DIABETIC NEPHROPATHY

DR PRASHANT BENDRE,DM(NEPHRO)

COMPLICATIONS (ADA)
Eye 12,000-24,000 loose sight due to diabetes; leading cause of new blindness in 20-74 yrs age. 10-21% of diabetics have kidney disorder; diabetic nephropathy-most common cause of end stage renal disease. 2-4 times more incidence of heart disease. 2-4 times more incidence of stroke. 60-70% pts have mild to severe nerve damage, most common cause of non traumatic lower leg amputation. 13% in Type 1 8% in Type 2 men 50 yrs, impotence rate 50-60%

Kidneys

Heart Stroke Nerve disease & amputation

Impotence

NEPHROPATHY

NEPHROPATHY

Intensive Therapy Reduces Risk of Retinopathy and Nephropathy

DCCT
Cumulative percent progressing

Retinopathy
Primary Prevention 60 50 -76% 40 P<0.001 30 20 10 0 60 Secondary Intervention 50

Conventional therapy Intensive therapy

Microalbuminuria

30 Primary Prevention 25 -34% 20 P<0.04 15 10 5 0 50 40 Secondary Intervention

40 30
20 10 0 0

-54% P<0.001

30
20

-43% P=0.001

10
1 2 3 4 5 6 7 8 9

Years DCCT Research Group. N Engl J Med. 1993;329:977-986

0 1 2 3 4 5 6 7 8 9

Intensive Insulin Therapy Reduces Risk of Retinopathy and Nephropathy

Kumamoto Study
Cumulative percent progressing 50 40 30 20 10 0 50 40 30 20 10 0

Retinopathy
Primary Prevention

Conventional therapy Intensive therapy

Microalbuminuria

Primary Prevention

-76% P=0.039

40 30 20 10
0

-62% P=0.032

Secondary Intervention

Secondary Intervention 40 30 20 10 0

-56% P=0.049

-52% P=0.044

Years

Ohkubo Y et al. Diabetes Res Clin Pract. 1995;28:103-117

Intensive Insulin Therapy

Microvascular Risk Reduction in Two Trials
Complication Study Retinopathy Nephropathy Neuropathy Reduction in Risk With 2% Reduction of A1C DCCT 63% 54%* 60% Kumamoto 69% 70% Significantly improved

* Albuminuria >300 mg/24 hr Worsening of albuminuria >300 mg/24 hr DCCT Research Group. N Engl J Med. 1993;329:977-986; Ohkubo Y et al. Diabetes Res Clin Pract. 1995;28:103-117

Relative Risk of the Development of Diabetic Complications

Variable Nephropathy

Relative risk (95% CI)

P Value

0.39 (0.17-0.87) 0.003

Retinopathy
Autonomic neuropathy Peripheral neuropathy

0.42 (0.21-0.86) 0.02

0.37 (0.18-0.79) 0.002

1.09 (0.54-2.22) 0.66

0.0

0.5 Intensive Therapy Better

1.0

1.5

2.0

2.5

Conventional Therapy Better

Steno-2 Study, NEJM, Jan 2003

Insulin Therapy Nephro Patients

Subcutaneous Insulin Therapy in Hospitalized Patients

Effective for in-hospital glycemic control Patients can be transitioned from IV insulin to subcutaneous insulin Dose is easily adjusted to individual patient needs and nutritional status Subcutaneous insulin is currently being studied as an alternative to IV insulin in the management of patients with diabetic ketoacidosis

Clement S et al. Diabetes Care. 2004;27:553-591. Umpierrez GE et al. Diabetes Care. 2004;27:1873-1878.

Limitations of Sliding Scale Insulin Regimens

Dose in reaction to a single retrospective blood glucose measurement Does not provide basal insulin coverage Provides supplemental insulin after hyperglycemia occurs Does not consider nutritional changes or diurnal insulin requirements Nonphysiologic dosing places patients at risk of large fluctuations in blood glucose levels
- Increased incidence of hyperglycemic and hypoglycemic episodes

Queale WS et al. Arch Intern Med. 1997;157:545-552.

Types of Subcutaneous Insulin for Optimal Glycemic Control

Subcutaneous insulin scheduled to meet total daily insulin requirement

- Basal component Continuous subcutaneous insulin infusion (CSII) Long-acting insulin (insulin glargine) Intermediate-acting insulin (NPH insulin) - Prandial/nutritional componentshort-acting or rapidacting insulins Humalog (insulin lispro), insulin aspart, insulin glulisine - Supplemental componentrapid-acting insulin

Adapted from: Clement S et al. Diabetes Care. 2004;27:553-591.

Comparison of Human Insulins and Analogues

Insulin Preparations Lispro/Aspart/Glulisine Regular human Human NPH/Lente Human Ultralente Insulin glargine

Onset of Action 5-15 min 30-60 min 1-2 h 2-4 h 1-2 h

Peak (h) 1-2 2-4 4-8 10-16 flat

Duration of Action (h) 3-6 6-10 10-20 16-20 ~24

Time course of action of any insulin can vary in different people or at different times in the same person; thus, time periods indicated here should be considered general guidelines only.
Mudaliar S et al. Endocrinol Metab Clin North Am. 2001;30:935-982.

The Risk of Severe Hypoglycemia in Intensively Treated Type 1 (DCCT)

Hypoglycemic events per 100 pt-years

62

Intensive Conventional
19

Both arms received human insulin in non-hospital setting

Regular Insulin Has Significant Activity Beyond Four Hours After Injection

600 Mean glucose infusion rate (mg/min) 500 400 300 200 100 0 0 1 2 3 4 5 6 7 8 9 10 11 46% of total activity of regular insulin occurs after 4 hours

Glucose Regular Human Insulin

12

Time (hours)

Basal-Bolus Insulin Therapy ( Should Mimic the normal physiology)

Breakfast

Insulin Effect

Lunch

Dinner Bedtime Insulin glargine

Insulin lispro

Leahy JL. Insulin Therapy. Marcel Dekker Inc; 2002:87-112.

ANALOGS

Humalog (insulin lispro injection [rDNA origin])

[Lys (B28), Pro (B29)] - Human Insulin Analog (recombinant DNA origin)
S S

A-chain
1 21

S
S
1

S S

B28 LYS

B29 PRO

30

B-chain

Analog insulins Modify time action of human insulin toward a more physiologic profile Improve patient convenience
See Important Safety Information included in this presentation.

Dissociation of Insulins

Regular Human Insulin

10-3 M

10-3 M

10-5 M

10-8 M

Peak time 2-4 hr

Formulation
Humalog

Capillary membrane

10-3 M

10-3 M

10-3 M

Peak time 1 hr

Ciszak E et al. Structure 1995;3:615-622.

Formulation Transient

Serum Insulin Levels After Subcutaneous Injection in Healthy Volunteers

Serum Insulin Levels (ng/mL)

5
(N=10)

4 3 2

Humalog (insulin lispro injection [rDNA origin]) Regular human Insulin

1 0
0 1 9 2 10 3 11 4 5 6 7 12 Time (Hours) 8

Howey DC, et al. Diabetes 1994; 43:396-402.

Humalog Resulted in Rapid Increase in Insulin After Test Meal

Plasma insulin concentration (ng/mL)

3.0 2.5 2.0 1.5 1.0

With Humalog, insulin concentrations peaked at 68 18 min vs. 116 27 min with regular human insulin after a high-fat, high-calorie meal (pizza, cola, dessert) and returned to baseline faster Humalog Humulin R

0.5
0.0 SC insulin injection + meal 0 60 120 180 240 Time (minutes) 300 360 420 480

Mean SEM N=10 type 1 pts

-60

Baseline insulin concentration was maintained by infusion of 0.2 mU/min/kg human insulin.
Data derived from Heinemann L et al. Diabetic Medicine.1996;13:625-629.

Limitations of Human NPH, Lente, and Ultralente Do not mimic normal basal insulin secretion profile
- Variable absorption - Pronounced peaks - <24-hour duration of action

Cause unpredictable hypoglycemia

- Major factor limiting insulin adjustments - More weight gain

Campbell RK et al. Clin Ther. 2001;23:1938-1957.

Switching from IV to Subcutaneous Insulin

IV insulin has a short half-life (<10 minutes) and should not be discontinued until subcutaneous medication has been initiated Timing of administration of subcutaneous insulin before discontinuation of IV insulin
- 1 to 2 hours in advance for short- or rapid-acting insulins - 2 to 3 hours in advance for intermediate- or long-acting insulins

Dosing
- Basal component is 40%-50% of total daily dose - Prandial/nutritional component is remainder divided into number of discreet meals

Clement S et al. Diabetes Care. 2004;27:553-591.

Switching from IV to Subcutaneous Insulin

Initiate prandial doses of rapid-acting analog with the first dietary tray, even if patient is on an intravenous insulin infusion Establish 24-hour insulin requirement Calculate the total daily dose of subcutaneous insulin at 80% of the projected 24-hour insulin requirement Stop intravenous infusion of insulin 2 hours after first basal insulin dose of insulin glargine Monitor BG preprandially, 2 hours postprandially, at bedtime, and at 3:00 AM Adjust total 24-hour dose of insulin daily

Campbell KB et al. Clinical Diabetes. 2004:22:81-88. Clement S et al. Diabetes Care. 2004;27:553-591. Bode BW et al. Endoc Pract. 2004;10(suppl 2):71-80.

Guidelines for Supplemental Insulin

Insulin glulisine, lispro, or aspart are administered only at mealtime(s)

- Prevent or correct blood glucose levels outside 120 to 180 mg/dL

Type 1 diabetes: add 1 unit of insulin for every 50 mg/dL over 180 mg/dL Type 2 diabetes: add 1 unit for every 30 mg/dL over 180 mg/dL* Insulin-resistant patients: initially add 1 unit for every 20 mg/dL over 180 mg/dL

*Same dose as type 1 for conservative approach.

Hirsch IB. Insulin in the Hospital Setting. Adelphi Inc; 2002.

Efficacy of Humalog
Compared to regular insulin
Blood Glucose (mg/dL)1

20 0

N=10 Regular insulin

Humalog returns glucose concentrations to premeal values in half the time1 The rise in 2-hour postprandial glucose was 53% lower with Humalog compared to regular insulin2

15 0

Humalog Humalog produces 40% Meal+sc insulin injection fewer nocturnal 10 hypoglycemic episodes3 0 0 30 60 90 120 150 180 210 2 40 Time (Minutes)
Baseline insulin concentration was maintained by infusion of 0.2 mU/min/kg human insulin

1. Heinemann L et al. Diabet Med. 1996;13(7):625-629. 2. Anderson JH Jr et al. Arch Intern Med. 1997;157(11):1259-1255. 3. Anderson JH Jr, et al. Diabetes. 1997;46(2):265-270.

Humalog vs Regular: A1C Reduction

(N=39)
0 -0.1
1. 2. 3.

Humalog

Regular

Decrease in A1C (%)

Patients in the Humalog group had greater reductions in A1C than patients who -0.2 remained on regular insulin. When used in and external insulin pump, Humalog should not be diluted or mixed -0.3any other insulin. with -0.3 Use of Humalog with pumps improves glycemic control without an increase in risk -0.4 of hypoglycemia.

Patients using CSII

Superior A1C reduction with Humalog vs regular

-0.5 -0.6 -0.7

-0.6

2-Hour Postprandial Glucose Excursions With Insulin Lispro and Regular Human Insulin in T 1 DM
3

*p<.05

*
* *

Glucose 1. Patients with Humalog had significantly lower excursions at each visit. Excursion 2. There was no loss of effect of Humalog during the course of the trial. 0 3. The negative excursion does not represent hypoglycaemia but rather a closer (mmol/L) approximation to normal in patients with elevated premeal glucose values. ean 95% C.I.
-1

-2 0 1 2 3 4 5 6

Months Humulin R / Humalog (n = 467) Humalog / Humulin R (n = 455)

Hypoglycemic Rate in IDDM Patients With Insulin Lispro and Regular Human Insulin

10

Humulin R (n = 994)

*
1.
9

Humalog (n = 986)

This slide represents the hypoglycaemia rate per 30 I diabetes Episodes / 30 daysdays in nearly 1000 patients with type * with Humalog and Humulin R in a crossover Mean 95% C.I. treated 8 study 2. The hypoglycaemia rate is statistically less for Humalog 7

6 0 1 2 3

Months Within Period

Glucocorticoid Therapy

Glucocorticoid therapy increases insulin resistance and can

- Exacerbate existing hyperglycemia - Cause new onset hyperglycemia - Cause potential decrease or loss of insulin sensitivity

Fasting plasma glucose (FPG) is minimally affected, but postprandial plasma glucose (PPG) can increase rapidly

Clement S et al. Diabetes Care. 2004;27:553-591. Hirsch IB. Insulin in the Hospital Setting. Adelphi Inc; 2002.

Hospital Discharge Transition: Patients With Diabetes

Start new insulin regimen prior to discharge

- Stabilize blood glucose prior to discharge
- Obtain A1C for discharge planning if result not available for the previous 2-3 months - Refer patient to a certified diabetes educator (CDE) - Provide specific instructions on medication use - Provide instruction on glucose monitoring - Provide instruction on hypoglycemia prevention - Schedule a follow-up visit

Initiation of insulin at discharge can improve wound control

Clement S et al. Diabetes Care. 2004;27:553-591. Lien LF et al. Med Clin North Am. 2004;88:1085-1105.

Summary

Aggressive glycemic management and follow-up of hospitalized patients with elevated blood glucose levels is critical for
- Optimal glycemic control while in the hospital - Improved hospital outcomes - Early detection of diabetes in patients with hyperglycemia after discharge

Insulin should be used as the treatment of choice for optimal management of hyperglycemia in the hospital

Summary (cont)

Maintaining tight glycemic control with IV or subcutaneous (SC) insulin in the hospital can
- Significantly improve outcomes for mortality and morbidity - Significantly reduce direct and indirect costs currently associated with uncontrolled hyperglycemia in the hospital setting

Diabetes education, medical nutrition therapy, and discharge planning are also essential components of hospital care

Summary (cont)

Humalog offers particular advantages in hospitalized Nephro patients

Rapid acting, therefore less chances of hypoglycemia relative to regular human insulin because of shorter residence time Better postprandial control compared to regular human insulin

Flexible Dosing
Can be injected immediately before meals; convenient in hospital setting Can be injected after meals. This is of particular advantage in situations where food intake is erratic or unpredictable Available in easy and simple to use disposable pens