PARHOFER

Management of Dyslipidemia and Hypertension in Diabetic Patients

Klaus Parhofer Medical Department II - GroĂ&#x;hadern Ludwig-Maximilians-University, Munich, Germany

RM

Dyslipidemia and Hypertension in Diabetic Patients

• Case • Dyslipidemia • Hypertension • Multifactorial Therapy • Case C1

Case 1: KF, 63 years, male Diagnoses: • Diabetes mellitus type 2 for 8 years • Obesity Grade 1, BMI 31.3 kg/m² • Diabetic nephropathy • Diabetic neuropathy • Diabetic dyslipidemia • CAD (MI 3 years ago)

Case 1: KF, 63 years, male Complaints: no specific complaints Current medications: • Metformin 1000 mg • Aspirin 100 mg • Ramipril 5 mg • Metoprolol 50 mg • Simvastatin 40 mg

BID qd qd BID qd

Case 1: KF, 63 years, male Physical exam: • Height 176 cm • Weight 97 kg • Waist circumference 101 cm, • Blood pressure 145/83 mmHg • Pulse 80/min.

• Pedal pulses palpable • Pretibial edema bilaterally • Neuropathy bilaterally

Case 1: KF, 63 years, male Clinical chemistry: • HbA1c 7.2% • Fasting glucose 137 mg/dl (7.6 mmol/l) • Creatinine 1.2 mg/dl • BUN 32 mg/dl (10.2 mmol/l) • Uric acid 7.8 mg/dl (460 μmol/l) • Gamma-GT 91 U/l, AST 71 U/l, ALT 55 U/l Lipid profile (taking 40 mg Simvastatin): • Total cholesterol 210 mg/dl (5.4 mmol/l) • Triglycerides 233 mg/dl (2.6 mmol/l) • LDL-cholesterol 128 mg/dl (3.4 mmol/l) • HDL-cholesterol 34 mg/dl (0.9 mmol/l) • Lipoprotein(a) 36 mg/dl Q1

Case 1: Question 1 Which factor is most important with respect to preventing recurrent CAD events ?

1. Better glucose control 2. Better blood pressure control 3. Better lipid control 4. All are similarly important

RM

Hazard Ratios for Coronary Heart Disease by Fasting Glucose, Total (and non-HDL) Cholesterol, and Systolic Blood Pressure (Meta-analysis; 102 prospective studies; 698782 people)

The Emerging Risk Fact. Coll. Lancet 2010;375: 2215-22

Dyslipidemia and Hypertension in Diabetic Patients

• Case • Dyslipidemia • Hypertension • Multifactorial Therapy • Case Athero

Lipid Changes Associated with Atherosclerosis

↑ LDL-cholesterol ↓ HDL-cholesterol ↑ Triglycerides (DM, metabolic syndrome, family history) ↑ Lipoprotein (a)

Det

Postprand. TG

Postprandial TG

hours

• ↑ fasting TG • ↑ postprandial TG

Spezif. Aktivität

Combined Dyslipoproteinemia HDL-catabolism

days

• ↓ HDL-cholesterol

LDL-profile

Pattern A Pattern B

• (small dense LDL)

Elevated Risk for Atherosclerosis ApoBProd

Apolipoprotein-B Metabolism in Type 2 Diabetes mellitus controls (n=5)

DM-2 (n=5)

400

40

10

200

20

5

0

0

0

Triglycerides (mg/dl)

ApoB Secretion (mg/kg/d)

VLDL-FCR (pool/d)

* p<0.05 Diab. Stoffw. 1996

2Step

2-Step Model of Lipoprotein Secretion MTP

TG

ApoB

TG

degradation

Shelness et al. Curr.Op.Lipid 2001 Twist et al. J. Clin. Invest 2000

secretion VLDL

• availability of FFA, chol.

• LDL-receptors

pp

Triglyceride Concentration Following an Oral Fat Load 800

metabolic syndrome with hypertriglyceridemia

700

triglycerides (mg/dl)

600 500 400 300

controls

200 100 0 0

2

4

6

8

10

12

14

time after fat meal (h) Parhofer et al. JCEM 2000 (85): 4224-4230 J. Lipid Res. 2003 (44): 1192-1198

HDL

Reverse Cholesterol Transport â&#x20AC;&#x201C; Interaction with Triglyceride Rich Particles cell membrane increased production

FC

CE

CE

CETP

LCAT HDL

HDL

TG

triglyceride-rich HDL

triglyceride-rich lipoproteins

decreased catabolism

HL catabolism HDL

antiinflammatory

reverse cholesterol transport

inhibits â&#x20AC;&#x17E;tissue factorâ&#x20AC;&#x153;

stimulates eNOS

anti-oxidative

HDL

antithrombotic

HDL as transporter of cholesterol, anti-oxidants, pro-/anti-inflammatory signals

sdLDL

LDL-Subtype Distribution (n=30) LDL-chol:

controls

fam. hyperchol.

diab. mell. 2

116±20 3.0±0.5

227±30 5.9±0.8

162±34 4.2±0.9

mg/dl mmol/l

60 Percent of total LDL

40 20

Large buoyant LDL Geiss et al. Metabolism 2001

intermediate LDL

small-dense LDL

* p<0.05 clinsig

Dyslipidemia im Metabolic Syndrome: clinical significance

cholesterol ↑ triglycerides ↑ ↑

risk for atherosclerosis ↑ risk for pancreatitis ↑

HDL-cholesterol ↓ small-dense LDL ↑

Deterioration of insulin sensitivity

goals

NCEP ATP* III: LDL Goals and Treatment Thresholds Risk group

LDL-cholesterol goal

Drug therapy

< 100 mg/dl (2,6 mmol/l) (optional: <70 mg/dl; 1,8 mmo/l)

≥ 100 mg/dl (2,6 mmol/l)

Moderate risk: ≥ 2 RF (10-year risk 10-20%)

< 130 mg/dl (3,4 mmol/l)

≥ 130 mg/dl (3,4 mmol/l)

Moderate risk: ≥ 2 RF (10-year risk <10%)

< 130 mg/dl (3,4 mmol/l)

≥ 160 mg/dl (4,1 mmol/l)

Low risk: ≤1 RF

< 160 mg/dl (4,1 mmol/l)

≥ 190 mg/dl (4,9 mmol/l)

High risk: CAD* or CAD-equivalent (peripheral arterial disease, abdominal aneurysma, cerebro-vascular disease; diabetes) (10-year risk >20%)

Risk factors: Smoking, hypertension, low HDL-cholesterol (<40 mg/dL), positive family history for premature CAD (male <55 years; female <65 year), age (male ≥45 years; female ≥ 55 years) Grundy SM et al.; Circulation 2004; 110: 227-239 RRR

A

SC

C

AR

D

O

T

S

ER SP PR O

H

PS

A FC A

LI PI D

O W

AR C

4S

E

SC

O

PS

PS

Relative Risk Reduction with Statins

37%

36%

0

10 15% 20 24% 30

24%

24%

29% 34%

40

37%

4S=Scandinavian Simvastatin Survival Study1; CARE=Cholesterol and Recurrent Events2; WOSCOPS=West of Scotland Coronary Prevention Study; LIPID=Long-term Intervention with Pravastatin in Ischemic Disease; AFCAPS=Air Force/Texas Coronary Atherosclerosis Prevention Study; HPS=HeartProtection Study; PROSPER=Prospective Study of Pravastatin in Elderly at RISK; CARDS=Collaborative Atorvastatin Diabetes Study; ASCOTLLA=Anglo-Scandinavian Cardiac Outcomes Trial.

A

SC

C

AR

D

O

T

S

ER SP PS H

PR O

A FC A

LI PI D

O W

AR C

4S

E

SC

O

PS

PS

Relative Risk Reduction with Statins â&#x20AC;&#x201C; Residual Risk

37%

36%

0 10

15%

20

24%

30 40 50 60 70 80 90

34%

29%

24%

24% 37%

Further lowering of LDLcholesterol ?

By optimizing LDL, HDL and triglycerides ?

100 4S=Scandinavian Simvastatin Survival Study1; CARE=Cholesterol and Recurrent Events2; WOSCOPS=West of Scotland Coronary Prevention Study; LIPID=Long-term Intervention with Pravastatin in Ischemic Disease; AFCAPS=Air Force/Texas Coronary Atherosclerosis Prevention Study; HPS=Heart-Protection Study; PROSPER=Prospective Study of Pravastatin in Elderly at RISK; CARDS=Collaborative Atorvastatin Diabetes Study; ASCOT-LLA=Anglo-Scandinavian Cardiac Outcomes Trial. lower

Coronary events and LDL-cholesterol

Non-statin studies

POSCH

POSCH

Coronary events (%)

25

Secondary prevention Placebo

4S

LRC

Verum Verum I

20

Verum II

POSCH

CARE LIPID

4S

15 CARE TNT(A10)

10 5 0

LIPID

HPS

TNT(A80) IDEAL (S) IDEAL (A) PROVE-IT(P) HPS ASCOT PROVE-IT(A) JUPITER JUPITER ASCOT AFCAPS

50

70

90

110

130

WOS WOS

LRC

Primary prevention Placebo

LRC

Verum

AFCAPS

150

170

190

210

LDL-cholesterol (mg/dl) FOS

The incremental benefits of raising HDL-cholesterol during lipid therapy after adjustment for other blood lipid levels (Framingham Offspring Study) Change in HDL during lipid therapy: Q1: -37 to -3 mg/dl Q2: -2.7 to 2.3 mg/dl Q3: 2.5 to 7.0 mg/dl Q4: 7.5 to 35 mg/dl

Arch Intern Med. 2009 Oct 26;169(19):1775-80

Med

Drugs for Dyslipoproteinemia effect on lipids Statins Fibrates Ezetimibe

LDL

↓ ↓ ↓, TG ↓

LDL ↓, TG

↓ ↓ ↓, HDL ↑

LDL ↓

↓

↓ ↓, TG ↑

Outcome data ++++ / +/?

+

Resins

LDL

Omega 3 FA

TG ↓ ↓, HDL ↑

+ /(-)

LDL ↓ ↓, TG ↓ ↓, HDL ↑ ↑

+

Niacin

ACC-Fib

Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus (n=5518; fenofibrate vs. placebo on simvastatin background; 4.7 years)

The ACCORD Study Group. N Engl J Med 2010;10.1056/NEJMoa1001282 Fib

Meta-analysis of the Effect of Nicotinic Acid Alone or in Combination on Cardiovascular Events

Bruckert E. et al. Atherosclerosis 2010 Med

Drugs for Dyslipoproteinemia effect on lipids Statins Fibrates Ezetimibe

LDL

↓ ↓ ↓, TG ↓

LDL ↓, TG

↓ ↓ ↓, HDL ↑

LDL ↓

↓

↓ ↓, TG ↑

Outcome data ++++ / +/?

+

Resins

LDL

Omega 3 FA

TG ↓ ↓, HDL ↑

+ / (-)

LDL ↓ ↓, TG ↓ ↓, HDL ↑ ↑

+

Niacin

Stat-DM

Statin Therapy and the Risk of Developing Type 2 Diabetes (Meta-Analysis) (6 studies; n=57593; follow-up 3.9 years)

Rajpathak S.N. et al. Diabetes Care 2009;32: 1924-1929 Algo

Treatment of Dyslipidemias Define lipid goals Life Style Modification Drug Therapy Hypertriglyceridemia

Combined dyslipidemia LDL-hypercholesterolemia

Fibrate/ Ď&#x2030;3FS/ Niacin

(

Statin

)

Statin + Fibrate

Statin + Ď&#x2030;3FS

Parhofer K Vasc Health Risk Man. 2009 (5): 901-8

Statin + Niacin

Statin + Statin + Ezetimibe Colesev. new

Dyslipidemia and Hypertension in Diabetic Patients

• Case • Dyslipidemia • Hypertension • Multifactorial Therapy • Case HOT

Effect of Blood Pressure Control on Cardio-Vascular Event Rates and Mortality in Patients with Diabetes (HOT-Study; n=17890; 8% Diabetic)

Hansson et al. Lancet 1998 (351): 1755-62

ACC-HTN

Effects of Intensive Blood-Pressure Control in Type 2 Diabetes Mellitus (n=4733; systolic BB <120 vs <140 mmHG; 4.7 years)

The ACCORD Study Group. N Engl J Med 2010;10.1056/NEJMoa1001286

Med

Effect of Antihypertensive Medications on New Onset Type 2 Diabetes Meta-analysis of 22 studies with 143153 patients

Elliott WJ, Meyer PM, Lancet 369:201 (2007) i-Resp

Effect of Irbesartan vs. Hydrochlorothiazide on Glucose Metabolism in Patients with Metabolic Syndrome (i-RESPOND; n=426; 16 weeks; Irbesartan 300 mg/d vs. HCTZ 25 mg/d)

Parhofer et al. Int. J. Clin. Pract.2010 (64): 160-168 RM

Dyslipidemia and Hypertension in Diabetic Patients

• Case • Dyslipidemia • Hypertension • Multifactorial Therapy • Case Steno

Intensive vs. Conventional Diabetes Therapy: Steno-2 Study (n=160; study: 0-8 years; follow-up: 8-13 years)

Gaede P et al. N Engl J Med 2008;358:580-591 REACH

Diabetic Patients with Symptomatic Atherothrombosis (REACH Registry; 2390 diabetic, 852 with CAD, 286 with CVD, 176 with PAD)

CAD

CVD

pad

Blood Pressure (mmHg)

141/81

145/83

145/81

LDL-cholesterol (mg/dl) (mmol/l)

106 (2,7)

122 (3,1)

124 (3,2)

At LDL-goal

49%

30%

33%

At BP-goal

30%

25%

25%

Reaching all goals

9,5%

8,5%

0%

CAD patients take significantly more statins, beta-blockers, diuretics, nitrates No differences with respect to antidiabetics, ACE-inhibitors, aspirin Parhofer KG et al. Exp. Clin. Endocrin. Diabetol. 2010; 118: 51-6 RM

Dyslipidemia and Hypertension in Diabetic Patients

• Case • Dyslipidemia • Hypertension • Multifactorial Therapy • Case

Case 1: KF, 63 years, male Diagnoses: • Diabetes mellitus type 2 for 8 years • Obesity Grade 1, BMI 31.3 kg/m² • Diabetic nephropathy • Diabetic neuropathy • Diabetic dyslipidemia • CAD (MI 3 years ago) Presentation to office for better lipid control

Case 1: KF, 63 years, male Complaints: no specific complaints Current medications: • Metformin 1000 mg • Aspirin 100 mg • Ramipril 5 mg • Metoprolol 50 mg • Simvastatin 40 mg

BID qd qd BID qd

Case 1: KF, 63 years, male Physical exam: • Height 176 cm • Weight 97 kg • Waist circumference 101 cm, • Blood pressure 145/83 mmHg • Pulse 80/min.

• Pedal pulses palpable • Pretibial edema bilaterally • Neuropathy bilaterally

Case 1: KF, 63 years, male Clinical chemistry: • HbA1c 7.2% • Fasting glucose 137 mg/dl (7.6 mmol/l) • Creatinine 1.2 mg/dl • BUN 32 mg/dl (10.2 mmol/l) • Uric acid 7.8 mg/dl (460 μmol/l) • Gamma-GT 91 U/l, AST 71 U/l, ALT 55 U/l Lipid profile (taking 40 mg Simvastatin): • Total cholesterol 210 mg/dl (5.4 mmol/l) • Triglycerides 233 mg/dl (2.6 mmol/l) • LDL-cholesterol 128 mg/dl (3.4 mmol/l) • HDL-cholesterol 34 mg/dl (0.9 mmol/l) • Lipoprotein(a) 36 mg/dl Q lipid

Case 1: Question 2 How should the dyslipidemia in this patient be approached?

1.

2.

3.

4.

5.

Wait until better glucose control is achieved Combine statin with fibrate Combine statin with ezetimibe Combine statin with niacin/laropiprant Combine statin with omega-3 fatty acids

Q HTN

Case 1: Question 5 How should blood pressure control be improved in this patient ?

1.

2.

3.

4.

5.

Increase dose of ramipril Increase dose of metoprolol Continue ramipril, add ARB Continue ramipril, add HCT Continue ramipril, add Ca-channel blocker

control

Case 1: KF, 63 years, male New medication: • Metformin 1000 mg → • Simvastatin 40 mg → • Ramipril 5 mg →

Metformin + Sitagliptin Simvastatin + ER Niacin/Laropiprant Ramipril + HCT

• Metoprolol (unchanged) • Aspirin (unchanged) control

Case 1: KF, 63 years, male Control visit (3 months after change in therapy) • Stable weight • BP 130/82 mmHg • HbA1c 6.8 % • Fasting glucose 127 mg/dl (7.6 mmol/l) • Creatinine 1.3 mg/dl • Gamma-GT 66 U/l, ALT 45 U/l, AST 42 U/l • Total cholesterol 178 mg/dl (4.6 mmol/l) • Triglycerides 196 mg/dl (2.2 mmol/l) • LDL-Cholesterol 96 mg/dl (2.5 mmol/l) • HDL-Cholesterol 43 mg/dl (1.1 mmol/l) End

End