Effect of Dosage Reduction of Hypoglycemic Multidrug Regimens on the Incidences of Acute Glycemic Complications in People With Type 2 Diabetes Who Fast During Ramaḍān: A Randomized Controlled Trial

Abstract

ObjectiveWe aimed to investigate the effect of dosage reduction of four hypoglycemic multidrug regimens on the incidences of acute glycemic complications in people with type 2 diabetes who fast during Ramaḍān.MethodsWe conducted an open-label, parallel-group, randomized controlled trial at a tertiary care center in Amman, Jordan. We recruited adults with type 2 diabetes who expressed an intention to fast during Ramaḍān and were adherent to one of four regimens—namely: metformin and glimepiride; metformin and vildagliptin; metformin and insulin glargine U100; or, metformin, insulin glargine U100, and human regular insulin. We randomly assigned participants in a 2:1 ratio to low- or regular-dosage therapy. The primary outcomes were the incidences of hypoglycemia and hyperglycemia during the 29 days of Ramaḍān 2017, and the secondary outcomes were the incidences of diabetic ketoacidosis and hyperosmolar hyperglycemic state during the same period.ResultsWe randomly assigned 687 participants to low-dosage therapy (n = 458) or regular-dosage therapy (n = 229) and included 678 (452 and 226, respectively) in the final analysis. The incidence of hypoglycemia was lower in the low-dosage group compared with the regular-dosage group (19 [4.2%] vs. 52 [23.0%], respectively; OR, 0.15 [95% CI, 0.08–0.26]; P < 0.001). The incidence of hyperglycemia did not differ between the low- and regular-dosage groups (319 [70.6%] vs. 154 [68.1%], respectively; OR, 1.12 [95% CI, 0.79–1.58]; P = 0.5). No participants experienced diabetic ketoacidosis or hyperosmolar hyperglycemic state. Each 1% decrease in the baseline HbA1c concentration was associated with a 19.9-fold (95% CI, 9.6–41.5; P < 0.001) increase in the odds of hypoglycemia, and each 1% increase in the baseline HbA1c concentration was associated with a 15.7-fold (95% CI, 10.0–24.6; P < 0.001) increase in the odds of hyperglycemia.ConclusionDosage reduction decreases the incidence of hypoglycemia without a concomitant increase in the incidences of hyperglycemia, diabetic ketoacidosis, and hyperosmolar hyperglycemic state in people with type 2 diabetes who fast during Ramaḍān.Clinical Trial Registrationwww.ClinicalTrials.gov, identifier NCT04237493.

A Systematic Review of Insulin Management Recommendations to Improve Glycemic Control and Reduce Hypoglycemic Events During Ramadan Fasting in Patients With Insulin-Requiring Type 2 Diabetes

“…Three studies (two RCTs) out of four demonstrated that insulin dosage reduction of between 25 and 40% TDD decreases rates of hypoglycemia for some participants ( 23 , 24 , 28 ). The average hypoglycemic incidence rate from these two RCTs was 22.5% [21.4% in Shehadeh et al ( 23 ), 23% in Zaghlol et al ( 24 )] in the control group and 4.5% [4.8% from Shehadeh et al ( 23 ), 4.2% in Zaghlol et al ( 24 )] in the intervention group.…”

“…Three studies (two RCTs) out of four demonstrated that insulin dosage reduction of between 25 and 40% TDD decreases rates of hypoglycemia for some participants ( 23 , 24 , 28 ). The average hypoglycemic incidence rate from these two RCTs was 22.5% [21.4% in Shehadeh et al ( 23 ), 23% in Zaghlol et al ( 24 )] in the control group and 4.5% [4.8% from Shehadeh et al ( 23 ), 4.2% in Zaghlol et al ( 24 )] in the intervention group. Another study compared premixed twice-daily dosing to short-acting insulin at iftar with intermediate at suhur (the meal consumed early in the morning before dawn and before fasting commences) and found no difference in hypoglycemia ( 26 ).…”

“…Two RCTs and four observational cohort studies analyzed how insulin dosage adjustment affects glycemic control. Three of the studies reduced the total insulin daily dose by 25% in the experimental groups, and the result was no difference in hyperglycemia compared to regular dosing ( 24 ), no episodes of DKA or NKHS (no comparator) ( 28 ), and no difference in A1c or average blood glucose compared to regular dosing ( 29 ). Shehadeh et al reduced TDD by 40% in their intervention group, giving 60% of the reduced dose as biphasic insulin 70 for iftar and 40% as Levemir at suhur, and their result showed no difference in A1c compared to usual care.…”

“…Reducing the pre-Ramadan TDD of insulin by 25–40% during the fasting month appears to effectively decrease the rate of hypoglycemia ( 23 , 24 , 28 ) from a combined average incidence rate of 22.5–4.5% ( 23 , 24 , 28 ). By comparison, the CREED epidemiologic study recorded a hypoglycemia incidence rate of 13.8% in a similar demographic during Ramadan ( 7 ).…”

“…By comparison, the CREED epidemiologic study recorded a hypoglycemia incidence rate of 13.8% in a similar demographic during Ramadan ( 7 ). Theoretically, lowering the insulin dose may consequently increase rates of hyperglycemia, however, studies have shown that decreasing the pre-Ramadan TDD of insulin does not subsequently increase the rate of hyperglycemia ( 23 , 24 ), DKA ( 28 ), or A1c ( 23 , 29 ). In fact, the large epidemiologic EPIDIAR study reported a severe hyperglycemic event rate of 4% during Ramadan compared to a 3% event rate in the intervention group in Shehadeh et al's study ( 23 ).…”