Glargine Dosing in Hospitalized Patients With Type 2 Diabetes and Renal Insufficiency

• Sponsor: Loyola University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00911625
• Collaborator: Sanofi (Industry)
• Enrollment: 114
• Locations: 3
• Arms: 2
• Actual Duration (Months): 29.2
• Patients Per Site: 38
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

It is imperative to devise easy to follow, yet appropriate, guidelines for insulin use in renal-impaired patients. This will be done by comparing two regimens: 1) glargine once daily plus mealtime glulisine based on weight alone and 2) a predetermined dosing reduction algorithm with glargine/glulisine based on weight with reduction for decreased estimated GFR by MDRD as follows: < 30 ml/min/1.73m2 or on dialysis reduce dose by 50% from weight based calculation.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes; Renal Insufficiency	Drug: 0.5 units/kg daily insulin; Drug: 0.25 units/kg daily insulin	Phase 4

Detailed Description

This study will enroll 180 hospitalized patients with Type 2 diabetes and moderate to end stage renal insufficiency (estimated glomerular filtration rate is < 30 ml/min/1.73m2 or dialysis) in the Chicagoland area. Participants will be randomized into 1 of 2 protocols after hospital admission. Blood glucose levels will be obtained before meals, at bedtime and whenever necessary for any signs or symptoms of hypoglycemia. The primary endpoint will be the percentage of blood glucose levels reaching goal of 80-180mg/dl. A secondary endpoint will be the percentage of hypoglycemic events, defined as blood glucose values < 60 mg/dl. In addition the percentage of glucose levels within the goal range of 80-180mg.dl will be further separated into excellent control (80-140mg/dl) and acceptable control (141-180mg/dl).

The 2 study groups will be:

1. Glargine & glulisine. The total daily insulin dose will be 0.6 units/kg. Half of this will be given as glargine once daily. The other half will be given as glulisine, divided equally between breakfast, lunch, and dinner with correction factor dosing as needed for elevated premeal hyperglycemia.

2. Glargine & glulisine The calculation for the total daily insulin dose will be 0.3 units/kg. Half of this will be given as glargine in the morning. The other half will be given as glulisine, divided equally between breakfast, lunch, and dinner, with correction factor dosing as needed for elevated premeal hyperglycemia.

All oral agents will be discontinued on admission.

Study Design

• Study Type: Interventional
• Actual Enrollment: 114 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Eligible participants are randomized to one of the two dosing groups using a 1:1 allocationEligible participants are randomized to one of the two dosing groups using a 1:1 allocation
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Glargine Dosing in Hospitalized Patients With Type 2 Diabetes and Renal Insufficiency
• Actual Study Start Date: Jan 21, 2009
• Actual Primary Completion Date: Jun 30, 2011
• Actual Study Completion Date: Jun 30, 2011

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 0.5 units/kg Participants randomized to this arm will receive a standard-dose of 0.5 units/kg daily insulin. Half of this dose will be given as glargine and the other half will be given as glulisine.	Drug: 0.5 units/kg daily insulin; Participants randomized to receive this intervention will receive a standard-dose of 0.5 units/kg daily insulin. Half of this dose will be given as glargine and the other half will be given as glulisine.; Other Names: Lantus Apidra
Experimental: 0.25 units/kg Participants randomized to this arm will receive an experimental dose of 0.25 units/kg daily insulin. Half of this dose will be given as glargine and the other half will be given as glulisine.	Drug: 0.25 units/kg daily insulin; Participants randomized to receive this intervention will receive an experimental dose of 0.25 units/kg daily insulin. Half of this dose will be given as glargine and the other half will be given as glulisine.; Other Names: Lantus Apidra

Outcome Measures

Primary Outcome Measures

1. Average Blood Glucose Over 6 Days [6 Days]

   Participants have their blood glucose measured daily for six days. The average blood glucose measure over all six days is compared between the two treatment cohorts.

Secondary Outcome Measures

1. The Number of Participants Who Experience at Least One Blood Glucose Level Below 70 Milligrams Per Deciliter [6 Days]

   At the end of the study, the number of participants who experience at least one blood glucose level below 70 milligrams per deciliter (mg/dL) is compared between the two treatment cohorts

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Type 2 Diabetes Mellitus of mor than 1year

• GFR less than 30 ml/min/1.73m2 or dialysis

• Age greater than 18years

• Entry blood glucose (fasting or random) greater than 180mg%

Exclusion Criteria:

• Type 1 Diabetes Mellitus

• New onset hyperglycemia

• Pregnant

• Solid organ transplant within 1 year

• Steroids prednisone greater than 7.5mg/day or equivalent

• Hospital LOS predicted less than 2 days

• Severe liver disease

• Known hypopituitarism or adrenal insufficiency

• Patients in the ICU

• Patients with hypoglycemic unawareness

• Outpatient insulin dose less than 0.6 units/kg

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Northwestern University Medical Center	Chicago	Illinois	United States	60611
2	Rush University Medical Center	Chicago	Illinois	United States	60612
3	Loyola University Hospital	Maywood	Illinois	United States	60153

Sponsors and Collaborators

• Loyola University
• Sanofi

Investigators

• Principal Investigator: Mary Ann Emanuele, MD, Loyola University

Study Documents (Full-Text)

None provided.

More Information

Publications

• American Diabetes Association. Economic costs of diabetes in the U.S. In 2007. Diabetes Care. 2008 Mar;31(3):596-615. doi: 10.2337/dc08-9017. Review. Erratum in: Diabetes Care. 2008 Jun;31(6):1271.
• Bailon RM, Cook CB, Hovan MJ, Hull BP, Seifert KM, Miller-Cage V, Beer KA, Boyle ME, Littman SD, Magallanez JM, Fischenich JM, Harris JK, Scoggins SS, Uy J. Temporal and geographic patterns of hypoglycemia among hospitalized patients with diabetes mellitus. J Diabetes Sci Technol. 2009 Mar 1;3(2):261-8.
• Baldwin D, Villanueva G, McNutt R, Bhatnagar S. Eliminating inpatient sliding-scale insulin: a reeducation project with medical house staff. Diabetes Care. 2005 May;28(5):1008-11.
• Bernard JB, Munoz C, Harper J, Muriello M, Rico E, Baldwin D. Treatment of inpatient hyperglycemia beginning in the emergency department: a randomized trial using insulins aspart and detemir compared with usual care. J Hosp Med. 2011 May;6(5):279-84. doi: 10.1002/jhm.866.
• Biesenbach G, Raml A, Schmekal B, Eichbauer-Sturm G. Decreased insulin requirement in relation to GFR in nephropathic Type 1 and insulin-treated Type 2 diabetic patients. Diabet Med. 2003 Aug;20(8):642-5.
• Clement S, Braithwaite SS, Magee MF, Ahmann A, Smith EP, Schafer RG, Hirsch IB; American Diabetes Association Diabetes in Hospitals Writing Committee. Management of diabetes and hyperglycemia in hospitals. Diabetes Care. 2004 Feb;27(2):553-91. Review. Erratum in: Diabetes Care. 2004 Mar;27(3):856. Hirsh, Irl B [corrected to Hirsch, Irl B]. Diabetes Care. 2004 May;27(5):1255.
• DeSantis AJ, Schmeltz LR, Schmidt K, O'Shea-Mahler E, Rhee C, Wells A, Brandt S, Peterson S, Molitch ME. Inpatient management of hyperglycemia: the Northwestern experience. Endocr Pract. 2006 Sep-Oct;12(5):491-505.
• Fischer KF, Lees JA, Newman JH. Hypoglycemia in hospitalized patients. Causes and outcomes. N Engl J Med. 1986 Nov 13;315(20):1245-50.
• Horton ES, Johnson C, Lebovitz HE. Carbohydrate metabolism in uremia. Ann Intern Med. 1968 Jan;68(1):63-74.
• Kagansky N, Levy S, Rimon E, Cojocaru L, Fridman A, Ozer Z, Knobler H. Hypoglycemia as a predictor of mortality in hospitalized elderly patients. Arch Intern Med. 2003 Aug 11-25;163(15):1825-9.
• Mak RH. Impact of end-stage renal disease and dialysis on glycemic control. Semin Dial. 2000 Jan-Feb;13(1):4-8. Review.
• Moen MF, Zhan M, Hsu VD, Walker LD, Einhorn LM, Seliger SL, Fink JC. Frequency of hypoglycemia and its significance in chronic kidney disease. Clin J Am Soc Nephrol. 2009 Jun;4(6):1121-7. doi: 10.2215/CJN.00800209. Epub 2009 May 7.
• Moghissi ES, Korytkowski MT, DiNardo M, Einhorn D, Hellman R, Hirsch IB, Inzucchi SE, Ismail-Beigi F, Kirkman MS, Umpierrez GE; American Association of Clinical Endocrinologists; American Diabetes Association. American Association of Clinical Endocrinologists and American Diabetes Association consensus statement on inpatient glycemic control. Diabetes Care. 2009 Jun;32(6):1119-31. doi: 10.2337/dc09-9029. Epub 2009 May 8.
• Murad MH, Coburn JA, Coto-Yglesias F, Dzyubak S, Hazem A, Lane MA, Prokop LJ, Montori VM. Glycemic control in non-critically ill hospitalized patients: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2012 Jan;97(1):49-58. doi: 10.1210/jc.2011-2100. Epub 2011 Nov 16. Review.
• Rave K, Heise T, Pfützner A, Heinemann L, Sawicki PT. Impact of diabetic nephropathy on pharmacodynamic and Pharmacokinetic properties of insulin in type 1 diabetic patients. Diabetes Care. 2001 May;24(5):886-90.
• Rubin DJ, Rybin D, Doros G, McDonnell ME. Weight-based, insulin dose-related hypoglycemia in hospitalized patients with diabetes. Diabetes Care. 2011 Aug;34(8):1723-8. doi: 10.2337/dc10-2434. Epub 2011 Jun 23.
• Schmeltz LR, DeSantis AJ, Thiyagarajan V, Schmidt K, O'Shea-Mahler E, Johnson D, Henske J, McCarthy PM, Gleason TG, McGee EC, Molitch ME. Reduction of surgical mortality and morbidity in diabetic patients undergoing cardiac surgery with a combined intravenous and subcutaneous insulin glucose management strategy. Diabetes Care. 2007 Apr;30(4):823-8. Epub 2007 Jan 17.
• Turchin A, Matheny ME, Shubina M, Scanlon JV, Greenwood B, Pendergrass ML. Hypoglycemia and clinical outcomes in patients with diabetes hospitalized in the general ward. Diabetes Care. 2009 Jul;32(7):1153-7. doi: 10.2337/dc08-2127.
• Umpierrez GE, Hellman R, Korytkowski MT, Kosiborod M, Maynard GA, Montori VM, Seley JJ, Van den Berghe G; Endocrine Society. Management of hyperglycemia in hospitalized patients in non-critical care setting: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2012 Jan;97(1):16-38. doi: 10.1210/jc.2011-2098.
• Umpierrez GE, Hor T, Smiley D, Temponi A, Umpierrez D, Ceron M, Munoz C, Newton C, Peng L, Baldwin D. Comparison of inpatient insulin regimens with detemir plus aspart versus neutral protamine hagedorn plus regular in medical patients with type 2 diabetes. J Clin Endocrinol Metab. 2009 Feb;94(2):564-9. doi: 10.1210/jc.2008-1441. Epub 2008 Nov 18.
• Umpierrez GE, Smiley D, Jacobs S, Peng L, Temponi A, Mulligan P, Umpierrez D, Newton C, Olson D, Rizzo M. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes undergoing general surgery (RABBIT 2 surgery). Diabetes Care. 2011 Feb;34(2):256-61. doi: 10.2337/dc10-1407. Epub 2011 Jan 12.
• Umpierrez GE, Smiley D, Zisman A, Prieto LM, Palacio A, Ceron M, Puig A, Mejia R. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes (RABBIT 2 trial). Diabetes Care. 2007 Sep;30(9):2181-6. Epub 2007 May 18.
• Varghese P, Gleason V, Sorokin R, Senholzi C, Jabbour S, Gottlieb JE. Hypoglycemia in hospitalized patients treated with antihyperglycemic agents. J Hosp Med. 2007 Jul;2(4):234-40.

• Responsible Party: Mary Ann Emanuele, Professor of Medicine, Loyola University
• ClinicalTrials.gov Identifier: NCT00911625
• Other Study ID Numbers: 201463
• First Posted: Jun 2, 2009
• Last Update Posted: Apr 6, 2017
• Last Verified: Mar 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Mary Ann Emanuele, Professor of Medicine, Loyola University: glargine; glulisine; type 2 diabetes; renal insufficiency
• Additional relevant MeSH terms: Renal Insufficiency; Diabetes Mellitus; Diabetes Mellitus, Type 2; Insulin; Insulin, Globin Zinc; Insulin Glargine; Insulin glulisine

Study Results

Participant Flow

Recruitment Details	Recruitment for this study took place at Loyola University Medical Center (Maywood, IL), Rush University Medical Center (Chicago, IL), and Northwestern University Medical Center (Chicago, IL) between January 2009 and May 2011

Arm/Group Title	0.5 Units/kg	0.25 Units/kg
Arm/Group Description	Participants randomized to this arm receive a standard-dose of 0.5 units/kg daily insulin. Half of this dose is given as glargine and the other half as glulisine.	Participants randomized to this arm receive an experimental dose of 0.25 units/kg daily insulin. Half of this dose is given as glargine and the other half as glulisine.
Period Title: Overall Study
STARTED	57	57
COMPLETED	50	57
NOT COMPLETED	7	0

Baseline Characteristics

Arm/Group Title	0.5 Units/kg	0.25 Units/kg	Total
Arm/Group Description	Participants randomized to this arm will receive a standard-dose of 0.5 units/kg daily insulin. Half of this dose will be given as glargine and the other half will be given as glulisine. 0.5 units/kg daily insulin: Participants randomized to receive this intervention will receive a standard-dose of 0.5 units/kg daily insulin. Half of this dose will be given as glargine and the other half will be given as glulisine.	Participants randomized to this arm will receive an experimental dose of 0.25 units/kg daily insulin. Half of this dose will be given as glargine and the other half will be given as glulisine. 0.25 units/kg daily insulin: Participants randomized to receive this intervention will receive an experimental dose of 0.25 units/kg daily insulin. Half of this dose will be given as glargine and the other half will be given as glulisine.	Total of all reporting groups
Overall Participants	50	57	107
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.3 (10.6)	63.7 (13.0)	64.0 (11.0)
Sex: Female, Male (Count of Participants)
Female	30 60%	28 49.1%	58 54.2%
Male	20 40%	29 50.9%	49 45.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	1 1.8%	1 0.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	17 34%	22 38.6%	39 36.4%
White	32 64%	32 56.1%	64 59.8%
More than one race	1 2%	2 3.5%	3 2.8%
Unknown or Not Reported	0 0%	0 0%	0 0%
Glomerular filtration rate (mL/min/1.73 squared meters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mL/min/1.73 squared meters]	30.4 (8.3)	29.6 (10)	29.9 (9.0)
Years of Diabetes (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	18.6 (8.8)	16.6 (9.9)	17.6 (10.0)
Glycated hemoglobin (Percentage (%)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percentage (%)]	8.2 (2.1)	7.9 (1.9)	8.0 (2.0)
Insulin therapy before admission (Count of Participants)
Insulin before admission	39 78%	42 73.7%	81 75.7%
No insulin before admission	11 22%	15 26.3%	26 24.3%
Total home daily insulin dose (units of insulin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units of insulin]	54.3 (40.7)	51.6 (46.3)	52.0 (43.0)

Outcome Measures

1. Primary Outcome

Title	Average Blood Glucose Over 6 Days
Description	Participants have their blood glucose measured daily for six days. The average blood glucose measure over all six days is compared between the two treatment cohorts.
Time Frame	6 Days

Outcome Measure Data

Analysis Population Description

The analysis population for the primary outcome comprises all participants who were randomized and completed all study activities

Arm/Group Title	0.5 Units/kg	0.25 Units/kg
Arm/Group Description	Participants randomized to this arm receive a standard-dose of 0.5 units/kg daily insulin. Half of this dose is given as glargine and the other half as glulisine.	Participants randomized to this arm receive an experimental dose of 0.25 units/kg daily insulin. Half of this dose is given as glargine and the other half as glulisine.
Measure Participants	50	57
Mean (Standard Deviation) [milligrams per deciliter]	174 (52.3)	174.5 (46)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	0.5 Units/kg, 0.25 Units/kg
	Comments	The null hypothesis is that there is no difference between the two treatment cohorts on their average blood glucose level
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.958
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.50
	Confidence Interval	(2-Sided) 95%; -19.341 to 18.341
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.502
	Estimation Comments

2. Secondary Outcome

Title	The Number of Participants Who Experience at Least One Blood Glucose Level Below 70 Milligrams Per Deciliter
Description	At the end of the study, the number of participants who experience at least one blood glucose level below 70 milligrams per deciliter (mg/dL) is compared between the two treatment cohorts
Time Frame	6 Days

Outcome Measure Data

Analysis Population Description

This analysis comprises all participants who were randomized and completed all study activities

Arm/Group Title	0.5 Units/kg	0.25 Units/kg
Arm/Group Description	Participants randomized to this arm receive a standard-dose of 0.5 units/kg daily insulin. Half of this dose is given as glargine and the other half as glulisine.	Participants randomized to this arm receive an experimental dose of 0.25 units/kg daily insulin. Half of this dose is given as glargine and the other half as glulisine.
Measure Participants	50	57
At least one blood glucose level below 70 mg/dL	15 30%	9 15.8%
No blood glucose level below 70 mg/dL	35 70%	48 84.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	0.5 Units/kg, 0.25 Units/kg
	Comments	The null hypothesis is that there is no difference in the odds of experiencing at least one blood glucose level below 70 mg/dL between the two treatment cohorts.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.0828
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.438
	Confidence Interval	(2-Sided) 95%; 0.172 to 1.114
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse event data were collected for 2 years, 3 months
Arm/Group Title	0.5 Units/kg		0.25 Units/kg
Arm/Group Description	Participants randomized to this arm receive a standard-dose of 0.5 units/kg daily insulin. Half of this dose is given as glargine and the other half as glulisine.		Participants randomized to this arm receive an experimental dose of 0.25 units/kg daily insulin. Half of this dose is given as glargine and the other half as glulisine.
All Cause Mortality
	0.5 Units/kg		0.25 Units/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/57 (0%)		0/57 (0%)
Serious Adverse Events
	0.5 Units/kg		0.25 Units/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/57 (0%)		0/57 (0%)
Other (Not Including Serious) Adverse Events
	0.5 Units/kg		0.25 Units/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/57 (0%)		0/57 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.