Type 2 Diabetes MellitusType 2 Diabetes MellitusTreating to TargetTreating to Target

January 22, 2004.

Dr. William Harper

Endocrinology & Metabolism

Assisstant Professor of Medicine

McMaster University

www.drharper.ca

Macrovascular Microvascular

Stroke

Heart disease and hypertension

2-4 X increased risk

Foot problems

Diabetic eye disease(retinopathy and cataracts)

Renal disease

Peripheral Neuropathy

Peripheral vascular disease

Diabetes: ComplicationsDiabetes: Complications

Meltzer et al. CMAJ 1998;20(Suppl 8):S1-S29.

Complications

Erectile Dysfunction

Disease Burden of Diabetes MellitusDisease Burden of Diabetes Mellitus

• Leading cause of blindness (12.5% of cases)• Leading cause of ESRD (42% of cases)• 50% of all non-traumatic amputations• 2.5x increase risk of stroke• 2-4x increase in cardiovascular mortality• DM responsible for 25% of cardiac surgeries• Mortality in DM: 70% due to Cardiovascular

disease

Haffner et al, NEJM, 339(4):229-34, 1998.Haffner et al, NEJM, 339(4):229-34, 1998.

Evans et al.Evans et al.

BMJ 324: 939-942 April 2002 Cross-sectional study

DM 1155 patients MI 1347 patients

Cohort study DM 3477 patients MI 7414 patients

How is CAD Different in Diabetics ?How is CAD Different in Diabetics ?

> CAD extent Multi-vessel disease Distal disease – more difficult to revascularize

Silent ischemia/MIYoungerWomenWorse outcomes despite revascularization

Increased re-stenosis after PCI even with stents ACB: worse periop & long-term outcomes

T2DM: “Rx to Targets”T2DM: “Rx to Targets”What are the targets?

What are the targets?What are the targets?

Cardiovascular risk factor modification ASA, Smoking Cessation Lipids Blood Pressure

• Proteinuria/DM nephropathy• Angiotensin II attenuation benefits independent of BP

Glycemic control Microvascular benefit Macrovascular benefit ? Target insulin resistance > insulin deficiency ?

Canadian Lipid Working Group:Canadian Lipid Working Group:Target Levels in DiabetesTarget Levels in Diabetes

Canadian recommendations place patients with diabetes in “very high” risk group for CAD

LDL TC/HDL ratio TG

< 2.5 mmol/L < 4 < 2.0

mmol/L

Statins effective in lowering LDL1

Fibrates are useful for raising HDL, lowering TG1,2

Some OHA may improve lipids, but are not indicated for lipid management3

may need to use combo or Niacin cautiously

Heart Protection Study & DMHeart Protection Study & DM n = 20,530 (3982 with Diabetes Mellitus) hi-risk patients

age 40-80, prior CAD or PVD, DM, HTN (males age > 65) Non-fasting TC > 3.5 mM

5.5 year RCT: Simvastatin 40 mg od vs placebo Mortality ARR 1.8% (NNT 56) Vascular Event ARR 5.4% (NNT 19)

– Coronary event, Stroke, Revascularisation

Benefit obtained even in low cholesterol patients: LDL baseline 2.5 mM 1.7 mM with Rx Prior LDL targets for hi-risk patients too high?

– Canadian Lipid Work Group 2.5 mM– NCEP 2.6 mM– CARE 3.2 mM

Heart Protection StudyHeart Protection Study

Lipids & DMLipids & DM

What about HDL & TG?Fibrates > Statins at HDL and TGVA-HIT, a “low HDL Study”

2531 patients (620 DM), hi-risk with prior CAD HDL < 1.0 mM, TG < 3.4 mM, LDL < 3.6 mM RCT Gemfibrozil 600 mg po bid Coronary death or MI ARR 4.4% (NNT 23) LDL 2.3-3.6 mM at baseline Not on a statin despite LDL > 2.5 mM

Lipids & DMLipids & DM

In DM patients where LDL is already adequately controlled by a statin, will the addition of a fibrate provide further benefit?

ACCORD: 10,000 patients with ½ Lipid control arm RCT: simvastatin + fenofibrate v.s. placebo Results…

What are the targets?What are the targets?

Cardiovascular risk factor modification ASA, Smoking Cessation Lipids Blood Pressure

• Proteinuria/DM nephropathy• Angiotensin II attenuation benefits independent of BP

Glycemic control Microvascular benefit Macrovascular benefit ? Target insulin resistance > insulin deficiency ?

DM: BP cntrlDM: BP cntrl

Difficult to consider BP cntrl in DM without also taking into account:

Proteinuria/DM nephropathy Cardiovascular benefit of reducing angiotensin II

action independent of BP

Renin-Angiotensin-Aldosterone AxisRenin-Angiotensin-Aldosterone Axis

Angiotensinogen(Renin substrate)

Angiotensin I Angiotensin II

Renin+

ACE

BradykininCoughRash -

Aldosterone

Na retentionK+ & H+ loss

ARB (ex. Losartan/Cozaar)

ACE-IACE-I (ex. Ramipril/Altace)

BP Trials in DM patients (some)BP Trials in DM patients (some)

UKPDSHOTALLHATLIFEHOPE

BP Trials in DM patientsBP Trials in DM patients

UKPDS atenolol = captopril at

reducing outomes

(UKPDS 39) Benefit to reducing SBP <

120 (UKPDS 36, post-hoc subgroup analysis)

Currently SBP target < 120 being assessed in BP arm of the ACCORD Study

BP Trials in DM patientsBP Trials in DM patients

UKPDS: atenolol = captopril in events HOT: felodipine, CV events with DBP < 80 ALLHAT

Chlorthalidone > lisinopril or amlodipine (less CHF) Chlorthalidone BS/diagnosis of DM

LIFE (DM substudy) 1195 patients with DM/HTN/LVH Losartan > atenolol in CV death/MI/CVA despite equivalent

BP lowering effects

HOPE: not a BP trial per se

Effect of ACE InhibitionEffect of ACE Inhibitionin Diabetesin Diabetes

HOPE StudyHOPE StudyRelative Risk Reduction of Ramipril vs. Placebo in Subjects with Diabetes

22% Myocardial infarction p = 0.01

33% Stroke p = 0.0074

37% Cardiovascular death p = 0.0001

24% Overt nephropathy p = 0.027

17% Revascularization p = 0.031

20% Heart failure p = 0.019

HOPE investigators. Lancet 2000;355:253-259.

Complications

DM > 55 yo & 1 additional CV risk factor

(HTN, microalbuminuria, current smoker, TC > 5.2 mM, HDL < 0.9 mM)

DM NephropathyDM Nephropathy

Microalbuminuria: 30-300 mg/d (20-200 ug/min)Macroalbuminuria: > 300 mg/d (> 200 ug/min)

DM Nephropathy & BPDM Nephropathy & BP

T1DM: ACE-I albumin excretion and progression to overt

nephropathy (macroalbuminuria) in patients with microalbuminuria even if BP is normal

ACE-I progression to ESRD or death in patients with overt nephropathy and serum creat > 132 uM

DM Nephropathy & BPDM Nephropathy & BP

T2DM: ACE-I & ARB progression of micro to macro albuminuria In contrast to T1DM, no demonstrated benefit of ACE-I over

other anti-HTN (ex. UKPDS 39 captopril vs atenolol) in preventing ESRD in patients with overt nephropathy

ARBs have been shown to be renal protective in T2DM with overt nephropathy:

• IDNT: irbesartan (Avapro) ESRD/death/creat 2x• RENAAL: losartan (Cozaar) creat 2x and ESRD

• Note: in both IDNT and RENAAL all ACE-I were stopped during the study

ACE-I & ARB Combination?ACE-I & ARB Combination?

STENO-2: part of a multifactorial approach (only 28% patients)

CHF Studies: CHARM: candesartan (Atacand) mortality, CHF admits, and

onset of DM Val-HeFT: valsartan (Diovan) CHF admits

CALM Study: Mogensen et.al. BMJ 2000;321:1440-1444 T2DM, HTN, microalbuminuria candesartan & lisinopril (Zestril, Prinivil) 12 wk study outcomes: BP, proteinuria

CALM StudyCALM Study

Combo Rx with candesartan & lisinopril reduced BP

Lisinopril reduced proteinuria Candesartan reduction of

proteinuria was NS either alone or in combination with lisinopril

BP Cntrl in DM: BP Cntrl in DM: CHEPCHEP guidelines guidelines

Canadian Hypertension Education Program BP target:

< 130/80 (SBP 120? (ACCORD) / HOT target DBP 80) < 125/75 Proteinuria > 1 gm/d

Initial therapy 2nd line therapy

DM with nephropathy ACE-I or ARB Addition of 1 or more of thiazide, -blocker, CCB, or

an ACE-I/ARB combo

DM without nephropathy ACE-I, ARB, or thiazide Combo of 1st line drugs or addition of -blocker and/or

CCB

What are the targets?What are the targets?

Cardiovascular risk factor modification ASA, Smoking Cessation Lipids Blood Pressure

• Proteinuria/DM nephropathy• Angiotensin II attenuation benefits independent of BP

Glycemic control Microvascular benefit Macrovascular benefit ? Target insulin resistance > insulin deficiency ?

Glycemic ControlGlycemic Control

UKPDS 33, Lancet 352:837-53, 1998.RCT of a policy of intensive BS control

FPG < 6 mM v.s. FPG < 15 mM Achieved a number of ways:

– Sulfonylurea (chlorpropamide or glibenclamide/glyburide)

– Metformin (overweight subgroup, add-on)

– Insulin (bedtime basal +/- basal/bolus regimens)

UKPDS 33: Main studyAny DM related end point: 12% RRRMicrovascular complications: 25% RRR

Reduced eye disease: retinal laser Sx (19%), cataract Sx (24%), DM retinopathy (21%)

33% RRR microalbuminuria, 74% RRR in doubling of creatinine

MI: 16% RRR (P = 0.052 NS)No mortality benefit

Glycemic Control & ComplicationsGlycemic Control & Complications

UKPDS 34: overweight metformin substudy Unlike sulfonylurea & insulin: no weight gain Any DM related end point: 32% RRR DM related death: 42% RRR All cause mortality: 36% RRR MI: 39% RRR Metformin + SU: increased mortality?

DM related 96%, All-cause 60%

Glycemic Control & MetforminGlycemic Control & Metformin

T2DM & Macrovascular diseaseT2DM & Macrovascular disease

Why no clear benefit in UKPDS to glycemic cntrl? Low CV risk patients:

UKPDS cntrl death rate: 1.2 % per year HOPE cntrl death rate: per year 2.5% per year

Unable to maintain glycemic cntrl due to limited interventions: Available: glyburide, chlorpropamide, metformin, regular insulin No newer sulfonylureas: glimepiride (Amaryl), gliclazide (diamicron) No meglitinides: repaglinide (Gluconorm), nateglinide (Starlix) No TZD’s: rosiglitazone (Avandia), pioglitazone (Actos) No insulin analogues: (Humalog, Novorapid, Lantus)

Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes

Normal Impaired glucosetolerance

Type 2 diabetes

Time

Insulinresistance

Insulinproduction

Glucoselevel

-celldysfunction

Henry. Am J Med 1998;105(1A):20S-6S.

DCCT, NEJM 329:977-86, 1993.

UKPDS 33, Lancet 352:837-53, 1998.

Traditional Therapies Do Not Traditional Therapies Do Not Influence Influence -Cell Failure-Cell Failure

cohort, median valuesoverweight patients

06

7

8

9

10

-1 0 2 4 6 8 10Years from randomisation

ChlorpropamideConventionalGlibenclamideInsulin

Metformin

HbA

1c (

%)

UKPDS 34. Lancet 1998; 352: 854-865

0

20

40

60

80

100

0 1 2 3 4 5 6 7ß

cel

l fun

ctio

n (%

)0

20

40

60

80

100

0 1 2 3 4 5 6 7

ß c

ell f

unct

ion

(%)

Years from randomisationConventional Sulphonylurea Metformin

Non obese � ObeseOverweightNon-Overweight

UKPDS 16: Diabetes 1995; 44: 1249-1258

Control Zucker Rats ROSIG Zucker Rats

12 weeks

16 weeks

Thiazolidinedione Thiazolidinedione ββ-cell preservation: -cell preservation: Animal studiesAnimal studies

GLUCOSE ABSORPTION

GLUCOSE PRODUCTION

Metformin Thiazolidinediones

MUSCLE

PERIPHERAL GLUCOSE UPTAKE Thiazolidinediones Metformin

PANCREAS

INSULIN SECRETION Sulfonylureas: Glyburide, Gliclazide, Glimepiride Non-SU Secretagogues: Repaglinide, Nateglinide

ADIPOSE TISSUELIVER

Alpha-glucosidase inhibitors

INTESTINE

Adapted from Sonnenberg, Kotchen Curr Opin Nephrol Hypertens 1998; 7:551-5.

Sites of Action of Currently Sites of Action of Currently Available Therapeutic OptionsAvailable Therapeutic Options

Drug Trade Dose Cost ODB

Glyburide Diabeta Start 1.25-5 mg od

Spit dose bid > 10mg/d

Max 10 mg bid

$14/mos Yes

Gliclazide Diamicron Start 80 mg bid

Max 160 mg bid$90/mos No

Gliclazide

MRDiamicron

MR

Start 30 mg od

Max 120 mg od$30/mos Exp Sect 8

Glimepiride Amaryl Start 1-2 mg od

Max 8 mg od$30/mos No

Repaglinide Gluconorm Start 0.5 mg tid-qid

Max 4 mg qid$45/mos Exp Sect 8

Nateglinide Starlix Start 60-120 mg tid

Max 180 mg tid$45/mos No

Metformin Glucophage Start 500 mg od-bid

Max 1000 mg bid$14/mos Yes

Pioglitazone Actos Start 15-30 mg od

Max 45 mg od$92/mos Exp Sect 8

Rosiglitazone Avandia Start 4 mg od

Max 4 mg bid$ 60/mos

$ 120/mos

Exp Sect 8

Gliclazide 2+ + 0 0 +

Glimepiride 2+ + 0 0 +

Repaglinide 1+ + 0 0 0 0 +

Nateglinide 1+ ? 0 0 0 0 +

Metformin 0 0 0 2+ + 0 -

Acarbose 0 0 0 3+ 0

Rosiglitazone 0 + + 0 0 * +

Pioglitazone 0 + + 0 0 * +

Hypoglycemia Wt. Gain Edema GI Lactic Liver Use in effects Acidosis Toxicity Renal Failure

Adapted from Lebovitz H: Endocrinol & Metab Clinics of NA; 30 (4)909-933

* Liver enzyme monitoring recommended in product monographs

Glyburide 4+ + 0 0 -

TZD adverse effectsTZD adverse effects Edema

4-5% of patients get mild-moderate edema 15% if TZD used in combo with insulin

Mild anemia (dilutional) Weight gain

Increase in subcutaneous not visceral fat

Myalgia (pioglitazone only) Myalgia 5.4% pioglitaz. versus 2.7% placebo Few patients with unexplained CK > 10x ULN

Contraindicated in class II, III and IV CHF

Contraindicated if ALT > 2.5x ULN or active liver disease

Metabolic Syndrome: Clinical DiagnosisMetabolic Syndrome: Clinical Diagnosis

Presence of any 3 of the following: Abdominal obesity (M > 102 cm, F > 88 cm) TG > 1.7 mM Low HDL (M < 1.0 mM, F < 1.3 mM) BP > 130/85 FPG > 6.1 mM

TZDs: effect on Metabolic SyndromeTZDs: effect on Metabolic Syndrome

Reduce insulin resistance/blood sugar Mild decrease in diastolic BP (2-4 mmHg) Decrease PAI-1 (reduces procoagulant state) Lipids:

– ↓TG ↑HDL (pioglitazone > rosiglitazone?)– ↓LDL (pioglitazone)– ↑LDL (rosiglitazone)

No change in ApoB so ↑ due to larger less atherogenic particle size

Decrease in carotid artery intimal-media thickness (IMT)

Targeting Insulin Resistance?Targeting Insulin Resistance?

Does targeting insulin resistance > insulin secretion reduce CV risk?

We don’t know yet! BARI-2D:

CV outomes Insulin sparing regimen (avandia, metformin)

versusInsulin providing regimen (sulfonylurea, insulin)

PPAR, RECORD, PROACTIVE TZD’s, CV outcomes

Targeting insulin Secretion?Targeting insulin Secretion?

Improve glycemic control in hi-risk patients to reduce CV risk Using novel agents to get there! ACCORD – glycemic cntrl arm HbA1c < 6 %

glimepiride, insulin glargine, (and rosiglitazone)

NAVIGATOR – nateglinide DIGAMI II - insulin ORIGIN, STREAM – insulin glargine

InsulinInsulin

Type Starts Peaks Duration

Humalog

NovoRapid

5-10 min 0.5-1hrs 3.5 hrs

Regular 30 min 2-4 hrs 6-8 hrs

NPH

Lente

1-2 hrs 6-10 hrs 16-24 hrs

Ultralente 4-6 hrs 8-24 hrs 24-36 hrs

Glargine 1.5h None Up to 24 hrs

Insulin Glargine (Lantus)Insulin Glargine (Lantus)

Substitution of glycine and arginine residues gives name “glargine” 2 arginine residues make glargine more soluble in acidic pH of injection medium

but less soluble in physilogic pH of subQ tissues Once injected, glargine precipitates leading to slower absorption Glycine substitution prevents degradation in subQ tissues

Insulin Glargine (Lantus)Insulin Glargine (Lantus)

Little to no peak effect Less hypoglycemia

Insulin Glargine (Lantus)Insulin Glargine (Lantus)

BIDS TherapyBIDS Therapy

T2DM: “Introduction to insulin”Keep on OHAsStart 0.2 U/kg SC qhs NPH or LantusIncrease by 2-4 U q4d until FBS 4-7

Putting it all togetherPutting it all together

Any evidence that a multifactorial approach (targeting glycemic cntrl, BP, lipids, proteinuria, etc.) works?

Multifactorial DM Rx: STENO-2Multifactorial DM Rx: STENO-2Jan 2003, NEJM 348:383-93RCT mimicking real life clinic160 T2DM patients with microalbuminuriaRandomized:

Conventional Rx as per National Guidelinesversus

Intensive Rx• Behaviour modification• Pharmacotherapy: targeting BS, BP, Lipids,

proteinuria, ASA (initially 2 prevention only, 1 prevention after 1999)

Multifactorial DM Rx: STENO-2Multifactorial DM Rx: STENO-2

Multifactorial DM Rx: STENO-2Multifactorial DM Rx: STENO-2

UKPDS 33, Lancet 352:837-53, 1998.

STENO-2, NEJM, 348:383-93, 2003.

DCCT, NEJM 329:977-86, 1993.

Multifactorial DM Rx: STENO-2Multifactorial DM Rx: STENO-2

Bottom Line: T2DM SurveillanceBottom Line: T2DM Surveillance

HbA1c, BP: q3mos UMALB/Creat ratio: q6mos - q1y Dilated eye exam q1-2y Feet exam at least q1y Cardiac GxT:

as indicated (symptoms, prior to new exercise regime)

Bottom Line: T2DM InterventionBottom Line: T2DM Intervention BP cntrl:

Target: < 130/80 (< 120/75 if proteinuria > 1g/d) 1st Line:

– HOPE criteria met: ACE-I, ARB if ACE-I intolerant

– No HOPE criteria: ARB 2nd Line: Thiazide 3rd Line: -blocker or DHP-CCB (Norvasc, Plendil) Combine ACE-I + ARB ? (watch K+!)

– CHF (as per CHARM or Val-HeFT)

– Overt nephropathy + HOPE criteria met

Angiotensin II blockade: Altace even if normal BP if HOPE criteria met

> 55 y & 1 CV risk factor: HTN, microalbuminuria, current smoker, TC > 5.2 mM, HDL < 0.9 mM

Bottom Line: T2DM InterventionBottom Line: T2DM Intervention Proteinuria

BP < 120/75, HbA1c < 7.0 % No HOPE: ARB HOPE Criteria met, microalbuminuria: ACE-I HOPE Criteria met, macroalbuminuria: ACE-I + ARB (watch K+!)

Lipids age > 40 or vascular disease, regardless of lipid profile Zocor 40 mg/d target LDL 2.5 mM Still hi TG, low HDL: consider gemfibrozil or niacin

• TG > 6.0-11.0 mM: risk of pancreatitis

ECASA 81 mg/d, Smoking cessation 2 prevention CAD: -blocker, ACE-I

CDA Guidelines 2003CDA Guidelines 2003www.diabetes.ca/cpg2003www.diabetes.ca/cpg2003

HbA1c FBS

Preprandial

2h Postprandial

Target < 7.0 % 4-7 mM 5-10 mM

Normal Range*

< 6.0 % 4-6 mM 5-8 mM

* “Lowering Glycemic levels towards the normal range should be considered for patients in whom it can be achieved safely.”* Awaiting results of ACCORD

Clinical assessment and initiation of nutrition and physical activity

Mild to moderate hyperglycemia (A1C <9.0%)

Overweight(BMI 25 kg/m2)

Non-overweight(BMI 25 kg/m2)

Biguanide alone or incombination with 1 of:

• insulin sensitizer*• insulin secretagogue• insulin• alpha-glucosidase inhibitor

1 or 2† antihyperglycemicagents from differentclasses

• biguanide• insulin sensitizer*• insulin secretagogue• insulin• alpha-glucosidase inhibitor

Add a drug from a different class orUse insulin alone or in combination with:

• biguanide• insulin secretagogue• insulin sensitizer*• alpha-glucosidase inhibitor

Marked hyperglycemia (A1C 9.0%)

2 antihyperglycemic agentsfrom different classes †

• biguanide• insulin sensitizer*• insulin secretagogue• insulin• alpha-glucosidase inhibitor

Basal and/orpreprandial insulin

Add an oral

antihyperglycemic agentfrom a differentclass of insulin*

Intensify insulinregimen or add

• biguanide• insulin secretagogue**• insulin sensitizer*• alpha-glucosidase inhibitor

If not at targetIf not at targetIf not at targetIf not at target

L

I

F

E

S

T

Y

L

E

Timely adjustments to and/or additions of oral antihyperglycemic agentsand/or insulin should be made to attain target A1C within 6 to 12 months

Bottom Line: T2DM InterventionBottom Line: T2DM Intervention

Glycemic control: HbA1c < 7.0 % 1st line: insulin sensitizer (no hypoglycemia)

• Metformin (UKPDS sub-study, weight-sparing, $)• Thiazolidinedione (potential pleiotrophic benefits)• Metformin + Thiazolidinedione also possible

2nd line: insulin secretagogue• elderly, CrCl ?• Amaryl, Diamicron, Gluconorm, Starlix > Glyburide

3rd line: insulin (analogues > regular)• Lantus: lower FBS, less nocturnal hypo• Humalog, Novorapid: lower postprandial BS, less hypo

The EndThe End