Glucose Targets for Patients with Diabetes: 2011

Irl B. Hirsch, M.D.

Professor of Medicine

University of Washington

School of Medicine

The Problem With Today’s Glycemic Guidelines

There are always caveats!

Part of the Problem:

We keep changing the

targets!

What to consider in November, 2011

Case 1

A 55-year-old man with type 1 diabetes for 51 years•20 years ago, he required laser surgery on both of his eyes•Otherwise, he has no albuminuria, minimal neuropathy, and no history of heart disease

Case 1 (cont.)

Based on this patient’s history, his A1C target should be:

A.<6.5%

B.<7.0%

C.<7.5%

D.<8.0%

E.As low as reasonable without excessive hypoglycemia

Conclusions from Studiesof Type 1 Diabetes

• Intensive control of type 1 diabetes prevents the development and reduces the progression of microvascular disease. (DCCT Research Group. N Engl J Med. 1993;329:977-986.)

• Intensive control of type 1 diabetes early in the course of disease prevents the development of macrovascular disease years later. (DCCT/EDIC Research Group. N Engl J Med. 2005;353:2643-2653.)

• The major risk of this therapy is hypoglycemia, but these episodes have no long-term cognitive consequences (DCCT/EDIC Research Group. N Engl J Med. 2007;356:1842-1852.)

Type 1 Diabetes:What Else to Consider

• The DCCT need not be extrapolated to young children or older adults with >20-25 years of type 1 diabetes.

• Glycemic goals for these populations (both growing in the United States) for primary prevention or secondary intervention of micro- or macrovascular complications are not clear and not evidence-based.

What About Type 2 Diabetes?

Type 2 Diabetes:UKPDS Intensive Therapy (Sulfonylurea/Insulin)

• Population: newly diagnosed patients with type 2 diabetes, at high risk for myocardial infarction (MI) but having little to no cardiovascular disease (CVD) when entering the study

• Microvascular disease: reduced 21-34%

(all P <0.01)• MI: reduced 16% (P = 0.052)

U.K. Prospective Diabetes Study Group. Lancet. 1998;352:837–853.

But what about the big problem of glycemic control and macrovascular disease (CAD, CVD, PVD) in long-standing type 2 diabetes?

Macrovascular Disease and Type 2 Diabetes

• About two-thirds of all people with type 2 diabetes die from CVD.

• There is major suffering and loss of productivity from microvascular disease.

• Epidemiological and prospectively followed populations show a relationship between CVD and glycemia.

• Intervention studies up until 2009 have not been as clear.

What Was the Highlight of 2008?

Knowing that Sarah Palin could see Russia from her house?

No!

• The report of FOUR LANDMARK studies to better characterize the impact of glycemic control and CVD

ADA 2008:ACCORD Versus ADVANCE

• ACCORD = Action to Control Cardiovascular Risk in Diabetes

• ADVANCE = Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation

• Both published June 12, 2008, in the New England Journal of Medicine

• Both large studies of patients with established type 2 diabetes with primary endpoint of new CVD events

VA Diabetes Trial (VADT)

• Similar study design: intensive therapy versus standard therapy

• Primary endpoint: first CVD event after randomization

• Subjects with longer durations of diabetes, more CVD, higher baseline A1C

Duckworth W, Abraira C, Moritz T, et al. N Engl J Med. 2009;360:129-139.

Differences in ACCORD/ADVANCE/VADT

Skyler JS, Bergenstal R, Bonow RO, et al. Diabetes Care. 2009;32:187-192.

Gerstein HC et al. The ACCORD Study Group. N Engl J Med. 2008;358:2545–2559.

Results of the Randomized Comparison of an Intensive Versus a Standard Glycemic Strategy

Unadjusted HR for P-valueIntensive vs. Standard (95% CI)

All-cause mortality 1.22 (1.01-1.46) 0.04

Primary endpoint:CV death, MI, stroke 0.90 (0.78-1.04) 0.16

CV death 1.35 (1.04-1.76) 0.02Non-fatal MI 0.76 (0.62-0.92) 0.004Non-fatal stroke 1.06 (0.75-1.50) 0.74

Baseline Characteristics:HR for Death with Intensive Versus Standard Strategies

for Baseline Subgroups

0 1 2 3 4

Hba1c

< 7.5

7.5 to 8.4

8.5+

Self-report History of Neuropathy

Yes

No

Aspirin Use

Yes

No

4.40% (1022)

4.09% (2200)

3.60% (1887)

4.11% (1410)

3.84% (3646)

3.83% (2771)

4.12% (2352)

4.83% (1036)

4.18% (2226)

6.14% (1857)

7.84% (1327)

4.10% (3708)

5.73% (2808)

4.14% (2320)

0.0444

0.0008

0.0309

Intensive Therapy Better Standard Therapy Better

Subgroup Standard Glycemia Intensive Glycemia Intensive to Standard Hazard Ratio Interaction P-Value% Deaths (N) % Deaths (N)

Risk of Death (all-cause) in Intensive vs. Standard Glycemia

Hazard Ratio

1 2 3 40

<7.5

7.5-8.4

≥8.5

Yes

No

Yes

No

Aspirin use

Self-report of neuropathy

A1C

Interaction P

0.044

0.0008

0.031

Calles-Escandon, Lovato LC, Simons-Morton DG, et al. Diabetes Care. 2010;33:721-727.

5-Year Outcomes After 3.7 Yrs Intensive Therapy

NEJM 2011;364:818-28

So What Can We Conclude About Hypoglycemia in ACCORD?

How in the World Do We Interpret This?

As in other trials, higher average A1C in ACCORDassociates with higher risk of death

Conclusion from EpidemiologicalAnalyses of the Whole Population

For 1% higher A1C

HOPE +12%UKPDS +14%ACCORD +22%

Riddle MC, Ambrosius WT, Brillon DJ, et al. Diabetes Care. 2010;33:983-990.

Association of Average A1C with Mortality by Strategy:Cox Proportional Hazards Model Adding Glycemic

Strategy Assignment to Other Covariates

Hazard ratio for 1% higher average A1C (95% CI)

Intensive strategy 1.66 (1.46, 1.89) P = 0.0001

Standard strategy 1.14 (0.95, 1.38) P = 0.17

Interaction between Intensive and Standard P = 0.0007

The relationships between average A1C and mortalitydiffered between treatment strategies

Riddle MC, Ambrosius WT, Brillon DJ, et al. Diabetes Care. 2010;33:983-990.

Risk of Cardiovascular Death over a Range of AverageA1C Levels for the Intensive and Standard Strategies

U-shaped curve with standard strategy

Steady increase of risk from 6 to 9% A1C with intensive strategy

6 7 8 9

Ad

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ted

lo

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azar

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Intensive Strategy

Standard Strategy

CV Death

Average A1CRiddle MC, Ambrosius WT, Brillon DJ, et al. Diabetes Care. 2010;33:983-990.

Rates of Death During 3.4 Years of Treatmentover a Range of 1-year Change of A1C

A1C decline from baseline over 12 months (%)

0.00.0 0.50.5 1.01.0 1.51.5 2.02.0

Dea

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per

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eath

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ear

Adjusted Mortality Rates by Treatment Strategy

Riddle MC, Ambrosius WT, Brillon DJ, et al. Diabetes Care. 2010;33:983-990. Excess risk with intensive vs. standard strategy occurred

when intensive participants failed to reduce A1C in year 1

• Are risks of cardiovascular death, MI, and stroke all greater with higher A1C in the whole ACCORD population?

• Are the relationships between A1C and these endpoints different for the intensive and standard strategies?

• How do cardiovascular death and non-fatal MI differ with the intensive strategy?

Questions About the Primary Composite Endpoint and Its Components

Unadjusted Adjusted for baseline, site, and post-randomization factors

CV death 1.21 (1.04-1.40) 1.19 (1.02-1.39)n = 229 P = 0.01 P = 0.0001

Non-fatal MI 1.20 (1.08-1.33) 1.20 (1.08-1.34)n = 421 P = 0.0007 P = 0.0007

Non-fatal stroke 1.23 (1.03-1.46) 1.18 (0.99-1.40) n = 128 P = 0.02 P = 0.07

Associations of Average A1C withCardiovascular Death, MI, and Stroke

Cox Proportional Hazards ModelsHazard Ratios for 1% greater value (95% CI)

Risk of each CV outcome is greater with higher average A1C

Riddle MC, Ambrosius WT, Brillon DJ, et al. Diabetes Care. 2010;33:983-990.

What Should You Take Away from This?

• An intensive glycemic treatment strategy was associated with a higher risk of death over 3.4 years of follow-up

• In the whole population, a 20-22% greater risk of death was associated with each 1% higher average A1C

• Higher risk of death with an intensive than with a standard strategy was associated with three baseline characteristics:– A1C ≥8.5%– History of neuropathy– History of aspirin use

More Take-Away Points

• The excess risk of death with intensive treatment occurred in participants:– Whose average A1C was >7%, not <7%– Who did not reduce A1C from baseline in the first

year• Relationships differed between intensive and standard

strategies; with an intensive strategy:– Risk of all-cause and cardiovascular death was

higher when average A1C was >7%– Risk of MI was lower when A1C was <7%

ADVANCE

ADVANCE Collaborative Group, et al. N Engl J Med. 2008;358:2560-2572.

ADVANCE: Primary Outcomes

ADVANCE Collaborative Group, et al. N Engl J Med. 2008;358:2560-2572.

ADVANCE: Primary Outcomes (cont.)

ADVANCE Collaborative Group, et al. N Engl J Med. 2008;358:2560-2572.

ADVANCE

ADVANCE Collaborative Group, et al. N Engl J Med. 2008;358:2560-2572.

ADVANCE: Secondary Endpoints

• All-cause mortality: P = NS• Total renal events: 11% RR with intensive,

P <0.001• Eye events: P = NS• CHF, PVD, neuropathy: P = NS

ADVANCE Collaborative Group, et al. N Engl J Med. 2008;358:2560-2572.

VADT

• 1,791 subjects; intensive versus conventional therapy; primary endpoint cardiovascular events

• Baseline A1C: 9.5%− Standard: 8.4%− Intensive: 6.9% (6 months)

Duckworth W, Abraira C, Moritz T, et al. N Engl J Med. 2009;360:129-139.

VADT: Final Results

Exploratory analyses (presented but not published) suggested that severe hypoglycemia within the past

90 days was a strong predictor of the primary outcome and of CVD mortality.

And . . .

Standard (n = 899) Intensive (n =92)

Incidence (%)

264 (33.5)

Incidence (%)

235 (29.5)

P-value 0.14

Non-significant 12% decrease in composite CVD in IT

Hazard Ratio for Primary Outcome in Intensive Arm by Duration of Diabetes

P<0.05

P = NS

P <0.05

But What About Microvascular Disease in VADT?

• Initial publication: no evidence of improvement in endpoints

• But . . . on September 3, 2009, a correction is reported in the New England Journal of Medicine– Error was discovered in the initial computer code;

actual results were different from those initially reported

– Progression from normal to microalbuminuria was significant (P = 0.04) and progression from micro- to macroalbuminuria was also significant (P = 0.03), favoring intensive therapy

As in the ADVANCE trial, the VADT showed an improvement in the primary renal outcome, despite the fact that these patients were much more advanced in their disease process than those in the UKPDS.

What This Means:

Maybe the Most Important Report from 2008

But the one that gets the least respect

UKPDS• Newly diagnosed type 2

diabetes; intensive versus conventional policy; primary report published September 1998

• Follow-up observation published October 2008

Holman RR, Paul SK, Bethel MA, Neil HA, Matthers DR. N Engl J Med. 2008;359:1565-1576.

Post-Trial Changes in A1C

UKPDS resultspresented

Mean (95%CI)

Holman RR, Paul SK, Bethel MA, Neil HA, Matthers DR. N Engl J Med. 2008;359:1565-1576.

MI Hazard RatioFatal or Non-Fatal MI or Sudden Death)

Intensive (Sulfonylurea/Insulin) Versus Conventional Glucose Control

HR (95%CI)

Holman RR, Paul SK, Bethel MA, Neil HA, Matthers DR. N Engl J Med. 2008;359:1565-1576.

After median 8.5 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: 0.0099 0.001

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

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

RRR = Relative Risk Reduction, P = Log Rank

Legacy Effect of Earlier Glucose Control

Holman RR, Paul SK, Bethel MA, Neil HA, Matthers DR. N Engl J Med. 2008;359:1565-1576.

Impact of Intensive Therapy in Diabetes Summary of Impact of Intensive Therapy in Diabetes Summary of Major Clinical TrialsMajor Clinical Trials

StudyStudy MicrovascularMicrovascular CVDCVD MortalityMortality

DCCT/EDIC DCCT/EDIC ↓↓ ↓↓ ↔↔ ↓↓ ↔↔ ↔↔

UKPDSUKPDS ↓↓ ↓↓ ↔↔ ↓↓ ↔↔ ↓↓

ACCORDACCORD ↓↓ ↔↔ ↑↑

ADVANCEADVANCE ↓↓ ↔↔ ↔↔

VADTVADT ↓↓ ↔↔ ↔↔

Long Term Follow-up Long Term Follow-up

Initial Trial Initial Trial

Big Picture Messages

• Type 1 and type 2 diabetes: early meticulous glucose control can prevent microvascular and neuropathic complications

• Type 1 and type 2 diabetes: early meticulous glucose control appears to prevent CVD many years later (“metabolic memory” and “legacy effect”)

More Big Picture Messages

• Type 2 diabetes: patients with known CVD or a long duration of diabetes may be harmed by meticulous control; although the mechanism(s) for this are not known, the leading candidate mechanism is hypoglycemia

Still More Big Picture Messages

• Type 1 diabetes: impact of glycemia on microvascular disease not present after 20-25 years (probably true for type 2 diabetes, too)

• After long duration of either type 1 or type 2 diabetes (or known CVD), it appears that blood pressure and LDL cholesterol levels better predict CVD mortality than A1C

• Impact of hypoglycemia is not consistent between populations (children <5 years of age, geriatrics, inpatients)

So, What Are the A1C Targets?

A1C TARGETS

• Several societies have published targets, but it is clearly complicated as so many factors involved, in addition to the fact A1C itself is at best a fair marker of average glycemia for an individual patient

• Our thoughts…

Most Intensive Less Intensive Least Intensive

Patient Age

Disease Duration

40 45 50 55 60 65 70 75

5 10 15 20

Other ComorbiditiesNone Few/Mild Multiple/Severe

Hypoglycemia RiskLow HighModerate

8.0%6.0% 7.0%

Established Vascular ComplicationsNone Early Micro Advanced Micro

Psychosocioeconomic ConsiderationsHighly Motivated, Adherent,Knowledgeable, Excellent Self-Care Capacities, & Comprehensive Support Systems

Less motivated, Non-adherent, Limited insight,

Poor Self-Care Capacities, & Weak Support Systems

Cardiovascular

Individualizing Glycemic Targets in T2DM

Ismail-Beigi, F., et al. Ann Inter Med. 154:554-559, 2011

Ismail-Beigi, F., et al. Ann Inter Med. 154:554-559, 2011

Individualized Targets

• The available evidence, albeit limited, suggests that in younger patients with relatively recent onset of T2DM and little, if any, micro- and macrovascular complications, near-normal glycemic targets should be the standard. Here, the aim is to help prevent complications over the many years of life. In older individuals with longstanding T2DM and evidence of CVD (or multiple CVD risk factors), somewhat higher targets should be considered.

Ann Inter Med. 154:554-559, 2011

Metabolic Control: Bottom Line

Mother Nature keeps score.*

*especially early in the course of diabetes

Thank You