a combination of life style interaction and the use of drugs

Glycemic control –

A combination of life style interaction

and the use of drugs

Eberhard Standl

Munich Diabetes Research Institute

at the Munich Helmholtz Center

Master class in preventive cardiology –

Focus on diabetes and cardiovascular disease

April 14, 2011

Geneva

Multifactorial management to reduce

cardiovascular risk in patients with diabetes mellitus

UKPDS

Landmark study

in type 2 diabetes

1977 - 1997

Patients studied

n=5102

UKPDS: Clinical Outcomes after 10 yearsLife style plus drugs

12%

16%

25%

21%

P=0.029

P=0.052

P=0.0099

P=0.015

Any diabetes related endpoint

Myocardial infarction

Microvascular complications

Retinopathy at 12 years

Intensive policy

7.0% HbA1c

Conventional policy

7.9% HbA1cversus

UKPDS Group. Lancet 1998;352:837–853.

Cardiovascular and all cause mortality NS

G Lowering Intensity & Diabetes Complications

Trials in People with Dysglycemia and Type 2 Diabetes

Yrs from Dx 0 5-10 -5 10 15

VADT

Eye, Kidney, Nerve Disease

CVD

IFG &/or IGT Type 2 Diabetes (T2DM)High

Dysglycemia - - - - - - - - - - - - - - - - - - - - - - -

ADVANCE

ACCORD

UKPDS

(DCCT)

Glycemic controlMeta-analysis of 5 prospective randomised trials (intensive vs standard)

(Ray K et al. Lancet 2009;373:1765)

Non-fatal MI (17% reduction)

0.83 (0.75 -0.93)

n=33 040 Mean HbA1c difference 0.9%

All cause mortality

1.02 (0.87-1.19)

…watch out for potential severe

downsides,

e.g. severe hypoglycemia and

weight gain, especially in

patients with preexisting CVD!

Issues beyond

Hb

A1

c(%

)

Time of follow up (years)

(Gerstein et al. NEJM 2008;358:2545)

(Patel et al. NEJM 2008;358: 2560)

Glycemia trial (n=10 251)

HbA1c <6.0% vs HbA1c 7.0-7.9%

Severe hypoglycemia: 1.0 vs 3.1 %/yr

Severe hypoglycemia: 0.4 vs 0.7 %/yr

Intensive Glucose Lowering in Type 2 Diabetes

ACCORD and ADVANCE

Standard

Intensive

Time of follow up (months)

Hb

A1

c (

%)Glycemia trial (n=11 140)

HbA1c ≤ 6.5% vs local guidelines

Standard

Intensive

Hypoglycaemia requiring third-party assistance

Stand Inten Stand Inten

HbA1c % Hypo %/yr

UKPDS 1998 10+ Newly

diagnosed7.9 7.0 0.7 1.4 – 1.8

SU Ins

PROactive 2005 3 High SV risk 7.5 6.9 0.14 <0.25

ADOPT 2006 4+ Recently

diagnosed- 6.9-7.4 - <0.2

Steno-2 2006 13.3 + microalbu 8.0 7.7 ~1 ~1

4T 2007 1+ No ins, >1yr

diagnosed- 7.2-7.6 - 0

ACCORD 2008 3.5+ Older high

CV risk7.5 6.4 1.4 4.6

ADVANCE 2008 5+ Older high

CV risk7.3 6.5 0.4 0.7

VADT 2008 6+ Older high

CV risk8.4 6.9 ~1.6 ~ 4 ?

Standard Intensive

Differences between the

ACCORD and ADVANCE studies

Characteristic ACCORD ADVANCE

Baseline

N 10,251 11,140

Mean age (Y) 62 66

Duration of diabetes (Y) 10 8

Median HbA1c at baseline 8.1 7.2

History of macrovascular disease (%) 35 32

Intervention

Target HbA1c (%) <6.0 ≤6.5

Median duration (Y) 3.4 5.0

Medical treatment at study completion

(intensive vs standard) (%)

Insulin 77 vs 55 41 vs 24

Metformin 95 vs 87 74 vs 67

Secretagoue (sulphonylurea or glinide) 87 vs 74 94 vs 62

Thiazolidinedione 92 vs 58 17 vs 11

Dluhy et al. N Engl J Med 2008;358:2630-3

use of

Acarbose

in 19%

Adjusted cause of death in relation to treatment strategy and by occurrence of hypoglycemia

All cause mortality

CVD death

Cancer death

Non CVD/

Non cancer death

Unable to classify

Standard participants Intensive participants

No hypo event

n=4.832

At least one severe hypo

n=175

No hypo event

n=4.290

At least one severe hypo

n=528

4%

2%

1%

1%

<1%

10%

5%

2%

1%

1% <1% <1%

1% 1%

1% 1%

2% 4%

5% 6%

ACCORD

Bonds DE et al. BMJ 2010: 340:b4909 doi:10.1136/bmj.b4909

Riddle M et al. ADA Congress, New Orleans June 2009

-1

0

1

6 7 8 9Average HbA1c %

Risk of Death over a Range of Average HbA1c

Adjusted log (Hazard Ratio) by Treatment Strategy

Relative to Standard at HbA1c of 6%

Standard strategy

Intensive strategy

Steady increase of risk from 6 to 9% HbA1c with

intensive strategy

Excess risk with intensive strategy vs standard occurred

above HbA1c 7%

HR for 1% higher

average HbA1c

Intensive Strategy:

1.66

Standard Strategy:

1.14

Calles-Escandon et al NEJM 2010

Raising A1c to 7.2 % in the intensive group

did not reduce excess mortalityNEJM 2011; 364:818

Primary outcome subgroup analyses

(Gerstein et al. NEJM 2008;358:2545)

Subgroup Patient Eventsno no

UKPDS 30 y Follow-up:

Reduction of diabetes-related endpoints

and myocardial infarction

Holman R et al. New Engl J Med 2008;359, epub 10 September 2008

1ADA. Diabetes Care 2007; 30 (Suppl. 1):S4–S41. 2ACE/AACE Diabetes Road Map Task Force, 2005. Available at:

www.aace.com/meetings/consensus/odimplementation/roadmap.pdf 3IDF Clinical Guidelines Taskforce, 2005. Available at:

www.idf.org/webdata/docs/IDF%20GGT2D.pdf. 4CDA. Can J Diabetes 2003; 27 (Suppl. 2):S1–S152. 5NICE, 2002. Available at: www.nice.org.uk. 6ALAD.

Rev Asoc Lat Diab 2000; 8 (Suppl. 1):101–167. 7Asian-Pacific Type 2 Diabetes Policy Group, 2005. Available at:

www.idf.org/webdata/docs/T2D_practical_tt.pdf. 8NSW Health Department, 1996.

Guidelines recommend target HbA1c as near to normal as safely possible

The AACE recommendations

on glycaemic control

No problem even to normalize glycemia, provided it

can be achieved without side effects

Near-normal targets (without hypoglycaemia) are

advocated:

– HbA1c ≤6.5%

– Fasting plasma glucose <110 mg/dL

– 2-h post-prandial glucose <140 mg/dL

Post-prandial hyperglycaemia is linked to

macrovascular disease

– Effective management of post-prandial glucose

can reduce this burdenAACE Diabetes Mellitus Clinical Proactice Guidelines Task Force. Endocrine Practice vol 13 (Suppl 1); May/June 2007.

A HbA1c of 7 % is a reasonable deal:

It can be attained – by the patient – by the doctor

Needs less intensive polypharmacy (less costs)

Reduces microvascular complications

Reduces macrovascular complications (legacy effect)

Further aggressive HbA1c reduction may increase the risk of side effects, e.g. weight gain, hypoglycemia, even cardiovascular mortality

Conversely, the further gain of further HbA1c lowering is rather little (NNT 30 to 50) and only proven for (functional) renal parameters (e.g. microalbuminuria), not for macrovascular outcomes

5

6

7

8

9

10

11

12

13

14

15

0 2 4 6 8 10 12 14 16 18 20 22 24

Postabsorptive (Night phase) Postprandial (Day phase)

0,7

4,4

8,4

10,0

11,5

Duration of

Diabetes mellitus (in years) )

Breakfast

Morning

phase

Blood glucose patterns with progressive Type 2

Diabetes

L. Monnier et al. Diabetes Care 2007

HbA1c-Value

< 6,5 %

6,5–6,9 %

7–7,9 %

8–8,9 %

≥ 9 %

GUIDELINES ON DIABETES, PRE-DIABETES

AND CARDIOVASCULAR DISEASES

New ESC/EASD Guidelines

Suggested policy for the selection of glucose-

lowering therapy according to the glucometabolic situation

ESC Pocket Guidelines adapted from European Heart Journal (2007) 28, 88 - 136

,DPP4-I, GLP1-A.

,DPP4-I, GLP1-A.

22

Mean efficacy of pharmacotherapeutic

options in Type 2 diabetes*

Drug Option Mean HbA1c Lowering Capacity (%)

Incretin enhancers (DPP-IV-inhibitors) 0.7-1.0

GLP-1 analogues 1.0

-Glucosidase inhibitors 0.5-1.0

Biguanides 1.0-1.5

Glitazones (TZDs) 0.5-1.5

Sulfonylureas (and analogues) 1.0-1.5

Insulins 1.0-2.0

CB-1 receptor antagonist 0.7

CB-1=cannabinoid Type 1. DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1.

DeFronzo RA. Ann Intern Med. 1999;131:281-303. Nathan DM. N Engl J Med. 2002;347:1342-1349.

Todd JF, Bloom SR. Diabet Med. 2007;24:223-232. Scheen AJ. Best Pract Res Clin Endocrinol Metab.

2007;21:535-553. Vinik A. Clin Ther. 2007;29 Spec No:1236-1253.

* Treatment effects vary with treatment dose and patient characteristics.

Early combination strategy in

blood glucose lowering therapy

• additive efficacy through different mode of actions

• therapy of different abnormalities

• at medium dose 70-80% of maximum effect less

side effects

Glitazones

α-Glucosidase

inhibitors

Metformin

Sulfonylureas

und Analogs

Incretin enhancers/GLP1-Ag.

Drug Combinations with Different Mechanisms

2007

AACE

Guidelines—Combination therapy

with different

mechanisms anti-

hyperglycemic drugs

is more beneficial

2009

ADA /EASDConsensus

—combination of

anti-hyperglycemic

drugs with different

mechanisms can

achieve the

maximum synergy

Guideline Recommendations:

+Monotherapy Insulin +/- oral agents

Campbell IW. Br J Cardiol 2000;7:625-31

Target-driven strategy

for sustained glycaemic control

7

6

9

+Combinations of oral

agents

8

Diet

HbA1C

(%)

HbA1C < 7%

approach

ULN

Diagnosis +5 yrs +10 yrs + 15 years

Failure-based

treatment

of symptoms

approach

Options of insulin therapy

in type 2 diabetes

fasting hyperglycemia:long acting insulin (or analogue) at bedtimepostprandial hyperglycemia:prandial insulin therapy with rapid actinginsulin analogues or regular insulinconstant hyperglycemia:pre-mixed insulin (50/50 to 25/75) beforebreakfast and supper, respectivelyNB! All options may by combined with oral agents: e.g. Metformin!

N Engl J Med 2009;361:1736-47

4TStudy: Results over 3 Years incl. Hypoglycaemia

Mean±1SD

N Engl J Med 2009;361:1736-47

Adverse Events

Biphasic

N=235

Prandial

N=239

Basal

N=234

p

value

Any serious event 105

(44.7%)

79

(33.1%)

78

(33.3%)

0.011

Death from any cause 7

(3.0%)

9

(3.8%)

4

(1.7%)

0.23

Cardiovascular death 4

(1.7%)

9

(3.8%)

1

(0.4%)

0.002

Any adverse event 228

(97.0%)

235

(98.3%)

227

(97.0%)

0.58

No significant differences were seen between groups in:

Serious adverse events occurring in more than 1% in any group

Non-serious adverse events occurring in more than 10% in any group




Potential downsides of pharmacological

treatment modalities in patients with type 2 diabetes


, DPP4-Inhibitors

, DPP4-Inhibitors

, GLP1-A

Look AHEAD Trial: 1 year follow-up

Look AHEAD research group. Diabetes Care 2007;30:1374-83

Look AHEAD trial: changes of glycaemic

and blood pressure control after 1 yearMeasure Intensive lifestyle

intervention

Diabetes support

and education

P

N 2496 2463

Use of diabetes medications (%)Baseline

Year 1

Change

86.3±0.7

78.6±0.8

-7.8±0.6

86.5±0.7

88.7±0.6

2.2±0.5

0.93

<0.001

<0.001

Fasting glucose (mg/dL)

Baseline

Year 1

Change

151.9±0.9

130.4±0.8

-21.5±0.9

153.6±0.9

146.4±0.9

-7.2±0.9

0.21

<0.001

<0.001

HbA1c (%)Baseline

Year 1

Change

7.25±0.02

6.61±0.02

-0.64±0.02

7.29±0.02

7.15±0.02

-0.14±0.02

0.26

<0.001

<0.001

Use of antihypertensives (%)Baseline

Year 1

Change

75.3±0.9

75.2±0.9

-0.1±0.6

73.7±0.9

75.9±0.9

2.2±0.6

0.23

0.54

0.02

SBP (mmHg)Baseline

Year 1

Change

128.2±0.4

121.4±0.4

-6.8±0.4

129.4±0.3

126.6±0.4

-2.8±0.3

0.01

<0.001

<0.001

DBP (mmHg)Baseline

Year 1

Change

69.9±0.2

67.0±0.2

-3.0±0.2

70.4±0.2

68.6±0.2

-1.8±0.2

0.11

<0.001

<0.001

Look AHEAD research group. Diabetes Care 2007;30:1374-83




Recommended treatment targets for

patients with diabetes and CAD (2)


Di Loreto et al , Diabetes Care, 2005

• T2D

• n = 182

• 2 year follow up

• HbA1c baseline: 7.6%

• Diabetes duration: 7.6 years

• Advice for physical activity: moderate, aerobic

endurance training (30-60% of max. HF), aim: > 10 MET/ h /wk)

• 7 visits, total of ca 2 h counselling, 1 visit every 3 Month

Effects of physical activity in T2D

Walking / Hours / Week*

0 1,5 4 5,5* 7,5 12

Weight (kg) + 0,8 + 0,6 + 0,1 - 2,2 -3,0 -3,2

Waist (cm) + 1,0 + 1,0 - 0,9 - 3,8 - 5,5 - 7,1

HbA1c (%) + 0,03 - 0,06 - 0,44 - 0,8 - 1,11 - 1,19

BD syst. (mmHg) - 1,8 - 1,5 - 6,4 - 5,5 - 6,6 - 9,2

BD diast. (mmHg) - 4,6 - 2,4 - 2,9 - 4,8 - 5,3 - 7,1

Chol. (mg/dl) - 3,8 - 5,6 - 10,2 - 10,7 - 7,4 - 10,9

LDL-Chol. (mg/dl) - 4,5 - 7,1 - 3,4 - 5,3 - 6,3 - 7,7

HDL-Chol. (mg/dl) + 0,1 + 1,1 + 2,9 + 5,6 + 10,4 + 6,3

Triglycer. (mg/dl) + 3,4 + 2,1 - 48,2 - 55,2 - 57,4 - 68,4

CAD Risk (%) + 0,1 - 0,3 - 2,6 - 3,7 - 4,8 - 4,3

Di Loreto C. et al. Diabetes Care (2005)28:1295-1302

p <0,05* e.g. 21-30 MET: 45 min walking (4 mph) /day, ca. 5 km/day)

Effects of physical activity in T2D

Walking / Hours / Week*

0 1,5 4 5,5* 7,5 12

Weight (kg) + 0,8 + 0,6 + 0,1 - 2,2 -3,0 -3,2

Waist (cm) + 1,0 + 1,0 - 0,9 - 3,8 - 5,5 - 7,1

HbA1c (%) + 0,03 - 0,06 - 0,44 - 0,8 - 1,11 - 1,19

BD syst. (mmHg) - 1,8 - 1,5 - 6,4 - 5,5 - 6,6 - 9,2

BD diast. (mmHg) - 4,6 - 2,4 - 2,9 - 4,8 - 5,3 - 7,1

Chol. (mg/dl) - 3,8 - 5,6 - 10,2 - 10,7 - 7,4 - 10,9

LDL-Chol. (mg/dl) - 4,5 - 7,1 - 3,4 - 5,3 - 6,3 - 7,7

HDL-Chol. (mg/dl) + 0,1 + 1,1 + 2,9 + 5,6 + 10,4 + 6,3

Triglycer. (mg/dl) + 3,4 + 2,1 - 48,2 - 55,2 - 57,4 - 68,4

CAD Risk (%) + 0,1 - 0,3 - 2,6 - 3,7 - 4,8 - 4,3

Di Loreto C. et al. Diabetes Care (2005)28:1295-1302

p <0,05* e.g. 21-30 MET: 45 min walking (4 mph) /day, ca. 5 km/day)

-593 $

dru

g c

osts

ADA and EASD consensus

At diagnosis:

Lifestyle

+

Metformin

Lifestyle + Metformin

+

Basal insulin


+

Sulfonylurea


+

Intensive insulin

1. Well-validated

core therapies

2. Less well-

validated

therapies

STEP 1 STEP 2

STEP 3


+

Pioglitazone


+

GLP-1 agonist


+

Pioglitazone

+

Sulfonylurea


+

Basal insulin

(Nathan et al. Diabetes Care 2009;32:193)

Sulfonylurea

or

α-Glucosidase inhibitor

Metformin

Consider second line

Consider third line

Consider fourth line

Sulfonylurea

GLP-1 mimetic

Then, at each step, if not to target (generally HbA1c <7.0 %)

Lifestyle measures

Consider first line

Metformin

(if not first line)

Thiazolidinedione, or

DPP-4 inhibitor, or

α-Glucosidase inhibitor

or

Basal insulin,

or

Pre-mix insulin

Thiazolidinedione, or

DPP-4 inhibitor, or

α-Glucosidase inhibitoror

Basal +

meal-time

insulin

Basal insulin, or

Pre-mix insulin

(later basal+meal-time)

= usual approach

= alternatives as

per Guideline

The New IDF Therapeutic Algorithm (still under review)

Present approach to diabetes management

in type 2 diabetic patients

Consult endocrinologist / diabetologist for

Structured education

Blood glucose self-monitoring (also post-prandial glucose)

Appropriate nutrition counselling

Pharmacotherapy discussing pros and cons

Benefits Caveats

Insulin Yes Heart?

Metformin Yes Impaired kidney function

Sulfonylureas Yes Cardiac K-channels?

α-glucosidase-inhibitors Yes

Glitazones Yes(pio)/? CHF (CHD rosiglitazone?)

Glinides No (NAVIGATOR)

Incretin-based agents ?

CHF=congestive heart failure CHD=coronary heart disease

Beyond HbA1c targets after

ADVANCE/VADT/ACCORD/UKPDS 2011

No change of targets (<7% or <6.5%), in particular in view of the

prevention of microvascular (and most likely also cardiovascular)

complications but…

– Go slow, especially in patients with high baseline HbA1c

values and pre-existing CV disease

– Avoid hypoglycaemia and weight gain

Early treatment and – perhaps – prevention appears to give the

best results

Some pharmacotherapies (e.g. insulin, rosiglitazone, SUs) cannot

be excluded as a culprit in patients with cardiovascular disease

The beneficial effects of improved blood glucose therapy on

cardiovascular disease do emerge longer term and there is a

―legacy effect‖ (metabolic memory)

Weight neutral, nonhypoglycemic options (e.g. metformin,

acarbose, DPP4-inhibitors) appear to be preferable

1. Lifestyle intervention (healthy eating, weight control, physical activity)

2. Metformin (glycaemic control, reduced CV events)No hypoglycaemia, no weight gain

3. Second (oral) agent (glycaemic control)

SU

Cheap

Hypo

BW

TZD

ø Hypo

Costs

BW

CV safety

-Gluc. Inh.

CV Ev. ?

ø Hypo

Weak

GI-AE

Glinide

Rapid acting

Costs

Hypo

BW

Nauck 2008

Incretin Mimetic

ø Hypo

BW

ß-cell health?

Nausea etc.

DPP-4 Inh.

ø Hypo

ø BW

No AE

ß-cell health?

Insulin(basal)

Always works

Hypo

BW

WHO 15.05.09

CAD: coronary artery disease; OGTT: oral glucose tolerance test; FPG: fasting plasma glucose;

IFG: impaired fasting glucose; IGT: impaired glucose tolerance

1. Bartnik M, et al. Eur Heart J 2004;25:1880–90.

2. Hu DY, et al. Eur Heart J 2006;27:2573–9.

China Heart Survey2

(n=3,513)

~3/4 of

patients have

hyperglycaemia

Euro Heart Survey1

(n=4,961)

2/3 of

patients have

hyperglycaemia

Previously known diabetesNormal glucose tolerance

Prediabetes (IGT)

Newly diagnosed diabetes

33%23%

24%

20%21%

Hyperglycaemia is common and often undiagnosed in patients with CAD in Europe and Asia

25%

31%

12%3%

29%

Prediabetes (IFG)

44© Prof. Eberhard Standl

Anselmino, Malmberg, Standl, Rydén, EuroHeartJ, (2008) 29:177-184

Euro Heart Survey: Improved cardiovascular

outcomes in patients with newly detected diabetes

and implementation of diabetes pharmacotherapy

Mortality trends in subjects with and without diabetes

during 33 years of follow-up

Jansson SPO et al, Diabetes Care 2010; 33:551-556

CVD CVD

CHDCHD

The first Joint

ESC/EASD Guidelines

in ”Cardio-Diabetology”:

A perspective in

reducing CV risk

L. Ryden & E.Standl

Co-chairs

www.easd.org

www.escardio.org

Guidelines of the European Society of Cardiology

(Euro Heart J: 2007; 28: 88-136)

European guidelines: diabetes and cardiovascular disease

Multifactorial intervention in type 2 diabetesThe Steno 2 study

Composite endpointCV-death, MI or stroke, CABG or PCI, limb amputation or vascular surgery

(Gaede et al N Engl J Med 2008;358:580-91)

Steno 2 Study – 13 year follow up: negative trends

in weight management may have challenged

the benefits of blood glucose lowering therapy

(Gaede et al N Engl J Med 2008;358:580-91)

Ten important recommendations (1)

To reach (all) treatment targets including those for

glycaemic control

To screen for DM and IGT by means of an OGTT in all patients

with coronary artery disease and in other high risk individuals

To let life style counselling be the cornerstone in preventing

DM and CVD

To offer patients with DM and ACS standard guideline based

treatment, early angiography and mechanical revascularisation

To apply strict, when needed insulin based, glucose control in

acutely ill DM patients

Europ Heart J 2007; 28: 88-136

Ten important recommendations (2)

To favour CABG over PCI when revascularising DM patients

To use drug-eluting stents in PCI with stent implantation

To include investigations for cardiac autonomic dysfunction, heart

failure, arrhythmias, hypotension, PVD (Doppler-Index), GFR and

(micro) - albuminuria

To use a multifactorial (tight glucose, BP and lipid-control and

antiplatelet therapy) approach

To establish a collaboration between cardiologists

and diabetologists

Europ Heart J 2007; 28: 88-136

Lifestyle modification Structured education

Smoking cessation Obligatory

BP <130 / 80 mm Hg

Renal dysf <125/75

HbA1c (DCCT standard) ≤ 6.5%

mmol/l mg/dl

Venous plasma glucose <6.0 108

Cholesterol <4.5 175

LDL <1.8 70

HDL male >1.0; female >1.2 40; 46

Triglycerides <1.7 150

ESC/EASD Guidelines

Treatment targets

of multifactorial therapy

Variable Target

a combination of life style interaction and the use of drugs

Documents