The duration of daily fasting ranges from a few hours up to 20 hours, depending on the geographical location and season. Apart from fasting (including drinking), Muslims are also expected to abstain from using oral medications and smoking from predawn to after sunset.1

More than a billion Muslims with diabetes worldwide may choose to fast during Ramadan of which about 10% will develop complications

There are no restrictions on food or fluid intake between sunset and dawn. Most people consume two meals per day during this month, one after sunset, referred to in Arabic as Iftar (breaking of the fast meal), and the other before dawn, referred to as Suhur (predawn).1

Fasting during Ramadan is an obligation for all adult Muslims. However, the Koran specifically exempts the sick from fasting – especially if it might lead to harmful consequences for the individual.

Although patients with diabetes fall under this category because of their chronic disorder, many insist on fasting during Ramadan, creating a medical challenge for themselves and their physicians. It is therefore important that medical professionals are aware of potential risks that may be associated with fasting during Ramadan, and how to manage them.1

Potential risks associated with fasting during Ramadan

Patients with diabetes are at risk of major potential complications associated with fasting. These include:1,2,3

Hypoglycaemia

Decreased food intake is a well-known risk factor for the development of hypoglycaemia. The Epidemiology of Diabetes and Ramadan 1422/2001 (EPIDIAR) study showed that fasting during Ramadan increased the risk of severe hypoglycaemia (defined as hospitalisation due to hypoglycaemia) some 4.7-fold in patients with type 1 diabetes (T1DM) and ∼7.5-fold in patients with type 2 diabetes (T2DM).2

Hyperglycaemia

Long-term morbidity and mortality studies in people with diabetes, such as the Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study, demonstrated the link between hyperglycaemia, microvascular complications, and possibly macrovascular complications.1

The extensive EPIDIAR study showed a ∼5-fold increase in the incidence of severe hyperglycaemia (requiring hospitalisation) during Ramadan in patients with T2DM and about a ∼3-fold increase in the incidence of severe hyperglycaemia with or without ketoacidosis in patients with T1DM.2

Diabetic ketoacidosis is a serious complication of diabetes that can be life-threatening. However, new evidence suggests that the risk of diabetic ketoacidosis is not increased during Ramadan fasting.3

Dehydration and thrombosis

Prolonged limitation of fluid intake is a well-known cause of dehydration. Combined hyperglycaemia it can result in osmotic diuresis ( inhibition of reabsorption of water and sodium) and contribute to volume and electrolyte depletion.1

Some patients may experience orthostatic hypotension, resulting in dizziness, light headedness, blurred vision, weakness, fatigue, nausea, palpitations and headache. Patients with pre-existing autonomic neuropathy are particularly at risk. Syncope, falls, injuries and bone fractures may result from hypovolemia and the associated hypotension.1

In addition, contraction of the intravascular space can contribute to a hypercoagulable state due to an increase in clotting factors, a decrease in endogenous anticoagulants, and impaired fibrinolysis.1

The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) emphasise the importance of patient factors and comorbidities when choosing diabetes medications including the presence of comorbidities, atherosclerotic cardiovascular disease, heart failure, chronic kidney disease, hypoglycaemia risk, weight issues and costs.4

According to Ibrahim et al, the key to successful diabetes management in Ramadan should be no different and the general aim is the control of symptoms, prevention of deterioration in glycaemic control and acute complications.4

Table 1: Categories of risk in patients with T2DM who fast during Ramadan4

risks to fasting during Ramadan

It is important to inform patients that blood glucose testing during Ramadan does not break the fast. A common misconception in some parts of the world. Blood glucose should be regularly monitored during fasting, especially those on insulin or insulin secretagogues.4

All patients should be educated about the symptoms of hypoglycaemia, and to stop the fast in case of symptoms of hypoglycaemia, hyperglycaemia, dehydration, or acute illness occur and blood glucose level of <3.9 mmol/L or >16.6 mmol/L.4

Use of self-monitoring of blood glucose should be individualised during Ramadan with need for more frequent monitoring in those at higher risk of hypoglycaemia, especially in regions with longer fasting hours or warmer climate.4

Managing patients during Ramadan

Medical nutrition

Medical nutrition therapy should be provided by a registered dietitian or nutrition professional and should include principles of healthy eating behaviours, preventive methods for hypoglycaemia, and proper portion intake.4

Since foods consumed during Ramadan tend to be higher in carbohydrate, strategies should include portion control as well as the possible incorporation of physical activity after meal. The Diabetes and Ramadan International Alliance has developed the Ramadan Nutrition Plan, a web-based tool designed to help HCPs in delivering patient-specific nutrition education for Ramadan.4,5

Physical activity and Taraweeh prayers

Although increased physical activity should generally be encouraged in all patients with T2DM, it has to be approached with caution during Ramadan. The Taraweeh prayer during Ramadan after the Iftaar meal involves repeated cycles of rising, kneeling, and bowing and should be considered as part of daily exercise. Physical activity should be encouraged for people with diabetes and normal levels may be maintained during the month of Ramadan. However, excessive physical activity may lead to a higher risk of hypoglycaemia and should be avoided, especially before the sunset meal, in those with high risk of hypoglycaemia and those on insulin or insulin secretagogues.4

It is recommended that decision to start a new glucose-lowering medication should be made in advance of start of Ramadan and dose adjustments or medication reviews are done accordingly, especially if hypoglycaemia or tolerability becomes a concern during fasting.4

A key recommendation by the ADA and EASD is the introduction of combination therapy including metformin in newly diagnosed patients. Ibrahim et al recommend against starting patients on a sodium-glucose cotransporter-2 inhibitor (SGLT2i) as a new medication during or immediately prior to Ramadan. Patients should be well established on these drugs prior to start of Ramadan.4

In addition, caution Ibrahim et al, elderly patients, those with renal impairment, hypotensive patients, or those on diuretics if they are planning to fast for Ramadan, should proceed with caution and consider stopping or reducing the dose of the SGLT2i.4

Injectables

It is very important that patients requiring injectable therapy (either a glucagon-like peptide-1 receptor agonist [GLP-1RA] or insulin) are well established on stable injectable therapy preferably for at least four weeks prior to start of Ramadan.4

The efficacy and safety of insulin is dependent on its appropriate use during Ramadan including patient training and education, diet and activity, dose titration, timing (Suhoor and Iftaar) and type of insulin used.4

The ADA and EASD recommend the addition of a GLP-1RA prior to insulin as a first-line injectable therapy if HbA1c is above target despite dual or triple oral therapy. In addition, initial combination of GLP-1RA plus insulin is recommended if HbA1c is >10% and/or >2% above target.4

Depending on the formulation used, the GLP-1RA may need to be injected daily or once-weekly. Weekly preparations are an attractive option for fasting patients who prefer a simplified regimen.4

The most common adverse events (AEs) of GLP-1RA are gastrointestinal effects including nausea and vomiting, increasing the risk of dehydration. Thus, it is recommended that GLP-1RA should be started at least four to eight weeks prior to fasting with titration to tolerated dose before the start of Ramadan.4

Two recent real-world studies look at the safety and efficacy of insulin glargine 300U/mL (GLA-300) and iGlarLixi, a once-daily fixed-ratio combination of basal insulin glargine and lixisenatide (a GLP-1RA) in patients with T2DM who fast during Ramadan.6,7

The ORION study

The ORION study by Hassanein et al (2020) evaluated the safety and effectiveness of Gla-300 in insulin-treated people with T2DM before, during and after Ramadan, in a real-world setting.6

This prospective, observational study across 11 countries included participants with T2DM treated with Gla-300 in pre-Ramadan, Ramadan, and post-Ramadan periods. The primary endpoint was the percentage of participants experiencing ≥1 event of severe and/or symptomatic documented hypoglycaemia with self-monitored plasma glucose (SMPG) 3.9mmol/L during Ramadan. Secondary endpoints included change in HbA1c and insulin dose and AEs.6

The mean ± SD number of fasting days was 30.1 ± 3.2. The percentage of participants experiencing ≥1 event of severe and/or symptomatic documented hypoglycaemia (SMPG ≤7%) was low in the pre-Ramadan (2.2%), Ramadan (2.6%) and post-Ramadan (0.2%) periods.6

No participants reported severe hypoglycaemia during Ramadan or post-Ramadan. One participant reported severe hypoglycaemia in pre-Ramadan. HbA1c fell pre- to post-Ramadan, and Gla-300 daily dose (mean ± SD) was reduced pre-Ramadan to Ramadan (from 25.6 ± 11.9 U/0.32 ± 0.14U/kg to 24.4 ± 11.5U/0.30 ± 0.13U/kg). Incidence of AEs was 5.5%.6

The SOLIRAM study

The SOLIRAM study by Hassanein et al (2021), which will be conducted in two waves, evaluated the real-World safety and efficacy of iGlarLixi in patients with T2DM.7

In wave 1 of the study, adults with T2DM who had taken iGlarLixi for ≥3 months before inclusion and who planned to fast for ≥15 days during Ramadan, were enrolled from five countries. During the study, iGlarLixi treatment was adjusted as per routine practice by the treating physician.7

Overall, 155 people with T2DM (54.2% male) were eligible. Mean ±SD age was 58.4±9.5 years, body mass index was 30.5±6.0kg/m² and 64.5% of people had ≥1 diabetes-related complications.7

Proportion of patients with ≥1 macro- and microvascular complications were 11.0% and 48.4%, respectively. Mean ±SD duration of diabetes was 14.0±6.6 years and duration of iGlarLixi treatment prior to study participation was 5.7±3.3 months.7

Mean ±SD length of fasting was 28.7±3.3 days and only 5.9% broke the fast during Ramadan. Reported reasons for breaking the fast were travel, pre-existing conditions, AEs (not related to iGlarLixi), hypoglycaemia, and menses.7

Change in anti-hyperglycaemic treatment class was minimal during the study with 79.4% and 54.2% of people taking biguanides and sulfonylureas during Ramadan, respectively.7

The mean ±SD iGlarLixi dose changed from 24.8±11.6U (pre-Ramadan) to 23.8±10.5U (Ramadan period) and 24.9±11.6U (post-Ramadan). During Ramadan, 89.5% and 7.2% of people took iGlarLixi at Iftar and before Suhur, respectively.7

The number of participants reporting ≥1 severe and/or symptomatic documented hypoglycaemia (plasma glucose [PG] 3.9mmol/L, primary endpoint) was 1.3% during pre-Ramadan, 2.0% during Ramadan, and none during post-Ramadan.7

No participant reported hypoglycaemia with PG <3mmol/L and there were no severe or serious hypoglycaemia events. The rate of severe and/or symptomatic documented hypoglycaemia (PG ≤3.9mmol/L) was 0.02 per patient-month.7

Improvements were observed for mean ±SD HbA1c and fasting PG (pre-Ramadan, 8.4±1.1% and 146.9±32.1mg/dL to post-Ramadan, 7.5±0.8% and 122.5±28.8mg/dL) with an average reduction of -0.8±1.1% and -24.4±32.6 mg/dL, respectively. AEs were low (5.8%) and were not considered related to iGlarLixi, and there were no serious AEs.7

Conclusions

In the ORION study, people with T2DM treated with Gla-300 who fasted during Ramadan had a low risk of severe/symptomatic hypoglycaemia and improved glycaemic control.6

In the SOLIRAM study, people with T2D treated with fixed-ratio combination, iGlarLixi, were able to fast for most of the month of Ramadan. The incidence of hypoglycaemia was low and glycaemic control was improved.7

REFERENCES:

1. Al-Arouj M, Bouguerra R, Buse J, et al. Recommendations for Management of Diabetes During Ramadan. Diabetes Care, 2005.
2. Salti I, Benard E, Detournay B, et al. A Population-Based Study of Diabetes and Its Characteristics During the Fasting Month of Ramadan in 13 Countries. Diabetes Care, 2004.
3. Beshyah SA, Chowdhury TA, Ghouri N, et al. Risk of diabetic ketoacidosis during Ramadan fasting: a critical reappraisal. Diabetes Res Clin Pract 2019.
4. Ibrahim M, Davies MJ, Ahmad E, et al. Recommendations for the management of diabetes during Ramadan: update 2020, applying the principles of the ADA/EASD consensus. BMJ Open Diabetes Res Care, 2020.
5. Handy O, Yusof BNM, Reda WH, et al. Chapter 7: the Ramadan nutrition plan (RNP) for patients with diabetes, 2016. Available: http://www.daralliance.org/daralliance/
6. Hassanein M, Buyukbese MA, Malek R, et al. Real-world safety, and effectiveness of insulin glargine 300 U/mL in participants with type 2 diabetes who fast during Ramadan: The observational ORION study. Diabetes Res Clin Pract, 2020.
7. Hassanein M, Sahay RK, Malek R, et al. Real-World Safety and Effectiveness of iGlarLixi in People With Type 2 Diabetes who Fast During Ramadan: Results From Wave 1 of the SOLIRAM Study. J Endocr Soc, 2021.