Neurology India Medknow Publications on behalf of the Neurological Society of India ISSN: 0028-3886 EISSN: 1998-4022 Vol. 51, Num. 3, 2003, pp. 355-358

Neurology India, Vol. 51, No. 3, July, 2003, pp. 355-358

Effect of losartan on albuminuria, peripheral and autonomic neuropathy in normotensive microalbuminuric type 2 diabetics

Kubba S, Agarwal SKK, Prakash A, Puri V, Babbar R, Anuradha S
Departments of Medicine, Maulana Azad Medical College & Associated Lok Nayak and GB Pant Hospitals, New Delhi - 110002

Correspondence Address:
5, LF, Todar Mal Square, Bengali Market, New Delhi - 110001
prakashanupam@hotmail.com

Code Number: ni03115

ABSTRACT

Background: Angiotensin converting enzyme (ACE) inhibitors are emerging as effective agents for preventing microvascular complications of diabetes. Losartan (angiotensin II antagonist) has an antihypertensive efficacy equivalent to ACE inhibitors, however its role in microvascular complications is not yet known. Material and Methods: We studied the efficacy of losartan (50 mg once daily for 12 weeks) on albuminuria, peripheral and autonomic neuropathy in 25 normotensive microalbuminuric type 2 diabetics who were asymptomatic for neuropathy. Results: Mean age was 46.6 ± 4.34 years with the average duration of diabetes being 8.1 ± 1.54 years. Albuminuria improved significantly from 54 ± 9.35 mg/L to 32.8 ± 25 mg/L (Paired student's t-test, P=0.0005) after therapy. Autonomic neuropathy was observed in 64% while 76% had peripheral neuropathy; but there was no improvement with losartan. The duration of diabetes had a negative correlation with autonomic neuropathy. It also had a similar negative correlation with median and common peroneal nerve motor conduction velocities (Pearson's correlation coefficient, r = -0.53, P<0.01 and r = -0.56, P<0.01 respectively) implying that autonomic and peripheral neuropathy worsen as a diabetic ages. However, no correlation existed between albuminuria and autonomic or peripheral nerve function. Conclusion: Autonomic and peripheral neuropathy are highly prevalent in normotensive microalbuminuric diabetic patients. Losartan remarkably improves albuminuria but a similar benefit in autonomic or peripheral neuropathy is not seen over 12 weeks. The future may see a defining role for losartan in microvascular complications in normotensive diabetics.

INTRODUCTION

Diabetic microvascular complications have always generated a lot of interest. Microalbuminuria reflects microangiopathy in the renal tissues and precedes the development of overt diabetic nephropathy. It is also increasingly being considered as an independent risk factor for diabetic neuropathy.[1] Therefore, microalbuminuria besides having a diagnostic benefit, may also have a therapeutic advantage. Angiotensin converting enzyme (ACE) inhibitors reverse microalbuminuria and prevent nephropathy. Extending the same analogy, ACE inhibitors should benefit all vascular beds, including neuropathy and retinopathy; and reports exist in their support.[2],[3] The antihypertensive efficacy of losartan, an angiotensin II-antagonist (AT-antagonist), is similar to ACE inhibitors; however, its efficacy in microvascular complications has not been extensively studied.[4] We studied the efficacy of losartan on albuminuria, peripheral and autonomic neuropathy in normotensive microalbuminuric type 2 diabetics.

MATERIAL AND METHODS

Twenty-five normotensive type 2 diabetic patients asymptomatic for neuropathy and positive for microalbuminuria [Urinary albumin excretion rate (UAER) of 20-200 mg/liter (equivalent to 20-200mg/min) in at least 2 out of 3 samples tested over a 6-month period] were included in the study, after obtaining an informed written consent. UAER was determined by the semi-quantitative micral dipstick test [Micral II sticks (Boehringer Mannheim UK, Ltd, Bell lane, Lewes East Sussex, BN7 ILG, GB)] in a first morning urine sample, collected immediately after rising. Normotension was taken as an office blood pressure < 140/90 mm Hg in the sitting position, taken on separate visits coinciding with urine microalbuminruia testing over a 6-month period. No postural drop in blood pressure or sudomotor changes on examination were evident. None of these patients had any positive or negative sensory symptoms or motor weakness; and hence these patients were taken to be asymptomatic for neuropathy. A complete metabolic, hematologic and biochemical profile was performed for each patient including a urine examination prior to inclusion in the study. A baseline assessment for autonomic and peripheral neuropathy was done by performing autonomic function tests and nerve conduction studies for each patient. Each subject was started on losartan 50 mg per oral once daily (taken in the morning soon after getting up) for a period of 12 weeks; following which UAER determination and neuropathy assessment were repeated.

The autonomic function tests performed were: Standing to lying ratio (S/L ratio), 30:15 ratio, valsalva ratio, blood pressure response to sustained handgrip, and cold pressor response (CPR). These were done by a single investigator using a highly sensitive oscillograph, the Polyrite-8 Medicare Machine (Inco Ambala make). These tests and the blood pressure measurements were performed in the forenoon (9 am to 11 am).
The methodology adopted for autonomic assessment was as under:

1. Standing to Lying Ratio (S/L Ratio): Each subject was asked to stand quietly and then lie down without any support while a continuous ECG was recorded from 20 beats before to 60 beats after lying down. The point at which the subject started to lie down was marked. The S/L ratio was calculated as follows
S/L Ratio = (longest R-R interval during 5 beats before lying down)/ (shortest R-R interval during 10 beats after lying down).
The maximum ratio of three trials was taken. An S/L ratio of >1.01 was taken as normal.

2. 30:15 Ratio: Each subject lay quietly for 3 minutes, then stood up and remained motionless and a continuous ECG was recorded and a point was marked to identify the point of standing. The 30:15 ratio was calculated by taking the ratio of the R-R interval at beat 30 and at beat 15 after standing. Normal values were taken as >1.04.

3. Valsalva Ratio: Each subject performed the valsalva maneuver for 15 seconds by blowing against a closed glottis through a mouthpiece attached to an aneroid manometer and maintained a pressure of 40 mm Hg for 15 sec. Three trials were performed at intervals of 5 minutes. A continuous ECG was recorded 1 min before the maneuver (resting period), during the maneuver (strain period, 15 sec.) and 60 seconds subsequent to the strain period. The valsalva ratio was calculated as the ratio of the maximum R-R interval after the strain to that of the shortest R-R interval during the strain, with values >1.21 as normal.

4. Blood Pressure Response to Static Exercise (Hand Grip Test, HGT): The subject was asked to apply pressure on a handgrip dynamometer for 1 minute at 30% of maximal voluntary contraction and simultaneously the blood pressure changes were observed. The difference between the diastolic blood pressure (DBP) just before the release of contraction and that before handgrip began was taken as a measure of the response. A rise in DBP >16 mm Hg was considered normal.

5. Cold Pressor Response (CPR): Resting BP was recorded with the subject sitting comfortably following which his hand was immersed in cold water and the temperature maintained at 4-60C throughout the procedure. BP measurement was made from the other arm at 30-second intervals for a period of 2 minutes. After 2 minutes, the subject was allowed to remove his hand. The maximum increase in the systolic and diastolic pressures was determined and the results recorded. The difference between the systolic blood pressure before and after immersion in cold water was taken as a measure of response, with a rise of >16 mm Hg considered as normal.

Autonomic dysfunction is common in microalbuminuric patients and the above 5 tests are simple tests for detecting autonomic dysfunction. 5 For assessment of peripheral neuropathy, median motor and common peroneal motor nerve conduction velocities (NCV) of the dominant limb of the patients were measured on a Medlec Premiere computerized machine with surface electrodes. The skin temperature was kept above 320C with a surface heater. A median motor NCV of < 52m/s and/or a common peroneal motor NCV of <41m/s of the dominant limb was taken as evidence of peripheral neuropathy. This was based on the standardized results of nerve conduction studies in our laboratory.

All the data generated was analyzed on a Windows 2000-based Microsoft Excel software (paired student's t-test and Pearson's coefficient of correlation) and a P value >0.05 was taken as rejection for null hypothesis.

RESULTS

The mean age of our study group was 46.6 ± 4.34 years and the average duration of diabetes mellitus was 8.1 ± 1.54 years. The male to female ratio was 1.08:1. The average BMI was 25.376 ± 1.8 kg/m2. The blood pressure, metabolic and biochemical profile before and after the completion of the study has been delineated in [Table-1]; there was no significant change in the various parameters.

Albuminuria improved significantly (paired student's t-test; P=0.0005) after 12 weeks of losartan therapy from 54 ± 9.35 mg/L (range 50-75 mg/L) to 32.8 ± 25 mg/L (range 0-75 mg/L). [Table-2] depicts the autonomic and peripheral nerve function parameters assessed. Sixty-four per cent of our subjects had autonomic neuropathy as evidenced by at least 3 abnormal tests out of the 5 performed for the assessment of autonomic neuropathy. Over three-fourths of our subjects (76%) had peripheral neuropathy. This is striking since all our patients were asymptomatic for neuropathy. As is obvious from the table, no significant change in the autonomic or peripheral nerve function was appreciable after 3 months of losartan therapy.

The correlation of various autonomic function parameters with the duration of diabetes is shown in [Table-3]. A negative correlation was observed between the duration of diabetes and autonomic function parameters (except for the 30:15 ratio) suggesting that autonomic dysfunction progresses with an increasing duration of diabetes. A significant negative correlation was also noted between the duration of diabetes and median and common peroneal nerve motor conduction velocities (r = -0.53, P<0.01 and r = -0.56, P<0.01 respectively) implying that peripheral neuropathy worsens as a diabetic ages.

There was a positive correlation between autonomic function parameters (except S/L ratio) and peripheral nerve function as outlined in [Table-3]. However, no correlation existed between UAER and autonomic or peripheral nerve function.

DISCUSSION

Scientific research is on for early markers of diabetic microvascular complications. Apart from being a marker of nephropathy, microalbuminuria is being evaluated as a marker of microangiopathy in other vascular beds viz. the nervous system and the retinal vasculature. Recent reports have projected it to be an independent risk factor for diabetic autonomic and peripheral neuropathy;[1],[5],[6] opening up avenues for intervention and throwing open the discussion of whether neuropathy can also be prevented. Angiotensin II has been implicated as a causative factor in the development of diabetic microvascular complications[7],[8],[9] and ACE inhibition has revolutionized the management of diabetics with improvements in nephropathy, neuropathy and retinopathy, the 3 dreaded microvascular complications of diabetes.[2],[10],[11],[12] The main handicap with ACE inhibitors is cough as a side-effect; which fortunately is not present with AT-antagonists.

Losartan in our study improved albuminuria remarkably over a period of 12 weeks. ACE inhibitors are accepted as candidate drugs for microalbuminuric diabetics despite normotension; this effect is believed to be independent of their antihypertensive effect. It is believed that they improve intraglomerular hypertension, which occurs well before systemic hypertension in these patients. Losartan has benefits apart from its antihypertensive effect in overt nephropathy in hypertensive type 2 diabetics as it retards progression to end-stage renal disease.[13] Our study authentically proves the efficacious role of losartan in reducing albuminuria in normotensive diabetics with microalbuminuria; thus improving nephropathy. There was no significant change in the metabolic or biochemical profile of the subjects; hence, the improvement in nephropathy cannot be attributed to an improvement in glycemia or dyslipidemia. Blood pressure reduction in normotensive diabetics has been reported to benefit nephropathy irrespective of the antihypertensive agent (nisoldipine or enalapril) used.[14] The RENAAL study also reported lower blood pressure with losartan at 1 year.[13] The absence of a significant reduction in blood pressure despite losartan therapy can be attributed to the fact that our patients were normotensive and the duration of therapy was 12 weeks only.

In sharp contrast to nephropathy, neither autonomic nor peripheral neuropathy showed any significant change over a 12-week period. One earlier study had recorded a significant improvement in the motor NCV with trandolapril (an ACE inhibitor) but this effect was observed only after 12 months of therapy.[2] A study using quinapril, showed that there was a significant improvement in autonomic function.[15] Another study which showed the beneficial effect of lisinopril on the median and peroneal nerve motor NCV after 3 months of therapy used a high dose of lisinopril (20 mg/day) and the patients included in this study were hypertensive.[12] It was also seen that lisinopril reduced the blood pressure significantly in these patients and that there was a significant correlation between the improvement in motor NCV and the reduction in the blood pressure. It may be that a longer duration of therapy or a higher dose of losartan may be warranted for any discernible benefit. A placebo group could have made this study more interesting but it would have been unethical to administer placebo to microalbuminuric diabetics, since ACE inhibitors/ AT-II antagonists are the principal drugs for intervention in this group and their use is advocated at the earliest.

There was a significant negative correlation between all the parameters of autonomic function and the duration of diabetes (except the 30:15 ratio). A similar significant negative correlation has also been reported by other authors.[16],[17]

Although some earlier studies have shown UAER to correlate with diabetic autonomic and peripheral neuropathy,[1],[5],[6] we could not establish such a correlation in our study suggesting that the worsening of microvascular disease in the renal and nervous system may be guided by separate factors. Autonomic neuropathy has been reported to be over two times more common in diabetics with nephropathy than in diabetics without nephropathy in south India;[18] although a direct comparison cannot be made since our patients had microalbuminuria and not overt nephropathy. Perhaps genetic, ethnic, immunological or other factors hitherto unknown may be responsible in the development of diabetic autonomic and peripheral neuropathy.

Losartan in a dose of 50 mg/day for 12 weeks significantly improved albuminuria. However, improvement in autonomic or peripheral neuropathy over such duration was not noticed. Although no significant correlation between the albumin excretion rate and neuropathy was evident, a high prevalence of autonomic and peripheral neuropathy was detected in normotensive diabetics with microalbuminuria even though they were asymptomatic for neuropathy. Further studies on similar lines may well confirm the status of angiotensin antagonists like losartan as the drugs of choice in normotensive diabetics for prevention of microvascular complications.

REFERENCES

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