John B. Buse, MD, PhDProfessor of Medicine

Chief, Division of EndocrinologyDirector, Diabetes Care Center

University of North CarolinaChapel Hill, NC

jbuse@med.unc.edu

Diabetes Management

CVD and Glycemia

*If A1C remains above the desired target, postprandial levels, usually measured 90–120 min after a meal, may be checked. They should be <180 mg/dl to achieve A1C levels in the target range.

†An A1C of ≥7% should serve as a call to action to initiate or change therapy with the goal of achieving an A1C level as close to the nondiabetic range as possible or, at a minimum, decreasing the A1C to 7%.

Diabetes Care 30: S4-41, 2007 (http://care.diabetesjournals.org/cgi/reprint/30/suppl_1/S4)http://www.aace.com/pub/press/releases/diabetesconsensuswhitepaper.php

Goal

Premeal plasma glucose (mg/dl)

2-h postprandial plasma glucose

HbA1c

ADA

70-130

(<180)*

<7%†

ACE

<110

<140

<6.5%

Glycemic Goals of Therapy

Recent Glycemia CVD StudiesCharacteristic ACCORD ADVANCE VADT

N 10,251 11,140 1,791

Mean age 62 66 60

Hx CVD 35% 32% 40%

BMI 32.2 28 31.3

BL mean A1C 8.3% 7.5% 9.4%

BL meds 34% Ins/1.4 OAD 1% Ins/1.5 OAD 51% Ins/??

Statin use 62% 88% 28% 47% 58% 84%

Antiplatelet use 54.5% 75.5% 48% 62% 76% 93%

Study duration 3.4 5.0 6.0

Target A1C <6% vs 7-8% <6.5% vs “Usual” <6% vs 8-9%

Achieved mean A1C 6.5% and 7.5% 6.3% and 7.0% 6.9% and 8.4%

LDL at end 91 102 75

BP at end 127 / 67 136 / 74 127 / 69

Smokers at end 9.9% 8% 17%

Skyler J, et al. Diabetes Care. 2009; 32:187-92.

*P=0.04

Summary: Glucose Lowering on CVD in Type 2 Diabetes

VADT ACCORD ADVANCE

Primary outcome

Non-fatal MINon-fatal stroke

CVD deathHospitalization for CHF

Revascularization

Non-fatal MINon-fatal stroke

CVD death

Non-fatal MINon-fatal stroke

CVD death

Hazard Ratio forprimary outcome

(95% CI)0.87 (0.73 – 1.04) 0.90 (0.78 – 1.04) 0.94 (0.84 – 1.06)

Hazard Ratio for mortality (95% CI)

1.07 (0.80 – 1.42) 1.22 (1.01 – 1.46)* 0.93 (0.83 – 1.06)

ACCORD Treatment Effect onPrimary Outcome

2525

00

2020

1515

1010

55

0011 22 33 44 55

Standard therapyStandard therapy

Intensive therapyIntensive therapy

Pat

ien

ts w

ith

eve

nts

%

Pat

ien

ts w

ith

eve

nts

%

Time (yrs)Time (yrs)

HR=0.90 (0.78-HR=0.90 (0.78-1.04), P=0.161.04), P=0.16

2.29%/yr2.29%/yr2.11%/yr2.11%/yr

ACCORD Study Group ACCORD Study Group N Engl J Med N Engl J Med 358:2545-59; 2008358:2545-59; 2008

66

Protocol Defined N Events Interaction P-value Subgroups Overall 10251 723

Primary Prevention 6643 330 0.04 Secondary Prevention 3608 393

Women 3952 212 0.74 Men 6299 511

Baseline Age<65 6779 383 0.65 Baseline Age≥65 3472 340

Baseline A1C≤8.0 4868 284 0.03 Baseline A1C>8.0 5360 438 Non-White 3647 222 0.29 White 6604 501

ACCORD: Hazard Ratios for Primary Outcome by Subgroup

0.6 1.0 1.4HR (Intensive vs. Standard)

ACCORD Study Group ACCORD Study Group N Engl J Med N Engl J Med 358:2545-59;2008.358:2545-59;2008.

A1C

(%

)

YearDCCT

11

10

9

8

7

6

091 2 3 4 5 6 7 8 1 2 3 4 5 6 7DCC

T end EDIC

Conventional group encouraged to switch to intensive treatment

Adapted from: N Engl J Med 329:977–86,1993; EDIC: JAMA 287: 2563–9;2002

A1C During DCCT and Follow-Up

Intensive

Conventional

Cumulative Incidence of the First of Any Predefined CVD Outcomes

Years since entry

Cumulative Cumulative incidence incidence

of any CVD of any CVD outcomeoutcome

Conventional treatment

Intensive treatment

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Risk reduction 42%, CI - 9,63

Log-rank p = 0.016

nonfatal MI, stoke, death from cardiovascular disease, confirmed angina, or the need for coronary-artery revascularization

Fatal MI, CVA, or CVD death ↓57%DCCT/EDIC Study Research Group, N Engl J Med 2005; 353:2643-53.

After median 8.8 years post-trial follow-up

Aggregate Endpoint 1997 2007

Any diabetes related endpoint RRR: 12% 9% P: 0.029 0.040

Microvascular disease RRR: 25% 24% P: 0.009 0.001

Myocardial infarction RRR: 16% 15% P: 0.052 0.014

All-cause mortality RRR: 6% 13% P: 0.44 0.007

UKPDS: “Legacy Effect”of Insulin/Sulfonylurea Therapy

RRR = Relative Risk Reduction P = Log Rank

Holman RR, et al. New England Journal of Medicine 2008; 359:1577-1589

6.0

6.5

7.0

7.5

8.0

8.5

9.0

9.5

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

TIME (yrs since diagnosis)

A1C (%)

Drive the risk for complications

Drive the risk for complications

Build up “bad” metabolic memory

Build up “bad” metabolic memory

The “Natural History” of Type 2 Diabetes

12

• Lowering A1C to below or around 7% has been shown

to reduce microvascular and neuropathic complications

of type 1 and type 2 diabetes. Therefore, for

microvascular disease prevention, the A1C goal for non-

pregnant adults in general is <7%. (A)

ADA – AHA – ACCRevised Glycemic Control Recommendations

ADA/AHA/ACC. Diabetes Care. 2009; 32:187-92.

13

ADA – AHA – ACCRevised Glycemic Control Recommendations

• In type 1 and type 2 diabetes, randomized controlled trials of intensive vs. standard glycemic control have not shown a significant reduction in CVD outcomes during the randomized portion of the trials. Long-term follow-up of the DCCT and UKPDS cohorts suggests that treatment to A1C targets below or around 7% in the years soon after the diagnosis of diabetes is associated with long-term reduction in risk of macrovascular disease. Until more evidence becomes available, the general goal of <7% appears reasonable for many adults for macrovascular risk reduction. (B)

ADA/AHA/ACC. Diabetes Care. 2009; 32:187-92.

14

• Subgroup analyses of clinical trials such as the DCCT and UKPDS, and the microvascular evidence from the ADVANCE trial, suggest a small but incremental benefit in microvascular outcomes with A1C values closer to normal. Therefore, for selected individual patients, providers might reasonably suggest even lower A1C goals than the general goal of <7%, if this can be achieved without significant hypoglycemia or other adverse effects of treatment. Such patients might include those with short duration of diabetes, long life expectancy, and no significant cardiovascular disease. (B)

ADA – AHA – ACCRevised Glycemic Control Recommendations

ADA/AHA/ACC. Diabetes Care. 2009; 32:187-92.

15

• Conversely, less stringent A1C goals than the general goal of <7% may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, and those with longstanding diabetes in whom the general goal is difficult to attain despite diabetes self-management education, appropriate glucose monitoring, and effective doses of multiple glucose lowering agents including insulin. (C)

ADA – AHA – ACCRevised Glycemic Control Recommendations

ADA/AHA/ACC. Diabetes Care. 2009; 32:187-92.

Risk of Death over a Range of Average A1c

Average A1c %

Adjusted log(Hazard Ratio) by Treatment StrategyRelative to Standard at A1c of 6%

Standard strategy

6 8 97

Steady increase of risk from 6 to 9% A1c with intensive strategy

Excess risk with intensive strategy vs standard occurred above A1c 7%

Intensive strategy

Rates of Death During 3.4 Years of Treatmentover a Range of 1-year Change of A1c

A1c decline from baseline over 12 months (%)0.0 0.5 1.0 1.5 2.0

Intensive strategy

Standard strategy

Dea

th r

ates

per

yea

r

Excess risk with intensive strategy vs standard occurredwhen intensive participants failed to reduce A1c in year 1

Adjusted Mortality Rates by Treatment Strategy

The Algorithm

Screen, Diagnose, Treat

Screening Triggers for Prediabetes and Type 2 Diabetes

Preferred screening test is a venous FPG Screen all individuals aged ≥ 45 years; if normal, repeat at 3-year intervals Consider earlier and more frequent screening in individuals who are

overweight (BMI ≥ 25 kg/m2) with additional risk factors:– Habitual physical inactivity

– First-degree relative with diabetes

– Members of a high-risk ethnic population (eg, African American, Latino, Native American, Asian American, Pacific Islander)

– History of delivering a baby weighing > 9 lbs and/or GDM

– Hypertension (≥ 140/90 mm Hg)

– HDL-C < 35 mg/dL and/or triglyceride level > 250 mg/dL

– Polycystic ovarian syndrome

– History of IGT or IFG

– Other conditions associated with insulin resistance (eg, acanthosis nigricans)

– History of vascular disease

American Diabetes Association. Diabetes Care. 2008;31(suppl 1):S12-S54.

ADA and WHO Glucose Tolerance Categories

Fasting PlasmaGlucose

Normal

2-hr Plasma Glucose on OGTT

Diabetes Mellitus

* Diagnosis of DM can also be made based on unequivocal symptoms and a random glucose >200 mg/dL. Any abnormality should be repeated and confirmed on a separate day.

“Pre-Diabetes”100

mg/dL

Impaired Fasting

Glucose (IFG)

Normal

Diabetes Mellitus

Impaired Glucose

Tolerance (IGT)

126 mg/dL

200 mg/dL

140 mg/dL

Glucose is NOT a Standardized Analyte CAP survey for glucose “120-170 mg/dL”, mean 144 mg/dl*

– In order for an institution to be considered “proficient”, results should deviate by no more than 12 mg/dL or 20% from the peer group

– Inter-laboratory CV is 15.1%- Variability in part due to differences between instruments- CVs for individual instruments range from 3.9-10.9%

– Bottom line, depending on the type of device used, the mean glucose measurement for a particular sample reported by CAP certifiable institutions varies across an approximately 30% range

– In comparison, this is ~5% for many other analytes

*Dungan K, et al. Diabetes Care 30: 403-409, 2007.

NGSP Standardizationof the HbA1c Assay

7.0

8.0

9.0

10.0

11.0

12.0

13.0

14.0

15.0

16.0

17.0

18.0

19.0

20.0

21.0

%G

HB

1993 2007

Total GHB

HbA1

HbA1c

CAP Survey: Mean +/- 2sd

DCCTTarget

20011999

NGSPCertified

Not Certified

NGSP Certified

Not Certified

NGSP Certified Not Certified

©2007 David M. Nathan

CAP = College of American Pathologists

HbA1c assay to be standardized worldwide using the new IFCC standard and expressed as:

Consensus StatementIFCC, EASD, IDF, ADA

All clinical guidelines should be expressed in these units

• % as currently used (DCCT values)

• IFCC units in mmol/mol

• eAG (estimated average glucose) in mg/dL

Diabetes Care 30:2399-2400, 2007

ADA Expert Committee, 1997

ADA Expert Committee on Diagnosis, 1997Relation of FPG, 2hPG, HbA1c to Retinopathy: Egypt

The HbA1c assay is standardized and aligned to DCCT/UKPDS

Better index of overall glycemic exposure

Equivalent in predicting risk for long-term complications

Predicts CVD

Substantially less laboratory variability

Substantially less pre-analytic instability

No need for fasting or timed samples

Unaffected by acute (e.g. stress or illness-related) perturbations in glucose levels

Used to guide management and adjust therapy

HbA1c Advantages Compared with FPG, OGTT

Laboratory

► Expense

► Not universally available

Patient-related: determinants in addition to glycemia

► Hemoglobinopathies

► Variation in red cell lifespan (hemolysis, blood loss, etc.)

► Unexplained racial differences

Not useful as acute measure

Selecting a diagnostic cut point

► On what basis?

► Will not always agree with diagnoses by FPG or OGTT

► Break with the past

HbA1c: Limitations

2-hr PG (n=237)10%

HbA1c (n=182)7%

FPG (n=165)7%

73

221

1837

17

125

None = 2142Any = 293 (12%)Total = 2435

Numbers of people with HbA1c ≥ 6.5%, FPG ≥ 126 mg/dl, or 2hPG ≥ 200 mg/dl.

2435 adult Pima Indians without previous dx.

Study Subjects InterventionRelative Risk

Reduction

DaQingFinnish DPSUS DPP

IGTIGT

IGT + “IFG”

Diet or Exercise or BothLifestyleLifestyle

64%/53%/61%IGTIGT

US DPPSTOP-NIDDMEDITTRIPODXENDOSDREAMACT-NOWORIGINNAVIGATOR

IGT + “IFG”IGTIFG

Prior GDMIGTIGTIGT

IFG or IGTIGT+IFG

MetforminAcarbose

Metformin or Acarbose or BothTroglitazone

OrlistatRosiglitazone or Ramipril or Both

PioglitazoneGlargine or Fish oil or Both

Nateglinide or Valsartan or Both

31%25%NS

35%45%

61%/NS81%

~2010 ~2009

Prevention of Type 2 DiabetesB

ehav

ior

Med

icat

ion

Li et al., Lancet 2008;371:1783-1789. ADA Position Statement on the Prevention or Delay of Type 2 Diabetes. Diabetes Care. 2002;25:742-749. Torgerson JS, et al. Diabetes Care. 2004;27:155-161. DREAM Trial Investigators. Lancet. 2006;368:1096-1105. DREAM Trial Investigators. N Engl J Med. 2006;355:1551-1562. DeFronzo RA, et al. ADA 68th Scientific Sessions 2008. Origin Trial Investigators. Am Heart J 2008;155:26-32.

Lifestyle therapy can be very effective in preventing or delaying diabetes

The lifestyle therapy that works involves three core features– Balanced low-calorie nutrition:

- low fat, high in fiber (vegetables, fruits, whole grains)– Regular physical activity:

- aerobic and resistance, 30+ minutes most days of the week– Frequent intervention with dietitians and lifestyle coaches:

- ~weekly for first month- ~monthly for the first three months- ~every three months for life

Prevention Of Type 2 Diabetes: Completed Lifestyle Trials In IGT

Key Points

Study Subjects InterventionRelative Risk

Reduction

DaQingFinnish DPSUS DPP

IGTIGT

IGT + “IFG”

Diet or Exercise or BothLifestyleLifestyle

64%/53%/61%IGTIGT

US DPPSTOP-NIDDMEDITTRIPODXENDOSDREAMACT-NOWORIGINNAVIGATOR

IGT + “IFG”IGTIFG

Prior GDMIGTIGTIGT

IFG or IGTIGT+IFG

MetforminAcarbose

Metformin or Acarbose or BothTroglitazone

OrlistatRosiglitazone or Ramipril or Both

PioglitazoneGlargine or Fish oil or Both

Nateglinide or Valsartan or Both

31%25%NS

35%45%

61%/NS81%

~2010 ~2009

Prevention of Type 2 DiabetesB

ehav

ior

Med

icat

ion

Li et al., Lancet 2008;371:1783-1789. ADA Position Statement on the Prevention or Delay of Type 2 Diabetes. Diabetes Care. 2002;25:742-749. Torgerson JS, et al. Diabetes Care. 2004;27:155-161. DREAM Trial Investigators. Lancet. 2006;368:1096-1105. DREAM Trial Investigators. N Engl J Med. 2006;355:1551-1562. DeFronzo RA, et al. ADA 68th Scientific Sessions 2008. Origin Trial Investigators. Am Heart J 2008;155:26-32.

NO

T F

DA

AP

PR

OV

ED

FO

R P

RE

VE

NT

ION

NO

T F

DA

AP

PR

OV

ED

FO

R P

RE

VE

NT

ION

Screening and Diagnosis: Intervention and Follow-Up

Screen for Diabetes:FPGor

2-hour, 75-g OGTT

American Diabetes Association. Diabetes Care. 2009;32(suppl 1):S13-S61.

Normal

Re-evaluate in ≤3 years if risk factors remain

Diabetes

Lifestyle intervention plus metformin; follow-up† @ 3 mo.

• Diabetes: fasting ≥126 mg/dl or 2-hour ≥200 mg/dl; should be confirmed on a separate day unless unequivocally elevated and/or symptomatic

IFG and IGT + Other Features*

Lifestyle intervention and/or metformin; follow-up† @ 6 mo.

* “Other features”: < 60 years of age and BMI ≥ 30 kg/m2 and either A1C > 6.0%, hypertension, low HDL, high triglycerides or family history of diabetes in first-degree relative

• IFG: fasting (8 hours) plasma glucose 100-125 mg/dL• IGT: 2-hour value in 75-g OGTT 140-199 mg/dL

Lifestyle intervention;follow-up† @ 1 year

IFG or IGT

† Follow-up here refers to formal reassesment of glycemic status. Follow-up should be individualized with respect to venue, frequency and goals.

METFORMIN IS NOT FDA APPROVED FOR PREVENTION

Updated ADA/EASD Consensus Algorithm

Nathan DM, et al., Diabetes Care 2008;31:1-11.

At Diagnosis:Lifestyle

+Metformin Lifestyle + Metformin

+Sulfonylureaa

Lifestyle + Metformin+

Basal Insulin

Lifestyle + Metformin+

Intensive Insulin

Lifestyle + Metformin+

Pioglitazone

Lifestyle + Metformin+

GLP-1 agonistb

Lifestyle + Metformin+

Basal Insulin

Lifestyle + Metformin+

Pioglitazone+

Sulfonylureaa

STEP 1 STEP 2 STEP 3

Tier 2: Less well-validated therapies

Tier 1: Well-validated therapies

Reinforce lifestyle interventions at every visit and check A1C every three months until A1C < 7.0 %, then at least every 6 months thereafter. Change interventions whenever A1C ≥ 7.0 %. aSulfonylureas other than glybenclamide (glyburide) or chlorpropamide. bInsufficient clinical use to be confident regarding safety.

0.75 1.25 1.5 1.751.0

1.4 FDA: all ischemic events, no CI given

Hazard Ratio

1.43 Nissen meta-analysis: MI

1.64Nissen meta-analysis: CV death

1.31 GSK analysis:CV death, MI, stroke

1.16RECORD: MI

Psaty/Furberg (RECORD, ADOPT, DREAM, all small trials): MI 1.33

FDA: CV death, MI, stroke1.2

FDA-PIO meta-analysis0.75

PROactive 2°0.84

0.83

FDA-PIO meta-analysis + PROactive

Adapted from: Lincoff AM, et al. JAMA. 2007;298:1180-1188; Singh S, et al. JAMA. 2007;298:1189-1195.

PROactive 1° 0.90

Hazard Ratio for Cardiovascular Events Rosiglitazone vs Pioglitazone

Kahn SE, et al. Diabetes Care. 2008;31:845-851.

Fractures in Women Treated With Glitazones

ClassA1C

ReductionFastingvs PPG

Hypo-glycemia

WeightChange

Dosing(times/day)

OutcomeStudies

Metformin 1.5 Fasting No Neutral 2 UKPDS

Insulin, long acting 1.5 - 2.5 Fasting Yes Gain 1, Injected DIGAMI, UKPDS, (DCCT)

Insulin, rapid acting 1.5 - 2.5 PPG Yes Gain 1-4, Injected DIGAMI, UKPDS, (DCCT)

Sulfonylureas 1.5 Fasting Yes Gain 1 UKPDS

Thiazolidinediones 0.5 - 1.4 Fasting No Gain 1 PROactive, RECORD

GLP-1 agonists 0.5 - 1.0 PPG No Loss 2, Injected None

Repaglinide 1 - 1.5 Both Yes Gain 3 None

Nateglinide 0.5 - 0.8 PPG Rare Gain 3 NAVIGATOR Pending

α-Glucosidase inhibitor 0.5 - 0.8 PPG No Neutral 3 ACE pending

Amylin mimetics 0.5 - 1.0 PPG No Loss 3, Injected None

DPP-4 inhibitors 0.6 - 0.8 Both No Neutral 1 TECOS pending

Bile acid sequestrant 0.5 Fasting No Neutral 1-2 None

Bromocriptine 0.7 PPG No Neutral 1 None

Adapted from: Nathan DM, et al. Diabetes Care. 2007;30:753-759. Nathan DM, et al. Diabetes Care. 2006;29:1963-1972. Nathan DM, et al. Diabetes Care. 2009;32:193-203. ADA. Diabetes Care. 2008;31:S12-S54. WelChol PI. 1/2008. Cycloset PI. 5/2009.

13 Classes of Antihyperglycemic Agents Available for Treatment of Type 2 Diabetes

Suggested Treatment Goals in Patients with CMR and Lipoprotein Abnormalities

 

Goals

LDL cholesterol

Non-HDL cholesterol ApoB

(mg/dl)

Highest-risk patients, including those with 1) known CVD or 2) diabetes plus one or more additional major CVD risk factor

<70 <100 <80

High-risk patients, including those with 1) no diabetes or known clinical CVD but two or more additional major CVD risk factors or 2) diabetes but no other major CVD risk factors

<100 <130 <90

Other major risk factors (beyond dyslipoproteinemia) include smoking, hypertension, and family history of premature CAD.

Brunzell JD, et al. Diabetes Care 31:811-822, 2008

Effectiveness of Aspirin in Diabetes

PatientsExperiencing

CardiovascularEvents

(%)

* * Physician’s Health Study, NEJM 1989† Antiplatelet Trialists’ Collaboration, BMJ 1994‡ Early Treatment Diabetes Retinopathy Study, JAMA 1992

25

20

15

10

5

0

10%

Placebo ASA

4%

22%

Placebo ASA

18%

Placebo

12%

ASA

9%

US MDs* APT† ETDRS‡

RR .39p = ns

RR .81p < 0.002

RR .83p = 0.004

Improvement In Key Clinical Measures

% of Adult Patients with% of Adult Patients with

26.7

51.6

56.4

33.8

15.8

44.1

10.9

55.1

7.5

45.3

74.1

64.1

61.2

83.8

75.4

0 20 40 60 80 100

LDL Control (<100 mg dl)

LDL Control (<130 mg dl)

BP Control (< 140/90 mm Hg)

Good A1C Control (<7.0%)

Poor A1C Control* (>9.0%)

1999 2002 2005

``

* Lower is better for this measure.* Lower is better for this measure.

Gaede P. Gaede P. N Engl J MedN Engl J Med 2008; 2008; 358: 580-591

STENO -2 Multi-Risk Factor Intervention in Type 2 DM

STENO -2 Multi-Risk Factor Intervention in Type 2 DM

Intensive group end results: A1C 7.7%, BP 140/74, LDL 71 mg/dL, HDL 51 mg/dl, TG 99 mg/dL, aspirin 85%

Room for Improvement in Therapy Implementation and Change

A1C (%) BP (mm Hg) LDL (mg/dL)

>8 >9 >130 >160>140/90 >150/100

<50% of Patients With A1C Above Goal had Their Medication Changed

Even Lower Percentage of Patients Whose CV Goals Were not Met had Medication Started

% of Patients

N=1765 Patients With Diabetes

*P<.05 for A1C and LDL (P values are derived from Mantel-Haenszel test for trend).Grant RW, et al. Diabetes Care. 2005;28:337-442.

Rates of Medical Regimen Change in 30 US Academic Medical Centers

>7 >1000

10

20

30

40

50

60

70

80

90

100

>130/80