Joel Zonszein Call Iris Carrasquillo RN, CDE for Diabetes Issues 718 904-2883 The Conundrum of...

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The Conundrum of DiabetesIn hospitalized patients

Joel Zonszein, MD, CDE, FACP, FACE

Albert Einstein College of Medicine Montefiore Medical Center

Bronx, New York

HYPERGLYCEMIA

MICROVASCULOPATHY

INSULINSECRETION

IGT T y p e 2 d I a b e t e s

CARDIOVASCULAR DISEASE

Zonszein J. in Hurst’s the Heart (Ch 78) 1998;2117-2142

INSULIN RESISTANCE

Retinopathy

Nephropathy

NeuropathyCVD Mortality10 years letter

DCCT9 7%

57% p=.02*

Kumamoto9 7%

UKPDS8 7%

17-21%

24-33%

13% p=.007**

** N Eng J Med September 10, 2008

Glycemic Control and ComplicationsOlder Studies -10 years latterGlycemic Control and ComplicationsOlder Studies -10 years latter

UKPDS Study Group: Lancet 352:837-53, 1998 *DCCT/EDIC Study Research Group, N Engl J Med December 353:2643-, 2005

Ohkubo Y: Diabetes Res Clin Prac 28:103-17, 1995DCCT Study Group: N Engl J Med 329:977-86, 1993

Is Tighter Glycemic Control Better?Newer Studies

Characteristics ADVANCE VADT ACCORD

No. participants

Mean age (yr)

Median study duration (yr)

11,140

10,251

Baseline A1c

Outcome A1c (intensive /control)

6.3 vs. 7.0

6.9 vs. 8.5

6.4 vs. 7.5

Major Hypoglycemia (% yr) 2.7 vs. 1.5 21.2 vs. 9.9 16.2 vs. 5.1

Weight gain (Kg) 0.1 vs. 1.0 7.8 vs. 3.4 3.5 vs. 0.4

HR Primary outcomes (95% CI)

HR Mortality (95% CI)

0.94 (0.84-1.06)

0.93 (0.83-1.06)

0.88 (0.74-1.05)

1.07 (0.81-1.42)

0.90 (0.78-1.04)

1.22 (1.01-1.46)

ACCORD. N Engl J Med 2008;358ADVANCE. N Engl J Med 2008;358 VADT N Engl J Med 2009;360

Del Prato S Diabetologia 2009;52:1259

VADT in the context of the “natural history of Type 2 Diabetes

TIME (years since diagnosis)

Drive risk for complications

Build up “bad” metabolic memory

Multiple Risk Interventions in Type 2 Diabetes (STENO-2 Trial)• 160 patients with type 2 diabetes and microalbuminuria, randomized

to conventional or intensive treatment for multiple risks for 8 years

Conventional IntensiveBlood Pressure <160/95 <140/85HbA1c <7.5% <6.5%Total Chol <250 mg/dL <190

mg/dLACE-Inhibitor No YesAspirin with known CAD Yes Yes with PVD No Yes No PVD or CAD No Yes

Gaede P et al. N Engl J Med. 2003;348:383-393.

Multiple Risks Interventions in Type 2 Diabetes (STENO -2 Trial)

Relative Risk End Points Reduction

Cardiovascular Composite 53% (P=0.007)

Nephropathy 61% (P=0.003)

Retinopathy 58% (P=0.02)

Autonomic neuropathy 63% (P=0.002)

Gaede P et al. N Engl J Med. 2003;348:383-393.

*Gaede P et al. N Engl J Med. 2008;358:580 -591.

Lower CVD mortality (@7.8 years) 43% (P=0.04) *

Smoking cessation

Treatment of:

HypertensionDyslipidemia

Hyperglycemia

Approved Antidiabetic Medications in the US

Medicaton Route Year (FDA approved)

Insulin Inhaled

ParenteralPulmonary

19212006-2007

Sulfonylureas Oral 1946

Biguanides Phenphormin Metformin

OralOral

1957- 19771995

Alpha-glycosidase inhibitors Oral 1995

Thiazolidinediones Troglitazone Rosiglitazone Pioglitazone

OralOralOral

1997-200019991999

Glinides Oral 1997

GLP analogues Byetta® Parenteral 2005

Amylin analogues Symlin® Parenteral 2005

DPP-IV inhibitors Januvia® and Onglyza Oral 2006 and 2009

Modified from Nathan D. N Eng J Med 2007;356:437-440

Combination Therapy; Different Sites of Action

Muscle and adipose tissue:Peripheral glucose uptakeTHIAZOLIDINEDIONES

Liver: GlucoseproductionBIGUANIDES

Pancreas: InsulinsecretionSULFONYLUREASMEGLITINIDES

Intestine: Digestion and absorption of carbohydratesa-GLUCOSIDASE INHIBITORS

Injectables: INSULINS EXENATIDE and PRAMLINTIDEglucagon, insulin, gastric, orectins

SITAGLIPTIN

The 2006 ADA Treatment Algorithm

*Check A1C every 3 months until <7% and then at least every 6 months thereafter. Nathan DM, et al. Diabetes Care. 2006;29:1963-1972.

Yes*No A1C7%

Diagnosis

Lifestyle Intervention + Metformin

Add Basal Insulin – Most effective

Add Sulfonylurea– Least expensive

Add Glitazone– No hypoglycemia

Intensify Insulin Add Glitazone Add Basal Insulin Add Sulfonylurea

Yes*No A1C7%Yes*No A1C7%

Add Basal or Intensify Insulin

Intensive Insulin + Metformin Glitazone

Yes*No A1C7% Yes*No A1C7% Yes*No A1C7%

How are we managing hyperglycemia in 2008… What drug to use when combination of SUO and Metformin fails?

• Patient: Maria

• Age: 51

• Height: 5' 3“, Weight: 224 lbs

• FBG between 110 and 140 mg/dl A1c 8.1%

• Treatment: maximum doses of MET (5 y) and an SFU (2 y)

• Patient goal: motivated;

• Choices:– Add pioglitazone– Add neutral protamine Hagedorn (NPH) h,s.– Add exenatide twice daily

N Engl J Med 2008;358:293-297.

• Patient: Maria● USA Diabetologist:

● 53% add exenatide twice daily● 32 % add NPH insulin before bedtime● 15% add pioglitazone (15%)

● USA other specialties:● 52% add NPH before bedtime● 24% add exenatide twice daily● 24% add pioglitazone

How are we managing hyperglycemia in 2008… What drug to use when combination of SUO and Metformin fails?

N Engl J Med 2008;358:293-297.

*Check A1C every 3 months until <7% and then at least every 6 months thereafter. Nathan DM, et al. Diabetes Care. 2006;29:1963-1972.

Yes*No A1C7%

Diagnosis

Lifestyle Intervention + Metformin

Add Basal Insulin – Most effective

Add Sulfonylurea– Least expensive

Add Glitazone– No hypoglycemia

Intensify Insulin Add Glitazone Add Basal Insulin Add Sulfonylurea

Yes*No A1C7%Yes*No A1C7%

Add Basal or Intensify Insulin

Intensive Insulin + Metformin Glitazone

Yes*No A1C7% Yes*No A1C7% Yes*No A1C7%

The 2006 ADA Treatment Algorithm

Lifestyle + MET+

Basal/Bolus Insulin

Lifestyle + MET+

Basal/Bolus Insulin

Lifestyle + MET+

Basal Insulin

Lifestyle + MET+

Basal InsulinAt Diagnosis:

Lifestyle+

At Diagnosis:

Lifestyle+

STEP 1 STEP 2 STEP 3

Tier 1: Well-validated core therapies*

Lifestyle + MET+

SFU†

Lifestyle + MET+

SFU†

Lifestyle + MET + GLP-1 Agonist‡

No hypoglycemiaWeight loss

Nausea/vomiting

Lifestyle + MET + PioNo hypoglycemia

Edema/CHFBone loss

Lifestyle + MET+

Pio + SFU†

Lifestyle + MET+

Pio + SFU†

Lifestyle + MET+

Basal insulin

Lifestyle + MET+

Basal insulin

Tier 2: Less well-validated therapies*

†SFUs other than glybenclamide (glyburide) or chlorpropamide. ‡Insufficient clinical use to be confident regarding safety.Adapted from Diabetes Care. 2009;32:193-203 For Important Safety Information about exenatide (GLP-1 agonist), see slides 9-11 and the accompanying full Prescribing Information.

*Validation based on clinical trials and clinical judgment

A1c ≥7%

Another Day….. another new Consensus Algorithm the 2009…

Lifestyle + MET+

Basal/Bolus Insulin

Lifestyle + MET+

Basal/Bolus Insulin

Lifestyle + MET+

Basal Insulin

Lifestyle + MET+

Basal InsulinAt Diagnosis:

Lifestyle+

At Diagnosis:

Lifestyle+

STEP 1 STEP 2 STEP 3

Tier 1: Well-validated core therapies*

Lifestyle + MET+

SFU†

Lifestyle + MET+

SFU†

Nausea/vomiting

Edema/CHFBone loss

Lifestyle + MET+

Pio + SFU†

Lifestyle + MET+

Basal insulin

Tier 2: Less well-validated therapies*

†SFUs other than glybenclamide (glyburide) or chlorpropamide. ‡Insufficient clinical use to be confident regarding safety.Adapted from Diabetes Care. 2009;32:193-203 For Important Safety Information about exenatide (GLP-1 agonist), see slides 9-11 and the accompanying full Prescribing Information.

*Validation based on clinical trials and clinical judgment

A1c ≥7%

Another Day….. another new Consensus Algorithm the 2009…

Management of Hyperglycemia in Hospitalized patients

Intensive insulin therapy in critically ill patients. • NON-DIABETES

– Sodi-Pallares “polarizing GIK solution”– Metabolic control in SICU patients– Metabolic control in MICU patients– Intensive insulin therapy in sepsis (German SepNet)– NICE-SUGAR

• DIABETES– DIGAMI– DIGAMI 2

Sodi-Pallares D, 1963 Dis Chest 43: 424Diaz R, 1998 Circulation 24:2227–2234

Kjellman UW, 2000 Scand Cardiovasc J 34:321–330Van Den Berghe G, 2001 N Engl J Med 345:1359 –1367

SepNet. Study. N Engl J Med 2008;358:125-139NICE-SUGAR Study. N Engl J Med 2009;360:1283-1297

Dr. Demetrio Sodi Pallares1913 - 2003

Glucose Insulin and Potassium Infusion (GIK)

Overview of Glucose-Insulin-Potassium Therapy for AMI: A 40-Year Prospective

Overview of GIK Therapy for AMI: A 30-Year Prospective

CREATE-ECLA: Effect of GIK Therapy on Mortality in Patients With STEMI*

Glucose Insulin and Potassium Infusion (GIK)in STEMI: Death at 30 Days by Predefined Subgroups

van den Berghe G, et al. N Engl J Med. 2001;345:1359–1367.

Conventional: insulin when blood glucose > 215 mg/dL.Intensive: insulin when glucose > 110 mg/dL and maintained at 80–110 mg/dL

Survival in ICU (%)

0 20 40 60 80 100 120 140 160

Intensive treatment

Conventional treatment

Days After Admission

RR 43% (95% CI 15 - 62)

Intensive insulin therapy in SICU patients: Improves survival

Intensive insulin therapy in SICU patientsbaseline characteristics

Conventional

Intensive

Age 62.2 63.4

BMI 25.8 26.2

Cardiac surgery (%) 63 62

History of Diabetes 13 13

Glucose >110 (%)

Glucose >200 (%)

Van den Berghe G. New Engl J Med 2001;345:1359-1367

Intensive insulin therapy in SICU patients

Conventional

Intensive

Insulin therapy n

(39.2)

(98.7)

<0.001

Median Insulin does IU/D 33 71 <0.001

Morning glucose 173 103 <0.001

% BG < 40 mg/dL 6 39 <0.001

Van den Berghe G. New Engl J Med 2001;345:1359-1367

Glycemic Targets in Hospital Patients 2004

Glycemic Targets (ACE)1

110 mg/dL

Medical/Surgical Units

Preprandial: 110 mg/dL

Maximal glucose: 180 mg/dL

Glycemic Targets (ADA)2

<180 mg/dL (target, 110 mg/dL)

Preprandial: 90-130 mg/dL(target, 110 mg/dL)

Postprandial <180 mg/dL

ACE indicates American College of Endocrinology; ADA, American Diabetes Association; ICU, intensive care unit.1. Garber AJ, Moghissi ES. Endocr Pract. 2004;10(suppl 2):4-9.2. American Diabetes Association. Diabetes Care. 2005;28(suppl 1):S4-S36.

Treating hyperglycemia aggressively “may be beneficial” and should be done in a sane and cost effective manner

Counterpoint: Inpatient management.A premature call to arms

Inzucchi and Rosenstock Diabetes Care April 2005 28:976

3054 received IIT goal: 81-108 mg/dL(time weighted BG = 118 mg/dL)

3050 received CIT goal: <180 mg/dL(time-weighted BG = 145 mg/dL)

• 90-day mortality: IIT: 829 patients (27.5%), CIT: 751 (24.9%)

• Absolute mortality difference: 2.6% (95% CI, 0.4-4.8)

• Odds ratio for death with IIT: 1.14 (95% CI, 1.02-1.28; P=.02)

Finfer S, et al. N Engl J Med. 2009;360::1283

1 2 3 4 5 86 7 9 10 11 12 13 14Base-line

Days After Randomization

Conventional

Intensive

10 20 30 40 50 8060 70 900

Days After Randomization

Conventional

Intensive

NICE-SUGAR: Outcomes

Glycemic Targets in Hospital Patients 2009

Glycemic Targets (ACE)1

110 mg/dL

Preprandial: 110 mg/dL

Maximal glucose: 180 mg/dL

Glycemic Targets (ADA)2

<180 mg/dL (target, 110 mg/dL)

Preprandial: 90-130 mg/dL(target, 110 mg/dL)

Postprandial <180 mg/dL

Glycemic Targets (ADA) and (ACE) 3 2009

(target, 140 to 180 mg/dL)Medical/Surgical Units

Preprandial: target < 140 mg/dLPostprandial or random <180 mg/dL

ACE indicates American College of Endocrinology; ADA, American Diabetes Association; ICU, intensive care unit.1. Garber AJ, Moghissi ES. Endocr Pract. 2004;10(suppl 2):4-9.2. American Diabetes Association. Diabetes Care. 2005;28(suppl 1):S4-S36.3. Consensus: Inpatient Hyperglycemia. Endocr Practice 2009;15 (No.4) 353-369

DIGAMI: Intensive insulin therapy improves mortality: AMI in patients with Diabetes

Malmberg K, et al. BMJ. 1997;314:1512–1515. (Reproduced with permission from the BMJ Publishing Group.)

All subjects

(N = 620)Risk reduction (28%) P = 0.011

Standard treatment

Follow-up (years)

2 3 4 5

Low-risk and not previously on insulin

IV insulin 48 hours, then 4 injections daily

Follow-up (years)

2 3 4 5

DIGAMI = Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction.

Mortality(%)

Malmberg K, et al. BMJ. 1997;314:1512–1515. (Reproduced with permission from the BMJ Publishing Group.)

All subjects

Standard treatment

Follow-up (years)

2 3 4 5

Low-risk and not previously on insulin

IV insulin 48 hours, then 4 injections daily

Follow-up (years)

2 3 4 5

DIGAMI = Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction.

Mortality(%)

DIGAMI: Intensive insulin therapy improves mortality: AMI in patients with Diabetes

DIGAMI 2:Intensive insulin therapy during AMI n1253

European Heart Journal 2005;26:650-661

Grup 1 n=474 Intensive Insulin Control IV insulin + glucoseGrup 2 n=473 Standard Control IV insulin + glucoseGrup 3 n=306 Routine use of insulin

HbA1c7.2%7.3%7.3%

FG mg/dlAdmision 24hrs Final230 164 144225 164 150232 180 150

DIGAMI 2: Time to first major event Death, Reinfarction, or Stroke

European Heart Journal 2005;26:650-661

TREATING THE PATIENT, NOT THE BLOOD SUGARS

Insulin replacement therapy in type 1 diabetesInsulin supplementation in type 2 diabetes

INSULIN DOSE IS RELATED TO THE DEGREEOF ISENSITIVITY NOT GLYCEMIC LEVEL

Case 1: 52-year-old male

• Hospitalized with atypical chest pain ROMI

• Reports previous good health, on no meds,

no prior Hx of DM, his 57-year-old brother has T2DM

• Ht: 5’9”; Wt: 221 lb Abdominal obesity, Acanthosis

• BP: 130/92 mm Hg

• Random plasma glucose: 219 mg/dL

• Lipids: – TG: 380 mg/dL – HDL-C: 28 mg/dL– LDL-C: 170 mg/dL

• What tests will your order?

• What diet will your order?

• How will you treat his hyperglycemia?

• Continuity of care…..

Case 1: 52-year-old male

Programmed Insulin Therapy

• Insulin replacement therapy in type 1 diabetes Basal Bolus

• Insulin supplementation in type 2 diabetes

Change RISSC for PIT– Avoid oral antidiabetic agents– Use basal insulin for supplementation– Avoid insulin meal coverage in T2DM

• Intensive Intravenous Insulin Therapy

Programmed Insulin Therapy (PIT): Goals

• Provide education and improve patient care

• Better but less intensive and cost effective glycemic control– Optimize Point of care CBG– Avoid HYPOGLYCEMIA– Avoid HYPERGLYCEMIA– Avoid “glucose toxicity”

• Continuity of care

• Improve LOS

Programmed Insulin Therapy (PIT):Insulin dose

• Use intermediate or long-acting insulins:– Lantus (glargine) can be given at AM, bed time, or at any time,

but should be “synchronized to the same hour every day– NPH, 7AM (50% of daily dose) and bed-time (50% of daily dose)

• Starting dose by weight and other factors– 0.3 units/Kg/day in end-organ failure– 0.5 units/Kg/day in stable medical patients– 0.7 units/Kg/day in surgical interventions or acute illnesses

• Constant dose adjustments

Insulins Peak (duration) hrs• RAPID-ACTING

– Humalog lispro 1-2 (2-6)– Novolog aspart 1-2 (2-6)– Apidra glulisine 1-2 (2-6)

• SHORT-ACTING– Regular 2-4 (3-6)

• INTERMEDIATE-ACTING– NPH 6-12 (10-24)

• LONG ACTING– Lantus glargine none (24)– Levemir detemir none (20-24)

Insulin analoguesModified from: Ragucci E, Zonszein J, Frishman WH. Heart Dis. 2003;5:18-33

Insulins Peak (duration) hrs• RAPID-ACTING

– Humalog lispro 1-2 (2-6)– Novolog aspart 1-2 (2-6)– Apidra glulisine 1-2 (2-6)

• SHORT-ACTING– Regular 2-4 (3-6)

• INTERMEDIATE-ACTING– NPH 6-12 (10-24)

• LONG ACTING)– Lantus glargine none (24)– Levemir detemir none (20-24)

Insulin analoguesModified from: Ragucci E, Zonszein J, Frishman WH. Heart Dis. 2003;5:18-33

Fixed-Mixed Insulins

HUMULIN (NPH/REG)– 70/30– 50/50

HUMALOG (Prot-lispro/free lispro)– 75/25– 50/50

NOVOLIN (NPH/REG)– 70/30

NOVOMIX (Prot-aspart/aspart)– 70/30

Insulin analogues

Pathophysiology of Type 1 Diabetes

ADA. Diabetes Care. 2002;25(suppl 1):S1

Loss of -cell mass

Insufficient insulin

Absolute insulin deficiency

Insulin Therapy “Basal – Bolus” Concept

· Some insulin is secreted at all times – the basal insulin

· Incremental amounts of insulin are secreted in response to rising postprandial glucose levels –the bolus insulin

• T1DM Insulin replacement 0.3-0.5 U/Kg/D – 2/3 given in the AM, 1/3 in the PM– 2/3 long acting, 1/3 short acting

• T2DM Insulin supplementation 0.5-1.0 U/K/D– Bedtime only (h.s.)– AM + h.s.– If elevated postprandials: change to “insulin

replacement”

Insulin Dosage Schedules

12 6 12 6 12

GLUCOSE

INSULIN

Breakfast Lunch Tea Dinner

Difficult to replicate

prandial

Normal insulin secretion

PlasmaInsulin(U/mL)

4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00

Breakfast Lunch Dinner

T1DM a state of insulin deficiencyInsulin as replacement basal/bolus pattern

GlucoseBolus InsulinBase Insulin

Skyler J, Kelley’s Textbook of Internal Medicine 2000.

• T1DM Insulin replacement 0.3-0.5 U/Kg/D – 2/3 given in the AM, 1/3 in the PM– 2/3 long acting, 1/3 short acting

• T2DM Insulin supplementation 0.5-1.0 U/K/D– Bedtime only (h.s.)– AM + h.s.– If elevated postprandials: change to “insulin

replacement”

Insulin Dosage Schedules

GLUCOSE

INSULIN

Glucose and insulin in T2DM and acute illness

300 mg/dl

100 mg/dl

5-20 mcu/L

20-200 mcu/L

GLUCOSE

Insulin therapy in T2DM and acute illness

300 mg/dl

100 mg/dl

BG mg/dl Insulin units

<250 0

251-300 4

301-350 6

351-400 8

>400 10

Regular Insulin30 units/D in 100 K

GLYCEMIC CONTROL “REGULAR INSULIN SLIDING SCALE” (RISSC)

• HYPERGLYCEMIA ……………...40% – severity of illness– high admission glucose level– infection disorders– corticosteroids

• HYPOGLYCEMIC EPISODES……23% – African-American– low serum albumin

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

Blood Glucose Levels During Isulin Treatment

Days of Therapy

Admit 1 2 3 4 5 6 7 8 9 10

Lantus + glulisine

Mean Blood Glucose Levels During Insulin Therapy

* p<0.01

¶ p<0.05

¶* * *

¶ ¶ ¶

Day 3: P=0.06

GLUCOSE

Insulin therapy in T2DM Long-acting insulinFewer POC glucose monitoring

300 mg/dl

100 mg/dl

Insulin Glargine50-70 units/D in 100 K

CBG CBG

GLUCOSE

300 mg/dl

100 mg/dl

Insulin therapy in T2DM Intermediate-acting insulinFewer POC glucose monitoring

NPH50-70 units/D in 100 K

CBGCBG

• Indications*

1. AMI

2. Revascularization

3. Selective surgical cases

• Labor intensive and expensive– More feasible in acute care units

• Changed early to aggressive subcutaneous insulin regimens

Montefiore: Intravenous Insulin Protocol

* Not for DKA and or HHC

Montefiore Length of Stay –LOS

MOSES WEILER NORTH

NONDIABETES DIABETES

2002 5.9 5.3 5.9 5.7

2007 4.3 4.8 5.4 4.6

2008 5.7 4.6 5.2 4.2 6.9 6.3

THANKSQUESTIONS ?

Joel Zonszein Call Iris Carrasquillo RN, CDE for Diabetes Issues 718 904-2883 The Conundrum of...

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