Dm
ORIGINAL ARTICLES
Risk Factors for Peripheral Vascular Disease in Hypertensive Subjects with Type 2 Diabetes Mellitus J.C. Alcolado, P.J. Pacy, M. Beevers, P.M. Dodson Diabetes Unit, East Birmingham Hospital, Birmingham, UK
Possible factors predisposing to peripheral vascular disease (PVD) in hypertensive subjects with Type 2 diabetes mellitus were studied. Details of age, sex, duration of diabetes, blood pressure, and smoking habit were recorded in 180 subjects of either White, West Indian Black or Asian ethnic origin. Clycosylated haemoglobin, fasting serum total cholesterol, total high density lipoprotein (HDL), HDLZ, low density lipoprotein (LDL-cholesterol), and triglycerides were measured in all subjects. Peripheral vascular disease was defined as an anklelbrachial systolic pressure < 1.O as measured by the Doppler technique. Multivariate analysis was performed and the following factors were identified as being strongly associated with the presence of PVD with a statistical significance of p < 0.001; LDLcholesterol, total HDL-cholesterol, age, male sex, diet or oral hypoglycaemic therapy, diastolic blood pressure, and of p < 0.003; systolic blood pressure. When blood pressure was excluded from the analysis the other factors retained their predictive value. We conclude that hypertension and dyslipidaemia are important risk factors for peripheral vascular disease in Type 2 diabetes mellitus. KEY WORDS
Type 2 diabetes Peripheral vascular disease Complications
Introduction Peripheral vascular disease (PVD) is a common cause of morbidity in subjects with diabetes mellitus. Intermittent claudication is often followed by critical limb ischaemia, ischaemic ulceration, and the requirement for amputation.’ Recently attention has focused on the importance of hypertension as a risk factor for diabetic complications. In Type 1 (insulin-dependent) diabetes, hypertension often occurs in conjunction with nephropathy and may be a manifestation of the abnormal renal function rather than its cause. In Type 2 (non-insulin-dependent)diabetes mellitus, Reaven and others have suggested that hypertension may be directly related to hyperinsulinaemia and insulin r e s i ~ t a n c e . ~ ~ In the presence of hypertension, the risk of peripheral vascular disease in patients with Type 2 diabetes increases ~ubstantially.~ If the Reaven hypothesis is correct, insulin treatment of these patients could potentially increase the risk of peripheral vascular disease. Several other factors may modulate the development of macrovascular disease including smoking, total cholesterol and lipoprotein subtypes, serum triglycerides, duration of diabetes, and diabetic control.6 A few studies have examined risk factors for PVD in Early studies did not consider Type 2 diabetic lipoprotein subfractionslo and there has been a lack of uniformity in defining peripheral vascular disease. Absent foot pulses, intermittent claudication or ischaemic ulcerCorrespondence to: Dr J.C. Alcolado, Diabetic Unit, East Birmingham Hospital, Bordesley Green East, Birmingham, U.K.
904
0742-3071 I921100904-04$07.00
0 1992 by John Wiley & Sons,
Ltd.
ation may all occur at differing stages of the disease. In the present study we rely on the measurement of the ankle/brachial systolic pressure ratio (ankle pressure index, API) in an attempt to define an earlier and more objective stage of peripheral vascular disease.”,12 In subjects without peripheral vascular disease the systolic pressure measured at the ankle is normally greater than the brachial pressure and the API > 1 . In peripheral vascular disease the ankle systolic pressure falls and the API is reduced. However, sclerotic or calcified, noncompressible arteries in the lower limbs will lead to a falsely elevated API and this phenomenon is more common in patients with diabetes.l3 Although this phenomenon will lead to an underestimate of the prevalence and severity of peripheral vascular disease in the study population, we believe the API to be a better indicator of vascular disease than clinical assessment alone. The aim of the present study was to examine the role of potential risk factors in hypertensive subjects with Type 2 diabetes and peripheral vascular disease defined by objective laboratory measurements of lower limb arterial pressures.
Patients and Methods All subjects with Type 2 diabetes mellitus attending hospital out-patient clinics were interviewed as part of a study designed to determine the ethnic prevalence of hypertension in diabetes. All subjects met WHO diagnostic criteria.14 Age, sex, duration of diabetes, and smoking habit were recorded. Systemic arterial pressure was Accepted 23 July 1992 DIABETIC MEDICINE, 1992; 9: 904-907
Drn
ORIGINAL ARTICLES
recorded with the Hawksley random zero sphygmomanometer with appropriate cuff size. A total of 180 hypertensive (systolic pressure >160, diastolic pressure > 90 mmHg) subjects with Type 2 diabetes thus identified gave informed consent for further study. Venous blood samples were obtained from subjects following a 12 h fast. Glycosylated haemoglobin (HbA,,) was measured by affinity chromatography. LDL cholesterol was measured by the sodium dodecyl sulphate precipitation method, total HDL-cholesterol by heparin manganese chloride precipitation and HDL2-cholesterol by low molecular weight dextran precipitation (Boehringer lngelheim Ltd, Berkshire, UK). Ankle systolic pressure was recorded ultrasonographically by the Doppler phenomenon. Ankle systolic pressure was defined as the pressure recording when a doppler signal returned on deflation of an occluding cuff placed above the malleoli.” The ankle pressure index (API) was calculated by dividing the ankle pressure by the brachial systolic pressure measured with the randomzero sphygmomanometer. Subjects were divided into one of two groups depending on the API. Subjects with an API < 1 were considered to have peripheral vascular disease. Statistical analysis was repeated using an API < 0.9, with no difference in the results. It should be appreciated that some patients with lower limb vessel sclerosis may have had falsely elevated APls and this may have led to an underestimate of true peripheral vascular disease.
Statistical Analysis
Table 2. Clinical features of study group With PVD (n= 75)
Without PVD (n= 105)
31 34 12
36 45 30
Smoking habit Never Current Previous
58 13 6
77 24 9
Insulin treated (%)
20
21
Anti hypertensives
52
42
Racial origin
White West Indian Black Asian
ResuI ts Clinical details of all subjects recruited by racial group are shown in Table 1. There were significantly more females amongst the West Indian Black group than in the Asian group ( p < 0.01). Both Asian and Black groups tended to be younger than Whites. Smoking, insulin treatment and use of hypotensive agents were least common amongst Asians although this did not reach statistical significance by the Chi-square test. Doppler studies revealed 75 patients with an API < 1.O (42 %). The remaining 105 subjects were considered free of significant peripheral vascular disease, although some may have had non-compressible arteries confounding the assessment. Comparisons between subjects with and without PVD were made (Tables 2 and 3). By the test, subjects with PVD tended to be older and have a higher systolic arterial pressure than those free of this diabetic complication; however no statistically significant difference was found in racial origin, smoking or insulin treatment between subjects with and without PVD. Multivariate analysis identified the following factors as strongly associated with PVD in hypertensive Type 2 subjects; LDL-cholesterol, total HDL-cholesterol, age, male sex, non-insulin treatment, diastolic arterial press-
x2
Chi-square analysis of sex, duration of diabetes, insulin treatment, ideal body weight, HbA,,, cigarette smoking, and the use of hypotensive agents was performed between subjects in the three racial groups with and without PVD. Multivariate analysis (Wilks lambda) was performed of HbA,, LDL-cholesterol, HDL-cholesterol, age, sex, insulin treatment, brachial systolic and brachial diastolic pressures in all 180 hypertensive subjects with Type 2 diabetes and with or without PVD.
Table 1. Clinical details of the hypertensive Type 2 diabetic patients studied ~
White Total (male) Age (years) Insulin treated (%)
ideal body weight (%) HbAlc (%) Cigarette smoking (%) Hypotensive agents (%)
67 (36) 57.5 f 8.5 20.9 132.2 +- 22.9 11.4 ? 3.2 29.9 46.3
Black 79 55.8 ? 25.3 130.5 11.3 15.2 48.1
(32)” 5.5b
* 20.2 * 3.7
Asian 42 51.7 11.9 126.2 -C 11.6 ? 11.9 33.3
*
(29) 6.6‘ 17.0 3.0
Mean f SD. Difference examined Chi-square with Yates correction if required. p < 0.01 difference between Blacks and Asians. p < 0.01 difference between Blacks and Asians. p < 0.001 difference between Asians and Whites.
a
PVD HYPERTENSION AND TYPE 2 DIABETES
905
Dm
ORIGINAL ARTICLES Table 3. Details of patients with (Doppler ratio disease
Age (years)” Sex (M) Ideal body weight (%) Duration of disease HbA,, (%) Cholesterol (mmol I-’) Triglycerides (mmol I-,) Total HDL (mmol IF1) LDL-cholesterol HDL2-subfraction Systolic BP (mmHg)b Diastolic BP (mmHg)
< 1.0) and without peripheral vascular
With PVD (n=75)
Without PVD (n= 105)
56.9 (55-58) 33 130.2 (125-1 34) 6.3 (5-8) 10.9 (10.2-1 1.5) 6.1 (5.7-6.5) 1.7 (1.5-2.0) 1.35 (1.3-1.44) 3.1 (2.8-3.4) 0.42 (0.3-0.47) 183.7 (177-189) 97.2 (94-100)
54.5 (53-55.6) 60 129.3 (125-1 33) 5.6 (4.5-7.0) 11.8 (11.&12.5) 5.8 (5.5-6.1) 2.0 (1.5-2.6) 1.38 (1.3-1.5) 2.7 (2.6-3.0) 0.43 (0.38-1.76) 172.5 (1 68-1 76) 99.8 (97-102)
Results as mean (95 % confidence intervals) or as shown p < 0.05, by Chi-square; p < 0.01, by Chi-square.
a
ure, and systolic arterial pressure (Table 4). When blood pressure was excluded from the analysis, the other factors retained their predictive value. A lower glycosylated haemoglobin (HbA,,) value was associated with the presence of PVD. When the sexes were analysed separately, all factors were similarly predictive except the lower HbA1, which only reached significance in women.
Discussion This study has examined the role of a number of potential risk factors in the development of PVD amongst hypertensive subjects with Type 2 diabetes mellitus. The use of laboratory measurementsto detect peripheral vascular disease may increase objectivity but in subjects with diabetes the API may be falsely elevated due to large vessel sclerosis. Some workers have attempted to overcome this problem by the measurement of toe pressures or analysis of the Doppler-velocity waveform.’ Increased serum total cholesterol, LDL-cholesterol and lower HDL-cholesterol were found to be associated with PVD. This finding is in keeping with associations previously described in diabetic subjects and non-diabetic control^.^ Thus lipid estimations may be useful clinically Table 4. Multivariate analysis of factors predicting the presence of peripheral vascular disease in the whole group Wilk’s lambda HbAk LDL-cholesterol Tota I H DL-choIestero I Age Sex Non-insulin treated Diastolic pressure Systolic pressure
906
0.882 0.867 0.858 0.851 0.845 0.839 0.907 0.949
Significance
p p p p p p p p
< 0.00001 < 0.00001 < 0.00001 < 0.00001 < 0.00001 < 0.00002 < 0.00002 < 0.002
to define a proportion of diabetic subjects at increased risk of macrovascular disease. However at present there is little evidence to suggest that normalizing dyslipidaemia will decrease the risk of PVD amongst diabetic subjects or improve blood flow once the peripheral circulation is compromised. Both systolic and diastolic arterial pressures were associated with PVD in this hypertensive group. Systolic pressure was more predictive than diastolic pressure. This observation is in keeping with the findings of other groups which suggest that systolic pressure may be a more important risk factor in atherosclerosis than diastolic pressure, especially in the elderly.“j Controversy still surrounds the importance of blood glucose control in the prevention and limitation of diabetic complications.’ Retrospective studies have suggested that a lower HbA,, i s associated with decreased prevalence of microvascular disease.18 Other studies have questioned the value of tight glycaemia control, especially once complications have become estab1 i ~ h e d . The l ~ present study has shown an association between a lower HbA,, and the presence of PVD although this did not reach statistical significance when males where analysed separately. The interpretation of this observation is unclear. Subjects with diabetes may be prompted into tighter blood glucose control when complications become manifest and therefore selective and cross-sectional studies of this sort are always liable to bias. Large prospective studies of Type 2 diabetes will be required to clarify the situation. Peripheral vascular disease in hypertensive Type 2 diabetes is associated with a number of risk factors amenable to therapeutic intervention. Prospective studies are currently under way and will define which treatment regimens are most likely to result in a reduction of this important complication. Until such studies are completed we advocate the pragmatic treatment of hypertension and dyslipidaemia in these subjects. J.C. ALCOLADO E l AL.
DTT7 References 1.
2.
3. 4.
5.
6.
Pecoraro RE, Reiber GE, Burgess EM. Pathways to diabetic limb amputation; Basis for prevention. Diabetes Care 1990; 13: 513-521. Reaven GM, Hollenbeck CB, Chen Y. Relationship between glucose tolerance, insulin secretion, and insulin action in non-obese individuals with varying degrees of glucose tolerance. Diabetologia 1989; 32: 52-55. Reaven GM, Barrett-Connor EL, Browner DK. Abnormal glucose tolerance and hypertension. Diabetes Care 1990; 13: 119-125. DeFronzo RA, Ferrannini E. Insulin resistance; A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidaemia and atherosclerotic cardiovascular disease. Diabetes Care 1991; 14: 173-1 94. 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. Pirart J. Diabetes mellitus and its degenerative complications; a prospective study of 4,400 patients observed bemeen 947 and 973. Diabetes Care 978; :
168-1 88. 7. Zirnrnerman BR, Palumbo PJ, O’Fallon WM, Ellefson RD, Osmundson PJ, Kazmier FJ. A prospective study of peripheral occlusive arterial disease in diabetes. Ill: Initial lipid and lipoprotein findings, Mayo Clin 981; 56: 233-242. 8. Beach KW, Brunzell JD, Conquest LL, Strandness DE. The correlation of arteriosclerosis obliterans with lipoproteins in insulin-dependent and non-insulin dependent diabetes. Diabetes 1979; 28: 836-840. 9. Laasko M, Pyoralla K. Lipid and lipoprotein abnormalities in diabetic patients with peripheral disease. Atherosclerosis 1988; 74: 55-63.
PVD HYPERTENSION A N D TYPE 2 DIABETES
ORIGINAL ARTICLES 10.
11.
12.
Welborn TA, Knuiman M, McCann V, Stanton K, Constable I]. Clinical macrovascular disease in Caucasoid diabetic subjects: logistic regression analysis of risk variables. Diabetologia 1984; 27: 568-573. Yao JST, Hobbs JT, lrvine WT. Ankle systolic pressure measurements in arterial disease affecting the lower extremities. Brit ) Surg 1969; 56: 676679. Goss DE, de Trafford J, Roberts VC, Flynn MD, Edmonds ME, Watkins PJ. Raised ankle/systolic pressure index in insulin-treated diabetic patients. Diabetic Med 1989; 6: --576-578.
Emanuele MA, Buchanan BJ, Abraira C. Elevated leg systolic pressures and arterial calcification in diabetic occlusive vascular disease. Diabetes Care 1981; 4: 289-292. 14. World Health Organisation Expert Committee on Diabetes Mellitus. Second Report. Technical Report Series 646. Geneva: World Health Organisation, 1980. Martin DCf 5. Beach KW, Bedford GR, Vandenberghe N, Zaccardi M, et a/. Progression of lowerextremity arterial occlusive disease in type II diabetes mellitus. Diabetes 1988; 11 : 464-472. 16. SHEP Co-operative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the systolic hypertension in the elderly program (SHEP). 1 Amer Med ASSOC 1991; 265: 3255-3264. 17. Rosenstock J, Raskin P. Diabetes and its complications; blood glucose control vs genetic susceptibility. Diabetes Metab Rev 1988; 4: 41 7-435. 18. Brinchmann-Hansen 0, Dahl-Jorgensen K, Sandvik L, Hansenn KF. Blood glucose concentrations and progression of diabetic retinopathy: the seven year results of the Oslo study. Brit Med ) 1992; 304: 19-22. 19. The KROC Collaborative Study Group. Diabetic retinopathy after two years of intensified insulin treatment. Follow UD of the KROC Collaborative Studv. I Amer Med Assoc 1988; 260: 37-41.
13.
907
ORIGINAL ARTICLES
Risk Factors for Peripheral Vascular Disease in Hypertensive Subjects with Type 2 Diabetes Mellitus J.C. Alcolado, P.J. Pacy, M. Beevers, P.M. Dodson Diabetes Unit, East Birmingham Hospital, Birmingham, UK
Possible factors predisposing to peripheral vascular disease (PVD) in hypertensive subjects with Type 2 diabetes mellitus were studied. Details of age, sex, duration of diabetes, blood pressure, and smoking habit were recorded in 180 subjects of either White, West Indian Black or Asian ethnic origin. Clycosylated haemoglobin, fasting serum total cholesterol, total high density lipoprotein (HDL), HDLZ, low density lipoprotein (LDL-cholesterol), and triglycerides were measured in all subjects. Peripheral vascular disease was defined as an anklelbrachial systolic pressure < 1.O as measured by the Doppler technique. Multivariate analysis was performed and the following factors were identified as being strongly associated with the presence of PVD with a statistical significance of p < 0.001; LDLcholesterol, total HDL-cholesterol, age, male sex, diet or oral hypoglycaemic therapy, diastolic blood pressure, and of p < 0.003; systolic blood pressure. When blood pressure was excluded from the analysis the other factors retained their predictive value. We conclude that hypertension and dyslipidaemia are important risk factors for peripheral vascular disease in Type 2 diabetes mellitus. KEY WORDS
Type 2 diabetes Peripheral vascular disease Complications
Introduction Peripheral vascular disease (PVD) is a common cause of morbidity in subjects with diabetes mellitus. Intermittent claudication is often followed by critical limb ischaemia, ischaemic ulceration, and the requirement for amputation.’ Recently attention has focused on the importance of hypertension as a risk factor for diabetic complications. In Type 1 (insulin-dependent) diabetes, hypertension often occurs in conjunction with nephropathy and may be a manifestation of the abnormal renal function rather than its cause. In Type 2 (non-insulin-dependent)diabetes mellitus, Reaven and others have suggested that hypertension may be directly related to hyperinsulinaemia and insulin r e s i ~ t a n c e . ~ ~ In the presence of hypertension, the risk of peripheral vascular disease in patients with Type 2 diabetes increases ~ubstantially.~ If the Reaven hypothesis is correct, insulin treatment of these patients could potentially increase the risk of peripheral vascular disease. Several other factors may modulate the development of macrovascular disease including smoking, total cholesterol and lipoprotein subtypes, serum triglycerides, duration of diabetes, and diabetic control.6 A few studies have examined risk factors for PVD in Early studies did not consider Type 2 diabetic lipoprotein subfractionslo and there has been a lack of uniformity in defining peripheral vascular disease. Absent foot pulses, intermittent claudication or ischaemic ulcerCorrespondence to: Dr J.C. Alcolado, Diabetic Unit, East Birmingham Hospital, Bordesley Green East, Birmingham, U.K.
904
0742-3071 I921100904-04$07.00
0 1992 by John Wiley & Sons,
Ltd.
ation may all occur at differing stages of the disease. In the present study we rely on the measurement of the ankle/brachial systolic pressure ratio (ankle pressure index, API) in an attempt to define an earlier and more objective stage of peripheral vascular disease.”,12 In subjects without peripheral vascular disease the systolic pressure measured at the ankle is normally greater than the brachial pressure and the API > 1 . In peripheral vascular disease the ankle systolic pressure falls and the API is reduced. However, sclerotic or calcified, noncompressible arteries in the lower limbs will lead to a falsely elevated API and this phenomenon is more common in patients with diabetes.l3 Although this phenomenon will lead to an underestimate of the prevalence and severity of peripheral vascular disease in the study population, we believe the API to be a better indicator of vascular disease than clinical assessment alone. The aim of the present study was to examine the role of potential risk factors in hypertensive subjects with Type 2 diabetes and peripheral vascular disease defined by objective laboratory measurements of lower limb arterial pressures.
Patients and Methods All subjects with Type 2 diabetes mellitus attending hospital out-patient clinics were interviewed as part of a study designed to determine the ethnic prevalence of hypertension in diabetes. All subjects met WHO diagnostic criteria.14 Age, sex, duration of diabetes, and smoking habit were recorded. Systemic arterial pressure was Accepted 23 July 1992 DIABETIC MEDICINE, 1992; 9: 904-907
Drn
ORIGINAL ARTICLES
recorded with the Hawksley random zero sphygmomanometer with appropriate cuff size. A total of 180 hypertensive (systolic pressure >160, diastolic pressure > 90 mmHg) subjects with Type 2 diabetes thus identified gave informed consent for further study. Venous blood samples were obtained from subjects following a 12 h fast. Glycosylated haemoglobin (HbA,,) was measured by affinity chromatography. LDL cholesterol was measured by the sodium dodecyl sulphate precipitation method, total HDL-cholesterol by heparin manganese chloride precipitation and HDL2-cholesterol by low molecular weight dextran precipitation (Boehringer lngelheim Ltd, Berkshire, UK). Ankle systolic pressure was recorded ultrasonographically by the Doppler phenomenon. Ankle systolic pressure was defined as the pressure recording when a doppler signal returned on deflation of an occluding cuff placed above the malleoli.” The ankle pressure index (API) was calculated by dividing the ankle pressure by the brachial systolic pressure measured with the randomzero sphygmomanometer. Subjects were divided into one of two groups depending on the API. Subjects with an API < 1 were considered to have peripheral vascular disease. Statistical analysis was repeated using an API < 0.9, with no difference in the results. It should be appreciated that some patients with lower limb vessel sclerosis may have had falsely elevated APls and this may have led to an underestimate of true peripheral vascular disease.
Statistical Analysis
Table 2. Clinical features of study group With PVD (n= 75)
Without PVD (n= 105)
31 34 12
36 45 30
Smoking habit Never Current Previous
58 13 6
77 24 9
Insulin treated (%)
20
21
Anti hypertensives
52
42
Racial origin
White West Indian Black Asian
ResuI ts Clinical details of all subjects recruited by racial group are shown in Table 1. There were significantly more females amongst the West Indian Black group than in the Asian group ( p < 0.01). Both Asian and Black groups tended to be younger than Whites. Smoking, insulin treatment and use of hypotensive agents were least common amongst Asians although this did not reach statistical significance by the Chi-square test. Doppler studies revealed 75 patients with an API < 1.O (42 %). The remaining 105 subjects were considered free of significant peripheral vascular disease, although some may have had non-compressible arteries confounding the assessment. Comparisons between subjects with and without PVD were made (Tables 2 and 3). By the test, subjects with PVD tended to be older and have a higher systolic arterial pressure than those free of this diabetic complication; however no statistically significant difference was found in racial origin, smoking or insulin treatment between subjects with and without PVD. Multivariate analysis identified the following factors as strongly associated with PVD in hypertensive Type 2 subjects; LDL-cholesterol, total HDL-cholesterol, age, male sex, non-insulin treatment, diastolic arterial press-
x2
Chi-square analysis of sex, duration of diabetes, insulin treatment, ideal body weight, HbA,,, cigarette smoking, and the use of hypotensive agents was performed between subjects in the three racial groups with and without PVD. Multivariate analysis (Wilks lambda) was performed of HbA,, LDL-cholesterol, HDL-cholesterol, age, sex, insulin treatment, brachial systolic and brachial diastolic pressures in all 180 hypertensive subjects with Type 2 diabetes and with or without PVD.
Table 1. Clinical details of the hypertensive Type 2 diabetic patients studied ~
White Total (male) Age (years) Insulin treated (%)
ideal body weight (%) HbAlc (%) Cigarette smoking (%) Hypotensive agents (%)
67 (36) 57.5 f 8.5 20.9 132.2 +- 22.9 11.4 ? 3.2 29.9 46.3
Black 79 55.8 ? 25.3 130.5 11.3 15.2 48.1
(32)” 5.5b
* 20.2 * 3.7
Asian 42 51.7 11.9 126.2 -C 11.6 ? 11.9 33.3
*
(29) 6.6‘ 17.0 3.0
Mean f SD. Difference examined Chi-square with Yates correction if required. p < 0.01 difference between Blacks and Asians. p < 0.01 difference between Blacks and Asians. p < 0.001 difference between Asians and Whites.
a
PVD HYPERTENSION AND TYPE 2 DIABETES
905
Dm
ORIGINAL ARTICLES Table 3. Details of patients with (Doppler ratio disease
Age (years)” Sex (M) Ideal body weight (%) Duration of disease HbA,, (%) Cholesterol (mmol I-’) Triglycerides (mmol I-,) Total HDL (mmol IF1) LDL-cholesterol HDL2-subfraction Systolic BP (mmHg)b Diastolic BP (mmHg)
< 1.0) and without peripheral vascular
With PVD (n=75)
Without PVD (n= 105)
56.9 (55-58) 33 130.2 (125-1 34) 6.3 (5-8) 10.9 (10.2-1 1.5) 6.1 (5.7-6.5) 1.7 (1.5-2.0) 1.35 (1.3-1.44) 3.1 (2.8-3.4) 0.42 (0.3-0.47) 183.7 (177-189) 97.2 (94-100)
54.5 (53-55.6) 60 129.3 (125-1 33) 5.6 (4.5-7.0) 11.8 (11.&12.5) 5.8 (5.5-6.1) 2.0 (1.5-2.6) 1.38 (1.3-1.5) 2.7 (2.6-3.0) 0.43 (0.38-1.76) 172.5 (1 68-1 76) 99.8 (97-102)
Results as mean (95 % confidence intervals) or as shown p < 0.05, by Chi-square; p < 0.01, by Chi-square.
a
ure, and systolic arterial pressure (Table 4). When blood pressure was excluded from the analysis, the other factors retained their predictive value. A lower glycosylated haemoglobin (HbA,,) value was associated with the presence of PVD. When the sexes were analysed separately, all factors were similarly predictive except the lower HbA1, which only reached significance in women.
Discussion This study has examined the role of a number of potential risk factors in the development of PVD amongst hypertensive subjects with Type 2 diabetes mellitus. The use of laboratory measurementsto detect peripheral vascular disease may increase objectivity but in subjects with diabetes the API may be falsely elevated due to large vessel sclerosis. Some workers have attempted to overcome this problem by the measurement of toe pressures or analysis of the Doppler-velocity waveform.’ Increased serum total cholesterol, LDL-cholesterol and lower HDL-cholesterol were found to be associated with PVD. This finding is in keeping with associations previously described in diabetic subjects and non-diabetic control^.^ Thus lipid estimations may be useful clinically Table 4. Multivariate analysis of factors predicting the presence of peripheral vascular disease in the whole group Wilk’s lambda HbAk LDL-cholesterol Tota I H DL-choIestero I Age Sex Non-insulin treated Diastolic pressure Systolic pressure
906
0.882 0.867 0.858 0.851 0.845 0.839 0.907 0.949
Significance
p p p p p p p p
< 0.00001 < 0.00001 < 0.00001 < 0.00001 < 0.00001 < 0.00002 < 0.00002 < 0.002
to define a proportion of diabetic subjects at increased risk of macrovascular disease. However at present there is little evidence to suggest that normalizing dyslipidaemia will decrease the risk of PVD amongst diabetic subjects or improve blood flow once the peripheral circulation is compromised. Both systolic and diastolic arterial pressures were associated with PVD in this hypertensive group. Systolic pressure was more predictive than diastolic pressure. This observation is in keeping with the findings of other groups which suggest that systolic pressure may be a more important risk factor in atherosclerosis than diastolic pressure, especially in the elderly.“j Controversy still surrounds the importance of blood glucose control in the prevention and limitation of diabetic complications.’ Retrospective studies have suggested that a lower HbA,, i s associated with decreased prevalence of microvascular disease.18 Other studies have questioned the value of tight glycaemia control, especially once complications have become estab1 i ~ h e d . The l ~ present study has shown an association between a lower HbA,, and the presence of PVD although this did not reach statistical significance when males where analysed separately. The interpretation of this observation is unclear. Subjects with diabetes may be prompted into tighter blood glucose control when complications become manifest and therefore selective and cross-sectional studies of this sort are always liable to bias. Large prospective studies of Type 2 diabetes will be required to clarify the situation. Peripheral vascular disease in hypertensive Type 2 diabetes is associated with a number of risk factors amenable to therapeutic intervention. Prospective studies are currently under way and will define which treatment regimens are most likely to result in a reduction of this important complication. Until such studies are completed we advocate the pragmatic treatment of hypertension and dyslipidaemia in these subjects. J.C. ALCOLADO E l AL.
DTT7 References 1.
2.
3. 4.
5.
6.
Pecoraro RE, Reiber GE, Burgess EM. Pathways to diabetic limb amputation; Basis for prevention. Diabetes Care 1990; 13: 513-521. Reaven GM, Hollenbeck CB, Chen Y. Relationship between glucose tolerance, insulin secretion, and insulin action in non-obese individuals with varying degrees of glucose tolerance. Diabetologia 1989; 32: 52-55. Reaven GM, Barrett-Connor EL, Browner DK. Abnormal glucose tolerance and hypertension. Diabetes Care 1990; 13: 119-125. DeFronzo RA, Ferrannini E. Insulin resistance; A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidaemia and atherosclerotic cardiovascular disease. Diabetes Care 1991; 14: 173-1 94. 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. Pirart J. Diabetes mellitus and its degenerative complications; a prospective study of 4,400 patients observed bemeen 947 and 973. Diabetes Care 978; :
168-1 88. 7. Zirnrnerman BR, Palumbo PJ, O’Fallon WM, Ellefson RD, Osmundson PJ, Kazmier FJ. A prospective study of peripheral occlusive arterial disease in diabetes. Ill: Initial lipid and lipoprotein findings, Mayo Clin 981; 56: 233-242. 8. Beach KW, Brunzell JD, Conquest LL, Strandness DE. The correlation of arteriosclerosis obliterans with lipoproteins in insulin-dependent and non-insulin dependent diabetes. Diabetes 1979; 28: 836-840. 9. Laasko M, Pyoralla K. Lipid and lipoprotein abnormalities in diabetic patients with peripheral disease. Atherosclerosis 1988; 74: 55-63.
PVD HYPERTENSION A N D TYPE 2 DIABETES
ORIGINAL ARTICLES 10.
11.
12.
Welborn TA, Knuiman M, McCann V, Stanton K, Constable I]. Clinical macrovascular disease in Caucasoid diabetic subjects: logistic regression analysis of risk variables. Diabetologia 1984; 27: 568-573. Yao JST, Hobbs JT, lrvine WT. Ankle systolic pressure measurements in arterial disease affecting the lower extremities. Brit ) Surg 1969; 56: 676679. Goss DE, de Trafford J, Roberts VC, Flynn MD, Edmonds ME, Watkins PJ. Raised ankle/systolic pressure index in insulin-treated diabetic patients. Diabetic Med 1989; 6: --576-578.
Emanuele MA, Buchanan BJ, Abraira C. Elevated leg systolic pressures and arterial calcification in diabetic occlusive vascular disease. Diabetes Care 1981; 4: 289-292. 14. World Health Organisation Expert Committee on Diabetes Mellitus. Second Report. Technical Report Series 646. Geneva: World Health Organisation, 1980. Martin DCf 5. Beach KW, Bedford GR, Vandenberghe N, Zaccardi M, et a/. Progression of lowerextremity arterial occlusive disease in type II diabetes mellitus. Diabetes 1988; 11 : 464-472. 16. SHEP Co-operative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the systolic hypertension in the elderly program (SHEP). 1 Amer Med ASSOC 1991; 265: 3255-3264. 17. Rosenstock J, Raskin P. Diabetes and its complications; blood glucose control vs genetic susceptibility. Diabetes Metab Rev 1988; 4: 41 7-435. 18. Brinchmann-Hansen 0, Dahl-Jorgensen K, Sandvik L, Hansenn KF. Blood glucose concentrations and progression of diabetic retinopathy: the seven year results of the Oslo study. Brit Med ) 1992; 304: 19-22. 19. The KROC Collaborative Study Group. Diabetic retinopathy after two years of intensified insulin treatment. Follow UD of the KROC Collaborative Studv. I Amer Med Assoc 1988; 260: 37-41.
13.
907
