Achieving Optimal Control In Type 2 DiabetesAchieving Optimal Control In Type 2 Diabetes Case Study ¬58 Year Old Journalist58 Year Old Journalist ¬Type 2 DM Just DiagnosedType 2

Achieving Optimal Control Achieving Optimal Control In Type 2 DiabetesIn Type 2 Diabetes

Case StudyCase Study

58 Year Old Journalist58 Year Old JournalistType 2 DM Just DiagnosedType 2 DM Just DiagnosedHbA1C 7.1%HbA1C 7.1%

Screening For DiabetesScreening For Diabetes……..

ADAADA’’s Recommendations: s Recommendations:

FBS FBS ≥≥ 126 mg/dl126 mg/dlRandom Glucose Random Glucose ≥≥ 200 mg/dl200 mg/dl

A1C A1C ≥≥ 6.5%6.5%

PrePre--diabetes HbAdiabetes HbA1c 1c = 5.9% 6.1% = 5.9% 6.1% …………………….7.9%.7.9%

PrePre--diabetes HbAdiabetes HbA1c1c= 6.1% 6.5% = 6.1% 6.5% …………....…….12.6%.12.6%

Neuropathy (%)Neuropathy (%)

PrePre--diabetesdiabetes………………....……13%*13%*

*Prevalence.Diabetes Prevention Program Research Group. Diabet Med. 2007;24:137-144; Singleton JR, et al. Diabetes Care. 2001;24:1448-1453; Ziegler D, et al. Diabetes Care. 2008;31:464-469.

Diabetic Retinopathy (%)Diabetic Retinopathy (%)

Incidence of Microvascular Incidence of Microvascular Complications in PreComplications in Pre--DiabetesDiabetes

Association of Retinopathy Association of Retinopathy and Albuminuria with Glycemiaand Albuminuria with Glycemia

Tapp RJ, et al. Tapp RJ, et al. Diabetes Res Clin Pract Diabetes Res Clin Pract 2006;73:3152006;73:315--321.321.

A1c Thresholds Similar For Both A1c Thresholds Similar For Both Retinopathy And Microalbuminuria Retinopathy And Microalbuminuria

Prevalence Of Microalbuminuria Prevalence Of Microalbuminuria Increases With Rising Glucose Levels, Increases With Rising Glucose Levels, Even When Slightly ElevatedEven When Slightly Elevated

Weight Loss Of 7% Of Body WeightPhysical Activity At Least 150 Min/Week

Of Moderate ActivityMetformin, Especially If BMI >35, Age

> 60 Or Prior Gestational DMScreen For Modifiable CVD Risk

Factors

Prevention/Delay of Type 2 DMPrevention/Delay of Type 2 DM

Therapy of DiabetesTherapy of Diabetes

DietDiet

ExerciseExercise

MedicationsMedications

WhatWhat’’s The A1C Goal For s The A1C Goal For This Patient??This Patient??

Intensive Therapy for Diabetes Intensive Therapy for Diabetes Reduction in Incidence of Reduction in Incidence of

ComplicationsComplications

Type 2 Type 2 UKPDSUKPDS8 8 →→ 7%7%

1717--21%21%2424--33% 33%

--

HbA1cHbA1c

RetinopathyRetinopathyNephropathyNephropathyNeuropathyNeuropathy

Type 1 Type 1 DCCTDCCT

9 9 →→ 7%7%

76%76%54% 54% 60%60%

Type 2 Type 2 KumamotoKumamoto

9 9 →→ 7%7%

69%69%70% 70%

--

What About Glycemic What About Glycemic Control And Control And

Macrovascular Macrovascular Disease?Disease?

Recent Trials Modify The Recent Trials Modify The ParadigmParadigm

NEJMNEJM 358: 129358: 129--139, 2008 139, 2008

NEJMNEJM 358: 2545358: 2545--2559, 20082559, 2008

NEJMNEJM 360: 2560360: 2560--2572, 20092572, 2009

Diabetic Control and Macrovascular Diabetic Control and Macrovascular DIseaseDIsease

ADVANCE Collaborative Group. NEJM 358: 2560-2572, 2008.

553.43.45.65.6FollowFollow--Up (Yrs)Up (Yrs)~1.5~1.5~35~35~50~50Insulin Use (%)Insulin Use (%)~32~32~35~35~40~40CV Events (%)CV Events (%)7.57.58.18.19.49.4HbA1cHbA1c88101011.511.5DM Duration (Yrs)DM Duration (Yrs)

58/4258/4262/3862/3897/397/3Gender (% M/F)Gender (% M/F)666662626060Age (Yrs)Age (Yrs)

11,14011,14010,25110,2511,7911,791Number Number

VADTVADT ACCORDACCORD ADVANCEADVANCE

VADT, ACCORD, ADVANCE: Primary VADT, ACCORD, ADVANCE: Primary Outcome CV EventsOutcome CV Events

CV Death, MI StrokeCV Death, MI Stroke

Cum

ulat

ive

Cum

ulat

ive

inci

denc

e (%

)in

cide

nce

(%)

FollowFollow--up (months)up (months)

2525

2020

1515

1010

55

0000 66 1212 1818 2424 3030 3636 4242 4848 5454 6060 6666

HR 0.94 (0.84-1.06)P = 0.32

Standard ControlStandard Control

Intensive ControlIntensive Control

Hypoglycemia In Recent Major Clinical TrialsHypoglycemia In Recent Major Clinical Trials

Hypoglycemia and CV DiseaseHypoglycemia and CV DiseaseHemodynamic Responses To HypoglycemiaHemodynamic Responses To Hypoglycemia

Heart Rate IncreasesHeart Rate IncreasesSystolic BP IncreasesSystolic BP Increases

Diastolic BP DecreasesDiastolic BP DecreasesCardiac Output IncreasesCardiac Output Increases

Myocardial Contractility IncreasesMyocardial Contractility IncreasesEKG Changes EKG Changes

T wave flattening or inversionT wave flattening or inversionST depressionST depression

QT prolongatioQT prolongationn

Wright R et al Diabetes/ Metabolism Research and Reviews 2008

Hypoglycemia and CV DiseaseHypoglycemia and CV DiseaseHematologic Responses To HypoglycemiaHematologic Responses To Hypoglycemia

Increased RBCs Leading To Increased Increased RBCs Leading To Increased Blood ViscosityBlood Viscosity

Enhanced Platelet AggregationEnhanced Platelet AggregationIncreased Platelet Factor 4Increased Platelet Factor 4Increased ThromboglobulinIncreased Thromboglobulin

Increased Coagulation Factor VIIIIncreased Coagulation Factor VIIIIncreased Von Willebrand FactorIncreased Von Willebrand FactorIncreased Thrombin GenerationIncreased Thrombin Generation

Wright R et al Diabetes/ Metabolism Research and Reviews , 2008

Is intensive glucose Is intensive glucose control ever control ever

beneficial to the beneficial to the vasculature?vasculature?

UKPDSUKPDSUnited Kingdom Prospective United Kingdom Prospective

Diabetes StudyDiabetes Study

UKPDS Group Lancet 352: 837-853 and 854-865, 1998

~10~10553.43.45.65.6FollowFollow--Up (Yrs)Up (Yrs)00~1.5~1.5~35~35~50~50Insulin Use (%)Insulin Use (%)--~32~32~35~35~40~40CV Events (%)CV Events (%)

7.17.17.57.58.18.19.49.4HbA1cHbA1c0088101011.511.5DM Duration (Yrs)DM Duration (Yrs)

61/3961/3958/4258/4262/3862/3897/397/3Gender (% M/F)Gender (% M/F)5353666662626060Age (Yrs)Age (Yrs)

4,2094,20911,14011,14010,25110,2511,7911,791Number Number

VADTVADT ACCORDACCORD ADVANCEADVANCE UKPDSUKPDS

UKPDSUKPDSUnited Kingdom Prospective United Kingdom Prospective Diabetes Study FollowDiabetes Study Follow--UpUp

Holman R et al NEJM 359: 1565-1576, 2008.

Myocardial InfarctionMyocardial Infarction

Metabolic MemoryMetabolic Memory

Or Or

Legacy EffectLegacy Effect

Summary: Trials and Metabolic Memory

Get In There Early With Tight Glycemic Get In There Early With Tight Glycemic Control BUT Relax Glycemic Control Control BUT Relax Glycemic Control Later!Later!

If CV Risk Factors Are Controlled, There If CV Risk Factors Are Controlled, There Is Is No Benefit And Potential Harm To No Benefit And Potential Harm To Intensive Glycemic Control In High Intensive Glycemic Control In High Risk Patients With A Long Duration Of DM Risk Patients With A Long Duration Of DM

Multiple Factors Drive Progressive Multiple Factors Drive Progressive Decline Of Decline Of ββ--Cell FunctionCell Function

β-Cell

Hyperglycemia(Glucose Toxicity)

ProteinGlycation

AmyloidDeposition

Insulin Resistance

“Lipotoxicity”Elevated FFA,TG

Interleukin 1 α and β

MultiMulti--factorial Pathogenesis of factorial Pathogenesis of Type 2 DiaType 2 Diabetesbetes

Fat Topography in Insulin Resistance

Adiponectin: IncreasesInsulin Sensitivity

Fat Topography In Insulin ResistanceFat Topography In Insulin Resistance

Hi TGHi FFA

Intramuscular

Intrahepatic

Subcutaneous

Intra-Abdominal

FFATNF αResistinLeptinIL-6 CRPTissue FactorPAI-1Angiotensinogen

Medications To Break Insulin Medications To Break Insulin Reistance: MetforminReistance: Metformin

The GoodThe GoodEfficacious (↓A1C 1.2%)Long Track Record↓ Hepatic Glucose

Production (90%)Helps Muscle Glucose

Uptake (10%)Colon Cancer Protection

Not So GoodNot So GoodGI UpsetHold For Procedures

and CT Dye LoadWatch Creat Stop If

> 1.5mg

Medications To Break Insulin Medications To Break Insulin Reistance: ThiazoladinedionesReistance: Thiazoladinediones

Efficacious (Efficacious (↓↓A1C 1.2%)A1C 1.2%)Reasonably Long Reasonably Long ExperienceExperienceNo HypoglycemiaNo Hypoglycemiaββ Cell PreservationCell Preservation

The Good:The Good:

TZDTZD’’s s

EfficaciousEfficaciousReasonably Long Reasonably Long

ExperienceExperienceNo HypoglycemiaNo Hypoglycemiaββ Cell PreservationCell Preservation

Increased CV Risk?Increased CV Risk?EdemaEdemaWeight GainWeight GainFracturesFracturesBladder CancerBladder Cancer

The Good:The Good: Not So Good Not So Good


GLPGLP--1 Modes of Action in Humans1 Modes of Action in Humans

GLPGLP--1 Is Secreted1 Is SecretedFrom the LFrom the L--cellscells

In the IntestineIn the Intestine

This in TurnThis in Turn……

Stimulates Insulin SecretionStimulates Insulin Secretion

Suppresses GlucagonSuppresses Glucagon

Slows Gastric EmptyingSlows Gastric Emptying

Reduces Food IntakeReduces Food Intake

Upon Ingestion of FoodUpon Ingestion of Food……

Drucker DJ. Curr Pharm Des 2001; 7:1399Drucker DJ. Curr Pharm Des 2001; 7:1399--14121412Drucker DJ. Mol Endocrinol 2003; 17:161Drucker DJ. Mol Endocrinol 2003; 17:161--171171

One More PointOne More PointGoing Back to Those Going Back to Those

ββ CellsCells……....

Natural History of Type 2 Natural History of Type 2 Diabetes Diabetes

050

100150200250

-10 -5 0 5 10 15 20 25 30Years of Diabetes

Glucose(mg/dL)

Relative Function

(%)

Insulin Resistance

Insulin Levelβ-Cell Failure

*IFG=impaired fasting glucose.

50100150200250300350

Fasting Glucose

Post-meal Glucose

Obesity IFG* Diabetes Uncontrolled Hyperglycemia

ββ--cell Neogenesis, cell Neogenesis, Proliferation and ApoptosisProliferation and Apoptosis

GLP-1Stimulates

Islet

Neoge

nesis

Prol

ifera

tion

Apopt

osis

Ductal Ductal Progenitor Progenitor CellsCells

GLP-1Inhibits

Gastric Emptying Gastric Emptying And Acid SecretionAnd Acid Secretion

GLPGLP--11

Kieffer, Habener. Endocr Rev 1999;20:876Kieffer, Habener. Endocr Rev 1999;20:876––913. Flint Et Al. J Clin Invest 1998;101:515913. Flint Et Al. J Clin Invest 1998;101:515––520. Wettergren Et Al. Dig Dis Sci 1993;38:665520. Wettergren Et Al. Dig Dis Sci 1993;38:665––673. 673. During Et Al. Nat Med 2003;9:1173During Et Al. Nat Med 2003;9:1173––1179. Perry Et Al. J Pharmacol Exp Ther 2002;302:8811179. Perry Et Al. J Pharmacol Exp Ther 2002;302:881––888. Perry Et Al. J. Neurosci Res 2003;72:603888. Perry Et Al. J. Neurosci Res 2003;72:603––612.612.Bose Et Al. Diabetes 2005;54:146Bose Et Al. Diabetes 2005;54:146--151. Kavianipour Et Al. Peptides 2003;24:569151. Kavianipour Et Al. Peptides 2003;24:569--578. Thrainsdottir Et Al. Diab Vasc Dis Res 2004;1:40578. Thrainsdottir Et Al. Diab Vasc Dis Res 2004;1:40--43. Nikolaidis, 43. Nikolaidis, Mankad Et Al. Circulation 2004;109:962Mankad Et Al. Circulation 2004;109:962--965. Nystrom Et Al. Am J Physiol Endocrinol Metab 2004;287:E1209965. Nystrom Et Al. Am J Physiol Endocrinol Metab 2004;287:E1209--1215. Nystrom Et Al. Regul Pept 2005;125:1731215. Nystrom Et Al. Regul Pept 2005;125:173--177. 177.

SatietySatiety

Food IntakeFood Intake

Learning And Learning And Memory Function Memory Function (Animal Studies) (Animal Studies)

GLPGLP--1: Effects On The Gastrointestinal, 1: Effects On The Gastrointestinal, Cardiac And Central Nervous SystemsCardiac And Central Nervous Systems

NeuroprotectionNeuroprotection(Animal Studies)(Animal Studies)

Protection Protection And Improved And Improved

FunctionFunction

GLPGLP--1 Modes of Action in Humans1 Modes of Action in Humans

GLPGLP--1 Is Secreted1 Is SecretedFrom the LFrom the L--cellscells

In the IntestineIn the Intestine

This in TurnThis in Turn……

Stimulates Insulin SecretionStimulates Insulin Secretion

Suppresses GlucagonSuppresses Glucagon

Slows Gastric EmptyingSlows Gastric Emptying

Long Term EffectsLong Term EffectsDemonstrated in AnimalsDemonstrated in Animals……

Increases Increases ββ Cell Mass & EfficiencyCell Mass & Efficiency

Reduces Food IntakeReduces Food Intake

Upon Ingestion of FoodUpon Ingestion of Food……

Drucker DJ. Curr Pharm Des 2001; 7:1399Drucker DJ. Curr Pharm Des 2001; 7:1399--14121412Drucker DJ. Mol Endocrinol 2003; 17:161Drucker DJ. Mol Endocrinol 2003; 17:161--171171

*

*

**

* * *

*** **

* **

** * *

GLP-1GLP-1 GLP-1GLP-1GLP-1GLP-1

Glucose Dependent Effects of GLP-1Type 2 Diabetics (n=10)Type 2 Diabetics (n=10)

Mean (se) <p.05 Nautack MA Diabetelogia 1983

GLPGLP--1 Effect : Blocked By DPP1 Effect : Blocked By DPP--44

GLP-1 ActionsGLP-1 Actions

Mixed Meal

GLP-1(7-36)Active

Plasma

IntestinalGLP-1

Secretion

GLP-1(9-36)Inactive

DPP-IV

Rapid Inactivation

Renal ClearanceDeacon et al. Diabetes 1995; 44:1126

GLP-1: Rapidly Degraded by DPP-4

GLPGLP--1: Rapidly Degraded by 1: Rapidly Degraded by DPPDPP--44

Mentlein, R Regulatory Peptides 85:9-24, 1999

Secreted GLPSecreted GLP--1 Rapidly Degraded1 Rapidly Degraded

Enhance GLPEnhance GLP--1 Effect By1 Effect By……

GLPGLP--1 RECEPTOR AGONISTS1 RECEPTOR AGONISTS

Exenatide Exenatide (Byetta/Bydureon) (Byetta/Bydureon) scsc

Liraglutide Liraglutide (Victoza) (Victoza) scsc

Lixisenatide scLixisenatide sc

GLP-1 MimeticsThe Good:The Good:

Efficacious Efficacious ((↓↓A1C 1.2A1C 1.2--1.5%)1.5%)Decrease PostDecrease Post--Prandial GlucosePrandial GlucoseNo HypoglycemiaNo HypoglycemiaPotential For Weight LossPotential For Weight LossPerhaps Perhaps ßß Cell PreservationCell Preservation

The Not So Good:The Not So Good:Daily/Twice Daily/Weekly InjectionDaily/Twice Daily/Weekly Injection

GI UpsetGI UpsetRare Reports Of PancreatitisRare Reports Of Pancreatitis

Cost Cost

GLPGLP--1 Effect : Blocked By DPP1 Effect : Blocked By DPP--44

GLP-1 ActionsGLPGLP--1 Actions1 Actions

Mixed MealMixed Meal

GLPGLP--1(71(7--36)36)ActiveActive

PlasmaPlasma

IntestinalIntestinalGLPGLP--11

SecretionSecretion

GLP-1(9-36)Inactive

DPPDPP--44

Rapid Inactivation

Renal Renal ClearanceClearance

Deacon Deacon et al.et al. Diabetes 1995; 44:1126Diabetes 1995; 44:1126

GLP-1 Agonists

DPP 4 DPP 4 InhibitorsInhibitors

X

Enhance GLPEnhance GLP--1 Effect By1 Effect By……

GLPGLP--1 RECEPTOR 1 RECEPTOR AGONISTSAGONISTS

Exenatide scExenatide sc(Byetta/Bydureon)(Byetta/Bydureon)

Liraglutide scLiraglutide sc(Victoza)(Victoza)

Lixisenatide scLixisenatide sc

DPPDPP--4 INHIBITORS4 INHIBITORS

Sitagliptin poSitagliptin po(Januvia)(Januvia)

Saxagliptin poSaxagliptin po(Onglyza)(Onglyza)

Linagliptin po Linagliptin po (Tradjenta)(Tradjenta)

Alogliptin poAlogliptin po(Nesina) (Nesina)

DPP-4 InhibitorsThe Good:The Good:

Efficacious (Efficacious (↓↓A1C 0.7%)A1C 0.7%)Decrease PostDecrease Post--Prandial GlucosePrandial GlucoseNo HypoglycemiaNo HypoglycemiaWeight NeutralWeight NeutralSafe In Renal DiseaseSafe In Renal DiseaseNo GI UpsetNo GI UpsetPerhaps Perhaps ßß Cell PreservationCell Preservation

The Not So Good:The Not So Good:CostCost

Rare Reports Of PancreatitisRare Reports Of Pancreatitis


Carbohydrate absorption

αα Glucosidase InhibitorsGlucosidase Inhibitors

Efficacious (Efficacious (↓↓A1C 0.6%)A1C 0.6%)Long ExperienceLong ExperienceNo HypoglycemiaNo HypoglycemiaNo Weight GainNo Weight Gain

Not So Good Not So Good Dosing With MealsDosing With MealsGI IntoleranceGI Intolerance

GoodGood


Dopamine Receptor AgonistsDopamine Receptor Agonists

Type 2 Diabetics Have Low Levels Of Type 2 Diabetics Have Low Levels Of Brain DopamineBrain Dopamine

Quick Release Bromocriptine Increases Quick Release Bromocriptine Increases Brain Dopamine LevelsBrain Dopamine Levels

Lower Posterior Hypothalamus

Mag

nitu

de o

f Inh

ibito

ryR

espo

nse

(%)

0

4

8

Obese/DM Lean

P<0.01

Tim

e to

Max

Inhi

bito

ryR

espo

nse

(min

)

0

4

8

Obese/DM Lean

P<0.0112

Matsuda M, et al. Diabetes. 1999;48:1801-1806.

Altered Hypothalamic Function in Response to Altered Hypothalamic Function in Response to Glucose Ingestion in Obese and DM HumansGlucose Ingestion in Obese and DM Humans

Bromocriptine MesylateBromocriptine Mesylate : Proposed : Proposed Mechanism Of Action Mechanism Of Action

Morning administration(within 2 hoursof waking) of Cycloset

Corrects Restoration of morning peak in dopaminergic activity (via D2 receptor-mediated activity)

Decreased postprandial glucose levelsReduction in insulin resistance

Day-long reduction in plasma glucose, TGs and FFAs

Sympathetic toneHPA axis toneHepatic gluconeogenesisFFA and TGInsulin resistanceInflammation/hypercoagulation

Low dopaminergic tone in hypothalamus in early morning in diabetes

Sympathetic toneHPA axis toneHepatic gluconeogenesisFFA and TGInsulin resistanceInflammation/hypercoagulation

Impaired glucose metabolism, hyperglycemia and insulin resistance

Adverse cardiovascular pathology

Fonseca. Use of Dopamine agonists in TypeFonseca. Use of Dopamine agonists in Type--22--Diabetes. Oxford American Pocket Cards. OUP, 2010Diabetes. Oxford American Pocket Cards. OUP, 2010Cincotta. Hypothalamic role in Insulin Resistance and insulin RCincotta. Hypothalamic role in Insulin Resistance and insulin Resistance Syndrome. Frontiers in Animal Diabetes Research Seriesesistance Syndrome. Frontiers in Animal Diabetes Research Series. . Taylor and Francis, Eds Hansen, B Shafrir, E London, pp 271Taylor and Francis, Eds Hansen, B Shafrir, E London, pp 271--312, 2002312, 2002

Quick Release BromocriptineThe GoodThe Good

Efficacious (Efficacious (↓↓A1C 0.6%)A1C 0.6%)Resets Hypothalamic Circadian ClockResets Hypothalamic Circadian ClockSurprisingly Good CV ProfileSurprisingly Good CV Profile

Not So GoodNot So GoodHypotensionHypotensionShort Track RecordShort Track RecordCostCost

MultiMulti--factorial Pathogenesis of factorial Pathogenesis of Type 2 DiabetesType 2 Diabetes

SodiumSodium--Glucose Transport InhibitorsGlucose Transport Inhibitors(SGLT(SGLT’’s)s)

Inhibit SodiumInhibit Sodium--Glucose Glucose CoCo--TransporterTransporter--2 Located In Segment S1 Of 2 Located In Segment S1 Of

Proximal Tubule Of The NephronProximal Tubule Of The Nephron

This Transporter Reabsorbs Most Glucose This Transporter Reabsorbs Most Glucose Filtered By The GlomerulusFiltered By The Glomerulus

SGLT1SGLT1

(180 L/day) (900 mg/L)=162 g/day(180 L/day) (900 mg/L)=162 g/day

10%10%

GlucoseGlucose

No GlucoseNo Glucose

S1S1

S3S3

Renal Handling of GlucoseRenal Handling of Glucose

SGLT2SGLT2

90%90%

CanaglifozinCanaglifozin

Selective Inhibitor Of SGLT2Selective Inhibitor Of SGLT2

Inhibits Renal Glucose Reabsorption, Inhibits Renal Glucose Reabsorption, Promotes Glucose ExcretionPromotes Glucose Excretion

Decreases Hyperglycemia In Insulin Decreases Hyperglycemia In Insulin Independent MannerIndependent Manner

CanaglifozinCanaglifozin

The GoodThe GoodEfficacious (Efficacious (↓↓A1C 1.0%)A1C 1.0%)Inhibits Glucose Reabsorption At Renal LevelInhibits Glucose Reabsorption At Renal LevelWeight ReductionWeight ReductionNo Drug InteractionsNo Drug Interactions

Not So GoodNot So GoodIncreased UTIIncreased UTI’’s/Vaginitiss/VaginitisShort Track RecordShort Track RecordCostCost

Combination Pills for Type 2 Combination Pills for Type 2 DiabetesDiabetes

Glyburide/Metformin (Glucovance)Glyburide/Metformin (Glucovance)Glipizide/Metformin (Metaglip)Glipizide/Metformin (Metaglip)

Sitagliptin/Metformin (Janumet)Sitagliptin/Metformin (Janumet)Saxaglitin/Metformin (Kombiglyze)Saxaglitin/Metformin (Kombiglyze)Tradjenta/Metformin (Jentadueto)Tradjenta/Metformin (Jentadueto)

AntiAnti--Hyperglycemic Monotherapy:Hyperglycemic Monotherapy:Maximum Therapeutic Effect on A1CMaximum Therapeutic Effect on A1C

Insulin

Precose [PI]. West Haven, CT: Bayer; 2003; Aronoff S, et al. Diabetes Care. 2000;23:1605–1611; Garber AJ, et al. Am J Med. 1997;102:491–497; Goldberg RB, et al. Diabetes Care. 1996;19:849–856; Hanefeld M, et al. Diabetes Care. 2000;23:202–207; Lebovitz HE, et al. J Clin Endocrinol Metab. 2001;86:280–288; Simonson DC, et al. Diabetes Care. 1997;20:597–606; Wolfenbuttel BH, van Haeften TW. Drugs. 1995;50:263–288; Nelson P, et al. Diabetes Technol Ther. 2007;9:317–326. Garber AJ, et al. ADA 2008; 07–LB.

-0.50 -1.0 -1.5 -2.0Reduction in A1C Level (%)

Metformin

Nateglinide

Glipizide GITSGlimepiride

Pioglitazone

Acarbose

Exena/Liragluide

Sita/Saxa//linagliptin

SGLT’sQR Bromocriptine

A Basic Principle: A Basic Principle:

Fix The Fasting FirstFix The Fasting First

Physiologic Insulin Secretion :Physiologic Insulin Secretion :Basal/Bolus ConceptBasal/Bolus Concept

Breakfast Lunch Supper

Insu

lin(µ

U/m

L)G

luco

se(m

g/dL

)

Basal Glucose

150

100

50

07 8 9 101112 1 2 3 4 5 6 7 8 9

A.M. P.M.Time of Day

Basal Insulin

50

25

0

Prandial Glucose

Prandial Insulin

Suppresses Glucose Production Between Meals & Overnight

Basal Basal ≅≅ 50% of Daily Needs50% of Daily Needs

Basal InsulinsBasal Insulins

NNeutral eutral PProtamine rotamine HHagedorn (1946)agedorn (1946)

Glargine (2001)Glargine (2001)

Detemir (2006)Detemir (2006)

Degludec (2013)Degludec (2013)

Starting Basal InsulinStarting Basal Insulin

Continue Oral Agent(s) at Same Dosage Continue Oral Agent(s) at Same Dosage (Eventually Reduce)(Eventually Reduce)

Add Single Insulin Dose (~ 15 units)Add Single Insulin Dose (~ 15 units)Glargine (Anytime)Glargine (Anytime)Increase Insulin Dose 1 unit Daily Until Increase Insulin Dose 1 unit Daily Until FBS<100 mg &/or HbA1C < 7%FBS<100 mg &/or HbA1C < 7%

Suggested Titration Options Suggested Titration Options For GlargineFor Glargine

1.1. Gerstein HC et al. Gerstein HC et al. Diabet MedDiabet Med. 2006;23:736. 2006;23:736--742.742.2.2. Riddle MC et al. Riddle MC et al. Diabetes CareDiabetes Care. 2003;26:3080. 2003;26:3080--3086.3086.

Start with 10Start with 10--15 units15 units basal insulin and adjust weeklybasal insulin and adjust weekly2*2*

Mean of selfMean of self--monitored FPG values monitored FPG values from preceding 2 daysfrom preceding 2 days

Increase in insulin Increase in insulin dosedose(IU/d)(IU/d)

≥≥180 mg/dL180 mg/dL +8+8140140--179 mg/dL179 mg/dL +6+6120120--139 mg/dL139 mg/dL +4+4100100--119 mg/dL119 mg/dL +2+2

Increase by 1 unit daily until FBS Increase by 1 unit daily until FBS ≤≤ 100mg/dl 100mg/dl

REPEATREPEAT

OrOr

Insulin Pens Insulin Pens

More Convenient Than Vial And Syringe More Convenient Than Vial And Syringe Repeatedly More Accurate Dosages Repeatedly More Accurate Dosages Easier To Use For Those With Visual Or Fine Easier To Use For Those With Visual Or Fine Motor Skills Impairments Motor Skills Impairments Less Injection Pain Less Injection Pain

Coated Needles Not Dulled By Insertion Into A Vial Coated Needles Not Dulled By Insertion Into A Vial Before Insertion Into The Skin Before Insertion Into The Skin

Natural History of Type 2 Natural History of Type 2 DiabetesDiabetes

005050

100100150150200200250250

--1010 --55 00 55 1010 1515 2020 2525 3030Years of DiabetesYears of Diabetes

GlucoseGlucose(mg/dL)(mg/dL)

Relative Relative FunctionFunction

(%)(%)

Insulin ResistanceInsulin Resistance

Insulin LevelInsulin Levelββ--Cell FailureCell Failure

*IFG=impaired fasting glucose.*IFG=impaired fasting glucose.

5050100100150150200200250250300300350350

Fasting Fasting GlucoseGlucose

PostPost--meal meal GlucoseGlucose

Obesity IFGObesity IFG** Diabetes Uncontrolled HyperglycemiaDiabetes Uncontrolled Hyperglycemia

€€

Glucose PatternsGlucose Patternsin Type 2 Diabetes Mellitusin Type 2 Diabetes Mellitus

Plas

ma

Glu

cose

(mg/

dL)

200

120

00600 1200

Time of Day1800 2400 0600

150

250

50

GlucoseBasal InsulinRapid Acting Insulin

30 units

~10 units

Continue SU/Tide/DPP-4 Inhibitor, Metformin, TZD

Currently AvailableCurrently AvailableBolus InsulinsBolus Insulins

Regular (1921)Regular (1921)Insulin Lispro (1996)Insulin Lispro (1996)Insulin Aspart (2000)Insulin Aspart (2000)

Insulin Glulisine (2006)Insulin Glulisine (2006)

Dosing Prandial Insulin

Considerations For Initial DosingConsiderations For Initial Dosing11--33

55--10 u/meal 10 u/meal OR 0.1 OR 0.1 -- 0.15 u/kg/meal0.15 u/kg/mealUse Glargine Dose As A Guide Use Glargine Dose As A Guide 30% At Breakfast, 30% At Breakfast, 30% Lunch, 40% Dinner30% Lunch, 40% Dinner

Considerations For Dosing AdjustmentsConsiderations For Dosing Adjustments11--33

Variable Meal Dosing To Adjust For Carbohydrate IntakeVariable Meal Dosing To Adjust For Carbohydrate IntakeSupplemental Dosing To Correct For BG Before Meals Supplemental Dosing To Correct For BG Before Meals

1.1. Mooradian AD et al. Mooradian AD et al. Ann Intern MedAnn Intern Med. 2006;145:125. 2006;145:125--134.134.2.2. Dailey GE. Dailey GE. J Fam PractJ Fam Pract. 2007;56:735. 2007;56:735--742.742.3.3. Leahy JL. Leahy JL. Am J Med SciAm J Med Sci. 2006;332:24. 2006;332:24––31. 31.

Fine Tuning The BolusFine Tuning The Bolus

The Bolus Has 2 Components:The Bolus Has 2 Components:PrandialPrandial→→

Fine Tune By Carbohydrate CountingFine Tune By Carbohydrate CountingCorrection FactorCorrection Factor →→

Adjustment For PreAdjustment For Pre--Meal Meal HyperglycemiaHyperglycemia


Plas

ma

Glu

cose

(mg/

dL)

200

120

00600 1200

Time of Day1800 2400 0600

150

250

50

GlucoseBasal InsulinRapid Acting Insulin

30 units

~10 units~10 units~10 units

Discontinue SU/Tide/DPP-4 Inhibitor; Continue Metformin, TZD


58 Year Old Journalist58 Year Old JournalistType 2 DM Just DiagnosedType 2 DM Just DiagnosedHbA1C 7.1%HbA1C 7.1%Metformin StartedMetformin Started


58 Year Old Journalist58 Year Old JournalistType 2 DM Just DiagnosedType 2 DM Just DiagnosedOn Metformin On Metformin Hb A1C 6.2%Hb A1C 6.2%

3 Months Later3 Months Later


61 Year Old Journalist61 Year Old JournalistType 2 DM x 4 YearsType 2 DM x 4 YearsOn Metformin On Metformin Hb A1C 8.2%Hb A1C 8.2%

4 Years Later4 Years Later

Decisions, DecisionsDecisions, Decisions……

Failure On 1 Failure On 1 Oral AgentsOral Agents

Add 2nd Oral Add 2nd Oral AgentAgent

Add InsulinAdd Insulin

Add GLPAdd GLP--1 1 AgentAgent


61 Year Old Journalist61 Year Old JournalistType 2 DM X 4 YearsType 2 DM X 4 YearsOn Metformin On Metformin Hb A1C 8.2%Hb A1C 8.2%Second Oral Agent AddedSecond Oral Agent Added


61 Year Old Journalist61 Year Old JournalistType 2 DM x 4 YearsType 2 DM x 4 YearsOn Metformin + Second Oral On Metformin + Second Oral

AgentAgentHb A1C 6.9%Hb A1C 6.9%




AgentAgentHbA1C 8.9%HbA1C 8.9%

2 Year Later2 Year Later

What To Do If/When What To Do If/When Two Oral Agents Are Two Oral Agents Are

Not Enough?Not Enough?

Decisions, DecisionsDecisions, Decisions……

Failure On 2 Failure On 2 Oral AgentsOral Agents

Add 3rd Oral Add 3rd Oral AgentAgent

Add InsulinAdd Insulin

Add GLPAdd GLP--1 1 AgentAgent

Change in Body WeightChange in Body Weight

* *

Weeks0 2 4 8 12 18 26

-6

-4

-2

0

2

4

6

* ** *

Change in Body Weight

(lbs)

ExenatideInsulin Glargine

+4.0 lbs

-5.1 lbs

ITT sample shown; Mean ± SE shown* p<0.0001, exenatide vs insulin glargine at same time point

Heine, R. J. et. al. Ann Intern Med 2005;143:559-569

Overall Incidence of Adverse Events Occurring in at Least 2% of Treated Patients



AgentAgentHb A1C 8.9%Hb A1C 8.9%Basal Insulin AddedBasal Insulin Added



Agent + Basal InsulinAgent + Basal InsulinHbA1C 6.9%HbA1C 6.9%



64 Year Old Journalist64 Year Old JournalistType 2 DM x 9 YearsType 2 DM x 9 YearsOn Metformin + Second Oral Agent + On Metformin + Second Oral Agent +

Basal InsulinBasal InsulinHbA1C 7.8%HbA1C 7.8% With Fasting Sugars With Fasting Sugars Between 100 and 110 mg%Between 100 and 110 mg%


WhatWhat’’s Going On?s Going On?

Postprandial Postprandial Glucose Must Be Glucose Must Be

ElevatedElevated

Natural History of Type 2 Diabetes Natural History of Type 2 Diabetes

050

100150200250

-10 -5 0 5 10 15 20 25 30Years of Diabetes

Glucose(mg/dL)

Relative Function

(%)

Insulin Resistance

Insulin Levelβ-Cell Failure

*IFG=impaired fasting glucose.

50100150200250300350

Fasting Glucose

Post-meal Glucose

Obesity IFG* Diabetes Uncontrolled Hyperglycemia

€

Bolus InsulinBolus Insulin

Add Rapid Acting Insulin For Add Rapid Acting Insulin For Mealtime CoverageMealtime Coverage

Rule Of Thumb For Glargine:Rule Of Thumb For Glargine:50% Basal 50% Basal

50% Prandial, Divided Over 3 Meals 50% Prandial, Divided Over 3 Meals


Plas

ma

Glu

cose

(mg/

dL)

200

120

00600 1200

Time of Day1800 2400 0600

150

250

50

GlucoseBasal InsulinRapid Acting Insulin Lispro/Aspart/Glulisin

30 units

~10 units

Continue SU/GLP-1 Agonsit/DPP-4 Inhibitor, Metformin, TZD


64 Year Old Journalist64 Year Old JournalistType 2 DM x 9 YearsType 2 DM x 9 YearsOn Metformin + Second Oral Agent + On Metformin + Second Oral Agent +

Basal Insulin + 1 Shot Bolus InsulinBasal Insulin + 1 Shot Bolus InsulinHbA1C 6.7%HbA1C 6.7%



66 Year Old Journalist66 Year Old JournalistType 2 DM X 11 YearsType 2 DM X 11 YearsOn Metformin + Second Oral Agent + On Metformin + Second Oral Agent +

Basal Insulin + 1 Shot Bolus InsulinBasal Insulin + 1 Shot Bolus InsulinHb A1C 8.8%Hb A1C 8.8%



Plas

ma

Glu

cose

(mg/

dL)

200

120

00600 1200

Time of Day1800 2400 0600

150

250

50

GlucoseBasal InsulinRapid Acting InsulinLispro/Aspart/Glulisin

30 units

~10 units~10 units~10 units

Discontinue SU/GLP-1 Agent/DPP-4 Inhibitor; Continue Metformin, TZD


66 Year Old Journalist66 Year Old JournalistType 2 DM x 11 YearsType 2 DM x 11 YearsOn Metformin + Basal Insulin + On Metformin + Basal Insulin +

Bolus Insulin Before Each MealBolus Insulin Before Each MealHbA1C 6.9%HbA1C 6.9%

Finally, For Your Larger Patients….

Extreme Insulin ResistanceExtreme Insulin Resistance> 200 units/day> 200 units/day Consider Using Consider Using

U500U500

5 Times As Concentrated5 Times As Concentrated------> 500 units/ml> 500 units/mlDosed BID or TID Dosed BID or TID Cost SavingsCost Savings

DonDon’’t Forget The ABCst Forget The ABCs

AA = Aspirin = Aspirin (if over age 50)(if over age 50)

BB = Blood Pressure = Blood Pressure CC = Cholesterol= Cholesterol

SBP <140SBP <140SBP <130 If Can Achieve Without Undue SBP <130 If Can Achieve Without Undue

Treatment Burden, Such As Younger Pts. Treatment Burden, Such As Younger Pts.

DBP <80DBP <80

Of Note, Suggest That At Least One AntiOf Note, Suggest That At Least One Anti--hypertensive Be Administered At Bedtimehypertensive Be Administered At Bedtime

BP Goals:BP Goals:

Goal LDL<100 If No Overt CVD

Goal LDL<70 If CVD Or > 40 With One Or More CVD Risk Factor (Fam Hx, HTN, Smoking, Albuminuria)

HDL > 40 and TG <150 Desirable However LDL Targeted Statin Therapy However LDL Targeted Statin Therapy Is Preferred StrategyIs Preferred Strategy

Lipid Goals:Lipid Goals:

Combination Therapy Provides No Additional CVD Benefit Over Statin And Is Not Recommended

If Goal LDL Not Reached On Max Tolerated Statin, Treat To Goal Of 30-

40% Reduction In LDL From Baseline

Lipids: Statins Trump Other MedsLipids: Statins Trump Other Meds

Screening Asymptomatic Patients Not Recommended

β-Blocker For At Least 2 Years After MI

Metformin May Be Used In Patients With Stable Compensated CHF If Renal Function Normal; Avoid If Unstable CHF Or Hospitalized

Coronary DiseaseCoronary Disease

Documents

Achieving Optimal Control In Type 2 DiabetesAchieving Optimal Control In Type 2 Diabetes Case Study ¬58 Year Old Journalist58 Year Old Journalist ¬Type 2 DM Just DiagnosedType 2