Article 3

Treatment of Type 1 Diabetes with Insulin Lispro
During Ramadan
Ramadan is the ninth lunar month of the Islamic year and fasting during the month is one of
the five pillars of Islam. It is obligatory for all healthy adults of the Islamic faith to fast
between the hours of dawn and sunset. Although certain people, including those with
serious illness, are exempt, many patients with diabetes insist on following the fast, often
without informing the treating physician or obtaining proper instructions [ [1], [2]]. Depending
on geographical area and time of year when Ramadan occurs, the fast is approximately 11
to 19 hours per day. No food or drink is taken during sunlight hours and the main meals are
taken before sunrise (Sahur) and after sunset (Iftar). There may also be abstention from
oral and injected medications and, in some cultures, from withdrawal of blood.
As well as the change in dietary pattern there may be a change in content, with increased
intake of fat and carbohydrates [ [3]]. These changes in dietary habits present serious
problems for patients with diabetes [ [1],[4]] and glycaemic control deteriorates [ [5], [6]]. There
is often excessive intake at the evening meal resulting in hyperglycaemia [ [7]]. During
daylight hours hypoglycaemia is a particular problem when patients do not want to take
snacks. They may try to compensate for fasting by reducing the morning dose of insulin but
this may then result in hyperglycaemia.
Optimisation of insulin therapy during Ramadan fasting is, therefore, essential to try to
control both hyperglycaemia and hypoglycaemia. However, very few studies have examined
insulin treatment of patients with diabetes during Ramadan. In patients with type 1
diabetes, short-acting insulin before meals and intermediate-acting insulin given late
evening has been used safely [ [8]]. A recent study [ [9]] of patients with type 2 diabetes
during Ramadan reported better glycaemic control during insulin lispro treatment compared
with regular human insulin. The present multi-national study was carried out to compare
efficacy and safety of insulin lispro and regular human insulin in the treatment of patients
with type 1 diabetes who wished to fast during Ramadan.
This open-label comparative crossover study was carried out with appropriate ethical
approval at six centres in Saudi Arabia, United Arab Republic, Kuwait, Pakistan, Egypt and
Morocco. After being informed about the legitimacy of abstaining from fasting, all patients
confirmed that they wanted to follow Ramadan and gave written informed consent for study
participation. The study involved 67 patients with type 1 diabetes mellitus who had received
twice daily insulin treatment for at least 2 months prior to entry. Patients were not included
if they had vascular disease, retinopathy, renal impairment, liver disease, insulin resistance
defined as daily insulin dose > 2 units/kg or a history of clinically significant hypoglycaemia
unawareness.
During the study, patients attended the clinic for four visits, starting at one month before
Ramadan. At the first visit, baseline demographic data was collected and each patient was
trained to carry out glucose measurements using a glucose meter (Accutrend, Boehringer
Mannheim, Germany). Patients continued to use twice daily insulin treatments, consisting of
soluble insulin plus intermediate-acting insulin, given morning and evening before breakfast
and dinner, respectively, during the run-in period. One day prior to the start of Ramadan,
patients returned for the second clinic visit at which time they were randomised to one of
two treatment sequences. The sequences consisted of either insulin lispro (Humalog , Eli
Lilly and Company, Indianapolis, IN, USA) or regular human insulin (Humulin R, Eli Lilly
and Company) for two weeks, followed by the alternate treatment for a further two weeks.
The insulin lispro or regular human insulin was given, together with intermediate-acting
insulin (Humulin N, Eli Lilly and Company), twice daily before the morning and evening
meals throughout the one-month period of Ramadan. Patients returned for clinic visits at
the cross-over point when the soluble insulin treatment was changed, and at the endpoint of
the study.
The study was carried out on an open-label basis in order for the insulin lispro and regular
human insulin to be administered at the recommended times before meals. Patients were
instructed to administer insulin lispro, together with the NPH insulin, immediately before
starting a meal, whereas regular human insulin, together with the NPH insulin, was to be
given 30 minutes before starting a meal. The soluble and NPH insulins were supplied either
in pen devices or in vials with syringes and patients were instructed to mix the soluble and
NPH insulins in syringes immediately before administration. The dosage regimen could be
adjusted by investigators in accordance with the metabolic needs of the patients. However,
when changing treatments patients were advised to start the new treatment on the same
insulin dose as that used just prior to the change. Investigators recommended regular selfmonitoring of blood glucose according to their usual practice and this was used as the basis
for insulin dose adjustments.
On three consecutive days at the end of each two-week treatment period, patients were
asked to record glucose profiles using the Accutrend glucose meters. Glucose
determinations were not taken between the hours of sunrise and sunset in order to respect
those patients who considered that withdrawal of blood was contrary to the religious
practice of the fast. This precluded postprandial measurements after the morning meal so a
simplified 4-point profile was used. Capillary blood glucose was determined while fasting
before sunrise, fasting after sunset and at 1-h and 2-h postprandial after the evening meal.
On the days when glucose profiles were determined, the glucose values, insulin doses and
timing, and the times of each meal were recorded by the patients in study diaries.
Hypoglycaemic episodes were also recorded in the diaries throughout the study.
Hypoglycaemia was defined as any time a patient felt, or another person observed, signs or
symptoms associated with hypoglycaemia, or a blood glucose measurement less than 3.0
mmol/l (54 mg/dl).
The blood glucose profiles determined on the three consecutive days were averaged across
days for each patient. Blood glucose excursions were calculated from the differences
between the 1-h or 2-h postprandial values and the respective fasting after sunset value. All
data are expressed as mean SEM. The two insulin treatments were compared using an
analysis of variance model for a crossover design to evaluate both carryover and treatment
effects. No evidence for a statistically significant carryover effect was found for any of the
variables analysed. Treatment effects for categorical variables such as frequency of
hypoglycaemia were determined using a chi-square test or Fisher's exact test.

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Treatment of Type 1 Diabetes with Insulin Lispro

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