The document discusses diabetic dyslipidemia and its treatment strategies, focusing on a case of a 45-year-old woman with Type 2 diabetes and dyslipidemia. It highlights the importance of statin therapy for both primary and secondary prevention of cardiovascular disease in diabetic patients, emphasizing LDL-c targets and intensity of treatment based on various guidelines. The document also outlines the various risk factors for cardiovascular disease and the efficacy of different medications including statins, ezetimibe, and monoclonal antibodies like PCSK9 inhibitors.

1. DIABETIC DYSLIPIDEMIA
IS LOWER ,BETTER ?
DR. MOHAMMAD DAOUD
CONSULTANT ENDOCRINOLOGIST- ABIM CERTIFIED
KAMC-NGHA JEDDAH

2. WHAT DO YOU THINK?
A 45 year old woman
She was diagnosed with DM2 one year ago
Also has HTN diagnosed 2 years ago
No history CHD, CKD or Atrial fibrillation
Non smoker No F.Hx of premature CHD
BP 128 /78 on ACE-I daily
Height 165 cm Weight 84 kg
Total -C 220 mg/dl (5.7 mmol/L)
HDL-C 45 (1.16 mmol/L) ,TAG 140 (1.6 mmol/L)
LDL-C 140 (3.65 mmol/L)

3. WHAT DO YOU THINK ?
Does this patient need pharmacologic Rx for lipids?
Will you apply primary vs secondary prevention?
What is your objective : Target vs Intensity of Rx?
What is your medication choice ? One vs combination
Which guidelines do you follow ?

4. THE AGENDA…
INTRODUCTION
RISK ASSESSMENT
MANAGEMENT GUIDELINES
MANAGEMENT : STATINS +/-
CONCLUSION

5. CARDIOVASCULAR DISEASE (CVD)
(CVD) =
Disease of the heart and blood vessels caused by the
process of atherosclerosis;
Includes CHD; ACS/Angina,
TIA/Stroke and PAD

7. CARDIOVASCULAR DISEASE (CVD)
(CVD) predominantly affects people older than 50 years
Risk factors
Non-modifiable
Age
Sex
Family history of CVD
Ethnic background
Modifiable
Smoking
HTN
Dyslipidemia
DM
Social : Low income and
social deprivation

8. Type 2 Diabetes Prevalence
MI, myocardial infarction.
1. IDF Diabetes Atlas 6th Edition 2014 http://www.idf.org/diabetesatlas; 2. The Emerging
Risk Factors Collaboration. JAMA. 2015;314(1):52-60.
8
This will rise to
592 million by
20351
Disease status
at baseline
Hazard
ratio
(95% Cl)a
Diabetes, stroke,
and MI
6.9 (5.7,
8.3)
Stroke and MI
3.5 (3.1,
4.0)
Diabetes and
stroke
3.8 (3.5,
4.2)
Diabetes and MI
3.7 (3.3,
4.1)
MI
2.0 (1.9,
2.2)
Stroke
2.1 (2.0,
2.2)
Diabetes
1.9 (1.8,
2.0)
None 1.0 (Ref)
Globally, 387 million
people are living with
diabetes1 All-cause mortality by disease
status of participants at
baseline2
Hazard ratio
(95% CI)
1.0 2.0 4.0 8.0 16.0
Type 2 Diabetes is a CVD

9. DM AND DYSLIPIDEMIA
WHAT MAKES PEOPLE WITH DIABETES
AT SUCH HIGH RISK?
Atherogenic Profile
Insulin resistance /Metabolic syndrome
Low HDL-C
High triglycerides
Higher number of Small dense LDL particles
High non-HDL-C

11. A

12. DM AND DYSLIPIDEMIA
Role of Statins

13. DM AND DYSLIPIDEMIA
HEART PROTECTION STUDY (HPS)
>20,000 Patients ; average follow-up of 5.5 years
Simvastatin (40 mg/day) Vs Placebo
33% with baseline LDL-C <116 mg/dL (<3 mmol/L),
25% with a level of 116 to 135 mg/dL (3 to 3.5 mmol/L)
42% with levels >135 mg/dL (>3.5 mmol/L)
History of CVD (CAD ,CVA or PAD), DM, or HTN on Rx)
Most patients were treated for secondary prevention.

14. HPS: Simvastatin Vs PBO
CHD death and nonfatal
(MI) were reduced by
27%

15. DM AND DYSLIPIDEMIA
(HPS)- RESULTS : PRIMARY PREVENTION
Significant benefits with Simvastatin
3982 DM patients without prior CVD
28 %
(14 versus 18.7 percent)
Reduction in the incidence of
MI and stroke

18. DM AND DYSLIPIDEMIA
CARDS TRIAL
2838 Type 2 DM without known CVD
LDL –C concentration ≤160 mg/dL (4.14 mmol/L), a
Fasting TAG ≤ 600 (6.78 mmol/L) + at least one of the
following: retinopathy, albuminuria, current smoking,
or hypertension
Randomly assigned
Atorvastatin 10 mg Vs Placebo

19. DM AND DYSLIPIDEMIA
CARDS TRIAL- RESULTS
●Terminated two years earlier than expected
●CV events was reduced by 37 % (95% CI -52 to -17)
(Treat 1000 pts for 4 yrs =Prevent 37 major vascular events)
●The absolute reduction in events with Atorvastatin
was similar Regardless of baseline LDL level
(LDL-C above or below 120 mg/dL (3.1 mmol/L)
(reduction from 9.5 to 6.1 % Vs from 8.5 to 3.6 %)

20. H.Ratio
(LDL-C to 62 mg/dL versus 95 mg/dL)
Reduced by 16%

21. LDL : 77 vs 101 mg/dl
Using 80 mg/day of atorvastatin with baseline LDL-C levels of 150 mg/dL,
Total CHD events were reduced 45% to 50%.

23. 18,000 patients with ACS within the preceding 10 days
Baseline LDL 50-125 mg/dl
Or 50-100 mg/dl on prior cholesterol drug
(Average baseline LDL-C was 93.8 mg/dL in each group)
Patients with DM represented 27% of each group
7-Years follow up

24. 24% further lowering of LDL-C

25. EZETIMIBE + STATIN VS PBO + STATIN
IMPROVE-IT TRIAL
-Composite primary endpoint
(CV death, major coronary events, or nonfatal stroke)
-33 % vs 35 % (a 2% lower)
-6.4% risk reduction of total CV events
(Modest impact)
Morbidity … Yes
Less risk by… MI 13 %
Stroke 14% Ischemic Stroke 21%
Mortality :No differences

26. DM AND DYSLIPIDEMIA
LDL RECEPTORS AND CV RISK?
 The key target is the LDL-C receptor in the liver
If LDL receptors are not present in sufficient numbers,
>> Hyper-Cholesterolemia
>> High CV Risk.
1-Can be upregulated / increased by Statins
2-New class PCSK9 monoclonal antibodies,
increases the expression of the LDL-C receptors by
enhancing receptor recycling
PCSK9 = Proprotein Convertase Subtilisin/ Kexin type 9 (PCSK9) serine protease

27. PCSK9 = Proprotein Convertase Subtilisin/ Kexin type 9 (PCSK9) serine protease

28. PCSK9 = Proprotein Convertase Subtilisin/ Kexin type 9 (PCSK9) serine protease

31. DYSLIPIDEMIA AND (CVD)
PCSK9 INHIBITION- ODYSSEY COMBO
ALIROCUMAB VS EZETIMIBE
Efficacy and safety of Alirocumab as add-on to stable,
maximally tolerated, daily statin therapy (Patients with
hypercholesterolemia at high CV risk)
35% of patients have T2DM
An LDL-C of <1.8 mmol/L(<70 mg/dL) was achieved in:
77% with Alirocumab vs
45.6% with Ezetimibe
(P =.0001),

32. DYSLIPIDEMIA AND (CVD)
PCSK9 INHIBITION- ODYSSEY COMBO
ALIROCUMAB VS EZETIMIBE
Comparable reduction rate of the LDL-C level was
comparable in the diabetic and nondiabetic
The LDL-C level :
Reduced from 130 mg/dL to 50 mg/dL; i.e
average decline of 50% ( 60% for non DM )

33. DM AND DYSLIPIDEMIA
FIELD TRIAL / ACCORD-LLA
FIELD trial
9795 patients ages 50 to 75 with type 2 DM (2131 with prior CVD
; 2nd Prevention)
Median follow-up of 5 years
Micronized Fenofibrate 200 mg daily Vs Placebo
ACCOR-LLA
5518 patients with type 2 DM
Fenofibrate 160 mg Vs Placebo;
All patients were treated with Simvastatin
Mean follow-up of 4.7 years

34. Any Guidelines to Help ?

35. DM AND DYSLIPIDEMIA
GUIDELINES?
ATP III-2004
American College of Cardiology (ACC)/American Heart
Association (AHA) guideline- 2013
European Society of Cardiology (ESC)/European
Atherosclerosis Society (EAS) guideline 2014
NICE guideline 2014

36. DM AND DYSLIPIDEMIA
ACC/AHA
Statin Lowering Intensity ;
Lower LDL-C
with an anticipated percentage from base line
Example
High intensity level :
≥ 50% LDL-C in high-risk patients and
Moderate intensity level :
> 30% to <50% in low-risk patients with diabetes.

37. DM AND DYSLIPIDEMIA
NICE
Statin Lowering Intensity
Lower non -HDL-C
with an anticipated percentage from base line
Example
High intensity level :
>40% in high-risk patients and
Moderate intensity level :
31-40% in low-risk patients with diabetes.

38. DM AND DYSLIPIDEMIA
ESC/EAS
Europeans still favor, very much, the target-treated
lower LDL-C approach (like ATP III )
Target LDL-C <70 mg/dL
in almost all patients with T2D
Still evaluate for non-HDL

39. DYSLIPIDEMIA GUIDELINES
WHERE ARE WE NOW?
FROM ….TO

40. 1.Diabetes Mellitus
2.Symptomatic Carotid Artery Disease
3.Peripheral Arterial Disease
4.Abdominal Aortic Aneurysm
5.CRF with Cr > 1.5 or GFR< 60
6.Multiple risk factors with a 10 year risk of CHD> 20%
ATP III –NCEP
CHD RISK EQUIVALENTS

42. LIPIDS ADA 2014… WAS
 To get specified LDL target
Statin therapy should be added, regardless of baseline
lipid levels, for DM patients:
- With overt CVD
-Without CVD who is > 40 years old and
have ≥ 1 other CVD risk factors. (A)
 An alternative therapeutic goal :
Reduction in LDL cholesterol by 30–40% from baseline
(A)

43. LIPIDS ADA 2014… WAS
If targets are not reached;
Use combination therapy
No outcome studies; CVD outcomes or safety.
(E)

44. Statins use is based on desired
LDL-C Intensity lowering rather than LDL target number
Adjustment of intensity of statin therapy
may be needed based on individual patient response to medication
(e.g., side effects, tolerability, LDL cholesterol levels). E
LIPIDS ADA 2015 … 2013 ACC/AHA

45. Combination therapy
(statin/ fibrate and statin/niacin)
has not been shown to provide additional
cardiovascular benefit above statin therapy alone
and is Not generally recommended
A
LIPIDS ADA 2015 … 2013 ACC/AHA

48. NICE CLINICAL GUIDELINE 181
GUIDANCE.NICE.ORG.UK/CG181
NICE 2014
An update of existing National Institute for Health and
Care Excellence (NICE) guidance (published in 2008)

49. NICE GUIDELINES-2014
DYSLIPIDEMIA AND (CVD)
No Risk Assessment tool use for people
1-With pre-existing CVD
2-Familial hyper-cholesterolemia
3- With type 1 DM
4-With CKD ; e GFR < 60 ml/min/1.73 m2 and/or
albuminuria

50. STATINS INTENSITY CATEGORIES
NICE VS ACC/AHA
NICE
low intensity
20% to 30%
medium intensity
31% to 40%
high intensity > 40%
ACC/AHA
low intensity
<30%
medium intensity
30% to <50%
high intensity ≥ 50%
Targeting LDLTargeting non-HDL

51. NICE - DYSLIPIDEMIA AND (CVD)
STATINS INTENSITY
Modest potency statins
Rosuvastatin 5-10 mg
Atorvastatin :10-20 mg
Simvastatin : 20-40 mg
Fluvastatin -XL : 80 mg
High potency statins
Rosuvastatin 20-40 mg
Atorvastatin :40-80 mg

52. NICE
COMBINATION RX
Do not routinely offer Fibrates
(Field trial & ACCORD –Lipid)
and
Do not offer Nicotinic acid (niacin) or Bile acid sequestrants (anion
exchange resins) or omega-3 fatty acid compounds for the
prevention of CVD to any of the following group of patients :
-Treated for primary prevention
-Treated for secondary prevention
-With CKD
-With type 1 DM
-With type 2 DM
[new 2014]

53. NICE
COMBINATION THERAPY FOR PREVENTING CVD
Ezetimibe treatment in addition to Statins
should be considered (IMPROVE IT)
For people with primary hyper- cholesterolemia
(heterozygous familial and non-familial hyper- cholesterolemia )

54. (2014)

55. ESC/EAS 2014
DYSLIPIDEMIA
 VERY HIGH or HIGH TOTAL CARDIOVASCULAR RISK
Known CVD
Type 2 DM or type 1 DM with micro-albuminuria
Chronic kidney disease (CKD)
Very high levels of individual risk factors
 All other people
Use of a risk estimation system such as SCORE to estimate total
CV risk

56. DYSLIPIDEMIA AND (CVD)
STATINS
EFFICACY , SAFETY , TOLERABILITY

57. NICE
ADVICE AND MONITORING FOR STATINS AE
.
Statins and pregnancy/lactation
Potential teratogenicity
Stop Statins if pregnancy is a possibility
Stop Statins 3 months before any attempt to conceive and
to not restart them until breastfeeding is finished

58. NICE
ADVICE AND MONITORING FOR STATINS AE
Statins and creatine kinase (CK)
1- Do not measure CK levels in asymptomatic people who are being
treated with a statin
2- If patient has suggestive myopathy symptoms ( persistent
generalized unexplained muscle pain, associated or not with
previous lipid-lowering therapy) before or after start of a statin
If they have, measure creatine kinase (CK) levels
3- Review medications list ; Look for Drug-Drug interaction
(CYP450 / Gemfibrozil ; Macrolides; Cyclosporine, Ketoconazole…)

59. NICE
ADVICE AND MONITORING FOR STATINS AE
Statins and creatine kinase (CK)
4- If patient has suggestive myopathy symptoms measure (CK):
If CK levels are > 5 times the ULN, re-measure it after 7 days.
If CK levels are still 5 times ULN, do not start statin treatment
If CK levels are raised but < 5 times ULN, start statin treatment at a
lower dose
5- If statin therapy was tolerated for > 3 months ; R/O other causes
of muscle pain or weakness and raised CK

60. NICE
ADVICE AND MONITORING FOR STATINS AE
Statins and Liver Transaminases
1- Measure baseline liver transaminase enzymes (ALT or AST ) ,at
baseline , 3 and 12 months of starting a statin
-No more testing unless clinically indicated
2- Do not routinely exclude from statin therapy people who have
liver transaminase levels that are raised but are < 3 times ULN

61. NICE
INTOLERANCE OF STATINS
If a patient is un-able to tolerate a high-intensity statin
Treat with the maximum tolerated dose
If a certain statin is not tolerated
Try another statin

62. Take Home Messages

63. DYSLIPIDEMIA AND DIABETES MELLITUS
TAKE HOME MESSAGES
 DM = Cardiovascular Disease
 Risk assessment tools
High risk groups = No need to calculate Risk
Diabetics are a very high risk group
Treat Regardless of the baseline LDL-C

64. 1.ASCVD / CHD equivalent
2-Diabetes Mellitus
3-Severe Dyslipidemia –Familial
4-CKD
5- Risk calculator : High risk over next 10yrs
HIGH CVD RISK GROUPS - SUMMARY

65. DYSLIPIDEMIA GUIDELINES
HEADTO HEAD
NICE
low intensity
20% to 30%
medium intensity
31% to 40%
high intensity >
40%
ACC/AHA
low intensity
<30%
medium intensity
30% to <50%
high intensity
≥ 50%
Targeting LDLTargeting
non-HDL
ATP-III
Target Level
Reduction in LDL-C
30–40%
from base line
ESC/EAS
Target Level
Reduction in LDL-C
30–40%
from base line

66. DYSLIPIDEMIA GUIDELINES
HEADTO HEAD
NICE
The QRISK2
Risk Calculator
ACC-AHA
ASCVD
Risk Calculator
ATP III
Framingham
Scoring Calculator
All
≥ 30-40 % minimum decrease from baseline
(from ≥ 30 % to > 50%)
ESC/EAS
SCORE
Risk Calculator

67. DYSLIPIDEMIA AND (CVD)
TAKE HOME MESSAGES
 Lipid-lowering drugs
-Statins for primary and secondary prevention
-Use the highest tolerated dose
-Residual risk reduction:
Add Ezetimibe / PCSK9
 Use simultaneously guidelines on
other modifiable risk factors for CVD (like HTN , DM)