diabetes 2013: achieving goals through comprehensive ... · nonfatal mi: 24% (p = .004) vadt 1,791...

Diabetes 2013: Achieving GoalsThrough Comprehensive Treatment

Session 2: Individualizing Therapy

Joshua L. Cohen, M.D., F.A.C.P.

Professor of Medicine

Interim Director, Division of Endocrinology &Metabolism

The George Washington University School ofMedicine

Session 2 Agenda• Diabetes treatment guidelines

» Standardized evaluation and treatment recommendations

» Establishing individualized treatment goals

» Review of major classes of oral agents

» Initial pharmacologic therapy and stepwise intensification

• Incretin-based therapy

» Incretin physiology

» GLP-1 analogues

» DPP-4 inhibitors

• Intensifying insulin therapy

» Implementation of basal bolus therapy

» Combined insulin – GLP-1 therapy

STANDARDS OF MEDICAL CAREIN DIABETES—2013

Supplement 1

January 2013

Treatment of Type 2 Diabetes:Lifestyle Intervention

• Diabetes education Knowledge about: disease process, potential

risks, treatments, glucose monitoring, self-care

• Weight loss

• Nutrition

• Exercise

• Stop smoking

• Patients on multiple-dose insulin (MDI) or insulinpump therapy should do SMBG

At least prior to meals and snacks

Occasionally post-prandially

At bedtime

Prior to exercise

When they suspect low blood glucose

After treating low blood glucose until they arenormoglycemic

Prior to critical tasks such as driving

Recommendations:Glucose Monitoring (1)

Diabetes Care 2013;36(suppl 1):S17.

• When prescribed as part of a broader educationalcontext, SMBG results may be helpful to guidetreatment decisions and/or patient self-management for patients using less frequentinsulin injections or noninsulin therapies

• When prescribing SMBG, ensure that patientsreceive ongoing instruction and regular evaluationof SMBG technique and SMBG results, as well astheir ability to use SMBG data to adjust therapy

Recommendations:Glucose Monitoring (2)

• Advise people with diabetes to perform at least150 min/week of moderate-intensity aerobicphysical activity (50–70% of maximum heart rate),spread over at least 3 days per week with no morethan 2 consecutive days without exercise

• In absence of contraindications, adults with type 2diabetes should be encouraged to performresistance training at least twice per week

Recommendations: Physical Activity

Recommendations:

Blood Pressure Measure at each visit

Dilated eye exam At diagnosis. Initially annually, then every 2-3 years after normal exam

Foot exam Annually

Examination

Laboratory Evaluation

A1C Twice yearly for patients meeting treatment goalson stable therapy

Lipids Yearly

Creatinine Yearly

Urine albumin Yearly (spot urine albumin:creatinine ratio)

Guidelines for Blood Pressure & Lipid Control

Blood pressure < 130/80 mmHg

Lipids

LDL: < 100 mg/dL (2.59 mmol/l)

< 70 mg/dL (1.81 mmol/l) (with overt CVD)

HDL: > 40 mg/dL (1.04 mmol/l) Men

> 50 mg/dL (1.30 mmol/l)Women

TG: < 150 mg/dL (1.69 mmol/l)

Statin therapy regardless of baseline lipids forpatients with overt CVD or multiple risk factors

ADA. Diabetes Care. 2013;36 (Suppl 1):S11-66

CHD Screening and Treatment

• Routine CAD screening notrecommended in asymptomatic patients

If CVD risk factors are treated, CADscreening does not improve outcomes


• Consider aspirin therapy (75–162 mg/day) As a primary prevention strategy in those with

type 1 or type 2 diabetes at increasedcardiovascular risk (10-year risk >10%)

Includes most men >50 years of age orwomen >60 years of age who have at leastone additional major risk factorFamily history of CVDHypertensionSmokingDyslipidemiaAlbuminuria

Recommendations:Antiplatelet Agents (1)


• Aspirin should not be recommended for CVDprevention for adults with diabetes at low CVDrisk, since potential adverse effects frombleeding likely offset potential benefits

10-year CVD risk <5%: men <50 and women <60years of age with no major additional CVD risk factors

• In patients in these age groups with multipleother risk factors (10-year risk 5–10%), clinicaljudgment is required

Recommendations:Antiplatelet Agents (2)


• Provide influenza vaccine annually to all diabeticpatients ≥6 months of age

• Administer pneumococcal polysaccharide vaccineto all diabetic patients ≥2 years

One-time revaccination recommended for those >64years previously immunized at <65 yearsif administered >5 years ago

Other indications for repeat vaccination: nephroticsyndrome, chronic renal disease, immunocompromisedstates

Recommendations: Immunization (1)


• Administer hepatitis B vaccination to unvaccinatedadults with diabetes who are aged 19 through 59years

• Consider administering hepatitis B vaccination tounvaccinated adults with diabetes who are aged≥60 years

Recommendations: Immunization (2)

• Lowering A1C to below or around 7% has beenshown to reduce microvascular complicationsand, if implemented soon after the diagnosis ofdiabetes, is associated with long-term reductionin macrovascular disease

• Therefore, a reasonable A1C goal for many non-pregnant adults is <7%

• Plasma glucose: Pre-prandial PG <130 mg/dl (7.2 mmol/l)

Post-prandial PG <180 mg/dl (10.0 mmol/l)

Recommendations:Glycemic Goals in Adults (1)

ADA. V. Diabetes Care. Diabetes Care 2013;36(suppl 1):S19.

Mean plasma glucose

A1C (%) mg/dL mmol/L

6 126 7.0

7 154 8.6

8 183 10.2

9 212 11.8

10 240 13.4

11 269 14.9

12 298 16.5

Correlation of A1C withAverage Glucose

These estimates are based on ADAG data of ~2,700 glucose measurements over 3 months per A1Cmeasurement in 507 adults with type 1, type 2, and no diabetes. The correlation between A1C andaverage glucose was 0.92. A calculator for converting A1C results into estimated average glucose (eAG),in either mg/dL or mmol/L, is available at http://professional.diabetes.org/eAG.

• Providers might reasonably suggest more

stringent A1C goals (such as <6.5%) for

selected individual patients, if this can be

achieved without significant hypoglycemia or

other adverse effects of treatment

• Appropriate patients might include those with

short duration of diabetes, long life expectancy,

and no significant CVD


ADA. V. Diabetes Care. Diabetes Care 2013;36(suppl 1):S19.


• Less stringent A1C goals (such as <8%) may beappropriate for patients with

History of severe hypoglycemia, limited life expectancy,advanced microvascular or macrovascularcomplications, extensive comorbid conditions

Those with longstanding diabetes in whom the generalgoal is difficult to attain despite diabetes self-management education, appropriate glucosemonitoring, and effective doses of multiple glucoselowering agents including insulin

Cardiovascular Outcomes inRecent Prospective Trials

n

Knowndiabetesduration

(y)

Length oftreatment

intervention(y)

A1c differencebetween groups

Reduction ofCV Events

(CVcomposite)

ADVANCE 11,140 8 5.0 0.7% (7.3 vs 6.5) 6% (NS)

ACCORD 10,251 10 3.7 1.1% (7.5 vs 6.4) 10% (NS)Nonfatal MI:24% (p = .004)

VADT 1,791 11.5 5.6 1.5% (8.4 vs 6.9) 12% (NS)

Subsequent meta-analysis of these studies and the UKPDSshowed no significant effect of intensive glycemic control onoverall cardiovascular events or mortality, but did show asignificant 15% decrease in fatal or non-fatal MI

Glycemic Control Decision Making

Inzucchi S et al. 2012; DiabetesCare. 35:1364-1379

TargetHbA1C

Lower Higher

Selecting Anti-HyperglycemicMedications

• Efficacy

• Risk of hypoglycemia

• Weight gain

• Side effects

• Costs

• Safety concerns and contraindications

Major Distinguishing Features

Antihyperglycemic Agents:Major Sites of Action

SulfonylureasMeglitinidesNateglinide

InsulinLiver

Plasma glucose

Glitazones-Glucosidase

inhibitors

+

GI tract

Pancreas

Metformin

Muscle/Fat

–

(–) (+)

(–)

(+)

(+)

CarbohydrateAbsorption

GlucoseProduction

InsulinSecretion

GlucoseUptake

InsulinSecretion

GLP-1 agonist

DPP-4inhibitor

(–)

Kidney

Glycosuria

SGLT2inhibitor

(–)

Glucose-Lowering Therapy inType 2 Diabetes (1)

Inzucchi S et al. 2012; Diabetes Care. 35:1364-1379

Sulfonylurea

Efficacy High

Hypoglycemia Moderate risk

Weight Gain

Major side effects Hypoglycemia

Costs Low

Advantages Disadvantages

Good initial efficacy Risk of hypoglycemia

Extensive experience, widelyavailable

Weight gain

Well tolerated Possible cardiovascular riskcompared to metformin

Inexpensive

Thiazolidinedione

Efficacy High

Hypoglycemia Low risk

Weight Gain

Major side effects Fluid retention

Costs High (However, soon will be generic)

Advantages Disadvantages

Decrease manifestations of insulinresistance

Weight gain

Durable activity, may diminish rate ofdeterioration of beta cell function

Fluid retention and increased risk ofCHF

? Decrease in cardiovascular events Increased osteoporotic fractures inwomen

Safety concerns

Pioglitazone

Thiazolidinediones

• Increased risk of MI (rosiglitazone)

» Initial concerns not supported by furtherstudies

• Fluid retention and CHF

» Not associated with increased risk ofdeath, MI or stroke

• Increased risk of bone fracture in olderwomen

• Possible association betweenpioglitazone and bladder cancer

Safety Concerns

Clinical Inertia in theTreatment of Type 2 Diabetes• For patients on one oral agent with HbA1C

≥7% the median time until addition of another oral agent was 1.6 – 2.9 years

• For patients on two oral agents with HbA1C

≥7% the median time until addition of another oral agent was >6.9 years

• For patients on two or three oral agents withHbA1C ≥7.5% the median time until initiation of insulin therapy was >6 years

Khunti K, et al. Diabetes Care. 2013; 36:3411-3417

peripheralglucoseuptake

hepaticglucoseproduction

pancreaticinsulinsecretion

pancreaticglucagonsecretion

Main Pathophysiological Defects in T2DM

gutcarbohydratedelivery &absorption

incretineffect

HYPERGLYCEMIAHYPERGLYCEMIA

Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

Incretin-Based Therapy:

GLP-1 Analogs

&

DPP-4 Inhibitors

32Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-498.

The Incretin Effect: Difference inResponse to Oral vs IV Glucose

0 60 120 180

Time (min)

C-P

ep

tide

(nm

ol/L

)

Pla

sm

aG

luco

se

(mg

/dL

)

200

100

0

2.0

1.5

1.0

0.5

0.0

**

*

*

**

*

0 60 120 180

Time (min)

Oral glucose (50g)or isoglycemic infusion

IV glucose

Oral glucose

Glucagon-Like Peptide–1 (GLP-1)

Cleaved from proglucagon in intestinal L-cells and neurons inhindbrain/hypothalamus2

Rapid release from intestinal L cells in response to meals

Potentiates insulin release

Multiple biologic actions2

Rapidly degraded by protease dipeptidyl peptidase IV (DPP-4)

N-terminalregion

Helical region(7–14)

Linker region (15–17)

Helical region(18–29)

1. Image courtesy of Cyril Sarrauste de Menthière, PhD, Institute of Human Genetics, Montpellier, France (www.igh.cnrs.fr).2. Vilsbøll T, Holst JJ. Diabetologia. 2004;47:357-366.

35

The Insulinotropic Effects of Infusion ofGLP-1 and GIP in Healthy Subjects

Adapted from Vilsbøll T et al. Regul Pept. 2003;114:115–121.

0

50

100

150

200

250

Insu

lin

,p

mo

l/L

–20 30 80 130 180 230

Time, min

Insulin Concentration

0 60 90 120 150 210 240

Time, min

Fasting level6mmol/L

7mmol/L

Glucose clamp

Meal test

GLP-1 clamp

GIP clamp

N=8, healthy males

GLP-1 and GIP infusion

Plasma glucose levels duringthe 3 stepwise glucose clamps

37

• Stimulates glucose-dependent insulinrelease

• Suppresses glucose-dependent glucagonrelease

• Increases insulin gene transcription andinsulin biosynthesis

• Improves beta-cell responsiveness toglucose– Increases expression of glucose

transporter-2 (GLUT 2) and glucokinase– Decreases proinsulin to insulin ratio

• Promotes differentiation of duct progenitorcells to beta cells, inhibits apotosis of betacells

GLP-1(produced byL cells in thesmall intestine)

alpha cellsbeta cells

Incretins Improve Multiple Aspects ofIslet-Cell Function

GIP(produced byK cells in thesmall intestine) • Stimulates glucose-dependent insulin release

Drucker DJ. Molecular Endocrinology. 2003;17:161–171. Orskov C et al. Endocrinology. 1988;123:2009–2013Farilla L et al. Endocrinology. 2002;143;4397–4408. Quddusi S et al. Diabetes Care. 2003;26:791–798Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441. Stumvoll M et al. J Clin Endocrinol Metab.

2001;86:1235–1239.

39

Time, minIR

Ins

uli

n,

mU

/L

nm

ol/L

0.6

0.5

0.4

0.3

0.2

0.1

0

80

60

40

20

0

18060 1200

The Incretin Effect in Subjects Withoutand With Type 2 Diabetes

Control Subjects(n=8)

Patients With Type 2 Diabetes(n=14)

Time, min

IRIn

su

lin

,m

U/L

nm

ol

/L

0.6

0.5

0.4

0.3

0.2

0.1

0

80

60

40

20

0

18060 1200

Oral glucose load

Intravenous (IV) glucose infusion

IncretinEffect

The incretin effectis diminished

in type 2 diabetes.

Adapted with permission from Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag.

Continuous GLP-1 Infusion inPatients with Diabetes

Rachman J, et al. Diabetologia 1997; 40:205-211

Adapted from Deacon CF, et al. Diabetes. 1995;44:1126-1131.

GLP-1 and GIP Secretion andInactivation

IntestinalGLP-1release

GLP-1 (9-36)inactive

(>80% of pool)

GLP-1 (7-36)active

Mixedmeal

DPP-4

t½ = 1 to 2 min

DPP-4: Dipeptidyl peptidase 4

Incretin Pharmacotherapy

• GLP-1 has a very short half-life andtherefore is not suitable forpharmacologic therapy

• Approaches to therapeutic use ofincretins:

GLP-1 agonists resistant to DPP-4

DPP-4 inhibition to extend the half-life ofendogenous GLP-1

Effect of Exenatide on FastingPlasma Glucose and Insulin in

Type 2 Diabetes

Kolterman OG, et al. J Clin Endocrinol Metab 2003; 88:3082-3089

-1 0 1 2 3 4 5 6 7 8

InsulinGlucose

-1 0 1 2 3 4 5 6 7 85

7.5

10

12.5

15

0

50

100

150

200

250

300

Mean

(SE

)P

lasm

aG

luco

se

(mm

ol/

L)

Mean

(SE

)S

eru

mIn

su

lin

(pm

ol/

L)

Time (h) Time (h)

Placebo

0.05 µg/kg exenatide



Placebo




diabetes 2013: achieving goals through comprehensive ... · nonfatal mi: 24% (p = .004) vadt 1,791...

Documents