13th May 2019, Dr Chee L Khoo
Ramadan is the holy month for Muslims, falling in the ninth lunar month in the Islamic calendar year. Because the timing of Ramadan is linked to the sighting of the new moon, the timing of this month varies. Ramadan is a period of worship, self-discipline, austerity and charity. The most important significance of Ramadan is that Muslims are required to observe fasting during daylight hours. During this period, foods and fluids are only allowed at night so fasting extends from dawn to sunset – the exact length of time dependent on geographical location and season.
The pathophysiology of fasting
During fasting, circulating glucose levels tend to fall, leading to decreased secretion of insulin. Levels of glucagon and catecholamines rise, stimulating the breakdown of glycogen and at the same time, gluconeogenesis is augmented. As fasting becomes protracted for more than several hours, glycogen stores become depleted fatty acid is released from adipocytes. Oxidation of fatty acids generates ketones that can be used as fuel by skeletal and cardiac muscle, liver, kidney, and adipose tissue, leaving glucose for the brain and erythrocytes.
In patients with diabetes, glucose homeostasis is perturbed by the underlying pathophysiology and by the anti-diabetic drugs designed to enhance or supplement insulin secretion. In patients with type 1 diabetes, glucagon secretion may fail to increase appropriately in response to hypoglycaemia. Patients may have autonomic neuropathy and may have defective sympathetic response to hypoglycaemia especially if there is recurrent hypoglycaemia. In patients with severe insulin deficiency, a prolonged fast in the absence of adequate insulin can lead to excessive glycogen breakdown and increased gluconeogenesis and ketogenesis, leading to hyperglycaemia and ketoacidosis.
The potential dangers of fasting
Not unexpectedly, decreased food intake during Ramadan is a risk factor for hypoglycaemia especially in patients with severe insulin deficiency and in patients on sulphonyurea and insulin. The EPIDIAR study showed that fasting during Ramadan increased the risk of severe hypoglycaemia 4.7 X in patients with type 1 diabetes (T1D).
DAR MENA T2DM is an international prospective study designed to evaluate the care of patients with type 2 diabetes (T2D) during Ramadan. 1749 participants from the Middle East and North African region were followed up during Ramadan 2016. While HbA1c, fasting and postprandial glucose improved significantly during Ramadan, major hypoglycaemia was increased during Ramadan (10.4% vs 4.9%, p<0.001). A review of hypoglycaemia management will be helpful especially in patients at high risk of hypoglycaemia.
The EPIDIAR study showed a fivefold increase in the incidence of severe hyperglycaemia during Ramadan in patients with T2D. It may have been due to excessive reduction in dosages of medications to prevent hypoglycaemia and/or the increase in food and/or sugar intake at sunset.
Diabetic ketoacidosis including euglycaemic diabetes ketoacidosis (eDKA)
Patients with diabetes, especially those with T1D, who fast during Ramadan, are at increased risk for development of diabetic ketoacidosis (DKA), particularly if their diabetes is poorly controlled before Ramadan. In addition, the risk for diabetic ketoacidosis may be increased due to excessive reduction of insulin dosages based on the assumption that food intake is reduced during Ramadan. Further, dehydration during Ramadan further increase the risk of DKA.
Patients on SGLT2 inhibitors are at higher risk of eDKA especially when combined with insulin and dehydration.
Dehydration & its sequelae
The dehydration may become severe as a result of excessive perspiration in hot and humid climates and among individuals who perform hard physical labour. In addition, hyperglycaemia produces an osmotic diuresis, further contributing to volume and electrolyte depletion. Orthostatic hypotension may develop, especially in patients with pre-existing autonomic neuropathy. Syncope, falls, injuries, and bone fractures may result from hypovolemia and the associated hypotension. In addition, contraction of the intravascular space can further exacerbate the hyper-coagulable state that is well demonstrated in diabetes. Increased blood viscosity secondary to dehydration may enhance the risk of thrombosis and stroke.
Once again, patients on SGLT2 inhibitors are at higher risk of dehydration. Patients with impaired renal function are similarly at higher risk of rapid dehydration.
Many of the guidelines are general in nature and does not help us poor GPs. Ideally, Muslim patients with diabetes should have a full review of their diabetes control 2-3 months leading up to Ramadan. The conversation begins with a risk assessment.
Patients with very high risk:
- Severe hypoglycemia within the last 3 months prior to Ramadan
- Patient with a history of recurrent hypoglycemia
- Patients with hypoglycemia unawareness
- Patients with sustained poor glycemic control
- Ketoacidosis within the last 3 months prior to Ramadan
- Type 1 diabetes
- Acute illness
- Hyperosmolar hyperglycemic coma within the previous 3 months
- Patients who perform intense physical labor
- Patients on chronic dialysis
Patients with high risk
- Patients with moderate hyperglycemia (HbA1c 7.5–9.0%)
- Patients with renal insufficiency
- Patients with advanced macrovascular complications
- People living alone that are treated with insulin or sulfonylureas
- Patients living alone
- Patients with comorbid conditions that present additional risk factors
- Old age with ill health
- Drugs that may affect mentation
Patients on diet controlled only, metformin and DPP4 inhibitors can safely continue their usual medications during Ramadan although emphasis should be given about maintain adequate hydration prior to commencing of the fast.
Patients on sulphonylureas (SU) should be reviewed to see whether newer oral anti-diabetic agents can be used instead. If it is not possible to switch to newer agents or newer agents are already being used, SU with the shorter half life should be used. The morning pre-fast dose should be halved and the full dose given in the evening with the sunset meal. Close monitoring of blood glucose is recommended.
SGLT2 inhibitors (SGLT2i) generally do not increase the risk of hypoglycaemia unless they are used in conjunction with insulin and/or SU. Studies of SGLT2i use during Ramadan are limited although volume depletion has been reported with SGLT2i during fasting (3). This may result in hypotension, postural dizziness and vasovagal episodes. A review of the patient’s anti-hypertensive agents and diuretics is warranted. A temporary dose reduction may be necessary.
Patients on short acting GLP1-RA (e.g Byetta) can continued to be given with meals (before and after fasting) while patients on longer acting GLP1-RA (e.g liraglutide, exenatide LAR, dulaglutide) may experience GI side effects during fasting. Temporarily reduction of dose may be necessary.
The newer, second generation basal insulin, Glargine 300 (Toujeo®) has a flatter pharmacokinetic profile and has been shown to have a significantly lower incidence of hypoglycaemia with the same efficacy. Pre-mixed insulins should be switched to a basal-bolus or basal plus regimen if possible. If this is not possible, then use the usual morning dose at the sunset meal and half the usual evening dose at predawn meal.
The diet during Ramadan should not differ significantly from a healthy and balanced diet. The common practice of ingesting large amounts of foods rich in carbohydrate and fat, especially at the sunset meal, should be avoided. It is also recommended that fluid intake be increased during non-fasting hours and that the predawn meal be taken as late as possible before the start of the daily fast.
Normal levels of physical activity may be maintained. However, excessive physical activity may lead to higher risk of hypoglycaemia and should be avoided, particularly during the few hours before the sunset meal.
Because of changes in lifestyle and physical activity, closer monitoring of glucose (and ketones, if necessary) during the fast in essential. This particularly critical in patients on sulphonylureas and insulin (whether T1D or T2D) and patients with renal impairment.
All patients should understand that they must always and immediately end their fast if hypoglycaemia (blood glucose of 3.9 mmol/L]) occurs, since there is no guarantee that their blood glucose will not drop further if they wait or delay treatment. The fast should also be broken if blood glucose reaches 3.9 mmol/l in the first few hours after the start of the fast, especially if insulin or sulfonylurea drugs are taken at predawn. Patients should avoid fasting on “sick days.”
Most of us have a significant number of Muslim patients who has diabetes. The decision to fast is an important personal decision. patients who insist on fasting need to be aware of the associated risks and be ready to adhere to the recommendations of their health care providers to achieve a safer fasting experience.
Pre Ramadan preparation is vital to minimise significant hypoglycaemia during the fasting periods. Many of the patients will see improvement in their glycaemic control during this period as well provided they don’t end their daily fast with high carbohydrate foods.
This year’s Ramadan is in session now and next year’s Ramadan will begin on 23rd April 2020. Identification of patients who are at high risk of adverse events is critical to reduce the incidence of adverse events in those who choose to fast.
- Ibrahim Salti, Eric Bénard, Bruno Detournay, et al. A Population-Based Study of Diabetes and Its Characteristics During the Fasting Month of Ramadan in 13 Countries. Results of the Epidemiology of Diabetes and Ramadan 1422/2001 (EPIDIAR) study. Diabetes Care 2004 Oct; 27(10): 2306-2311
- Hassanein, F. F. Al Awadi, K. E. S. El Hadidy et al., The characteristics and pattern of care for the type 2 diabetes mellitus population in the MENA region during Ramadan: An international prospective study (DAR-MENA T2DM), Diabetes Research and Clinical Practice, https://doi.org/10.1016/j.diabres.2019.02.020
- Ehab Mudher Mikhael. Effectiveness and Safety of Newer Antidiabetic Medications for Ramadan Fasting Diabetic Patients. J Diabetes Res. 2016; 2016: 6962574.