Safety and Efficacy of Sulfonylurea Drugs in Type 2 Diabetes Mellitus

ww.sciencedirect.com

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

Available online at w

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

Research Article

Safety and efficacy of sulfonylurea drugs in type 2 diabetesmellitus

Jyothsna Kudaravalli*, Gali Vijayalakshmi, K. Kiran Kishore

Dept. of Pharmacology, Bhaskar Medical College, Yenkapally (V), Moinabad (M), Rangareddy District, Andhra Pradesh 500075, India

a r t i c l e i n f o

Article history:

Received 21 August 2012

Accepted 6 May 2013

Available online 6 June 2013

Keywords:

Type 2 diabetes

Sulfonylureas

Glipizide

Glimepiride

* Corresponding author.E-mail address: kudaravallij@yahoo.in (J.

0976-0016/$ e see front matter Copyright ªhttp://dx.doi.org/10.1016/j.apme.2013.05.002

a b s t r a c t

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

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

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

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

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

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

Results: 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).

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 Diabetes is due to increased glucose levels and increased

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.

Kudaravalli).2013, Indraprastha Medic

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

al Corporation Ltd. All rights reserved.

a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 6 5e1 6 8166

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, glime-

piride and glipizide.4 Choosing among available oral hypo-

glycemic 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 hypoglycemicmedications. 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 be-

tween 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 individ-

ual sulfonylurea drugs. Our study also includes comparison

between safety and efficacy of glimepiride and glipizide at

different time intervals.

0

5

10

15

20

25

30

35

40

45

0-20 20-30 30-40

Fre

qu

en

cy

Age(years)

Distribution of diabetes in different sexes

Female

Male

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

were shown.

3. 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 experimentwas 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 glycosy-

lated hemoglobin (HbA(1C)) >7.0% while using either glime-

piride, 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) concentra-

tions 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

120mg/dLandmaintain the same range for 6months.Changes

in bodyweight (BW)werenoted at the endof the study, and the

number of hypoglycemic events during the last 4 weeks of the

study was determined.

3.1. Inclusion criteria

� We selected original studies in nonpregnant persons aged

18 years or older with type 2 diabetes

� 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 backgroundmedications 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 pre-

scribed in theUnited States; have lower efficacy for glycemic

control; and have high rates of gastrointestinal adverse ef-

fects, limiting their tolerability.

� We also excluded colesevelam, which was only recently

approved by the FDA.

� Ethical committee approval has to be taken. Informed con-

sent should be taken.

4. Result

Distribution of diabetes at different age and sexwere shown in

Fig. 1. Pre-prandially (0e3 h) blood glucose levels were signif-

icantly lower ( p < 0.0001) after the administration of glime-

piride (3.7þ/� 0.24 and 3.5þ/� 0.3mM 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 (5.7þ/� 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-

0

20

40

60

80

100

120

140

Glipizide Glimipiride

Glyco

sylated

h

em

og

lo

bin

(m

g/d

l)

Changes in glycosylated hemoglobin

Fig. 2 e Glycosylated hemoglobin with sulfonylureas.

40.5

49 5045 42

Fasting 30min 2hr 4hr 6hr

Decrease in Blood glucose

Levels with Glipizide

Fig. 4 e Decrease in blood glucose levels with glipizide.

a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 6 5e1 6 8 167

prandial period, especially with glimepiride and its action

lasted for 4e6 h.

5. Discussion

The goals of pharmacologic therapy are to reduce symptoms

of hyperglycemia and the long-term complications of dia-

betes. 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 un-

clear 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 dia-

betes in 2007.11,12 The agency requested an update of this re-

view to includemedication classes newly approved by the U.S.

Food and Drug Administration (FDA) and evidence on com-

binations of medications, including oral medications com-

bined with insulin.12e14

The inclusion of additional trials and drug comparisons

since the 2007 review did not provide sufficient evidence to

0

10

20

30

40

50

60

70

Glipizide Glimipiride

Weig

ht(K

g)

Weight gain with sulfonylureas

Fig. 3 e Weight gain with sulfonylureas.

definitively support one drug or combination of drugs over

another for long-term clinical outcomes of mortality and

macrovascular and microvascular complications of dia-

betes.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 sul-

fonylureas, which increased the risk for hypoglycemia.17e19

Lower incidence of hypoglycemia occurs with glimepiride

than with glipizide especially in elderly patients in non-in-

sulin dependent diabetes.20 Studies have shown that no

intrinsic differencewas observed in oral dose of glimepiride in

obese patients compared to non-obese patients. The average

weight reductionwith glimepiridewas 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 glime-

piride 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 post-

prandial period were shown better results with glimepiride

than glipizide. In a study, it was shown that there was sig-

nificant improvement in the levels of glycosylated hemoglo-

bin and also FBS and PPBS at 6 and 12monthswith glimepiride

and glipizide.

45

6372 68

50

Decrease in Blood glucose levels at different time

intervals with Glimipiride

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

a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 6 5e1 6 8168

6. 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 end-

organs damage.

Conflicts of interest

All authors have none to declare.

r e f e r e n c e s

1. Alexander GC, Sehgal NL, Moloney RM, Stafford RS. Nationaltrends in treatment of type 2 diabetes mellitus, 1994e2007.Arch Intern Med. 2008;168:2088e2094.

2. United Kingdom Prospective Diabetes Study 24: a 6-year,randomized, controlled trial comparing sulfonylurea, insulin,and metformin therapy in patients with newly diagnosedtype 2 diabetes that could not be controlled with diet therapy.United Kingdom Prospective Diabetes Study Group. Ann InternMed. 1998c;128:165e175. 11.

3. Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulintherapy prevents the progression of diabetic microvascularcomplications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract. 1995;28:103e117.

4. Effect of intensive blood-glucose control with metformin oncomplications in overweight patients with type 2 diabetes(UKPDS 34). UK Prospective Diabetes Study (UKPDS34) Group.Lancet. 1998a;352:854e865.

5. Oral sulfonylurea hypoglycemic agents prevent ischaemic preconditioning in humanmyocardium. Circulation. 1997;96:29e32.

6. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes.N Engl J Med. 2008;359:1577e1589.

7. Shichiri M, KishikawaH, OhkuboY,WakeN. Long-term resultsof the Kumamoto study on optimal diabetes control in type 2diabetic patients. Diabetes Care. 2000;23(suppl 2):B21eB29.

8. Intensive blood-glucose control with sulphonylureas orinsulin compared with conventional treatment and risk ofcomplications in patients with type 2 diabetes (UKPDS 33). UKProspective 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 fortype 2 diabetes mellitus. Ann Intern Med. 2007a;147:386e399.

10. Bolen S, Wilson L, Vassy J, et al. Comparative Effectiveness andSafety of Oral Diabetes Medications for Adults with Type 2Diabetes. Rockville, MD: Agency for Healthcare Research andQuality; 2007b.

11. Kahn SE, Haffner SM, Heise MA, et al, ADOPT Study Group.Glycemic durability of rosiglitazone, metformin, or glyburidemonotherapy. N Engl J Med. 2006;355:2427e2443.

12. Rodbard HW, Jellinger PS, Davidson JA, et al. Statement by anAmerican Association of Clinical Endocrinologists/AmericanCollege of Endocrinology consensus panel on type 2 diabetesmellitus: an algorithm for glycemic control. Endocr Pract.2009;15:540e559.

13. Nathan DM, Buse JB, Davidson MB, et al, American DiabetesAssociation. Medical management of hyperglycemia in type 2diabetes: a consensus algorithm for the initiation andadjustment of therapy: a consensus statement of theAmerican Diabetes Association and the European Associationfor the Study of Diabetes. Diabetes Care. 2009;32:193e203.

14. Temple R, Ellenberg SS. Placebo-controlled trials and active-control 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 withbasal insulin supplement, sulfonylurea, or biguanide therapyin 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 non-insulin dependent diabetes followed for three years. BMJ.1995;310:83e88.

17. Kamoun M, Jemmali B, Selmi H, et al. Monitoring milk urealevel 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: areview. J Physiol Pharmacol Adv. 2012;2(2):97e108.

19. Nissen SE, Nicholls SJ, Wolski K, et al, PERISCOPEInvestigators. Comparison of pioglitazone vs glimepiride onprogression of coronary atherosclerosis in patients with type2 diabetes: the PERISCOPE randomized controlled trial. JAMA.2008;299:1561e1573.

20. Shukla Umesh A. Glimepiride pharmacokinetics in obese vsnon obese patients. Ann Pharmacother. 2004;38(1):30e35.

Apollo hospitals: http://www.apollohospitals.com/Twitter: https://twitter.com/HospitalsApolloYoutube: http://www.youtube.com/apollohospitalsindiaFacebook: http://www.facebook.com/TheApolloHospitalsSlideshare: http://www.slideshare.net/Apollo_HospitalsLinkedin: http://www.linkedin.com/company/apollo-hospitalsBlog:Blog: http://www.letstalkhealth.in/