Intensive risk factors management in diabetic subjects CLARAMUNT.pdf · Intensive. risk factors ....

Intensive risk factors management in diabetic subjects

Yes: M. Khattab (Egypt) No: X. Cos Claramunt (Spain)


Francesc Xavier Cos Claramunt EAP Sant Martí de Provençals. SAP Litoral. Barcelona. ICS Grup d’Estudi de la Diabetis a l’Atenció Primària de Salut (RedGedapS) Executive member of Primary Care Diabetes Europe




YES / NO NO for all !


Duality of Interest

• XC: honoraria clinical trials, consultant and advisory board Boehringer Ingelheim, Lilly, MSD, Abbott, Novartis, Novo Nordisk, Sanofi-Aventis y Astra-Zeneca.


Agenda

Diabetes trials “real life” Explanations & Challenges Guidelines/recomendations Take-home messages


years

Postprandial glucose

Fasting glucose

0

100

200

Insulin Risk of diabetes

Impaired islet cell function

Insulin resistance

–10 0 10 15 20 25 30 5 –5

Diabetes

10 15 20

5

Glu

cose

mm

ol/l

Prop

ortio

nal a

mou

nt o

f ns

ulin

in in

rela

tion

to

norm

al (%

)

Pre diabetes (IFG / IGT) NGT

IFG: impaired fasting glucose; IGT: impaired glucose tolerance Adapted from International Diabetes Center. Type 2 Diabetes BASICS. Minneapolis, Minn: International Diabetes Center; 2000.


HbA1c and microvascular complications

NHANES III

~6.5%

T2DM is defined by the point beyond which risk of

microvascular complications increases.


Khaw KT et al. Ann Intern Med 2004;141:413–20

The Association Between HbA1c Diabetes and Mortality


Glucose Lowering and CVD trials

Yrs from Dx 0 5 -10 -5 10 15

ACCORD

VADT

Eye, Kidney, Nerve Disease

CVD

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

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

ADVANCE

UKPDS


UKPDS randomized years

0

6

7

8

9

0 5 10 15

Conventional

Intensive

6.2% = upper limit of normal range Med

ian

HbA

1C (%

) UKPDS Intensive control reduces complications in type 2 diabetes

–30

–25

–20

–15

–10

–5

0

Rel

ativ

e ris

k re

duct

ion

(%)

12%

25%

16%

6%

P = 0.029

P = 0.0099

P = 0.052

P = 0.44

Lancet 1998; 352:837–853.


–30

–25

–20

–15

–10

–5

0

Rel

ativ

e ris

k re

duct

ion

(%)

9%

24%

15% 13% P = 0.040

P = 0.001

P = 0.014 P = 0.007

UKPDS Long-term follow-up and legacy effect

10 9 8 7 6

0 5 10 15 5 10 1977 1997 2007 Years from randomization

UKPDS Active

Conventional

Intensive

Intervention ends UKPDS

Follow-up

Med

ian

HbA

1c (%

)

Biochemical data no longer collected


Glycemic control and CVD outcome

HbA

1c %

7

7.5

8

8.5

9

ACCORD 10.251

ADVANCE 11.140

VADT 1.791

UKPDS 3.867

STENO-2 160

Intervention studies in Type 2 Diabetes

Age 62y DM 10y

Age 66y DM 8y

Age 60y DM 12y

Age 54y DM 0y

Age 55y DM 6y


Meta-analysis: impact of intensive glucose control on coronary heart disease* events

Ray KK, et al. Lancet 2009; 373:1765–1772.

Intensive treatment/standard treatment

Odds ratio (95% CI)

Odds ratio (95% CI)

Participants Events

UKPDS 3,071/1549 426/259 0.75 (0.54–1.04)

PROactive 2,605/2633 164/202 0.81 (0.65–1.00)

ADVANCE 5,571/5,569 310/337 0.92 (0.78–1.07)

VADT 892/899 77/90 0.85 (0.62–1.17)

ACCORD 5,128/5123 205/248 0.82 (0.68–0.99)

Overall 17,267/15,773 1,182/1,136 0.85 (0.77–0.93)

0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0

Intensive treatment better Standard treatment better

*Included non-fatal myocardial infarction and death from all cardiac mortality.


Variable CHD Stroke (all) Cardiovascular disease

The epidemiological and interventional relationships of cholesterol, blood pressure and HbA1c with cardiovascular disease

NNT are calculated by assuming a 5 year level of risk equivalent to that of the conventional treatment limb of the meta-analysis (CHD 7.4%,stroke 3.3%, see ESM Table 1), applying a factor of 5/4.4 (1.136) to derive these from the 4.4 year data

Turnbull FM, Abraira C, Anderson RJ et al (2009) Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia


Variable CHD Stroke (all) Cardiovascular disease

The epidemiological and interventional relationships of cholesterol, blood pressure and HbA1c with cardiovascular disease Variable

NNT are calculated by assuming a 5 year level of risk equivalent to that of the conventional treatment limb of the meta-analysis (CHD 7.4%,stroke 3.3%, see ESM Table 1), applying a factor of 5/4.4 (1.136) to derive these from the 4.4 year data



Intensified glycaemic control on rates of macrovascular and microvascular events, mortality and serious hypoglycaemia


CHD Stroke

Intensified glycaemic control on rates of macrovascular and microvascular events, mortality and serious hypoglycaemia



CDC Diabetes Cost-effectiveness Group (2002) Cost-effectiveness of intensive glycemic control, intensified hypertension control, and serum cholesterol level reduction in type 2 diabetes. JAMA 287:2542–2551

The costs (per QALY based on UKPDS data and expressed in 1,997 US$) Ex: 65-year-old new-onset patient $154,376 for decreasing A1c about 8% to 7% $43,331 for cholesterol lowering –$413 for blood pressure lowering Glucose control Aged 75- 84 years rise to $401,883 Aged over 84 years $2.1 million; Blood pressure control is cost-saving at every age below 85 years


Despite advances in treatment, a significant proportion of patients with Type 2 diabetes still fail to reach target HbA1c levels

0102030405060708090

100

HbA1c checkedMet HbA1c target

Stone MA et al. Diabetes Care. 2013 April 23.

Per

cent

GUIDANCE Study 7,597 T2DM patients Gap exists between checking HbA1c and achieving target HbA1c <7%

HbA1c checked Met HbA1c target


Vinagre et al. Diabetes Care 2012;35.


Challenges associated with achieving optimal glycaemic goals

6,5

7,0

7,5

8,0

8,5

9,0

2001 2002 2003 2004 2005 2006 2007

3,5

4,0

4,5

5,0

5,5

6,0

2001 2002 2003 2004 2005 2006 2007

Type 1 diabetes

Type 2 diabetes + insulin

Year Year

Mea

n H

bA1c

(%)

Mea

n Tc

hol (

mm

ol/l

)

In patients with type 1 diabetes or type 2 diabetes on insulin, there was a 0.1% relative improvement in HbA1c vs. improvements in total cholesterol of 15% and

29%, respectively between 2001 and 2007

Currie et al. Diabetic Medicine 2010; 27:938-948


Comorbidity of top 10 common conditions

Guthrie B et al. BMJ 2012;345:e6341


Elderly patients

7

6

5

4

3

2

1

0 0 40 50 70 80 90 60

Age (yr)

Year

s of

Life

Los

t

Men 7

6

5

4

3

2

1

0 0 40 50 70 80 90 60

Age (yr)

Women

Death from unknown causes Noncancer, nonvascular deaths Cancer deaths Vascular deaths

ERFC (Emerging Risk Factor Collaboration). NEJM 2011;364:829-841.


Medications most commonly associated with emergency hospitalisation

0%

5%

10%

15%

20%

25%

30%

35%

0

5 000

10 000

15 000

20 000

25 000

30 000

35 000 Percentage of estimated

number of hospitalisations

Estim

ated

num

ber

of

hosp

ital

isat

ions

Data given are number and percentage of annual national estimates of hospitalisations. Data from the NEISS-CADES project. ER visits n=265,802/Total cases n=12,666. ER, emergency room Budnitz et al. N Engl J Med 2011;365:2002–12


Consequences of delayed intervention – Interpreting the VADT results

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

(años desde el Diagnóstico)

HbA1

c (%

)

Bad Glycaemic “legacy”

Del Prato S Diabetologia 2009;52:1219

Before entering VADT intensive treatment arm After entering VADT intensive treatment arm

Drive risk for complications


2008 2009

NICE Canadian ADA/EASD

Guias

RedGedaps

MSyC

2010

NICE

SED

ACE/AACE

2012

ADA/EASD

2013

ACE/AACE

Canadian

2014 2015

RedGedaps ADA/EASD

NICE

Guidelines · Recomendations

AACE


HbA1c targets generally 6.5–7% when safe and appropriate

ADA/EASD HbA1c < 7%

IDF (Europe)

HbA1c ≤ 6.5%

CDA (Canada)

HbA1c ≤ 7%

NICE (UK)

HbA1c 6.5%/7.5%

AACE (US)

HbA1c ≤ 6.5% ALAD (Latin America) HbA1c < 6–7%

APPG (Asia-Pacific)

HbA1c ≤ 6.5%

Australia

HbA1c ≤ 7%

ADA. Diabetes Care 2015; 32(Suppl 1):S13–S61; Endocr Pract. 2015;21: In Press.IDF. Global guideline for type 2 diabetes, IDF 2012. Available at: http://www.idf.org/sites/default/files/IDF-Guideline-for-Type-2-Diabetes.pdf JBS2. Heart 2005; 91(Suppl. V):1–52. European Diabetes Policy Group.

Diabet Med 1999; 16:716–730. CDA. Can J Diabetes 2008; 32(Suppl. 1):S1–S201. NICE. 2009. Available at: http://www.nice.org.uk/nicemedia/pdf/CG87ShortGuideline.pdf; ALAD. Rev Assoc Lat Diab 2000; Suppl. 1. Asian-Pacific Policy Group. Practical Targets and Treatments (3rd Edn). Available at: http://www.idf.org/webdata/docs/T2D_practical_tt.pdf. NSW Health Department. The Principles of Diabetes Care

and Guidelines for the Clinical Management of Diabetes Mellitus in Adults. NSW Health Department 1996.

Joint British Societies (JBS 2) HbA1c < 6.5%

http://www.idf.org/sites/default/files/IDF-Guideline-for-Type-2-Diabetes.pdf

http://www.nice.org.uk/nicemedia/pdf/CG87ShortGuideline.pdf


Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach: Update to a Position Statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015 Jan;38(1):140-149.



Based on an original figure by Ismail-Beigi et al. Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach: Update to a Position Statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015 Jan;38(1):140-149.



At diagnosis Treatment review Older patients

Clear guidance1

• Diet and exercise plan

• Metformin given • Avoid diabetes

complications

Complications arise1-3

• Complications such as CVD or renal impairment may become more frequent

• More individualised approach to treatment required

QoL becomes one of the most important considerations4

Management of T2D Becomes More Complex Over Time

Disease progression

1,2. Adapted from National Institute for Health and Clinical Excellence. Clinical Guideline 87. Type 2 diabetes – newer agents (a partial update of CG66): quick reference guide. NICE clinical guideline 66: Type 2 Diabetes Management. Available at: http://www.nice.org.uk/nicemedia/pdf/CG66NICEGuideline.pdf (accessed November 2012). 3. Go AS, et al. N Engl J Med. 2004;351:1296–1305; 4. Morley JE. Diabet Med. 1998;15 (Suppl. 4): S41–6.

Comparison of study populations

Lixisenatide ELIXA

Within 180 days of ACS

Alogliptin EXAMINE

Within 15–90 days of ACS

Aleglitazar ALECARDIO

Enrolled 2–6 wks after ACS; also other CVDs/RFs needed

Empagliflozin EMPA-REG OUTCOME

Enrolled >2 months after ACS, UA, PCI, stroke, PAD

Aleglitazar ALEPREVENT

≥40 y with prior MI or stroke ≥3 months OR ≥55 y and evidence of CVD

Sitagliptin TECOS

Pre-existing CVD

Linagliptin CAROLINA

CVD OR end-organ damage OR age ≥70 y OR ≥2 RFs

Saxagliptin SAVOR-TIMI 53

Established CVD or RFs

Liraglutide LEADER

≥50 y + CVD, cerebrovascular disease or PVD or CHF or CRF OR ≥60 y and RFs

Dulaglutide REWIND

≥50 y + established disease OR ≥55 y + subclinical disease

OR ≥60 y + ≥2 RFs

Exenatide QW EXSCEL With CVD

Dapagliflozin DECLARE-TIMI 58 High risk for CVD

Recent ACS Established disease DM with Risk Factors Post-ACS (<6 m)

Lessening risk

39

Semaglutide SUSTAIN 6

≥50 y + established disease OR ≥60 y + subclinical disease

Canagliflozin CANVAS/CANVAS-R

≥30 y and documented CVD OR ≥50 y and ≥2 RFs

Insulin degludec DEVOTE

≥50 y + CVD or renal disease OR ≥60 y and RFs

Linagliptin CARMELINA

Albuminuria + CVD ± impaired renal function

Ertugliflozin NCT01986881 Established disease


• Hyperglycaemia is a substantially weaker risk factor for CVD than

cholesterol or blood pressure.

• Good glucose control beneficial on microvascular complications,

cataracts and neuropathy, but the added benefits of an HbA1c of 7%,

as against 8%, diminish with age and life expectancy.

• Little attention to the unwanted effects of intensified therapy, and its

low utility in those with established complications or a limited life

expectancy.

• Challenge to translate RCT results on “real life” patients

• INDIVIALIZED approach in new Recommendation and GL

Take-home message


“Lending a hand” to patients with type 2 diabetes; a simple way to communicate treatment goals. AM Fam Physician 2014; 89(4):256258

Quit smoking - Mortality reduction (NNT =11 in 10 years)

Glucose control - No impact on mortality and cardiovascular complications

Blood preassure control - Mortality reduction (NNT =15 in 10 years) - Complications reduction (NNT = 6 in 10 years)

Metformin - Mortality reduction (NNT =15 in 10 years) - Complications reduction (NNT = 10 in 10 years)

Lipid controls - Cardiovascular events reduction (NNT =10-15 in 10 years) - Extend life expectancy 3 years men and 2 in women


@Xaviercos Thanks

Intensive risk factors management in diabetic subjects CLARAMUNT.pdf · Intensive. risk factors ....

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