Inpatient DiabetesTreatment Goals, Strategies, Safety

Amish A. Dangodara, MD, FACPProfessor of Medicine

Internal Medicine, Hospitalist Program

University of California, Irvine

School of Medicine

2015

Disclosures

None

Learning Objectives

• Review physiology of glucose regulation

• Describe the duration of action of various types of insulin

• Distinguish differences between nutritional, correctional, and basal insulin treatment strategies

• Describe appropriate action for NPO patients

• Describe appropriate prevention and treatment of hypoglycemia

Glucose Regulation

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1

2

3

4

1

2

2

3

Incretin Pathway

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GLP-1

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DPP4

DPP4 is an intrinsic membrane glycoprotein (serine exopeptidase) expressed on the surface of most cell types.

•antigenic enzyme that cleaves X-proline dipeptides from the N-terminus of polypeptides

•immune regulation, signal transduction, and apoptosis

•suppressor in the development of cancer and tumors

•Rapidly degrades incretins (GLP-1)

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Normal GI Response to Meal

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Intestinal GLP-1 Release

GLP-1 [9-36] Inactive

GLP-1 [7-36] Active

DPP-4

Rapid Inactivation (>80%)

Mixed Meal

GLP-1 actions to control glucose:•Inhibits glucagon secretion•Inhibits hepatic gluconeogenesis•Augments glucose-induced insulin secretion•Slows gastric emptying•Promotes satiety

Additional features of GLP-1 based treatment:•Restores beta-cell function•Increases insulin synthesis•Promotes beta-cell differentiation

Drucker, DJ. Diabetes Care. 2003; 26: 2929-2940.

Normal Glucose Response to Meal

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Normal GI Response to Meal

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Incretins increase insulin release from Beta cells in pancreas

Normal Pancreas Response to Meal

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Diabetes, Type II

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Incretin Effect in Diabetes

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GLP-1 Effect in Diabetes

Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist ProgramAmish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

Pancreas Response in Diabetes

Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist ProgramAmish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

NGT - normal glucose toleranceT2DM - Type 2 Diabetes Mellitus

Diabetic Therapies

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Na-glucose transport (SGLT); blocks glucose reabsorption in kidney

Prevents digestion of carbohydrates

Slows gastric emptying

Reduce gluconeogenesis and increase insulin sensitivity

Decrease insulin resistance

Increase insulin secretion

Binds FFA to increase insulin secretion

Exogenous insulin

Increase insulin secretion

Pancreatic Beta cells

Multiple effects

GLP-1

Decrease insulin resistance

Case

63 yo M admitted with (L) foot ulcer/cellulitis, not responding to outpatient Abx. Weight 100 Kg. He is NPO for LE angiogram.

PMHx: PVD s/p (L) distal tibial artery bypass, DM II, CRIMeds: 70/30 insulin 70 units in AM, 30 units in PM, Metformin 1000 mg

BID (takes after breakfast & bedtime)Labs: HgbA1c=11.4, glucose 325, BUN 20, creatinine 0.9

In addition to holding Metformin, what should you do with insulin?A. Hold 70/30 and start regular insulin sliding scale q4hB. Reduce 70/30 to 35 units in AM and 15 units in PMC. Change 70/30 to Lantus 25 units/d & use corrective insulin scale q4hD. Change 70/30 to Lantus 50 units/d & use corrective insulin scale q6hE. Continue home dose of insulin

Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist ProgramAmish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

What’s Wrong With Sliding Scale Alone?

Glucose Units

180 - 200 2

201 - 250 4

251 - 300 6

301 - 350 8

351 - 400 10

>400 12

Cor

rect

ive

Insu

lin

Dos

e

185

223

264

241

2

4

6

?

Time q4 h

Insulin Level

Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist ProgramAmish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

What’s Wrong With Using Home Dose To

Estimate Insulin Dose?

Home Hospital

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Insulin Strategy: Goal Glucose = 140-180

Hypoglycemia

Cortisol, Epinepherine, Glucagon, Glycogenolysis

180

126

80

0

Fasting EuglycemiaNutrition, Glycogenolysis, Insulin

Post-prandial Hyperglycemia

Insulin, GLP-1, Incretins

Severe HyperglycemiaInsulin resistance or DM

Basal Therapy

Nutritional Therapy

Corrective Therapy

Hypoglycemia Tx

Sliding Scale Insulin

Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist ProgramAmish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

Some Endogenous Insulin Activity

Hypoglycemia

Cortisol, Epinepherine, Glucagon, Glycogenolysis

180

126

80

0

Fasting Euglycemia

Nutrition, Glycogenolysis, Insulin

Post-prandial Hyperglycemia

Insulin, GLP-1, Incretins

Severe Hyperglycemia

Insulin resistance or DM

Basal Insulin

Nutritional Insulin

Corrective Insulin

Hypoglycemia Tx

Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist ProgramAmish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

Types of Nutrition

Bolus: meal or bolus TF Continuous: TF or TPN

Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist ProgramAmish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

Inpatient Diabetes Treatment

Basal-Bolus Nutritional insulin:

Basal insulin for fasting & nutritional insulin for meals

Breakfast Lunch Dinner

Glu

cose

Time 18:0012:008:00 21:00

Nutritional Insulin

AnalogAnalog Analog

Long-acting

Basal Insulin

Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist ProgramAmish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

Umpierrez GE et al. [RaBBIT-2 Trial] Diabetes Care, 2007; 30: 2181-2186.

Inpatient Diabetes Treatment

Basal-Continuous Nutritional insulin:

Basal insulin for fasting & nutritional insulin for meals

Glu

cose

Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist ProgramAmish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

Time 16:0012:008:00 20:004:00 24:00Long-acting

Basal InsulinNutritional Insulin

Long-acting

Basal glucoseContinuous nutrition

Umpierrez GE et al. [RaBBIT-2 Trial] Diabetes Care, 2007; 30: 2181-2186.

Inpatient Diabetes Treatment

Basal-Continuous Nutritional insulin:

Umpierrez GE et al. [RaBBIT-2 Trial] Diabetes Care, 2007; 30: 2181-2186.

Basal insulin for fasting & nutritional insulin for meals

Glu

cose

Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist ProgramAmish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

Long-actingTime 16:0012:008:00 20:004:00 24:00

Nutritional InsulinBasal Insulin

Short-acting

Basal glucoseContinuous nutrition

Which Insulin Is Best For What Strategy?

Basal: GFR<30-50

-Lantus q24h q24h

-Levemir q12h q24h

-NPH q8h q12h

Nutritional (Bolus):

-Analog qAC qAC

-Regular qAC qAC

Nutritional (Continuous):

-Regular q4h q6h

-Analog q4h q6h

Corrective and/or NPO:

-Same as nutritional!

Analog Insulins:

(Lispro)

(Glulisine)

(Aspart)

(Glargine)

Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist ProgramAmish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

Basal-Nutritional Strategy

D/C all home diabetic therapy Estimate initial Total Daily Dose (TDD):

TDD = Weight (Kg) x 0.3 units/d for DM I or non-diabetic hyperglycemia TDD = Weight (Kg) x 0.4 units/d for controlled DM II (FBS<200) TDD = Weight (Kg) x 0.5 units/d for uncontrolled DM II

Correct for renal clearance (adjusted TDD): GFR >50%, no change in TDD GFR <50%, reduce initial estimated TDD by 50%

Basal-Bolus (Nutritional) dosing: Basal dose = 50% adjusted TDD (not needed if endogenous insulin ok) Nutritional dose = 50% adjusted TDD Bolus dose per meal = (Nutritional Dose)/(meals/d)

Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist ProgramAmish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

Basal-Nutritional Strategy

Adjust dose after 24 hours: If zero events of hypoglycemia in past 24h and glucose >180:

Increase adjusted TDD by up to 20% If one or more events hypoglycemia in past 24h:

Decrease adjusted TDD by 20% and consider holding nutritional insulin Evaluate nutrition intake Assess for nutrition-insulin mismatch Assess for improving insulin resistance as acute illness improves Assess for worsening renal function

Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist ProgramAmish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

RaBBIT-2 Trial

Corrective insulin sliding scale vs basal-bolus insulin trial: Schedule qAC & qHS if eating or q4 hrs if NPO or q6 hrs if NPO with

GFR < 30 using short-acting insulin: aspart, glulisine, humalog, regular

Insulin sensitive/Type 1:

Glucose at treatment goal = 0 units

141 - 180 = 2 units

181 - 220 = 4 units

221 - 260 = 6 units

261 - 300 = 8 units

301 - 350 = 10 units

351 - 400 = 12 units

>400 = 14 units

Usual treatment/Type 2:

Glucose at treatment goal = 0 units

141 - 180 = 4 units

181 - 220 = 6 units

221 - 260 = 8 units

261 - 300 = 10 units

301 - 350 = 12 units

351 - 400 = 14 units

>400 = 16 units

Insulin resistant:

Glucose at treatment goal = 0 units

141 - 180 = 6 units

181 - 220 = 8 units

221 - 260 = 10 units

261 - 300 = 12 units

301 - 350 = 14 units

351 - 400 = 16 units

>400 = 18 units

Umpierrez GE et al. [RaBBIT-2 Trial] Diabetes Care, 2007; 30: 2181-2186.

Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist ProgramAmish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

Mean Blood Glucose Levels During Insulin Tx

Blood Glucose Levels During Insulin Treatment

Days of Therapy

Bloo

d glucose (m

g/dL)

100

120

140

160

180

200

220

240

Admit 1 2 3 4 5 6 7 8 9 10

Regular ISS

Lantus + glulisine

* p<0.01

¶ p<0.05

¶* * *

¶ ¶ ¶

< Day 3: P=0.06

Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist ProgramAmish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

Umpierrez GE et al. [RaBBIT-2 Trial] Diabetes Care, 2007; 30: 2181-2186.

• Treatment success– BG target of < 140 mg/dL was

achieved in 66% of patients on Basal-Bolus (Lantus® + Apidra®) and 38% regular insulin (SSI)

• Treatment failure– One out of 5 patients using SSI

remained with BG >240 mg/dL and switched to Basal-Bolus (Lantus® + Apidra®)

Basal–Bolus Insulin Outcomes

Days of Therapy

Blo

od

Glu

cose

(m

g/dL

)

100

120

140

160

180

200

220

240

Admit 1 2 3 4 1 2 3 4 5 6 7

Sliding-ScaleInsulin Delivery

LANTUS® + APIDRA®

260

280

300

Sliding-ScaleInsulin

Basal-Bolus

66%

38%

0%

25%

50%

75%

100%

Pa

tie

nts

wit

h B

G <

14

0

mg

/dL

, %

Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist ProgramAmish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

Umpierrez GE et al. [RaBBIT-2 Trial] Diabetes Care, 2007; 30: 2181-2186.

Hypoglycemia

• Basal Bolus Group:– 1,005 BG readings– Two patients (3%) had BG < 60 mg/dL– Four BG readings (0.4%) < 60 mg/dL – No BG < 40 mg/dL

• Regular ISS:– 1,021 BG readings – Two patients (3%) had BG < 60 mg/dL– Two BG readings (0.2%) < 60 mg/dL – No BG < 40 mg/dL

• None of the episodes of hypoglycemia in either group were associated with adverse outcomes

Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist ProgramAmish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

Umpierrez GE et al. [RaBBIT-2 Trial] Diabetes Care, 2007; 30: 2181-2186.

NPO - Hold Nutritional Insulin

Hypoglycemia

Cortisol, Epinepherine, Glucagon, Glycogenolysis

180

126

80

0

Fasting EuglycemiaNutrition, Glycogenolysis, Insulin

Post-prandial Hyperglycemia

Insulin, GLP-1, Incretins

Severe HyperglycemiaInsulin resistance or DM

Basal Insulin

Nutritional Insulin

Corrective Insulin

Hypoglycemia Tx

Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist ProgramAmish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

NPO (No Nutrition) Treatment

Hold nutritional insulin Continue basal insulin (reduce to 0.15 – 0.25 units/Kg/day) Continue corrective insulin If no other carbohydrate (CHO) source:

Start D5 (+/- saline) @ minimum 100 mL/h or D10 (+/- saline) @ minimum 50 mL/h

Equivalent to 17 KCal/h or 408 Kcal/d Order prn hypoglycemia therapy

Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist ProgramAmish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

Inpatient Diabetes Safety

Hypoglycemia: Definition <80 :

Glucose lower than desired treatment goal Clinically insignificant: Glucose 60 - 80

Associated with either mild or no symptoms of hypoglycemia This level can be occasionally tolerated

Clinically significant: <60 Confirm with serum blood test Glucose 40 - 60, usually associated with significant symptoms of

hypoglycemia, including confusion and lethargy; avoid if possible Glucose <40, associated with lethargy, coma, possible permanent

parkinsonian dementia with extrapyramidal symptoms, and increased mortality; goal would be to avoid 100% of the time

Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist ProgramAmish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

Inpatient Diabetes Safety

Hypoglycemia Treatment: Clinically stable:

Glucose 40 - 80, give meal first, then recheck q15 minutes until >70 Give D50 IVP or glucagon if unable to take PO, start D5 or D10 until

>70 Reduce nutritional insulin dose and corrective sliding scale dose by

20+ %

Clinically significant: Glucose <40, give D50 IVP and start D5 or D10-IVF Hold all diabetic medications. Once >70, use insulin sensitive corrective sliding scale @ >200 If corrective scale needed >2 times/24h, restart basal insulin at lower

dose

Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist ProgramAmish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

Basal-Bolus (Basal-Nutritional) Strategy

Remember this!: Inpatient goal: glucose 140 - 180 I, II, rII = 0.3, 0.4, 0.5 (DM I, II, resistant II, use 0.3, 0.4, 0.5 units/Kg/d as TDD) GFR <50, adjustment 50% reduction of TDD 50/50 basal to nutritional (50% TDD = Basal, 50% TDD = nutritional) D5 @100 mL/h or D10 @ 50 mL/h if no nutrition source

Forget this: Insulin sliding scale Estimating inpatient requirement based on home therapy Using last 24h IV insulin dose to estimate SQ insulin dose

Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist ProgramAmish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

Questions?