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*****
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
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.
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
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Paper presented at The First Dutch Balint Conference, Oegstgeest, Netherlands, Oct 17th 2008. Can primary care recover patient-centered medicine? Donald E. Nease, Jr., MD President, American Balint Society Vice President, International Balint Federation Associate Professor of Family Medicine University of Michigan – Ann Arbor, Michigan USA Introduction First, I would like to say a word of thank
The American Association of Orthodontists recommends all children get a check-up with an orthodontic specialist no later than age 7. HERE’S WHY: • Orthodontists can spot subtle problems with jaw growth and emerging teeth while• While your child’s teeth may appear to be straight, there could be a problem that• A check-up may reveal that your child’s bite is fine. Or, the