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Factors associated with diabetic microangiopathy: A study of 157 type I (insulin-dependent) diabetic patients
Factors Associated Study of 157 Type Patients
Bernadette M. Billault Philippe L. Passa
Department of Diabetes (B. M. B., P. 1. P.), Saint Louis Hospital, and INSERM U 194 (B.M.B.), La Piti&Salp&ri&e Hospital, Paris, France
With Diabetic Microangiopathy: I (Insulin-Dependent) Diabetic
A
ABSTRACT The relation between poor glycemic control and the development of diabetic microangiopathy has long been recognized. However hy perglycemia alone cannot account for the striking heterogeneity of diabetic patients regarding the presence or absence of microangiopathic lesions. This study was therefore designed to determine the prevalence of retinopathy, nephropathy, and neuropathy, and to identify the factors respectively associated with these lesions. In 157 patients with type I (insulin-dependent) diabetes, the following parameters were recorded: sex, age, duration of diabetes, body mass index, fasting plasma glucose, HbA,,, blood pressure, antihypertensive treatment, tobacco consumption, urinary albumin excretion, plasma creatinine, and presence of retinopathy and neuropathy. One-half of these patients had retinopathy, 32% neuropathy, and 29% nephropathy. Patients with nephropathy exhibited concomitantly high prevalences of retinopathy (69%) and neuropathy (49%). Among patients with retinopathy, 39% had nephropathy; 79% of those with neuropathy had concomitant retinopathy. For each microangiopathic localization, patients with the disease had significantly higher values (p < 0.05) than those without for duration of diabetes, prevalence of hypertension, and systolic blood pressure. Stepwise logistic regression analysis showed that the following were independent predictive factors of each localization: for nephropathy, systolic blood pressure; for retinopathy, duration of diabetes; and for neuropathy, duration of diabetes, age, and HbA,,. (The Journal of Diabetic Complications 5;4:238-243, 1991.)
INTRODUCTION
Reprint requests to be sent to: Prof. Philippe L. Passa, Service de Diabbtologie, H6pital Saint Louis, 1 avenue Claude Vellefaux, 75010 Paris, France.
0 1991 Elsevier Science Publishing Co., Inc. 0891-6632/91/$3.50
238
Poor metabolic control is known to be related to the development of diabetic microangiopathy.’ However, striking differences are commonly observed between individual patients with respect to the presence or absence of microangiopathic lesions regardless of long-term metabolic controL2 Great disparities in the prevalence of retinopathy and heavy proteinuria were reported in the World Health Organization (WHO) Study,3 and it has been demonstrated that the association of deterioration in nerve function and the concomitant development of retinopathy and microalbuminuria was statistically independent of glycemia.4 In controlled studies, the long-term alleviation of hyperglycemia did not significantly alter the course of clinical nephropathy5 and led to controversial results for retinopathy.6-8 Consequently the pattern of occurrence and course of the various microangiopathic lesions indicate that hyperglycemia alone does not account for the observed heterogeneity. Microvascular complications appear to reflect complex interactions between poor metabolic control and genetic9~‘0 and/or environmental factors. This study was therefore designed to determine the prevalence of the three microangiopathic localizations and to identify the factors associated with these complications in a cohort of type I (insulin-dependent) diabetic patients who were regularly attending our clinic.
MICROANGIOPATHY
239
AN0 IODM
MATERIALSAND METHODS Patients The study was carried out in our diabetic clinic, which is a primary care unit, at St. Louis Hospital, Paris. The study was approved by the local ethics committee. All diabetic patients who were hospitalized from January 1st to May 1st 1988 and who fulfilled the following inclusion criteria were eligible: 1) negative C-peptide and on insulin treatment, and 2) regular follow-up in the department for at least 1 year. Excluded were pregnant women, patients on continuous subcutaneous insulin infusion, and patients suffering from serious diseases other than diabetes because of specific referral to the clinic for these patients. Patients with urinary tract infection documented by urine cultures and patients with a history of renal disease unrelated to diabetes were excluded because of possible enhancement in urinary albumin excretion regardless of the diabetic disease. None of the patients included was suffering from end-stage renal failure.
Procedures
is the present use in the literature. Patients with nephrop athy were then divided into those with incipient nephrog
athy (UAE 30-300 mg/24hr) and those with clinical nephropathy (UAE more than 300 mg!24 hr). Statldcal Analysk Statistical analyses were done using the BMDP statistical software package-l3 Results are expressed as mean f 1SD. Differences between groups were tested by Students t test for quantitative pararneters or by the chi-square test for qualitative variabks. Stepwise logistic regression analysis was performed to identify the factors independently associated with each microangiopathic localization. This method is used to test the contribution of a particular variabfe in predicting the outcome when other variabks are included in the model. The dependent variables were successively ne phropathy, retinopathy, and neuropathy. dichotomized to absent or present as defined in methods. The independent variables were sex, age, body mass index (BMI), duration of diabetes, HbA,,, fasting blood glucose, systolic blood pressure, diastolic blood pressure, and tobacco consumption. These variables were included in the model as continuous variables, except sex which was categorized. Arterial hypertension was not included in this analysis because we preferred to evaluate the specific influence of blood pressure values.
RESULTS
was evaluated as pack years (one pack year equals 20 cigarehes daily for one year). Blood pressure was recorded with a standard mercury sphygmomanometer after the patient had been in the recumbent position for at least 15 min. Systolic and diastolic blood pressure readings, from three separate occasions within the third day in the ward, were averaged and the mean used for the analysis. All measurements were made by the specially trained medical staff of the clinic. Arterial hypertension was diagnosed when systolic and/or diastolic values reached 160 and/or 95 mm Hg or more, or when the patient was on antihypertensive treatment.‘* Age was the current age at the time of examination. The duration of diabetes was taken as the period between age at diagnosis and age at time of examination. Neuropathy was evaluated from clinical neurological findings. No electrophysiological examination was performed. Clinical neuropathy was diagnosed on the basis of the absence of ankle tendon reflexes. Retinopathy was assessed by direct ophthalmoscopy through dilated pupils and fluorescein angiography. Patients were considered to be affected by retinopathy on the basis of background retinopathy defined by the presence of at least two microaneurysms at the posterior pole in one eve. For nephropathy, patients were divided into two groups according to their 24-hr UAE. Normoalbuminuria was defined as UAE less than 30 mg; diagnosis of nephropathy was considered when UAE was above 30 mg/24 hr, as it
Included in the study were 157 patients (see fable 1 for their main characteristics). The prevalence of the three microangiopathic lesions was as follows: nephropathy, 29% (incipient nephropathy or UAE 30-300 mg124 hr, 22%; clinical nephropathy or UAE greater than 300 mgl 24 hr, 7%), retinopathy, 50%, neuropathy, 32%. The associations of microangiopathic complications are shown in Figure 1. Of the patients with nephropathy, 69% also had retinopathy and 49% had neuropathy. However, only 39% of the patients with retinopathy had nephropathy. Of those with neuropathy, 79% had concomitant retinopathy. The probabilities (p) of developing all
TABLE 1
Main Characteristics of our Series of 157 Patients With Type I Diabetes Parameter
n (negative (-peptide) Sex (%, m/f) Age (yr) Diabetes duration (yr) Body mass index (kg/m’) Fasting plasma glucose (mmolk) HbA,c (%) Systolic BP (mm Hg) Diastolic BP (mm Hg) Arterial hypertensiona (%) Plasma creatinine (MmollL) Tobacco consumption (packyr)
Data 157 55145 41.6 ?I 15.3 13.5 2 10.9 22.9 I 3.7 9.6 ” 4.4 9.5 zk 2.4 126.7 2 18.3 76.9 k 10.3 22 91.0 2 29.9 8.7 2 14.6
Results are expressed as mean 2 1 SD. BP, blood pressure. e Arterial hypertension defined as blood pressure values of 160 mm Hg or more and/or 95 mm Hg or more, or presence of antihypertensive treatment.
FIG. 1 The associations of microangiopathic plications.
TABLE 2
com-
Characteristics of the Patients According to the Presence or Absence of Nephropathy (UAE Nephropethy Present 230 mg n = 45)
Sex (“9 m/f) Age (yr) Duration of diabetes (yr) Body mass index (kg/m2) Fasting plasma glucose (mmol/L) HbA,, (%) Systolic BP (mm Hg) Diastolic BP (mm Hg) Arterial hypertensiona Tobacco consumption (pack/yr)
.
60140 45.1 * 17.3 17.6 2 9.3 23.70 f 4.21 10.50 f 4.91 9.64 f 2.22 137.03 f 19.6 79.54 f 9.65 40.5% 10.4 f 17.2
(UAE Nephropathy Absent <30 mg n = 112)
Statistical Significance
53147 40.4 f 14.4 12.5 2 11.3 22.72 f 3.57 9.32 f 4.20 9.36 * 2.44 125.5 f 17.46 76.10 f 10.26 16.4% 6.2 t 13.6
p
p p p
NS NS < 0.005 NS NS NS < 0.001 < 0.05 < 0.005 NS
Results are expressed as mean 2 1 SD. UAE, urinary albumin excretion; BP, blood pressure. a Arterial hyptension defined as blood pressure values of 160 mm Hg or greater and/or 95 mm Hg or greater, or the presence of antihypertensive treatment.
TABLE 3
Characteristics of the Patients According to the Presence or Absence of Retinopathy Retinopathylyes
Sex (%, m/f) Age (yr) Duration of diabetes (yr) Body mass index (kg/m2) Fasting plasma glucose (mmol/L) HbA,, (%) Systolic BP (mm Hg) Diastolic BP (mm Hg) Arterial hypertensiona Tobacco consumption (pacWyr)
Retinopathylno
Statistical
n = 79
n = 78
Significance
52148 44.3 ? 13.7 20.07 + 13.6 23.16 -c 3.8 9.52 r 4.4 9.58 h 2.0 131.68 k 20.62 77.97 t 11.82 33.8% 6.31 + 13.19
57143 38.54 f 16.5 6.63 f 6.5 22.6 +- 3.4 9.78 _’ 4.38 9.38 ? 2.78 125.63 f 15.3 75.9 ? 8.65 10.5% 6.95 f 16.03
NS NS p < 0.001 NS NS NS p < 0.05 NS p < 0.001 NS
Results are expressed as mean r 1 SD. a Arterial hypertension defined as blood pressure values of 160 mm Hg or greater and/or 95 mm Hg or greater, or the presence of antihypertensive treatment.
240
MICROANGIOPATHYAND IOOM
TABLE 4
Characteristics
of the Patients According
Sex (%, m/f) Age (yr) Duration of diabetes (yr) Body mass index (kg/m’) Fasting plasma glucose (mmol/L) HbA1, Systolic BP (mm Hg) Diastolic BP (mm Hg) Arterial hypertensiona Tobacco consumption (packyr)
to the Presence
or Absence
of Neuropathy
Neuropathylyes n = 51
Neuropathylno n = 106
Significance
64136 48.6 +- 14.8 19.7 2 11.8 23.45 ? 3.15 9.93 ? 4.58 9.92 IT 2.46 133.50 2 22.5 77.3 ” 10.9 42% 11.98 ? 17.43
51149 38.3 2 15.3 10.5 2 9.8 22.73 ? 3.94 9.48 2 4.33 9.26 2 2.34 126.25 2 15.8 76.8 2 10.02 11.3% 7.19 * 12.93
NS p < 0.001 p < 0.001 NS NS NS p < 0.05 NS p < 0.001 NS
Results are expressed as mean ? 1 SD. ‘Arterial hypertension defined as blood pressure values of 160 mm Hg or greater and/or 95 mm Hg or greater, or the presence of antihypertensive treatment.
localizations estimated from the presence of each one were, respectively, 0.38 for the 29% of patients with nephropathy, 0.21 for the 50% with retinopathy, and 0.33 for the 32% with neuropathy. Characteristics of the patients according to the presence or absence of each complication are displayed in Tables 2-4. For each microangiopathic lesion, patients with the disease had significantly higher values (p < 0.05) than those without for duration of diabetes, prevalence of hypertension, and systolic blood pressure. Concerning nephropathy, patients with clinical nephropathy, compared with those with incipient nephropathy, had higher values for all parameters, but the differences were not statistically significant. Stepwise logistic regression analysis showed that the independent predictive factors of each localization were, respectively, 1) for nephropathy, systolic blood pressure (coefficient _+ SEM = 0.0377 ? 0.0113, t = 3.33, p < 0.001); 2) for retinopathy, duration of diabetes (coefficient 2 SEM = 0.209 ? 0.0353, t = 5.93, p < 0.001); and 3) for neuropathy, duration of diabetes (coefficient ? SEM = 0.0788 rt 0.0213, t = 3.69, p = 0.001) age (coefficient ? SEM = 0.0318 2 0.0144, t = 2.21, p < 0.05) and HbA,, (coefficient t SEM = 0.201 f 0.0945, t = 2.12, p < 0.05).
DISCUSSION The aim of this study was to determine, in a cohort of 157 insulin-dependent diabetic patients, the prevalence of the three localizations of diabetic microangiopathy and to identify the factors associated with each one. In the population we studied, the prevalence of abnormal albuminuria, defined as UAE above 30 mg124 hr, was 29%. This value has been recommended as being indicative of incipient diabetic nephropathy.14 On this basis, nearly one-third of our 157 patients were affected by nephropathy. It has been shown in longitudinal studies’5.‘6 that 35-45% of all insulin-dependent diabetic patients develop diabetic nephropathy. The prevalence rate we report trends to these results as our study was cross-sectional where the mean age of the patients was 42 years. Admittedly, Parving et al.” reported a higher prevalence of 41%, but patients with diabetes of less than 5 years duration were excluded for their study; this might explain the difference.
The prevalence of retinopathy among our patients was 50%; this is close to the results of Teusher et al.” The higher prevalences observed in the studies by Palmberg et al.lg and Klein et al.*O may be due to the application of different criteria for the diagnosis of diabetic retinopathy. In the literature, estimates of the prevalence of diabetic neuropathy range broadly; no reliable method of evaluation of the disease having yet been found. Our classification using loss of ankle reflexes as the diagnostic criterion resembled that suggested by Dyck.*’ On this basis, we found a prevalence of 32%, which is close to the results observed in the feasibility phase by the DCCT research group.** In the population studied here, patients with increased UAE exhibited concomitantly high prevalence of retinopathy (69%) and neuropathy (49%) and were those with the highest probability to have all three complications. On the other hand, only 39% of the patients with retinopathy had concomitant nephropathy, and presence of retinopathy and neuropathy were highly associated. These findings support the Steno hypothesis reported by Deckert et al.23 I.e. that elevated albuminuria reflects widespread diabetic vascular damage. Moreover, as suggested by other authors,24.25 the different microvascular lesions may not evolve in the same way, but presence of elevated albuminuria characterizes severe patients. Patients with nephropathy had higher values (p < 0.005) for duration of diabetes, arterial hypertension, systolic and diastolic blood pressure than those without, but, in the regression analysis, the only predictive factor of nephropathy was systolic blood pressure. Various authors reported association between UAE and diabetes duration’5.‘6 and described a peak in cumulative incidence of diabetic nephropathy after 15-16 years of diabetes. So this association could be expected in this population where the mean duration of the disease was 13 years. The relationship between UAE and blood pressure has been widely investigated. Previous authors’0.26 reported that in diabetic nephropathy, hypertension is not simply a secondary consequence of the renal lesions but an important factor contributing to it. Our findings indicate that even a very small increase in blood pressure predicts albuminuria as the mean systolic blood pressure of the
BILLAULT AND PASSA
242 whole population
studied was at the very acceptable level of 128 mmHg. Our study design, which is cross-sectional, cannot establish causal relationship; however, this result suggests that treatment may be considered in normotensive insulin-dependent diabetic patients with persistent microalbuminuria, as it has been demonstrated that such an intervention may alter UAE and prevent the incidence of clinical nephropathy.” Retinopathy in our patients was strongly correlated with the duration of diabetes both in the bivariate and the regression analysis. That is in keeping with other authors who demonstrated that the frequency of retinopathy increases with the duration of diabetes.‘g~20 Surprisingly, glycemic control was not found to be associated with retinopathy. Although the link between poor long-term glycemic control and retinopathy is well documented,‘*20~28 it is known, too, that once retinal lesions have occurred, improved glycemic control no longer has a great impact on their progression6,*’ The apparent discordance between our results and those of others in this respect may be due to the fact that our study was a cross-sectional one, and that successful attempts to improve metabolic control were made for patients with established retinopathy; this is close to the findings of other authors who demonstrated a strong correlation between the mean HbA;, for a 6-year period and retinopathy, but found no correlation when only the most recent HbA,,.value was taken into account.** The predictive factors of neuropathy were duration of diabetes, HbA,, and age. Although our findings are based on clinical examination only, the same associations have been demonstrated regardless of whether or not the authors assessed nerve function clinically or electrophysiologically.‘~4~22 In this study, presence of neuropathy or retinopathy was significantly associated with hypertension and systolic blood pressure. Little information is available in the literature about hypertension and these microvascular lesions in insulin-dependent diabetic patients. In the Wisconsin Epidemiologic Study,“’ retinopathy was found to correlate with diastolic blood pressure after ten years of duration of diabetes, and Teuscher et al.‘* showed that, in their whole population, the incidence of nonproliferative retinopathy rose significantly with systolic blood pressure. To our knowledge, it has never been demonstrated that antihypertensive treatment may improve diabetic vascular retinal lesions or neurologic lesions. In the present study, patients with neuropathy or retinopathy were significantly older than those without these diseases, and the presence of elevated blood pressure values has to be considered as an age-dependent factor.
In conclusion, in the population we studied, arterial hypertension, duration of diabetes, and HbA,, were the most powerful factors associated with diabetic microangiopathy. Increased albuminuria was of great pronostic significance for generalized microvascular disease.
REFERENCES 1.
Deckert T, Poulsen JE: Diabetic nephropathy: fault or destiny? Diabetologia 21:178-183, 1981. 3. World Health Organization: Multinational study of vascular disease in diabetics. Diabetologia 28:615-640,.1985. 4. Youna RJ. Maclntvre CCA. Martvn CN. Prescott RJ. Ewina 2.
DJ, Shith’AF, Vib&ti G, Clarke BF: Prdgression of &bclinI ical polyneuropathy in young patients with Type 1 (insulindependent) diabetes: associations with glycaemic control and microangiopathy (microvascular complications). Diabetologia 29:156-l 61, 1986. 5. Viberti GC, Bilous RW, Mackintosh D, Bending JJ, Keen H: Long term correction of hyperglycaemia and progression of renal failure in insulin-dependent diabetes. Br Med J 286:598-602, 1983. 8. Ramsay RC, Goetz FC, Sutherland ER, et al.: Progression of diabetic retinopathy after pancreas transplantation for insulin dependent diabetes mellitus. N Engl J Med 318:208214, 1988. 7. Lauritzen T, Frost-Larsen K, Larsen HW, Deckert T, and the Steno Study Group: Two-year experience with continuous subcutaneous insulin infusion in relation to retinopathy and neuropathy. Diabetes 34(suppl 3):74-79, 1985 8. Rosensock J, Friberg T, Raskin P: Effect of glycemic control on microvascular complications in patients with Type I diabetes mellitus Am J Med81:1012-1018, 1986.
9. Seaquist ER, Goetz FC, Rich S, Barbosa J: Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy. IV EnglJ Med320:11611165, 1989. 10. Krolewski AS, Canessa M, Warram JH, Laffel LMB, Christlieb AR, Knowler WC, Rand LI: Predisposition to hypertension and susceptibility to renal disease in insulin-dependent diabetes mellitus. N Eng J Med318:140-145, 1988. 11. Marre M, Claude1 JP, Ciert P, Luis N, Suarez L, Passa P: Laser immunonephelometry for routine quantification of urinary albumin excretion. Clin Cbem 33:209-213, 1987. 12. World Health Organization: Report of an expert committee on hypertension. WHO Technical Report Series, Geneva,
WHO, 1979. 13. Dixon WJ, Brown MB, Engelman
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Pirart J: Diabete et complications degeneratives. Presentation dune etude prospective portant sur 4 400 cas observes entre 1947 et 1973. Diabete Metab 3:97-l 07,173-l 82,245156, 1977.
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N, Franc JW, Hill MA, Jenrich RI, Toporek JD (eds): BMDP Statistical Software Berkeley, University of California Press 1985. Moaensen CE. Chachati A. Christensen CK. et al: Microalbuminuria: an early marker’of renal involvement in diabetes. Uremia invest 9:85-95, 1985. Krolewski AS, Warram JH, Christlieb AR, Busick EJ, Kahn CR: The changing natural history of nephropathy in type I diabetes Am J Med 78:785-794, 1985. Andersen AR, Christiansen JS, Andersen JK Kreiner S, Deckert T: Diabetic nephropathy in type 1 (insulin-dependent) diabetes: an epidemiological study. Diabetologia 25:496-501, 1983. Parving HH, Hommel E, Mathiesen E, Skott P, Edsberg B, Bahnsen M, Lauritzen M, Hougaard P, Lauritzen E: Prevalence of microalbuminuria. arterial hypertension, retinopathy and neuropathy in patients with insulin dependent diabetes. Br Med J 296:156-l 60, 1988. Teuscher A, Schnell H, Wilson PWF: Incidence of diabetic retinopathy and relationship to baseline plasma glucose and blood pressure. Diabetes Care 11:246-251, 1988. Palmberg P, Smith M, Waltman S, et al: The natural history of retinopathy in insulin-dependent juvenile onset diabetes. Ophtalmology88:613-618, 1981. Klein R, Klein BEK, Moss SE, Davis MD, DeMets DL: Wisconsin epidemiologic study of diabetic retinopathy. II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years. Arch Ophtalmol 102:520-526, 1984. Dyck PJ: Detection, characterization and staging of polyneuropathy: assessed in diabetics. Muscle and Nerve 11:2132, 1988. The DCCT Research Group: Factors in development of diabetic neuropathy. Baseline analysis of neuropathy in feasibility phase of diabetes control and complications trial (DCCT). Diabetes 37:476-481, 1988. Deckert T, Feldt-Rasmussen B, Borch-Johnsen K, Jensen T,
MICROANGIOPATHYAND IDDM
Kofoed-Enevoldsen A: Albuminuria reflects widespread vascular damage. The Steno hypothesis. Diabetologia 32:219226, 1989. 24. Lindegard B: Milignant diabetic retinopathy. Lancet 1:271, 1985. 25. Barnett AH, Dallinger K, Jennings P, Fletcher J, Odugbesan 0: Microalbuminuria and diabetic retinopathy. Lancer1 :5354, 1985. 26. Viberti G: Etiology and prognostic significance of albuminuria in diabetes. Diabetes Care 11:840-845, 1988.
243
27. Marre M, Chatellier G, Leblanc H, Guyenne TT, Menard J, Passa P: Prevention of diabetic nephropathy with enalapril in normotensive diabetics with microalbuminuria. Br Med./ 297:1092-1906, 1988. 28. McCance DR, Atkinson AB, Hadden DR, Archer DB, Kennedy L: Long-term glycaemic control and diabetic retinopathy. Lancet 2:824-828, 1989. 2g Bonomo M, Seidenari P, Spelta B, Berti R, Mainardi P, Santagostino A: Long-term evolution of diabetic macular oedema: influence of metabolic control. Diabetologia32:468A, 1989
Bernadette M. Billault Philippe L. Passa
Department of Diabetes (B. M. B., P. 1. P.), Saint Louis Hospital, and INSERM U 194 (B.M.B.), La Piti&Salp&ri&e Hospital, Paris, France
With Diabetic Microangiopathy: I (Insulin-Dependent) Diabetic
A
ABSTRACT The relation between poor glycemic control and the development of diabetic microangiopathy has long been recognized. However hy perglycemia alone cannot account for the striking heterogeneity of diabetic patients regarding the presence or absence of microangiopathic lesions. This study was therefore designed to determine the prevalence of retinopathy, nephropathy, and neuropathy, and to identify the factors respectively associated with these lesions. In 157 patients with type I (insulin-dependent) diabetes, the following parameters were recorded: sex, age, duration of diabetes, body mass index, fasting plasma glucose, HbA,,, blood pressure, antihypertensive treatment, tobacco consumption, urinary albumin excretion, plasma creatinine, and presence of retinopathy and neuropathy. One-half of these patients had retinopathy, 32% neuropathy, and 29% nephropathy. Patients with nephropathy exhibited concomitantly high prevalences of retinopathy (69%) and neuropathy (49%). Among patients with retinopathy, 39% had nephropathy; 79% of those with neuropathy had concomitant retinopathy. For each microangiopathic localization, patients with the disease had significantly higher values (p < 0.05) than those without for duration of diabetes, prevalence of hypertension, and systolic blood pressure. Stepwise logistic regression analysis showed that the following were independent predictive factors of each localization: for nephropathy, systolic blood pressure; for retinopathy, duration of diabetes; and for neuropathy, duration of diabetes, age, and HbA,,. (The Journal of Diabetic Complications 5;4:238-243, 1991.)
INTRODUCTION
Reprint requests to be sent to: Prof. Philippe L. Passa, Service de Diabbtologie, H6pital Saint Louis, 1 avenue Claude Vellefaux, 75010 Paris, France.
0 1991 Elsevier Science Publishing Co., Inc. 0891-6632/91/$3.50
238
Poor metabolic control is known to be related to the development of diabetic microangiopathy.’ However, striking differences are commonly observed between individual patients with respect to the presence or absence of microangiopathic lesions regardless of long-term metabolic controL2 Great disparities in the prevalence of retinopathy and heavy proteinuria were reported in the World Health Organization (WHO) Study,3 and it has been demonstrated that the association of deterioration in nerve function and the concomitant development of retinopathy and microalbuminuria was statistically independent of glycemia.4 In controlled studies, the long-term alleviation of hyperglycemia did not significantly alter the course of clinical nephropathy5 and led to controversial results for retinopathy.6-8 Consequently the pattern of occurrence and course of the various microangiopathic lesions indicate that hyperglycemia alone does not account for the observed heterogeneity. Microvascular complications appear to reflect complex interactions between poor metabolic control and genetic9~‘0 and/or environmental factors. This study was therefore designed to determine the prevalence of the three microangiopathic localizations and to identify the factors associated with these complications in a cohort of type I (insulin-dependent) diabetic patients who were regularly attending our clinic.
MICROANGIOPATHY
239
AN0 IODM
MATERIALSAND METHODS Patients The study was carried out in our diabetic clinic, which is a primary care unit, at St. Louis Hospital, Paris. The study was approved by the local ethics committee. All diabetic patients who were hospitalized from January 1st to May 1st 1988 and who fulfilled the following inclusion criteria were eligible: 1) negative C-peptide and on insulin treatment, and 2) regular follow-up in the department for at least 1 year. Excluded were pregnant women, patients on continuous subcutaneous insulin infusion, and patients suffering from serious diseases other than diabetes because of specific referral to the clinic for these patients. Patients with urinary tract infection documented by urine cultures and patients with a history of renal disease unrelated to diabetes were excluded because of possible enhancement in urinary albumin excretion regardless of the diabetic disease. None of the patients included was suffering from end-stage renal failure.
Procedures
is the present use in the literature. Patients with nephrop athy were then divided into those with incipient nephrog
athy (UAE 30-300 mg/24hr) and those with clinical nephropathy (UAE more than 300 mg!24 hr). Statldcal Analysk Statistical analyses were done using the BMDP statistical software package-l3 Results are expressed as mean f 1SD. Differences between groups were tested by Students t test for quantitative pararneters or by the chi-square test for qualitative variabks. Stepwise logistic regression analysis was performed to identify the factors independently associated with each microangiopathic localization. This method is used to test the contribution of a particular variabfe in predicting the outcome when other variabks are included in the model. The dependent variables were successively ne phropathy, retinopathy, and neuropathy. dichotomized to absent or present as defined in methods. The independent variables were sex, age, body mass index (BMI), duration of diabetes, HbA,,, fasting blood glucose, systolic blood pressure, diastolic blood pressure, and tobacco consumption. These variables were included in the model as continuous variables, except sex which was categorized. Arterial hypertension was not included in this analysis because we preferred to evaluate the specific influence of blood pressure values.
RESULTS
was evaluated as pack years (one pack year equals 20 cigarehes daily for one year). Blood pressure was recorded with a standard mercury sphygmomanometer after the patient had been in the recumbent position for at least 15 min. Systolic and diastolic blood pressure readings, from three separate occasions within the third day in the ward, were averaged and the mean used for the analysis. All measurements were made by the specially trained medical staff of the clinic. Arterial hypertension was diagnosed when systolic and/or diastolic values reached 160 and/or 95 mm Hg or more, or when the patient was on antihypertensive treatment.‘* Age was the current age at the time of examination. The duration of diabetes was taken as the period between age at diagnosis and age at time of examination. Neuropathy was evaluated from clinical neurological findings. No electrophysiological examination was performed. Clinical neuropathy was diagnosed on the basis of the absence of ankle tendon reflexes. Retinopathy was assessed by direct ophthalmoscopy through dilated pupils and fluorescein angiography. Patients were considered to be affected by retinopathy on the basis of background retinopathy defined by the presence of at least two microaneurysms at the posterior pole in one eve. For nephropathy, patients were divided into two groups according to their 24-hr UAE. Normoalbuminuria was defined as UAE less than 30 mg; diagnosis of nephropathy was considered when UAE was above 30 mg/24 hr, as it
Included in the study were 157 patients (see fable 1 for their main characteristics). The prevalence of the three microangiopathic lesions was as follows: nephropathy, 29% (incipient nephropathy or UAE 30-300 mg124 hr, 22%; clinical nephropathy or UAE greater than 300 mgl 24 hr, 7%), retinopathy, 50%, neuropathy, 32%. The associations of microangiopathic complications are shown in Figure 1. Of the patients with nephropathy, 69% also had retinopathy and 49% had neuropathy. However, only 39% of the patients with retinopathy had nephropathy. Of those with neuropathy, 79% had concomitant retinopathy. The probabilities (p) of developing all
TABLE 1
Main Characteristics of our Series of 157 Patients With Type I Diabetes Parameter
n (negative (-peptide) Sex (%, m/f) Age (yr) Diabetes duration (yr) Body mass index (kg/m’) Fasting plasma glucose (mmolk) HbA,c (%) Systolic BP (mm Hg) Diastolic BP (mm Hg) Arterial hypertensiona (%) Plasma creatinine (MmollL) Tobacco consumption (packyr)
Data 157 55145 41.6 ?I 15.3 13.5 2 10.9 22.9 I 3.7 9.6 ” 4.4 9.5 zk 2.4 126.7 2 18.3 76.9 k 10.3 22 91.0 2 29.9 8.7 2 14.6
Results are expressed as mean 2 1 SD. BP, blood pressure. e Arterial hypertension defined as blood pressure values of 160 mm Hg or more and/or 95 mm Hg or more, or presence of antihypertensive treatment.
FIG. 1 The associations of microangiopathic plications.
TABLE 2
com-
Characteristics of the Patients According to the Presence or Absence of Nephropathy (UAE Nephropethy Present 230 mg n = 45)
Sex (“9 m/f) Age (yr) Duration of diabetes (yr) Body mass index (kg/m2) Fasting plasma glucose (mmol/L) HbA,, (%) Systolic BP (mm Hg) Diastolic BP (mm Hg) Arterial hypertensiona Tobacco consumption (pack/yr)
.
60140 45.1 * 17.3 17.6 2 9.3 23.70 f 4.21 10.50 f 4.91 9.64 f 2.22 137.03 f 19.6 79.54 f 9.65 40.5% 10.4 f 17.2
(UAE Nephropathy Absent <30 mg n = 112)
Statistical Significance
53147 40.4 f 14.4 12.5 2 11.3 22.72 f 3.57 9.32 f 4.20 9.36 * 2.44 125.5 f 17.46 76.10 f 10.26 16.4% 6.2 t 13.6
p
p p p
NS NS < 0.005 NS NS NS < 0.001 < 0.05 < 0.005 NS
Results are expressed as mean 2 1 SD. UAE, urinary albumin excretion; BP, blood pressure. a Arterial hyptension defined as blood pressure values of 160 mm Hg or greater and/or 95 mm Hg or greater, or the presence of antihypertensive treatment.
TABLE 3
Characteristics of the Patients According to the Presence or Absence of Retinopathy Retinopathylyes
Sex (%, m/f) Age (yr) Duration of diabetes (yr) Body mass index (kg/m2) Fasting plasma glucose (mmol/L) HbA,, (%) Systolic BP (mm Hg) Diastolic BP (mm Hg) Arterial hypertensiona Tobacco consumption (pacWyr)
Retinopathylno
Statistical
n = 79
n = 78
Significance
52148 44.3 ? 13.7 20.07 + 13.6 23.16 -c 3.8 9.52 r 4.4 9.58 h 2.0 131.68 k 20.62 77.97 t 11.82 33.8% 6.31 + 13.19
57143 38.54 f 16.5 6.63 f 6.5 22.6 +- 3.4 9.78 _’ 4.38 9.38 ? 2.78 125.63 f 15.3 75.9 ? 8.65 10.5% 6.95 f 16.03
NS NS p < 0.001 NS NS NS p < 0.05 NS p < 0.001 NS
Results are expressed as mean r 1 SD. a Arterial hypertension defined as blood pressure values of 160 mm Hg or greater and/or 95 mm Hg or greater, or the presence of antihypertensive treatment.
240
MICROANGIOPATHYAND IOOM
TABLE 4
Characteristics
of the Patients According
Sex (%, m/f) Age (yr) Duration of diabetes (yr) Body mass index (kg/m’) Fasting plasma glucose (mmol/L) HbA1, Systolic BP (mm Hg) Diastolic BP (mm Hg) Arterial hypertensiona Tobacco consumption (packyr)
to the Presence
or Absence
of Neuropathy
Neuropathylyes n = 51
Neuropathylno n = 106
Significance
64136 48.6 +- 14.8 19.7 2 11.8 23.45 ? 3.15 9.93 ? 4.58 9.92 IT 2.46 133.50 2 22.5 77.3 ” 10.9 42% 11.98 ? 17.43
51149 38.3 2 15.3 10.5 2 9.8 22.73 ? 3.94 9.48 2 4.33 9.26 2 2.34 126.25 2 15.8 76.8 2 10.02 11.3% 7.19 * 12.93
NS p < 0.001 p < 0.001 NS NS NS p < 0.05 NS p < 0.001 NS
Results are expressed as mean ? 1 SD. ‘Arterial hypertension defined as blood pressure values of 160 mm Hg or greater and/or 95 mm Hg or greater, or the presence of antihypertensive treatment.
localizations estimated from the presence of each one were, respectively, 0.38 for the 29% of patients with nephropathy, 0.21 for the 50% with retinopathy, and 0.33 for the 32% with neuropathy. Characteristics of the patients according to the presence or absence of each complication are displayed in Tables 2-4. For each microangiopathic lesion, patients with the disease had significantly higher values (p < 0.05) than those without for duration of diabetes, prevalence of hypertension, and systolic blood pressure. Concerning nephropathy, patients with clinical nephropathy, compared with those with incipient nephropathy, had higher values for all parameters, but the differences were not statistically significant. Stepwise logistic regression analysis showed that the independent predictive factors of each localization were, respectively, 1) for nephropathy, systolic blood pressure (coefficient _+ SEM = 0.0377 ? 0.0113, t = 3.33, p < 0.001); 2) for retinopathy, duration of diabetes (coefficient 2 SEM = 0.209 ? 0.0353, t = 5.93, p < 0.001); and 3) for neuropathy, duration of diabetes (coefficient ? SEM = 0.0788 rt 0.0213, t = 3.69, p = 0.001) age (coefficient ? SEM = 0.0318 2 0.0144, t = 2.21, p < 0.05) and HbA,, (coefficient t SEM = 0.201 f 0.0945, t = 2.12, p < 0.05).
DISCUSSION The aim of this study was to determine, in a cohort of 157 insulin-dependent diabetic patients, the prevalence of the three localizations of diabetic microangiopathy and to identify the factors associated with each one. In the population we studied, the prevalence of abnormal albuminuria, defined as UAE above 30 mg124 hr, was 29%. This value has been recommended as being indicative of incipient diabetic nephropathy.14 On this basis, nearly one-third of our 157 patients were affected by nephropathy. It has been shown in longitudinal studies’5.‘6 that 35-45% of all insulin-dependent diabetic patients develop diabetic nephropathy. The prevalence rate we report trends to these results as our study was cross-sectional where the mean age of the patients was 42 years. Admittedly, Parving et al.” reported a higher prevalence of 41%, but patients with diabetes of less than 5 years duration were excluded for their study; this might explain the difference.
The prevalence of retinopathy among our patients was 50%; this is close to the results of Teusher et al.” The higher prevalences observed in the studies by Palmberg et al.lg and Klein et al.*O may be due to the application of different criteria for the diagnosis of diabetic retinopathy. In the literature, estimates of the prevalence of diabetic neuropathy range broadly; no reliable method of evaluation of the disease having yet been found. Our classification using loss of ankle reflexes as the diagnostic criterion resembled that suggested by Dyck.*’ On this basis, we found a prevalence of 32%, which is close to the results observed in the feasibility phase by the DCCT research group.** In the population studied here, patients with increased UAE exhibited concomitantly high prevalence of retinopathy (69%) and neuropathy (49%) and were those with the highest probability to have all three complications. On the other hand, only 39% of the patients with retinopathy had concomitant nephropathy, and presence of retinopathy and neuropathy were highly associated. These findings support the Steno hypothesis reported by Deckert et al.23 I.e. that elevated albuminuria reflects widespread diabetic vascular damage. Moreover, as suggested by other authors,24.25 the different microvascular lesions may not evolve in the same way, but presence of elevated albuminuria characterizes severe patients. Patients with nephropathy had higher values (p < 0.005) for duration of diabetes, arterial hypertension, systolic and diastolic blood pressure than those without, but, in the regression analysis, the only predictive factor of nephropathy was systolic blood pressure. Various authors reported association between UAE and diabetes duration’5.‘6 and described a peak in cumulative incidence of diabetic nephropathy after 15-16 years of diabetes. So this association could be expected in this population where the mean duration of the disease was 13 years. The relationship between UAE and blood pressure has been widely investigated. Previous authors’0.26 reported that in diabetic nephropathy, hypertension is not simply a secondary consequence of the renal lesions but an important factor contributing to it. Our findings indicate that even a very small increase in blood pressure predicts albuminuria as the mean systolic blood pressure of the
BILLAULT AND PASSA
242 whole population
studied was at the very acceptable level of 128 mmHg. Our study design, which is cross-sectional, cannot establish causal relationship; however, this result suggests that treatment may be considered in normotensive insulin-dependent diabetic patients with persistent microalbuminuria, as it has been demonstrated that such an intervention may alter UAE and prevent the incidence of clinical nephropathy.” Retinopathy in our patients was strongly correlated with the duration of diabetes both in the bivariate and the regression analysis. That is in keeping with other authors who demonstrated that the frequency of retinopathy increases with the duration of diabetes.‘g~20 Surprisingly, glycemic control was not found to be associated with retinopathy. Although the link between poor long-term glycemic control and retinopathy is well documented,‘*20~28 it is known, too, that once retinal lesions have occurred, improved glycemic control no longer has a great impact on their progression6,*’ The apparent discordance between our results and those of others in this respect may be due to the fact that our study was a cross-sectional one, and that successful attempts to improve metabolic control were made for patients with established retinopathy; this is close to the findings of other authors who demonstrated a strong correlation between the mean HbA;, for a 6-year period and retinopathy, but found no correlation when only the most recent HbA,,.value was taken into account.** The predictive factors of neuropathy were duration of diabetes, HbA,, and age. Although our findings are based on clinical examination only, the same associations have been demonstrated regardless of whether or not the authors assessed nerve function clinically or electrophysiologically.‘~4~22 In this study, presence of neuropathy or retinopathy was significantly associated with hypertension and systolic blood pressure. Little information is available in the literature about hypertension and these microvascular lesions in insulin-dependent diabetic patients. In the Wisconsin Epidemiologic Study,“’ retinopathy was found to correlate with diastolic blood pressure after ten years of duration of diabetes, and Teuscher et al.‘* showed that, in their whole population, the incidence of nonproliferative retinopathy rose significantly with systolic blood pressure. To our knowledge, it has never been demonstrated that antihypertensive treatment may improve diabetic vascular retinal lesions or neurologic lesions. In the present study, patients with neuropathy or retinopathy were significantly older than those without these diseases, and the presence of elevated blood pressure values has to be considered as an age-dependent factor.
In conclusion, in the population we studied, arterial hypertension, duration of diabetes, and HbA,, were the most powerful factors associated with diabetic microangiopathy. Increased albuminuria was of great pronostic significance for generalized microvascular disease.
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