DIABETES MELLLITUS Strategies for Achieving Control in an Office Setting

Type 2 Diabetes

Global Prevalence of Diabetes Projected to More Than Double by 2030

Prevalence of Overweight/Obesity* in NHANES , by Sex and Age†

Total Prevalence of Diabetes in Americans Aged =20 Years by Age Group (2005)

Number of Newly Diagnosed Cases of Diabetes by Age Group in the US (2005)

Greater Prevalence of Diabetes in Certain Ethnic Populations in the US (2005)

Burden on Healthcare System

Diabetes Reduces Lifespan

Risk Reduction for Key Endpoints with Intensive Therapy (UKPDS)

Tight Glycemic Control Reduces Incidence of Microvascular Complications

Intensive Glycemic Control in Type 2 Diabetes Reduces Risk of Complications (UKPDS)

Tight Glycemic Control Reduces Long-Term Cardiovascular Risk (DCCT/EDIC Study)

Current Treatment Goals for Glycemic Control

Glycemic Goals Are Not Being Met

Most Patients with Type 2 Diabetes Also Do Not Achieve Risk-Factor Control

Mechanism of Postprandial Hyperglycemia: Glucose Production

Mitrakou A, et al. N Engl J Med. 1992;326: Glucose Glucagon Impaired Glucagon Suppression in IGT

Mitrakou A, et al. N Engl J Med. 1992;326: Insulin Glucagon Impaired Glucagon Suppression in IGT Time (min) Glucagon (pmol/L) NGT IGT

Impaired Glucagon Suppression in Type 2 Diabetes Müller WA, et al. N Engl J Med. 1970;283: Glucose Glucagon

Impaired Glucagon Suppression in Type 2 Diabetes Müller WA, et al. N Engl J Med. 1970;283: Insulin Glucagon

TYPE 1 DIABETES 15% of the total INSULIN DEPENDENCE v REQUIRING GLUCAGON SUPPRESSION

TYPE 2 DIABETES INVOLVES 2 PRIMARY PATHOGENETIC MECHANISMS –PROGRESSIVE DECLINE IN BETA CELL MASS AND FUNCTION ASSOCIATED WITH THE LACK OF GLUCAGON SUPPRESSION –THE PRESENCE OF A RESISTANCE TO INSULIN ACTION AT THE TISSUE LEVEL

ISSUES TO DEAL WITH AWARENESS EDUCATION IMPLEMENTATION OF TREATMENT

TREATMENT OPTIONS FOOD EXERCISE ORAL PARENTERAL BETA CELL FUNCTION GLUCAGON SUPPRESSION INSULIN RESISTANCE

TREATMENT OPTIONS ORAL –SECRETAGOGUES SULFONYLUREAS NONSULFONYLUREAS –INSULIN RESISTANCE THIAZOLIDINEDIONES (TZD) METFORMIN –GLUCAGON SUPPRESSION INCRETINS (INtestinal SECRETION of Insulin) –JANUVIA –STARCH BLOCKERS ACARBOSE

TREATMENT OPTIONS PARENTERAL –SUBCUTANEOUS INCRETIN MIMETICS INSULIN –TRANSPULMONARY

TREATMENT OPTIONS ORAL –SECRETAGOGUES SULFONYLUREAS NONSULFONYLUREAS –INSULIN RESISTANCE THIAZOLIDINEDIONES (TZD) METFORMIN –GLUCAGON SUPPRESSION INCRETINS (INtestinal SECRETION of Insulin) –JANUVIA –STARCH BLOCKERS ACARBOSE

TREATMENT OPTIONS ORAL ORAL –SECRETAGOGUES SULFONYLUREAS –GLYBURIDE –GLIPIZIDE –GLIMEPIRIDE (LONG ACTING) NONSULFONYLUREAS –NATEGLINIDE (STARLIX) –REPAGLINIDE (PRANDIN)

TREATMENT OPTIONS ORAL ORAL –INSULIN RESISTANCE THIAZOLIDINEDIONES (TZD) –PIOGLITAZONE (ACTOS) –ROSIGLITAZONE (AVANDIA) METFORMIN

TREATMENT OPTIONS ORAL ORAL –GLUCAGON SUPPRESSION INCRETINS (GLP-1) –SECRETED BY THE L-CELLS OF THE DISTAL ILEUM –CIRCULATES TO THE PANCREAS –STIMULATES INSULIN SECRETION –INHIBITS GLUCAGON SECRETION

TREATMENT OPTIONS ORAL GLUCAGON SUPPRESSION –INCRETINS (GLP-1)---”GLIP-ONE” THERE ARE NO ORAL INCRETINS –BUT THERE IS AN ORAL WAY TO HELP NATURALLY OCCURRING INCRETINS GLIPTINS (DPP-4 INHIBITORS) –SITAGLIPTIN (JANUVIA) –VILDAGLIPTIN (GALVUS -not yet released)

Synthesis, Secretion, and Metabolism of GLP-1 and GIP

DPP-4 Degrades GLP-1

TREATMENT OPTIONS PARENTERAL INCRETIN MIMETICS –DIRECT STIMULATION OF INSULIN –DIRECT INHIBITION OF GLUCAGON Exenatide (BYETTA) Amylin (SYMLIN) –NOT DEGRADED BY DPP-4 LONG-ACTING

TREATMENT OPTIONS PARENTERAL –SUBCUTANEOUS INCRETIN MIMETICS INSULIN –TRANSPULMONARY INSULIN

INSULIN THERAPY LONG ACTING ANALOGUES –LANTUS –LEVEMIR RAPID ACTING ANALOGUES –HUMALOG –NOVOLOG –APIDRA

INSULIN THERAPY MIXTURES –75/25 HUMALOG MIX –70/30 NOVOLOG MIX

INSULIN THERAPY IS INSULIN INEVITABLE ?

b-Cell Function Declines Regardless of Intervention in Type 2 Diabetes

AVAILABLE INSULINS

INSULINONSETPEAKDURATION HUMALOG< 30 minutes30-90 minute< 90 minutes

AVAILABLE INSULINS INSULINONSETPEAKDURATION HUMALOG< 30 minutes30-90 minute< 90 minutes NOVOLOG< 15 minutes1-3 hours3-5 hours

AVAILABLE INSULINS INSULINONSETPEAKDURATION HUMALOG< 30 minutes30-90 minute< 90 minutes NOVOLOG< 15 minutes1-3 hours3-5 hours REGULAR30-60 min2-4 hours6-12 hours

AVAILABLE INSULINS INSULINONSETPEAKDURATION HUMALOG< 30 minutes30-90 minute< 90 minutes NOVOLOG< 15 minutes1-3 hours3-5 hours REGULAR30-60 min2-4 hours6-12 hours NPH1-2 hours4-14 hours10-24 hours

AVAILABLE INSULINS INSULINONSETPEAKDURATION HUMALOG< 30 minutes30-90 minute< 90 minutes NOVOLOG< 15 minutes1-3 hours3-5 hours REGULAR30-60 min2-4 hours6-12 hours NPH1-2 hours4-14 hours10-24 hours LENTE1-3 hours6-16 hours12-24 hours

AVAILABLE INSULINS INSULINONSETPEAKDURATION HUMALOG< 30 minutes30-90 minute< 90 minutes NOVOLOG< 15 minutes1-3 hours3-5 hours REGULAR30-60 min2-4 hours6-12 hours NPH1-2 hours4-14 hours10-24 hours LENTE1-3 hours6-16 hours12-24 hours ULRALENTE4-8 hours10-30 hours18-36 hours

NEWER INSULINS INSULINONSETPEAKDURATION NOVOLOG MIX 70/30 < 15 min1-4 hours12-24 hours HUMALOG MIX 75/25 <30 min2-4 hours6-12 hours LANTUS1 hourNONE24 hours LEVEMIR1 hourNONE24 hours

NEWER INSULINS INSULINS ONSET PEAKDURATION APIDRA<15 minutes1-2 hour3-4 hours

THERAPEUTIC GOALS  HbA1C as low as possible  REDUCE BASAL HYPERGLYCEMIA  Provide a basal amount of insulin  REDUCE POSPRANDIAL EXCURSIONS  Supplemental insulin with the meal

REDUCING BASAL HYPERGLYCEMIA  NPH bid  LANTUS qd  LEVEMIR qd  INSULIN PUMP w  HUMALOG  NOVOLOG  APIDRA METFORMIN AMARYL BYETTA JANUVIA TZD

REDUCE POSTPRANDIAL GLUCOSE HUMALOG NOVOLOG APIDRA BYETTA STARLIX PRANDIN JANUVIA

TREATMENT STRATEGIES FOR SIGNIFICANTLY ELEVATED HbA1C –GET THE FBS DOWN FIRST –AS THE HbA1C DECLINES THE POST-PRANDIAL GLUCOSES PLAY A GREATER ROLE

TREATMENT STRATEGIES FOR FASTING GLUCOSE  NPH bid  LANTUS q HS  LEVEMIR q HS METFORMIN AMARYL BYETTA JANUVIA

TREATMENT STRATEGIES FOR POST PRANDIAL GLUCOSES APPROACH WITH RAPID ACTING INSULIN –TWO ISSUES DETERMINE THE PPG CARB CONTENT OF THE MEAL PRE-MEAL GLUCOSE LEVEL

TREATMENT STRATEGIES FOR POST PRANDIAL GLUCOSES CARB CONTENT CORRECTION –1 unit for every (15 grams) carbs consumed 1:15 carb ratio PRE MEAL GLUCOSE CORRECTION 1 Unit drops FS 50 mg%

TREATMENT STRATEGIES FOR POST PRANDIAL GLUCOSES CHOOSE A TARGET FOR CORRECTION e.g., 100 mg% FORMULA combines CORRECTION + CARBS FS CORRECTION + CARB RATIO = TOTAL (FS-target)/50 + 1:15 = TOTAL

SAMPLE COMPUTATION Patient has a 60 gm CHO meal –Uses 1 unit for 15 gm 4 units Patient has a target of 120 mg% –Correction factor = 40 (1 unit drops 40mg%) Current FS is 240 –Will need 3 units (FS-target)/ units for carbs ( ) = 120/4 =3 units for FS

SUMMARY –TYPE 2 DIABETES IS MULTIFACTORIAL –GO AFTER FBS FIRST METFORMIN GLIMEPIRIDE hs LEVEMIR or LANTUS –MEALTIME CONTROL NATEGLINIDE or REPAGLINIDE EXENATIDE JANUVIA RAPID ACTING INSULIN ANALOGUES

SUMMARY DIET and EXERCISE –Cannot be emphasized more