Treatment of Diabetes Treatment of Diabetes MellitusMellitus

ContentsContents

�� Novel therapeutic agentsNovel therapeutic agents

�� Risk factor managementRisk factor management

Novel Therapeutic AgentsNovel Therapeutic Agentsfor Diabetes Managementfor Diabetes Management

�� GLPGLP--11--based therapy for Type 2 DMbased therapy for Type 2 DM

AmylinAmylin analogs analogs �� AmylinAmylin analogs analogs

�� GlycosuricGlycosuric agentsagents

�� Inhaled insulinInhaled insulin

Some Limitations of Some Limitations of Current Diabetes Therapy Current Diabetes Therapy

�� Risk of hypoglycemiaRisk of hypoglycemia

�� Weight gainWeight gain

�� Inadequate postprandial glucose controlInadequate postprandial glucose control

Unpredictable glucose fluctuationsUnpredictable glucose fluctuations�� Unpredictable glucose fluctuationsUnpredictable glucose fluctuations

�� Progressive Progressive ββ--cell failurecell failure�� Over time, most patients will fail to maintain goal Over time, most patients will fail to maintain goal glycemiaglycemia with oral therapy for Type 2 DM.with oral therapy for Type 2 DM.

�� Daily injections… For all taking insulin!Daily injections… For all taking insulin!�� ±± insulin deferred for longinsulin deferred for long������������� �������������������� �������

Target 1: Target 1: IncretinsIncretins

�� Hormones produced by the GIT in Hormones produced by the GIT in response to incoming nutrients, and have response to incoming nutrients, and have important actions that contribute to important actions that contribute to glucose homeostasis.glucose homeostasis.glucose homeostasis.glucose homeostasis.

�� Two hormones:Two hormones:

-- Gastric inhibitory polypeptide (GIP) Gastric inhibitory polypeptide (GIP) -- GlucagonGlucagon--like peptidelike peptide--1 (GLP1 (GLP--1). 1).

In healthy individuals, (1) ingestion of food results in (2) release of gastrointestinal peptides (GLP-1 & GIP) as well as (3) pancreatic beta cell hormones (insulin and amylin). GLP-1 & amylin, in particular, have inhibitory effects on (4) gastric emptying, (5) glucagon release, and (6) appetite. (7) Following the absorption of food, GLP-1 & GIP promote insulin secretion (the incretin effect)… DM, these steps are disrupted.

• ↓ GLP-1 in type 2 DM. … ± abnormal in type 1.

How?.... How?.... IncretinIncretin TherapyTherapy

↓ glucose following meal

GLPGLP--1 Characteristics1 Characteristics

�� HalfHalf--life of life of 11--2 minutes 2 minutes due due to degradation by the to degradation by the enzyme enzyme dipeptidyldipeptidylpeptidase IV (DPPpeptidase IV (DPP--IV). IV).

For therapeutic effect:For therapeutic effect:

Continuous IVContinuous IV-- infusion of infusion of �� Continuous IVContinuous IV-- infusion of infusion of GLPGLP--1… impractical1… impractical

�� IncretinIncretin mimeticsmimetics

(GLP(GLP--1 analogs)1 analogs)

…resistant to DPP…resistant to DPP--IV. IV.

�� DPPDPP--IV inhibitors: IV inhibitors: increase increase GLPGLP--1.1.

ExenatideExenatide�� The first The first incretinincretin--related therapy related therapy

available approved for type 2 DM available approved for type 2 DM management. management.

�� Is a synthetic exendinIs a synthetic exendin--4 4 (naturally occurring peptide from (naturally occurring peptide from the saliva of the Gila Monster). the saliva of the Gila Monster).

Use:• Adjunctive: Type 2 the saliva of the Gila Monster). the saliva of the Gila Monster).

�� Binds to GLPBinds to GLP--1 receptors and 1 receptors and behaves as GLPbehaves as GLP--1. 1.

�� Resistant to DPPResistant to DPP--IV inactivation…IV inactivation…

long halflong half--life. life.

�� Suitable for twice a day Suitable for twice a day administration by subcutaneous administration by subcutaneous injection (5injection (5--10 10 µg�BID)�µg�BID)�

• Adjunctive: Type 2 DM not sufficiently controlled with oral agents. • With sulfonylurea, thiazolidinedione, or metformin(combination)

ExenatideExenatide :Pros & Cons:Pros & Cons

�� Modest A1C reductions. Modest A1C reductions.

�� Glucose dependent Glucose dependent �� ↓�hy��g ye���↓�hy��g ye���

�� Weight lossWeight loss�� BP & lipidsBP & lipids�� BP & lipidsBP & lipids

�� Major side effects are Major side effects are nausea, vomiting.nausea, vomiting.�� ↓����u ���↓����u ����e�et�g�gue��e�et�g�gue� ������

hhypoglycemia prevention!ypoglycemia prevention!

�� ?? Pancreatitis?? Pancreatitis

DPPDPP--IV InhibitorsIV Inhibitors�� can be administered orally.can be administered orally.

SitagliptinSitagliptin

�� UseUse: Type 2 DM … adjunct to diet and exercise : Type 2 DM … adjunct to diet and exercise as as monotherapymonotherapy or in combination therapy with or in combination therapy with other other antidiabeticantidiabetic agents (2agents (2ndnd/3/3rdrd agent).agent).other other antidiabeticantidiabetic agents (2agents (2ndnd/3/3rdrd agent).agent).

�� DoseDose: 100 mg once daily, : 100 mg once daily, ↓↓ for moderate to for moderate to severe renal insufficiency. severe renal insufficiency.

�� CharacteristicsCharacteristics::�� Modest glucose lowering effectiveness. Modest glucose lowering effectiveness.

�� Weight neutral.Weight neutral.

�� ↓�GI↓�GI side effects. side effects.

�� ↓�↓�risk of hypoglycemia.risk of hypoglycemia.

Where? .... GLPWhere? .... GLP--11--based Therapybased Therapy

GLPGLP--1 analogs1 analogs

�� ExenatideExenatide ((ByettaByetta))... FDA approved in 2005... FDA approved in 2005

�� LiraglutideLiraglutide (phase 3 trials)(phase 3 trials)

DPPDPP--IV inhibitorsIV inhibitors

�� SitagliptinSitagliptin (postmarking surveillance) (postmarking surveillance)

�� VildagliptinVildagliptin (phase 3 trials) (phase 3 trials)

Target 2: Target 2: AmylinAmylin�� AmylinAmylin … co… co--secreted secreted with insulin and is with insulin and is deficient in DM deficient in DM patients. patients.

How? How? How? How?

�� AmylinAmylin suppresses suppresses pancreatic glucagon pancreatic glucagon secretion, secretion, �� satiety, satiety, ↓�↓�gastric emptying, gastric emptying, no effect on insulin. no effect on insulin.

PramlintidePramlintide

�� The first injectable antidiabetic agent after insulinThe first injectable antidiabetic agent after insulin�� Amylin analog with same functions as native amylin.Amylin analog with same functions as native amylin.�� Approved for type 1 and type 2 DM only for Approved for type 1 and type 2 DM only for insulininsulin--

treatedtreated patients. patients. �� ↓↓es postprandial glycemic excursions & a modest es postprandial glycemic excursions & a modest ↓�↓���n A1C, weight loss; No hypoglycemia if alone. n A1C, weight loss; No hypoglycemia if alone.

UseUsen A1C, weight loss; No hypoglycemia if alone. n A1C, weight loss; No hypoglycemia if alone.

UseUse�� Type 1 DM… 15Type 1 DM… 15--g SC injection before each meal g SC injection before each meal → →

max. 30max. 30––60 g.60 g.�� Type 2 DM… 60Type 2 DM… 60--g SC injection before each meal g SC injection before each meal → →

max. 120 g. max. 120 g. Side effectsSide effects�� nausea and vomiting. nausea and vomiting. �� At��t��t���Rx…↓�At��t��t���Rx…↓�insulin dose to avoid hypoglycemia.insulin dose to avoid hypoglycemia.

Target 3: Renal Glucose Target 3: Renal Glucose reabsorptionreabsorption•Plasma glucose filtered by kidneys …… <1% excreted in urine. •Saturable process… Glycosuria when plasma levels exceed 180–200 mg/dL, as in DM. mg/dL, as in DM.

SGLT2 transporter… RationalSGLT2 transporter… Rational

�� Exclusively expressed in the kidney.Exclusively expressed in the kidney.

�� Responsible for most glucose Responsible for most glucose reabsorptionreabsorption. .

�� Mutations… familial renal Mutations… familial renal glucosuriaglucosuria……�� Mutations… familial renal Mutations… familial renal glucosuriaglucosuria……

(approx 10(approx 10--120 g/day)…benign. 120 g/day)…benign.

…Selective pharmacologic inhibition is unlikely to …Selective pharmacologic inhibition is unlikely to have major have major sequelaesequelae other than induction of other than induction of glucosuriaglucosuria..

�� DapagliflozinDapagliflozin, , SergliflozinSergliflozin … potent & selective … potent & selective inhibitor (>1000x over SGLT1) … inhibitor (>1000x over SGLT1) … GlycosuricGlycosuric agent.agent.

How? …. How? …. GlycosuricGlycosuric AgentsAgentsInhibition of renal reabsorption process Inhibition of renal reabsorption process

�� ↓↓the renal threshold for glucose the renal threshold for glucose ����excretionexcretion of of excess glucose in the urine excess glucose in the urine ��…�↓…�↓hyperglycemia.hyperglycemia.

�� B/c no requirement for insulinB/c no requirement for insulin secretion or insulin secretion or insulin �� B/c no requirement for insulinB/c no requirement for insulin secretion or insulin secretion or insulin action to effect glucose lowering… action to effect glucose lowering… ±± efficacious efficacious in in a wide variety of diabetic patients. a wide variety of diabetic patients.

�� Hyperglycemia per se Hyperglycemia per se →→ impair impair ββ--cell function cell function & & ↓↓insulininsulin sensitivitysensitivity in animal models…in animal models…Glucose toxicity Glucose toxicity improvement of theseimprovement of these important physiological important physiological defects defects in type 2 DM. in type 2 DM.

DapagliflozinDapagliflozin (BMS 512148)(BMS 512148)

�� 389 treatment389 treatment--naïve type 2 DMnaïve type 2 DM

�� Significant Significant glucosuriaglucosuria (51.8(51.8--85 g/day) 85 g/day)

�� a dosea dose--dependent dependent �� urinary volume urinary volume from 107mL(2.5 mg)from 107mL(2.5 mg)-- 470mL (50 mg).470mL (50 mg).

�� Only 1.4% complained of Only 1.4% complained of polyuriapolyuria, , none complained of none complained of nocturianocturia. .

�� Weight (2.5Weight (2.5--3.4 kg, Vs 1.2 kg with 3.4 kg, Vs 1.2 kg with placebo and 1.7 kg with placebo and 1.7 kg with metforminmetformin) ≈ ) ≈

A 3-month phase 2b study presented at ADA meeting, 2008

recent onset DM,

average 58 yrs

A1C 7.7-8.0%)

placebo and 1.7 kg with placebo and 1.7 kg with metforminmetformin) ≈ ) ≈ energy loss of 200energy loss of 200--300 kcal/day), 300 kcal/day),

no compensatory no compensatory �� in hunger in hunger

�� ≈ rates of bacterial UTI & relatively ≈ rates of bacterial UTI & relatively few cases of genitourinary fungal few cases of genitourinary fungal infections (most at higher doses). infections (most at higher doses).

�� �� urinary sodium … did not translate urinary sodium … did not translate into significant changes in serum into significant changes in serum sodium but may explain the slight sodium but may explain the slight drop in systolic blood pressure that drop in systolic blood pressure that was observed in this study.was observed in this study.

dapagliflozin (2.5-50 mg daily),

Placebo,

1.5 g metformin XR

Where?... Where?... GlucosuricGlucosuric agentsagentsPotentialPotential

�� +�↓�+�↓�risk for hypoglycemia, potential for weight loss. risk for hypoglycemia, potential for weight loss.

�� Will SGLT2 inhibition be added to list of drugs for Will SGLT2 inhibition be added to list of drugs for the management of people with type 2 DM?? the management of people with type 2 DM??

DapagliflozinDapagliflozin�� A Multicenter, Randomized, DoubleA Multicenter, Randomized, Double--Blind, PlaceboBlind, Placebo--

Controlled, Parallel Group, Phase 3 Trial to Evaluate the Controlled, Parallel Group, Phase 3 Trial to Evaluate the Safety and Efficacy of Safety and Efficacy of DapagliflozinDapagliflozin as as MonotherapyMonotherapy in in Subjects With Type 2 Diabetes Who Have Inadequate Subjects With Type 2 Diabetes Who Have Inadequate GlycemicGlycemic Control With Diet and Exercise…. End in Jan 2009. Control With Diet and Exercise…. End in Jan 2009.

Inhaled InsulinInhaled Insulin�� Less invasive options for insulin Rx.. Less invasive options for insulin Rx..

�� Inhaled form of rapidInhaled form of rapid--acting insulin was acting insulin was available for a short time…discontinued at available for a short time…discontinued at end of 2007 by manufacturer (end of 2007 by manufacturer (↓�↓�sales).sales).

�� In Type 1 DM…include a longerIn Type 1 DM…include a longer--acting insulin.acting insulin.�� In Type 1 DM…include a longerIn Type 1 DM…include a longer--acting insulin.acting insulin.

�� In Type 2DM… In Type 2DM… monotherapymonotherapy/ combination / combination with oral agents or longerwith oral agents or longer--acting acting insulinsinsulins. .

�� No difference Vs SC insulin in hypoglycemia, No difference Vs SC insulin in hypoglycemia, weight gain, ?? Lung cancer. weight gain, ?? Lung cancer.

�� Associated with a dry nonAssociated with a dry non--productive cough productive cough & mild non& mild non--progressive decline in PFT. progressive decline in PFT.

Summary, Novel Agents in DMSummary, Novel Agents in DM�� GLPGLP--11--based therapies based therapies

�� Control glucose, postprandial hyperglycemia while Control glucose, postprandial hyperglycemia while promoting satiety & weight management. promoting satiety & weight management.

�� AmylinAmylin analog… analog… AmylinAmylin analog… analog… �� Postprandial hyperglycemia; multiple injections. Postprandial hyperglycemia; multiple injections.

�� GlycosuricGlycosuric agentsagents… on the horizon. … on the horizon.

�� Beyond these & others being developed to Beyond these & others being developed to meet the challenges of DM epidemics, meet the challenges of DM epidemics, �� Central place of insulin in diabetes care!!Central place of insulin in diabetes care!!

�� Improvements in insulin delivery, kinetics, actionImprovements in insulin delivery, kinetics, action

CVD Risk Management in DiabetesCVD Risk Management in Diabetes

�� A cornerstone of diabetes care!!...A cornerstone of diabetes care!!... ABC ABC

AA-- A1c, A1c, BB-- Blood pressure, CBlood pressure, C-- Cholesterol Cholesterol Mg’tMg’t..

Why important?....Why important?....�� CVD major cause of morbidity & mortality in DM… CVD major cause of morbidity & mortality in DM… �� CVD major cause of morbidity & mortality in DM… CVD major cause of morbidity & mortality in DM…

75% of deaths in Type 2; leading 75% of deaths in Type 2; leading inTypeinType 1. 1.

�� DM…DM…↑↑eded risk of CVD(risk of CVD(↑↑22--4x non4x non--DM)≈ CHD patient DM)≈ CHD patient

�� DM…DM…↑↑ risk of dying when CVD is present.risk of dying when CVD is present.

�� ↑↑ burden of burden of atherogenicatherogenic risk factors in Diabetics…risk factors in Diabetics…

(obesity, hypertension, (obesity, hypertension, dyslipidemiadyslipidemia, smoking), smoking)

…. …. Insulin resistanceInsulin resistance. .

Risk factor Management in DMRisk factor Management in DM

��Screen and intervene: Screen and intervene:

Hypertension Hypertension

DyslipidemiaDyslipidemiaDyslipidemiaDyslipidemia

SmokingSmoking

ObesityObesity

AlbuminuriaAlbuminuria

CHDCHD

B…. B…. Hypertension (HTN)Hypertension (HTN)

�� ≈ 50% Type2 DM at ≈ 50% Type2 DM at DxDx. . Type1+renal…1/4 to3/4.Type1+renal…1/4 to3/4.

�� HTN����DMHTN����DM--�� progression progression to renal & CVD. to renal & CVD.

�� From 115/75 mmHg… From 115/75 mmHg… �� From 115/75 mmHg… From 115/75 mmHg… Each Each ��20mmHg systolic 20mmHg systolic & 10 mm Hg diastolic & 10 mm Hg diastolic doubles CVD events. doubles CVD events.

�� Aggressive BP mgt in Aggressive BP mgt in DMDM::-- ↓↓ any complications any complications related to DM!related to DM!

�� DxicDxic cutoff: ≥ 130/80cutoff: ≥ 130/80

UKPDS… Each 10mm Hg ↓BP• 12%↓ DM complication.• 11% ↓ MI

• 13% Microvascular Cxn.

7

8

9

10

In type 2 DM… benefits of tight BP control may be ≥ benefit of strict glycemic control!

0

1

2

3

4

5

6

7

HbA1c%>160 140 to 150 130-140 <130

<6

6 to 7

7 to 8

>8

Blood Pressure

Risk of Diabetes Complications

Hypertension in DMHypertension in DM

ADA/ AHAADA/ AHA

�� Systolic 130 Systolic 130 -- 139 mmHg/ diastolic 80139 mmHg/ diastolic 80--89 mmHg,89 mmHg,

Initial therapy… Initial therapy… nonpharmacologicnonpharmacologic methods…methods…

wweight reduction, increased consumption of fresh fruits, eight reduction, increased consumption of fresh fruits, wweight reduction, increased consumption of fresh fruits, eight reduction, increased consumption of fresh fruits, vegetables, & lowvegetables, & low--fat dairy products, exercise, sodium fat dairy products, exercise, sodium restriction, & avoidance of smoking & excess alcohol intake.restriction, & avoidance of smoking & excess alcohol intake.

After 3 After 3 mthsmths… … ±± drug Rx. drug Rx.

�� All diabetics with BP ≥ 140/90 mmHg… All diabetics with BP ≥ 140/90 mmHg… Antihypertensive drugs.Antihypertensive drugs.

Hypertension in DMHypertension in DM�� ADA, JNCADA, JNC--VII, National kidney foundationVII, National kidney foundation

�� Target BPTarget BP… 130/80 mm Hg, … 130/80 mm Hg, ±±↓↓ albuminuriaalbuminuria��

�� Multiple meds, often ≥ 3, to achieve goal BP! Multiple meds, often ≥ 3, to achieve goal BP!

�� <30%DM patients …BP controlled(western figure!<30%DM patients …BP controlled(western figure!

�� Regular BP (supine & upright)! Regular BP (supine & upright)! �� Regular BP (supine & upright)! Regular BP (supine & upright)!

�� Drug Choice:Drug Choice:�� Generally, Generally, BP controlBP control, rather than specific drug or drug , rather than specific drug or drug

class, is the principal determinant of the CV benefit!! class, is the principal determinant of the CV benefit!!

�� Choice: based upon ability to help prevent adverse CV Choice: based upon ability to help prevent adverse CV events & slow progression of renal d/se if present.events & slow progression of renal d/se if present.

�� Start with Start with ACEiACEi or ARB/ or ARB/ thiazidethiazide......then the other. then the other.

�� Second line: CCBs, Beta blockers (Second line: CCBs, Beta blockers (CarvedilolCarvedilol better).better).

HTN in DM: Clinical Trial EvidencesHTN in DM: Clinical Trial Evidences

Study Agent Outcome

ADVANCE (11,000 Type 2 DM patients)

perindopril + indapamideVs placebo

No target BP,↓ rate of major macrovascular or microvascularevents, ↓rate of CV mortality

ALLHAT (high risk with HTN)

Thiazide diuretic, Amlodipine, Lisinopril

similar protection from CHD death & nonfatal MI.Thiazides better CV outcomes;

risk with HTN) Amlodipine, Lisinopril death & nonfatal MI.Thiazides better CV outcomes;↑ metabolic Cxn

LIFE (high-risk patients with moderate HTN + LVH)

Losartan Vs Atenolol Losartan … ↓↓ CV morbidity & mortality

ACE inhibitors and ARBs protect against development of progressive nephropathy due to type 1 & 2 DM.

C…C… Lipids in DiabetesLipids in Diabetes

�� 3030--40 % DM pts…triglycerides > 200 mg/dl.40 % DM pts…triglycerides > 200 mg/dl.

�� 80% of DM pts ... LDL > 100mg/dl. 80% of DM pts ... LDL > 100mg/dl.

Features of diabetic dyslipidemia:Features of diabetic dyslipidemia:Features of diabetic dyslipidemia:Features of diabetic dyslipidemia:�� Modest Modest ↑↑ triglyceridestriglycerides

�� ↓↓ HDLHDL--C… cleared more rapidly, C… cleared more rapidly, ±± dysfunctionaldysfunctional

�� LDL… LDL… ↑↑small dense LDL particles (phenotype B).small dense LDL particles (phenotype B).

→→ ↑↑ atherogenic particles. atherogenic particles.

Diabetes Lipid Diabetes Lipid ManagmentManagment

ScreeningScreening

�� In most adult patients, measure fastingIn most adult patients, measure fasting

lipid profile at least annually.lipid profile at least annually.

�� In adult with lowIn adult with low--risk lipid values :risk lipid values :�� LDL cholesterol < 100 mg/dl, LDL cholesterol < 100 mg/dl,

�� HDL cholesterol > 50 mg/dl, HDL cholesterol > 50 mg/dl,

�� Triglycerides <150 mg/dl)Triglycerides <150 mg/dl)

�� �� ipid assessments may be repeated 2 yearly.ipid assessments may be repeated 2 yearly.

*Second-line treatment: fibric acid derivative, ezetimibe, niacin, or bile acid–binding resin.

pharmacologic treatment based on age and risk profile.

Diabetes Diabetes StatinStatin trials trials

�� HPS (DM subset)HPS (DM subset)�� 5963 DM/???5963 DM/???

�� Baseline LDLBaseline LDL--C= 127 C= 127 mg/dlmg/dl

�� ↓�1↓�1�t�t ��j���CV�eve�t�by���j���CV�eve�t�by�

33%��33%��

�� By�18%�(��eBy�18%�(��e--ex��t��g�CVD)ex��t��g�CVD)

Collaborative Atorvastatin Diabetes Collaborative Atorvastatin Diabetes Study (CARDS): Major CVD EventsStudy (CARDS): Major CVD Events

Cumulative hazard (%)

Relative risk –37%, P=0.001

Placebo (n=1,410)

Atorvastatin 10 mg/day (n=1,428)

20

15

Colhoun HM et al. Lancet. 2004;364:685-696.

Cumulative hazard (%)

Years

0 1 2 3 4 4.7 5

10

5

0

Diabetes… Lipid targetsDiabetes… Lipid targetsADA/ AHA… DM patientADA/ AHA… DM patient�� No CVD , < 40 yrs age…. No CVD , < 40 yrs age….

�� LDL < 2.6 LDL < 2.6 mmolmmol/L (100 mg//L (100 mg/dLdL))

�� HDL > 1.1 HDL > 1.1 mmolmmol/L (40 mg//L (40 mg/dLdL) in men , ) in men ,

>1.38 >1.38 mmolmmol/L (50 mg//L (50 mg/dLdL) in women) in women>1.38 >1.38 mmolmmol/L (50 mg//L (50 mg/dLdL) in women) in women

�� Triglycerides < 1.7 Triglycerides < 1.7 mmolmmol/L (150 mg//L (150 mg/dLdL). ).

�� CVD… CVD… �� LDL goal of <1.8 LDL goal of <1.8 mmolmmol/L (70 mg//L (70 mg/dLdL) as an "option" (ADA, ATP) as an "option" (ADA, ATP--III)III)

�� StatinsStatins regardless of baseline lipid. regardless of baseline lipid.

�� > 40 years + one or more other CVD risk factors. > 40 years + one or more other CVD risk factors. �� StatinsStatins regardless of baseline lipid, to regardless of baseline lipid, to ↓�↓�LDL by 30LDL by 30––40%. 40%.

�� Goal: Goal: ↓↓ 40% LDL from baseline despite max. 40% LDL from baseline despite max. statinstatin. .

DM & Lipid Lowering AgentsDM & Lipid Lowering Agents�� Combination therapy with Combination therapy with

statinstatin + + fibratefibrate or another or another agent (agent (ezetimibeezetimibe, niacin) , niacin) ±± to to reach LDL or HDL goals.reach LDL or HDL goals.

StatinStatin//fibratefibrate combinations combinations –– Side effects Side effects –– Side effects Side effects

�� FibratesFibrates … consider … consider ↓↓HDL + HDL + mild mild ��L��LDL; DL;

�� Nicotinic acid…Nicotinic acid…��HDL, >2 g/d HDL, >2 g/d ±± worsen worsen glycemicglycemic control & control & �� insulin resistance. insulin resistance.

�� StatinsStatins contraindicated in contraindicated in pregnancy!pregnancy!

Smoking CessationSmoking Cessation�� One of the most One of the most

important aspects of important aspects of therapy in diabetic therapy in diabetic smokers.smokers.

����risk of CVDrisk of CVD����risk of CVDrisk of CVD

��premature premature microvascmicrovasc..

±± role in type 2 DM role in type 2 DM developmentdevelopment

�� Stopping smoking had Stopping smoking had much greater benefit much greater benefit on survival than most on survival than most other interventions. other interventions.

Aspirin in DiabetesAspirin in DiabetesWhy?.........Why?......... Merits of daily ASA therapy in patients Merits of daily ASA therapy in patients

with with macrovascularmacrovascular disease is widely accepted.disease is widely accepted.

�� ASA for 1ry prevention in DM..Randomized studies?ASA for 1ry prevention in DM..Randomized studies?

ADA recommendations for DM patients: ADA recommendations for DM patients: �� Aspirin (75 to 162 mg/day) … for 2ry prevention with CVD history.Aspirin (75 to 162 mg/day) … for 2ry prevention with CVD history.�� Aspirin (75 to 162 mg/day) … for 2ry prevention with CVD history.Aspirin (75 to 162 mg/day) … for 2ry prevention with CVD history.

�� Aspirin (75 to 162 mg/day) … for 1ry prevention if + additional CV Aspirin (75 to 162 mg/day) … for 1ry prevention if + additional CV risk factor (risk factor (egeg, age >40 yrs, smoking, HTN, obesity, , age >40 yrs, smoking, HTN, obesity, albuminuriaalbuminuria, , ��lipidemialipidemia, or a family history of CHD)., or a family history of CHD).

�� Not recommended in < 30 yrs ..lack of evidence of benefit Not recommended in < 30 yrs ..lack of evidence of benefit

& Contraindicated in < 21 yrs . & Contraindicated in < 21 yrs .

�� ±± Other Other antiplateletantiplatelet agents…if unable to take aspirin ?agents…if unable to take aspirin ?

�� But low use in DM patients… (74 with CVD & 38% But low use in DM patients… (74 with CVD & 38% without). without).

•• To ensure the best outcomes for DM patientsTo ensure the best outcomes for DM patients

Treat Early!Treat Early!

Be Aggressive! Be Aggressive!

•• Risk factor management is a core component!Risk factor management is a core component!

Summary

SUMMARY SUMMARY

•• Risk factor management is a core component!Risk factor management is a core component!

•• PolypharmacyPolypharmacy is often needed! is often needed!

ReferencesReferences

�� Standards of Medical Care in DiabetesStandards of Medical Care in Diabetes——2008 ADA. 2008 ADA. Diabetes Care Diabetes Care 31: S1231: S12--54,200854,2008

�� Harrison’s Principles of Internal Medicine. Harrison’s Principles of Internal Medicine. 1717thth eded, 2008. , 2008. 1717 eded, 2008. , 2008.

�� UptodateUptodate 16.216.2

�� Internet sources (demonstrations, studies)Internet sources (demonstrations, studies)

Thank you!!Thank you!!Thank you!!Thank you!!