DIABETES IN THE TRANSPLANT PATIENT

Susan Alexander, DNP, CNS, CRNP, BC-ADM

College of NursingUniversity of Alabama in Huntsville

Clinical Affiliation:Outpatient Diabetes Self-Management

EducationCrestwood Medical Center

Huntsville, AL

Diabetes in the Transplant Patient

Describe factors associated with worsening of DM control in the patient with pre-TXP DM.

Describe risk factors associated with development of DM in the post-TXP patient

Discuss management strategies for optimization of DM control in the post-TXP patient.

Definition of Diabetes

Diabetes Mellitus: Heterogeneous Condition With

Hyperglycemia and Common Complications

Insulin Deficiency: Relative or Absolute

Risk Factors for Post Transplant Diabetes

Diabetes occurs post transplant at rate of:9% at 3 months16% at 12 months24% at 36 months

Risk factors: Age >40-45, Obesity, AA and Hispanic Race, Family History, Hepatitis

C and CMV, Polycystic kidneys

Post-transplant Diabetes Mellitus in Renal Transplant Recipiants. Tobin, G et al, UpToDate, May 31, 2008.

Diabetogenic Factors and Screening for Diabetes

Calcineurin Inhibitors Reversible islet cell toxicity, (tacrolimus)

Glucocorticoids are insulin antagonists that insulin resistance, hepatic glucose production and inhibit glucose transport into cells

Screening for Diabetes: -Monitor blood sugar prior to transplant -Monitor blood sugar post transplant with FBS

weekly X4, recheck in 3 months, 6 months and annually thereafter

Post-transplant Diabetes Mellitus in Renal Transplant Recipients. Tobin, G et al, UpToDate, May 31, 2008.

Fat

Adapted from Kruszynska YT, et al. J Invest Med. 1996;44:413-428.Henry RR. Ann Intern Med. 1996;124:97-103.

Liver

Pancreas

Peripheral Tissues(Skeletal Muscle andAdipose Tissue)

Glucose

InsulinResistance

IncreasedGlucose

Production

Impaired InsulinSecretion

Hyperglycemia in Type 2 Diabetes

Pre-existing Diabetes Type 1: -Steroids increase insulin

requirement and dose-Insulin dose will increase from

ESRD to having a working kidney

Type 2-Cannot use all oral agents-Usually require insulin-Insulin and/or oral agent dose

will increase from ESRD to having a working kidney

Chronic Effects of Diabetes Large blood vessel disease MI, stroke,

peripheral artery disease and LE amputation

Small vessel disease retinopathy/vision loss and blindness, kidney damage/renal failure

Neuropathy with pain, loss of protective sensation

Managing Diabetes In Hospitalized Patients

Hyperglycemia

Severe hyperglycemia (BG>250)

Does improving glycemic control relate to improved outcomes for patients?

Medical ICU, CV surgery and general

surgery patients have higher risk of death if hyperglycemia is present.

Factors Effecting Treatment Strategies in Hospitalized Patients

Medications Food intake Tests and procedures Prior history Nutritional status

Inzucchi, S. N Engl J Med 2006;355:1903-11

Insulin Treatment of Patients in ICU

IV insulin infusion Hourly BG monitoring Transition to subcutaneous Overlap IV and subcutaneous

Insulin Type 2 DM with <2u/h

Inzucchi, S. N Engl J Med 2006;355:1903-11

Insulin Use in Non-ICU Setting

Before meals:

- Regular insulin (R)- Rapid-actingAnalogCorrection Dose:

insulin sensitive/resistant

Adjust dose based on BG before lunch, supper or HS

Inzucchi, S. N Engl J Med 2006;355:1903-11

Guidelines for Glycemic Targets in Hospitalized Patients

ADA: ICU target = As close to 110 as possible and <180. General med. target = 90-130 and <180 after meals.

ACE: ICU target = <110. General med. Target = <110 with max of 180.

Guidelines are controversial, not based on clinical data from non-ICU patients.

Inzucchi, S. N Engl J Med 2006;355:1903-11

Insulin Dosing in Hospital: Impact of Nutrition Status

No Food Intake: Give IV infusion or basal insulin qd or bid + regular or rapid acting analog q 6h based on blood glucose.

Continuous Enteral Feeding: Basal insulin + correction dose q 6h. If feeding interrupted, give IV glucose to prevent hypoglycemia.

Total Parenteral Nutrition: Add regular insulin to IV bag and titrate dose in increments of 5-10u/liter.

Reassess insulin requirement with any change in nutritional status.Inzucchi, S. N Engl J Med 2006;355:1903-11

Proposed Moderate Glycemic Targets and Insulin Dosing in Hospitalized Patients

Medical and surgical ICU targets: Suggest <140 and consider <110

IV insulin allows more rapid titration and absorption in critically ill

Non critically ill target: 90-150 pre meals

Adjust dose q 1-2 days to optimize glycemic control ASAP

Inzucchi, S. N Engl J Med 2006;355:1903-11

Proposed Moderate Glycemic Targets and Insulin Dosing in Hospitalized Patients (Cont’d)

Before making insulin adjustment, consider factors that can cause hyperglycemia:

-Missed insulin doses -Snacking -Infection -BG testing and/or insulin administration

after versus before meals Frequent monitoring and dose adjustment

is essential. Adjust dose based on fingerstick BG before each meal and HS.

Transition to out patient regimen requires education of patient and a manageable regimen.

Transition to Subcutaneous Insulin: Basal Insulin Dose

Insulin NPH QD or BID 0.2-0.3 u/kg/day or 50% of IV insulin dose

Insulin Detemir QD or BID 0.2-0.3 u/kg/day or 50% of IV insulin dose

Insulin Glargine Q day

0.2u/kg/day or 50% of IV insulin dose

Transition To Subcutaneous Insulin: Meal Dose Insulin

Regular, Lispro, Aspart, Glulisine

0.20 units/kg/meal or 50% of IV insulin dose

type 2 Diabetes

0.30 units/kg/meal or 50% of IV insulin dose High Steroid Dose

Consistent carb intake across meals (45-60 grams/meal) to avoid hypo- and hyperglycemia

Adjust each dose by 10-20 % q 1-2 days until pre-meal BG is in target

Outpatient Management of Diabetes: ADA Glycemic Targets

Normal Goal

HbA1c 4-6% <7% *

Pre-prandialBlood Sugar

70-100 mg/dl 90-130 mg/dl(70-120)

Post-prandialBlood sugar

<140 mg/dl <180 mg/dl(<160)

Diabetes Care 29:S4-S42, 2006 *As close to 6.0% as possible

ADA Recommendation: Check A1c at least 2 x/yr if in target and stable; q 3 months if therapy has changed or not meeting goals. Diabetes Care 29:S4-S42, 2006

Self Blood Glucose Monitoring Provides vital data for clinical

decision making Provides patient with

accountability and feedback about his/her behavior

Advise patient about:-Appropriate meter -When to test-How to record results-How to interpret and respond to

results-Insurance/financial issues,

prescription required for reimbursement

The Plate Method

DM Management Strategies: Increase Physical Activity

Set small, reasonable goals: Something is better than nothing

Long term goal: Aerobic activity 30 minutes per day, 5 days per week, 1-3 sessions per day; resistance/strength training 3x/week

Exercise for Patients with Limited Mobility

Chair exercises

Strength training

Water exercise

Walking Leads to Reductions in Mortality in People with Diabetes

2896 adults with DM interviewed from 1990-1991

Outcomes: All cause and CVD mortality over 8-years

RESULTS:

Walking 17-minutes/day 39% in all cause mortality; 34% in CVD

Walking 30 minutes/day 46% all cause mortality; 47% in CVD

Arch Intern Med. 2003 Jun 23;163(12):1440-7.

Matching Pharmacology to Pathophysiology

HepaticGlucose Output

PeripheralGlucose Uptake

Glucose Influx

InsulinSecretion

HyperglycemiaBiguanides,TZD, DPP4,

InsulinTZD

BiguanidesInsulin

SulfonylureasMeglitinidesInsulin, DPP4

AGI

25

Oral Diabetes Meds

Drug Class Action Names

InsulinSecretagogues

Increaseinsulin secretion

Sulfonylureas: Glipizide, Glyburide, Glimepiride (Amaryl®) Meglitinides: Nateglinide (Starlix®) Repaglinide (Prandin®)

Biguanides

hepatic glucose output insulin sensitivity

Metformin(Glucophage®)

Alphaglucosidase Inhibitors (AGIs)

Inhibit absorption of glucose from gut

Acarbose (Precose®), Miglitol (Glyset®)

Thiazoladindiones (TZDs)

Increase insulin sensitivity

Rosiglitazone (Actos®)Pioglitazone (Avandia®)

DPP4 Inhibitors insulin secretion Sitagliptin (Januvia®) glucagon secretion. Saxagliptin (Onglyza®)

Effects of Incretin Hormones

Ingestion of food

Pancreas2,3

β-cellsα-cells

Release of gut hormones — Incretins1,2

insulin from beta cells

(GLP-1 and GIP)

Glucose-dependentGlucose uptake

by muscles

Glucose production

by liver

Blood glucose

Glucagon from alpha

cells(GLP-1)

Glucose dependent

•Active incretins physiologically regulate glucose by modulating insulin secretion in a glucose-dependent manner.•GLP-1 also modulates glucagon secretion in a glucose-dependent manner.

GI tract

ActiveGLP-1 & GIP

Inactive GLP-1and GIP

DPP-4 Enzym

e

2,4

1. Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913. 3. Drucker DJ. Diabetes Care. 2003;26:2929–2940.2. Ahrén B. Curr Diab Rep. 2003;2:365–372. 4. Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441.

Incretin Mimetics: Exenatide (Byetta®) and Liraglutide (Victoza®): Clinical Use

Treatment of type 2 diabetes in patients on metformin or sulfonylurea and not taking insulin

Byetta 5 mcg bid x 1 month, the 10 mcg bid within 1 hour of meal

Liraglutide 0.6 mg per day for one week, then 1.2 mg daily with max. dose ofto 1.8 mg (2).

Incretin Mimetics: Exenatide (Byetta®) and Liraglutide (Victoza®): Mechanism of Action

Stimulates first phase insulin release by pancreas when glucose levels are elevated

Reduces glucagon secretion

Slows Gastric Emptying (gastric emptying is accelerated in diabetes)

Reduces caloric intake by promoting satiety

AmylinomimeticsPramlintide (Symlin®)

Symlin=synthetic Amylin. Amylin is co-secreted with insulin by pancreatic beta cells in response to food intake.

Reduces Postprandial Glucagon

Postprandial Glucagon is Excessive andNot Corrected by Exogenous Insulin in Diabetes

Slows Gastric Emptying Gastric Emptying Is Accelerated in Diabetes

Reduces Caloric Intake by promoting satiety

*** Slowed gastric emptying will effect immunosuppressive drug levels***

Insulin As A Drug Described by duration of action

-Absorption-Clearance

Maintenance Insulin (Basal)-Dose effectiveness evident in fasting blood

glucose-Dose is based on body mass and insulin

sensitivity

Meal Insulin-Impacts post prandial blood glucose-Dose based on meal timing and size, insulin

sensitivity

Normal Endogenous Insulin Secretion

0

20

40

60

80

100

7:0

0

9:0

0

11

:00

13

:00

15

:00

17

:00

19

:00

21

:00

23

:00

3:0

0

7:0

0

9:0

0

11

:00

15

:00

19

:00

23

:00

3:0

0

7:0

0

mSeru

m insu

lin c

once

ntr

ati

on (U/m

L)

BreakfastLunch

Dinner

Fasting

Insulin is normally produced endogenously at a constant (i.e., basal) rate of 0.5 - 1.0 units/hour as well as in response to increases in blood glucose concentration after a meal.

INSULIN TYPES AND ACTIONS

Type Generic/ Brand Name

Onset Peak Duration

RAPIDACTING

Glulisine/Apidra

Lispro/Humalog

Aspart/Novolog

5-15 Min.

5-15 Min.

5-15 Min.

1-2 Hours

1-2 Hours

1-2 Hours

3-4 Hours

4 Hours

4-6 Hours

Short Acting Regular/Humulin R, Novolin R

½-1 hour 2-3 hours 4-8 hours

Insulin Types and Action

Type Generic/ Brand Name

Onset Peak Duration

IntermediateActing

NPH/ Humulin N

Novolin N

Reli-on N

1-1.5 Hours 4-12 Hours

18-25 Hours

Long Acting Glargine/Lantus

Detemir/Levemir

4-6 Hours

1-2 Hours

4-12 Hours1-7 Hours

24+ Hours

6-23 Hours

Idealized Insulin Action Times

The Basal/Bolus Insulin Concept

Basal Insulin – NPH, Levemir, Lantus 50% of daily needs Suppresses glucose production between

meals and overnightBolus Insulin (Mealtime or Prandial)

Novolog, Humalog, Apridra Regular Limits hyperglycemia after meals Immediate rise and sharp peak at 1 to 1½

hour 10% to 20% of total daily insulin

requirement at each meal

Pre-mixed Insulin

Protamine + Short or Rapid-Acting Insulin-Novolin 70/30® = 70% NPH+30% Regular-Humulin 70/30®, Humulin 50/50®-Humalog 75/25® = 75% NPL+25% Lispro-Novolog 70/30® = 70% NPH + 30% AspartOnset: 0.5-2.5 hoursTime to Peak: 4-8 hoursDuration: 17-25 hoursClinical Use: Elderly, cognitive or psych.

impairment, multiple co-morbid illnesses

Average Retail Cost Of Insulin In 2009*(10ml,1000 u in vial or 15ml,1500u in pens**)

Humalog/Novolog 10ml

Humalog/Novolog cartridges 15ml

Lantus 10ml vial

Hum/Novo R,N, 10ml vial

Hum/Novo, R, N Pen, cartridges 15ml

$112.00

$225.00

$107.99

$47-64.00 Walmart $20.00

$130-150.00

* 1 vial = 30-day supply if using <33u per day

** 5 pens of 3ml each = 15ml, 1500 units

Challenges of Diabetes Management in Transplant Patients

Fluctuating prednisone dose requires frequent monitoring of blood sugar and flexibility in insulin and/or oral medication dosing

Prednisone will increase appetite

Insulin or oral medication doses will increase after kidney transplant

Outpatient Follow-up Adjust dose and number of injections based

on home capillary glucose readings

Monitor in 1-2 week intervals

Steroid-induced hyperglycemia is less severe when dose is < 10mg/day

Prednisone dosed in morning elevated lunch and suppertime glucose, minimally elevated FBG

Continuous Glucose Monitoring Sensor

Continuous, automatic monitoring of glucose in the subcutaneous tissue

Hypoglycemia

Target blood glucose 70-120 mg/dl

Below 70: Rule of 15

Causes

Severe Hypoglycemia - rare

Hypoglycemia Unawareness