insights in recent guidelines in management of diabetic hypertensive dyslipidemic

Recent Guidelines For Management of Diabetic Hypertensive Dyslipidemic Patients

BY ASHRAF OKBA

PROF.OF INTERNAL MEDICINE AIN SHAMS UNIVERSITY

Agenda

• Silent killers• DM and HTN• Atherogenic Diabetic Dyslipidemia.

The Silent Killers

Adapted from Dzau VJ, Braunwald E. Am Heart J 1991;121:1244–63CVD = cardiovascular (CV) disease

Diabetes,Hypertension,Dyslipidemia

Risk factors

Athero-sclerosis

Myocardialischaemia

Ventricularremodelling

Ventriculardilatation

Heartfailure

End stageCVD

Death

HYPERTENSION IN DIABETICS

4

Diseases Attributable to Hypertension

5

Hypertension

Heart failureStroke

Coronary heart disease

Myocardial infarction

Left ventricular hypertrophy

Aortic aneurysm

Retinopathy

Peripheral vascular disease

Hypertensive encephalopathy

Chronic kidney failure

Cerebral hemorrhage

Adapted from: Arch Intern Med 1996; 156:1926-1935.

AllVascular

ESH-ESC 2013 , Diabetic hypertensive is high risk grade I hypertension

Global cardiovascular risk in all hypertensive patients

2014

91%

Rantala A, et al. J Intern Med 1999;245;163-74. Wannamethee S, et al. J Hum Hypertens 1998;12;735-41

Risk factors = Global CV risk

91% of hypertensive patients have at least 1 additional risk factor

East West Study: Patients with Diabetesat Similar Risk to No Diabetes with MI

0

10

20

30

40

50

7-ye

ar in

cide

nce

rate

of

MI

(%)

No prior MIMI

p<0.001

p<0.001

No diabetes (n=1373) Diabetes (n=1059)

Adapted from Haffner SM et al. N Engl J Med 1998;339:229–234

How Common DM&HTN Duo?HTN is twice as common in DM

New onset DM is 2.5 times in HTN

20 to 40% of IGT pts have HTN

40 to 50% of Type 2 DM have HTN

Only 1/4 of HTN in DM is controlled

DM + HTN – CV Risk 3 fold

What Causes HTN in DM

• Metabolic Syndrome – Mainly IR, ED, BG• Excessive RAAS activity is the main mechanism• HTN due to nephropathy in T2DM – GS - KWL• Renal scarring - Recurrent pyelonephritis• Endocrine causes for both HTN & DM

– Cushing’s, Conn’s, Pheochromo, Acromegaly • Coincidental – DM on existing HTN• Diabetogenic antihypertensive drugs (D and B) • Drugs causing both HTN & DM – OCP, CS

Relative Risk of DM + HTN

Diabetes + HTN versus Diabetes• Neuropathy 1.6

• Nephropathy 2.0

• Retinopathy 2.0

• Stroke 4.0

• CHD 3.0• Mortality 2.0

Difficulties of HTN in DM• Systolic HTN more common in DM• S-HTN is a stronger predictor of CVE• 65% of T2DM have S-HTN• S-HTN is more difficult to control• Depression is more in DM –

Adherence Rx• ‘Clinician Inertia’ is a big problem• Glycemic control only is the focus

Angiotensin II is correlated to hypertensive disease progression

Adapted from: Chung O. & Unger T., Am J Hypertens 1999;12:150S–156S

Risk factors: diabetes, obesity, smoking, age

VasoconstrictionVascular hypertrophy

Endothelial dysfunctionAtherosclerosis

Hypertension

Pro-thrombotic state

Vascular disease

ApoptosisLVHFibrosis

ArrhythmiaHeart failureMI

StrokeCognitive dysfunction

Renal failure

Death

Decreased GFRProteinuria/albuminuriaGlomerulosclerosis

Ang II via AT1

ESH/ESC 2013 One Goal For All

2013 ESH/ESC Guidelines for the management of arterial hypertension

Drugs to be preferred in specific conditions ESC/ESH 2013

CURRENT CHRONIC KIDNEY DISEASE (CKD) NOMENCLATURE USED BY KDIGO CKD

KDIGO Guidelines, December, 2012

B.P. Target

KDIGO Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl. 2013;3:136-150. http://www.kdigo.org/clinical_practice_guidelines/pdf/CKD/KDIGO_2012_CKD_GL.pdf Accessed February 26, 2013.

JNC 8

Treatment strategiesLifestyle change:

• Smoking cessation • Moderation of alcohol consumption • Sodium restriction • Weight reduction • Physical exercise

ESC/ESH 2013, The advantage of initiating with combination therapy

• Synergies between different classes of agent.• Prompter response in a larger number of patients (potentially

beneficial in high-risk patients).• Achieving the target BP in patients with higher BP values. • Encouraging patient adherence by minimizing treatment

changes.• Considering initiation with a drug combination in patients at

high risk or with markedly high baseline BP.


ESH–ESC 2013 : Algorithm for Treatment of Hypertension


‘The extra blood pressure reduction from combining drugs from 2 different classes

is approximately 5 times greater than doubling the dose of 1 drug’

Conclusions from a meta-analysis comparing combination antihypertensive therapy with monotherapy in 11,000 patients

from 42 trials

Adding an antihypertensive agent with a different MOA is more effective than titrating

Wald et al. Am J Med 2009;122:290–300

MOA: mechanism of action

ATHEROGENIC DIABETIC DYSLIPIDEMIA

32

33

CHD=coronary heart disease.1. Centers for Disease Control and Prevention. National diabetes fact sheet: national estimates and general information on diabetes and

prediabetes in the United States, 2011. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2011.

Most Patients With Diabetes Die of Cardiovascular Disease1

• National Diabetes Fact Sheet 2011: among people ≥65 years of age– Heart disease was noted on 68% of diabetes-

related death certificates.– Risk of stroke is 2 to 4 times greater among people

with diabetes compared with those without diabetes.

– Stroke was noted on 16% of diabetes-related death certificates.

34

CVD=cardiovascular disease; MRFIT=Multiple Risk Factor Intervention Trial.1. Stamler J et al. Diabetes Care. 1993;16:434–444.

CVD

Mor

talit

y pe

r10

,000

Per

son-

Year

s

DiabetesNo diabetes

Serum Cholesterol at Baseline, mg/dL

0

20

40

60

80

100120140

<180 180–199 200–219 220–239 240–259 260–279 ≥280

160

Higher CVD Mortality Risk in Patients With Diabetesand Low Cholesterol Than in Patients Without Diabetes and High Cholesterol1

• Cohort study in 347,978 men aged 35 to 57 years, screened in 20 centers for MRFIT• Vital status ascertained over an average of 12 years• Outcome measure was CVD mortality

n = 1105n = 972 n = 1038 n = 823

n = 529

n = 343n = 353

n = 62,448 n = 64,363 n = 75,112 n = 60,386 n = 40,090n = 22,802

n = 17,604

Patients With T2DM Are More Likely to Have Small, Dense LDL Particles1–3

apoB=apolipoprotein B; CHD=coronary heart disease; LDL=low-density lipoprotein; LDL-C=low-density lipoprotein cholesterol; T2DM=type 2 diabetes mellitus.1. Selby JV et al. Circulation. 1993;88:381–387. 2. Feingold K et al. Arterioscler Thromb. 1992;12:1496–1502. 3. Sniderman AD et al. Diabetes Care. 2002;25:579–582.

LDL-C levels in people with diabetes can be misleading;Patients may have more LDL particles at a given LDL-C level

35

Large, buoyant LDL Small, dense LDL

Same LDL-C

Cholesterol

ApoB

Large LDL Small Dense LDL

Apo B LDL-C

130 mg/dL

Fewer Particles &Less Risk/Particle

More Particles &More Risk/Particle

More Apo-B

Otvos JD, et al. Am J Cardiol. 2002;90:22i-29i.

TC 198 mg/dLLDL-C 130 mg/dLTG 90 mg/dLHDL-C 50 mg/dLNon–HDL-C148 mg/dL

TC 210 mg/dLLDL-C 130 mg/dLTG 250 mg/dLHDL-C 30 mg/dLNon–HDL-C180 mg/dL

Same LDL-C Levels, Different Cardiovascular Risk.

Lipid ProfileLipid Profile

ADD, Atherogenic Diabetic Dyslipidemia

Increased susceptibility to oxidation

Increased vascular permeability

Conformational change in apo B

Decreased affinity for LDL receptor

Association with insulin resistance syndrome

Association with high TG and low HDL

Small Dense LDL and CHD Potential Atherogenic Mechanisms

Austin MA et al. Curr Opin Lipidol 1996;7:167-171.

aFor world populations the IAS recommends using the Lloyd-Jones/Framingham algorithm2 for estimating absolute risk for total ASCVD to age 80 years. The calculated risk should then be recalibrated based on the coefficients determined by national comparisons with Framingham estimates. If recalibration values are not available, it may be more prudent to focus treatment on individual risk factors..

bAll patients with established ASCVD, including a history of CHD, stroke, PAD, carotid artery disease, and other forms of atherosclerotic vascular disease.IAS = International Atherosclerosis Society; ASCVD = atherosclerotic cardiovascular disease; CHD = coronary heart disease; PAD = peripheral arterial disease.1. International Atherosclerosis Society Web site. www.athero.org/IASPositionPaper.asp. Accessed November 11, 2013. 2. Lloyd-Jones DM et al. Circulation. 2006;113:791–798.

IAS 2013 Position Paper: LDL-C and Non–HDL-C as Major Targets of Therapy1

LDL-C is the major target of therapy; non–HDL-C is an alternate target. Total apoB is considered an optional target of therapy

– The IAS does not specify treatment goals for LDL-C and non–HDL-C, but rather identifies optimal levels

• The optimal LDL-C level for primary prevention is <100 mg/dL (2.6 mmol/L) (or non–HDL-C of <130 mg/dL), especially in high-risk populations

– Risk to age 80 for ASCVD: high (≥45%), moderately high (30%–44%), moderate (15%–29%), and low (<15%)a

– Near-optimal LDL-C levels (100–129 mg/dL [2.6–3.3 mmol/L]) (or non–HDL-C <130–159 mg/dL [3.4–4.1 mmol/L]) may be acceptable in low-risk patients or those with a paucity of other risk factors

• Optimal levels for LDL-C and non–HDL-C for secondary prevention are <70 mg/dL (1.8 mmol/L) and <100 mg/dL (2.6 mmol/L), respectivelyb

Predisposition to thrombosis - Atherogenic Diabetic Dyslipidemia - Platelet hyper-aggregability - Elevated concentrations of pro-coagulants - Decreased concentration and activity of antithrombotic

factors Predisposition to attenuation of fibrinolysis - Decreased t-PA activity - Increased PAI-1 - Decreased concentrations of 2-antiplasmin

Imbalance Between Thrombosis and Fibrinolysis in Subjects with Diabetes

Sobel BE. Circulation 1996;93:1613-1615.

Case Study• 49-year-old white man with a history of type 2 diabetes,

obesity and hypertension.• Non smoker

• weight fluctuating between 75 and 83 Kg.

• Most recent hemoglobin A1c of 7.4%.

• Hypertension was diagnosed 5 years ago 160/90 mmHg, treated with Enalapril, starting at 10 mg daily and increasing to 20 mg daily, yet his BP control has fluctuated.

Case Study

• The man comes into the office today for his usual follow-up visit for diabetes.

• Physical examination reveals an obese man with a BP of 154/86 mmHg and a pulse of 78 bpm.

• Total cholesterol : 180 mg/dl• LDL-c:101 mg/dl• HDL: 35 mg/dl• TG:220 mg/dl

Definition of Cardiovascular Risk and Treatment GoalsEAS/ESC Guidelines

Patient group LDL-C treatment goal

Very high-risk - Established CVD, type 2 diabetes,

type 1 diabetes with target organ damage, moderate to severe CKD or a SCORE level ≥10%

(~<70 mg/dL) and/or ≥50% reduction when target level cannot be reached

High-risk - Markedly elevated single risk

factors, a SCORE level ≥5 to <10% (~<100 mg/dL)

Moderate-risk - SCORE level >1 to ≤5% (~<115 mg/dL)

Low-risk - SCORE level <1%† -

Reiner Z et al. Eur Heart J 2011; 32: 1769–818SCORE=Systematic Coronary Risk Estimation; †Lifestyle advice recommended to maintain this level of risk

Reiner Z et al. Eur Heart J. 2011;32:1769-1818.Catapano AL et al. Atherosclerosis. 2011;217S:S1-S44.

44

2013 ACC/AHA Cholesterol Treatment Guideline Recommendations

45

Focus on ASCVD Risk Reduction: 4 statin benefit groups*

46Stone NJ, et al. J Am Coll Cardiol. 2013: doi:10.1016/j.jacc.2013.11.002. Available at: http://content.onlinejacc.org/article.aspx?articleid=1770217. Accessed November 13, 2013.

Clinical ASCVD† LDL-C level ≥190 mg/dL

Diabetes, aged 40-75 years, with LDL-C 70-189

mg/dL

Estimated 10-year risk of ASCVD of ≥7.5%,‡ 40-75

years of age, and with LDL-C 70-189

mg/dL

* Moderate- or high-intensity statin therapy recommended for these 4 groups

† Clinical ASCVD defined as acute coronary syndromes, history of MI, stable or unstable angina, coronary or arterial revascularization, stroke, transient ischemic attacks, or peripheral artery disease‡ Estimated using Pooled Cohort Risk Assessment Equations

http://content.onlinejacc.org/article.aspx?articleid=1770217

Primary Prevention

* Estimated using Pooled Cohort Risk Assessment Equations

Stone NJ, et al. J Am Coll Cardiol. 2013: doi:10.1016/j.jacc.2013.11.002. Available at: http://content.onlinejacc.org/article.aspx?articleid=1770217. Accessed November 13, 2013.

Moderate-Intensity Statin

Patients with Diabetes and LDL-C 70-189 mg/dL

(age 40-75 years) without clinical ASCVD

High-Intensity Statin if ≥7.5% estimated 10-year ASCVD risk*


YesYes

No

No

No

No

Yes

Yes

YesCalculate 10-yr

ASCVD risk using Pooled Cohort

Equations

Adults > 21 years of age and candidate for statin

Clinical ASCVD?

LDL-C > 190 mg/dL?

Diabetes?

> 7.5% 10-yr ASCVD risk?

High-intensity statin(Moderate-intensity if > 75 yo or not candidate for high-intensity statin)

High intensity statin(Moderate-intensity if not candidate for

high-intensity)

Moderate-intensity statin(High-intensity if 10-yr

ASCVD risk > 7.5%)

Moderate-to-high intensity statin

ASCVD prevention benefit less clear, but may be consideredStone NJ, et al. J Am Coll Cardiol. 2013: doi:10.1016/j.jacc.2013.11.002. Available at: http://content.onlinejacc.org/article.aspx?articleid=1770217. Accessed November 13, 2013.


Recommendations for Non-statin Therapies

• No data supporting the routine use of non-statin drugs combined with statin therapy to further decrease ASCVD events

• In high-risk patients who have an insufficient response to statin therapy, or who are unable to tolerate either a statin or the recommended statin intensity, addition of a non-statin cholesterol-lowering therapy can be considered



Role of Biomarkers and Non-invasive Tests in Assessing ASCVD Risk


Treatment decisions in selected individuals who are not included in the 4 statin benefit groups may be informed by other factors as recommended by the Risk Assessment Work Group guideline

Factors include: Primary LDL–C ≥160 mg/dL or other evidence of genetic hyperlipidemias Family history of premature ASCVD with onset <55 years of age in a first degree

male relative or <65 years of age in a first degree female relative High-sensitivity C-reactive protein ≥2 mg/L Coronary Artery Calcium score ≥300 Agatston units or ≥75 percentile for age,

sex, and ethnicity Ankle-brachial index <0.9 Elevated lifetime risk of ASCVD


2011 ESC/EAS1 2013 ACC/AHA2

Diagnosis and risk stratification SCORE system for CV risk estimation; 4 patient groups at highest risk of CVD

Pooled Cohort Equations for 10-year ASCVD risk estimation; 4 statin benefit groups

Management Statin as first-line therapy LDL-C is primary target; treat to goals

Statin as first-line therapyLDL-C is primary target; do not treat to goals

Monitoring Lipid panel and ALT before and after treatment initiation

Lipid panel before and after treatment initiation to monitor response and adherence. For safety, ALT before treatment

Summary

References1.Catapano AL et al. Atherosclerosis. 2011;217:3–46. (Pages 6, 7, 8, 17, 25 and 41)2.Stone NJ et al. J Am Coll Cardiol. 2014;63(25 Pt B):2889–2934. (Pages 2894, 2899, 2900–2902, 2907, 2908, 2911 and 2914)

©2014Ashfield Healthcare

Communications

SMILE AT YOUR PATIENT AND CUSTOMIZE

ASHRAF OKBA

56

Approach to management of hyperglycemia

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print](Adapted with permission from: Ismail-Beigi F, et al. Ann Intern Med 2011;154:554)

1. Type 2 diabetes, hypertension and dyslipidemia are silent killers

2. Angiotensin II is correlated to hypertension in diabetes3. The combination of two blockers of RAAS system is not

recommended and should be discouraged. 4. CVD Mortality Risk in Patients With Diabetes

and Low Cholesterol is Higher Than in Patients Without Diabetes and High Cholesterol.

5. Diabetic patients (age 40-75 years) and LDL more than 70 mg/dl must receive Statins.

Take Home messages

01/05/2023 09:19:38 AM 60

Thank you

The Effect of Rosuvastatin on Low-DensityLipoprotein Subfractions in Patients With

Impaired Fasting Glucose

Christos V. Rizos, MD1, Michael S. Kostapanos, MD1, Evangelos C. Rizos, MD1,Alexandros D. Tselepis, MD2, and Moses S. Elisaf, MD, FASA, FRPSH

J CARDIOVASC PHARMACOL THER published online 18 September 2014

Objective

• We examined the effect of rosuvastatin on the quantity and quality of low-density lipoprotein cholesterol (LDL-C) in patients with dyslipidemia having impaired fasting glucose (IFG) compared to normoglycemic patients with dyslipidemia

Design

This was a prospective observational study including 127 patientswith dyslipidemia and IFG (IFG group, n = 49) matched with normoglycemic patients with dyslipidemia (control group, n = 64) prescribed rosuvastatin 10 or 20 mg/d to achieve LDL-C goals. Baseline as well as 24 weeks posttreatment changes in the serum lipid profile were evaluated and analysis of the LDL subfraction profile was conducted using a polyacrylamide tube gel electrophoresis method.

Conclusion

Targeting dyslipidemia with rosuvastatin was associated with more favorable changes in the LDL subfraction profile in patients with IFG compared to normoglycemic ones

Accumulation of chylomicron remnants Accumulation of VLDL remnants Generation of small, dense LDL-C Association with low HDL-C Increased coagulability - plasminogen activator inhibitor (PAI-1) - factor VIIc - Activation of prothrombin to thrombin

Hypertriglyceridemia and CHD Risk: Associated Abnormalities

Increased plasma fibrinogen Increased plasminogen activator inhibitor 1 Increased platelet aggregability

Factors Promoting Thromboembolic Disease in Diabetes

Thompson SG et al. N Engl J Med 1995;332:635-641.

Predisposition to thrombosis - Platelet hyperaggregability - Elevated concentrations of procoagulants - Decreased concentration and activity of

antithrombotic factors Predisposition to attenuation of fibrinolysis - Decreased t-PA activity - Increased PAI-1 - Decreased concentrations of 2-antiplasmin

Imbalance Between Thrombosis and Fibrinolysis in Subjects with Diabetes

Sobel BE. Circulation 1996;93:1613-1615.

LDL cholesterol lowering* - First choice: HMG CoA reductase inhibitor (statin) - Second choice: Bile acid binding resin or fenofibrate HDL cholesterol raising - Behavior interventions such as weight loss, increased physical activity and

smoking cessation - Glycemic control - Difficult except with nicotinic acid, which is relatively contraindicated, or fibrates Triglyceride lowering - Glycemic control first priority - Fibric acid derivative (gemfibrozil, fenofibrate) - Statins are moderately effective at high dose in hypertriglyceridemic

subjects who also have high LDL cholesterol * Decision for treatment of high LDL before elevated triglyceride is based on clinical trial

data indicating safety as well as efficacy of the available agents.

Order of Priorities for Treatment of Diabetic Dyslipidemia in Adults*

Adapted from American Diabetes Association. Diabetes Care 2000;23(suppl 1):S57-S60.

Intensity of Statin Therapy

High-Intensity Statin Therapy Moderate-Intensity Stain Therapy

Low-Intensity Statin Therapy

LDL–C ↓ ≥50% LDL–C ↓ 30% to <50% LDL–C ↓ <30%

Atorvastatin (40†)–80 mg Rosuvastatin 20 (40) mg

Atorvastatin 10 (20) mg Rosuvastatin (5) 10 mg Simvastatin 20–40 mg‡ Pravastatin 40 (80) mg Lovastatin 40 mg Fluvastatin XL 80 mg Fluvastatin 40 mg bid Pitavastatin 2–4 mg

Simvastatin 10 mg Pravastatin 10–20 mg Lovastatin 20 mg Fluvastatin 20–40 mg Pitavastatin 1 mg


Lifestyle modification remains a critical component of ASCVD risk reduction, both prior to and in concert with the use of cholesterol lowering drug therapies. Statins/doses that were not tested in randomized controlled trials (RCTs) reviewed are listed in italics†Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in IDEAL‡Initiation of or titration to simvastatin 80 mg not recommended by the FDA due to the increased risk of myopathy, including rhabdomyolysis.


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insights in recent guidelines in management of diabetic hypertensive dyslipidemic