controversies in type 2 diabetes - scripps health · n engl j med 2008;358:2545-59. controversies...

Controversies in Type 2 Diabetes Michael W. Lee, MD

Controversies in Type 2 DiabetesControversies in Type 2 Diabetes

Michael W. Lee, M.D.Michael W. Lee, M.D.Scripps Clinic Center for Weight ManagementScripps Clinic Center for Weight Management

San Diego, CASan Diego, CA

Educational ObjectivesEducational Objectives

1. Discuss recent clinical data regarding diabetes treatment goals

2. Select appropriate therapies to help patients with type 2 diabetes meet current treatment goals


Question #1Question #1What is your target A1c for the majority of What is your target A1c for the majority of

your patients with type 2 diabetes?your patients with type 2 diabetes?

A. < 6%

B. < 6.5%

C. < 7%

D. < 7.5%

E. < 8%

Question #2Question #2What is your preferred 2What is your preferred 2ndnd line therapy for line therapy for

your patients with type 2 diabetes?your patients with type 2 diabetes?

A. Sulfonylurea

B. Thiazolidinedione

C. DPP-IV inhibitor

D. Glucagon-like peptide 1 (GLP-1) agonist

E. Insulin


Diabetes and Gestational Diabetes Trends Diabetes and Gestational Diabetes Trends Among Adults in the U.S.Among Adults in the U.S.

1990 1995

2001

Mokdad AH, Ford ES, Bowman BA, et al. Prevalence of obesity, diabetes,and other obesity-related health risk factors, 2001. JAMA 2003 Jan 1;289(1).

No Data <4% 4-6% 6-8% 8-10% >10%

Controversy #1:Controversy #1:Target A1cTarget A1c

(Action to Control Cardiovascular Risk in Diabetes)

N Engl J Med 2008;358:2545-59


ACCORD Study HypothesisACCORD Study Hypothesis

In middle aged/older people with type 2 DM at high risk for a CVD event, does a therapeutic strategy that targets an A1C < 6.0% reduce CVD event rates more than a strategy that targets an A1C between 7.0% & 7.9% (with the expectation of achieving a median level of 7.5%)?

N Engl J Med 2008;358:2545-59

ACCORD DesignACCORD Design

Multi-center, randomized, controlled, double 2x2 factorial – Glycemia and BP Trials: Open Label with Blinded

Endpoint Assessment – Lipid Trial: placebo controlled

Simvastatin ± Fenofibrate

Primary outcome:

– First occurrence of nonfatal MI or nonfatal stroke or CV death

N Engl J Med 2008;358:2545-59


Double 2 X 2 Factorial DesignDouble 2 X 2 Factorial Design

IntensiveGlycemia(A1C<6%) 5128*

StandardGlycemia

(A1C 7-7.9%)5123*

LipidStatin + Masked Study Drug

Statin + Masked Study Drug

BPIntensive(SBP<120)

Standard(SBP<140)

2765*2753*2362* 2371*

1178 1193

11781184

1374

13911370

1383

10,251*Primary analyses compare the marginals for main effects

N Engl J Med 2008;358:2545-59

ACCORD Participant EligibilityACCORD Participant Eligibility

Stable Type 2 Diabetes for 3+ months

A1C >7.5%

Age 40-79 with previous CVD events

Age 55-79 with:

– anatomical ASCVD, albuminuria, LVH OR

– > 2 additional CVD risk factors (dyslipidemia, hypertension, smoking, obesity)

BMI < 45; Cr < 1.5 mg/dL

No frequent/recent serious hypoglycemia

Able/willing to take insulin, do glucose monitoring

N Engl J Med 2008;358:2545-59


Baseline CharacteristicsBaseline Characteristics

Intensive(N = 5128)

Standard(N = 5123)

Age 62.2 62.2

Women 38.7 38.4

Median DM Duration 10 10

Previous CVD Event 35.6 34.8

White/Black 64.4/19.7 64.5/18.9

Current Smoker 14.3 13.7

Mean BMI 32.2 32.2

Mean SBP/DBP 136.2/74.8 136.5/75.0

Mean/Median A1C 8.3 / 8.1 8.3 / 8.1

Mean FG 175 176

Mean LDL / HDL 105 / 47 105 / 47

N Engl J Med 2008;358:2545-59

ACCORD ACCORD GlycemiaGlycemia FormularyFormulary

Metformin

Rosiglitazone

Glimepiride

Repaglinide

Acarbose

Glargine Insulin

Aspart Insulin

70/30, N, R Insulin

Exenatide

N Engl J Med 2008;358:2545-59


Participant FollowParticipant Follow--upup

N Engl J Med 2008;358:2545-59

Median AMedian A11C and C and InterquartileInterquartile RangesRanges

The mean difference during the trial was 1.1%

N Engl J Med 2008;358:2545-59


Primary & Secondary Outcomes Primary & Secondary Outcomes

IntensiveN (%)

StandardN (%) HR (95% CI) P

Primary 352 (6.86) 371 (7.23) 0.90 (0.78-1.04) 0.16

Secondary

Mortality 257 (5.01) 203 (3.96) 1.22 (1.01-1.46) 0.04

Nonfatal MI 186 (3.63) 235 (4.59) 0.76 (0.62-0.92) 0.004

Nonfatal Stroke 67 (1.31) 61 (1.19) 1.06 (0.75-1.50) 0.74

CVD Death 135 (2.63) 94 (1.83) 1.35 (1.04-1.76) 0.02

CHF 152 (2.96) 124 (2.42) 1.18 (0.93-1.49) 0.17

N Engl J Med 2008;358:2545-59

Primary OutcomePrimary Outcome

2.29%/yr

2.11%/yr

HR = 0.90 (0.78-1.04)P = 0.16

N Engl J Med 2008;358:2545-59


All Cause MortalityAll Cause Mortality

1.41%/yr

1.14%/yr

HR = 1.22 (1.01-1.46)P = 0.04

N Engl J Med 2008;358:2545-59

Lower A1CTargets (achieved median) <6% (6.4%) vs 7-7.9% (7.5%)

Greater use of medications:More multiple oral medsMore insulin More combination orals + insulin

70% vs 45% on 3-5 oral classes77% vs 55% on insulin62% vs 18% on 3-5 orals + insulin

More consequences of therapy:Severe hypoglycemia

Weight gain

More SAEs

10.5% vs 3.5% w/ hypoglycemia event requiring medical assistance

28% vs 14% >10 kg gain

2.2% vs 1.6% w/ non-hypo SAE

Compared with the standard strategy, Compared with the standard strategy, the intensive strategy had:the intensive strategy had:

N Engl J Med 2008;358:2545-59


In people with type 2 diabetes at high risk for CVD and an A1C of 7.5% or more, a therapeutic strategy that targeted an A1C <6% vs. 7.0-7.9% increased mortality over 3.5 years.

There was no significant effect of the glycemicintervention on reducing major cardiovascular events.

ConclusionsConclusions

N Engl J Med 2008;358:2545-59

ACCORD BP ResultsACCORD BP Results

N Engl J Med 2010;362:1575-85


ACCORD BP ResultsACCORD BP Results

In patients with type 2 diabetes at high risk for cardiovascular events, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events.

N Engl J Med 2010;362:1575-85

ACCORD Lipid ResultsACCORD Lipid Results

N Engl J Med 2010;362:1563-74


ACCORD Lipid ResultsACCORD Lipid Results

Compared with simvastatin alone, the combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke.

N Engl J Med 2010;362:1563-74

Stratton IM, et al. BMJ. 2000;321:405-412.

The Need for Tight The Need for Tight GlycemicGlycemic ControlControl

According to the United Kingdom Prospective Diabetes Study (UKPDS) 35,

every 1% drop in HbA1c resulted in:

Decrease in any diabetes-

relatedend point

Decrease in risk of

myocardial infarction

Decrease in risk of stroke

Decrease in risk of

microvasculardisease

21%14% 12%

37%


Risk

Reduction

(%)

Any Diabetes-RelatedEndpoint

UKPDS: Blood Pressure Control in Type 2 DMUKPDS: Blood Pressure Control in Type 2 DM

Effect of BP Lowering on RiskEffect of BP Lowering on Risk ofofMicro & Micro & MacrovascularMacrovascular ComplicationsComplications

UKPDS Group. UKPDS 38. BMJ. 1998;317:703-713.

Benefits of 144/82 vs 154/87

Diabetes-RelatedDeath Retinopathy Stroke

HeartFailure

-24-32 -34

-44

-56

-70

-20

0

-10

-50

-60

-30

-40

MyocardialInfarction

-21

RenalFailure

-42-47

Vision Deterioration

Benefits of Aggressive Benefits of Aggressive LDLLDL--C Lowering in DiabetesC Lowering in Diabetes

Shepherd J et al. Diabetes Care 2006. Sever PS et al. Diabetes Care 2005. HPS Collaborative Group. Lancet 2003. Colhoun HM et al. Lancet 2004.

Difference in LDL-C

(mg/dL)

Aggressive lipid-lowering

better

Aggressive lipid-loweringworse

0.026

0.036

0.001

<0.0001

0.0003

Primary event rate (%)

17.9

11.9

9.0

12.6

13.5

Control

13.8

9.2

5.8

9.4

9.3

Treatment

0.63

0.67

0.73

P

TNTDiabetes, CHD

ASCOT-LLADiabetes, HTN

CARDSDiabetes, no CVD

HPSAll diabetes

Diabetes, no CVD

*Atorvastatin 10 vs 80 mg/day†Statin vs placebo

Relative risk

0.7 0.9 10.5 1.7

0.77

22*

35†

46†

39†

39†

0.75


Summary of Treatment Goals Summary of Treatment Goals in Type 2 Diabetesin Type 2 Diabetes

Blood pressure <130/80 mmHg

LDL cholesterol <100 mg/dl (without overt CVD)

<70 mg/dl (with overt CVD)

Hemoglobin A1C ≤6.5% (AACE)

<7.0% (ADA)

Diabetes Care, Vol. 34, Suppl. 1, Jan. 2011


More stringent A1C goals?

– Short duration of diabetes

– Long life expectancy

– No significant cardiovascular disease

Diabetes Care, Vol. 34, Suppl. 1, Jan. 2011



Less stringent A1C goals?

– History of severe hypoglycemia

– Limited life expectancy

– Advanced microvascular or macrovascular

complications

– Extensive comorbid conditionsDiabetes Care, Vol. 34, Suppl. 1, Jan. 2011

~2x~2x

Mor

talit

y R

ate

(%)

Mean Glucose Value (mg/dL)

Krinsley JS. Mayo Clin Proc. 2003;78:1471-1478.

N=1826 ICU patients.

0

5

10

15

20

25

30

35

40

45

80-99 100-119 120-139 140-159 160-179 180-199 200-249 250-299 >3000

5

10

15

20

25

30

35

40

45

0

5

10

15

20

25

30

35

40

45

Hyperglycemia and Mortality in the Medical Intensive Care Unit Hyperglycemia and Mortality in the Medical Intensive Care Unit

~4x~4x~3x~3x

Controversy #2:Controversy #2:Intensive Inpatient Glucose ControlIntensive Inpatient Glucose Control


Intensive Insulin Therapy in Critically Ill Intensive Insulin Therapy in Critically Ill Patients: The Leuven Patients: The Leuven SICUSICU StudyStudy

Randomized controlled trial: 1548 patients admitted to a surgical ICU, receiving mechanical ventilation. Patients were assigned to receive either:

Conventional therapy: IV insulin only if BG >215 mg/dL

– Target BG levels: 180-200 mg/dL

– Mean daily BG: 153 mg/dL

Intensive therapy: IV insulin if BG >110 mg/dL

– Target BG levels: 80-110 mg/dL

– Mean daily BG: 103 mg/dL

Van den Berghe G, et al. N Engl J Med. 2001;345:1359-1367.

Intensive Insulin Therapy in Intensive Insulin Therapy in Critically Ill Patients: SICUCritically Ill Patients: SICU

**

**

**

**

**

**

**P P < 0.01< 0.01

Relative Risk Reduction (%)Relative Risk Reduction (%)

00 2020 4040 6060 8080

Prolonged (>14 d) ICU stayProlonged (>14 d) ICU stay

DialysisDialysis

Prolonged (>14 d) ventilationProlonged (>14 d) ventilation

Prolonged (>10 d) antibioticsProlonged (>10 d) antibiotics

BacteremiaBacteremia

MortalityMortality

Van den Berghe G, et al. N Engl J Med. 2001;345:1359-1367.


• Multicenter-multinational RCT (Australia, New Zealand, and Canada) in 6104 ICU patients, randomized to:

• Intensive, BG target: 4.5 and 6.0 mmol/L (81 - 108 mg/dL)• Conventional, BG target: < 10.0 mmol/L (180 mg/dL)• Primary Outcome: • Death from any cause within 90 days after randomization

NICENICE--SUGAR SUGAR StudyStudy

Finfer S, et al. N Engl J Med. 2009;360:1283-1297.

Age: ~ 60 years

Gender: ~ 36% female

Diabetes: ~ 20% (BMI ~ 28 kg/m2)

Interval, ICU admission to randomization: 13.4 hrs

Reason for ICU admission:

– Surgical* ~ 37%

– Non-surgical† ~ 63%

Sepsis: ~ 22%

Trauma: ~ 15%

NICENICE--SUGAR: Baseline CharacteristicsSUGAR: Baseline Characteristics

† Did not include significant numbers of CCU patients

* Did not include significant numbers of CT surgery patients



NICENICE--SUGAR: Intensive SUGAR: Intensive vsvs Conventional Conventional Glucose Control in Critically Ill PatientsGlucose Control in Critically Ill Patients

Bars are 95% confidence intervals.

The dashed line indicates 108 mg/dL, the upper limit of target range for intensive glucose control.


Outcome Measure

Intensive Group

Conventional Group

Morning BG (mg/dL) 118 + 25 145 + 26

Hypoglycemia

(≤ 40mg/dL)

206/3016

(6.8%)

15/3014

(0.5%)

28 Day Mortality (p=0.17) 22.3% 20.8%

90 Day Mortality (p=0.02) 27.5% 24.9%

NICENICE--SUGAR SUGAR StudyStudy OutcomesOutcomes



NICENICE--SUGAR: Intensive SUGAR: Intensive vsvs Conventional Conventional Glucose Control in Critically Ill PatientsGlucose Control in Critically Ill Patients

Kaplan–Meier Estimates For The Probability Of Survival

HR = 1.11 (95% confidence interval, 1.01-1.23)


NICENICE--SUGAR: SUGAR: Probability of Survival and OddsProbability of Survival and OddsRatios for Death, According to Treatment GroupRatios for Death, According to Treatment Group



Intensive glucose control did not offer any benefit Intensive glucose control did not offer any benefit in critically ill patientsin critically ill patients

Blood glucose target of less than 180 mg/Blood glucose target of less than 180 mg/dLdLresulted in lower mortality than a target of 81resulted in lower mortality than a target of 81--108 108 mg/mg/dLdL

There was increased hypoglycemia with lower There was increased hypoglycemia with lower glucose targetsglucose targets

NICE SUGAR: ConclusionsNICE SUGAR: Conclusions


AACE/ADA Consensus StatementAACE/ADA Consensus Statementon Inpatient on Inpatient GlycemicGlycemic ControlControl

Endocr Pract. 2009;15:353-69. Diabetes Care. 2009;32:1119-31.


Endocr Pract. 2009;15:353-69.

ICU setting:

– Starting threshold of no higher than 180 mg/dL

– Once IV insulin is started, the glucose level should be maintained between 140 and 180 mg/dL

– Lower glucose targets (110-140 mg/dL) may be appropriate in selected patients

– Targets <110 mg/dL or >180 mg/dL are not recommended

Recommended140-180

Acceptable110-140

Not recommended<110

Not recommended>180

AACE/ADA AACE/ADA Target Glucose Levels in ICU PatientsTarget Glucose Levels in ICU Patients

Non–ICU setting:

– Premeal glucose targets <140 mg/dL

– Random BG <180 mg/dL

– To avoid hypoglycemia, reassess insulin regimen if BG levels fall below 100 mg/dL

– Occasional patients may be maintained with a glucose range below and/or above these cut-points

Hypoglycemia = BG <70 mg/dLSevere hypoglycemia = BG <40 mg/dL

Endocr Pract. 2009;15:353-69.

AACE/ADA AACE/ADA Target Glucose Levels in NonTarget Glucose Levels in Non––ICU PatientsICU Patients


Inpatient Glycemic Control: Inpatient Glycemic Control: ConclusionsConclusions

Hyperglycemia is associated with poor clinical outcomes across many disease states in thehospital setting

Good glucose control, as opposed to near-normal control, is likely sufficient to improve clinical outcomes in the ICU setting

Controversy #3Controversy #3Treatment Options in Type 2 DiabetesTreatment Options in Type 2 Diabetes

Metformin

DPP-4 inhibitor/GLP-1 agonist

Sulfonylurea

TZD

Insulin

Bariatric Surgery

• Meglitinide

• Glucosidase inhibitor

• Colesevelam

• Pramlintide


Nathan DM, Buse JB, Davidson MB, et al. Diabetes Care. 2009;32:193-203.

A1C 6.5 – 7.5%**

Monotherapy

MET +

GLP-1 or DPP4 1

TZD 2

Glinide or SU 5

TZD + GLP-1 or DPP4 1

MET +Colesevelam

AGI 3

2 - 3 Mos.***

2 - 3 Mos.***

2 - 3 Mos.***

Dual Therapy

MET +

GLP-1 or DPP4 1

+TZD 2

Glinide or SU 4,7

A1C > 9.0%

No Symptoms

Drug Naive Under Treatment

INSULIN

± Other Agent(s) 6

Symptoms

INSULIN

± Other Agent(s) 6

INSULIN

± Other Agent(s) 6

Triple Therapy

AACE/ACE Algorithm for Glycemic Control Committee

Cochairpersons:Helena W. Rodbard, MD, FACP, MACEPaul S. Jellinger, MD, MACE

Zachary T. Bloomgarden, MD, FACEJaime A. Davidson, MD, FACP, MACEDaniel Einhorn, MD, FACP, FACEAlan J. Garber, MD, PhD, FACEJames R. Gavin III, MD, PhDGeorge Grunberger, MD, FACP, FACEYehuda Handelsman, MD, FACP, FACEEdward S. Horton, MD, FACEHarold Lebovitz, MD, FACEPhilip Levy, MD, MACEEtie S. Moghissi, MD, FACP, FACEStanley S. Schwartz, MD, FACE

* May not be appropriate for all patients** For patients with diabetes and A1C < 6.5%,

pharmacologic Rx may be considered*** If A1C goal not achieved safely

† Preferred initial agent

1 DPP4 if PPG and FPG or GLP-1 if PPG

2 TZD if metabolic syndrome and/ornonalcoholic fatty liver disease (NAFLD)

3 AGI if PPG

4 Glinide if PPG or SU if FPG

5 Low-dose secretagogue recommended

6 a) Discontinue insulin secretagoguewith multidose insulin

b) Can use pramlintide with prandial insulin

7 Decrease secretagogue by 50% when added to GLP-1 or DPP-4

8 If A1C < 8.5%, combination Rx with agents that cause hypoglycemia should be used with caution

9 If A1C > 8.5%, in patients on Dual Therapy,insulin should be considered

MET +

GLP-1or DPP4 1 ± SU 7

TZD 2

GLP-1or DPP4 1

± TZD 2

A1C 7.6 – 9.0%

Dual Therapy 8

2 - 3 Mos.***

2 - 3 Mos.***

Triple Therapy 9

INSULIN

± Other Agent(s) 6

MET +

GLP-1 or DPP4 1

or TZD 2

SU or Glinide 4,5

MET +

GLP-1

or DPP4 1+ TZD 2

GLP-1

or DPP4 1 + SU 7

TZD 2

MET † DPP4 1 GLP-1 TZD 2 AGI 3

Available at www.aace.com/pub© AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE


* The abbreviations used here correspond to those used on the algorithm (Fig. 1).** The term ‘glinide’ includes both repaglinide and nateglinide.

Benefits are classified according to major effects on fasting glucose, postprandial glucose, and nonalcoholic fatty liver disease (NAFLD). Eightbroad categories of risks are summarized. The intensity of the background shading of the cells reflects relative importance of the benefit or risk.*

Available at www.aace.com/pub© AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE

Treatment ConsiderationsTreatment Considerationsin Type 2 Diabetesin Type 2 Diabetes

Hemoglobin A1c

Body mass index

Age/Kidney disease

Congestive heart failure

Liver failure

Cost of medications


Treatment Options in Type 2 Diabetes:Treatment Options in Type 2 Diabetes:A1c > 9%A1c > 9%

Metformin plus:

DPP-4 inhibitor/GLP-1 agonist, or

Sulfonylurea, or

TZD, or

Insulin

Bariatric Surgery

• Meglitinide


• Colesevelam

• Pramlintide

Treatment Options in Type 2 Diabetes:Treatment Options in Type 2 Diabetes:BMI > 35BMI > 35

Metformin


Sulfonylurea

TZD

Insulin

Bariatric Surgery

• Meglitinide


• Colesevelam

• Pramlintide


Treatment Options in Type 2 Diabetes:Treatment Options in Type 2 Diabetes:Age < 35Age < 35

Metformin


Sulfonylurea

TZD

Insulin

Bariatric Surgery

• Meglitinide


• Colesevelam

• Pramlintide

Treatment Options in Type 2 Diabetes:Treatment Options in Type 2 Diabetes:Age > 75 and/or Renal InsufficiencyAge > 75 and/or Renal Insufficiency

Metformin


Sulfonylurea

TZD

Insulin

Bariatric Surgery

• Meglitinide


• Colesevelam

• Pramlintide


Treatment Options in Type 2 Diabetes:Treatment Options in Type 2 Diabetes:Congestive Heart FailureCongestive Heart Failure

Metformin


Sulfonylurea

TZD

Insulin

Bariatric Surgery

• Meglitinide


• Colesevelam

• Pramlintide

Treatment Options in Type 2 Diabetes:Treatment Options in Type 2 Diabetes:Liver FailureLiver Failure

Metformin


Sulfonylurea

TZD

Insulin

Bariatric Surgery

• Meglitinide


• Colesevelam

• Pramlintide


Treatment Options in Type 2 Diabetes:Treatment Options in Type 2 Diabetes:Cost of MedicationsCost of Medications

Metformin


Sulfonylurea

TZD

Insulin (Regular, NPH)

Bariatric Surgery

• Meglitinide


• Colesevelam

• Pramlintide

controversies in type 2 diabetes - scripps health · n engl j med 2008;358:2545-59. controversies...

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