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BENEFICIAL EFFECTS OF TRIPLE DRUG COMBINATION OF
ROSIGLITAZONE WITH GLIBENCLAMIDE AND METFORMIN IN TYPE
2 DIABETES MELLITUS PATIENTS ON INSULIN THERAPY

V Panikar*, H B Chandalia**, S Joshi***, A Fafadia****, C Santvana*****

ABSTRACT
In conclusion, triple oral drug therapy with rosiglitazone, glibenclamide and metformin can be safely used in type The thiazolidinediones are a class of anti-diabetic 2 diabetes patients receiving insulin with significantly medication that enhances the action of insulin in the improved metabolic control. With this combination it muscle, liver and adipose tissue. Data has been lacking was possible to significantly reduce the insulin dose or on their use in combination with both sulfonylurea and discontinue insulin therapy in a large number of patients. metformin among patients of type 2 diabetes who are on insulin therapy secondary to failure of routine oral KEY WORDS : Type 2 diabetes; Combination therapy;
hypoglycemic drugs in controlling their diabetes. The Insulin; Rosiglitazone; Metformin; Glibenclamide. objective of this study was to determine the effects of rosiglitazone in combination with sulphonylurea and INTRODUCTION
metformin on diabetes control in patients being treated with insulin due to secondary failure of oral Type 2 diabetes mellitus is characterized by the presence hypoglycemic agents. of insulin resistance with concomitant or eventual beta cell dysfunction. Resistance to insulin-stimulated glucose 151 consecutive type 2 diabetes patients (mean age 56.49 uptake is present in most patients with this disease (1). years) attending 4 centers in Mumbai, who were being Treatment is aimed at reducing blood glucose levels to treated with insulin were selected. They were switched normal or near-normal values (2, 3). Diet and exercise on to triple drug combination of glibenclamide 5mg, are the first treatments of choice for patients with type 2 metformin 500mg and rosiglitazone 4 mg along with diabetes mellitus. However, when they do not achieve insulin. Study participants were required to have type 2 adequate blood glucose control (4) initiation with oral diabetes mellitus for at least 5 years. Patients were anti-diabetic therapy is then advocated. excluded if they had any of the following: serum creatinine concentration greater than 1.5 mg/dl, alanine First-line monotherapy typically begins with aminotransferase (ALT) level more than 2 times the sulfonylurea (an insulin secretagogue) or metformin upper limit of normal, symptomatic angina, cardiac (which inhibits hepatic gluconeogenesis) (5). When insufficiency or history of myocardial infarction. monotherapy fails, these agents are frequently prescribed in combination (6). However, when patients continue to Rosiglitazone 4 mg once a day with glibenclamide 5mg experience suboptimal control on maximum doses of and metformin 500mg given three times daily, these drugs, insulin injection therapy has to be started (7, significantly decreased hemoglobin A1c level from 8). 12.4+1.87% to 7.79+0.41% (p<0.001), average fasting blood glucose from 194.8+73.7 mg/dl to 124.06+26.14 Thiazolidinediones are a class of peroxisome mg/dl (p<0.01) Average post prandial blood glucose proliferator-activated receptor- drugs that, unlike from 256.24+41.36 to 162.32+14.33 mg/dl(p<0.01). At 6 sulfonylureas and metformin, stimulate increased months, 49% of patients did not need to be continued on peripheral glucose disposal and reduce insulin resistance insulin. The total insulin requirement in 151 patients was in the muscle, liver, and adipose tissue (9-12). Studies reduced by 73.37%. There were no significant side have shown that rosiglitazone used as monotherapy or in effects and hepatic transaminoferases were within combination with sulfonylurea and metformin improves acceptable levels. Average weight gain was 1.88+1.93kg. glucose control (13-15). The addition of an insulin- Significant hypoglycemia was observed in 11.26% (17 sensitizing agent, such as rosiglitazone, to complement patients) with none requiring hospitalization. the insulin-stimulatory and hepatic glucose–suppressive * Honorary Assistant Professor, KJ Somaiya Medical College and Consultant Diabetologist Lilavati Hospital. ** Formerly Honorary Professor Grant Medical College and JJ Group of Hospitals, Director, Diabetes Endocrine Nutrition Management and Research Centre. *** Consultant Endocrinologis, Lilavati Hospital. **** Resident in Diabetology, Lilavati Hospital. ******Lecturer, K. J. Somaiya Medical College INT. J. DIAB. DEV. COUNTRIES (2003), VOL. 23 effects of sulfonylurea and metformin has been Once the patient was off insulin, and continued to show a considered an attractive therapeutic alternative to insulin. fall in plasma glucose levels, glibenclamide was However, the use of triple drug combination of periodically reduced. The rosiglitazone and metformin rosiglitazone, sulphonylurea and metformin in patients was continued in full doses except in a few patients who already on insulin therapy has not been studied. Whether could not tolerate full doses of metformin. Repeat a thiazolidinedione would be efficient at a stage of the measurements of Hemoglobin A1c levels were done at 3 disease when â-cell secretion is failing (16) remains to be demonstrated. The current study with triple drug therapy was under taken to see it’s effect in glycemic control in patients of type 2 diabetes mellitus who were already on 151 patients who had complete records of follow-up and completed six months of triple drug therapy were analyzed. 17 patients (11.26%) experienced significant hypoglycemia with none requiring hospitalization. These Patients: 151 consecutive type 2 diabetes patients (mean
patients were those who did not stick to follow-up age, 56.49 years) males 69 and females 82 attending 4 schedules. Most patients reporting hypoglycemia, at any centers in Mumbai, who were being treated with insulin were selected. They were switched on to triple drug combination of glibenclamide 5mg t.i.d, metformin Fig 1: HbA1c Pre and Post Trial.
500mg t.i.d and rosiglitazone 4 mg O.D along with insulin. Only subjects with duration of type 2 diabetes mellitus of at least 5 years duration and who were being treated with insulin were included in the study. The exclusion criteria included any patients with any cardiac abnormality, including history of symptomatic angina, cardiac insufficiency or history of myocardial infarction or an abnormal ECG. Patients with known renal failure or increased S. creatinine levels >1.5 mg/dl. Patients with SGOT/SGPT more than 2 times the upper limit of normal and patients having more than 60 ml Study Design: 151 patients who met the inclusion criteria had their base line ECG, fasting and post prandial blood profile done. They were then treated with rosiglitazone 4 mg/d and glibenclamide 5mg, metformin 500mg three Mean values for hemoglobin A1c, fasting and times a day in addition to insulin. They were advised to postprandial glucose and insulin requirement decreased repeat their plasma glucose every three weeks and report significantly from baseline during the course of therapy for follow-up. They were educated regarding for 6 months. The combination therapy at the end of 6 hypoglycemia and were to report it telephonically if they months significantly increased the proportion of patients experienced it before their follow-up date. Fasting and postprandial plasma glucose level and compared to earlier therapy. The average HbA1c in 151 biochemical measures of safety, including chemistry patients was reduced from 12.4+1.87% to 7.79+0.41% a tests (SGOT, SGPT), hematological tests, were reduction of 36.35% (p<0.001) (Fig 1 and Table 1). performed at 3-weekly intervals throughout the study. Among 58 males the reduction was 39.16% compared to Self-monitoring of blood glucose was encouraged, if the 35.32% in 82 female patients. The average fasting patients had glucose meters. At every follow-up if the plasma glucose levels reduced from 194.8+73.7 mg/dl to plasma glucose levels reduced, the insulin doses were 124.06+26.14 mg/dl a reduction of 36% (p<0.01). The appropriately reduced. Some patients who experienced average postprandial plasma glucose levels reduced from hypoglycemia before the follow-up date were 256.24+ 41.36 mg/dl to 162.32+14.33mg/dl a reduction telephonically instructed to reduce their insulin doses. of 36.65% (p<0.01) (Fig 2 and Table 1). INT. J. DIAB. DEV. COUNTRIES (2003), VOL. 23 requiring hospitalization. No patient required intervention other than a snack or beverage. Many Fig 2: Effect of Triple Drug Therapy on Fasting and
reports of hypoglycemic symptoms were associated with Post Prandial Glucose
Effect of triple drug therapy on fasting
DISCUSSION
& PP glucose
Patients with type 2 diabetes mellitus are often treated according to a stepped progression, starting with a regimen of nutrition counseling and exercise and progressing to monotherapy with a sulfonylurea, metformin, or acarbose. As hyperglycemia worsens, combinations of oral agents are often required. When a combination of a sulfonylurea and metformin cannot achieve the treatment goals, insulin injections must be The total insulin being taken by 151 patients prior to Addition of an insulin-sensitizing agent, such as starting triple drug therapy was 5210 units /day. After 6 rosiglitazone, to complement the insulin-stimulatory and months of therapy the requirement of insulin dropped to hepatic glucose–suppressive effects of sulfonylurea and 1387 units/day, a reduction of 73.37%. Further in 74 metformin has been considered an attractive therapeutic (49.01%) patients, insulin therapy was totally alternative to insulin. The triple drug combination could discontinued (Fig 3 and Table 1). work synergistically in reducing insulin resistance, thereby reducing the requirements of insulin Fig 3: Insulin Usage Pre and Post Trial
significantly. However, the use of triple drug combination of rosiglitazone, glibenclamide and metformin in patients already on insulin therapy has not Total insulin requirement
been studied. Our study provides evidence, supporting use of a triple drug therapy of glibenclamide 5mg, metformin 500mg and rosiglitazone 4 mg in patients of type 2 diabetes as a therapeutic means of improving glycemic control in patients with inadequate glycemic The triple drug therapy method used in this study demonstrated early and sustained reductions in fasting glucose levels, followed more slowly by similar Before and after treatment
were specifically designed to test the effects of triple Table1: Effect of Triple Drug Combination on drug therapy in patients on insulin therapy. Patients with
Fasting and Post Prandial Glucose, HbA
cardiac or renal compromise were strictly not included. Insulin usage.

The 73.37% reduction in total insulin dose paralleled the findings suggest that the triple drug therapy is quite effective in improving insulin-mediated glucose utilization through increased insulin sensitivity. Mean body weight at baseline and 6 months was 67.45+0.87 kg and 69.33+11.70kg. There was an increase of 1.88+1.93 kg after 6 months. The patients gained 1.88 kg SD + 1.93, which may be explained in part by a decrease in glycosuria secondary Triple drug therapy was well tolerated throughout the to improved glycemic control and resultant caloric study. No patients withdrew from the study because of retention. Rosiglitazone and glibenclamide are also elevated ALT levels. Symptoms associated with known to contribute to weight gain. hypoglycemia were reported by 17 patients with none INT. J. DIAB. DEV. COUNTRIES (2003), VOL. 23 17 patients reported occurrences of symptomatic 5. Cusi K, DeFronzo RA. Metformin: a review of its hypoglycemia with none requiring hospitalization. This metabolic effects. Diabetes Reviews 1998; 6: 89-131. happened in patients who did not stick to follow-up schedules as advised. Rosiglitazone is capable of 6. Trischitta V, Italia S, Raimondo M, Guardabasso V, Licciardello C, Runello F, et al. Efficacy of combined reducing glucose levels when used in combination with treatments in NIDDM patients with secondary failure to an insulin secretagogue and metformin, timely decrease sulphonylureas. Is it predictable? J Endocrinol Invest in concurrent insulin therapy is warranted to avoid severe hypoglycemia or sustained activity-limiting 7. Lardinois CK. Type 2 diabetes: glycemic targets and oral therapies for older patients. Geriatrics 1998; 53: 22-3. With respect to hepatic events, the SGOT/SGPT levels showed marginal variations but never enough to warrant 8. Johnson M, Krosnick A, Carson P, McDade AM, Laraway discontinuation of therapy as none of the patients had K. A retrospective chart review of uncontrolled use of levels greater than 2.5 times the normal. metformin as an add-on therapy in type 2 diabetes. Clin Ther. 1998; 20: 691-8. Our study shows that a triple drug combination of 9. Spiegelman BM. PPAR-: adipogenic regulator and rosiglitazone, glibenclamide and metformin is effective thiazolidinedione receptor. Diabetes. 1998;47:507-14. and well tolerated and can be safely used in type 2 diabetes patients receiving insulin with significantly 10. Maggs DG, Buchanan TA, Burant CF, Cline G, Gumbiner improved metabolic control. With this combination it is B, Hsueh WA, et al. Metabolic effects of troglitazone possible to significantly reduce the insulin dose or monotherapy in type 2 diabetes mellitus. A randomized, discontinue insulin therapy in a large number of patients. double-blind, placebo-controlled trial. Ann Intern Med. The addition of a rosiglitazone also offers an alternative to patients with inadequate glycemic control despite 11. Inzucchi SE, Maggs DG, Spollett GR, Page SL, Rife FS, treatment with full doses of a sulfonylurea and Walton V, et al. Efficacy and metabolic effects of metformin. The triple drug combination could help a metformin and troglitazone in type II diabetes mellitus. N good proportion of such patients to reach target levels of hemoglobin A1c and allow postponement of insulin therapy. 12. Yu JG, Kruszynska YT, Mulford MI, Olefsky JM. A comparison of troglitazone and metformin on insulin REFERENCES
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