Safety and efficacy of sulfonylurea drugs in type 2 diabetes mellitus

Safety and efficacy of sulfonylurea drugs in type 2 diabetes mellitus

a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 6 5 e1 6 8 Available online at www.sciencedirect.com journal homepage: www.elsevier.com/locate/apme R...

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a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 6 5 e1 6 8

Available online at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/apme

Research Article

Safety and efficacy of sulfonylurea drugs in type 2 diabetes mellitus Jyothsna Kudaravalli*, Gali Vijayalakshmi, K. Kiran Kishore Dept. of Pharmacology, Bhaskar Medical College, Yenkapally (V), Moinabad (M), Rangareddy District, Andhra Pradesh 500075, India

article info

abstract

Article history:

Introduction: In subjects with type 2 diabetes mellitus, glycemic control will be established

Received 21 August 2012

while patients use sulfonylurea drugs during the course of the disease.

Accepted 6 May 2013

Material-methods: Two groups of 100 diabetic patients, and 24 healthy controls were

Available online 6 June 2013

recruited. The study was conducted to characterize the new sulfonylurea glimepiride and to compare its profile of action with the second generation sulfonylurea glipizide. Blood

Keywords:

samples were collected at fasting, 0 h, 2 h, 4 h and 6 h, after a standard mixed meal was

Type 2 diabetes

given. Glycosylated hemoglobin, weight gain and blood sugar levels were measured.

Sulfonylureas

Results: Pre-prandially (0e3 h) blood glucose levels were significantly lower ( p < 0.0001)

Glipizide

after the administration of glimepiride (3.7 þ/ 0.24 and 3.5 þ/ 0.3 mM respectively)

Glimepiride

compared to placebo (4.63 þ/ 0.31 mM), and also compared to glipizide. Post-prandially (3e5 h) blood glucose was significantly higher after glipizide (6.54 þ/ 0.8 mM) ( p < 0.0001) than after 2 mg glimepiride (5.75 þ/ 0.5 mM). Discussion and conclusion: It was shown that the decrease in HbA1c value was from 8.0 to 6.9%. The lowering of blood glucose levels in fasting and post-prandial period were shown better results with glimepiride than glipizide. In a study, it was shown that there was significant improvement in the levels of glycosylated hemoglobin and also FBS and PPBS at 6 and 12 months with glimepiride and glipizide. Glimepiride was associated with lower risk of hypoglycemic attacks, less weight gain and better glycemic control than glipizide. Glimepiride has lower risk of gaining weight than other sulfonylureas. Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.

1.

Introduction

In subjects with type 2 diabetes mellitus, glycemic control will be established while patients use sulfonylurea drugs during the course of the disease. However, data regarding direct comparison between various sulfonylureas in this regard are lacking. Weight loss usually improves blood glucose levels for people with type 2 diabetes. However, many also need oral medications or insulin.

Diabetes is due to increased glucose levels and increased glucose resistance. Controlling blood glucose levels for people with type 2 diabetes often requires several strategies. The clinical approach begins with lifestyle modifications, including increased physical activity and diet control.1 Weight loss usually improves blood glucose levels for people with type 2 diabetes. However, many also need oral medications or insulin.2 There is a large body of clinical evidence that can help inform decisions about hypoglycemic medications. This

* Corresponding author. E-mail address: [email protected] (J. Kudaravalli). 0976-0016/$ e see front matter Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved. http://dx.doi.org/10.1016/j.apme.2013.05.002

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summarizes evidence from both observational studies and controlled trials that compare the effectiveness and safety of oral hypoglycemic.3 Standard oral hypoglycemic regimens include single drugs (monotherapy) like sulfonylurea, glimepiride and glipizide.4 Choosing among available oral hypoglycemic requires consideration of their benefits as well as their adverse effects and cost. It does not include evidence about the effectiveness of diet, exercise, and weight loss. There is a large body of clinical evidence that can help inform decisions about hypoglycemic medications. This guide summarizes evidence from both observational studies and controlled trials that compare the effectiveness and safety of oral hypoglycemics. Our study objective is, comparison between two second generation sulfonylurea drugs, glimepiride and glipizide, at different time intervals.

2.

Objective

To examine comparative efficacies of therapy with second generation sulfonylureas in subjects with type 2 diabetes and comparing glycemic control while receiving various individual sulfonylurea drugs. Our study also includes comparison between safety and efficacy of glimepiride and glipizide at different time intervals.

 We included only randomized, controlled trials (RCTs) for intermediate end points and both trials and observational studies for major clinical outcomes and adverse events

3.2.

Exclusion criteria

 We excluded studies that followed patients for less than 3 months, had age higher than 60 years, did not have a drug comparison of interest, or used background medications for diabetes without stratification of the outcomes by the combination of medications.  The eligibility criteria for this review differed from those for the initial review.  We excluded studies of a-glucosidase inhibitors (for example, acarbose) because they are infrequently prescribed in the United States; have lower efficacy for glycemic control; and have high rates of gastrointestinal adverse effects, limiting their tolerability.  We also excluded colesevelam, which was only recently approved by the FDA.  Ethical committee approval has to be taken. Informed consent should be taken.

4. Materials and methodology

The study was conducted on diabetic patients who were attending outpatient department in Bhaskar Medical College, Yenkapally village, Andhra Pradesh, India. Two groups of 100 diabetic patients, and 24 healthy controls were recruited. Ethical committee approval was taken. Informed consent was taken. It is a single-center, randomized, placebo-controlled, open label, cross-over study was conducted to characterize the new sulfonylurea glimepiride and to compare its profile of action with the second generation sulfonylurea glipizide. The total duration of each experiment was 6 h. At zero time an oral administration of glimepiride and glipizide or placebo was given to 24 healthy volunteers. Blood samples were collected at fasting, 0 h, 2 h, 4 h and 6 h, after a standard mixed meal was given (20%, of a 30 kcal/kg body weight diet). Two groups of 100 subjects, each presenting with glycosylated hemoglobin (HbA(1C)) >7.0% while using either glimepiride, and glipizide were recruited. Twelve from each group were randomized to receive placebo; the others continued the same drug. Fasting plasma glucose, and HbA(1C) concentrations were determined prior to the study and at 2 h, 4 h and at 6 h of the study. The dose of the drug should be adjusted as necessary to attain fasting blood glucose levels between 80 and 120 mg/dL and maintain the same range for 6 months. Changes in body weight (BW) were noted at the end of the study, and the number of hypoglycemic events during the last 4 weeks of the study was determined.

Distribution of diabetes at different age and sex were shown in Fig. 1. Pre-prandially (0e3 h) blood glucose levels were significantly lower ( p < 0.0001) after the administration of glimepiride (3.7 þ/ 0.24 and 3.5 þ/ 0.3 mM respectively) compared to placebo (4.63 þ/ 0.31 mM), and also compared to glipizide. Post-prandially (3e5 h) blood glucose was significantly higher after glipizide (6.54 þ/ 0.8 mM) ( p < 0.0001) than after 2 mg glimepiride (5.75 þ/ 0.5 mM). Both glimepiride and glipizide had similar effects on insulin secretion. Despite this C-peptide was significantly higher ( p < 0.002) glimepiride (5.7 þ/ 1.5 ng/ ml) compared to glipizide (5.1 þ/ 1.3 ng/ml); the trend was the same for insulin but the results were not significantly different ( p ¼ 0.06). The significant changes in glycosylated hemoglobin, blood glucose levels and weight gain were observed in Figs. 2e5. Peak changes in values of glucose were observed at post-

Distribution of diabetes in different sexes 45 40 35

Frequency

3.

Result

30

Female

25

Male

20 15 10 5 0

3.1.

Inclusion criteria

 We selected original studies in nonpregnant persons aged 18 years or older with type 2 diabetes

0-20

20-30 Age(years)

30-40

Fig. 1 e Distribution of diabetes at different age and sex were shown.

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Glycosylated hemoglobin(mg/dl)

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140 120

50

49

100

45

40.5

42

80 60 40 20

Fasting

30min

2hr

4hr

6hr

0

Glipizide

Glimipiride

Fig. 2 e Glycosylated hemoglobin with sulfonylureas. prandial period, especially with glimepiride and its action lasted for 4e6 h.

5.

Decrease in Blood glucose Levels with Glipizide

Changes in glycosylated hemoglobin

Discussion

The goals of pharmacologic therapy are to reduce symptoms of hyperglycemia and the long-term complications of diabetes. Glycemic control is known to reduce the risk for microvascular complications, including retinopathy and neuropathy.5 The risk for death from cardiovascular disease is increased in adults with type 2 diabetes3; however, it is unclear whether intensive glycemic control reduces that risk.6,7 To make well-informed choices among the options for achieving glucose control, clinicians and patients need comprehensive information about the effectiveness and the safety of therapies, with attention to patient-relevant outcomes.8e10 The Agency for Healthcare Research and Quality published its first systematic review on the comparative effectiveness and safety of oral hypoglycemic medications for type 2 diabetes in 2007.11,12 The agency requested an update of this review to include medication classes newly approved by the U.S. Food and Drug Administration (FDA) and evidence on combinations of medications, including oral medications combined with insulin.12e14 The inclusion of additional trials and drug comparisons since the 2007 review did not provide sufficient evidence to

Fig. 4 e Decrease in blood glucose levels with glipizide. definitively support one drug or combination of drugs over another for long-term clinical outcomes of mortality and macrovascular and microvascular complications of diabetes.2,15,16 Sulfonylureas were consistently associated with weight reduction or neutrality compared with most other diabetes medications, which generally increased weight.1 Overall, medication effects on lipid levels were small to moderate and of uncertain clinical importance. Conclusions on comparative risk for adverse events were clearest for sulfonylureas, which increased the risk for hypoglycemia.17e19 Lower incidence of hypoglycemia occurs with glimepiride than with glipizide especially in elderly patients in non-insulin dependent diabetes.20 Studies have shown that no intrinsic difference was observed in oral dose of glimepiride in obese patients compared to non-obese patients. The average weight reduction with glimepiride was 1.3%, but in our study it was 1.5%. It was observed that there was less frequent body weight gain in type 2 diabetic patients treated with glimepiride than glipizide. It was shown that the decrease in HbA1c value was from 8.2 to7.2% on glimepiride, but in our study, it was from 8.0 to 6.9%. The lowering of blood glucose levels in fasting and postprandial period were shown better results with glimepiride than glipizide. In a study, it was shown that there was significant improvement in the levels of glycosylated hemoglobin and also FBS and PPBS at 6 and 12 months with glimepiride and glipizide.

Decrease in Blood glucose levels at different time intervals with Glimipiride

Weight gain with sulfonylureas 70

72

Weight(Kg)

60

63

50

45

40

68 50

30 20 10 0

Glipizide

Glimipiride

Fig. 3 e Weight gain with sulfonylureas.

Fig. 5 e Decrease in blood glucose levels with glimepiride.

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6.

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Summary

Glimepiride was associated with lower risk of hypoglycemic attacks, less weight gain and better glycemic control than glipizide. Glimepiride has lower risk of gaining weight than other sulfonylureas.

6.1.

The future of sulfonylureas

The future development of the drug should be based on: 1. Lower incidence of hypoglycemic attacks. 2. Less changes in the weight gain. 3. Better control on fasting and post-prandial blood glucose levels.

6.2.

Note

The higher levels of glycosylated haemoglobin causes more incidence of atherosclerosis that predisposes to myocardial infarction and cerebrovascular accidents and other endorgans damage.

Conflicts of interest All authors have none to declare.

references

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5. Oral sulfonylurea hypoglycemic agents prevent ischaemic pre conditioning in human myocardium. Circulation. 1997;96:29e32. 6. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577e1589. 7. Shichiri M, Kishikawa H, Ohkubo Y, Wake N. Long-term results of the Kumamoto study on optimal diabetes control in type 2 diabetic patients. Diabetes Care. 2000;23(suppl 2):B21eB29. 8. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998b;352:837e853. 9. Bolen S, Feldman L, Vassy J, et al. Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Intern Med. 2007a;147:386e399. 10. Bolen S, Wilson L, Vassy J, et al. Comparative Effectiveness and Safety of Oral Diabetes Medications for Adults with Type 2 Diabetes. Rockville, MD: Agency for Healthcare Research and Quality; 2007b. 11. Kahn SE, Haffner SM, Heise MA, et al, ADOPT Study Group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355:2427e2443. 12. Rodbard HW, Jellinger PS, Davidson JA, et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Pract. 2009;15:540e559. 13. Nathan DM, Buse JB, Davidson MB, et al, American Diabetes Association. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32:193e203. 14. Temple R, Ellenberg SS. Placebo-controlled trials and activecontrol trials in the evaluation of new treatments. Part 1: ethical and scientific issues. Ann Intern Med. 2000;133:455e463. 15. U.K. prospective diabetes study. II. Reduction in HbA1c with basal insulin supplement, sulfonylurea, or biguanide therapy in maturity-onset diabetes. A multicenter study. Diabetes. 1985;34:793e798. 16. United Kingdom Prospective Diabetes Study (UKPDS). 13: relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed noninsulin dependent diabetes followed for three years. BMJ. 1995;310:83e88. 17. Kamoun M, Jemmali B, Selmi H, et al. Monitoring milk urea level and feed ration as a potential tool for milk quality. J Physiol Pharmacol Adv. 2012;2(1):69e76. 18. Kumar A, Rinwa P, Sharma N. Irritable bowel syndrome: a review. J Physiol Pharmacol Adv. 2012;2(2):97e108. 19. Nissen SE, Nicholls SJ, Wolski K, et al, PERISCOPE Investigators. Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA. 2008;299:1561e1573. 20. Shukla Umesh A. Glimepiride pharmacokinetics in obese vs non obese patients. Ann Pharmacother. 2004;38(1):30e35.