Table 2.

Clinical trials and studies considering time of day in the treatment of endocrine disorders.

DRUG CLASS	DRUG(S)	POPULATION	STUDY CONCLUSIONS	SUGGESTED TIME OF DAY	CITATION
Adrenal Insufficiency (AI) and Congenital Adrenal Hyperplasia (CAH)
Glucocorticosteroid	Hydrocortisone	2 AIH + 2 CAG patients	24-hour infusion regimen of HC that mimics circadian rhythms of cortisol levels can restore circulating cortisol rhythms, restore levels of ACTH, and reduce levels of plasma 17-OHP.	24-h	Merza, Rostami-Hodjegan et al. 2006
		AI patients	24-h sub-cutaneous HC administration on restoring cortisol, ACTH, and 17-OH rhythms as well as increasing nocturnal growth hormone and insulin growth factor levels in AI patients	24-h	Lovas and Husebye 2007; Bjornsdottir, Oksnes et al. 2015
Type I Diabetes Mellitus
Hormone - Insulin Analogue	Insulin	Open, randomized, cross-over design; 14 patients who experience evening hypoglycemia	Nighttime subcuntaneous continuous injections seem to be more effective at hypoglycemic control.	Continous nighttime	Kanc, Janssen et al. 1998
	Insulin Ultratard	9 Patients	No significant difference in blood glucose levels at any point.	No difference	Edsberg, Dejgaard et al. 1987
		Pediatric patients	Continuous subcutaneous injections of insulin glargine reduced HbA1C levels and controlled pre-meal glucose levels better than multiple daily injections	Continuous	Doyle, Weinzimer et al. 2004
	Insulin Glargine	292 Patients	Similar improvements were seen in morning, evening, or split dose groups. Split dosing results in weight gain.	No difference	Garg, Gottlieb et al. 2004
		Patients whose HbA1C and glycemic levels were not controlled by single injections	Split dosing was effective.	Split dosing	Albright, Desmond et al. 2004
		18 Patients with poorly managed T1DM	Transitioning from evening to morning administration, independent of dose, resulted in more favorable glucose control and lipid profile without affecting body weight.	Morning	Gradiser, Bilic-Curcic et al. 2015
	Insulin Glargine + Lispro		HbA1C levels and 24-hour glycemic control did not differ among groups administring insulin glargine in the morning, evening, or bedtime in conjunction with prandial insulin lispro; morning administration resulted in fewer nocturnal hypoglcemic episodes	No differences; morning had added benefits	Hamann, Matthaei et al. 2003
	Lispro	Randomized, cross-over study. 23 patients	Administration of insulin glargine at lunch, dinner, or bedtime resulted in hypoglycemia at distinct timepoints after each injection; the night-time hyperglycemia after bedtime glargine injections was avoided with lunch or dinner injection schedules		Ashwell, Gebbie et al. 2006
		13 Patients	More effective at evening and nocturnal glycemic control when the bedtime dose is greater than mealtime doses; Lower mealtime and higher bedtime doses might be most effective at evening glycemic control.	Low mealtime, higher bedtime	Ahmed, Mallias et al. 1998
	Detemir + Aspart		Combination therapy at mealtime provided equally effective glycemic control when administered as a morning/dinner or a morning/bedtime dose; however both regimens provided better glycemic control with no weight gain when compared to NPH morning/evening insulin regimen.		Pieber, Draeger et al. 2005
Octapeptides	Octreotide	8 T1DM patients who experience evening hypoglycemia: 4 Females 4 Males	Continuous subcuntaneous night injection is more effective at reducing hyperglycemia and growth hormone levels than single injections across the night.	Continous nighttime	Lunetta, Di Mauro et al. 1998
Type 2 Diabetes Mellitus
Hormone	Insulin	100 Patients	Higher morning:evening ratio seems to have greater safety and efficacy.	Higher morning:evening	Jung, Park et al. 2014
		143 Patients	For twice-daily doses of insulin, a higher morning:evening ratio might be more effective at managing glycemic levels.	Higher morning:evening	Lee, Lee et al. 2012,
	Insulin Glargine + Glimepiride	624 patients	Single daily dose was equally effective at glycemic control when given in the morning or evening.	No difference	Standl, Maxeiner et al. 2006
	Insulin Glargine	10 Patients	Total insulin activity is similar between morning/evening doses. However, evening administration controls nocturnal EGP, lipolysis, and glucagon concentration more consistently, whereas morning administration has greater protection against nocturnal hypoglycemia.	No difference	Porcellati, Lucidi et al. 2015
Incretin Mimetics	Lixisenatide	680 T2DM patients with inadequate control of glucose levels by metformin	Morning and evening injections similarly improve glucose control.	No difference	Ahren, Leguizamo Dimas et al. 2013
Meglitinide - Antidiabetic	Repaglinide	19 T2DM patients	Mealtime dosing is more effective than morning/evening split dose.	Mealtime	Schmitz, Lund et al. 2002
Dipeptidyl Peptidase-4 Inhibitor	Vildagliptin	48 Patients	Morning and evening dosing were equally effective at post-prandial and 24-h glucose control; however an evening dose was effective at reducing fasting plasma glucose.	No difference, but evening has additional benefits	He, Valencia et al. 2010
Gestational Diabetes Mellitus
Hormone	Insulin	274 Females w/ Gestational Diabetes 118 Females with Pregestational Diabetes	Insulin administered four times daily is more effective at glycemic control than twice daily. 30 mins before each meal and before bedtime.	Four times/day	Nachum, Ben-Shlomo et al. 1999
		480 Females, >30 weeks pregnant.	Four times daily. 30 mins before each meal, and before bed-time.	Four times/day	Saleem, Godman et al. 2016
Hypothyroidism
Thyroid hormone	Levothyroxine	50 Patients	Morning dose is more effective, but if evening dose is necessary for compliance, evening dose is acceptable.	Morning, before mealtime	Ala, Akha et al. 2015
		12 Females	Bedtime administration seems to improve thyroid hormone levels and reduced TSH levels.	Bedtime	Bolk, Visser et al. 2007, Banerjee, Hossain et al. 2018
		105 Patients	Bedtime administration improved thyroid hormone levels.	Bedtime	Bolk, Visser et al. 2010
		152 Patients	Morning and evening doses are equally effective	No difference	Rajput, Chatterjee et al. 2011
		163 Children: 125 Females 38 Males	No difference between bedtime and morning treatments.	No difference	Akin 2018
		Older adults	Clinical trial currently underway	TBD	Giassi, Piccoli et al. 2019
Fat-soluble vitamin	Vitamin D3	13 Patients: 5 Females, 8 Males with secondary hyperparathyroidism in end-stage renal failure.	Evening dose is more effective at managing hyperparathyroidism in patients with renal osteodystrophy.	Evening	Tsuruoka, Wakaumi et al. 2003
Osteoporosis
Mineral	Calcium	14 patients	Calcium-supplemented meals did not affect the levels of bone resorption or the circadian patterns of resorption in comparison to evening-only supplements	No difference	Aerssens, Declerck et al. 1999
		26 early-menopausal females	Split morning:evening dose of 500:1000 mg (Tot. 1500mg)	Higher evening:morning	Scopacasa, Need et al. 2002
		19 post-menopausal females	Single evening 1000 mg dose only suppressed bone resorption during the night.	Split morning/evening	Scopacasa, Horowitz et al. 1998
		19 Females	Split dosing improved daytime bone resorption but not nighttime resorption.	Split morning/evening	Scopacasa F, Need AG, Horowitz M, Wishart JM, Morris HA and Nordin BE (2000) Inhibition of bone resorption by divided-dose calcium supplementation in early postmenopausal women. Calcif Tissue Int 67:440–442.
		30 Females 21–34 y	Split, morning, or 4 x daily doses showed no difference on bone resorption across the day, However parathyroid hormones were differently affected based on the size and timing of calcium dose, Need for longitudinal studies.	No difference	Kärkkäinen MU, Lamberg-Allardt CJ, Ahonen S and Välimäki M (2001) Does it make a difference how and when you take your calcium? The acute effects of calcium on calcium and bone metabolism. Am J Clin Nutr 74:335–342.
Estrogen receptor modulator	Raloxifene	39 Post-menopausal females	The only difference between morning/evening dose was the increase of plasminogen activator inhibitor (PAI)-1 with morning administration. Authors recommend evening administration.	Evening	Ando, Otoda et al. 2013
Parathyroid Hormone	Teriparatide	50 Females, post-menopausal	Morning administration resulted in increase in lumbar spine BMD.	Morning	Michalska, Luchavova et al. 2012
	Etidronate	retrospective longitudinal study	Dosing was similarly effective when taken as single doses across the day if the patient adhered to a 2 h fast before and after dosing	No difference	Cook, Blake et al. 2000
Cathepsin K Inhibitor	ONO-5334	14 Females; single-blind crossover study	Morning dose is more effective at reducing bone resorption than evening dose.	Morning	Eastell, Dijk et al. 2016
Hormone	Salmon Calcitonin	9 Females, Post-Menopausal	Both 0800 h and 2100 h administration are effective with no obvious advantage to either. 0800 h versus 2100 h treatment transiently reduced bone resorption but did not effectively alter the circadian pattern of bone resorption.	No difference	Schlemmer, Ravn et al. 1997
		81 Females between 40–70 y/o	Pre-dinner (1700 h) administration resulted in the greatest reduction in bone resorption, when compared to 0800 h or 2200 h administration.	Evening	Karsdal, Byrjalsen et al. 2008
Growth Hormone Deficiency
Hormones	Growth Hormone		Evening administration of GH was more effective at restoration of normal hormone and metabolite circadian patterns.	Evening	Jorgensen, Moller et al. 1990
		8 adult patients	Compared to one dose at 1900 h, split dosing at 1900 h (2/3 dose) and 0800 h (1/3 dose), better matched normal physiological GH profile, increased serum IGF-1, and decreased serum IGFBP-1 while lowering non-esterified fatty acids.	Split dose at 0800 h, 1900 h	Laursen, Jorgensen et al. 1994
		34 children	No differences between morning, afternoon or evening administration, in growth, IGF-1, or GH-BP after 6 or 12 months of GH treatment	No difference	Zadik, Lieberman et al. 1993
Glucocorticoid	Prednisolone	8 Patients: 4 Females 4 Males	Morning administration attenuates nocturnal growth hormone suppression, therefore potentially attenuating stunted growth.	Morning	Wolthers, Ramshanker et al. 2017
Turner Syndrome
Hormone	Estradiol	9 girls with Turner Syndrome receiving GH injections	Estradiol was more effective at managing insulin, glucagon, IGF-1 levels when administered in the evening compared to morning, but further studies are needed.	Evening	Naeraa, Gravholt et al. 2001
Other Endocrine Treatments
Hormone Therapy	Cyclo-Progynova Therapy	62 patients	No obvious difference in efficacy of morning/evening treatment.	No difference	Pongsatha, Chainual et al. 2005
Artifical Hormones	Hydrocortisone	6 females	Morning and evening administration is equally effective.	No difference	Kiriwat and Fotherby 1983