A Nine Months Open Labelled, Multicentric, Non-comparative Study for Evaluation of Efficacy (Glycaemic Control), Safety and Tolerability of BetaglimTM in Type- 2 Diabetes

The present post marketing surveillance evaluated the efficacy, safety and tolerability of BetaglimTM (Glimepiride) in 558 patients with type 2 diabetes. It was an open labeled, non-comparative, multi centric study; which involved 35 investigators across the country. As per the doctors recording, the overall response to BetaglimTM was excellent to very good and the drug was reportedly well tolerated.

In type 2 diabetes, it is considered that the lowered insulin secretion and the lowered insulin sensitivity cause hyperglycaemia. Sulfonylureas have strong blood-glucose lowering effect by stimulating insulin secretion and have been widely used in the treatment of type 2 diabetes. However, the use of sulfonylureas has several issues (weight gain, hypoglycaemia, secondary failure etc.), some of which maybe due to stimulation of strong insulin secretion1.  Glimepiride is a new 3rd generation sulfonylurea with some advantages over the other members of this group, such as a lower risk of hypoglycaemia, no interaction with cardiovascular K+ATP- channels and a possibility that it may increase insulinsensitivity.2 Glimepiride, has a blood-glucose lowering effect as strong as those of existing sulfonylureas, but only induces mild insulin secretion1. This may explain the observation that glimepiride provides more stable blood glucose control and lower risk of hypoglycaemia over some second-generation sulfonylureas.3

Glimepiride has already been used in more than 60 countries in the world1. Literature reflects, that glimepiride is safe and well tolerated in patients with type 2 diabetes when used alone or in combination with other oral hypoglycaemic agents or with insulin treatment.3

BetaglimTM, the brand of glimepiride, manufactured and marketed by Panacea Biotec Ltd, is available in four strengths:1 mg, 2 mg, 3mg and 4mg, offering convenient dose titration. The present post marketing multicentric study was planned to evaluate the efficacy (glycaemic control), safety and tolerability of BetaglimTM in the Indian population during short-term therapy.

Patients and methods

Study Duration
Duration of study was 9 months, while duration of protocol therapy was 4 weeks.

Study centres
The study was conducted across 9 cities in India: Amritsar, Bhopal, Delhi, Indore, Jabalpur, Jaipur, Lucknow, Mumbai and Noida; with 35 investigators participating in the study.

Study population and sample size
The study was carried out in patients suffering from Type 2 diabetes mellitus inadequately controlled by diet or exercise or any other therapy, except study medication. A total of 581patients were screened for the study out of which 558 patients were evaluated at the end of the protocol therapy.

Study assessment criteria
During the study the patients was assessed for the following parameters: Reduction in fasting and post prandial blood glucose, occurrence of associated side effects (if any) including hypoglycaemic episodes.

Inclusion criteria
Male and female patients with type 2 diabetes, aged 30-65 years, having body mass index between 19-30 kg/m2, who were willing to give written informed consent and having fasting blood glucose ≥ 126 mg/dL and postprandial blood glucose ≥ 200 mg/dL.

Exclusion criteria
Patients who had a history of documented oral sulfonylurea treatment failure and hypersensitivity to sulfonylureas, who had been treated with insulin 12 months prior to enrolment, who had hepatic or renal impairment or gastrointestinal disorders or diseases of blood or haematopoetic organs, patients with known history of diabetic ketoacidosis, pregnant or breast-feeding women.

Ethical aspects
The study was conducted in accordance with the Declaration of Helsinki and ICH-GCP guidelines. Regular monitoring was done to ensure compliance with the protocol.

Documentation
The voluntary informed written consent in English/vernacular language by the subject along with the case report form for each subject was duly filled and maintained by the investigator. Completely filled Case Report Forms were provided to the sponsor at the end of the trial.

Serious adverse events
It was mentioned in the protocol that in case of a serious ADR, investigator would notify to the sponsor (within 48 hours) and take appropriate measures to safeguard the subject. Separate serious adverse event forms were also provided with each case report form.

Assessment periods
Patients were assessed at baseline (day 0), week 2, week 4 of the treatment period. Blood glucose was measured at baseline (day 0), week 2 and week 4 of the treatment period. Hypoglycaemic episodes and other associated side effects were accounted for at each visit, after initiation of therapy.

Dose administration
The starting dose of BetaglimTM was 1-4 mg per day, depending on the baseline glycaemic control of patients and physician judgment. Dose escalation was done whenever deemed necessary, at weekly intervals, with maximum escalation of 1 mg/ week, maximum dose given was 8mg/day. The drug was administered just before breakfast/ first main meal.

Concomitant medication
If deemed necessary by the investigator, concomitant medication was allowed and proper documentation of the same was done in the case report form of the patient.

 

Statistical analysis
The data was compiled and analyzed using the SPSS 11.0 software. Paired student t- tests, Chi square, McNemar's tests were applied, where ever applicable, to detect differences in blood glucose values.

Results

Demographic profile
A total of 581 patients were screened for this study of which 23 patients were not enrolled, as they did not meet the selection criteria. Nearly 63 percent of the patients were males while 37 percent were females. The overall demographic breakup of the patients is depicted in Table 1 and 2. Age breakup of the patients reveals that the bulk of them were between 40 to 59 years (68.8%)

Protocol deviation

Glycaemic control
Table 3, 4, 5 reflect that both fasting and post prandial blood glucose values showed a consistent decline during the 4 weeks of therapy with BetaglimTM .

Controlled and uncontrolled diabetics
We further analyzed the blood glucose values in all the patients, by categorizing them into two groups; controlled diabetics and uncontrolled diabetics. Patients having fasting blood glucose levels ≥ 130 mg/dL and / or having postprandial blood glucose levels ≥ 180 mg/dL were categorized as uncontrolled diabetes (goals for treatment of Type 2 Diabetes Mellitus in non-pregnant adults laid by American Diabetes Association 2004 (ADA)).

Paired data on blood sugar levels at Day 0 and Week 4 were analyzed for 520 patients. 17 patients (3.3%) had controlled diabetes on Day 0 as compared to 503 (96.7%) who had uncontrolled diabetes. However at Week 4, 295 (56.7%) patients had controlled diabetes as compared to 225 (43.3%) patients who had uncontrolled diabetes. This difference was statistically significant (p<0.001)(Table 6)

Effect of concomitant use of other oral hypoglycaemic medication
In the study, 14.3% of the patients were on concomitant antidiabetic medication (metformin, pioglitazone or otheroral hypoglycaemic agents). In comparing the mean decline in the blood sugar values (fasting and post prandial) between the 2 groups (patients with concomitant medication and patients without concomitant medication, it was found that mean decline was greater in the group which was on concomitant medication. This difference was statistically significant (p<0.05) (Table 7)

Effect on other biological parameters
No clinically significant change was observed in physical parameters like BP and pulse, at the end of protocol therapy. There was a reduction in body weight at the end of week 4,which was statistically significant (Table 8).

Safety and tolerability
A total of 24 hypoglycaemic episodes (defined as: occurrence of all the symptoms i.e. sweating, dizziness, headache, weakness, palpitation, blurred vision, poor concentration, tremors, intense hunger etc together) were observed in 14 of 558 patients (Table 9).

Thus, only 2.5% of the patients experienced hypoglycaemic episodes, with few patients having more than one such episode. There was no statistical link of hypoglycaemic episodes between the subjects who received only BetaglimTM and BetaglimTM plus other antidiabetic agents.

There were also reports of other adverse events like hypoglycaemic symptoms, gastrointestinal symptoms, dermatological and others. The details of these symptoms along with percentage incidence are depicted in Table 10. However, these adverse effects were not strong enough to warrant discontinuation of the therapy in any of the patients.

Discussion
Diabetes mellitus is a group of metabolic diseases characterized by hyperglycaemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycaemia of diabetes is associated with long-term damage, dysfunction and failure of various organs, especially the eyes, kidneys, nerves, heart and blood vessels.4 Type 2 diabetes, the most prevalent form of the disease,5 is prevalent worldwide and is associated with morbidity and mortality secondary to complications such as myocardial infarction, stroke and end-stage renal disease. The importance of tight control of blood glucose in either preventing or delaying the progression of complications is well recognized.6

Sulfonylureas, which have evolved through two generations since their introduction nearly 50 years ago, remain the most frequently prescribed oral agents for treatment of patients with type 2 diabetes mellitus.7 Sulfonylureas also represent the most cost effective therapeutic option a lone or in combination.8 There is an enormous amount of data concerning their efficacy and safety in humans. Despite their wide acceptance, however certain critical issues remain.9, 10

Hypoglycaemia remains an obligatory trade-off, especially with long acting agents (e.g. Glibenclamide) or short acting drugs with active metabolites that have a long t½ (e.g. Glipizide).

Long-term sulfonylurea therapy may lead to a weight increase and hyperinsulinaemia and thus deterioration in target disease. It may also increase the risk of CVS mortality, may be due to lack of differential tissue selectivity of sulfonylureas. As stated earlier, Glimepiride is a novel, 3rd generation sulfonylurea whose pre-clinical data and the emerging clinical studies Thus, only 2.5% of the patients experienced hypoglycaemic suggest several potential benefits - viz. low dose, OD episodes, with few patients having more than one such administration, rapid onset of action, having both insulin-episode. There was no statistical link of hypoglycaemic sensitizing and insulinmimetic effects, lower serum insulin episodes between the subjects who received only BetaglimTM levels, less pronounced glucagonotrophic effects, less prone and BetaglimTM plus other antidiabetic agents. to hypoglycaemia, remarkably safe in NIDDM patients at high risk viz., renally impaired, with hepatic dysfunction, elderly and physically very active persons.ll

This multicentric study conducted in more than 500 patients with uncontrolled type II diabetes mellitus, further confirms that Betaglim controls blood glucose effectively. In this study, the post treatment fasting glucose levels showed statistically significant decline with Betaglim, as compared to pretreatment fasting blood glucose levels; similar was the trend with postprandial blood glucose levels. The mean fasting blood glucose value declined by 31.61 % while the mean postprandial blood glucose value declined by 34.05% at the end of 4 week's therapy with the drug. Thus, Betaglim is a useful option for patients with type 2 diabetes not controlled by diet and exercise and who want to achieve tight glycaemic control. Moreover, 57% of patients at week 4 could achieve the current goals for treatment of Type 2 Diabetes Mellitus in non-pregnant adults as laid by American Diabetes Association2004 (ADA), (i.e. fasting blood glucose of < 130 mg/dL and 2-hour post prandial blood glucose of < 180 mg/dL).

In another study with glimepiride, conducted in 142 patients for 12 weeks, it was found that apart from providing a good glycaemic control, the levels of serum cholesterol and triglyceride also decreased.12

In the present study, 14.3% of the patients were on concomitant antidiabetic medication (metformin, pioglitazone or otheroral hypoglycaemic agents). On comparative analysis, it was found that the decline in mean fasting blood glucose from day 0 to week 4 was 30.26% in patients who were using only BetaglimTM. Whereas the fall in fasting blood glucose was greater, i.e. 37.44%, in those patients who were on concomitant anti diabetes medication along with BetaglimTM. Similar was the trend with post prandial blood sugar values. The decline in post prandial blood glucose value was 31 .75% (from day 0 to week 4) in the patients using only the test medication, while it was 45.29% (from day 0 to week 4) in the patients using concomitant medication along with the test drug. This supports the fact that glimepiride is also safe and effective in combination with other oral agents or with insulin treatment.3

The most common adverse events with glimepiride are dizziness, headache, sweating, weakness, abdominal discomfort and nausea. Glimepiride is generally safe and well tolerated. In earlier comparative trials, adverse events occurred in a similar proportions in glimepiride and glipizide patients and were less frequent with glimepiride than glibenclamide. Serious adverse events also followed this pattern in glimepiride, glipizide and glibenclamide recipients, though, serious adverse events were usually not thought to be glimepiride related.13 However, in our study none of the patients enrolled, reported any serious adverse event. Thus, glimepiride is safe and well tolerated in patients with type 2 diabetes.3

One of the most important side effects of sulfonylurea treatment is hypoglycaemia, which in rare cases can be fatal. A comparative study in 1044 patients showed 14% and 11% hypoglycaemic episodes with glibenclamide and glimepiride patients respectively. There were three episodes (patients needed help) of severe hypoglycaemia in glibenclamide patients and one in the glimepiride patients. Blood glucose decreased to < 50 mg/dL on 11 occasions (in six patients) in the glibenclamide and (in two patients) in the glimepiride group. In another double blind, glibenclamide-controlled study in NIDDM patients; significantly less hypoglycaemia occurred with glimepiride patients (1.7%) and glibenclamide (5.6%) during the first month of treatment even though fasting blood glucose reduction was similar (glimepiride and glibenclamide: 48 mg/dL).11 A meta-analysis of all glibenclamide controlled studies confirmed that the risk of hypoglycaemia was almost double for glibenclamide compared to glimepiride, during the first treatment week.

In another double blind trial with 802 NIDDM patients, the cumulative occurrence of hypoglycaemia was similar for the two treatments in the first four weeks (glimepiride 3.0% vs. glipizide 2.8%) as well as thereafter. However, the fasting plasma glucose reduction was significantly greater for glimepiride in the first 4 weeks of treatment (glimepiride - 51 .5 mg/dL vs. glipizide - 32.1 mg/dL; p>0.001 ).11

In this present post marketing study, only 2.5% of the patients experienced hypoglycaemic episodes. This is comparable to the hypoglycaemic episodes seen during other clinical studies with glimepiride therapy. Thus it supports the finding of lower hypoglycaemia risk with BetaglimTM (glimepiride).

Weight increase is another critical issue of sulfonylurea treatment. In UK Prospective Diabetes Study (UKPDS), the average weight gain during treatment with glyburide was 4.5kg at 10 years and 5-6kg in-patients on insulin monotherapy.

In a 22-week placebo-controlled study in 249 patients, the weight increase in the Glimepiride group was about 1.8kg,compared with a weight loss of about 0.7 kg in the placebo group. However, Glimepiride did give good metabolic control as well as a lowering of LDL-Cholesterol (- 3.5 mg/dL) compared to an increase in the placebo group (+ 4.0 mg/dL), which was statistically significant. Thus modest weight increase per se is more than compensated for by the therapeutically beneficial effects of Glimepiride therapy.

In a multicentric retrospective cohort glibenclamide controlled study in 520 patients it was found that the mean weight loss and reduction in body mass index from baseline to study end point were greater with glimepiride than with glibenclamide. Also, high-density lipoprotein cholesterol was higher in the glimepiride group.14

In two Austrian studies, no weight gain was observed with glimepiride treatment for upto 13 months. In fact the majority of patients in these studies actually lost weight while the HbA1c levels improved by 1.3 - 1.4%. Similarly in a large surveillance study of more than 22000 patients with type 2 diabetes in Germany, patients with the highest BMI at baseline, lost the most weight after 2 months of treatment with Glimepiride.

The results of present post marketing study are in consensus with the similar fact. There was a statistically significant reduction in weight, during the four weeks of therapy with the study medication.

Thus choosing a drug such as BetaglimTM, merits serious consideration. It offers convenience, dosing flexibility, favourable cardiovascular profile (it does not interact with cardio-vascular K+ channels and reduces LDL-oxidation 15), preserves cell function and has clearly definable pharmacokinetics in diabetic patients with renal impairment, while minimizing the common barrier to ideal control and the most common adverse effect of secretagogues, hypoglycaemia.11 Betaglim TM represents a reasonable choice for both initial therapy and for early combination therapy with metformin, thiazolidinediones and insulin.

Conclusion
The result of the study indicates that BetaglimTM provides effective glycaemic control, results in weight neutralizing or reducing effects in type 2 diabetes with minimal adverse effects, has a lower risk of hypoglycaemia, thus supporting its first - line use in type 2 diabetes, in different age groups.

Acknowledgements
We at Panacea Biotec Ltd, would like to thank all the doctors who participated in this study and submitted back their valuable feedback about BetaglimTM tablets. This study would not have been possible without their participation.

References

  1. Bando K, Yomoda Y. Glimepiride (Amaryl): a review of its pharmacological and clinical profile]. Nippon Yakurigaku Zasshi 2001; 118(1 ):59-67.

  2. Raptis SA, Dimitriadis GD. Oral hypoglycemic agents: insulin secretagogues, alpha-glucosidase inhibitors and insulin sensitizers. Exp Clin Endocrinol Diabetes 2001 ;109(2):5265-87.

  3. Jasik M. Glimepiride in daily practice. Przegl Lek 2003;60(6):409-12.

  4. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2004;27(1 ):55-5 10.

  5. American Diabetes Association. Screening for type 2 diabetes.

  6. Nourparvar A. Bulotta A, Di Mario U, Perfetti R. Novel strategies for the pharmacological management of type 2 diabetes. Trends Pharmacol Sci 2004;25(2):86-91.

  7. Korytkowski MT. Sulfonylurea treatment of type 2 diabetes mellitus: focus on glimepiride. Pharmacotherapy 2004;24(5):606-20. Campbell RK. Glimepiride: role of a new sulfonylurea in the treatment of type 2 diabetes mellitus. Ann Pharmacother 1998;32(10): 1 044-52.

  8. Kabadi UM. Cost-effective management of hypoglycemia in patients with type 2 diabetes using oral agents. Manag Care 2004:13(7):48-9,53-6,58-9.

  9. Loh KC. Current therapeutic strategies for type 2 diabetes mellitus. Annals academy Medicine 2002;31 :722-9.

  10. R Rob Kamp, et al; Diabetes Research And Clinical Practice 1996;31: 533-42.

  11. Jayoram BM and Jyanthi CR, Sulphonylureas-Quest for the next generation and beyond. Type-2 Diabetes: Urban-Rural 2004;(1): 1 04-15.

  12. Jasik M, Kasperska-Czyzykowa T, Karnafel W, Drzewoski J, lopatynski J. Evaluation of efficacy, safety and tolerance of glimepiride (Amaryl) in patients with type 2 diabetes. Przegl Lek 2000;57(4):23-7.

  13. Langtry HD, Balfour JA. Glimepiride. A review of its use in the management of type 2 diabetes mellitus. Drugs 1998;55(4):563-84.

  14. Martin S, Kolb H, Beuth J, van leendert R, Schneider B, Scherbaum WA. Change in patients' body weight after 12 months of treatment with glimepiride or glibenclamide in Type 2 diabetes: a multicentre retrospective cohort study. Diobetologia 2003;46(12): 1611-7.

  15. Bijlstra PJ, Lutterman JA, Russel FG, Thien T, Smits P. Interaction of sulphonylurea derivatives with vascular ATP-sensitive potassium channels in humans. Diobetologia 1996;39(9): 1 083-90.


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