronary artery disease in juvenile-onset, insulin-dependent diabetes mellitus. Am J Cardiol 1987, 59: 750-755. 49. Jensen, T., Borch-Johnsen, K., Kofoed-Enevoldsen, A. & Deckert, T. Coronary heart disease in young type 1 (insulindependent) diabetic patients with and without diabetic nephropathy: incidence and risk factors. Diabetologia 1987, 30: 144-148. 50. Stamler, J., Wentworth, D., Neaton, J., Schoenberger, J.A. & Feigal, D. for the MRFIT Research Group. Diabetes and risk of coronary, cardiovascular and all causes mortality: findings for 356,000 men screened by the Multiple Risk Factor Intervention Trial (MRFIT). Circulation 1984, 70 (Suppl 2): 161. 51. Nikkila, E.A. & Hormila, P. Serum lipids and lipoproteins in insulin-treated diabetes. Demonstration of increased high density lipoprotein concentrations. Diabetes 1978, 27: 1078- 1086. 52. Winocour, P.H., Durrington, P.N., Ishola, M., Hillier, V.F. & Anderson, D.C. The prevalence of hyperlipidaemia and related clinical features in insulin-dependent diabetes mellitus. Q J Med NS 1989, 70: 265-276. 53. Nikkila, E.A. High density lipoproteins in diabetes. Diabetes 1981, 30 (Suppl 2): 82-87. 54. Laakso, M., Voutilainen, E., Aro, A., Pyorala, K. & Penttila, I. Inverse relationship of serum HDL and HDL2 cholesterol to C-peptide level in middle aged insulin treated diabetics. Metabolism 1985, 34: 715-720. 55. Eckel, R.H., Albers, J.J., Cheung, M.C., Wahl, P.W., Lindgren, F.T. & Bierman, E.L. High density lipoprotein composition in insulin-dependent diabetes mellitus. Diabetes 1981, 30: 132-138. 56. Winocour, P.H., Ishola, M., Durrington, P.N. & Anderson, D.C. Lipoprotein abnormalities in insulin-dependent diabetes mellitus. Lancet 1986, i: 1176- 1178. 57. Vannini, P., Ciavarella, A., Flammini, M. et al. Lipid abnormalities in insulin-dependent diabetic patients with albuminuria. Diabetes Care 1984, 7: 151-154. 58. Jones, S.L., Close, C.F., Mattock, M.B., Jarrett, R.J., Keen, H. & Viberti, G.C. Plasma lipid and coagulation factor concentrations in insulin dependent diabetics with microalbuminuria. Br Med J 1989, 298: 487-490.
59. Borch-Johnsen, K., Anderson, P.K. & Deckert, T. The effect of proteinuria on relative mortality in type 1 (insulindependent) diabetes mellitus. Diabetologia 1985, 28: 590596. 60. Borch-Johnsen, K. & Kreiner, S. Proteinuria: value as a predictor of cardiovascular mortality in insulin dependent diabetes mellitus. Br Med J 1987, 294: 1651-1654. 61. Winocour, P.H., Durrington, P.N., Ishola, M., Anderson, D.C. & Cohen, H. Influence of proteinuria on vascular disease, blood pressure, and lipoproteins in insulin-dependent diabetes mellitus. Br Med J 1987, 294: 1648-1651. 62. Bierman, E.L., Amaral, A.P. & Belknap, B.H. Hyperlipidaemia and diabetes mellitus. Diabetes 1966, 15: 675-679. 63. Bagdade, J.D., Porte, D. Jr & Bierman, E.L. Diabetic lipaemia: a form of acquired fat-induced lipaemia. N Engl J Med 1967, 276: 427-433. 64. Weidman, S.W., Ragland, J.B., Fisher, J.N., Kitabchi, A.E. & Sabesin, S.M. Effects of insulin on plasma lipoproteins in diabetic ketoacidosis: evidence for a change in high density lipoprotein composition during treatment. J Lipid Res 1982, 23: 171-182. 65. Lopes-Virella, M.F., Wohltmann, H.J., Mayfield, R.K., Loadholt, C.B. & Colwell, J.A. Effect of metabolic control on lipid, lipoprotein, and apolipoprotein levels in 55 insulindependent diabetic patients. A longitudinal study. Diabetes 1983, 32: 20-25. 66. Pietri, A., Dunn, F.L. & Raskin, P. The effect of improved diabetic control on plasma lipid and lipoprotein levels: a comparison of conventional therapy and continuous subcutaneous insulin infusion. Diabetes 1980, 29: 1001-1005. 67. Falko, J.M., O'Dorisio, T.M. & Cataland, S. Improvement of high density lipoprotein-cholesterol levels. Ambulatory type I diabetics treated with the subcutaneous insulin pump. JAMA 1982, 247: 37-39. 68. Dunn, F.L., Pietri, A. & Raskin, P. Plasma lipid and lipoprotein levels with continuous subcutaneous insulin infusion in type I diabetes mellitus. Ann Intern Med 1981, 95: 426-431. 69. James, R.W. & Pometta, D. Differences in lipoprotein subfraction composition and distribution between type 1 diabetic men and control subjects. Diabetes 1990, 39: 1158-1164. 70. Kaufmann, R.L., Assal, J.Ph., Soeldner, J.S. et al. Plasma lipids in diabetic children. Effect of diet restricted in cholesterol and saturated fats. Diabetes 1975, 24: 672-679. 71. Hollenbeck, C.B., Connor, W.E., Riddle, M.C., Alaupovic, P. & Lecklem, J.E. The effects of a high-carbohydrate, low-fat, cholesterol restricted diet on plasma lipids, lipoprotein and apoprotein concentrations in insulin-dependent (type 1) diabetes mellitus. Metabolism 1985, 34: 559-566. 72. Stone, D. & Connor, W.E. The prolonged effects of a low-cholesterol, high carbohydrate diet upon serum lipids in diabetic patients. Diabetes 1963, 12: 127-132. 73. Jenkins, D.J.A., Wolever, T.M.S., Taylor, R.H., Reynolds, D., Nineham, R. & Hockaday, T.D.R. Diabetic glucose control, lipids and trace elements on long term guar. Br MedJ 1980, 280: 1353-1354. 74. Sosenko, J.M., Breslow, J.L., Miettinen, O.S. & Gabbay, K.H. Hyperglycaemia and plasma lipid levels. A prospective study of young insulin-dependent diabetic patients. N Engi J Med 1980, 302: 650-654. 75. Ostlund, R.E., Semenkovich, C.F. & Schechtman, K.B. Quantitative relationship between plasma lipids and glycohemoglobin in type I patients. Longitudinal study of 212 patients. Diabetes Care 1989, 12: 332-336. 76. Elkeles, R.S., Wu, J. & Hambley, J. Haemoglobin Al, blood glucose and high density lipoprotein cholesterol in insulinrequiring diabetics. Lancet 1978, i{: 547-549. 77. Gonen, B., White, N., Schonfeld, G., Skor, D., Miller, P. & Santiago, J. Plasma levels of apoprotein B in patients with diabetes mellitus: the effect of glycaemic control. Metabolism 1985, 34: 675-679.
DIABETES: TREATMENT AND SERUM LIPIDS 78. Lopes-Virella, M.F., Wohltmann, H.J., Loadholt, C.B. & Buse, M.G. Plasma lipids and lipoproteins in young insulindependent diabetic patients: relationship with control. Diabetologia 1981, 21: 216-223. 79. Semenkovitch, C.F., Ostlund, R.E. & Schechtman, K.B. Plasma lipids in patients with type I diabetes mellitus. Influence of race, gender, and plasma glucose controls: Lipids do not correlate with glucose control in black women. Arch Intern Med 1989, 149: 51-56. 80. Winocour, P.H. & Laker, M.F. Drug therapy for diabetic dyslipoproteinaemia: a practical approach. Diabetic Med 1990, 7: 292-298. 81. Winocour, P.H., Durrington, P.N., Bhatnagar, D. et al. Double blind placebo-controlled study on the effects of bezafibrate on blood lipids, lipoproteins, and fibrinogen in hyperlipidaemic type I diabetes mellitus. Diabetic Med 1990, 7: 736-743.
937
82. Editorial. Fish oils and diabetic microvascular disease. Lancet 1990, 1: 508-509. 83. Jensen, T., Stender, S., Goldstein, K. et al. Partial normalisation by dietary cod liver oil of decreased microvascular albumin leakage in patients with insulin-dependent diabetes and albuminuria. N Engl J Med 1989, 321: 1572-1577. 84. Mori, T.A., Vandongen, R. & Maserei, J.R.L. Fish oilinduced changes in apolipoproteins in IDDM subjects. Diabetes Care 1990, 13: 725-732. 85. Bagdade, J.D., Buchanan, W.E., Levy, R.A., Subbaiah, P.V. & Ritter, M.C. Effects of w-3 fish oils on plasma lipids, lipoprotein composition and postheparin lipoprotein lipase in women with IDDM. Diabetes 1990, 39: 426-431. 86. Stacpoole, P.W., Alig, J., Ammon, L. & Crockett, S.E. Dose-response effects of dietary marine oil on carbohydrate and lipid metabolism in normal subjects and patients with hypertriglyceridaemia. Metabolism 1989, 38: 946-956.
Postgrad Med J (1991) 67, 931 - 937
Treatment of diabetes: the effect on serum lipids and lipoproteins Peter K. Merrin and Robert S. Elkeles Department of Metabolic Medicine, St. Mary's Hospital, Praed Street, London W2 INY, UK
Introduction In both insulin dependent diabetes (IDDM) and non-insulin dependent diabetes (NIDDM), morbidity and mortality from cardiovascular disease is greatly increased. The causes of the accelerated cardiovascular disease are probably different in the two types. As yet there is no evidence that control of hyperglycaemia has reduced the incidence of cardiovascular disease in either type.' There is a large body of evidence that hyperlipidaemia in the general population is associated with cardiovascular disease. Furthermore there is considerable evidence that control of serum lipids results in the reduction of the incidence of coronary heart disease2'3 and that in those with established coronary heart disease, the rate of progression is reduced.4 It is therefore important to understand the effects of the treatments used in diabetes on serum lipids and lipoproteins.
Non-insulin dependent diabetes Prevalence of serum lipoprotein abnormalities In NIDDM there is a two- to three-fold increase in cardiovascular mortality' which accounts for between 50 and 75% of deaths.6 Risk factors for cardiovascular disease in the general population, such as hypertension, smoking and raised serum cholesterol, appear important in NIDDM.5 Crosssectional studies have indicated that increased serum triglyceride, total and low density lipoprotein (LDL) cholesterol, low high density lipoprotein (HDL) cholesterol and apoprotein Al are associated with cardiovascular disease in NIDDM.7'-0 Data from prospective studies have shown that serum triglyceride is an important risk factor.""2 In women, low HDL cholesterol,'3 and in middle aged men, serum cholesterol,'4 have emerged as important predictors of cardiovascular
Correspondence: R.S. Elkeles, M.D., F.R.C.P.
disease. The most common metabolic abnormalities in NIDDM are hypertriglyceridaemia and low HDL cholesterol.'5 There are sex differences in the distribution of the lipoprotein abnormalities in NIDDM.'6 The increase in serum triglyceride is relatively greater and the decrease in HDL cholesterol relatively lower in women than in men.'6 Hypertriglyceridaemia and low HDL cholesterol, often referred to as dyslipidaemia, are metabolically closely related and may well be important in the aetiology of macrovascular disease in NIDDM (see also Winocour, this issue, pp. 917-921). Diet
In the overweight, weight reduction reduces serum triglycerides and raises HDL cholesterol.'7"18 In the non-obese, diet may lower serum triglyceride but has little effect on HDL cholesterol.'7"8 Current advice is to encourage a high fibre, high carbohydrate, low saturated fat diet. It has been shown that a simple increase in digestible carbohydrate without a parallel increase in dietary fibre does not help in improving metabolic control.'9 Indeed, some high carbohydrate diets have been shown to increase serum triglyceride, lower HDL cholesterol and worsen glucose control.20 The hypoglycaemic and hypolipidaemic effects of high carbohydrate, high fibre diets are due mainly to the fibre content. It is important to remember that there are two types of fibre, soluble or viscous fibre and insoluble or fibrous fibre, such as bran. It is only soluble fibre, such as that contained in legumes and green vegetables, which has the desired metabolic effects whereas insoluble fibre has barely any. The pharmacological addition of fibre in the form of guar has been shown to reduce total and LDL cholesterol,21'22 but the quantity of fibre recommended in some diets is not acceptable to many patients. The benefits and disadvantages of fibre in the management of diabetes have been recently well debated.2324 Controversy therefore exists as to which constituent should replace the reduced saturated fat intake which is considered desirable. There is some evidence that partial replacement of complex
932
P.K. MERRIN & R.S. ELKELES
carbohydrate with mono-unsaturated fat improves shown to reduce serum triglyceride in non-diabetic glucose control, improves serum triglyceride and subjects.'" These data therefore suggest that metHDL cholesterol without raising LDL choles- formin does have a small effect in improving the terol.25 The current enthusiasm for high carbohy- lipid profile in patients with NIDDM. drate diets in NIDDM may need slight modification. Longer term studies are needed to define the most Insulin suitable diet for people with NIDDM. The decision as to when to use insulin in patients with NIDDM can be difficult. Insulin has been Oral hypoglycaemic drugs shown to reduce serum triglyceride and cholesterol, Doubts were expressed about the long term safety but not affect HDL cholesterol in a small group of of the sulphonylureas when the American Univer- patients with NIDDM.4' Lindstrom et al.42 comsity Group Diabetes Program Study showed that in pared two different insulin regimes in a group of people with NIDDM who were randomized to patients with NIDDM who were secondary sulreceive either diet alone, diet and tolbutamide or phonylurea failures. Insulin was given as either a 2 diet and insulin, the tolbutamide group had a or 4 dose regime. Both insulin regimes resulted in greatly increased cardiovascular mortality com- similar improvements in blood glucose control. pared with the other groups.26 The findings of this They also resulted in a decrease in serum cholesstudy have been disputed.27'28 Nevertheless, the terol, triglyceride and increases in total HDL, effects of sulphonylureas on serum lipids were HDL2 and HDL3 cholesterol as well as apolipoproinvestigated. Early cross-sectional studies showed tein Al. Insulin therapy has its disadvantages, that those taking sulphonylureas had lower HDL particularly in the obese subject and, clearly it cholesterol than those on diet or insulin.29'30 cannot be used in the majority of patients with Another study showed that those on sulphonyl- NIDDM. ureas had both higher triglycerides and lower HDL cholesterol than those on diet or insulin.3' How- Lipid-modifying drugs ever, subsequent prospective studies have failed to confirm these findings. Neutral or even beneficial There remain a large number of subjects with effects of sulphonylureas have been found. Paisey NIDDM who have a modestly increased serum et al.32 found a reduction in serum and very low triglyceride and reduced HDL cholesterol, despite density lipoprotein (VLDL) triglyceride with a rise diet and oral hypoglycaemic drugs. The important in HDL cholesterol with chlorpropamide, while question, therefore, arises as to whether such Greenfield et al.33 found a reduction in serum patients should be given a lipid-modifying agent. In triglyceride with glipizide, but no change in HDL the Helsinki Heart Study,3 middle aged men with cholesterol. Taylor et al.'8 found no significant mild hyperlipidaemia similar to that seen in change in serum lipids with glibenclamide though NIDDM were randomized into those receiving there was a rise in apoprotein A1. Rains et al.,34 placebo or the fibrate gemfibrozil. There was a comparing glibenclamide with metformin, found significant reduction in coronary events in the no significant change in serum lipids and lipopro- actively treated group during the 5-year period of teins with glibenclamide. It is of interest that follow-up. Gemfibrozil therapy was associated Glyburide (glibenclamide) given to insulin treated with a persistent increase in HDL cholesterol and non-insulin dependent diabetics35 had no signi- reductions in serum total and LDL cholesterol and ficant effects on lipids and lipoproteins. Taking all in triglyceride. Another fibrate, bezafibrate has the evidence together, sulphonylureas probably been shown to reduce serum triglyceride and have little overall effect on serum lipids and do not cholesterol and increase HDL cholesterol in correct the low HDL cholesterol of NIDDM.37 NIDDM.8 One of the new class of HMG CoA Metformin is the only biguanide drug in com- reductase inhibitors, lovastatin, has been shown to mon use in the United Kingdom. It has been shown reduce total and LDL cholesterol and LDL apoto have a small effect in reducing total and LDL protein B and triglycerides in NIDDM.43 The effect cholesterol.34 Furthermore, this effect was found to on HDL cholesterol was variable. A recent study be maintained in the long term.38 In another study compared the effects of gemfibrozil and lovastatin metformin was found to reduce only VLDL choles- on lipids and glucose control in NIDDM.4 Lovasterol in NIDDM.2' However, in those with a tatin significantly reduced total and LDL cholescholesterol greater than 6.5 mmol/l, metformin terol and raised HDL cholesterol but did not significantly reduced serum triglyceride.22 Wu et al. reduce triglyceride, while gemfibrozil did not signihave shown that metformin lowered both fasting ficantly reduced LDL cholesterol. Neither drug and post-prandial serum triglyceride and even affected blood glucose control. It is difficult to increased HDL cholesterol in a group of patients predict which class of drug will be the most effective with NIDDM.39 In addition metformin has been in this situation. However, since the dyslipidaemia
DIABETES: TREATMENT AND SERUM LIPIDS
933
minuria have higher total and LDL cholesterol, higher triglycerides and apolipoprotein B levels together with lower HDL cholesterol concentrations compared to those without albuminuria.57 Similar findings were reported in a group of patients with microalbuminuria.58 The presence of proteinuria in IDDM is associated with an increased mortality.59 In an analysis of 2,890 patients with proteinuria,W the relative mortality from cardiovascular disease was 37 times that of the Insulin dependent diabetes general population. In those without proteinuria it Prevalence ofserum lipid abnormalities andfactors was 4.2 times that in the general population. The influence of proteinuria on vascular disease, blood influencing it pressure and lipoproteins in IDDM was studied by In the pre-insulin era, death for those with juvenile Winocour et al.6' Of 22 patients who had proonset diabetes was invariably due to ketoacidosis. teinuria (but not renal failure), 10 had evidence of However, as insulin treatment became available, macrovascular disease, whilst this was only present there was a large increase in the numbers of in three patients with normal albumin excretion diabetics dying from cardiovascular disease.5 This rates. The patients with proteinuria had higher was even more evident in the female diabetic blood pressures, lower serum HDL concentrations population.45 Much of this increase in cardiovas- (as measured by a precipitation technique), lower cular mortality is from coronary artery disease.46-4' HDL2 concentrations (as isolated by ultracentriThere is a paucity of information on the relation- fugation) and high HDL3 concentrations. ship between serum lipids and cardiovascular disease in IDDM. Furthermore, there needs to be a Insulin therapy clear distinction drawn between the insulin treated non-insulin dependent and insulin dependent Lipid and lipoprotein abnormalities in insulin population. However, studies have indicated that dependent diabetes depend on the degree of insurisk factors for coronary artery disease in the linization of the individual. In the totally insulin insulin dependent diabetic include elevated LDL deficient state, i.e. ketoacidosis, gross hypertriglycholesterol,9 antecedent nephropathy49 and hyper- ceridaemia with greatly elevated levels of VLDL tension.' It is of interest that no inverse relation- cholesterol can occur.62'63 Weidman et al. showed, ship between HDL cholesterol concentrations and in a group of 13 patients, that these abnormalities vascular disease was found in the male insulin can largely be corrected within the 24 hours after treated diabetic.9 An early study5" indicated that the initiation of insulin treatment.' Mean levels of middle-aged diabetic patients treated with insulin intermediate density lipoprotein (IDL) cholesterol for a minimum period of 10 years had serum and LDL cholesterol were low and did not vary cholesterol and triglyceride concentrations similar with therapy. Mean basal levels of HDL cholesto that of non-diabetic controls. However, the terol were also low and did not vary during the first concentration of HDL cholesterol was significantly 12 hours of insulin therapy. However, from 12 to 24 higher in male and female diabetics than the hours the levels rose significantly. Plasma apolipoprotein B levels fell with the therapy due to respective control groups. The prevalence of hyperlipidaemia in 205 insu- significant decreases in VLDL cholesterol. lin-dependent individuals was examined by Winocour et al.52 They found that 40% ofthe individuals Intensive insulin therapy tested had some type of hyperlipidaemia. While the prevalence of hypertriglyceridaemia and combined Intensive insulin therapy was found to improve hyperlipidaemia was greater in patients with insu- lipid profiles by reducing the concentrations of lin-dependent diabetes than non-diabetics, this was total, LDL and VLDL cholesterol.65 The effects on not the case for hypercholesterolaemia. In this HDL cholesterol in this study were not as prostudy, hypertriglyceridaemia was associated with a nounced, although there were rises, particularly in decrease in the HDL2 cholesterol compared to male patients with poor overall control. In a patients with normal serum lipids or hypercholes- comparison of multiple injection therapy and conterolaemia. Nikkila53 demonstrated low HDL con- tinuous subcutaneous insulin infusion (CSII) by centrations in untreated type I diabetics, but most Pietri et al.66 both treatment modalities reduced other studies in treated patients have demonstrated serum triglyceride levels but only CSII reduced normal or above normal levels of this lipopro- serum and LDL cholesterol. Longer periods of tein. 54-6 The development of nephropathy has an subcutaneous insulin infusion are additionally adverse effect on serum lipids. Patients with albu- associated with elevations in HDL cholesterol67,6
of NIDDM is mainly elevated triglyceride and low HDL cholesterol, the fibrate group of drugs would seem to be more appropriate. There is a need for long term prospective studies in NIDDM to ascertain whether, by improving the dyslipidaemia with drug therapy, the progress of cardiovascular disease can be slowed and its incidence reduced.
934
P.K. MERRIN & R.S. ELKELES
and a reduction in plasma levels of apolipoprotein B.77 In a study of 10 normolipidaemic patients before and after improvement in metabolic control,69 changes in VLDL and LDL cholesterol composition were noted. Subfractions from the IDDM patients were cholesteryl-ester poor and triglyceride rich (particularly in the LDL subfractions) and contained higher proportions of nonapolipoprotein B apoproteins compared to the control group. The apolipoprotein abnormality responded to improved control, but did not normalize, and, although LDL and VLDL concentrations improved, the compositional abnormalities persisted. Diet In a study of 270 children by Kaufmann et al.70 the effects of a usual and modified diabetic diet on glycaemic control and serum lipids was assessed. The usual diabetic diet contained 700-1500 mg of cholesterol daily with a polyunsaturated/saturated (P/S) fatty acid ratio of 0.1, while the modified diet limited cholesterol to 300 mg daily with a P/S ratio of 1.0. Both diets contained similar amounts of protein and carbohydrate as calories. On admission to the study 24% of the subjects had hyperlipoproteinaemia (mostly combined hyperlipidaemia or hypertriglyceridaemia). After following the usual diet, hypertriglyceridaemia was only present in 1% of individuals, whereas 21% of the subjects still had a type II electrophoretic pattern, despite overall lower glucose levels. After consumption of the modified diet, hyperlipoproteinaemia was reduced to 5% with only 4% of subjects having a type II pattern and 1% hypertriglyceridaemia. Hollenbeck et al. studied the effects of diet in IDDM.7' They showed that after 6 weeks of a diet containing 65% of the calories as carbohydrate, plasma triglycerides were significantly increased, although this may not apply in well controlled patients.72 Decreases in concentrations of apolipoproteins Al, B and CIII were also shown in a group of IDDM patients treated with a low fat, high carbohydrate, cholesterol restricted diet.7' There have been few studies on the prolonged effects of dietary fibre on serum lipids in IDDM. In one study of 8 insulin-treated patients who received 14-26 grammes of guar/day there was a 15% reduction in LDL cholesterol without change in the serum HDL cholesterol." This was accompanied by a mean reduction in the insulin dose required to maintain glycaemic control. General considerations concerning the diet for IDDM, including the fibre content, are similar to those for NIDDM (see above).
Glycaemic control and serum lipids A number of investigators have examined the relationship between glycaemic control, as manifested by glycosylated haemoglobin levels, and serum lipids. Improved glycaemic control reduces serum cholesterol and triglycerides.74'75 There does not appear to be a correlation between haemoglobin Al and HDL cholesterol,757" although Lopes-Virella et al.78 found an inverse relationship between haemoglobin AIc and HDL cholesterol in men and women with poor overall diabetic control (as defined by haemoglobin Alc and 24 hour glycosuria). In a study of 544 patients haemoglobin Al was negatively correlated with HDL cholesterol and positively correlated with the levels of total cholesterol, total triglycerides and LDL cholesterol.79 These relationships were not present in black women suggesting that race and gender may be independent determinants of serum lipids in insulin-dependent diabetics.
Lipid modifying drugs There have been few studies on the action of hypolipidaemic agents in insulin-dependent diabetes. Fibric acid derivatives have been advocated as the drug of choice for diabetic dyslipidaemia.80 In Type 1 diabetes, bezafibrate therapy caused a significant reduction in fasting blood glucose, VLDL cholesterol, serum triglycerides and apolipoprotein B.8' There was no overall change in HDL cholesterol, but in those patients who were initially hypertriglyceridaemic, there was a significant increase in the HDL2 subfraction. The use of fish oil containing omega 3 fatty acids has been reviewed recently82 and there is some evidence for a beneficial effect on vascular permeability,83 suggesting a possible prophylactic use of these agents in the prevention of atherogenesis. However, the results in other studies have not shown consistent benefits in lipid profiles. In a group of male patients84 therapy caused elevations of total cholesterol and apolipoprotein B. In a further study of female patients, a fall in plasma triglycerides and a rise in HDL cholesterol was noted.85 Additionally, the use of 3-omega fatty acids may be associated with a deterioration in glycaemic control.86 Further studies on these and other newer hypolipidaemic agents in insulin-dependent diabetes are needed. The aetiology of macrovascular disease in IDDM appears more complex than in NIDDM and its relationship to dyslipidaemia is less well defined, although this may not be the case for those IDDM patients with proteinuria. The use of lipid-modifying drugs in both NIDDM and IDDM is considered in detail in another article in this series by Paul
Durrington (this issue, pp. 947-952).
DIABETES: TREATMENT AND SERUM LIPIDS
935
References 1. Pyorala, K. & Laakso, M. Macrovascular disease in diabetes mellitus. In: Mann, JI., Pyorala, K. & Teuscher, A. (eds), Diabetes in Epidemiological Perspective. Churchili Livingstone: Edinburgh, 1983, pp. 183-247. 2. The Lipid Research Clinic Program. The Lipid Research Clinics Coronary Primary Prevention Study Trial Results II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA 1984, 251: 365-374. 3. Frick, M.H., Elo, O., Happa, K. et al. Helsinki Heart Study: primary prevention trial with Gemfibrozil in middle-aged men with dyslipidaemia. NEngl JMed 1987, 317:1237-1245. 4. Blankenhorn, D.H., Nessim, S.A., Johnson, R.L., Sanmarco, M.E., Azen, S.P. & Cashin-Hemphill, L. Beneficial effects of combined Colestipol-Niacin therapy on coronary atherosclerosis and coronary venous bypass grafts. JAMA 1987, 257: 3233-3240. 5. Krannel, W.B. & McGee, D.L. Diabetes and cardiovascular disease. The Framingham Study. JAMA 1979, 241: 20352038. 6. Panzram, G. Mortality and survival in Type 2 (non-insulin dependent) diabetes. Diabetologia 1987, 30: 123-131. 7. Santen, R.J., Willis, P.W., Fajans, S.S. & Arbor, A. Atherosclerosis in diabetes mellitus. Correlations with serum lipid levels, adiposity and serum insulin level. Arch Intern Med 1972, 130: 833-843. 8. Seviour, P.W., Teal, T.K., Richmond, W.R. & Elkeles, R.S. Serum lipids and macrovascular disease in non-insulin dependent diabetics: A possible new approach to prevention. Diabetic Med 1988, 5: 166-171. 9. Reckless, J.P.D., Betteridge, D.J., Wu, P., Payne, B. & Galton, D.J. High density and low density lipoproteins and prevalence of vascular disease in diabetes mellitus. Br Med J 1978, 1: 883-886. 10. Laakso, M., Ronnemaa, T., Pyorala, K., Kallio, V., Puukka, P. & Penttila, I. Atherosclerotic vascular disease and its risk factors in non-insulin dependent diabetic and non-diabetic subjects in Finland. Diabetes Care 1988, 11: 449-463. 11. Janka, H.U. Five year incidence of major macrovascular complications in diabetes mellitus. Horm Metab Res 1985, 15 (Suppl): 15-19. 12. Fontbonne, A., Eschwege, E., Cemblen, F. et al. Hypertriglyceridaemia as a risk factor for coronary heart disease mortality in patients with impaired glucose tolerance or diabetes. Results from the eleven year follow up of the Paris Prospective Study. Diabetologia 1989, 32: 300-304. 13. Gordon, E., Casteli, W.P., Hjortland, M.C., Kannel, W.B. & Dawber, T.R. Diabetes, blood lipids, and the role of obesity in coronary heart disease risk for women. Arch Intern Med 1977, 137: 393-397. 14. Rosengren, A., Welin, L., Tsipogianni, A. & Wilhelmsen, L. Impact of cardiovascular risk factors on coronary heart disease and mortality among middle aged diabetic men: a general population study. Br Med J 1989, 299: 1127-1131. 15. Reaven, G.M. Non-insulin dependent diabetes mellitus, abnormal lipoprotein metabolism and atherosclerosis. Metabolism 1987, 36 (Suppl 1): 1-8. 16. Walden, C.E., Knopp, R.H., Wahl, P.W., Beach, K.W. & Strandness, E. Sex differences in the effect ofdiabetes mellitus on lipoprotein triglyceride and cholesterol concentrations. N Engl J Med 1984, 311: 953-959. 17. Kennedy, L., Walshe, K., Hadden, D.R., Weaver, J.A. & Buchanan, K.D. The effect of intensive dietary therapy on serum high density lipoprotein cholesterol in patients with type 2 (non-insulin dependent) diabetes mellitus, A prospective study. Diabetologia 1982, 23: 24-27. 18. Taylor, K.G., John, W.G., Matthews, K.A. & Wright, A.D. A prospective study of 12 months treatment on serum lipids and apolipoproteins A-1 and B in type 2 (non-insulin dependent) diabetes. Diabetologia 1982, 23: 507-510.
19. Riccardi, G., Rivellese, A., Pacioni, D., Genovese, S., Mastranzo, P. & Mancini, M. Separate influence of dietary carbohydrate and fibre on the metabolic control in diabetes. Diabetologia 1984, 26: 116-121. 20. Coulston, A.M., Hollenbeck, C.H., Swislocki, A.L.M. & Reaven, G.M. Deleterious metabolic effects of high carbohydrate, sucrose containing diets in patients with non-insulin dependent diabetes mellitus. Am J Med 1987, 82: 213-220. 21. Lalor, B.C., Bhatnager, D., Winocour, P.H. et al. Placebocontrolled trial of the effects on guar gum and Metformin on fasting blood glucose and serum lipids in obese, type 2 diabetic patients. Diabetic Med 1990, 7: 242-245. 22. Fuessl, H.S., Williams, G., Adrian, T.E. & Bloom, S.R. Guar sprinkled on food: effect on glycaemic control, plasma lipids and gut hormones in non-insulin dependent diabetic patients. Diabetic Med 1987, 4: 463-468. 23. Hockaday, T.D.R. Controversies in Therapeutics. Fibre in management of diabetes. 1. Natural fibre useful as a part of total dietary prescription. Br Med J 1990, 300: 1334-1336. 24. Tattersall, R. & Mansell, P. Controversies in Therapeutics. Fibre in the management ofdiabetes. 2. Benefits of fibre itself are uncertain. Br Med J 1990, 300: 1336-1337. 25. Garg, A., Bonanome, A., Grundy, S., Zhang, Z. & Ungar, R.H. Comparison of a high carbohydrate diet with a high mono-unsaturated fat diet in patients with non-insulin dependent diabetes mellitus. N Engl J Med 1988, 319: 629-634. 26. University Group Diabetes Program. A study of the effects of hypoglycaemic agents on vascular complications in patients with adult-onset diabetes. Diabetes 1970, 19 (Suppl 2). 27. Kilo, C., Miller P & Williamson, J.R The crux of the UGDP: spurious results and biologically inappropriate data analysis. Diabetologia 1980, 18: 179-185. 28. Fuller, J.H. Clinical trials in diabetes mellitus. In: Mann, J.I. et al. (eds) Diabetes in Epidemiological Perspective. Churchill Livingstone: Edinburgh, 1983, pp. 265-285. 29. Berry, E.M. & Bar-On, H. Comparison of sulphonylurea and insulin treatment on lipid levels in maturity-onset diabetic men and women. Isr J Med Sci 1981, 17: 384-387. 30. Calvert, G.D., Graham, J.J., Mannik, T., Wise, P.H. & Yeates, R.A. Effects of therapy on plasma- high-densitylipoprotein-cholesterol concentration in diabetes mellitus. Lancet 1978, if: 66-68. 31. Lisch, H.-J. & Sailer, S. Lipoprotein patterns in diet, sulphonylurea and insulin treated diabetics. Diabetologia 1981, 20: 118-122. 32. Paisey, R., Elkeles, R.S., Hambley, J. & Magill, P. The effects of chlorpropamide and insulin on serum lipids, lipoproteins and fractional triglyceride removal. Diabetologia 1978, 15: 81-85. 33. Greenfield, M.S., Doberne, L., Rosenthal, M., Vreman, H.J. & Reaven, G.M. Lipid metabolism in non-insulin diabetes mellitus. Effect of glipizide therapy. Arch Intern Med 1982, 142: 1498-1500. 34. Rains, S.G.H., Wilson, G.A., Richmond, W. & Elkeles, R.S. The effect of glibenclamide and metformin on serum lipoproteins in type 2 diabetes. Diabetic Med 1988, 5: 653-658. 35. Falko, J.M. & Ossei, K. Combination insulin/Glyburide therapy in type II diabetes mellitus. Am J Med 1985, 79 (Suppl 3B): 92- 101. 36. Seviour, P.W., Teal, T.K., Richmond, W. & Elkeles, R.S. Chlorpropamide lowers serum and lipoprotein cholesterol in insulin-dependent diabetes. Diabetic Med 1986, 3: 152-154. 37. Baynes, C., Feher, M. & Elkeles, R.S. The effect of treatment of non-insulin dependent diabetes mellitus on serum lipids and lipoproteins. Q J Med 1989, 72: 579-587. 38. Rains, S.G.H., Wilson, G.A., Richmond, W. & Elkeles, R.S. The reduction of low density lipoprotein cholesterol by metformin is maintained with long-term therapy. J R Soc Med 1989, 82: 93-94.
936
P.K. MERRIN & R.S. ELKELES
39. Wu, M.-S., Johnston, P., Sheu, W.H.-H. et al. Effect of metformin on carbohydrate and lipoprotein metabolism in NIDDM patients. Diabetes Care 1990, 13: 1-8. 40. Sirtori, C.R., Tremoli, E., Sirtori, M., Conti, F. & Paoletti, R. Treatment of hypertriglyceridaemia with metformin. Effectiveness and analysis of results. Atherosclerosis 1977, 26: 583-592. 41. Hollenbeck, C.H., Chen, Y.I., Greenfield, M.S., Lardinois, C.K. & Reaven, G.M. Reduced high density lipoprotein cholesterol concentrations need not increase when hyperglycaemia is controlled with insulin in non-insulin dependent diabetes mellitus. J Clin Endocrinol Metab 1986, 62: 605-608. 42. Lindstrom, T., Arnqvist, H.J. & Olsson, A.G. Effect of different insulin regimes on plasma lipoprotein and apolipoprotein concentrations in patients with non-insulin dependent diabetes mellitus. Atherosclerosis 1990, 81: 137-144. 43. Garg, A. & Grundy, S. Lovastatin for lowering cholesterol levels in non-insulin dependent diabetes mellitus. N Engl J Med 1988, 318: 81-86. 44. Goldberg, R., La Belle, P., Zupkis, R. & Ronca, P. Comparison of the effects of Lovastatin and Gemfibrozil on lipids and glucose control in non-insulin dependent diabetes mellitus. Am J Cardiol 1990, 66: 16B-21B. 45. Entmacher, P.S., Rout, H.F. & Marks, H.H. Longevity of diabetic patients in recent years. Diabetes 1964, 13: 373-377. 46. Jarrett, R.J. Risk factors of macrovascular disease in diabetes mellitus. Horm Metab Res 1985, 15 (Suppl): 1-3. 47. Dupree, E.A. & Meyer, M.B. Role of risk factors in complications ofdiabetes mellitus. Am JEpidemiol 1980, 112: 100-112. 48. Krolewski, A.S., Kosinski, E.J., Warram, J.H. et al. Magnitude and determinants of coronary artery disease in juvenile-onset, insulin-dependent diabetes mellitus. Am J Cardiol 1987, 59: 750-755. 49. Jensen, T., Borch-Johnsen, K., Kofoed-Enevoldsen, A. & Deckert, T. Coronary heart disease in young type 1 (insulindependent) diabetic patients with and without diabetic nephropathy: incidence and risk factors. Diabetologia 1987, 30: 144-148. 50. Stamler, J., Wentworth, D., Neaton, J., Schoenberger, J.A. & Feigal, D. for the MRFIT Research Group. Diabetes and risk of coronary, cardiovascular and all causes mortality: findings for 356,000 men screened by the Multiple Risk Factor Intervention Trial (MRFIT). Circulation 1984, 70 (Suppl 2): 161. 51. Nikkila, E.A. & Hormila, P. Serum lipids and lipoproteins in insulin-treated diabetes. Demonstration of increased high density lipoprotein concentrations. Diabetes 1978, 27: 1078- 1086. 52. Winocour, P.H., Durrington, P.N., Ishola, M., Hillier, V.F. & Anderson, D.C. The prevalence of hyperlipidaemia and related clinical features in insulin-dependent diabetes mellitus. Q J Med NS 1989, 70: 265-276. 53. Nikkila, E.A. High density lipoproteins in diabetes. Diabetes 1981, 30 (Suppl 2): 82-87. 54. Laakso, M., Voutilainen, E., Aro, A., Pyorala, K. & Penttila, I. Inverse relationship of serum HDL and HDL2 cholesterol to C-peptide level in middle aged insulin treated diabetics. Metabolism 1985, 34: 715-720. 55. Eckel, R.H., Albers, J.J., Cheung, M.C., Wahl, P.W., Lindgren, F.T. & Bierman, E.L. High density lipoprotein composition in insulin-dependent diabetes mellitus. Diabetes 1981, 30: 132-138. 56. Winocour, P.H., Ishola, M., Durrington, P.N. & Anderson, D.C. Lipoprotein abnormalities in insulin-dependent diabetes mellitus. Lancet 1986, i: 1176- 1178. 57. Vannini, P., Ciavarella, A., Flammini, M. et al. Lipid abnormalities in insulin-dependent diabetic patients with albuminuria. Diabetes Care 1984, 7: 151-154. 58. Jones, S.L., Close, C.F., Mattock, M.B., Jarrett, R.J., Keen, H. & Viberti, G.C. Plasma lipid and coagulation factor concentrations in insulin dependent diabetics with microalbuminuria. Br Med J 1989, 298: 487-490.
59. Borch-Johnsen, K., Anderson, P.K. & Deckert, T. The effect of proteinuria on relative mortality in type 1 (insulindependent) diabetes mellitus. Diabetologia 1985, 28: 590596. 60. Borch-Johnsen, K. & Kreiner, S. Proteinuria: value as a predictor of cardiovascular mortality in insulin dependent diabetes mellitus. Br Med J 1987, 294: 1651-1654. 61. Winocour, P.H., Durrington, P.N., Ishola, M., Anderson, D.C. & Cohen, H. Influence of proteinuria on vascular disease, blood pressure, and lipoproteins in insulin-dependent diabetes mellitus. Br Med J 1987, 294: 1648-1651. 62. Bierman, E.L., Amaral, A.P. & Belknap, B.H. Hyperlipidaemia and diabetes mellitus. Diabetes 1966, 15: 675-679. 63. Bagdade, J.D., Porte, D. Jr & Bierman, E.L. Diabetic lipaemia: a form of acquired fat-induced lipaemia. N Engl J Med 1967, 276: 427-433. 64. Weidman, S.W., Ragland, J.B., Fisher, J.N., Kitabchi, A.E. & Sabesin, S.M. Effects of insulin on plasma lipoproteins in diabetic ketoacidosis: evidence for a change in high density lipoprotein composition during treatment. J Lipid Res 1982, 23: 171-182. 65. Lopes-Virella, M.F., Wohltmann, H.J., Mayfield, R.K., Loadholt, C.B. & Colwell, J.A. Effect of metabolic control on lipid, lipoprotein, and apolipoprotein levels in 55 insulindependent diabetic patients. A longitudinal study. Diabetes 1983, 32: 20-25. 66. Pietri, A., Dunn, F.L. & Raskin, P. The effect of improved diabetic control on plasma lipid and lipoprotein levels: a comparison of conventional therapy and continuous subcutaneous insulin infusion. Diabetes 1980, 29: 1001-1005. 67. Falko, J.M., O'Dorisio, T.M. & Cataland, S. Improvement of high density lipoprotein-cholesterol levels. Ambulatory type I diabetics treated with the subcutaneous insulin pump. JAMA 1982, 247: 37-39. 68. Dunn, F.L., Pietri, A. & Raskin, P. Plasma lipid and lipoprotein levels with continuous subcutaneous insulin infusion in type I diabetes mellitus. Ann Intern Med 1981, 95: 426-431. 69. James, R.W. & Pometta, D. Differences in lipoprotein subfraction composition and distribution between type 1 diabetic men and control subjects. Diabetes 1990, 39: 1158-1164. 70. Kaufmann, R.L., Assal, J.Ph., Soeldner, J.S. et al. Plasma lipids in diabetic children. Effect of diet restricted in cholesterol and saturated fats. Diabetes 1975, 24: 672-679. 71. Hollenbeck, C.B., Connor, W.E., Riddle, M.C., Alaupovic, P. & Lecklem, J.E. The effects of a high-carbohydrate, low-fat, cholesterol restricted diet on plasma lipids, lipoprotein and apoprotein concentrations in insulin-dependent (type 1) diabetes mellitus. Metabolism 1985, 34: 559-566. 72. Stone, D. & Connor, W.E. The prolonged effects of a low-cholesterol, high carbohydrate diet upon serum lipids in diabetic patients. Diabetes 1963, 12: 127-132. 73. Jenkins, D.J.A., Wolever, T.M.S., Taylor, R.H., Reynolds, D., Nineham, R. & Hockaday, T.D.R. Diabetic glucose control, lipids and trace elements on long term guar. Br MedJ 1980, 280: 1353-1354. 74. Sosenko, J.M., Breslow, J.L., Miettinen, O.S. & Gabbay, K.H. Hyperglycaemia and plasma lipid levels. A prospective study of young insulin-dependent diabetic patients. N Engi J Med 1980, 302: 650-654. 75. Ostlund, R.E., Semenkovich, C.F. & Schechtman, K.B. Quantitative relationship between plasma lipids and glycohemoglobin in type I patients. Longitudinal study of 212 patients. Diabetes Care 1989, 12: 332-336. 76. Elkeles, R.S., Wu, J. & Hambley, J. Haemoglobin Al, blood glucose and high density lipoprotein cholesterol in insulinrequiring diabetics. Lancet 1978, i{: 547-549. 77. Gonen, B., White, N., Schonfeld, G., Skor, D., Miller, P. & Santiago, J. Plasma levels of apoprotein B in patients with diabetes mellitus: the effect of glycaemic control. Metabolism 1985, 34: 675-679.
DIABETES: TREATMENT AND SERUM LIPIDS 78. Lopes-Virella, M.F., Wohltmann, H.J., Loadholt, C.B. & Buse, M.G. Plasma lipids and lipoproteins in young insulindependent diabetic patients: relationship with control. Diabetologia 1981, 21: 216-223. 79. Semenkovitch, C.F., Ostlund, R.E. & Schechtman, K.B. Plasma lipids in patients with type I diabetes mellitus. Influence of race, gender, and plasma glucose controls: Lipids do not correlate with glucose control in black women. Arch Intern Med 1989, 149: 51-56. 80. Winocour, P.H. & Laker, M.F. Drug therapy for diabetic dyslipoproteinaemia: a practical approach. Diabetic Med 1990, 7: 292-298. 81. Winocour, P.H., Durrington, P.N., Bhatnagar, D. et al. Double blind placebo-controlled study on the effects of bezafibrate on blood lipids, lipoproteins, and fibrinogen in hyperlipidaemic type I diabetes mellitus. Diabetic Med 1990, 7: 736-743.
937
82. Editorial. Fish oils and diabetic microvascular disease. Lancet 1990, 1: 508-509. 83. Jensen, T., Stender, S., Goldstein, K. et al. Partial normalisation by dietary cod liver oil of decreased microvascular albumin leakage in patients with insulin-dependent diabetes and albuminuria. N Engl J Med 1989, 321: 1572-1577. 84. Mori, T.A., Vandongen, R. & Maserei, J.R.L. Fish oilinduced changes in apolipoproteins in IDDM subjects. Diabetes Care 1990, 13: 725-732. 85. Bagdade, J.D., Buchanan, W.E., Levy, R.A., Subbaiah, P.V. & Ritter, M.C. Effects of w-3 fish oils on plasma lipids, lipoprotein composition and postheparin lipoprotein lipase in women with IDDM. Diabetes 1990, 39: 426-431. 86. Stacpoole, P.W., Alig, J., Ammon, L. & Crockett, S.E. Dose-response effects of dietary marine oil on carbohydrate and lipid metabolism in normal subjects and patients with hypertriglyceridaemia. Metabolism 1989, 38: 946-956.
