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Effects of slow release bezafibrate on the lipid pattern and on blood glucose of type 2 diabetic patients with hyperlipidaemia
Pharmacological Research, Vol. 25, No. 3, 1992
237
EFFECTS OF SLOW RELEASE BEZAFIBRATE ON THE LIPID PATTERN AND ON BLOOD GLUCOSE OF TYPE 2 DIABETIC PATIENTS WITH HYPERLIPIDAEMIA A. ROVELLINI, D. SOMMARIVA*, A. BRANCHI, F. MARAFFIt, C. MONTALTOt, R. GANDINI? and A. FASOLI
Institute of lnternal Medicine and Medical Physiopathology, University of Milan, Italy; *Department of Medicine, Ospedale di Bollate, Milan, Italy; tCentro Ricerche Aterosclerosi e Nutrizione, Department of Medicine, Ospedale V. Buzzi, Milan, Italy Received in final form 10 September 1991
SUMMARY Ninety-eight type 2 diabetic patients with hyperlipidaemia in stable metabolic control with diet alone (41) or diet plus hypoglycaemic agents (57) were divided into two groups: group 1 was put on treatment with slow release bezafibrate 400 mg a day, while group 2 was considered as control. In group 1, after 1 month of bezafibrate, serum triglycerides fell by 47% and cholesterol by 13%. HDL cholesterol showed a non-significant trend toward an increase. Fasting blood glucose significantly decreased by 6%, fructosamine and glycated haemoglobin by 5%. During OGTT, the area under the curve of both serum C-peptide and blood glucose showed a trend toward a decrease after bezafibrate. However, the difference did not reach statistical significance. Thirty-six patients continued the treatment with the drug for 4 months and 23 for 8 months, without further changes of the lipid pattern and glycaemic control. In the control group no significant variation of the lipid levels occurred and diabetic control slightly worsened during the study. Bezafibrate has been proved to be effective in the treatment of hyperlipidaemia in type 2 diabetic patients. The drug seems moreover to improve glycaemic control. The mechanism by which bezafibrate produces this latter effect remains to be elucidated, though an increase of peripheral insulin sensitivity might be suggested. KEY WORDS: diabetes mellitus, hyperlipidaemia, bezafibrate, glucose metabolism.
Correspondence to: Dr. A. Rovellini, Institute of Internal Medicine and Medical Physiopathology, University of Milan, via F. Sforza 35, 20122 Milan, Italy. 1043-6618/92/030237-09/$03.00/0
© 1992 The Italian Pharmacological Society
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INTRODUCTION Dyslipidaemia is frequently seen in type 2 diabetes mellitus [1, 2]. Elevated levels of serum triglycerides and less commonly of serum cholesterol are often present in poorly controlled diabetes and the improvement of metabolic control is generally followed by a normalization of lipid pattern [3]. In many diabetic patients, however, dyslipidaemia is observed in spite of good glycaemic control, suggesting the presence of a genetic predisposition to lipoprotein abnormality [4]. In this case, a specific lipid-lowering therapy may be advisable in order to prevent atherosclerosis, which is the main cause of death in the diabetic population [5]. Data from the Framingham study show evidence that the presence of multiple independent risk factors for atherosclerosis, such as diabetes and dyslipidaemia, increases the overall risk of cardiovascular events in a more than additive way [6]. In these conditions the serum lipid levels, at which pharmacological lipid lowering treatment may be advisable, are lower than in non-diabetic patients and in dyslipidaemic patients without other atherosclerotic risk factors [7, 8]. In planning lipid lowering therapy, attention must be paid to the choice of drugs, which should be effective, safe and without adverse effects on glucose metabolism. The aim of the present study was to assess the effects of bezafibrate, a lipid lowering drug [9, 10], on lipid pattern and glucose tolerance in non-insulindependent diabetic patients with hyperlipidaemia.
PATIENTS AND M E T H O D S Ninety-eight non-insulin-dependent diabetic patients with hyperlipidaemia were recruited for the study. The patients were in stable metabolic control for more than 2 months before entering the study. The antidiabetic therapy (in 41 patients' diet alone and in 57 diet plus oral hypoglycaemic agent) was not changed during the overall period of the study. The patients, after a run-in period of at least 2 months, were divided into two groups. The groups were comparable for age (64+2.5 and 66+2.9 years in groups 1 and 2 respectively), sex (24 males and 26 females in group 1 and 21 males and 28 females in group 2), body mass index (25.4+1.2 and 25.6+1.3), duration of diabetes (8+2.3 and 8+3.6 years respectively), antidiabetic therapy (22 in diet alone and 28 in oral hypoglycaemic agents in group 1 and 19 in diet and 29 in oral hypoglycaemic agents in group 2) and lipoprotein phenotypes (17 type IIa, 10 type IIb and 23 type IV in group 1 and 19 type IIa, 8 type IIb and 21 type IV in group 2). The patients of group 1 were put on treatment with slow release bezafibrate 400mg a day after the evening meal, while the patients of group 2 were considered as controls. The patients of both groups were followed in the same way. At each visit (-2, 0, +1, +4 and +8 months), blood samples were drawn for determination of total and HDL cholesterol, serum triglycerides and blood glucose (Miles Italiana S.p.A., Cavenago Brianza, Italy), fructosamine (Roche S.p.A., Milan, Italy) and glycated haemoglobin (HPLC, Biorad Lab., Richmond, USA). OGTT (50 g of glucose) was performed in 18 subjects of group 1 before and after 1 month of bezafibrate treatment. Blood glucose and serum C-peptide
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(R.I.A., Biodata, Milan, Italy) were determined at 0, 30, 60, 90, 120 min during the glucose test. Statistical analysis was performed by Student's t-test for paired and unpaired data and by linear regression analysis.
RESULTS During the study nine patients dropped out, five in group 1 (one for headache, two for nausea and two for causes unrelated to bezafibrate treatment) and four in group 2. In the remaining 45 patients of the bezafibrate group, while no changes in lipid and glycaemic parameters occurred before the start of bezafibrate, after 1 month of treatment with the drug triglycerides fell on the average by 47% and total cholesterol by 13%. HDL-cholesterol showed only a non-significant trend towards an increase. Fasting blood glucose significantly decreased by 6%, fructosamine and glycated haemoglobin by 5% (Table I). The decrease of serum lipids was not significantly correlated with the change of blood sugar, of fructosamine and of glycated haemoglobin. Mean values of lipids, fasting blood sugar, fructosamine and glycated haemoglobin did not change further in 36 patients treated with bezafibrate for 4 months (Table II) and in 23 patients treated with the drug for 8 months (Table III). In group 2 no significant variation of the lipid pattern was observed during the period of the study (Tables I, II, III), while glycated proteins showed, on average, a small but significant increase at the fourth month of observation (Table II).
Table I Mean (±SEM) serum lipids, fasting blood sugar and glycated proteins in the bezafibrate group (45 patients) and in the cOntrol group (44 patients) before and 1 month after the beginning of the treatment Bezafibrate group -2 months
basal
+1 month
Serum cholesterol 267+7.80 279_+7.60 2 4 4 + (mg/dl) 6.10"* HDL-cholesterol 42_+1.60 42+1.70 44+1.30 (mg/dl) Serum 276+_30.1 288_+28.6 152+ triglycerides 10.4"** (mg/dl) Blood glucose 154+5.90 161_+6.00 151+ (mg/dl) 5.90" Fructosamine 3.02_+0.08 2.95_+0.08 2.81-+0.05 (mmol/l) Glycated 7.79_+0.18 7.62_+0.16 7.25_+ haemoglobin (%) 0.14"* Body weight (kg) 69.41_+1.60 69.4-+1.60 68.6+1.54 Student's t-test for paired data. *P<0.05, **P<0.01, ***P<0.001 versus basal value.
Control group -2 months
basal
+1 month
262_+7.10 257_+7.10 254_+7.20 43-+1.30 43-+1.40 43+1.20 261+27.2 251_+29.6 257_+29.0 159-+5.00 163+7.50 158-+6.20 2.93+0.05 2.91+_0.05 2.99_+0.05 7.80+0.18 7.79-+0.18 7.98_+0.17 71.9_+1.89 71.8_+1.88 72.2_+1.96
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Table II Mean +(sE~a) serum lipids, fasting blood sugar and glycated proteins in the bezafibrate group (36 patients) and in the control group (33 patients) before and 1 and 4 months after the beginning of the study Bezafibrate group basal
Serum cholesterol (mg/dl) HDL-cholesterol (mg/dl) Serum triglycerides (mg/dl) Blood glucose (mg/dl) Fructosamine (rnmol/1) Glycated haemoglobin (%) Body weight (kg)
1 month
basal
I month
4 months
243-+ 237-+ 6.90** 5.90*** 44_+1.60 46-+1.50
259+8.60
255_+8.10
261-+8.80
272+29.7
142_+ 9.90***
157-+ 10.9"**
241-+30.6
165-+6.60
7.63+0.17
156+ 6.50* 2.82-+ 0.06** 7.30-+0.16
69.3+1.79
68.5_+1.72
156_+ 6.50* 2.79_+ 0.06** 7.24-+ 0.18"* 68.5+1.77
275_+8.20 43-+2.00
3.01-+0.08
4 months
Control group
42_+1.80
42-+1.20
42_+1.40
252-+31.1
245+29.9
160_+8.20 159_+7.70 170-+8.80 2.88-+0.04 7.77-+0.18 71.9+1.94
2.94_+ 3.03-+ 0.06* 0.06** 7.97_+ 8.02_+ 0.18" 0.20* 72.3_+2.04 72.0+2.03
Student's t-test for paired data. *P<0.05, **P<0.01, ***P<0.001 versus basal value.
Table III Mean _+(sE~a) serum lipids, fasting blood sugar and glycated proteins in the bezafibrate group (23 patients) and in the control group (19 patients) at the beginning of the study and 8 months thereafter Bezafibrate group basal
Serum cholesterol (mg/dl) HDL-cholesterol (mg/dl) Serum triglycerides (mg/dl) Blood glucose (mg/dl) Fructosamine (mmol/1) Glycated haemoglobin (%) Body weight (kg)
275_+11.9 44_+2.70
8 months
235_+8.00*** 49+2.30
Control group basal
8 months
261_+12.6
260_+12.1
44_+2.30
43-+1.70 256_+45.3
285_+44.3
153+16.4"**
252_+46.2
162_+7.80
142-+6.80"**
152-+12.9
2.99-+0.10
2.82_+0.07*
2.82_+0.07
160+ 10.1** 2.99_+0.08
7.66_+0.20
7.17-+0.22"*
7.79_+0.19
8.06-+0.23
69.3_+2.43
68.7-+2.61
70.7_+2.39
71.2+2.56
Student's t-test for paired data. *P
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Table IV Mean (+SEM) serum lipids, fasting blood sugar and glycated proteins in the bezafibrate-group (20 patients) before, after 8 months of bezafibrate and 2 months after the withdrawal of the drug and in the control group (17 patients) during the 10 months of the study Bezafibrate group
Serum cholesterol (mg/dl) HDL-cholesterol (mg/dl) Serum triglycerides (mg/dl) Blood glucose (mg/dl) Fructosamine (retool/l) Glycated haemoglobin (%) Body weight (kg)
basal
8 months
280+13.3
231_+10.2
44-+2.80 283_+46.8
Control group
withdrawal
52_+2.40 140_+16.5
basal
8 months
10 months
258_+ 261_+13.7 266_+12.9 261_+12.1 11.6" 45_+2.70 44_+2.60 43_+2.40 43±2.20 181_+ 18.6"*
254_+41.8 258_+44.7 250_+46.3
160-+7.30 125_+6.10
140_+ 156+10.0 159_+10.6 161_+10.7 6.40* 2.96-+0.09 2.79_+0.07 3 . 0 9 - + 2.85_+0.08 2.93_+0.08 2.96_+0.07 0.11" 7.64-+0.22 7.19+0.28 7,15_+0.27 7.76_+0.21 7.99+0.29 8.03_+0.27 69.1_+2.73 68.9_+2.70 69.1+2.78
70.3_+2.79 71.0_+2.84 71.3_+2.89
Student's t-test for paired data. *P<0.05, **P<0.01 versus 8th month value.
Twenty patients were studied again 2 months after withdrawal of bezafibrate. In these patients serum triglycerides significantly increased by 29%, serum cholesterol by 12%, fructosamine and blood glucose by 10% with respect to values recorded at the eighth month of therapy (Table IV). Figure 1 shows the results of O G T T in 18 patients (five with phenotype IIa, six with phenotype IIb and seven with phenotype IV) before and after 1 month of therapy with bezafibrate. Mean values of blood glucose and of serum C-peptide showed a non-significant trend toward a decrease after 1 month of bezafibrate. The area under the curve of blood glucose was 31 620+2110 mg-min-l.d1-1 before and 29 850_+1782 after bezafibrate (P=NS), the one of C-peptide was 629_+ 53.1 mmol.min~l.1-1 before and 600_+67.1 after the drug (P=NS). In this subgroup of patients, glycated haemoglobin decreased from 7.41_+0.32% to 6.94_+0.30% (P< 0.01), serum cholesterol from 287_+14.0 to 246_+9.30 mg/dl (P<0.001) and serum triglycerides from 304_+49.3 to 155_+12.40 mg/dl (P<0.001).
DISCUSSION Diabetes is a possible cause of dyslipidaemia [4], and, in turn, derangement of lipid metabolism may interfere with glucose utilization [11, 12]. Some data suggest in fact that high triglyceride levels prevent the binding of insulin to the
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242 350 -
300
250 E
200
150
I00
7
I
I
I
I
I O'
i 30'
I 60'
I 90'
I
m
6-
.c zL
5-
2 E
4-
3-
. . . . Before bezafibrofe
I 120'
After bezefibrofe
Fig. 1. Mean values of blood glucose and serum C-peptide during OGTT before and after 1 month of bezafibrate in 18 patients.
specific receptors [13] and an elevation of free fatty acids concentration results in a decrease or delay of glucose oxidation [11, 14]. This supports the hypothesis that hypolipidaemic agents with antilipolytic activity may be helpful in the treatment of diabetes mellitus. In accord with previous data [15, 16], our study shows that bezafibrate produces a highly significant decrease of serum triglycerides and cholesterol in non-insulindependent diabetic patients. Quite surprisingly HDL cholesterol did not increase significantly. The increasing effect of bezafibrate on HDL cholesterol level is well known [9] and is greater in patients with hypertriglyceridaemia than in patients with hypercholesterolaemia [17, 18]. In the present series too, HDL cholesterol significantly increased in hypertriglyceridaemic subjects (phenotype IIb and IV) and the difference loses the statistical significance when the overall series of patients (IIa, IIb and IV) is considered together. The hypolipidaemic effect of bezafibrate is associated with the improvement of glycaemic control. Both fasting blood glucose and glycated proteins were observed, in fact, to be lower during the treatment than before, while in the control group a worsening of metabolic control was observed during the study. The possibility that the improvement of the glycaemic control in the bezafibrate treated
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group was due to a greater compliance to diet and antidiabetic therapy in group 1 than in group 2 patients may be ruled out since the same experimental conditions have been applied in both groups. Moreover it is noteworthy that blood sugar and glycated proteins did not change during the run-in period before the beginning of bezafibrate treatment and the withdrawal of the drug after 8 months of treatment was followed by a signifcant increase of plasma glucose and fructosamine levels. Our data about the effects of bezafibrate on blood glucose control agree with previous studies: a glucose-lowering effect during short and medium term therapy with bezafibrate was in fact reported in patients with both impaired glucose tolerance and moderately or poorly controlled non-insulin-dependent diabetes mellitus [16, 19-22]. Nevertheless, Alberti et al. [23] and Durrington et al. [24] did not find a lowering effect of bezafibrate on glycated haemoglobin. This might be due to analytical problems [23] or a too short period of therapy in these studies; though our data show significant decrease of glycated proteins after only 1 month of therapy with bezafibrate, the greatest decrements are seen after 4 and 8 months. The mechanism by which bezafibrate improves glucose control in hyperlipidaemic diabetic patients is not known. Serum C-peptide levels during OGTT were not significantly different after 1 month of bezafbrate as compared with the pretreatment ones. Although the period of treatment was relatively short, it was sufficient to show possible effects of the drug on glucose tolerance and insulin secretion [25-27]. The lack of a significant difference in serum C-peptide levels suggests, however, that the reduction of blood glucose is not due to an increase of insulin production, all the more that the area under the curve of C-peptide showed a trend toward a diminution rather than an increase after bezafibrate, in parallel with a similar trend in blood glucose. It may thus be suggested that the improvement of glycaemic control is due to an increase of peripheral insulin sensitivity. Besides bezafibrate, other lipid lowering drugs have been shown to have positive effects on glucose metabolism in diabetics. Among them, the parent drug clofibrate [28], which has been demonstrated to potentiate the activity of oral hypoglycaemic agents by competing with their binding to serum proteins [29]. In our study the effects of bezafibrate in patients taking oral hypoglycaemic drugs and in patients treated only by diet were similar. Acipimox, a nicotinic acid derivative, has been demonstrated to lower blood sugar in diabetic patients under both dietary and pharmacological therapy [30, 31]. The fact that the same effect is shared by different drugs, such as bezafibrate and acipimox, may suggest a common mechanism of action, possibly linked to their hypolipidaemic activity. Thus, the effect on glucose metabolism by bezafibrate should be compatible with the hypothesis of a potentiation of insulin activity on glucose metabolism. The reduction of serum triglyceride levels might improve insulin-binding to cell receptors [13] and the decrease of plasma free fatty acids, a known effect of bezafibrate [9], might mediate an increase in insulin sensitivity by increasing insulin-stimulated glucose uptake [14] and by decreasing hepatic glucose production [32, 33]. In conclusion, the drug has been demonstrated to have positive effects on glucose and lipid metabolism, which can be useful in the prevention of atherosclerosis in non-insulin-dependent diabetic patients.
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ACKNOWLEDGEMENTS The authors wish to thank Ms. Elena Valenti for her skilful assistance in the preparation of the manuscript.
REFERENCES 1. Goldberg RB. Lipid disorders in diabetes. Diabetes Care 1981; 4/5:561-72. 2. Kannel WB, McGee D. Diabetes and cardiovascular disease. The Framingham Study. JAMA 1979; 241: 2035-41. 3. Howard B. Lipoprotein metabolism in diabetes mellitus. J Lipid Res 1987; 28: 613-28. 4. Reaven GM. Non insulin dependent diabetes mellitus, abnormal lipoprotein metabolism and atherosclerosis. Metabolism 1987; 36: 1-8. 5. Pyorala K, Loasko U, Uusitupa M. Diabetes and atherosclerosis: an epidemiological view. Diabetes Metab Rev 1987; 3: 463-71. 6. Kannel W. Lipids, diabetes and coronary heart disease: insights from the Framingham Study. Am Heart J 1985; 110:1100-9. 7. Study Group, European Atherosclerosis Society. Strategies for the prevention of coronary heart disease: a policy statement of the European Atherosclerosis Society. Eur Heart J 1987; 8: 77-88. 8. The Expert Panel. Report of the National Cholesterol Education Program Expert Panel on detection, evaluation and treatment of high blood cholesterol in adults. Arch Intern Med 1988; 148: 36-69. 9. Monk JP, Todd AP. Bezafibrate: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hyperlipidemia. Drugs 1987; 33: 539-76. 10. Abshagen U, Bablok W, Koch K, Lang PD, Schmidt HAE. Disposition pharmacokinetics of bezafibrate in man. Eur J Clin Pharmacol 1979; 16:31-38. 11. Randle PJ, Kerbey AL, Espimel J. Mechanisms of decreasing glucose oxidation in diabetes and starvation: role of lipid fuels and hormones. Diabetes Metab Rev 1988; 4: 623-7. 12. Steiner G. Hypertriglyceridemia and carbohydrate intolerance: interrelations and therapeutic implications. Am J Cardiol 1986; 57" 27G-30G. 13. Bathena S, Berlin E, Judd JT, et al. Dietary fat menstrual-cycle effects on the erythrocyte ghost insulin receptor in premenopausal women. Am J Clin Nutr 1989; 50: 460-4. 14. Fraze E, Donner CC, Swislockki ALM. Ambient plasma free fatty acid concentrations in non insulin dependent diabetes mellitus: evidence for insulin resistance. J Clin Endocrinol Metab 1985; 61: 807-11. 15. Rtith E, Vollmar J, Verbesserung der Diabeteseinstellung unter der Therapie mit Bezafibrat. Dtsch Med Wschr 1982; 107: 1470-3. 16. Bruneder H. Effects of bezafibrate on patients with diabetes mellitus and hyperlipoproteinemia: a controlled comparative study of bezafibrate, 'essential' phospholipids and placebo. In: Crepaldi G, Greten H, Schettler G, Baggio G, eds. Lipoprotein metabolism and therapy of lipid disorders. Amsterdam: Excerpta Medica, 1982; 209-11. 17. Gavish D, Osxhry Y, Fainaru M, Eisenberg S. Change in very low-, low-, and highdensity lipoproteins during lipid lowering (bezafibrate) therapy. Studies in type ITa and IIb hyperlipoproteinemia. Eur J Clin Invest 1986; 16: 61-8. 18. Olsson AG, R6ssner S, Walldius G, Carlson LA, Lang PD. Effect of BM 15.075 on lipoprotein concentrations in different types of hyperlipoproteinemia. Atherosclerosis 1977; 27: 279-87. 19. Wahl P, Hasslacher CH, Lang PD, Vollmar J. Der lipidsenkende Effekt von Bezafibrat bei Patienten mit Diabetes Mellitus und Hyperlipid~imie. Dtsch Med Wschr 1978; 103: 1233-7.
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20. Jones IR, Alberti KGMM. Reducing lipid concentration improves glycemic control in patients with non insulin dependent diabetes mellitus. Clin Res 1988; 36: 154A. 21. Janka HU, Standl A, Holler HD, Hehnert H. Kholenhydratstoff-wechsel unter Bezafibrat-Therapie. M~mch Med Wschr 1982; 124: 535-7. 22. Mikhailidis DP, Mathur S, Barradas MA, Dandona P. Bezafibrate Retard in type II diabetic patients: effects on hemostasis and glucose homostasis. J Cardiovasc Pharmacol 1990; 16 (Suppl 9): $26-$29. 23. Alberti KGMM, Jones IR, Laker MF, Swai ABM, Taylor R. Effect of bezafibrate on metabolic profiles in non-insulin-dependent diabetes mellitus. J Cardiovasc Pharmacol 1990; 16 (Suppl 9): $21-$25. 24. Durrington PN, Winocour PH, Bhatnagar D. Bezafibrate Retard in patients with insulindependent diabetes: effect on serum lipoproteins, fibrinogen, and glycemic control. J Cardiovasc Pharmacol 1990; 16 (Suppl 9): $30-$34. 25. Bertolini S, Cordera R, Marcenaro A, et al. Metabolic effects of gemfibrozil in patients with primary hypertrigliceridemia. Diabetes Nutr Metab 1990; 3: 23-33. 26. Pagani A, Dalmotto M, Pagano G, Boghen M, Lepore R. Effect of short-term gemfibrozil administration on glucose metabolism and insulin secretion in non-insulin-dependent diabetics. Curr Ther Res 1989; 45: 14-20. 27. Senderey. Effect of bezafibrate in non insulin dependent diabetics. In: Crepaldi G, Greten H, Schettler G, Baggio G, eds. Lipoprotein metabolism and therapy of lipid disorders. Amsterdam: Excerpta Medica, 1982: 204-8. 28. Lithell H, Boberg J, Hedstrand H, Hellsing K, Ljung S, Vessby B. Effects of clofibrate on glucose tolerance, serum insulin, serum lipoproteins and plasma fibrinogen. Eur J Clin Pharmacol 1977; 12: 51-6. 29. Daubresse JC, Lyckx AS, Lefevbre PJ. Potentiation of hypoglycemic effect of sulfonylureas by clofibrate. New Engl J Med 1976; 294: 613-17. 30. Regal H, Lageder H, Irsigler K. Effect of a single oral dose of acipomox on glucose utilization after intravenous glucose load in obese patients. Drugs Exp Clin Res 1984; 10: 621-5. 31. Fulcher GR, Walker M, Catalano C, Alberti KGMM. Overnight suppression of lipolysis with acipimox increases carbohydrate oxidation and lowers fasting blood glucose in type 2 (non insulin dependent) diabetes. Diabetologia 1988; 32: 489A. 32. Lancet. Type 2 diabetes or NIDDM: looking for a better name. Lancet 1989; i: 589-91. 33. Ferrannini E, Barrett EJ, Bevilacqua S, De Fronzo RA. Effect of fatty acids on glucose production and utilisation in man. J Clin Invest 1983; 72: 1737-47.
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EFFECTS OF SLOW RELEASE BEZAFIBRATE ON THE LIPID PATTERN AND ON BLOOD GLUCOSE OF TYPE 2 DIABETIC PATIENTS WITH HYPERLIPIDAEMIA A. ROVELLINI, D. SOMMARIVA*, A. BRANCHI, F. MARAFFIt, C. MONTALTOt, R. GANDINI? and A. FASOLI
Institute of lnternal Medicine and Medical Physiopathology, University of Milan, Italy; *Department of Medicine, Ospedale di Bollate, Milan, Italy; tCentro Ricerche Aterosclerosi e Nutrizione, Department of Medicine, Ospedale V. Buzzi, Milan, Italy Received in final form 10 September 1991
SUMMARY Ninety-eight type 2 diabetic patients with hyperlipidaemia in stable metabolic control with diet alone (41) or diet plus hypoglycaemic agents (57) were divided into two groups: group 1 was put on treatment with slow release bezafibrate 400 mg a day, while group 2 was considered as control. In group 1, after 1 month of bezafibrate, serum triglycerides fell by 47% and cholesterol by 13%. HDL cholesterol showed a non-significant trend toward an increase. Fasting blood glucose significantly decreased by 6%, fructosamine and glycated haemoglobin by 5%. During OGTT, the area under the curve of both serum C-peptide and blood glucose showed a trend toward a decrease after bezafibrate. However, the difference did not reach statistical significance. Thirty-six patients continued the treatment with the drug for 4 months and 23 for 8 months, without further changes of the lipid pattern and glycaemic control. In the control group no significant variation of the lipid levels occurred and diabetic control slightly worsened during the study. Bezafibrate has been proved to be effective in the treatment of hyperlipidaemia in type 2 diabetic patients. The drug seems moreover to improve glycaemic control. The mechanism by which bezafibrate produces this latter effect remains to be elucidated, though an increase of peripheral insulin sensitivity might be suggested. KEY WORDS: diabetes mellitus, hyperlipidaemia, bezafibrate, glucose metabolism.
Correspondence to: Dr. A. Rovellini, Institute of Internal Medicine and Medical Physiopathology, University of Milan, via F. Sforza 35, 20122 Milan, Italy. 1043-6618/92/030237-09/$03.00/0
© 1992 The Italian Pharmacological Society
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INTRODUCTION Dyslipidaemia is frequently seen in type 2 diabetes mellitus [1, 2]. Elevated levels of serum triglycerides and less commonly of serum cholesterol are often present in poorly controlled diabetes and the improvement of metabolic control is generally followed by a normalization of lipid pattern [3]. In many diabetic patients, however, dyslipidaemia is observed in spite of good glycaemic control, suggesting the presence of a genetic predisposition to lipoprotein abnormality [4]. In this case, a specific lipid-lowering therapy may be advisable in order to prevent atherosclerosis, which is the main cause of death in the diabetic population [5]. Data from the Framingham study show evidence that the presence of multiple independent risk factors for atherosclerosis, such as diabetes and dyslipidaemia, increases the overall risk of cardiovascular events in a more than additive way [6]. In these conditions the serum lipid levels, at which pharmacological lipid lowering treatment may be advisable, are lower than in non-diabetic patients and in dyslipidaemic patients without other atherosclerotic risk factors [7, 8]. In planning lipid lowering therapy, attention must be paid to the choice of drugs, which should be effective, safe and without adverse effects on glucose metabolism. The aim of the present study was to assess the effects of bezafibrate, a lipid lowering drug [9, 10], on lipid pattern and glucose tolerance in non-insulindependent diabetic patients with hyperlipidaemia.
PATIENTS AND M E T H O D S Ninety-eight non-insulin-dependent diabetic patients with hyperlipidaemia were recruited for the study. The patients were in stable metabolic control for more than 2 months before entering the study. The antidiabetic therapy (in 41 patients' diet alone and in 57 diet plus oral hypoglycaemic agent) was not changed during the overall period of the study. The patients, after a run-in period of at least 2 months, were divided into two groups. The groups were comparable for age (64+2.5 and 66+2.9 years in groups 1 and 2 respectively), sex (24 males and 26 females in group 1 and 21 males and 28 females in group 2), body mass index (25.4+1.2 and 25.6+1.3), duration of diabetes (8+2.3 and 8+3.6 years respectively), antidiabetic therapy (22 in diet alone and 28 in oral hypoglycaemic agents in group 1 and 19 in diet and 29 in oral hypoglycaemic agents in group 2) and lipoprotein phenotypes (17 type IIa, 10 type IIb and 23 type IV in group 1 and 19 type IIa, 8 type IIb and 21 type IV in group 2). The patients of group 1 were put on treatment with slow release bezafibrate 400mg a day after the evening meal, while the patients of group 2 were considered as controls. The patients of both groups were followed in the same way. At each visit (-2, 0, +1, +4 and +8 months), blood samples were drawn for determination of total and HDL cholesterol, serum triglycerides and blood glucose (Miles Italiana S.p.A., Cavenago Brianza, Italy), fructosamine (Roche S.p.A., Milan, Italy) and glycated haemoglobin (HPLC, Biorad Lab., Richmond, USA). OGTT (50 g of glucose) was performed in 18 subjects of group 1 before and after 1 month of bezafibrate treatment. Blood glucose and serum C-peptide
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(R.I.A., Biodata, Milan, Italy) were determined at 0, 30, 60, 90, 120 min during the glucose test. Statistical analysis was performed by Student's t-test for paired and unpaired data and by linear regression analysis.
RESULTS During the study nine patients dropped out, five in group 1 (one for headache, two for nausea and two for causes unrelated to bezafibrate treatment) and four in group 2. In the remaining 45 patients of the bezafibrate group, while no changes in lipid and glycaemic parameters occurred before the start of bezafibrate, after 1 month of treatment with the drug triglycerides fell on the average by 47% and total cholesterol by 13%. HDL-cholesterol showed only a non-significant trend towards an increase. Fasting blood glucose significantly decreased by 6%, fructosamine and glycated haemoglobin by 5% (Table I). The decrease of serum lipids was not significantly correlated with the change of blood sugar, of fructosamine and of glycated haemoglobin. Mean values of lipids, fasting blood sugar, fructosamine and glycated haemoglobin did not change further in 36 patients treated with bezafibrate for 4 months (Table II) and in 23 patients treated with the drug for 8 months (Table III). In group 2 no significant variation of the lipid pattern was observed during the period of the study (Tables I, II, III), while glycated proteins showed, on average, a small but significant increase at the fourth month of observation (Table II).
Table I Mean (±SEM) serum lipids, fasting blood sugar and glycated proteins in the bezafibrate group (45 patients) and in the cOntrol group (44 patients) before and 1 month after the beginning of the treatment Bezafibrate group -2 months
basal
+1 month
Serum cholesterol 267+7.80 279_+7.60 2 4 4 + (mg/dl) 6.10"* HDL-cholesterol 42_+1.60 42+1.70 44+1.30 (mg/dl) Serum 276+_30.1 288_+28.6 152+ triglycerides 10.4"** (mg/dl) Blood glucose 154+5.90 161_+6.00 151+ (mg/dl) 5.90" Fructosamine 3.02_+0.08 2.95_+0.08 2.81-+0.05 (mmol/l) Glycated 7.79_+0.18 7.62_+0.16 7.25_+ haemoglobin (%) 0.14"* Body weight (kg) 69.41_+1.60 69.4-+1.60 68.6+1.54 Student's t-test for paired data. *P<0.05, **P<0.01, ***P<0.001 versus basal value.
Control group -2 months
basal
+1 month
262_+7.10 257_+7.10 254_+7.20 43-+1.30 43-+1.40 43+1.20 261+27.2 251_+29.6 257_+29.0 159-+5.00 163+7.50 158-+6.20 2.93+0.05 2.91+_0.05 2.99_+0.05 7.80+0.18 7.79-+0.18 7.98_+0.17 71.9_+1.89 71.8_+1.88 72.2_+1.96
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Table II Mean +(sE~a) serum lipids, fasting blood sugar and glycated proteins in the bezafibrate group (36 patients) and in the control group (33 patients) before and 1 and 4 months after the beginning of the study Bezafibrate group basal
Serum cholesterol (mg/dl) HDL-cholesterol (mg/dl) Serum triglycerides (mg/dl) Blood glucose (mg/dl) Fructosamine (rnmol/1) Glycated haemoglobin (%) Body weight (kg)
1 month
basal
I month
4 months
243-+ 237-+ 6.90** 5.90*** 44_+1.60 46-+1.50
259+8.60
255_+8.10
261-+8.80
272+29.7
142_+ 9.90***
157-+ 10.9"**
241-+30.6
165-+6.60
7.63+0.17
156+ 6.50* 2.82-+ 0.06** 7.30-+0.16
69.3+1.79
68.5_+1.72
156_+ 6.50* 2.79_+ 0.06** 7.24-+ 0.18"* 68.5+1.77
275_+8.20 43-+2.00
3.01-+0.08
4 months
Control group
42_+1.80
42-+1.20
42_+1.40
252-+31.1
245+29.9
160_+8.20 159_+7.70 170-+8.80 2.88-+0.04 7.77-+0.18 71.9+1.94
2.94_+ 3.03-+ 0.06* 0.06** 7.97_+ 8.02_+ 0.18" 0.20* 72.3_+2.04 72.0+2.03
Student's t-test for paired data. *P<0.05, **P<0.01, ***P<0.001 versus basal value.
Table III Mean _+(sE~a) serum lipids, fasting blood sugar and glycated proteins in the bezafibrate group (23 patients) and in the control group (19 patients) at the beginning of the study and 8 months thereafter Bezafibrate group basal
Serum cholesterol (mg/dl) HDL-cholesterol (mg/dl) Serum triglycerides (mg/dl) Blood glucose (mg/dl) Fructosamine (mmol/1) Glycated haemoglobin (%) Body weight (kg)
275_+11.9 44_+2.70
8 months
235_+8.00*** 49+2.30
Control group basal
8 months
261_+12.6
260_+12.1
44_+2.30
43-+1.70 256_+45.3
285_+44.3
153+16.4"**
252_+46.2
162_+7.80
142-+6.80"**
152-+12.9
2.99-+0.10
2.82_+0.07*
2.82_+0.07
160+ 10.1** 2.99_+0.08
7.66_+0.20
7.17-+0.22"*
7.79_+0.19
8.06-+0.23
69.3_+2.43
68.7-+2.61
70.7_+2.39
71.2+2.56
Student's t-test for paired data. *P
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Table IV Mean (+SEM) serum lipids, fasting blood sugar and glycated proteins in the bezafibrate-group (20 patients) before, after 8 months of bezafibrate and 2 months after the withdrawal of the drug and in the control group (17 patients) during the 10 months of the study Bezafibrate group
Serum cholesterol (mg/dl) HDL-cholesterol (mg/dl) Serum triglycerides (mg/dl) Blood glucose (mg/dl) Fructosamine (retool/l) Glycated haemoglobin (%) Body weight (kg)
basal
8 months
280+13.3
231_+10.2
44-+2.80 283_+46.8
Control group
withdrawal
52_+2.40 140_+16.5
basal
8 months
10 months
258_+ 261_+13.7 266_+12.9 261_+12.1 11.6" 45_+2.70 44_+2.60 43_+2.40 43±2.20 181_+ 18.6"*
254_+41.8 258_+44.7 250_+46.3
160-+7.30 125_+6.10
140_+ 156+10.0 159_+10.6 161_+10.7 6.40* 2.96-+0.09 2.79_+0.07 3 . 0 9 - + 2.85_+0.08 2.93_+0.08 2.96_+0.07 0.11" 7.64-+0.22 7.19+0.28 7,15_+0.27 7.76_+0.21 7.99+0.29 8.03_+0.27 69.1_+2.73 68.9_+2.70 69.1+2.78
70.3_+2.79 71.0_+2.84 71.3_+2.89
Student's t-test for paired data. *P<0.05, **P<0.01 versus 8th month value.
Twenty patients were studied again 2 months after withdrawal of bezafibrate. In these patients serum triglycerides significantly increased by 29%, serum cholesterol by 12%, fructosamine and blood glucose by 10% with respect to values recorded at the eighth month of therapy (Table IV). Figure 1 shows the results of O G T T in 18 patients (five with phenotype IIa, six with phenotype IIb and seven with phenotype IV) before and after 1 month of therapy with bezafibrate. Mean values of blood glucose and of serum C-peptide showed a non-significant trend toward a decrease after 1 month of bezafibrate. The area under the curve of blood glucose was 31 620+2110 mg-min-l.d1-1 before and 29 850_+1782 after bezafibrate (P=NS), the one of C-peptide was 629_+ 53.1 mmol.min~l.1-1 before and 600_+67.1 after the drug (P=NS). In this subgroup of patients, glycated haemoglobin decreased from 7.41_+0.32% to 6.94_+0.30% (P< 0.01), serum cholesterol from 287_+14.0 to 246_+9.30 mg/dl (P<0.001) and serum triglycerides from 304_+49.3 to 155_+12.40 mg/dl (P<0.001).
DISCUSSION Diabetes is a possible cause of dyslipidaemia [4], and, in turn, derangement of lipid metabolism may interfere with glucose utilization [11, 12]. Some data suggest in fact that high triglyceride levels prevent the binding of insulin to the
Pharmacological Research, Vol. 25, No. 3, 1992
242 350 -
300
250 E
200
150
I00
7
I
I
I
I
I O'
i 30'
I 60'
I 90'
I
m
6-
.c zL
5-
2 E
4-
3-
. . . . Before bezafibrofe
I 120'
After bezefibrofe
Fig. 1. Mean values of blood glucose and serum C-peptide during OGTT before and after 1 month of bezafibrate in 18 patients.
specific receptors [13] and an elevation of free fatty acids concentration results in a decrease or delay of glucose oxidation [11, 14]. This supports the hypothesis that hypolipidaemic agents with antilipolytic activity may be helpful in the treatment of diabetes mellitus. In accord with previous data [15, 16], our study shows that bezafibrate produces a highly significant decrease of serum triglycerides and cholesterol in non-insulindependent diabetic patients. Quite surprisingly HDL cholesterol did not increase significantly. The increasing effect of bezafibrate on HDL cholesterol level is well known [9] and is greater in patients with hypertriglyceridaemia than in patients with hypercholesterolaemia [17, 18]. In the present series too, HDL cholesterol significantly increased in hypertriglyceridaemic subjects (phenotype IIb and IV) and the difference loses the statistical significance when the overall series of patients (IIa, IIb and IV) is considered together. The hypolipidaemic effect of bezafibrate is associated with the improvement of glycaemic control. Both fasting blood glucose and glycated proteins were observed, in fact, to be lower during the treatment than before, while in the control group a worsening of metabolic control was observed during the study. The possibility that the improvement of the glycaemic control in the bezafibrate treated
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group was due to a greater compliance to diet and antidiabetic therapy in group 1 than in group 2 patients may be ruled out since the same experimental conditions have been applied in both groups. Moreover it is noteworthy that blood sugar and glycated proteins did not change during the run-in period before the beginning of bezafibrate treatment and the withdrawal of the drug after 8 months of treatment was followed by a signifcant increase of plasma glucose and fructosamine levels. Our data about the effects of bezafibrate on blood glucose control agree with previous studies: a glucose-lowering effect during short and medium term therapy with bezafibrate was in fact reported in patients with both impaired glucose tolerance and moderately or poorly controlled non-insulin-dependent diabetes mellitus [16, 19-22]. Nevertheless, Alberti et al. [23] and Durrington et al. [24] did not find a lowering effect of bezafibrate on glycated haemoglobin. This might be due to analytical problems [23] or a too short period of therapy in these studies; though our data show significant decrease of glycated proteins after only 1 month of therapy with bezafibrate, the greatest decrements are seen after 4 and 8 months. The mechanism by which bezafibrate improves glucose control in hyperlipidaemic diabetic patients is not known. Serum C-peptide levels during OGTT were not significantly different after 1 month of bezafbrate as compared with the pretreatment ones. Although the period of treatment was relatively short, it was sufficient to show possible effects of the drug on glucose tolerance and insulin secretion [25-27]. The lack of a significant difference in serum C-peptide levels suggests, however, that the reduction of blood glucose is not due to an increase of insulin production, all the more that the area under the curve of C-peptide showed a trend toward a diminution rather than an increase after bezafibrate, in parallel with a similar trend in blood glucose. It may thus be suggested that the improvement of glycaemic control is due to an increase of peripheral insulin sensitivity. Besides bezafibrate, other lipid lowering drugs have been shown to have positive effects on glucose metabolism in diabetics. Among them, the parent drug clofibrate [28], which has been demonstrated to potentiate the activity of oral hypoglycaemic agents by competing with their binding to serum proteins [29]. In our study the effects of bezafibrate in patients taking oral hypoglycaemic drugs and in patients treated only by diet were similar. Acipimox, a nicotinic acid derivative, has been demonstrated to lower blood sugar in diabetic patients under both dietary and pharmacological therapy [30, 31]. The fact that the same effect is shared by different drugs, such as bezafibrate and acipimox, may suggest a common mechanism of action, possibly linked to their hypolipidaemic activity. Thus, the effect on glucose metabolism by bezafibrate should be compatible with the hypothesis of a potentiation of insulin activity on glucose metabolism. The reduction of serum triglyceride levels might improve insulin-binding to cell receptors [13] and the decrease of plasma free fatty acids, a known effect of bezafibrate [9], might mediate an increase in insulin sensitivity by increasing insulin-stimulated glucose uptake [14] and by decreasing hepatic glucose production [32, 33]. In conclusion, the drug has been demonstrated to have positive effects on glucose and lipid metabolism, which can be useful in the prevention of atherosclerosis in non-insulin-dependent diabetic patients.
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ACKNOWLEDGEMENTS The authors wish to thank Ms. Elena Valenti for her skilful assistance in the preparation of the manuscript.
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