Insulin Regimens

There is no conclusive evidence supporting efficacy and safety of a particular insulin regime over another in adolescents with T1D who are fasting during Ramadan. The insulin regime is therefore based on affordability, access to treatment (medication, specialist and advanced technology), and cultural preferences (9).

Changing the insulin regime just before Ramdan is likely to result in dose errors and increase the risk of hypoglycemia. Hence, every effort should be made to continue the same regime, but with proper dose modifications and comprehensive counseling covering diet, lifestyle, physical activity, SMBG, and self-titration of insulin dose (10).

The most commonly used insulin regimens in adolescents are (9):

1.

Basal-bolus regimens –multiple dose injections (MDI) adjusted according to meal (preferred option)

2.

Conventional twice daily neutral protamine Hagedorn (NPH)/regular short acting (human) insulin

3.

Continuous subcutaneous insulin infusion (CSII) with or without sensors

4.

Premixed insulins (generally not recommended for T1DM)

Of these, MDI and CSII are closer to providing the physiological insulin secretion pattern.

Table 5 gives guidance on dose modifications of different insulin regimes.⁹ SMBG should be encouraged and the patients or their caregivers taught to self-titrate the insulin dose based on the BG levels (Table 6) (10).

Recommendations for Insulin Regimes

1.

T1D management during Ramadan should be individualized according to patient’s need, preference, affordability, acceptability, and access to treatment (9).

2.

The basal-bolus regime is the preferred regime and consists of a long-acting insulin analogue (basal insulin) and a premeal rapid acting insulin analogue (bolus insulin) (9).

3.

Associated with a lower risk of hypoglycemia when compared to conventional, twice-daily, insulin regimens

4.

The bolus insulin dose should be dependent on the carbohydrate count of the meal. It should ideally be given 20 minutes before the meal for better post-prandial BG control.

5.

Boluses covering Suhoor and Iftar should be based on Insulin Carbohydrate Ratio (ICRs) and Insulin Sensitivity Factor (ISFs)

Approximately 70% of hypoglycemia occur during the last six hours of fasting. Hence, the type of basal insulin used, reduction in basal insulin dose and modification of insulin timing are the tools used to avoid hypoglycemia:

1.

Ramadan fasting should be started with a reduction of basal insulin-starting with 20% and individualizing up to 40% as required

2.

Basal insulin can be administered earlier in the day to minimize insulin exposure during the last few hours of fasting when BG levels are low.

3.

Basal insulin can also be taken at Iftar or earlier in the evening

4.

First-generation basal insulin analogues (such as glargine U-100) are more likely to cause hypoglycemia than the second generation, long-acting insulin analogues (glargine U-300 and degludec). However, the choice of insulin should be individualized based on risk of hypoglycemia.

5.

Long-acting insulin analogues are preferred over intermediate acting (NPH/human insulin) as they provide a steady fall of BG towards normal levels by sunset time (9).

6.

Twice daily regimens are more likely to be associated with hyperglycemia (9).

7.

Twice daily regimens are usually not preferred during Ramadan, but if they are the only choice available to the patient, their timing and dose needs to be more closely monitored depending on the timing, portion size and carbohydrate content of meal (9).

8.

Premixed twice daily insulin regimes are not recommended during Ramadan period as they require fixed carbohydrate intake at fixed timing, and this may be difficult for adolescents to follow (9).

9.

There is emerging evidence that T1D patients can fast during Ramadan with fewer complications with the help of newer technologies such as insulin pump therapy, CGM and hybrid closed-loop systems (6).

10.

CSII with insulin pumps in adolescents help achieve the targeted glycemic control with reduction in hyperglycemia and severe hypoglycemia, and provides more flexibility, improved quality of life and decreased risk of complications like diabetic ketoacidosis (9).

• CSII allows for easier management of DM and reduces risk of complications than MDI (9)
• The basal and bolus doses are adjusted through algorithms on the pump or through sensors and mobile applications (in more advanced versions)
• Basal insulin is reduced by 20-35% in the last 4-5 hours before Iftar and increased by 10-30% after Iftar up to midnight
• Prandial insulin bolus calculation is based on usual ICR and ISR
• Bolus doses can be delivered in three different ways:
• Standard dosing: Immediately before meals
• Extended or square dosing: gradual dosing over a certain time period
• Combo or dual wave bolus: combination of standard and extended
• High fat content diet as seen during Iftar is likely to benefit from extended or combo bolus dosing (9).
• Insulin pumps augmented with CGM provide better glycemic control and reduce complications considerably in adolescents with T1D. These sensor-augmented pumps are of two types (9):
• Low Glucose Suspend (LGS) function pumps: The high-risk BG threshold for HE is pre-set in these pumps. The insulin administration can be automatically suspended for ≤2 hours when sensors detect BG levels below the pre-set threshold
• Predictive Low Glucose Suspend (PLGS) pumps: Insulin administration is automatically suspended before BG reaches hypoglycemic levels (70 mg/dL [3.9 mmol/L]).
• Automated insulin delivery (closed loop): These can suspend or increase insulin delivery based on sensor-based BG values. Thus, closed loops help increase time in range (TIR) and minimize hypoglycemia and hyperglycemia.
• Types: Hybrid closed-loop automated insulin delivery systems; Do-It-Yourself Artificial Pancreas Systems (DIY APS)
• However, CSII is a costly technology, has limited access in many countries, and therefore is not widely available due to cost and accessibility constraints (9).

Oral Glucose Lowering Drug Adjustments During Ramadan

• In general, non-sulfonylureas GLDs are superior in lowering hypoglycemia incidence than sulfonylureas (1).
• Metformin is the most commonly used first line oral GLD, and has minimal risk of hypoglycemia (10).
• Sulfonylureas are the most commonly used second line oral GLDs after metformin, especially in resource limited settings (10).
• Short-acting insulin secretagogues can be useful GLDs during Ramadan because of their short duration of action and low risk of hypoglycemia (10).
• DPP4 inhibitors are well tolerated during fasting and have a low hypoglycemia risk (10).
• SGLT2 inhibitors are the newest class of oral GLDs used in T2D. They have demonstrated effective glycemic control during Ramadan even in patients with cardiovascular diseases/chronic kidney disease, and have low risk of hypoglycemia (10, 36).
• An individual should be started on a SGLT2 inhibitor at least 2-4 weeks before Ramadan for the BG levels to stabilize during the fasting time.
• Of the thiazolidinediones, only pioglitazone is widely approved for T2DM, has low hypoglycemia risk, but clinical data on its use during Ramadan is limited (10).

Injectable Glucose Lowering Drug Adjustments During Ramadan

• Most patients with long-standing T2D eventually need insulin to manage their BG levels. Various insulin regimes are used in T2D (table 9) (1, 10) and in general, the use of insulin increases the risk of hypoglycemia during Ramadan.
• Insulin can be given as single daily injection, MDI or as CSII through insulin pumps. The insulin regime is therefore based on affordability, access to treatment (medication, specialist and advanced technology), and cultural preferences (9).
• Changing the insulin regime just before Ramdan is likely to result in dose errors and increase risk of hypoglycemia. Hence, every effort should be made to continue the same regime, but with proper dose modifications and comprehensive counseling covering diet, lifestyle, physical activity, SMBG, and self-titration of insulin dose (10).
• Table 5 shows the various insulins and how their doses and timing are adjusted during Ramadan.
• SMBG guided dose titrations for different insulin types are shown in Table 6.
• GLP-1 RAs can be safely used with other GLDs including metformin and insulin. They have low hypoglycemia risk, but the risk could be higher if given with insulin or sulfonylureas. However, dose needs to be titrated at least 2-4 weeks prior to Ramadan (10).

Individuals on Multiple Antidiabetic Therapy

Individuals on multiple GLDs are at higher risk of hypoglycemia during Ramadan (18). The risk of hypoglycemia is highest if they are on ≥4 GLDs or on a combination of metformin, DPP4I and basal insulin (37).

In individuals on multiple GLDs, the risk of hypoglycemia is dependent on several factors such as type and number of GLDs, duration of diabetes, pre-Ramadan glycemic control, renal function, and presence of other comorbidities (10).

Individuals on ≥3 GLDs who are fasting during Ramadan should receive comprehensive counseling and advice before the start of Ramadan, and it should cover diet, lifestyle, physical activity, SMBG, and dose and time modifications of GLDs (10).

Individuals on a combination of insulin and SUs are at highest risk of hypoglycemia and require a dose reduction GLDs (approximately 25-50% reduction in insulin dose) during Ramadan.

Flash glucose monitoring, CGM, activity monitoring, risk stratification, dose adjustments, and use of artificial intelligence-based algorithms that cover one or more of these aspects are the various tools that are likely to help high-risk patients with T2D fast with fewer hypoglycemia and hyperglycemia related complications (6, 10).

Management of Diabetes/Gestational Diabetes During Ramadan

Even in healthy pregnant women, fasting during Ramadan results in biochemical changes that almost mimic the effects of prolonged fasting (35). Ramadan fasting results in an increase in triglycerides (TG), free fatty acids (FFA), and ketones in healthy pregnant women along with a decrease in glucose and insulin (35). However, data on physiological and biochemical changes caused by fasting during Ramadan in pregnant women with diabetes is largely lacking.

Pregnancy is an exemption from fasting. However, many pregnant women choose to fast during Ramadan. A detailed discussion regarding the potential risks of fasting must be held with them.

While healthy pregnant women can generally fast safely with no maternal or fetal risk, those with hyperglycemia need to strictly monitor their BG levels to prevent hyperglycemia, hypoglycemia, and adverse maternal and fetal outcomes (35).

• Pre-Ramadan assessment should begin months before Ramadan, and apart from risk stratification, should focus on breaking general myths like ‘finger-prick testing for BG levels breaks their fast’, encourage SMBG, and educate about the maternal and fetal risks of both hypoglycemia and hyperglycemia (35).
• Pregnant women with diabetes should maintain normal physical activity while fasting. The Taraweeh prayer they offer should be considered as exercise for which insulin doses should be adjusted as required (35).
• Fiber rich food and drinking 2-3 liters of water a day should be encouraged. Suhoor should be taken as late as possible (35).
• Insulin and/or metformin are the treatment of choice in pregnancy with diabetes. Though glibenclamide is also used in some patients, its use should be discouraged during Ramadan. Some women with gestational diabetes may be managed on diet and/or metformin too.
• The metformin dose may not need any change during pregnancy but the dose of insulin should be modified as discussed in Table 5 (10, 35). Insulin dose titration should be guided by SMBG as shown in Table 6.
• SMBG should be carried out as guided in Figure 6. Pregnant women with diabetes should strictly monitor and maintain their BG levels as follows (35):

  ✓

  Fasting between 70-95 mg/dL (3.9 – 5.3 mmol/L).

  ✓

  Post-prandial < 120 mg/dL (6.7 mmol/L).

• Pregnant women with diabetes should break their fast if (35):

  ✓

  BG levels < 70 mg/dL (3.9 mmol/L) during fasting hours.

  ✓

  Feel unwell.

  ✓

  Feel reduced fetal movement.

• Pregnant women with diabetes should carry out regular SMBG at the following time points (35):

  ✓

  Before the sunset meal.

  ✓

  1-2 hours after meals

  ✓

  Once during the day while fasting, particularly in the afternoon.

  ✓

  Anytime they feel unwell.

Management of Diabetes in Elderly with Diabetes Fasting During Ramadan

Older age (≥ 65 years) by itself can be considered a high risk for fasting during Ramadan in individuals with diabetes, even though many elderly fast successfully during Ramadan (38). Older individuals with diabetes are less likely to fast than younger ones (DAR 2020 survey: 71.2% of ≥ 65 years intended to fast compared to 87.3% of those < 65 years) (39). However, fasting during Ramadan being a personal choice, many older adults with diabetes do choose to fast during Ramadan. The DAR Global Survey (2020) also showed that the elderly were more motivated to fast with 69% of those aged ≥ 65 years fasting for 30 days compared to 60% of those < 65 years (39).

Elderly (≥ 65 years) with diabetes were significantly more likely to break their fast than younger (<65 years) individuals with diabetes (17% vs. 11.5%; P<0.001) (39). Similarly, they were significantly more likely to break their fast due to hypoglycemia than their younger counterparts (67.7% vs.55.4%; P=0.02).

Fasting during Ramadan in elderly with diabetes needs special consideration and attention because:

• Diabetes related complications are higher in elderly and they need careful BG monitoring and GLD dose adjustments, which should be started well before Ramadan (38).
• Fasting related complications likely to be seen in elderly with diabetes can be due to both hyperglycemia and hypoglycemia, and also include impaired renal function, impaired postural balance, poor attention, and volume depletion. The risk increases with the number of days fasted (38).
• The DAR 2020 survey showed that hypoglycemia was significantly higher in elderly as compared to younger population (17.4% vs.15.2%; P<0.001) (39).
• 9.9% of those aged ≥ 65 visited the emergency department compared to 4.3% of individuals aged < 65
• Elderly were also more likely to get hospitalized due to hypoglycemia
• While 31.5% reduced their GLD dosing, 17% made no change to their medication dose
• The use of SUs and insulin increases risk of hypoglycemia. 32.7% of elderly need insulin, probably due to long standing diabetes.
• The DAR 2020 survey also showed that significantly greater number of elderly with diabetes who are fasting had hyperglycemia (BG levels > 16.6 mmol/L or 300 mg/dL) during Ramadan (19.3% vs. 15.6%; P=0.006) (39). 8.4% of the elderly had to attend the emergency department due to hyperglycemia related complications.
• The DAR 2020 survey showed that the majority (80%) do not break their fast even if they have hyperglycemia, and 20% do not change their behavior (food intake, medication change), 25% reduced their food intake, and 21% increased their medication dose (39).
• In the DAR 2020 Global Survey, 21% of participants with T2DM aged ≥ 65 years checked their BG levels once or less than once a week. Only around 10% checked their BG levels 3–4 times a day. There was no change in SMBG behavior during Ramadan (39).
• Research on elderly fasting during Ramadan is largely lacking.³⁸ Landmark trials in Ramadan like the EPIDIAR study which was used to formulate many recommendations for individuals with diabetes fasting during Ramadan, did not include the elderly.⁷
• The elderly population is growing fast, and therefore there will be more individuals with diabetes who are ≥ 65 years and intend to fast (40)
• The risk of fasting is much higher in elderly than in younger population with diabetes (38). This is because the elderly have more comorbidities (hypertension, hyperlipidemia, CVDs, CKD etc.) than the younger population (38, 39).
• Elderly with diabetes and impaired renal functions, CVD, dementia, frailty, and/or those with risk of falls are at higher risk for complications during fasting than elderly without comorbidities (38). Therefore, risk stratification of elderly with diabetes who decide to fast during Ramadan should be based not only on age, but also on their comorbidities, functional capacity, and ability to manage medications and carry out SMBG, cognition, and social circumstances (38).

Hence, the elderly with diabetes are a high-risk category for fasting during Ramadan. They need proper Pre-Ramadan risk stratification, education, and support to ensure that they can fast safely with proper SMBG and medication monitoring.

Table 11 covers the basic recommendations for elderly who intend to fast during Ramadan.