This document provides recent guidelines for managing patients with diabetes, hypertension, and dyslipidemia. It discusses the risks these conditions pose together, such as a 3-fold increased risk of cardiovascular events. Guidelines recommend treating all three conditions aggressively through lifestyle changes and medication to control blood pressure and lipid levels. The optimal LDL cholesterol level is below 100 mg/dL to minimize heart disease and stroke risk.

1. Recent Guidelines For Management
of Diabetic Hypertensive
Dyslipidemic Patients
BY
ASHRAF OKBA
PROF.OF INTERNAL MEDICINE
AIN SHAMS UNIVERSITY

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

3. The Silent Killers
Adapted from Dzau VJ, Braunwald E.
Am Heart J 1991;121:1244–63
CVD = cardiovascular (CV) disease
Diabetes,
Hypertension,
Dyslipidemia
Risk
factors
Athero-
sclerosis
Myocardial
ischaemia
Ventricular
remodelling
Ventricular
dilatation
Heart
failure
End stage
CVD
Death

4. HYPERTENSION IN DIABETICS
4

5. Diseases Attributable to Hypertension
5
Hypertension
Heart failure
Stroke
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.
All
Vascular

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

8. Global cardiovascular risk in all hypertensive
patients
201
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

13. East West Study: Patients with Diabetes
at Similar Risk to No Diabetes with MI
0
10
20
30
40
50
7-yearincidencerateofMI(%)
No prior MI
MI
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

14. 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

15. 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

16. 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

17. 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

18. 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
Vasoconstriction
Vascular hypertrophy
Endothelial dysfunction
Atherosclerosis
Hypertension
Pro-thrombotic
state
Vascular
disease
Apoptosis
LVH
Fibrosis
Arrhythmia
Heart failure
MI
Stroke
Cognitive
dysfunction
Renal failure
Death
Decreased GFR
Proteinuria/albuminuria
Glomerulosclerosis
Ang II via AT1

19. ESH/ESC 2013
One Goal For All
2013 ESH/ESC Guidelines for the management of arterial hypertension

20. Drugs to be preferred in specific conditions
ESC/ESH 2013

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

24. KDIGO Guidelines, December, 2012

25. 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.

26. JNC 8

28. Treatment strategies
Lifestyle change:
• Smoking cessation
• Moderation of alcohol consumption
• Sodium restriction
• Weight reduction
• Physical exercise

29. 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.
2013 ESH/ESC Guidelines for the management of arterial hypertension

30. ESH–ESC 2013 : Algorithm for
Treatment of Hypertension
2013 ESH/ESC Guidelines for the management of arterial hypertension

31. ‘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

32. ATHEROGENIC
DIABETIC DYSLIPIDEMIA
32

33. 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. 34
CVD=cardiovascular disease; MRFIT=Multiple Risk Factor Intervention Trial.
1. Stamler J et al. Diabetes Care. 1993;16:434–444.
CVDMortalityper
10,000Person-Years
Diabetes
No diabetes
Serum Cholesterol at Baseline, mg/dL
0
20
40
60
80
100
120
140
<180 180–199 200–219 220–239 240–259 260–279 ≥280
160
Higher CVD Mortality Risk in Patients With Diabetes
and 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 = 1105
n = 972
n = 1038 n = 823
n = 529
n = 343
n = 353
n = 62,448 n = 64,363 n = 75,112
n = 60,386 n = 40,090
n = 22,802
n = 17,604

35. 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

36. 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/dL
LDL-C 130 mg/dL
TG 90 mg/dL
HDL-C 50 mg/dL
Non–HDL-C 148 mg/dL
TC 210 mg/dL
LDL-C 130 mg/dL
TG 250 mg/dL
HDL-C 30 mg/dL
Non–HDL-C 180 mg/dL
Same LDL-C Levels, Different Cardiovascular Risk.
Lipid ProfileLipid Profile

37. ADD, Atherogenic Diabetic Dyslipidemia

38.  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.

39. 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

40.  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.

41. 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.

42. 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

43. Definition of Cardiovascular Risk and Treatment Goals
EAS/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: 1769–818
SCORE=Systematic Coronary Risk Estimation;
†Lifestyle advice recommended to maintain this level of risk

44. Reiner Z et al. Eur Heart J. 2011;32:1769-1818.
Catapano AL et al. Atherosclerosis. 2011;217S:S1-S44.
44

45. 45

46. Focus on ASCVD Risk Reduction:
4 statin benefit groups*
46
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.
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

47. 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*

49. Yes
Yes
No
No
No
No
Yes
Yes
Yes
Calculate 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 considered
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.

50. 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
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.

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

52. 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 therapy
LDL-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
References
1.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)

55. ©2014
Ashfield Healthcare
Communications

56. SMILE AT YOUR PATIENT
AND CUSTOMIZE
ASHRAF OKBA
56

57. 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)

59. 1. Type 2 diabetes, hypertension and dyslipidemia are silent
killers
2. Angiotensin II is correlated to hypertension in diabetes
3. 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

60. 09/04/2016 12:36:42 60

61. Thank you

62. The Effect of Rosuvastatin on Low-Density
Lipoprotein 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

63. 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

64. Design
This was a prospective observational study including 127 patients
with 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.

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

67.  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

68.  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.

69.  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.

70.  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.

71. 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
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.
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.