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A comparison of glycemic effects of glimepiride, repaglinide, and insulin glargine in type 2 diabetes mellitus during Ramadan fasting
Diabetes Research and Clinical Practice 75 (2007) 141–147 www.elsevier.com/locate/diabres
A comparison of glycemic effects of glimepiride, repaglinide, and insulin glargine in type 2 diabetes mellitus during Ramadan fasting Mustafa Cesur a, Demet Corapcioglu b, Alptekin Gursoy b,*, Sait Gonen c, Mine Ozduman b, Rifat Emral b, Ali Riza Uysal b, Vedia Tonyukuk b, Arif Ender Yilmaz b, Fahri Bayram d, Nuri Kamel b b
a Ankara Guven Hospital, Department of Endocrinology and Metabolic Diseases, Ankara, Turkey Ankara University School of Medicine, Department of Endocrinology and Metabolic Diseases, Ankara, Turkey c Selcuk University, Meram Medical Faculty, Division of Endocrinology and Metabolism, Konya, Turkey d Erciyes University Medical School, Department of Endocrinology, Kayseri, Turkey
Received 20 January 2006; accepted 31 May 2006 Available online 3 July 2006
Abstract Although diabetics may be exempted from Ramadan fasting, many patients still insist on this worship. Aim of the present study is to compare the effects of glimepiride, repaglinide, and insulin glargine in type 2 diabetics during Ramadan fasting on the glucose metabolism. Patients, who were willing to fast, were treated with glimepiride (n = 21), repaglinide (n = 18), and insulin glargine (n = 10). Sixteen non-fasting control type 2 diabetics matched for age, sex, and body mass index were also included. Fasting blood glucose (FBG), post-prandial blood glucose (PBG), HbA1c, and fructosamine as well as lipid metabolism were evaluated in preRamadan, post-Ramadan, and 1-month post-Ramadan time points. There was no significant change from pre-Ramadan in FBG, PBG, and HbA1c variables in fasting diabetics at post-Ramadan and 1-month post-Ramadan. However, PBG was found higher in non-fasting control diabetics at post-Ramadan and 1-month post-Ramadan ( p < 0.05 and p < 0.001, respectively). In fructosamine levels, a significant increase was noted both in fasting group and non-fasting group at 1-month post-Ramadan ( p < 0.01 for all). However, no significant difference was found in the comparison of the changes in fructosamine levels between fasting group and non-fasting group. Risk of hypoglycemia did not significantly differ between fasting and non-fasting diabetics. There was no significant difference between three drug therapies regarding glucose metabolism and rate of hypoglycemia. No adverse effects on plasma lipids were noted in fasting diabetics. In this fasting sample of patients with type 2 diabetes, glimepiride, repaglinide, and insulin glargine did not produce significant changes in glucose and lipid parameters. # 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Type 2 diabetes; Ramadan; Fasting; Glimepiride; Repaglanide; Insulin glargine; Glucose parameters; Lipid parameters
1. Introduction * Corresponding author at: Ankara University, Medical School, Department of Endocrinology and Metabolism, Ibn-i Sina Hospital, 10th Floor, 06100 Samanpazari, Ankara, Turkey. Tel.: +90 312 3094717; fax: +90 312 3094505. E-mail address: [email protected] (A. Gursoy).
Every year, millions of Muslims fast from dawn until dusk during the holy month of Ramadan. During the fast, a Muslim is required to abstain not only from food and drink but also from receiving oral medications. In
0168-8227/$ – see front matter # 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2006.05.012
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Islam belief, patients with diabetes mellitus (DM) are only exempted from Ramadan fasting if they are going to be affected adversely by fasting. However, some people refuse to accept this concession [1,2]. EPIDIAR study reported that 42.8% of patients with type 1 DM and 78.7% of patients with type 2 DM fasted for at least 15 days during Ramadan [3]. During Ramadan fasting, slight decrease in fasting serum glucose may occur in normoglycemic healthy subjects [4]. Most of the previous studies have shown that fasting during Ramadan did not adversely affect glycemic regulation in type 2 diabetics [5–8]. Moreover, some others have suggested an improved glycemic control [9–12]. Acute metabolic complications are thought to be important problem for the diabetics during Ramadan. Some studies reported increased frequency of hypoglycemia [3,5,13], whereas some others did not [2,6,9,12]. Diabetic ketoacidosis has also been reported during Ramadan fasting [3,14]. However, Gustaviani et al. reported that Ramadan fasting did not lead to an increased beta hydroxybutirate secretion in type 2 diabetics [11]. There is no consensus about the most appropriate drug therapy for type 2 diabetics during Ramadan. One study recommended glibenclamide for this purpose, but another comparative study considered repaglinide as a better choice than glibenclamide [15,16]. Sari et al. found both glimepiride and repaglinide to be effective for metabolic control during Ramadan fasting with repaglinide having lower rate of hypoglycemia [6]. Not only oral antidiabetics, but also insulin has been used during Ramadan fasting in some studies [17–19]. We aimed in this study to compare the effects of glimepiride, repaglinide, and insulin glargine in type 2 diabetics during Ramadan fasting on the glucose metabolism. 2. Material and methods 2.1. Study participants This was an open-label, multicenter, prospective, observational study carried out in three University hospitals and one private hospital in Turkey. The study was performed at the autumn, in 2004 (from 15 October to 13 November). The average fasting period was 12.5 h; the starting and finishing hours of the fasting were approximately 5:30 a.m. and 6:00 p.m. The mean daytime temperature was 20.8 8C and mean of the average humidity was 51.2% during Ramadan month in Ankara. Ankara, Konya and Kayseri (cities where the study was conducted) are all cities of Central Anatolian Region and have similar daytime temperature and humidity.
Type 2 diabetic patients aged 33–67 years on oral antidiabetic drugs, who were willing to fast throughout Ramadan month, were included in the study. Patients were reminded that Islamic belief specifically exempts the diabetics from fasting. They were also informed about the potential risks that may be associated with fasting during Ramadan, especially for poor glycemic control, hypoglycemia, diabetic ketoacidosis, dehydration, and thrombosis risks. Patients who insisted on Ramadan fasting despite these instructions were included to the study. The institutional ethic committees for human studies of each participant University and private hospital approved the study. All participants provided informed consent. The initial examination in the titration period involved medical history-taking and a physical assessment. Patients who had severe hypertension (higher arterial blood pressure than 179/109 mmHg despite antihypertensive treatment), repeated hypoglycemic episodes, severe cardiovascular and cerebrovascular disease, serum creatinine levels higher than 1.4 for women and 1.5 for men, and hepatic function tests at least 2.5 times higher than the normal level were excluded from the study. Patients with minimal elevated hepatic functions due to non-alcoholic fatty liver were included to the study. Women who were pregnant or breastfeeding were also excluded from the study. Forty-nine type 2 diabetic patients, who practiced Ramadan fasting (fasting group), and the control group consisting of 16 type 2 diabetic patients (non-fasting group) were included to the study. Fasting group was also divided into glimepiride group (n = 21), repaglinide group (n = 18), and insulin glargine group (n = 10). In non-fasting group six patients received glimepiride, five patients received repaglinide, and another five received insulin glargine. Metformin was given to all patients. 2.2. Treatment protocol and follow-up The major entry criteria for the current study was metabolically controlled (HbA1c 6.0–8.0%) type 2 diabetic patients with prior use of any oral antidiabetics. The choice of drug therapy for each patient was carried out in 6 months’ time before Ramadan fasting, which was called as the prestudy period. Patients were randomized to one of three treatment groups for the study. There was an initial titration period of 12 weeks before Ramadan for each patient who were taking glimepiride (Amaryl1, Aventis Pharmaceuticals), repaglinide (Novonorm1, Novo Nordisk Pharmaceuticals) or insulin glargine with a pen device (Lantus1, Aventis Pharmaceuticals). The optimal dosage of each drug was based on fasting and post-prandial glucose levels at three follow-up visits during the titration period. During the titration period, subjects took glimepiride as usually prescribed, once daily before the breakfast. During Ramadan, the time of administration was switched to before sunset meal without changing the dose. The maximal dosage was set at 8 mg. The maximal dose for patients started on repaglinide was 4 mg with each main meal. During Ramadan,
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the time of administration was switched to before sunset meal and dawn meal without changing the dose at each meal. Insulin glargine was given in various doses according to the needs of the patients (minimal 12 U, maximal 36 U) and was injected subcutaneously once a day at 22:00 p.m. The injection time was not changed during Ramadan. Patients were instructed to maintain their maximally effective dose of glimepiride, repaglinide, and insulin glargine unless hypoglycemia occurred, at which point they were instructed to reduce their dose to a half. Home glucose monitoring was performed at least 2 days a week (fasting; before dawn, before sunset meal, post-prandial; 2 h after dawn). Patients were also instructed to check blood glucose if they feel hypoglycemia. Every week during Ramadan fasting, patients were asked to complete a comprehensive questionnaire that was administered over the telephone to delineate hypoglycemia or hyperglycemia episodes or any other concurrent disturbances. The number of hypoglycemic events, either symptomatic or based on selfmonitoring of blood glucose (defined as <70 mg/dL), was recorded. 2.3. Blood tests Blood samples were obtained from all subjects at the beginning—1 or 2 days before the start of Ramadan (preRamadan), 4 days later following the fasting period finished, immediately after Bairam (post-Ramadan), and 1 month after Ramadan (1-month post-Ramadan) to test the fasting and post-prandial glucose, fructosamine, glycated hemoglobin (HbA1c), total cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), and triglycerides. Serum glucose was measured by the glucose oxidase technique (Roche Diagnostics GmbH, Mannheim, Germany). HbA1c levels were measured by turbidimetric inhibition immunoassay (Roche Diagnostics GmbH, Mannheim, Germany). Fructosamine levels were measured by using a calorimetric test on Conas Integra 400 system (Roche Diagnostics GmbH, Mannheim, Germany). Total cholesterol, HDL-C, and triglyceride concen-
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trations were measured by enzymatic assay (BoehringerMannheim, Mannheim, Germany). LDL-C was calculated with the Friedewald formula (LDL-C = total cholesterol (HDL-C + triglyceride/5). 2.4. Statistical analysis All continuous data were expressed as mean S.D. Data were analyzed using the Statistical Package for the Social Sciences (SPSS for Windows version 11.0; SPSS Inc., Chicago, IL, USA). Mann–Whitney U and Friedman tests were performed for statistical analyses.
3. Results The demographic characteristics and DM history of study population are presented in Table 1. At preRamadan, there were no significant differences in demographic characteristics, duration of DM, systolic and diastolic blood pressures, body mass index (BMI) and waist circumference among three different treatment groups in either fasting group or non-fasting group. 3.1. Glucose parameters Changes of glucose parameters were shown in Table 2. In fasting group, both FBG and PBG levels showed no significant changes at post-Ramadan and 1month post-Ramadan compared to pre-Ramadan. In non-fasting group, FBG levels did not change significantly throughout the study, whereas PBG levels increased at post-Ramadan and 1-month post-Ramadan compared to pre-Ramadan ( p < 0.05 and p < 0.001, respectively). At post-Ramadan and 1-month postRamadan, changes of PBG values of fasting group were lower than PBG values of non-fasting group ( p < 0.01 for both time points).
Table 1 Demographic features of the patients and duration of diabetes Fasting (n = 49)
Glimepiride (n = 21)
Repaglinide (n = 18)
Age (year)
56.5 9.2
57.4 8.3
56.3 11.3
Sex Male Female
29 20
15 6
10 8
Duration of diabetes (year) SBP (mmHg) DBP (mmHg) BMI (kg/m2) Waist (cm)
6.4 4.9 135.4 19.4 80.7 8.6 28.7 3.2 97.1 7.8
6.4 5.4 136.4 17.5 80.9 9.1 28.5 3.5 98.6 8.1
5.9 4.8 133.1 18.4 80.3 10.5 28.9 3.5 94.9 8.4
SBP: systolic blood pressure; DBP: diastolic blood pressure; BMI: body mass index.
Glargine (n = 10) 54.8 6.0 4 6 7.1 4.9 137.8 16.7 81.8 8.6 28.9 2.0 97.8 8.3
Non-fasting (n = 16) 53.4 4.7 6 10 7.0 6.0 138.8 18.9 85.6 7.0 30.9 3.3 101.9 8.2
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Table 2 Changes of the glucose and lipid parameters throughout the study Parameters
Patient groups
(1) Pre-Ramadan
(2) Post-Ramadan
(3) One-month post-Ramadan
FBG (mg/dL)
Fasting Non-fasting
141.8 39.5 155.6 59.7
137.4 38.0 157.3 46.0
140.6 31.9 162.6 47.9
PBG (mg/dL)
Fasting Non-fasting
194.9 67.8 219.4 50.5
192.8 76.1ô 249.1 52.8a
183.2 68.4ô 287.6 52.8b
HbA1c (%)
Fasting Non-fasting
7.0 1.1 7.8 1.1
6.9 1.1 7.9 1.2
6.9 1.1 8.0 1.1
Fructosamine (mg/dL)
Fasting Non-fasting
257.6 59.4 272.3 43.1
270.6 59.8 279.0 34.1
287.7 56.1£ 318.4 34.7¢
Total cholesterol (mg/dL)
Fasting Non-fasting
183.5 37.9 192.9 21.0
179.6 34.7 207.8 27.8
179.9 36.1 201.1 30.3
Triglyceride (mg/dL)
Fasting Non-fasting
139.0 51.1 137.8 65.3
152.3 67.6 158.4 68.8a
152.1 62.4 157.1 46.7
LDL (mg/dL)
Fasting Non-fasting
105.1 32.9 113.1 20.5
99.8 27.0 122.8 30.0a
99.5 29.1 123.1 29.2
HDL (mg/dL)
Fasting Non-fasting
46.6 9.8 52.0 8.8
50.2 12.4s 52.9 8.9
50.3 9.8 51.6 7.5
FBG: fasting blood glucose; PBG: post-prandial blood glucose; LDL: low density lipoprotein cholesterol; HDL: high density lipoprotein cholesterol; f: fasting; nf: non-fasting. a (1)–(2) p < 0.05. b (1)–(3) p < 0.001. s (1)–(2) p < 0.01. ¢ (2)–(3) p < 0.01. £ (2)–(3) p < 0.05. ô f–nf p < 0.01.
Although HbA1c levels increased somewhat in the NFG group, it was not a statistically significant increase, and the levels showed no significant changes in the fasting group. No differences were detected also in the comparison of the two groups in terms of percentages. However in fructosamine levels, a statistically significant change was detected both in fasting group and nonfasting group in the evaluation of the 2-month period ( p < 0.01 for both). Although the comparison of preRamadan period with the post-Ramadan period revealed no significant difference in fasting group, its comparison with 1-month-after-Ramadan period revealed a significant difference ( p < 0.01). The difference between postRamadan and 1-month-after-Ramadan periods was also significant ( p < 0.05). The comparison of pre-Ramadan period with the post-Ramadan period revealed no significant difference in non-fasting group also, while its comparison with 1-month-after-Ramadan period revealed a significant difference ( p < 0.001). The difference between post-Ramadan and 1-month-afterRamadan periods was also significant ( p < 0.01). However, no significant difference was found in the comparison of the changes in fructosamine levels in fasting and non-fasting groups ( p > 0.05).
BMI did not change during the study in fasting group. A gradual increase in BMI but not in the waist circumference was noted in non-fasting group (30.9 3.3 kg/m2 pre-Ramadan, 31.7 3.4 kg/m2 post-Ramadan, 32.2 1.9 kg/m2 1-month post-Ramadan, p < 0.05 between pre-Ramadan and post-Ramadan). The effect of drugs used in the fasting group on FBG, PBG and HbA1c levels was not found to be significantly different between each others, as shown in Table 3. At post-Ramadan and 1-month post-Ramadan, fructosamine levels were increased compared to preRamadan in glimepiride group ( p < 0.05 for both time points), repaglinide and insulin glargine groups ( p < 0.001 at 1-month post-Ramadan only). However, there was no significant difference between the three drug groups regarding the increase in fructosamine levels. 3.2. Lipid parameters While total cholesterol, LDL-C, and triglyceride levels did not change throughout the study period, HDL-C levels significantly increased at post-Ramadan in fasting group ( p < 0.01). In non-fasting group,
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Table 3 The effect of drugs on FBG, PBG, HbA1c and fructosamine levels Glimepiride
Repaglinide
Insulin glargine
FBG (mg/dL) Pre-Ramadan Post-Ramadan One-month post-Ramadan
140.6 32.6 137.7 44.6 142.9 35.8
133.9 29.1 131.9 33.0 132.7 27.2
158.6 62.6 146.4 32.9 150.2 30.2
PBG (mg/dL) Pre-Ramadan Post-Ramadan One-month post-Ramadan
211.1 55.9 202.1 78.2 195.4 80.8
159.7 68.1 177.7 73.2 153.2 56.2
224.0 69.3 200.4 80.5 211.0 38.9
HbA1c (%) Pre-Ramadan Post-Ramadan One-month post-Ramadan
6.93 1.33 6.68 1.06 6.72 1.02
6.61 0.75 6.56 0.97 6.48 0.89
7.76 0.90 7.76 0.91 7.84 0.94
Fructosamine (mg/dL) Pre-Ramadan Post-Ramadan One-month post-Ramadan
258.7 70.2 278.8 77.1d 271.5 54.2e
251.5 58.4 262.0 45.1 290.6 55.4b
266.4 35.2 268.8 41.1 316.4 54.2b
FBG: fasting blood glucose; PBG: post-prandial blood glucose. d (1)–(2) p < 0.05. b (1)–(3) p < 0.001. e (1)–(3) p < 0.05.
LDL-C and triglyceride levels significantly increased at post-Ramadan ( p < 0.05 for both). 3.3. Adverse events No diabetes-related adverse events were reported that required exclusion from the study or to quit fasting. At least one reported hypoglycemia was found in 12.2% of patients in fasting group and 12.5% of patients in non-fasting group. Hypoglycemia was observed in 14.3% of patients in glimepiride group, 11.1% of patients in repaglinide group, 10% of patients in insulin glargine group. There was no significant difference between three drug groups regarding the rate of hypoglycemia. 4. Discussion Fasting during Ramadan has been strongly discouraged by the physicians and diabetic care providers for patients with DM except well-controlled ones. However, it was shown that many diabetics fast during the holly month of Ramadan [3]. Noteworthy, fasting does not adversely affect blood glucose control, having no effect on fasting and post-prandial glucose levels, HbA1c, and fructosamine levels [5–12]. In contrast to previous studies, diabetics who were not fasting during Ramadan were selected as the control group in our study. No significant impairment was
observed in the parameters used for the evaluation of blood glucose regulation in the fasting group, while post-prandial glucose values were found to be higher in post-Ramadan time points in the non-fasting group. This has led to the thought that fasting diabetics might care more about their blood glucose regulation. Khatib and Shafagoj obtained similar results in their recently published study and reported that fasting diabetics obtained a better blood glucose regulation. However, non-fasting group was not included in their study [10]. HbA1c levels did not change significantly either in the fasting or non-fasting group during Ramadan, whereas fructosamine levels showed a significant increase at 1-month post-Ramadan compared to preRamadan and post-Ramadan in both groups. Ramadan is not only a month when eating and drinking is prohibited; it is also a period when people change their normal eating pattern after dawn. Muslims also arrange social activities such as invitations and treats. The common practice of ingesting large amounts of foods rich in carbohydrate and fat, between sunset and dawn, impairs dietary discipline during Ramadan month. We thought that fasting diabetics care more about their health than non-fasting diabetics, since they were instructed that fasting might adversely alter their glucose parameters. HbA1c is a reliable index of longterm (3 months) control of glucose in diabetic patients while measurement of fructosamine provides an index of glycemic status over the preceding 1–2 weeks [20].
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When time period of our study was considered, it would be more appropriate to use fructosamine instead of HbA1c, because measuring HbA1c at 1-month interval may not be ideal to evaluate glycemic control. This made us think that, similar to non-fasting ones, fasting type 2 diabetics paid less attention to the control of blood glucose after Ramadan, which probably explains increased fructosamine levels in fasting group after Ramadan. Moreover Ramadan Bairam, which is a 3 days festival following Ramadan fasting, may be another reason for increased fructosamine levels. In our country, Ramadan Bairam is also called as ‘‘Sugar Bairam’’. Sugar and fat rich foods are consumed in large quantities during this time. Non-fasting diabetics probably lost control of their nutrition discipline because of changing eating pattern of the fasting community during Ramadan. Although fasting and non-fasting groups in our study had a tendency to gain weight during Ramadan, non-fasting diabetics gained significantly more weight than fasting diabetics. In a recent review it was reported that various results including weight gain, loss and no change could be seen during Ramadan [1]. We thought that the higher fat and sugar content of the conventional food presented in Ramadan meals might result in a tendency to gain weight. The decreased physical activity might also be a reason for weight gain due to the fear of hypoglycemia and fasting itself. In our study, lipid metabolism did not adversely affected by Ramadan fasting, although slight increase in LDL-C and triglyceride were noted in the non-fasting group. HDL-C levels were found significantly higher in post-Ramadan than pre-Ramadan in the fasting group, but no difference was detected in the non-fasting group. Afrasiabi et al. demonstrated that fasting hyperlipidemic individuals had better lipid levels at the end of Ramadan, and that non-fasting individuals did not show such a change [21]. Studies performed on healthy individuals reported an increase in HDL-C after Ramadan [22,23]. In studies aiming to find the most appropriate drug therapy in type 2 diabetics, both sulphonylureas and repaglinide were suggested as a possible choice [2,6,15,16]. In one of the two comparative studies, repaglinide and glibenclamide were compared. Type 2 diabetic Muslims using repaglinide showed a trend towards better glycemic control and had a lower frequency of hypoglycemia than patients using glibenclamide [16]. In other comparative study, patients receiving glimepiride or gliclazide were compared with repaglinide, and no difference was observed either in terms of glycemic control or hypoglycemic event [6].
Clinical studies with various insulin preparations during fasting are limited. Studies on type 1 and type 2 diabetics revealed that insulin lispro or insulin aspart or insulin lispro Mix25 led to improvement in glycemic control and was associated with less hypoglycemic events [17–19]. Insulin glargine is a novel, long-acting human insulin analog that is indicated both in type 1 and type 2 diabetic patients who require basal insulin for glycemic control, and has been associated with less hypoglycemic episodes [24]. Only in one study using insulin glargine showed that glycemic control could be achieved safely and effectively in fasting type 1 diabetic patients [25]. In our study, insulin glargine safely and successfully maintained glycemic control during Ramadan fasting. No severe hypoglycemic episodes were observed in either fasting or non-fasting subjects of the study. Hypoglycemia event rate in fasting type 2 diabetics are reported differently in various studies. Although no hypoglycemia was reported in one study [9], in others it ranged between 1.9% and 19.5% [2,3,5,6,15,16]. The reason for this difference might be the variability in documentation of hypoglycemia and study designs, in addition to the drugs used. However severe hypoglycemia has not been reported, just like in our study. It might be concluded that fasting does not create an important problem in terms of hypoglycemic episodes. In this report both oral agents, glimepiride and repaglinide, and using one injection of a long-acting insulin analog, insulin glargine in combination with metformin did not adversely affect the glycemic control. In patients with type 2 DM who are in accepted glycemic control with oral antidiabetics, the risk associated with fasting is quite low. Therefore, well-controlled diabetics might not be strictly prohibited from engaging in Ramadan worship, fasting might even be beneficial for blood glucose regulation since it urges the individual to behave in a more disciplined way. However, it should be strongly advised for diabetics to receive appropriate education and instructions about signs and symptoms of hyper- and hypoglycemia, blood glucose monitoring, meal planning, physical activity, medication administration, and management of acute complications [1]. References [1] M. Al-Arouj, R. Bouguerra, J. Buse, S. Hafez, M. Hassanein, M.A. Ibrahim, et al., Recommendations for management of diabetes during Ramadan, Diabetes Care 28 (2005) 2305–2311. [2] The Glimepiride in Ramadan (GLIRA) Study Group, The efficacy and safety of glimepiride in the management of type 2 diabetes in Muslim patients during Ramadan, Diabetes Care 28 (2005) 421–422.
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A comparison of glycemic effects of glimepiride, repaglinide, and insulin glargine in type 2 diabetes mellitus during Ramadan fasting Mustafa Cesur a, Demet Corapcioglu b, Alptekin Gursoy b,*, Sait Gonen c, Mine Ozduman b, Rifat Emral b, Ali Riza Uysal b, Vedia Tonyukuk b, Arif Ender Yilmaz b, Fahri Bayram d, Nuri Kamel b b
a Ankara Guven Hospital, Department of Endocrinology and Metabolic Diseases, Ankara, Turkey Ankara University School of Medicine, Department of Endocrinology and Metabolic Diseases, Ankara, Turkey c Selcuk University, Meram Medical Faculty, Division of Endocrinology and Metabolism, Konya, Turkey d Erciyes University Medical School, Department of Endocrinology, Kayseri, Turkey
Received 20 January 2006; accepted 31 May 2006 Available online 3 July 2006
Abstract Although diabetics may be exempted from Ramadan fasting, many patients still insist on this worship. Aim of the present study is to compare the effects of glimepiride, repaglinide, and insulin glargine in type 2 diabetics during Ramadan fasting on the glucose metabolism. Patients, who were willing to fast, were treated with glimepiride (n = 21), repaglinide (n = 18), and insulin glargine (n = 10). Sixteen non-fasting control type 2 diabetics matched for age, sex, and body mass index were also included. Fasting blood glucose (FBG), post-prandial blood glucose (PBG), HbA1c, and fructosamine as well as lipid metabolism were evaluated in preRamadan, post-Ramadan, and 1-month post-Ramadan time points. There was no significant change from pre-Ramadan in FBG, PBG, and HbA1c variables in fasting diabetics at post-Ramadan and 1-month post-Ramadan. However, PBG was found higher in non-fasting control diabetics at post-Ramadan and 1-month post-Ramadan ( p < 0.05 and p < 0.001, respectively). In fructosamine levels, a significant increase was noted both in fasting group and non-fasting group at 1-month post-Ramadan ( p < 0.01 for all). However, no significant difference was found in the comparison of the changes in fructosamine levels between fasting group and non-fasting group. Risk of hypoglycemia did not significantly differ between fasting and non-fasting diabetics. There was no significant difference between three drug therapies regarding glucose metabolism and rate of hypoglycemia. No adverse effects on plasma lipids were noted in fasting diabetics. In this fasting sample of patients with type 2 diabetes, glimepiride, repaglinide, and insulin glargine did not produce significant changes in glucose and lipid parameters. # 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Type 2 diabetes; Ramadan; Fasting; Glimepiride; Repaglanide; Insulin glargine; Glucose parameters; Lipid parameters
1. Introduction * Corresponding author at: Ankara University, Medical School, Department of Endocrinology and Metabolism, Ibn-i Sina Hospital, 10th Floor, 06100 Samanpazari, Ankara, Turkey. Tel.: +90 312 3094717; fax: +90 312 3094505. E-mail address: [email protected] (A. Gursoy).
Every year, millions of Muslims fast from dawn until dusk during the holy month of Ramadan. During the fast, a Muslim is required to abstain not only from food and drink but also from receiving oral medications. In
0168-8227/$ – see front matter # 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2006.05.012
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Islam belief, patients with diabetes mellitus (DM) are only exempted from Ramadan fasting if they are going to be affected adversely by fasting. However, some people refuse to accept this concession [1,2]. EPIDIAR study reported that 42.8% of patients with type 1 DM and 78.7% of patients with type 2 DM fasted for at least 15 days during Ramadan [3]. During Ramadan fasting, slight decrease in fasting serum glucose may occur in normoglycemic healthy subjects [4]. Most of the previous studies have shown that fasting during Ramadan did not adversely affect glycemic regulation in type 2 diabetics [5–8]. Moreover, some others have suggested an improved glycemic control [9–12]. Acute metabolic complications are thought to be important problem for the diabetics during Ramadan. Some studies reported increased frequency of hypoglycemia [3,5,13], whereas some others did not [2,6,9,12]. Diabetic ketoacidosis has also been reported during Ramadan fasting [3,14]. However, Gustaviani et al. reported that Ramadan fasting did not lead to an increased beta hydroxybutirate secretion in type 2 diabetics [11]. There is no consensus about the most appropriate drug therapy for type 2 diabetics during Ramadan. One study recommended glibenclamide for this purpose, but another comparative study considered repaglinide as a better choice than glibenclamide [15,16]. Sari et al. found both glimepiride and repaglinide to be effective for metabolic control during Ramadan fasting with repaglinide having lower rate of hypoglycemia [6]. Not only oral antidiabetics, but also insulin has been used during Ramadan fasting in some studies [17–19]. We aimed in this study to compare the effects of glimepiride, repaglinide, and insulin glargine in type 2 diabetics during Ramadan fasting on the glucose metabolism. 2. Material and methods 2.1. Study participants This was an open-label, multicenter, prospective, observational study carried out in three University hospitals and one private hospital in Turkey. The study was performed at the autumn, in 2004 (from 15 October to 13 November). The average fasting period was 12.5 h; the starting and finishing hours of the fasting were approximately 5:30 a.m. and 6:00 p.m. The mean daytime temperature was 20.8 8C and mean of the average humidity was 51.2% during Ramadan month in Ankara. Ankara, Konya and Kayseri (cities where the study was conducted) are all cities of Central Anatolian Region and have similar daytime temperature and humidity.
Type 2 diabetic patients aged 33–67 years on oral antidiabetic drugs, who were willing to fast throughout Ramadan month, were included in the study. Patients were reminded that Islamic belief specifically exempts the diabetics from fasting. They were also informed about the potential risks that may be associated with fasting during Ramadan, especially for poor glycemic control, hypoglycemia, diabetic ketoacidosis, dehydration, and thrombosis risks. Patients who insisted on Ramadan fasting despite these instructions were included to the study. The institutional ethic committees for human studies of each participant University and private hospital approved the study. All participants provided informed consent. The initial examination in the titration period involved medical history-taking and a physical assessment. Patients who had severe hypertension (higher arterial blood pressure than 179/109 mmHg despite antihypertensive treatment), repeated hypoglycemic episodes, severe cardiovascular and cerebrovascular disease, serum creatinine levels higher than 1.4 for women and 1.5 for men, and hepatic function tests at least 2.5 times higher than the normal level were excluded from the study. Patients with minimal elevated hepatic functions due to non-alcoholic fatty liver were included to the study. Women who were pregnant or breastfeeding were also excluded from the study. Forty-nine type 2 diabetic patients, who practiced Ramadan fasting (fasting group), and the control group consisting of 16 type 2 diabetic patients (non-fasting group) were included to the study. Fasting group was also divided into glimepiride group (n = 21), repaglinide group (n = 18), and insulin glargine group (n = 10). In non-fasting group six patients received glimepiride, five patients received repaglinide, and another five received insulin glargine. Metformin was given to all patients. 2.2. Treatment protocol and follow-up The major entry criteria for the current study was metabolically controlled (HbA1c 6.0–8.0%) type 2 diabetic patients with prior use of any oral antidiabetics. The choice of drug therapy for each patient was carried out in 6 months’ time before Ramadan fasting, which was called as the prestudy period. Patients were randomized to one of three treatment groups for the study. There was an initial titration period of 12 weeks before Ramadan for each patient who were taking glimepiride (Amaryl1, Aventis Pharmaceuticals), repaglinide (Novonorm1, Novo Nordisk Pharmaceuticals) or insulin glargine with a pen device (Lantus1, Aventis Pharmaceuticals). The optimal dosage of each drug was based on fasting and post-prandial glucose levels at three follow-up visits during the titration period. During the titration period, subjects took glimepiride as usually prescribed, once daily before the breakfast. During Ramadan, the time of administration was switched to before sunset meal without changing the dose. The maximal dosage was set at 8 mg. The maximal dose for patients started on repaglinide was 4 mg with each main meal. During Ramadan,
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the time of administration was switched to before sunset meal and dawn meal without changing the dose at each meal. Insulin glargine was given in various doses according to the needs of the patients (minimal 12 U, maximal 36 U) and was injected subcutaneously once a day at 22:00 p.m. The injection time was not changed during Ramadan. Patients were instructed to maintain their maximally effective dose of glimepiride, repaglinide, and insulin glargine unless hypoglycemia occurred, at which point they were instructed to reduce their dose to a half. Home glucose monitoring was performed at least 2 days a week (fasting; before dawn, before sunset meal, post-prandial; 2 h after dawn). Patients were also instructed to check blood glucose if they feel hypoglycemia. Every week during Ramadan fasting, patients were asked to complete a comprehensive questionnaire that was administered over the telephone to delineate hypoglycemia or hyperglycemia episodes or any other concurrent disturbances. The number of hypoglycemic events, either symptomatic or based on selfmonitoring of blood glucose (defined as <70 mg/dL), was recorded. 2.3. Blood tests Blood samples were obtained from all subjects at the beginning—1 or 2 days before the start of Ramadan (preRamadan), 4 days later following the fasting period finished, immediately after Bairam (post-Ramadan), and 1 month after Ramadan (1-month post-Ramadan) to test the fasting and post-prandial glucose, fructosamine, glycated hemoglobin (HbA1c), total cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), and triglycerides. Serum glucose was measured by the glucose oxidase technique (Roche Diagnostics GmbH, Mannheim, Germany). HbA1c levels were measured by turbidimetric inhibition immunoassay (Roche Diagnostics GmbH, Mannheim, Germany). Fructosamine levels were measured by using a calorimetric test on Conas Integra 400 system (Roche Diagnostics GmbH, Mannheim, Germany). Total cholesterol, HDL-C, and triglyceride concen-
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trations were measured by enzymatic assay (BoehringerMannheim, Mannheim, Germany). LDL-C was calculated with the Friedewald formula (LDL-C = total cholesterol (HDL-C + triglyceride/5). 2.4. Statistical analysis All continuous data were expressed as mean S.D. Data were analyzed using the Statistical Package for the Social Sciences (SPSS for Windows version 11.0; SPSS Inc., Chicago, IL, USA). Mann–Whitney U and Friedman tests were performed for statistical analyses.
3. Results The demographic characteristics and DM history of study population are presented in Table 1. At preRamadan, there were no significant differences in demographic characteristics, duration of DM, systolic and diastolic blood pressures, body mass index (BMI) and waist circumference among three different treatment groups in either fasting group or non-fasting group. 3.1. Glucose parameters Changes of glucose parameters were shown in Table 2. In fasting group, both FBG and PBG levels showed no significant changes at post-Ramadan and 1month post-Ramadan compared to pre-Ramadan. In non-fasting group, FBG levels did not change significantly throughout the study, whereas PBG levels increased at post-Ramadan and 1-month post-Ramadan compared to pre-Ramadan ( p < 0.05 and p < 0.001, respectively). At post-Ramadan and 1-month postRamadan, changes of PBG values of fasting group were lower than PBG values of non-fasting group ( p < 0.01 for both time points).
Table 1 Demographic features of the patients and duration of diabetes Fasting (n = 49)
Glimepiride (n = 21)
Repaglinide (n = 18)
Age (year)
56.5 9.2
57.4 8.3
56.3 11.3
Sex Male Female
29 20
15 6
10 8
Duration of diabetes (year) SBP (mmHg) DBP (mmHg) BMI (kg/m2) Waist (cm)
6.4 4.9 135.4 19.4 80.7 8.6 28.7 3.2 97.1 7.8
6.4 5.4 136.4 17.5 80.9 9.1 28.5 3.5 98.6 8.1
5.9 4.8 133.1 18.4 80.3 10.5 28.9 3.5 94.9 8.4
SBP: systolic blood pressure; DBP: diastolic blood pressure; BMI: body mass index.
Glargine (n = 10) 54.8 6.0 4 6 7.1 4.9 137.8 16.7 81.8 8.6 28.9 2.0 97.8 8.3
Non-fasting (n = 16) 53.4 4.7 6 10 7.0 6.0 138.8 18.9 85.6 7.0 30.9 3.3 101.9 8.2
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Table 2 Changes of the glucose and lipid parameters throughout the study Parameters
Patient groups
(1) Pre-Ramadan
(2) Post-Ramadan
(3) One-month post-Ramadan
FBG (mg/dL)
Fasting Non-fasting
141.8 39.5 155.6 59.7
137.4 38.0 157.3 46.0
140.6 31.9 162.6 47.9
PBG (mg/dL)
Fasting Non-fasting
194.9 67.8 219.4 50.5
192.8 76.1ô 249.1 52.8a
183.2 68.4ô 287.6 52.8b
HbA1c (%)
Fasting Non-fasting
7.0 1.1 7.8 1.1
6.9 1.1 7.9 1.2
6.9 1.1 8.0 1.1
Fructosamine (mg/dL)
Fasting Non-fasting
257.6 59.4 272.3 43.1
270.6 59.8 279.0 34.1
287.7 56.1£ 318.4 34.7¢
Total cholesterol (mg/dL)
Fasting Non-fasting
183.5 37.9 192.9 21.0
179.6 34.7 207.8 27.8
179.9 36.1 201.1 30.3
Triglyceride (mg/dL)
Fasting Non-fasting
139.0 51.1 137.8 65.3
152.3 67.6 158.4 68.8a
152.1 62.4 157.1 46.7
LDL (mg/dL)
Fasting Non-fasting
105.1 32.9 113.1 20.5
99.8 27.0 122.8 30.0a
99.5 29.1 123.1 29.2
HDL (mg/dL)
Fasting Non-fasting
46.6 9.8 52.0 8.8
50.2 12.4s 52.9 8.9
50.3 9.8 51.6 7.5
FBG: fasting blood glucose; PBG: post-prandial blood glucose; LDL: low density lipoprotein cholesterol; HDL: high density lipoprotein cholesterol; f: fasting; nf: non-fasting. a (1)–(2) p < 0.05. b (1)–(3) p < 0.001. s (1)–(2) p < 0.01. ¢ (2)–(3) p < 0.01. £ (2)–(3) p < 0.05. ô f–nf p < 0.01.
Although HbA1c levels increased somewhat in the NFG group, it was not a statistically significant increase, and the levels showed no significant changes in the fasting group. No differences were detected also in the comparison of the two groups in terms of percentages. However in fructosamine levels, a statistically significant change was detected both in fasting group and nonfasting group in the evaluation of the 2-month period ( p < 0.01 for both). Although the comparison of preRamadan period with the post-Ramadan period revealed no significant difference in fasting group, its comparison with 1-month-after-Ramadan period revealed a significant difference ( p < 0.01). The difference between postRamadan and 1-month-after-Ramadan periods was also significant ( p < 0.05). The comparison of pre-Ramadan period with the post-Ramadan period revealed no significant difference in non-fasting group also, while its comparison with 1-month-after-Ramadan period revealed a significant difference ( p < 0.001). The difference between post-Ramadan and 1-month-afterRamadan periods was also significant ( p < 0.01). However, no significant difference was found in the comparison of the changes in fructosamine levels in fasting and non-fasting groups ( p > 0.05).
BMI did not change during the study in fasting group. A gradual increase in BMI but not in the waist circumference was noted in non-fasting group (30.9 3.3 kg/m2 pre-Ramadan, 31.7 3.4 kg/m2 post-Ramadan, 32.2 1.9 kg/m2 1-month post-Ramadan, p < 0.05 between pre-Ramadan and post-Ramadan). The effect of drugs used in the fasting group on FBG, PBG and HbA1c levels was not found to be significantly different between each others, as shown in Table 3. At post-Ramadan and 1-month post-Ramadan, fructosamine levels were increased compared to preRamadan in glimepiride group ( p < 0.05 for both time points), repaglinide and insulin glargine groups ( p < 0.001 at 1-month post-Ramadan only). However, there was no significant difference between the three drug groups regarding the increase in fructosamine levels. 3.2. Lipid parameters While total cholesterol, LDL-C, and triglyceride levels did not change throughout the study period, HDL-C levels significantly increased at post-Ramadan in fasting group ( p < 0.01). In non-fasting group,
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Table 3 The effect of drugs on FBG, PBG, HbA1c and fructosamine levels Glimepiride
Repaglinide
Insulin glargine
FBG (mg/dL) Pre-Ramadan Post-Ramadan One-month post-Ramadan
140.6 32.6 137.7 44.6 142.9 35.8
133.9 29.1 131.9 33.0 132.7 27.2
158.6 62.6 146.4 32.9 150.2 30.2
PBG (mg/dL) Pre-Ramadan Post-Ramadan One-month post-Ramadan
211.1 55.9 202.1 78.2 195.4 80.8
159.7 68.1 177.7 73.2 153.2 56.2
224.0 69.3 200.4 80.5 211.0 38.9
HbA1c (%) Pre-Ramadan Post-Ramadan One-month post-Ramadan
6.93 1.33 6.68 1.06 6.72 1.02
6.61 0.75 6.56 0.97 6.48 0.89
7.76 0.90 7.76 0.91 7.84 0.94
Fructosamine (mg/dL) Pre-Ramadan Post-Ramadan One-month post-Ramadan
258.7 70.2 278.8 77.1d 271.5 54.2e
251.5 58.4 262.0 45.1 290.6 55.4b
266.4 35.2 268.8 41.1 316.4 54.2b
FBG: fasting blood glucose; PBG: post-prandial blood glucose. d (1)–(2) p < 0.05. b (1)–(3) p < 0.001. e (1)–(3) p < 0.05.
LDL-C and triglyceride levels significantly increased at post-Ramadan ( p < 0.05 for both). 3.3. Adverse events No diabetes-related adverse events were reported that required exclusion from the study or to quit fasting. At least one reported hypoglycemia was found in 12.2% of patients in fasting group and 12.5% of patients in non-fasting group. Hypoglycemia was observed in 14.3% of patients in glimepiride group, 11.1% of patients in repaglinide group, 10% of patients in insulin glargine group. There was no significant difference between three drug groups regarding the rate of hypoglycemia. 4. Discussion Fasting during Ramadan has been strongly discouraged by the physicians and diabetic care providers for patients with DM except well-controlled ones. However, it was shown that many diabetics fast during the holly month of Ramadan [3]. Noteworthy, fasting does not adversely affect blood glucose control, having no effect on fasting and post-prandial glucose levels, HbA1c, and fructosamine levels [5–12]. In contrast to previous studies, diabetics who were not fasting during Ramadan were selected as the control group in our study. No significant impairment was
observed in the parameters used for the evaluation of blood glucose regulation in the fasting group, while post-prandial glucose values were found to be higher in post-Ramadan time points in the non-fasting group. This has led to the thought that fasting diabetics might care more about their blood glucose regulation. Khatib and Shafagoj obtained similar results in their recently published study and reported that fasting diabetics obtained a better blood glucose regulation. However, non-fasting group was not included in their study [10]. HbA1c levels did not change significantly either in the fasting or non-fasting group during Ramadan, whereas fructosamine levels showed a significant increase at 1-month post-Ramadan compared to preRamadan and post-Ramadan in both groups. Ramadan is not only a month when eating and drinking is prohibited; it is also a period when people change their normal eating pattern after dawn. Muslims also arrange social activities such as invitations and treats. The common practice of ingesting large amounts of foods rich in carbohydrate and fat, between sunset and dawn, impairs dietary discipline during Ramadan month. We thought that fasting diabetics care more about their health than non-fasting diabetics, since they were instructed that fasting might adversely alter their glucose parameters. HbA1c is a reliable index of longterm (3 months) control of glucose in diabetic patients while measurement of fructosamine provides an index of glycemic status over the preceding 1–2 weeks [20].
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When time period of our study was considered, it would be more appropriate to use fructosamine instead of HbA1c, because measuring HbA1c at 1-month interval may not be ideal to evaluate glycemic control. This made us think that, similar to non-fasting ones, fasting type 2 diabetics paid less attention to the control of blood glucose after Ramadan, which probably explains increased fructosamine levels in fasting group after Ramadan. Moreover Ramadan Bairam, which is a 3 days festival following Ramadan fasting, may be another reason for increased fructosamine levels. In our country, Ramadan Bairam is also called as ‘‘Sugar Bairam’’. Sugar and fat rich foods are consumed in large quantities during this time. Non-fasting diabetics probably lost control of their nutrition discipline because of changing eating pattern of the fasting community during Ramadan. Although fasting and non-fasting groups in our study had a tendency to gain weight during Ramadan, non-fasting diabetics gained significantly more weight than fasting diabetics. In a recent review it was reported that various results including weight gain, loss and no change could be seen during Ramadan [1]. We thought that the higher fat and sugar content of the conventional food presented in Ramadan meals might result in a tendency to gain weight. The decreased physical activity might also be a reason for weight gain due to the fear of hypoglycemia and fasting itself. In our study, lipid metabolism did not adversely affected by Ramadan fasting, although slight increase in LDL-C and triglyceride were noted in the non-fasting group. HDL-C levels were found significantly higher in post-Ramadan than pre-Ramadan in the fasting group, but no difference was detected in the non-fasting group. Afrasiabi et al. demonstrated that fasting hyperlipidemic individuals had better lipid levels at the end of Ramadan, and that non-fasting individuals did not show such a change [21]. Studies performed on healthy individuals reported an increase in HDL-C after Ramadan [22,23]. In studies aiming to find the most appropriate drug therapy in type 2 diabetics, both sulphonylureas and repaglinide were suggested as a possible choice [2,6,15,16]. In one of the two comparative studies, repaglinide and glibenclamide were compared. Type 2 diabetic Muslims using repaglinide showed a trend towards better glycemic control and had a lower frequency of hypoglycemia than patients using glibenclamide [16]. In other comparative study, patients receiving glimepiride or gliclazide were compared with repaglinide, and no difference was observed either in terms of glycemic control or hypoglycemic event [6].
Clinical studies with various insulin preparations during fasting are limited. Studies on type 1 and type 2 diabetics revealed that insulin lispro or insulin aspart or insulin lispro Mix25 led to improvement in glycemic control and was associated with less hypoglycemic events [17–19]. Insulin glargine is a novel, long-acting human insulin analog that is indicated both in type 1 and type 2 diabetic patients who require basal insulin for glycemic control, and has been associated with less hypoglycemic episodes [24]. Only in one study using insulin glargine showed that glycemic control could be achieved safely and effectively in fasting type 1 diabetic patients [25]. In our study, insulin glargine safely and successfully maintained glycemic control during Ramadan fasting. No severe hypoglycemic episodes were observed in either fasting or non-fasting subjects of the study. Hypoglycemia event rate in fasting type 2 diabetics are reported differently in various studies. Although no hypoglycemia was reported in one study [9], in others it ranged between 1.9% and 19.5% [2,3,5,6,15,16]. The reason for this difference might be the variability in documentation of hypoglycemia and study designs, in addition to the drugs used. However severe hypoglycemia has not been reported, just like in our study. It might be concluded that fasting does not create an important problem in terms of hypoglycemic episodes. In this report both oral agents, glimepiride and repaglinide, and using one injection of a long-acting insulin analog, insulin glargine in combination with metformin did not adversely affect the glycemic control. In patients with type 2 DM who are in accepted glycemic control with oral antidiabetics, the risk associated with fasting is quite low. Therefore, well-controlled diabetics might not be strictly prohibited from engaging in Ramadan worship, fasting might even be beneficial for blood glucose regulation since it urges the individual to behave in a more disciplined way. However, it should be strongly advised for diabetics to receive appropriate education and instructions about signs and symptoms of hyper- and hypoglycemia, blood glucose monitoring, meal planning, physical activity, medication administration, and management of acute complications [1]. References [1] M. Al-Arouj, R. Bouguerra, J. Buse, S. Hafez, M. Hassanein, M.A. Ibrahim, et al., Recommendations for management of diabetes during Ramadan, Diabetes Care 28 (2005) 2305–2311. [2] The Glimepiride in Ramadan (GLIRA) Study Group, The efficacy and safety of glimepiride in the management of type 2 diabetes in Muslim patients during Ramadan, Diabetes Care 28 (2005) 421–422.
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