Use of glucose-lowering medications during Ramadan
The preferred antidiabetic drugs during Ramadan are agents that provide sustained glucose control during prolonged fasting with low risk of hypoglycemia, especially during the fasting period. Table 1 lists the benefits and concerns of commonly used oral antidiabetic agents during Ramadan.
Pharmacological oral agents for the treatment of type 2 diabetes during Ramadan
Sulfonylureas and insulin secretagogues are widely used during Ramadan. Recent studies, however, have highlighted an increased risk of hypoglycemia during fasting in patients treated with insulin secretagogues.7–9 The risk of hypoglycemia increases exponentially in elderly patients and patients with renal failure and medical illnesses treated with sulfonylureas. In general, it is recommended that insulin secretagogues should be avoided during periods of prolonged fasting due to the increased risk of hypoglycemia. However, the STEADFAST study, a double-blind randomized controlled trial (RCT), compared vildagliptin with gliclazide as an add-on therapy to metformin during Ramadan. In that study, there were no significant differences in weight, glycated hemoglobin (HbA1c), or in the frequency of hypoglycemia between treatment groups.10
Metformin is the preferred agent for the management of patients with type 2 diabetes. Metformin is associated with a reduction in HbA1c of 1–2% and carries a low risk of hypoglycemia.11 These properties make metformin an attractive therapy for the majority of patients who will undergo prolonged fasting. It should be noted, however, that there are very few prospective RCT specifically designed to determine the safety and efficacy of metformin as monotherapy during Ramadan.12 The VECTOR study compared glipizide and vildagliptin in combination with metformin during Ramadan and reported low rates of hypoglycemia along with a lowering of the HbA1c concentration compared with the glipizide group.13 In these trials, no safety issues were found related to metformin use.
α-Glucosidase inhibitors are used successfully in the Middle Eastern population during Ramadan. The most common adverse events with these agents are gastrointestinal symptoms, usually at the beginning of treatment.14 The risk of hypoglycemia is low when used as monotherapy; there are, however, no prospective studies looking at the safety and efficacy of these agents during prolonged fasting periods.
Thiazolidinediones (TZDs), such as pioglitazone, are effective in lowering glucose by improving glucose uptake in peripheral tissues and by reducing insulin resistance. The use of TZDs is not associated with increased risk of hypoglycemia when used as monotherapy. These agents are effective in improving glucose control, resulting in a reduction of HbA1c between 1% and 2%.15 TZDs have long been thought of as a useful agent during Ramadan because of its low risk of hypoglycemia; however, these agents should be started long before the start of the fast as the maximal antihyperglycemic effect may take up to 10–12 weeks. In addition, long-term treatment with TZDs has been associated with fluid retention, peripheral edema, and weight gain. There is also concern with the higher risk of bone loss and increased risk of fractures seen in postmenopausal women. The safety and efficacy of TZD agents has not been established in clinical trials during Ramadan.
Dipeptidyl peptidase-4 (DPP4) inhibitors have been increasingly used during the past decade for the treatment of patients with type 2 diabetes during Ramadan. These agents work by increasing insulin secretion in a glucose-dependent mechanism; therefore, they are not associated with increased risk of hypoglycemia when used as monotherapy. DPP4 inhibitors also reduce glucagon concentration and delay gastric emptying. These agents are attractive during Ramadan because of the low rate of hypoglycemia. Vildagliptin has been compared with different sulfonylurea agents, with and without metformin combination, during Ramadan. The results of these studies indicate that DPP4 inhibitors are effective in improving glycemic control with low rates of hypoglycemia and less weight gain compared with insulin secretagogues.10 ,13 ,16 The vildagliptin expeRience compared wiTh sulfonylUrea obsErved during Ramadan (VIRTUE trial) that compared vildagliptin with sulfonylurea therapy during Ramadan reported a reduction in hypoglycemic events with the use of vildagliptin compared with sulfonylurea agents.16 Similar beneficial effects have also been reported with sitagliptin therapy during Ramadan.8
Few studies have determined the safety and efficacy of glucagon-like peptide 1 receptor agonists (GLP-1 RA) in patients with diabetes during Ramadan. A recent study of liraglutide compared with insulin secretagogues reported a significant improvement in glycemic control with weight loss with liraglutide treatment compared with patients treated with sulfonylureas.14 Severe hypoglycemic events were not increased with either treatment, but self-reported hypoglycemia was lower with liraglutide.14
The sodium glucose transporter-2 (SGLT-2) inhibitors are the newest class of approved oral antidiabetic agents for the treatment of type 2 diabetes. By increasing glucosuria, SGLT-2 inhibitors are associated with significant improvements of fasting hyperglycemia and HbA1c concentration, and with low risk of hypoglycemia in patients with type 2 diabetes. These agents, however, are associated with increased risk of urinary tract and genital infections, and with a mild increase in the risk of volume contraction and dehydration.17 The lower rates of hypoglycemia compared with sulfonylurea and insulin treatment make SGLT-2 inhibitors an attractive drug in patients with diabetes during Ramadan. However, the associated volume contraction and risk of dehydration represent a concern during prolonged fasting in warm or hot climates, in particular in elderly patients. Randomized controlled studies are needed to determine the safety and efficacy of SGLT-2 inhibitors during Ramadan, especially after the recent Food and Drug Administration (FDA) warning concerning the possible ketoacidosis.
Type 2 diabetes is associated with a progressive decline in insulin secretion and β-cell loss with increased duration of diabetes. Many patients soon after a clinical diagnosis of diabetes need to be treated with insulin injections. Although effective in improving glucose control, insulin treatment is associated with increased risk of hypoglycemia, especially during prolonged fasting. The total insulin dose frequently needs to be adjusted during Ramadan in patients with type 1 or type 2 diabetes. The use of basal (glargine or detemir) and rapid-acting insulin analogs (lispro, aspart, and glulisine) has been shown to be superior to human insulin formulations (NPH and regular) during Ramadan by reducing the risk of hypoglycemia. In one study, the administration of lispro insulin before meals was associated with better glycemic control and with a lower rate of hypoglycemia compared with treatment with regular insulin.18 In another study, switching from premixed insulin formulation (30% regular/70% NPH) to 50 regular/50NPH insulin during the evening meal demonstrated a reduction in HbA1c with less hypoglycemic episodes.19
The use of insulin pump therapy has been shown to be effective in improving glycemic control and in reducing the risk of hypoglycemia in patients with type 1 diabetes during Ramadan. The use of an insulin pump helps to provide a continuous basal rate of insulin during the fasting period and to rapidly cover for meals intake after the breaking of the fast. In one study, patients on insulin pumps were monitored during Ramadan with a continuous glucose-monitoring (CGM) device.20 There was no significant increase in the risk of hypoglycemia when comparing the periods before, during, and after the end of fasting. However, the insulin infusion rate needs to be adjusted, with a reduction in the basal insulin rate during the day and greater postprandial boluses after the breaking of the fast.20 The use of CGM devices have evolved during the past decade from being a research tool to serving as a device useful for clinical care in patients with type 1 and type 2 diabetes. CGM devices provide information about the current glucose concentration, direction, and rate of change in glucose concentration. Since it provides glucose values every 5–10 min 24 h a day, CGM may have an advantage over POC testing with respect to reducing the incidence of severe hypoglycemia during fasting. A recent report reported that the use of CGM reported benefits in detecting hypoglycemia during fasting in insulin-treated patients.21 No randomized controlled studies, however, have studied the impact of CGM in patients with diabetes during Ramadan.
Premixed insulin is a commonly prescribed formulation for the outpatient management of patients with type 2 diabetes. In many Muslim countries, premixed insulins are among the most frequently prescribed formulations in patients with type 2 diabetes. Of concern is the fact that some studies have reported a higher risk of hypoglycemia with the use of premixed insulin formulations compared with basal insulin analogs.22 The safety and efficacy of premixed insulin formulations during Ramadan is not known. Table 2 lists recommendations for insulin self-titration during the Ramadan period. The ‘Low-Ratio Premix Insulin Working Group’ recently reported a practical outline on how to adjust insulin during the fasting period, based on premeal blood glucose levels and the history of hypoglycemia.23 This group also recommended a trial fast for three consecutive days before Ramadan to help in detecting hypoglycemia risk and for guiding the self-titration of premix insulin dosage.
Algorithm for premixed insulin titration during Ramadan (adapted from Hassanein
et al23)
Illustrative examples for risks and recommendations for adjusting glucose-lowering therapy during Ramadan in patients with type 2 diabetes are shown in the management algorithm flow chart (figure 1).
Figure 1Management algorithm for people with type 2 diabetes intending to fast during Ramadan (HbA1c, glycated hemoglobin; SGLT-2, sodium glucose transporter-2 inhibitors; TZD, thiazolidinedione).