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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 1 155-158
Copyright © 2000 by The Endocrine Society

Original Studies

No Deleterious Effects of Tight Blood Glucose Control on 24-Hour Ambulatory Blood Pressure in Normoalbuminuric Insulin-Dependent Diabetes Mellitus Patients

P. L. Poulsen, K. W. Hansen, E. Ebbehøj, S. T. Knudsen and C. E. Mogensen

Medical Department M (Diabetes and Endocrinology), Aarhus Kommunehospital, DK 8000 Aarhus, Denmark

Address correspondence and requests for reprints to: Per Løgstrup Poulsen, Department of Medicine M (Diabetes and Endocrinology), Aarhus Kommunehospital, DK 8000 Aarhus C, Denmark. E-mail: Logstrup{at}dadlnet.dk


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Intensive therapy aiming at near normalization of glucose levels effectively delays the onset and slows the progression of complications in insulin-dependent diabetes mellitus (IDDM) and is recommended in most patients. However, in a recent report, intensive insulin treatment was found to be associated with deleterious effects on nocturnal blood pressure (BP), the proposed mechanisms being subclinical nocturnal hypoglycemia or hyperinsulinemia. The aim of the present study was to evaluate the association between glycemic control, insulin dose, and 24-h ambulatory BP (AMBP) in a group of well-characterized IDDM patients.

Twenty-four-h AMBP was measured in 123 normoalbuminuric [urinary albumin excretion (UAE) < 20 µg/min] IDDM patients using an oscillometric technique (SpaceLabs 90207) with readings at 20-min intervals. UAE was measured by RIA and expressed as geometric mean of three overnight collections made within 1 week. Tobacco use and level of physical activity was assessed by questionnaire. HbA1c was determined by high-pressure liquid chromatography (nondiabetic range, 4.4–6.4%), and patients were stratified into quartiles according to HbA1c levels.

Mean HbA1c values in the four groups were 7.0% (n = 31), 8.0% (n = 31), 8.6% (n = 31), and 9.7% (n = 30). The groups were comparable regarding age, gender, diabetes duration, body mass index, UAE, smoking status, and physical activity. AMBP levels were almost identical in the HbA1c quartiles with night values of (increasing HbA1c order): 110/63, 112/66, 112/66, and 113/65 mm Hg (P = 0.69/P = 0.32). There was no association between tight glucose control and higher nocturnal BP or a more blunted circadian BP variation. On the contrary, a weak positive correlation between night to day ratios of mean arterial BP and HbA1c values was found (r = 0.26, P = 0.005), i.e. blunted circadian BP variation is most frequent in patients with high HbA1c values. Neither did we find doses of insulin to be associated with night BP (r = 0.04, P = 0.68).

Tight blood glucose control is not associated with deleterious effects on 24-h AMBP in normoalbuminuric IDDM patients. Intensive therapy can be implemented without concerns of inducing high nocturnal BP and accelerating diabetic complications.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ON THE BASIS of several studies, most notably the Diabetes Control and Complication Trial (DCCT) (1, 2, 3, 4, 5), it is now recommended that closely monitored intensive regimens aiming at near normalization of glucose levels are implemented in most patients with insulin-dependent diabetes mellitus (IDDM). This is considered to be one of the major cornerstones in modern diabetology as intensive treatment has been proven to delay the onset and slow the progression of clinically important retinopathy, nephropathy, and neuropathy by a range of 35–70% (1).

It was, thus, with grave concern we read a very recent report by Azar and Birbari (6) in which intensive insulin therapy was found to be associated with severely increased night blood pressure (BP). There is a strong and well established relationship between BP elevation, perhaps especially night BP, and development and progression of several diabetic complications (7, 8, 9, 10, 11, 12, 13). Thus, the findings of Azar and Birbari (6), in fact, question the widely accepted strategy of preventing diabetic complications by tight blood glucose control because such regimens apparently could induce deleterious effects on nocturnal BP with harmful effects on diabetic nephropathy (7, 8, 14, 15, 16, 17, 18, 19, 20, 21) and other diabetic complications. The aim of the present study was to further evaluate the relationship between glycemic control, insulin consumption, and 24-h ambulatory BP (AMBP), especially nocturnal BP, in a larger group of well characterized IDDM patients.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
One hundred twenty-three IDDM patients were consecutively recruited for a prospective study addressing identification of risk factors for the development of complications in IDDM. Other aspects regarding these patients have been published previously (22). Participants had to be normoalbuminuric (UAE < 20 µg/min in at least two of three overnight collections) and without other chronic diseases. None received (or had earlier received) antihypertensive or other continuous medical treatment apart from insulin. UAE was measured by RIA and expressed as geometric mean of three overnight collections made within 1 week. HbA1c was determined by high-pressure liquid chromatography (nondiabetic range, 4.4–6.4%), and blood glucose was determined by Reflolux II (Roche Diagnostics, East Essex, UK). AMBP was measured by an oscillometric technique (SpaceLabs 90207) (23), with readings at 20-min intervals throughout 24 h. Measurements were performed during a day with normal activities at home or at work. Individually reported sleeping times were implemented in the calculation of day and night BP. No records with more than two missing hours were accepted. All patients followed their usual insulin regimen. None of the patients reported symptoms suggestive of hypoglyglycemia during the 24-h AMBP. Leisure-time physical activity was graded as passive (not participants), moderate (physical exercise once or twice a week), and active (physical exercise more than twice a week). Tobacco consumption was graded as nonsmokers (without daily use of tobacco for at least the last year), moderate smokers (less than 15 cigarettes per day), and heavy smokers (more than 15 cigarettes per day). Five patients smoking one packet of pipe tobacco per week were classified as moderate smokers. The study was approved by the local ethics committee, and patients gave their written informed consent.

Statistical analysis

Before analysis, UAE values were log transformed to approximate normal distribution. When ANOVA indicated significant differences between groups, pair-wise comparisons were assessed with significance levels appropriately modified using the method of Bonferroni. For noncontinuous variables, the {chi}2 test with Yates correction was used. Correlations were analyzed using Pearsons test. A two-tailed P value of less than 0.05 was considered significant. Results are expressed as mean ± SD, except for UAE, which is presented as geometric mean x/÷ tolerance factor. We have previously determined the SD of the difference of night diastolic AMBP determinations to 5.5 mm Hg(24). With an {alpha} value of 0.05 and a power of 0.80, our sample size is sufficient for detecting a difference of 4 mm Hg or more between the group with the lowest and the group with the highest HbA1c values [Azar and Birbari (6) reported a difference of 11 mm Hg].


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Clinical characteristics of the patients are given in Table 1Go. Patients were stratified into quartiles according to HbA1c levels, resulting in four groups each consisting of approximately 30 patients. The groups were similar regarding age, duration of diabetes, gender, body mass index, UAE, level of physical activity, and cigarette smoking. AMBP data are given in Table 2Go, and mean values for systolic and diastolic night BPs for the four groups are depicted in Fig. 1Go. Both 24-h, day, and night BPs were similar in the four groups with P values ranging from 0.32–0.80. Diastolic night BP in the group with the tightest blood glucose control was 2.3 mm Hg lower than the group with the poorest blood glucose control with 95% confidence intervals ranging between 6 and -1.5 mm Hg. Twenty-four-h blood pressure patterns are depicted in Fig. 2Go. As shown in Fig. 3Go, there were no indications of any association between low HbA1c values and high night BP or blunted circadian BP variation, as indicated by diastolic night to day ratio. Indeed, quite the reverse relationship was present, with high HbA1c values showing a weak but statistically significant (r = 0.26, P = 0.005) association with smoothing of circadian BP variation. Dose of insulin (units/kg body weight) was not associated with diastolic night BP (r = 0.04, P = 0.68), and comparing the quartile with the highest insulin dose (0.9 ± 0.11 units/kg) to the quartile with the lowest insulin dose (0.4 ± 0.07 units/kg) did not reveal any differences in night, day, or 24-h BP (night BP, 112/64 vs. 111/64 mm Hg, P = 0.86/P = 0.60).


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  		Table 1. Clinical characteristics (mean ± SD, except when indicated)

 

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  		Table 2. AMBP data (mean ± SD)

 


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  		Figure 1. Night AMBP in normoalbuminuric IDDM patients divided according to HbA1c quartiles.

 


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  		Figure 2. Twenty-four-h BP patterns in normoalbuminuric IDDM patients with good glycemic control (HbA1c < 7.5%, n = 31) and poor glycemic control (HGA1c > 9.0%).

 


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  		Figure 3. Diastolic night AMBP and HbA1c in normoalbuminuric IDDM patients (n = 123).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Comparing 18 patients receiving intensive insulin treatment (mean HbA1c value, 8.1%) with 18 patients receiving conventional insulin treatment (mean HbA1c value, 11.0%), Azar and Birbari (6) found diastolic night BP to be 11 mm Hg higher in the intensively treated group and conclude that intensive therapy has a deleterious effect on nocturnal BP in IDDM patients. We are not able to confirm this critical clinical finding, as we find similar BPs in the groups with low and high HbA1c values. Our sample size and power calculations rule out that this can be a matter of a type 2 error. Indeed, we find quite the reverse relationship: low HbA1c values are associated with low night BPs and a preserved circadian BP variation. One important point behind the difference between the two studies may be the calculation night BP. Rather than using fixed nighttimes we used individually reported sleeping times in the calculation of day and night BP, thus avoiding erroneously overestimation of the fraction of patients with abnormal circadian variation (25).

Another reason for the clear discrepancy may be differences in insulin doses: the patients in Azar and Birbari’s (6) intensively treated group received doses of insulin that would seem very high (in average, 1.0 U/kg). This is considerably higher than the average doses in our patients and also much higher than reported by the DCCT, where the mean dose of insulin was 0.72 U/kg and 0.67 U/kg in the intensive- and conventional-treated groups, respectively (26). In the early Danish insulin infusion study (2), one of the first studies to describe positive effects of strict metabolic control on incipient nephropathy, insulin doses were again far below the average in Azar and Birbari’s (6) intensively treated group. It, thus, seems important to stress that tight blood glucose control can be achieved without overinsulinization. Within the range of doses of insulin used by our patients we find no association between insulin dose and BP. In the DCCT, there were no differences in the cumulative incidence of hypertension in the two groups, and in the Danish insulin infusion study, BP rose significantly only in the conventional-treatment group, whereas BP in the group with strict metabolic control remained stable over the 2 yr study time. In addition, the overall finding of clear beneficial effects of intensive therapy on nephropathy in both these studies does not support the concerns raised by Azar and Birbari (6).

Our data are in concert with a prior multiple regression analysis (24) in which we (with slightly different BP devices and in another patient population) found no evidence of neither HbA1c nor insulin dose as determinants of 24-h or night BP in normoalbuminuric IDDM patients.

In conclusion, we find no evidence of harmful effects of tight blood glucose control on nocturnal BP in normoalbuminuric IDDM patients.

Received February 12, 1999.

Revised September 15, 1999.

Accepted September 23, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. The Diabetes Control and Complication Trial Research Group. 1993 The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 329:977–986.[Abstract/Free Full Text]
  2. Feldt Rasmussen B, Mathiesen ER, Deckert T. 1986 Effect of two years of strict metabolic control on progression of incipient nephropathy in insulin-dependent diabetes. Lancet. 2:1300–1304.[CrossRef][Medline]
  3. Dahl Jorgensen K, Hanssen KF, Kierulf P, BjoroT, Sandvik L, Aagenaes O. 1988 Reduction of urinary albumin excretion after 4 years of continuous subcutaneous insulin infusion in insulin-dependent diabetes mellitus. The Oslo Study. Acta Endocrinol Copenh. 117:19–25.[Medline]
  4. Reichard P, Nilsson BY, Rosenqvist U. 1993 The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus. N Engl J Med. 329:304–309.[Abstract/Free Full Text]
  5. Powrie JK, Watts GF, Ingham JN, Taub NA, Talmud PJ, Shaw KM. 1994 Role of glycaemic control in development of microalbuminuria in patients with insulin dependent diabetes. Br Med J. 309:1608–1612.[Abstract/Free Full Text]
  6. Azar ST, Birbari A. 1998 Nocturnal blood pressure elevation in patients with type 1 diabetes receiving intensive insulin therapy compared with that in patients receiving conventional insulin therapy. J Clin Endocrinol Metab. 83:3190–3193.[Abstract/Free Full Text]
  7. Rossing P, Hommel E, Smidt UM, Parving H-H. 1993 Impact of arterial blood pressure and albuminuria on the progression of diabetic nephropathy in IDDM patients. Diabetes. 42:715–719.[Abstract]
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  9. Microalbuminuria Collaborative Study Group, United Kingdom. 1993 Risk factors for development of microalbuminuria in insulin dependent diabetic patients: a cohort study. Br Med J. 306:1235–1239.
  10. Hansen KW, Mau Pedersen M, Marshall SM, Christiansen JS, Mogensen CE. 1992 Circadian variation of blood pressure in patients with diabetic nephropathy. Diabetologia. 35:1074–1079.[CrossRef][Medline]
  11. Sjolie AK, Stephenson JM, Aldington S, et al. 1997 Retinopathy and vision loss in insulin-dependent diabetes in Europe. The EURODIAB IDDM complications study. Ophthalmology. 104:252–260.[Medline]
  12. Stephenson JM, Fuller JH, Viberti GC, Sjolie AK, Navalesi R. 1995 Blood pressure, retinopathy and urinary albumin excretion in IDDM: the EURODIAB IDDM Complications Study. Diabetologia. 38:599–603.[Medline]
  13. Poulsen PL, Bek T, Ebbehøj E, Hansen KW, Mogensen CE. 1998 24-h ambulatory blood pressure and retinopathy in normoalbuminuric IDDM patients. Diabetologia. 41:105–110.[Medline]
  14. Mathiesen ER, Oxenboll B, Johansen K, Svendsen PA, Deckert T. 1984 Incipient nephropathy in type 1 (insulin-dependent) diabetes. Diabetologia. 26:406–410.[Medline]
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  22. Poulsen PL, Ebbehøj E, Hansen KW, Mogensen CE. 1997 Twenty-four-hour blood pressure and autonomic function is related to albumin excretion within the normoalbuminuric range in IDDM patients. Diabetologia. 40:718–725.[CrossRef][Medline]
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