Glycemic Control and Prognosis in Type I Diabetic ... - Diabetes Care

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Glycemic Control and Prognosis in Type I Diabetic Patients With Microalbuminuria RESEARCH DESIGN A N D M E T H O D S — A total of 109 patients with an onset of type I diabetes between 1961 and 1980, before age 15 years, had collected at least two 24-h urine samples for analysis of albumin after a diabetes duOBJECTIVE— To investigate the course of microalbuminuria during the 1980s in type I ration of > 3 years during 1977 to 1983 diabetes patients. and were subsequently included in the study. An AER of 20-200 jag/min (or AER RESEARCH DESIGN A N D METHODS— This was a 10-year follow-up of 109 patients in whom type I diabetes was diagnosed between 1961 and 1980 before 15 years of age and 30-300 mg/24 h) was defined as miwho were initially investigated between 1977 and 1983 after a diabetes duration of ^ 3 years. croalbuminuria if present in at least two of Microalbuminuria was defined as an albumin excretion rate (AER) of 20-200 /xg/min in two of three consecutive samples (in tables and text AER is presented as micrograms per three consecutive urine samples. minute). The interval between each samRESULTS — At the initial investigation, 81 patients had normal AER, 27 had microalbumin- ple was from 6 to 12 months. Two pauria, and 1 had macroalbuminuria. Between 1989 and 1992, 99 (91%) patients were reinvesti- tients who initially had microalbuminuria gated. Only 5 (19%) of the initially microalbuminuric patients developed macroproteinuria collected all their samples before 1980. during the 10-year follow-up period, and in 15 (58%) patients, AER decreased to normal. Three The 97 patients who still lived in our (4%) of the normoalbuminuric patients developed microalbuminuria but none macroproteinuria. The initially microalbuminuric patients, in whom AER normalized, improved their glyce- catchment area were invited to a special mic control from 1980-1983 to 1989-1991 (mean ± SE HbAlc 7.5 ± 0.2 to 6.6 ± 0.3%; P = 0.01). follow-up visit during 1989 to 1992 and were asked to collect three timed overCONCLUSIONS — In the majority of patients with microalbuminuria in whom it is possible night urine samples for measurement of to obtain good glycemic control, microalbuminuria will disappear and the risk of developing AER; 92 of these patients fulfilled the renephropathy will be markedly reduced. quirement. A questionnaire was sent to the 10 patients who had moved out of our area. They were asked to provide the adhe high relative mortality among morphological changes in early diabetic dress of the clinic they currently attended type I diabetes patients (1) affects nephropathy (9). Intervention studies for their diabetes care. Seven patients remainly those with diabetic nephrop- have shown that the development of mi- sponded, and data were received from athy (2,3). The cumulative incidence of croalbuminuria can be delayed by im- their physicians on AER and on any antidiabetic nephropathy has decreased sub- proved glycemic control (10,11). It is, hypertensive agent treatment. Seven of stantially in recent decades in our popu- however, still uncertain whether AER in the eight patients who were lost to follation from 30 to 9%, after 25 years' dia- patients with established microalbumin- low-up were normoalbuminuric at the betes duration, probably as a result of uria can be reverted to normal with im- initial investigation, and one was miimproved glycemic control (4). Mi- proved glycemic control. Earlier retro- croalbuminuric. Two patients had died croalbuminuria has previously been spective studies of the clinical course of during the study period; both were norshown to be a powerful predictor of dia- microalbuminuria (5-7) were carried out moalbuminuric at the initial investigabetic nephropathy (5-7) and cardiovas- before the importance of glycemic control tion. In total, 99 patients (91%) were recular mortality in type I diabetes (8). Al- was established. It is conceivable that investigated in 1989-1992. most all patients with microalbuminuria with proper glycemic control, the anticiPatients were seen at the Paediat(urinary albumin excretion rate [AER] pated risk of subsequent nephropathy ric Clinic at least every 3 months until 20-200 /xg/min) seem to develop diabetic may be considerably less than earlier renephropathy during a 10-year period (5- ported in patients with microalbuminuria they left school at the age of 18-20 years. 7). A close relationship has recently been (5-7). We have therefore investigated the The care was then transferred to the Dereported between the level of mean blood prognosis during the last decade for type I partment of Internal Medicine, where glucose and progression of glomerular diabetes patients with microalbuminuria. similar routines were followed. The importance of strict glycemic control was emphasized in the 1970s and became the principal aim of the treatment (12). Regular self-monitoring of blood glucose and From the Departments of Internal Medicine (M.B., H.J.A., B.E.K.) and Pediatrics (J.L.), University Hospital, Linkoping, Sweden. multiple injection therapy became rouAddress correspondence and reprint requests to Mats Bojestig, MD, Department of Medicine, Eksjo tine. Of the 27 patients with microalbuHospital, S-575 81 Eksjo, Sweden. minuria, 1 was treated with an insulin Received for publication 12 May 1995 and accepted in revised form 9 November 1995. pump, 1 with five doses a day, 21 with AER, albumin excretion rate; MAP, mean arterial blood pressure. MATS BOJESTIG, MD HANS J. ARNQVIST, MD, PHD

BENGT E. KARLBERG, MD, PHD JOHNNY LUDVIGSSON, MD, PHD

T

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Table 1—Characteristics of patients at the initial in\estigation Normoalbuminuria No. of patients (M/F) AER (jLtg/min)

Age at onset of diabetes (years) Duration of diabetes (years) Follow-up period (years)

81 (36/45) 10 (3-17) 7.0(1-14) 7.4 (3-17) 9.4 (6-14)

Microalbuminuria 27 48 9.0 8.3 9.8

Macroalbuminuria

(13/14) (26-188) (2-14) (3-17) (6-14)

1 (1/10) 476 6 15 12

Data are means (range). AERs are geometric means.

four doses a day, and 3 with three or two doses a day. Throughout the study, microalbuminuria was determined by an automated immunonephelometric assay at the department of clinical chemistry (13). A change in antibody was made in November 1989, the new antibody giving —2-4% higher values when run in parallel on serum albumin. The assay has always been run with appropriate albumin standards and control samples, but quality control data before 1989 have not been saved. The interassay coefficient of variation was 4-7% at high albumin levels. The follow-up samples were analyzed continuously. HbAx was determined with ionexchange chromatography. Between 1980 and 1982, minicolumns (Quicksep, Isolab, Akron, OH) were used and the analysis included the labile Schiff base fraction. From 1982 to 1984, the same method was used after elimination of the labile fraction. After 1984, HbA lc was measured using a high-pressure liquid chromatography method (Auto Ale HA 8810, Kyoto Daichi, Kyoto, Japan); reference values were 3.2-6.0%. Corresponding HbAlc values were calculated from HbAi values according to intermethod calibrations made by the analyzing laboratory. Every HbAlc value from each patient with microalbuminuria initially was included in the analysis (in total, 421 measurements, with a mean of 16 per patient). Patients who moved out of the area were not included in the analyses of differences regarding degree of glycemic control between 1980-1983 and 19891991 because of difficulties in calculating corresponding HbAlc values between different laboratories. Blood pressure was measured with the patient in the supine position after a 5-min rest, using a mercury sphygmomanometer. The blood pressure measurements in the analyses were taken at the diagnosis of microalbuminuria. 314

The study was approved by the Ethical Committee of the Medical Faculty, University of Linkoping.

Statistical analysis Values of AER are presented as geometric means. The ^ test was used to test the significance of differences of frequencies. The group means of the HbAlc levels in patients with and without microalbuminuria were compared using an unpaired Student's t test (two-tailed), taking the average of HbAlc values for each subject. A paired Student's t test (two-tailed) was used to compare the average of HbAlc values for each subject during each time period, 1980-1983 and 1989-1991. RESULTS — Of the type I diabetes patients, 81 (74%) were normoalbuminuric, 27 (25%) were microalbuminuric, and 1 (1%) had macroalbuminuria at the initial investigation (Table 1). At follow-up, 15 (58%) microalbuminuric patients had become normoalbuminuric, 6 (23%) remained microalbuminuric, and 5 (19%) had developed macroalbuminuria. Three (4%) of the normoalbuminuric patients developed microalbuminuria, but none developed macroalbuminuria (Fig. 1). The initially microalbuminuric patients in whom AER normalized had

lower HbAlc values (mean ± SE) from the diagnosis of microalbuminuria to the time of follow-up (6.7 ± 0.2%) than the microalbuminuric patients who remained microalbuminuric (7.7 ± 0.4%; P = 0.03) or developed macroalbuminuria (8.9 ± 0.5%; P = 0.0002). The patients in whom AER normalized improved their glycemic control from 1980-1983 to 1989-1991 from a mean HbAlc value of 7.5 ± 0.25 to 6.6 ± 0.3% (P = 0.005), but the other microalbuminuric patients did not (Table 2 and Fig. 2) The five patients whose condition progressed from microalbuminuria to macroalbuminuria had higher mean HbAlc values in 19801983 than the patients in whom AER normalized (8.9 ± 0.9 vs. 7.5 ± 0.2%; P = 0.04). AER normalized in more women than men (P = 0.02) (Fig. 2). Women with microalbuminuria initially improved their glycemic control from an HbAlc of 7.8 ± 0.4% in 1980-1983 to 6.6 ± 0.3% in 1989-1991 (P < 0.001), but the men with initial microalbuminuria did not. The corresponding HbAlc values were 7.9 ± 0.4% vs. 7.6 ± 0.3%, respectively. Patients with microalbuminuria initially who developed macroalbuminuria had, at the initial investigation, higher systolic blood pressure (126 ± 2.9 mmHg) and mean arterial blood pressure (MAP) (92 ± 3.2 mmHg) than those who remained microalbuminuric (111 ± 2.1 mmHg, P = 0.04; MAP 92 ± 2.9 mmHg, P = 0.046) and also higher than the patients in whom AER normalized (114 ± 2.4 mmHg, P = 0.018; MAP 8 6 + 1 . 4 mmHg, P = 0.054) (Table 2). There were no differences in blood pressure between

Microalbuminuria 27

Normoalbuminuria 81

Lost to follow up 1

Lost to follow up 9

Normoalbuminuria

Microalbuminuria

Macroalbuminuria

Normoalbuminuria

Microalbuminuria

Macroalbuminuria

69

3

0

15

6

5

Figure 1—Outcome of type I diabetes patients with normoalbuminuria and microalbuminuria initially.


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minima (14-16). Intensive blood glucose control has been shown in intervention studies to reduce the risk of microalbuminuria and the risk of macroalbuminuria (11,17-19). However, it is still uncertain if these findings are applicable among patients with established microalbuminuria (20). The five patients in our study who developed macroalbuminuria had higher HbAlc values at the initial investigation than the patients in whom AER normalized. Those patients who had microalbuminuria or macroalbuminuria at the end of the study did not improve their glycemic control during the study, and they had higher mean HbAlc values during the follow-up period than the patients in whom AER normalized. The 15 patients with microalbuminuria whose AERs became normal improved their glycemic control during the follow-up period. This suggests that glycemic control determines the development of nephropathy. The improved prognosis for our patients with microalbuminuria is probably the result of improved glycemic control.

Mean HbAlc /-I

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10

20

100

200

1000

Albumin Excretion Rate (ng/min) Figure 2—Urinary AER at the initial investigation (O) and at the follow-up (solid or striped arrow) (the scale is log-transformed) in relation to mean HbAlcfrom diagnosis of microalbuminuria to followup: men (solid arrow) and women (striped arrow).

the patients in whom AER had normalized and those in whom it was unchanged. None of the microalbuminuric patients in whom AER normalized had been receiving antihypertensive treatment, but two patients with macroalbuminuria took antihypertensive agents (Table 2). CONCLUSIONS— Only 5 of 26 patients with microalbuminuria developed macroalbuminuria during a 10-year period compared with 7 of 8, 7 of 7, and 12 of 14 patients in three previous studies (5-7). In our study, in 15 of 26 patients with microalbuminuria AER not only decreased but became normal. Our patients with poor glycemic control, predominantly men, had the same prognosis as in the previous studies (Fig. 2). Glycemic control Poor glycemic control has been shown to determine the development of microalbuDIABETES CARE, VOLUME 19, NUMBER 4, APRIL

Discrimination value of AER Since in one patient 6 months had elapsed between the measurements of AER and in all the others 1 year, it seems unlikely that the initial diagnosis of microalbuminuria should be sporadic and false because of the high day-to-day variation of AER. A

Table 2—Characteristics of initially microalbuminuric patients according to albuminuria at follow-up

Normalized No. of patients (M/F) Background data Age at initial investigation (years) Duration at initial investigation (years) Initial AER (jLtg/min)

Follow-up period (years) Initial blood pressure (mmHg) Systolic Diastolic MAP Glycemic control Mean HbA lc onset to follow-up Mean HbAlc 1980-1983 MeanHbA lc 1989-1991 No. of patients with antihypertensive therapy at follow-up

Microalbuminuria

Macroalbuminuria

6 (4/2)

5 (4/1)

16.0(11-19) 7.7 (3-14) 44(26-115) 9.8 (7-14)

19.2(17-21) 8.8 (7-10) 49(36-118) 10.6 (9-12)

114 ± 2.4 72 ± 1.4 86 ± 1.4

111 ± 5.2 68 ± 2.1 82 ± 2.9

126 ± 2.9 75 ± 4.1 92 ± 3.2

6.7 ±0.2 7.5 ± 0.2 6.6 ± 0.3

7.7 ± 0.4 7.9 ± 0.5 7.3 ± 0.3

8.9 ± 0.5 8.9 ± 0.9 8.7 ± 0.3

15(4/11) 17.2 8.0 50 9.4

(14-21) (3-17) (29-188) (5-14)

0

0

2

Data are means (range) or means ± SE. AERs are geometric means. Mean HbA lc onset to follow-up indicates HbAlc from diagnosis of microalbuminuria until diagnosis of nephropathy or follow-up.

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recent study based on one single 24-h urine collection showed a lower rate of patients who developed nephropathy (31%) during 5 years of follow-up (21); whether this would have changed with more measurements is uncertain. All our patients who developed nephropathy had microalbuminuria initially. This indicates that the sensitivity of the AER measurements was satisfactory, but the specificity for predicting nephropathy was less than in earlier studies (5-7). There were no initial differences in AERs between the patients with microalbuminuria in whom AER normalized or was maintained and those who developed nephropathy until follow-up. It has been shown that AER measurements during 24 h give 25% higher values than AER measured overnight (26). If we had used a 25% higher limit for microalbuminuria (26 jLtg/min), the number of initially microalbuminuric patients would have been unchanged, so the different methods of urine collection, initially 24-h measurements and timed overnight measurements at follow-up, cannot explain the high incidence of regression of microalbuminuria to normoalbuminuria and the low rate of development of macroalbuminuria. The level of microalbuminuria may be of importance for the prognosis. A combined analysis of the patients with microalbuminuria at entry in the Steno 1 and Steno 2 studies demonstrated no significant progression of disease among the patients with initial AERs of 30-99 mg/24 h during 5-8 years of follow-up (18). In our study, 23 patients had initial AERs in the range of 20-100 /xg/min. Of these patients, 4 developed macroalbuminuria, 5 had AERs in the same range, and 13 had AERs 15 years, 5 of 18 with microalbu- the majority microalbuminuria will disminuria developed macroalbuminuria appear. 316

Acknowledgments— The study was supported by Barndiabetesfonden (The Swedish Child Diabetes Foundation), The Swedish Diabetes Association, and the Research Funds of the County of Ostergotland and the County of Jonkoping. References 1. United States Renal Data Service: Annual report 1990. Am] Kidney Dis 16 (Suppl. 2):22-27, 1990 2. Borch-Johnsen K, Kragh Andersen P, Deckert T: The effect of proteinuria on relative mortality in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 28:590596,1985 3. 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 4. Bojestig M, Arnqvist AJ, Hermansson G, Karlberg BE, Ludvigsson J: Declining incidence of nephropathy in insulindependent diabetes mellitus. N EnglJ Med 330:15-18, 1994 5. Viberti GC, Hill RD, Jarret RJ, Argyropoulos A, Mahmud Y, Keen H: Microalbuminuria as a predictor of clinical nephropathy in insulin-dependent diabetes mellitus. Lancet i: 1430-1432, 1982 6. Parving HH, Oxenboll B, Svendsen PA, Christiansen JS, Andersen AR: Early detection of patients at risk of developing diabetic nephropathy: a longitudinal study of duration of urinary albumin. Ada Endocrinol 100:550-555, 1982 7. Mogensen CE, Christensen CK: Predicting diabetic nephropathy in insulindependent patients. N EnglJ Med 311:89— 93,1984 8. Messent JWC, Elliott TG, Hill RD, Jarret RJ, Keen H, Viberti GC: Prognostic significance of microalbuminuria in insulindependent diabetes mellitus: a twentythree year follow-up study. Kidney Int 41: 836-839, 1992 9. Bangstad HJ, 0sterby R, Dahl-Jorgensen K, Berg KJ, Hartmann A, Hanssen KF: Improvement of blood glucose control in IDDM patients retards the progression of morphological changes in early diabetic nephropathy. Diabetologia 37:483-490, 1994 10. Wang PH, Lau J, Chalmers TC: Metaanalysis of effects of intensive bloodglucose control on late complications of type 1 diabetes. Lancet 341:1306-1309, 1993 11. The Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes


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