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ORIGINAL ARTICLES

Lornpar ison of Tolbutamide and Metformin in Elderly Diabetic Patients S. Josephkutty, J.M.Potter Department of Geriatric Medicine, Nunnery Fields Hospital, Canterbury, UK

In a randomized double-blind cross-over study the efficacy, metabolic effects, and acceptability of metformin were compared with tolbutamide in 20 diabetic patients aged between 65 and 95 years. No significant differences were noted after treatment in blood glucose control (fasting plasma glucose, metformin 9.1 f 2.8 mmol I-l, tolbutamide 8.3 f 2.8 mmol I-’; mean change, metformin +1.1 mmol I-l, tolbutamide +0.02 mmol I-’, p = 0.21 5), domiciliary blood glucose control, fasting insulin, lactate, cholesterol or triglyceride levels. There was a significant difference in weight change between the two treatments (on metformin -2.0 kg, from 63.2 2 11.8 to 61.2 f 12.3; on tolbutamide, +1.6 kg, from 61.4 ? 11.1 to 63.0 f 12.3; p = 0.001). Initial gastro-intestinal side-effects occurred in 30 % of patients with metformin. These were transient and responded to temporary reduction in treatment dosage. Metformin could not be distinguished from tolbutamide in elderly diabetic patients, except in that it was associated with weight loss. KEY WORDS

Type 2 diabetes Oral hypoglycaemic agents

Introduction Sulphonylurea treatment of the elderly diabetic patient is complicated by the increased risk of hypoglycaemia, 1 ~ and 3 it is recognized that this can be severe, prolonged, and life-threatenir~g.~-~ Long-acting sulphonylurea agents should be avoided, and shorter-acting agents such as tolbutamide are increasingly favoured in this age-group.6, The increased risk associated with sulphonylurea drugs prompts a review of the potential benefits of biguanides as these drugs are effective anti-hyperglycaemic agents, do not cause hypoglycaemia,8 and have the additional .~ advantage that they are associated with weight 1 0 ~ sThe tendency to ignore or discount these drugs in the arises mainly from concern over the risk of lactic acidosis. However, the risk of this complication associated with metformin has been shown to be very low in the absence of significant renal or hepatic diseaseT3 and to be unrelated to age.14 Since there are no data related specifically to the clinical use of metformin in the elderly, the present study was designed as a double-blind randomized cross-over comparison of the efficacy, metabolic effects, and acceptability of metformin and tolbutamide in diabetic patients over the age of 65 years.



Patients and Methods Patients Patients from the diabetic clinic at Nunnery Fields Hospital aged 65 years or more and taking oral hypoglyCorrespondence to: Dr J.M. Potter, Nunnery Fields Hospital, Canterbury, CTl 3LP, UK

5 10

0742-3071/90/060510-05$05.00

0 1990 by John Wiley

& Sons, Ltd.

Diabetes in the elderly

caemic therapy (fasting blood glucose > 8.0 mmol I-’ or random blood glucose > 15.0 mmol I-’ despite diet treatment), were considered for the study. Patients were excluded if they had blood urea, creatinine or liver function tests outside the normal laboratory range, or if they had had a recent episode of cardiac failure. All patients gave informed consent and the study was approved by the Ethical Committee at the Kent and Canterbury Hospital.

Methods Patients were screened to assess their suitability for the study which included biochemical plasma analysis and an electrocardiogram. They were randomly allocated to initial treatment with either metformin or tolbutamide. Study treatment was continuous with previous therapy to avoid loss of diabetic control, and the initial dosage was from 1 tablet daily (500 mg) to 4 tablets daily (1 g twice daily) depending on the previous treatment level. The metformin and tolbutamide tablets had been specifically formulated for the study and were identical in appearance. It was accepted that early gastro-intestinal symptoms would be managed by a temporary reduction in dose, without determining which of the preparations the patient was on. Progress was monitored by 2-weekly plasma glucose profiles performed by a district nurse in the patient’s own home. Samples were obtained before breakfast, and at 1100, 1500, and 1900 h, and were stored overnight prior to laboratory plasma glucose estimation. Patients also attended the diabetic clinic at monthly intervals. At these visits they were reviewed regarding symptoms related to diabetes, to general health, and, using a standardized questionnaire, to side-effects of drug treatment. Compliance was checked by the use of a Accepted 9 March 1990 DIABETIC MEDICINE, 1990; 7: 510-514

Dm tablet count. The patients were weighed, had their blood pressure checked and were examined. Diabetic control was monitored by plasma glucose and HbA, estimation performed in the clinic, and by the results from domiciliary plasma glucose estimations. Dosage changes were based on the fasting plasma glucose level obtained during domiciliary profiles. If the fasting plasma glucose was greater than 8 mmol I-’ the dosage was increased by one tablet (500 mg of either drug) up to a maximum of 6 tablets daily (1 g three times daily of either drug) with the aim of achieving a fasting glucose of less than 8.0 mmol I-, and a HbA, less than 10.0 % (normal reference range 5.6-8.9 %). The metabolic and haematological status of the patients was checked at each clinic visit. Fasting insulin, lactate and lipid levels were measured at the first visit and at the end of each treatment period. After 3 months treatment, the patients were changed onto the alternative therapy with no alteration of the dosage regimen. The same monitoring was continued for a further 3 months. Plasma glucose estimations were performed on a Beckman Mark II glucose autoanalyser (Beckman Instruments UK, High Wycombe, UK). Serum urea, creatinine, and liver function testing were performed by automated clinical chemistry analysis using a Technicon SMA 2 autoanalyser (Technicon Instruments, Basingstoke, UK), and serum cholesterol and lipids were measured using a Greiner autoanalyser (Greiner Electronics GB, London, UK). Samples for insulin assay were immediately centrifuged and the plasma frozen and stored. The samples were assayed as a batch and in duplicate using a double antibody t e c h n i q ~ e . ’Lactate ~ was measured by an enzymatic fluorimetric method.I6 Statistical analyses were performed using an analysis of variance for a cross-over study by the method of Hills and Armitage.”

ORIGINAL ARTICLES Table 1 . Clinical characteristics of the patients studied Group 1 Metform in/ tolbutamide n Age (yr) Sex (F/M) Height (m) Weight (kg) Body mass index Duration of diabetes (yr)

Group 2 To1butam idel metformin

10 10 76.5 (67-94) 80.5 (72-90) 713 713 1.57 (1.49-1.73) 1.57 (1.48-1.71) 65.7 (43.0-83.4) 63.2 (54.2-83.9) 24.0 (1 8.9-29.8) 25.8 (20.9-32.7) 1.8 (0.5-1 5) 1.5 (0.1-8)

Number, or median (range)

Table 2. Diabetic control in 20 elderly patients changed between tolbutamide and metformin Before treatment

12 weeks

Change

p

Fasting plasma glucose (mmol I-’) Metformin 8.0 (2.1) 9.1 (2.8) Tolbutamide 8 . 3 (2.8) 8 . 3 (2.8)

+ 1 . 1 (2.4) NS 0.0 (3.2)

Fasting plasma insulin (mu I-’) Metformin 13.8 (7.1) 13.7 (9.4) Tolbutamide 14.3 (9.3) 13.9 (7.3)

-0.1 (4.7) NS -0.4 (4.3)

HbA, (%) Metform in Tolbutamide

10.2 (1.4) 10.1 (2.6)

10.8 (2.1) +0.6 (2.2) NS 10.0 (1.6) -0.1 (2.5)

Body weight (kg) Metformin 63.2 (11.8) 61.2 (12.3) -2.0 (2.4) 0.001 Tolbutamide 61.4 (11.1) 63.0 (12.3) +1.6 (2.6) Mean (SD). p Values are for the differences between treatment means applying an analysis of variance for a 2-period cross-over study. The treatment order and period effects were not statistically significant.

Results Twenty-one patients were recruited to the study. One patient dropped out of the study at the start of metformin treatment due to severe nausea and headache. The results are based on the 20 patients who completed the study. Details of the patients are given in Table 1.

Diabetic Control Comparison of the fasting plasma glucose levels, HbA, levels and fasting insulin levels obtained at the clinic, is shown in Table 2. There were no significant differences between the two treatment regimens. The effect on plasma glucose levels obtained during domiciliary profiles is shown in Figure 1 . At week 9, plasma glucose levels were higher on metformin compared with tolbutamide, fasting (+0.9 mmol I-’, p < 0.03), 2 h after breakfast, (+2.5 mmol I-’, p < 0.02), and 2 h after lunch (+2.4 mmol I-’, p < 0.002). No differences were noted between treatMETFORMIN VS TOLBUTAMIDE IN THE ELDERLY

ments by the end of the domiciliary assessments at week 11.

Metabolic and Clinical Control No significant changes were seen during the study in the following biochemical measures: urea, electrolytes, bilirubin, alkaline phosphatase, aspartate dehydrogenase, cholesterol or triglyceride. A possible rise in blood lactate concentration on metformin (before treatment, 1.33 2 0.52 mmol I-’; at 0.81 mmol I-’) was not statistically 12 weeks, 1.77 significant. Lactate levels on tolbutamide did not change during treatment and were not significantly different from those on metformin treatment (before treatment, 1.492 0.76 mmol I-’; at 12 weeks 1.46 k 0.61 mmol I-’). There was a highly significant difference in body weight on the two therapies, with an increase on tolbutamide ( + 1 . 6 kg) and a decrease on metformin

*

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ORIGINAL ARTICLES

Table 3. The number of patients reporting a symptom on either tolbutamide or metformin but not on both tablet regimens

Fasting

4 1

(rnmol 1 - 7 1

2 - h a f t e r breakfast

Tolbutamide

Metformin

B loatedness Nausea Vomiting Diarrhoea Constipation

-

6 "8

Agitationitrembling Sweating Dizziness Tiredness Headaches Metallic taste Skin rashiirritation

1 2

2

-

4

4

1

3 1 2

3 2 1 1

-

"2

-

2

2

-

4 1

J

1

1

"Includes the patient who withdrew from the study due to side-effects

Discussion

2 - h after lunch

T

2 - h after dinner

Weeks

Figure 1 . Domiciliary blood glucose control (mean t SD) during tolbutamide (- - - -) and metformin -( ) treatment periods. Medication cross-over at 12 weeks (........)

(-2.0 kg, p = 0.001). There were no changes in blood pressure during either treatment regimen (data not shown).

Side-effects The incidence of symptoms reported is shown in Table 3. There was a distinct trend to gastro-intestinal symptoms on metformin, with frequent bloatedness and nausea, sometimes leading to diarrhoea and vomiting. These symptoms were short-lived. In some cases a temporary reduction in dosage was required to ameliorate symptoms. Additional symptoms that occurred on metformin were headaches and a metallic taste. Tolbutamide was generally associated with milder sideeffects. Constipation and skin irritationhash appeared to occur more frequently than on metformin.

512

Blood glucose control in these elderly patients was assessed by home monitoring with laboratory analysis of glucose samples. This provided a continuing and precise profile of control during the 3-month treatment periods, which included the inevitable intercurrent illnesses and other problems associated with the elderly. The assessment of diabetic control in the community was augmented by and appeared related to fasting plasma glucose and HbA, estimations obtained in the clinic. A run-in and wash-out period prior to the study was not included, as the aim of the study was to compare the effect of tolbutamide and metformin in the elderly, rather than to prove their efficacy. Furthermore, it was not felt reasonable to permit loss of blood glucose control in known diabetic patients. The fasting blood glucose level has been suggested to be an accurate and simple measure of control in noninsulin-treated diabetes,l8 and in this respect there was no difference between the two agents. The results obtained with both drugs, whether as domiciliary glucose levels, or in the clinic as fasting glucose levels or glycosylated haemoglobin levels, were similar to those reported in the past for this type of ~ a t i e n t . ' ~ -Although ~' no other studies have specifically assessed metformin .and tolbutamide in the elderly, several studies have demonstrated effective blood glucose control using metformin compared with sulphonylurea agents in younger patients, and also the trend to weight gain on sulphonylurea agent^.^'-^^ In a study comparing glibenclamide and metformin in Type 2 diabetic patients under 70 years of age, Rains et a / . demonstrated that both agents were equally effective in reducing fasting glucose levels and confirmed the tendency for sulphonylurea agents to cause weight gain.21 In a study of non-obese Type 2 diabetic patients Clarke and Campbell22 included a subgroup S. JOSEPHKUTTY, J.M. POTTER

DTT1 aged 60-70 years. Control was similar when managed with chlorpropamide or metformin. Weight gain was noted on sulponylurea while weight loss occurred on metformin. Lim and K h 0 0 * ~have compared metformin and tolbutamide in 3 0 Type 2 diabetic patients aged 32 to 54 years, and noted similar efficacy between the drugs as first line therapy, while Ferner et a/. suggested that metformin is as effective as tolbutamide in improving fasting blood glucose levels in newly diagnosed Type 2 diabetic patients under the age of 65 years.24 Gastro-intestinal symptoms frequently arise on initial treatment with metformin. However, they are normally transient and are ameliorated by controlled dose escala t i ~ n .In~ ~ this study 3 0 % of patients experienced some initial gastro-intestinal disturbance o n metformin. However, in all but one case, this did not prevent them completing the treatment course. O n e patient was not prepared to persevere after the initial symptoms o n metformin treatment and withdrew from the study. These observations emphasize that i n the elderly, as in other age groups, it is important to introduce metformin at a low dose and build u p gradually to the required effective level. Highly significant changes i n weight occurred during the t wo treatment periods. Although the possibility of a Type 1 statistical error is appreciated when multiple analyses are carried out, such an error is unlikely when differences such as these are highly significant

(p = 0.001). It is well recognized that reduction in weight can markedly improve glucose tolerance i n Type 2 diabetes2"J7 and this i s often particularly relevant i n the elderly. Blood pressure levels were not affected by treatment, either with tolbutamide or metformin. The risk of lactic acidosis i s a concern when using biguanide drugs. In this study, a trend towards an increase in lactate levels was seen while patients were o n metformin treatment, although there was n o significant difference between treatment groups and the levels did not rise above the normal range.28 It was reassuring that in this study, which included some very elderly diabetic patients, and during which intercurrent illnesses inevitably occurred, there was no evidence of any significant deterioration in intermediary metabolism leading to lactate accumulation. It remains important, however, to exclude those with overt hepatic or renal disease, or overt cardiac failure, from the use of metformin. The study was designed to assess the practicality of using metformin in a group of truly elderly diabetic patients, and t o compare its efficacy with tolbutamide. The study has demonstrated that, in this age group, metformin i s an effective anti-hyperglycaemic agent. The advantage of metformin i n achieving weight loss has been clearly shown. As i n other age groups, initial metformin treatment was associated with a high incidence of gastro-intestinal symptoms which were transient and did not preclude patients from the use of metformin. Patients need not be denied metformin purely o n the basis of age. METFORMIN VS TOLBUTAMIDE IN THE ELDERLY

ORIGINAL ARTICLES Acknowledgements W e would like to thank C. Clark for her efforts in obtaining domiciliary blood glucose samples, and the Day Hospital staff at Nunnery Fields Hospital, for their help i n completing the study. W e would also thank D. Barnes for help with insulin assays, D . Sims for help with lactate assays, and A. Perkins for statistical advice. This study was supported by Lipha Pharmaceuticals Ltd.

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Shaw KM, Wheeley MStG, Campbell DR, Ward JR. Home blood glucose monitoring in non-insulin-dependent diabetics: the effect of gliclazide on blood glucose and weight control, a multi-centre study. Diabetic Med 1985; 2 : 484-490. 21. Rains SGH, Wilson GA, Richmond W, Elkeles RS. The effect of glibenclamide and metformin on serum lipoproteins in type 2 diabetes. Diabetic Med 1988; 5: 653-658. 22. Clarke BF, Campbell IW. Comparison of metformin and chlorpropamide in non-obese, maturity-onset diabetics uncontrolled by diet. B r Med / 1977; ii: 1576-1578. 23. Lim P, Khoo OT. Metformin compared with tolbutamide in the treatment of maturity-onset diabetes mellitus. Med / AUst 1970; 1: 271-273. 24. Ferner RE, Rawlins MD, Alberti KCMM. Impaired B cell responses improve when fasting blood glucose concentration is reduced in non-insulin dependent diabetes. Q / Med 1988; 250: 137-146.

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Campbell IW, Duncan C, Patten NW, Broadhead T, Tucker GT, Woods HF. The effect of metformin on glycaemic control, intermediary metabolism and blood pressure in non-insulin dependent diabetes mellitus. Diabetic M e d 1987; 4: 337-341. Hughes TA, Gwynne JT, Switzer BR, Herbst C, White G. Effect of caloric restriction and weight loss on glycaemic control, insulin release and resistance and atherosclerotic risk in obese patients with type II diabetes mellitus. Am I Med 1984; 7 7 : 7-1 7. Greenfield M, Kolterman 0,Olefsky JM, Reaven GM. The effect of ten days of fasting on various aspects of carbohydrate metabolism in obese diabetic subjects with significant fasting hyperglycaemia. Metabolism 1978; 27: 1839-1 852. Hermann LS, Magnussen S, Moller B, Casey C, Tucker GT, Woods HF. Lactic acidosis during metformin treatment in an elderly diabetic patient with impaired renal function. Acta Med Scand 1981 ; 209: 5 1 9-520.

S. JOSEPHKUTTY, J.M. POTTER

Comparison of tolbutamide and metformin in elderly diabetic patients.

In a randomized double-blind cross-over study the efficacy, metabolic effects, and acceptability of metformin were compared with tolbutamide in 20 dia...
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