DIABETIC
DYSLIPIDEMIA
or
Diabetes Lipidus
H. Delshad M.D
Endocrinologist
Research Institute for Endocrine Sciences
Outlines :
•
•
•
•
•
•
•
•
Diabetes as a CHD risk equivalent
How is dyslipidemia different in diabetes ?
Diagnosis of dyslipidemia in diabetes
Evidence for drug therapy to improve
outcomes
Which lipoprotein to target first and what
should be the initial drug for your patient?
Should all patients with diabetes take statins?
How low should LDL-C go to minimize risk ?
What risk remains after LDL-C management ?
Epidemiologic aspects of diabetic dyslipidemia
• Atherosclerosis accounts for 80% of
mortality in diabetics :
60% CAD
20% PVD
• Risk for CAD : 2 Χ Men , 4 Χ Women
• 77% of all hospitalizations of diabetics
due to CAD
Cardiovascular Risk Factors in Diabetes









Dyslipidemia
Hypertension
Cigarette smoking
Obesity
Sedentary lifestyle
Poorly controlled diabetes
Proteinuria
Autonomic Neuropathy
Emerging risk factors : (e.g., hs-CRP,
Homocysteine, LP (a), Fibrinogen, PAI-1,
postprandial hyperglycemia)
Modified from Diabetes Care, Vol 20, Suppl 1; Jan, 1997: p.S12
Mortality in Diabetes
50
% of Deaths
40
30
20
10
0
Ischemic Other Stroke
heart
heart
disease disease
Other
Cancer Infection
Diabetes
related causes
Geiss LS et al. In: Diabetes in America 2nd ed. 1995; chap 11
Other
Elevated risk of CVD prior to
diagnosis of type 2 DM
The increased risk for CHD may precede the clinical diagnosis
of diabetes by many years.
117,000 women in the NHS , of whom 6000 developed DM during 20 years of follow-up
Hu FB et al. Diabetes Care. 2002;25:1129-1134
Epidemiological studies, such as the Multiple Risk Factor Intervention Trial (MRFIT),
have shown that type 2 diabetes is a strong, independent risk factor for CVD mortality
.
Age-adjusted CVD deaths
per 10,000 person years
150
Nondiabetic (342,815)
130
Diabetic (n=5163)
100
92
85
62
50
46
29
0
20
14
<180
200–220
240–260
>280
Plasma cholesterol, mg/dL
MRFIT , an observational study of 348,000 men, of whom 5163 had DM , The presence of
DM was associated with threefold to fourfold increased risk for age-adjusted CV mortality
at comparable levels of cholesterol, BP, and cigarette smoking.
MRFIT study. Stamler J, et al. Diabetes Care. 1993;16:434-444.
Diabetes Increases Cardiovascular Mortality
Two-fold in Men
Four-fold in Women
50
40
60
Diabetes
No Diabetes
2x
30
20
10
0
0-3 4-7 8-11 12-15 16-19 20-23
Duration of Follow-up (Years)
Mortality Rate Per 1000
Mortality Rate Per 1000
60
50
40
30
4-5x
20
10
0
0-3 4-7 8-11 12-15 16-19 20-23
Duration of Follow-up (Years)
Krolewski AS et al. Evolving natural history of coronary disease in diabetes mellitus.Am J Med 1991;90(Supp 2A):56S-61S
Incidence of MI in Finland
7-year incidence of MI (%)
The 10-year risk of major CHD events in diabetics exceeds 20% ,
Which is comparable to that observed in non-diabetic with CHD.
45
40
35
No Diabetes
(n=1373)
Diabetes
(n=1059)
P<0.001
P<0.001
30
25
20
15
10
5
0
No MI
MI
No MI
MI
Haffner et al. N Engl J Med. 1998;339:229.
The ATP III panel recommendations ,
JAMA, 2001
Diabetes is regarded as a
CHD risk equivalent.
 10-year risk for CHD  20%
 High mortality with established CHD
 High mortality with acute MI
 High mortality post acute MI
Outlines :
•
•
•
•
•
•
•
•
Diabetes as a CHD risk equivalent
How is dyslipidemia different in diabetes ?
Diagnosis of dyslipidemia in diabetes
Evidence for drug therapy to improve
outcomes
Which lipoprotein to target first and what
should be the initial drug for your patient?
Should all patients with diabetes take statins?
How low should LDL-C go to minimize risk ?
What risk remains after LDL-C management ?
Characteristics and mechanism of
Lipoprotein abnormalities in T2DM
• The hallmarks of T2DM are :
• Hyperglycemia
• Insulin resistance
• Insulin deficiency
Insulin Resistance is central to the pathogenesis of
T2DM and contributes to characteristics dyslipidemia
Enzymatic activity (  LPL,  HL ,CETP)
T2DM : Development of atherogenic dyslipidemia
Insulin resistance
NEFAs
Large
VLDL
High TG
Catabolism
LPL
LPL/HL
Small
LDL
Small dense LDL
Chol
TG
HL
Smaller HDL
CETP
HDL
Remnants
Catabolism
The atherogenic triad of the diabetes mellitus
Low HDL-cholesterol
Small, dense
LDL particles
The
atherogenic
triad
Elevated
TG rich particles
Atherogenicity of small dense LDL
Outlines :
•
•
•
•
•
•
•
•
Diabetes as a CHD risk equivalent
How is dyslipidemia different in diabetes ?
Diagnosis of dyslipidemia in diabetes
Evidence for drug therapy to improve
outcomes
Which lipoprotein to target first and what
should be the initial drug for your patient?
Should all patients with diabetes take statins?
How low should LDL-C go to minimize risk ?
What risk remains after LDL-C management ?
Screening
● In most adult patients, measure fasting
lipid profile at least annually.
● In adults with low-risk lipid values
LDL = 100 mg/dl
HDL = 50 mg/dl
TG = 150 mg/dl
lipid assessments may be repeated every
2 years.
NCEP (Adult Treatment Panel III ) :
Target Lipid Levels for T2DM ,
TC ( mg/dl)
Classification
JAMA 2001
VLDL-C( mg/dl)
Classification
Normal
< 200
Desirable
≤ 30
200 - 239
Borderline high
HDL-C
≥ 240
High
< 40
Low
≥ 60
High
LDL-C
< 100
Optimal
TG
100 - 129
Near or above
optimal
<150
Normal
150 - 199
Borderline
high
130 - 159
Borderline high
160 - 189
High
200- 499
High
≥ 190
Very high
≥ 500
Very high
Which one does provide more-useful
information on CVD risk?
2013 American College of Cardiology–American
Heart Association Guidelines for Use of Statin
Therapy in Patients at Increased Cardiovascular
Risk.
Keaney JF Jr et al. N Engl J Med 2014;370:275-278.
Guideline Recommended High, Moderate,
and Low Intensity Statin Treatment
Treatment
Intensity
High
Target
(LDL-C decrease)
> 50%
Treatment
(Daily dose , mg)
Rosuvastatin ( 20 – 40 )
Atorvastatin ( 40 – 80 )
Moderate
Low
30 - 50%
< 30%
Rosuvastatine ( 5 – 10 )
Atorvastatin ( 10 – 20 )
Simvastadin ( 20 – 40 )
Lovostadin ( 40 )
Simvastadine ( 10 )
Lovastadin ( 20 )
•Most risk-score algorithms use total cholesterol or LDL and HDL
•Calculating CV risk solely on this basis is a oversimplicaton
•VLDL , IDL and Remnants that transport cholesteryl esters ( non-HDL)
are also proatherogenic
•non-HDL –C ( Total Chol. – HDL ) is more strongly associated with CVD
risk than LDL alon.
RR of future CHD in individuals with LDL< 100 and non-HDL >130 mg/dl
was 1.84 ( 95% CI 1.12 – 3.04) Arsenaul B.J. Et al. J. Am. Coll. Cardiol. 2009
Non-HDL Cholesterol is a better predictor of the number of
circulating atherogenic LDL particles than are levels of LDL
•Apo A-I : principal apoprotein on HDL (antiatherogenic)
•Apo B :
principal apoprotein on LDL (proatherogenic)
•Apo B molecules are also carried by VLDL & IDL
•Apo B : Is a more accurate measure of the total
atherogenic particles.
Quebec Cardiovascular Study
AMORIS
INTERHEART
Apo B / Apo A-I ratio was strongly associated with IHD
Outlines :
•
•
•
•
•
•
•
•
Diabetes as a CHD risk equivalent
How is dyslipidemia different in diabetes ?
Diagnosis of dyslipidemia in diabetes
Evidence for drug therapy to improve
outcomes
Which lipoprotein to target first and what
should be the initial drug for your patient?
Should all patients with diabetes take statins?
How low should LDL-C go to minimize risk ?
What risk remains after LDL-C management ?
Dose drug therapy improve outcomes?
YES
• Recent RCTs and a major meta-analysis ( CTT) ,
have emphasized the importance of LDL-C
lowering for CVD risk reduction in DM
• Lipid lowering therapy has proven to reduce
CV morbidity and mortality in diabetes
What Is The Evidence ?
• Primary Prevention
CARDS:
Collaborative Atorvastatin Diabetes Study
• Mixed
HPS : Heart Protection Study
FIELD : Fenofibrate Intervention and Event Lowering in Diabetes
ASPEN : Atorvastatin Study for Prevention of Coronary Heart Endpoint in NIDDM
ALLHAT: Antihypertensive and Lipid-Lowering Treatment of Prevent Heart Attack Trial
ASCOT- LLA : Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm
• Secondary Prevention
4S : Scandinavian Simvastatin Survival Study
TNT: Treating to New Target
CARE: Cholesterol And Recurrent Events
PROVE-IT: Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction
Study
Intervention
CVD Outcome
RRR %
CARDA
Atorvastatin 10 mg
Acute coronary events
CVA
36
48
HPS
Simvastatin 40 mg
Major CHD event
Any major CV event
27
22
ALLHAT
Pravastatin 10 mg
Major CHD event
11
ASCOT-LLA
Atorvastatin 10 mg
Major CHD event
16
GREACE
Atorvastatin 10 mg
CHD related death
58
4S
Simvastatin10-40mg
Total mortality
Major CHD event
43
55
CARE
Pravastatin 40 mg
Major CHD event
13
LIPID
Pravastatin 40 mg
Major CHD event
Any CV event
19
21
LIPS
Fluvastatin
CHD related death
47
Major Outcome Trials Summary
Event rates - Treatment vs. Control
Drug
34%
Control
SIMVA
27.9
Event rate (%)
30
SIMVA
Absolute Risk
24%
22%
GEMFIB
25.4
19.4
20
19.9
RR Reduction
31%
37%
10
PRAVA
5.3
7.5
21.7
24%
PRAVA
13.2
23%
PRAVA
15.7
17.3
12.3
10.2
LOVA
5.5
3.5
0
WOSCOPS AFCAPS
Primary Intervention
4S
HPS
CARE
LIPID
Secondary Intervention
HIT
Outlines :
•
•
•
•
•
•
•
•
Diabetes as a CHD risk equivalent
How is dyslipidemia different in diabetes ?
Diagnosis of dyslipidemia in diabetes
Evidence for drug therapy to improve
outcomes
Which lipoprotein to target first and what
should be the initial drug for your patient?
Should all patients with diabetes take statins?
How low should LDL-C go to minimize risk ?
What risk remains after LDL-C management ?
Which lipoprotein to target first?
LDL-c is the most atherogenic lipoprotein and
is considered the primary target of therapy
● In individuals without overt CVD
LDL cholesterol < 100 mg/dl
● In individuals with overt CVD
LDL cholesterol < 70 mg/dl
If drug-treated patients do not reach the above targets on maximal
tolerated statin therapy, a reduction in LDL cholesterol of 30–40%
from baseline is an alternative therapeutic goal
Which lipoprotein to target first?
If more than one lipoprotein is not at goal:
• TG > 500 mg/dl : focus should shift to TG
• TG = 200-499 mg/dl :
* Primary target is LDL
* Secondary target is Non-HDL
( Non-HDL = Total Cho. – HDL )
• TG = 150-199 mg/dl :
* Primary target is LDL
* Secondary target is TG&HDL
Initial drug for dyslipidemia in T2DM
• Statins are indicated for the majority of
patients with diabetes.
• Statins discovered in the 1970 , and
introduced into clinical practice in the 1980s
• Statins are competitive inhibitors of the
HMG-CoA reductase.
Equivalent doses of statins and
approximate effect on LDL-C
LDL
Reduction
Fluvastatin
Lescol
Lovastatin
Mevacor
Pravastatin
Pravachol
Simvastatin
Zocor
Atorvastatin
Lipitor
Rosuvastatin
Crestor
25%
20
10
10
-
-
-
30%
40
20
20
10
-
-
35%
80
40
40
20
10
5
40%
-
80
80
40
20
10
45%
-
-
-
80
40
20
50%
-
-
-
-
80
40
Anti-dyslipidimic drugs
LDL
HDL
TG
STATINES
20 – 62 %
5 – 15 %
7-30%
BILE ACID RESINS
15 – 25 %
3 -5 %
No change or
increase
NICOTINIC ACID
15 – 30 %
15 – 35%
24 – 50 %
15 -25 %
-
8%
Cholestyramine= 4-16 g
Colestipol=5-20 g
Colesevelan= 2.6 – 3.8 g
Immediate-release=1.5 –
3g
Extended –release =1-2 g
EZETIMIBE
Ezethicole = 10 mg
Gemfibrozil=600 mg BID
Fenofibrate = 200
mg/day
Clofibrate = 1000 mg BID
5 – 20%
May be increased in
patients with high TG
10 – 20%
20 - 50%
OMEGA-3 FATTY
ACID = 2 -4 g/day
45%
9.0%
30 - 45%
FIBRIC ACIDS
Ezetimibe: Efficacy "Add On" Study
After 8 weeks the addition of ezetimibe to ongoing statin therapy significantly reduced LDL-C ,
increased HDL-C, and decreased triglyceride levels compared with placebo plus statin.
5
0
-5
HDL
LDL
1.0
TG
2.7
(P<0.05)
–2.9
–3.7
-10
-15
–14.0
-20
-25
-30
(P< 0.01)
–25.1 (P<0.001)
Statin + placebo (n=390)
Gagné C et al.
Am J Cardiol 2002;90:1084-1091.
Statin + ezetimibe 10 mg (n=379)
Ezetimibe + Simvastatin:
Efficacy Results on LDL-C
EZE 10 mg
+
Simva.10 mg
Simvastatin
10 mg
20 mg
40 mg
80 mg
Mean % Change
0
-10
-20
-30
-27*
-40
-50
-36*
-38*
-45
-46
-60
EZE + Statin
Statin
Davidson M et al. ACC 2002: Abstract.
Outlines :
•
•
•
•
•
•
•
•
Diabetes as a CHD risk equivalent
How is dyslipidemia different in diabetes ?
Diagnosis of dyslipidemia in diabetes
Evidence for drug therapy to improve
outcomes
Which lipoprotein to target first and what
should be the initial drug for your patient?
Should all patients with diabetes take statins?
How low should LDL-C go to minimize risk ?
What risk remains after LDL-C management ?
Should all patients with diabetes take statins?
Primary and Secondary
CVD prevention trials
have shown that LDL
reduction leads to
highly significant
reductions in the
incidence of major
CVD events
Efficacy of cholestrol-lowering therapy in 18,686 people with diabetes
in 14 randomised trials of statins: a met-analysis.
Cholestrol Treatment Trial ( CTT ) Collaborators . Lancet 2008 ;371: 117-125
Cholestrol Treatment Trial (CTT)
A meta-analysis of 14 RCTs
Mean follow-up 4.3 years
NCEP-ATP III & ADA recommendation
Statin therapy should be considered for all diabetic individuals who are at high risk of vascular events
• Statin therapy should be added to lifestyle therapy, regardless
of baseline lipid levels, for diabetic patients:
● with overt CVD.
● without CVD who are over age 40 years and
have one or more other CVD risk factors.
● For patients at lower risk than above(-CVD,<40 y)
statin therapy should be considered if :
○ LDL cholesterol remains above 100 mg/dl
or
○ Presence of multiple CVD risk factors.
Outlines :
•
•
•
•
•
•
•
•
Diabetes as a CHD risk equivalent
How is dyslipidemia different in diabetes ?
Diagnosis of dyslipidemia in diabetes
Evidence for drug therapy to improve
outcomes
Which lipoprotein to target first and what
should be the initial drug for your patient?
Should all patients with diabetes take statins?
How low should LDL-C go to minimize risk ?
What risk remains after LDL-C management ?
Rationale for Lower LDL-C Targets
1-Epidemiological &
Clinical Trials Data
2- The Post-2001 Trials:
HPS
ASCOT
PROVE IT
TNT
A to Z
IDEAL
Log linear relation
of LDL & CHD
3.7
RR CHD
(log scale)
2.9
2.2
1.7
1.3
1.0
40
70
100
130
160
LDL (mg/dL)
For every 30-mg/dL change in LDL-C, relative risk for CHD is
changed in proportion by about 30%
Grundy et al. Circulation. 2004;110:227-239.
190
Meta –analysis of Cardiovascular Outcomes of
Intensive vs Moderate Statin Therapy
(n=27,548)
Intensive therapy produced a further 16 % reduction in the
incidence of coronary events and an 18 % further reduction
in the incidence of stroke
Efficacy and safety of more intensive lowering of LDL-C : a mete-analysis of
data from 170,000 participants in 26 randomised trials
Choleserol Treatment Trials ( CTT ) Collaborators
Lancet. 2010 November 13; 376(9753): 1670-1681
Cholestrol Treatment Trial (CTT)
A meta-analysis of 26 RCTs
5 RCTs
More vs less intensive
21 RCTs
Statin vs Control
Further reduction in LDL safely produce definite
further reductions ( 15 % ) in the incidence of heart
attack, revascularisation and ischemic stroke
How low should LDL-C go to minimize risk ?
Outlines :
•
•
•
•
•
•
•
•
Diabetes as a CHD risk equivalent
How is dyslipidemia different in diabetes ?
Diagnosis of dyslipidemia in diabetes
Evidence for drug therapy to improve
outcomes
Which lipoprotein to target first and what
should be the initial drug for your patient?
Should all patients with diabetes take statins?
How low should LDL-C go to minimize risk ?
What risk remains after LDL-C management ?
The atherogenic triad of the diabetes mellitus
Small, dense
LDL particles
HDL-cholesterol
TG rich particles
ACCORD Study Group. N Engl J Med. 2010;362:1563-74
Despite achieving LDL goal, T2DM Ptients with elevated TG and low
HDL are exposed to higher residual risk of a major CV event
PROVE ITTIMI 22*
TNT**
TG ≥ 200 mg/dl
50% higher risk
LDL < 70 mg/dl
Of death, MI or ACS
Vs. TG < 200 mg/dl
HDL < 37 mg/dl
64% higher risk
LDL < 70 mg/dl
* J Am Coll Cardiol. 2008;51:724-30
** New Engl J Med. 2007;357:1301-10
Of major CV events
Vs. HDL ≥ 55 mg/dl
Relationship Between LDL-C and HDL-C levels and CHD Risk
HDL-C
LDL-C
1 mg decrease
reduces CHD
risk by 1%
1 mg increase
reduces CHD
risk by 3%
The significant CV risk
associated with high TG
and low HDL requires
treatment beyond Statins
Combination Therapy:
Statin Plus Niacin
Simvastatin + Niacin1
Mean %  from Baseline
40
31
28
30
20
10
0
-10
-20
-30
-30
-40
-36
-39
-50
LDL-C
1Guyton
Fluvastatin + Niacin2
HDL-C
TG
-40
LDL-C
JR, Capuzzi DM. Am J Cardiol. 1998;82(12A):82U-84U.
TA, et al. Am J Cardiol. 1994;74(2):149-154.
2Jacobson
HDL-C
TG
HDL-Atherosclerosis Treatment Study (HATS)
Niacin and Statin Outcome Trial
25
23.7
21.4
89%
Reduction
20
*P<.05 vs Placebo
14.3
15
10
2.6*
5
0
Placebo
S+N
AV
S +N +AV
Coronary Death, MI, Stroke, or Revascularization
Brown BG et al. N Engl J Med 2001;345:1583-1592.
ACCORD-LIPID :
Combination Fenofibrate-Simvastatin was associated
with a 31 % lower incidence of major CV events
% change in TG
+12.9%
+7.3%
% change in HDL-C
- 24.1 %
- 35 %
Dyslipidemic subgroup
All others
ACCORD Study Group. N Engl J Med. 2010;362:1563-74
Combination Fibrate and Statin therapy
• Significantly improve triglyceride, LDL-C, and HDL-C levels
• Fibrates plus Statins are associated with increased risk for
myopathy and rhabdomyolysis
– Not thought due to cytochrome P450 drug interaction
– Gemfibrozil may impair glucuronidation of statins (with
cerivastatin being more susceptible than other statins such
as simvastatin and atorvastatin)
– Fenofibrate appears to have less potential for impairment
of statin metabolism, and thus this may account for the
reduced reports of fenofibrate plus statin–induced
myopathy and rhabdomyolysis compared with gemfibrozil
plus statin.
Ballantyne CM et al. Arch Intern Med 2003;163:553-564.
Bays H. Am J Cardiol 2002;90:30K-43K.
FISH OILS
► It reduces TG levels through inhibition of the
synthesis of VLDL
► 2 to 4 g of fish oils /day
can decrease TG level by 25% or
more Slightly and increases LDL-C levels by 4%
► Side effects : Nausea , Abdominal bloating, flatulence, diarrhea
Daily supplementation with 2 g of fish oil can lower
cardiac events and associated mortality in men with
CAD after 1 to 2 years.
1-Eur Heart J 1994;15:1152-1153
2-Cardiovasc Drugs Ther 1997;11:485-491
•Nonspecific muscle aches or joint pain
•Myositis occurs rarely
•Rhabdomyolysis occurs very rarely
─ Use the lowest dose
─ Choose other drugs carefully
─ Considering the potential for interferences
with the metabolism of the statins
•Liver enzyme elevation
•Abdominal discomfort
•Gallstones
•Interaction with warfarin
•Increase in serum creatinin
•Cutaneous flushing
•Insulin resistance
•Hyperuricemia and gout
•Elevation of LFT:
─ Lower incidence with < 1500 mg
─ Monitor LFT every 6 – 12 weeks for the first year
and every 6 months afterward
•Reactivation of peptic ulcer ( rare)
Case
:Enalapril 20
Goals of therapy?
•Office BP < 150/90 mmHg
•Office BP< 140/90 mmHg
•Office BP<130/80 mmHg
•Office BP< 140/80 mmHg
Diabetes & Hypertension
• Prevalence : HTN often coexist with DM
• in general population: 22%
• in type 2 diabetes: 50%
• in type 1diabetes: 25%
• Type 2 diabetics often hypertensive at time of
diagnosis
• Higher incidence with  age
• Type 1 DM : a complication of diabetic
nephropathy
CLASSIFICATION OF HYPERTENSION
( JNC Vll )
SYSTOLIC
• NORMAL
<120
• PRE-HTN
120-140
• HYPERTENSION :
STAGE-1
140-160
STAGE-2
≥ 160
DIASTOLIC
or
< 80
80-90
or
or
90-100
≥ 100
The seventh report Joint National Committee on Prevention, Detection, Evaluation, and Treatmen
Diabetes & Hypertension
• Because of the clear synergistic risks of HTN and
DM , the diagnostic cut off is lower in diabetics :
BP ≥130 / 80 mmHg
Diabetes Increases Cardiovascular Mortality
Four-fold in
Women
Two-fold in
Men
50
40
60
Diabetes
No Diabetes 2x
30
20
10
0
0-3 4-7 8-11 12-15 16-19 20-23
Duration of Follow-up (Years)
Mortality Rate Per 1000
Mortality Rate Per 1000
60
50
40
30
20
45x
10
0
0-3 4-7 8-11 12-15 16-19 20-23
Duration of Follow-up (Years)
Krolewski AS et al. Evolving natural history of coronary disease in diabetes mellitus.Am J Med 1991;90(Supp 2A):56S-61S
UKPDS
n=1148
DM + HTN
Tight BP control
Goal < 150 / 85 mmHg
Risk reduction :
Less tight control
Goal < 180 / 105 mmHg
Diabetes related deaths = 32%
All diabetes complications = 24%
Stroke = 44 %
Heart failure =56 %
Retinopathy = 34 %
HOT Study
n=1501
HTN+DM
Target DBP
< 80 mmHg
Target DBP
> 90 mmHg
Risk reduction :
50% Less risk of cardiovascular events
HOT : Hypertension Optimal Treatment
CV Events /1,000 Patient-Years in
Patients with Diabetes at Baseline
Lessons of the HOT Study in DM
30
25
20
15
10
5
0
Target:
(Achieved):
 90 mmHg DBP
 85 mmHg DBP
80 mmHg DBP
(mean 85.2 mmHg)
(mean 83.2 mmHg)
(mean 81.1 mmHg)
HOT : The Hypertension Optimal Treatment
ABCD
n=470
HTN=DM
Target DBP
80 - 90 mmHg
Target DBP
< 75 mmHg
5.5 %
Total mortality
ABCD : Appropriate Blood Pressure Control in Diabetes
10.7%
Goal BP in DM: how low to go in 2015?
“Newer guidelines for BP goals in patients
with DM are likely to suggest a goal of
< 140/90 mm Hg based on the totality of
evidence.”
Cochrane Database Syst Rev. 2013 Oct
Blood pressure targets for hypertension in people with diabetes mellitus.
Arguedas JA et al.
Goal BP In DM
How low to go in 2015?
“There is no clear optimal target BP in diabetes”
From: 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults: Report From the
Panel Members Appointed to the Eighth Joint National Committee (JNC 8)
JAMA. 2013;
Guideline
Goal BP (mmHg)
ESH/ESC , 2013
< 140 / 85
CHEP, 2013
< 130 / 80
JNC 8, 2014
< 140 / 90
ADA, 2015
< 140 / 90
Blood Pressure Control
The Goal to Achieve : JNC 8
General population
≥ 60 years
<150/90 mmHg
General population
< 60 years
<140 / 90 mmHg
Population with CKD
≥ 18 years
<140 / 90 mmHg
Population with DM
≥ 18 years
<140 / 90 mmHg
Blood Pressure Control : The Goal
to Achieve
• ALL hypertensive
patients
< 140/90 mm Hg
EXCEPTIONS
• Diabetes, renal
failure
130/85 mm Hg
• Renal failure with
proteinuria > 1 g/24 hs
125/75 mm Hg
Management
Strategies
 Lifestyle Modification
 Anti-hypertensive Drug
Therapy
Lifestyle Modification :
Measures
 Smoking cessation
 Weight reduction
 Reduction of salt intake
 Increase physical activity
 Psychological factors and stress
 Dietary changes

Vegetables, fruits and fibres

Reduction of fat intake

High intake of calcium, magnesium and potassium
Anti-hypertensive
Drug Therapy
Anti-hypertensive Drugs
 Diuretics
 Vasodilators
 Calcium Channel Blockers
 Anti-Adrenergic Agents
 ACE Inhibitors
 Angiotensin II Receptor Blockers (ARBs)
Thiazide diuretics
Usual dose range 􀂃
Hydrochlorothiazide 12.5–50 mg/d
􀂃 Chlorthalidone: 12.5–25 mg/d
􀂃 Indapamide: 1.25–2.5 mg/d
􀂃 Metolazone: 2.5–5 mg/d
CCBs - Mechanisms of Action
 Decreases peripheral vascular resistance
 Decreases cardiac work

Decreases force of contraction

Decreases conductivity

Decreases heart rate
Dihydropyridines (use only long-acting agents in this class)
􀂃 Amlodipine: 2.5–10 mg/d
􀂃 Felodipine: 2.5–10 mg/d
􀂃 Nifedipine, long acting: 30–90 mg/d
Nondihydropyridines
􀂃 Diltiazem, extended release: 180–300 mg/d
􀂃 Verapamil, long acting: 120–480 mg once or twice daily
􀂃 Verapamil: 30–120 mg 4 times daily
Anti-Adrenergic Agents - Classification
 Centrally Acting: e.g. clonidine, methyldopa
 Ganglion Blockers: e.g. methaphan
 Neurone Blockers: e.g. reserpine
 Adrenergic Receptors Blockers
  - Receptor Blockers: e.g. phentolamine
 ß - Receptor Blockers: e.g. propranolol
 1 / ß - Receptor Blockers: e.g. carvedilol
• Beta- Blockers : Usual dose range
– Atenolol: 25–100 mg/d
– Metoprolol: 50–100 mg bid
– Metoprolol, extended release: 50-100 mg/d
– Nadolol: 40–120 mg/d
– Propranolol: 40–160 mg bid
– Propranolol, long acting: 60–180 mg/d
– Timolol: 20–40 mg bid
– Labetalol: 200–800 mg bid
– Carvedilol: 12.5–50 mg bid
ANGIOTENSIN
CONVERTING ENZYME
INHIBITORS
(ACEI)
ACE Inhibitors :
Evidence of benefit in diabetic subjects
1- Renoprotective :
MICRO-HOPE = Ramipril showed a statistically
significant benefit over placebo in preventing the
progression from microalbuminuria to overt
nephropathy.
UKPDS = Did not show such a benefit when
comparing Captopril to Atenolol
ACE Inhibitors :
Evidence of benefit in diabetic subjects
2 - cardiovascular protection :
MICRO-HOPE = Ramipril vs placebo
CAPPP Study = Captopril vs Diuretics or
Beta blocker
ABCD Study = Enalapril vs Nisoldipin
FACET Study = Fosinopril vs Amlodipin
STOP-2 Study = ACE Inhibitor vs diuretics
All provided evidence for the superiority of ACE Inhibitors
in reducing various cardiovascular endpoints
ACE Inhibitors : Indications for Use
As first line therapy in :
• T1 DM with nephropathy
• T2DM older than 55-y with additional CV
risk factors.
• ACE Inhibitors : Usual dose range
o Benazepril: 10–40 mg/d
o Captopril: 25–100 mg bid
o Enalapril: 5–40 mg once or twice daily
o Fosinopril: 10–40 mg/d
o Lisinopril: 10–40 mg/d
o Moexipril: 7.5–30 mg/d
o Perindopril: 4–8 mg/d
o Quinapril: 10–80 mg/d
o Ramipril: 2.5–20 mg/d
o Trandolapril: 1–4 mg/d
ANGIOTENSIN
RECEPTOR BLOCKERS
(ARBs)
ARBs: evidence of benefit in DM
• 1- Renoprotective:
RENAAL : Losartan vs Others
IDNT
: Irbesartan vs Amlodipin
MARVAL : Valsartan vs Amlodipin
Which one is more effective for diabetic nephropathy?
ACE Inhibitor or ARB
•
•
•
•
CALM :
Candesartan vs Lisinopril
DETAIL :
Telmisartan vs Enalapril
Muirhead et al. : Valsartan vs Captopril
Lacouriciere et al. : Losartan vs Enalapril
All have shown similar efficacy of the 2
drugs in slowing progression of Albuminuria
and Nephropathy.
ARBs: evidence of benefit in DM
2- Cardiovascular protective
Evidence remains less clear-cut regarding their effects on CVD
outcomes
LIFE
: Losartan vs Atenolol
24% reduction in CV morbidity & mortality
CHARM
: Candesartan vs Plcebop
↓ CV death and admission for CHF
RENAAL : Losartan
vs Placebo
↓ rates of hospitalization for CHF
IDNT
VALUE
: Irbesartan vs Amlodipin vs Placebo
showed equivalence of the three treatment
groups
: Valsartan vs Amlodipin
Cardiovascular Protective
ARBs or ACE Inhibitors?
• VALIANT
: Valsartan vs Captopril
• OPTIMAL
: Losartan vs ACE Inh.
• CHARM-Overal : Candesartan vs ACE Inh.
All these studies showed no significant
differences between the effect of ARBs or
ACE Inhibitors therapy on CV death and
hospitalization for CHF.
:
•
Usual dose range
– Irbesartan: 150–300 mg/d
– Losartan: 25-100 mg once or
twice daily
– Valsartan: 80–320 mg/d
Choice of antihypertensive
agents
• Most antihypertensive drugs reduce BP by 10 to
15 % .
• Monotherapy is effective in about 50% of
unselected patients.
• Those with stage 2 hypertension often need
more than one agent.
• Multiple drug therapy is generally required to
achieve BP targets in DM.
Multiple Antihypertensive Agents Are Needed
to Achieve Target Blood Pressure
Trial
Target Blood
Pressure
(mm Hg)
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
MAP <92
ALLHAT
<140/90
No. of Antihypertensive Agents
0
1
2
3
4
What is the best initial choice for
antihypertensive therapy in DM?
• A NUMBER OF DRUG CLASSES ARE CURRENTLY
AVAILABLE.
• Published data concluded that reduction in BP was
more important in preventing CVD than the specific
antihypertensive regimen.
• The choice of certain drug over others is based on
their benefit in preventing complication of DM
especially CVD and the progression of
Nephropathy
ALL PATIENTS WITH DM AND
HTN SHOULD BE TREATED WITH
A REGIMEN THAT INCLUDES
EITHER AN:
● ACE-Inhibitor
● Ang.Recep. Bloker
Anti-hypertensive
Combination Therapy
Drug Therapy
JNC -8 : Recommendation 6 :
Each of the 4 drug classes:
Thiazides, ACEI, ARB, CCB
yield comparable effects on overall
mortality, CVD, CVA and kidney
outcomes, with one exception: HF
From: 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults: Report From the
Panel Members Appointed to the Eighth Joint National Committee (JNC 8)
JAMA. 2013;
Guideline
DM+HTN
ESH/ESC , 2013
CHEP, 2013
JNC 8, 2014
ADA, 2014
Initial Drug
ACEI or ARB
ACEI, ARB, TZD, or CCB
TZD, ACEI, ARB, CCB
ACEI or ARB
• Mono therapy :
Can attain goal when
BP=130-140/80-85mmHg
• Combination therapy:
When BP>140/85mmHg
ACCOMPLISH : ACE Inh. Or ARBs+Amlodipin
GEMINI
: ACE Inh. Or ARBs + Carvedilol
Combination Therapy – Effective Drug Combinations

Diuretics / -Blockers

Diuretics / ACE Inhibitors

Calcium Channel Blockers / -Blockers

Calcium Channel Blockers / ACE Inhibitors

-Blockers / -Blockers

Angiotensin Receptor Blockers / Diuretics
CARDS :
Collaborative Atorvastatine Diabetes Study
T2DM ,n=2838
Without previous Hx. of CVD
But with 1 CV risk factor
Atorva.
Placebo
10 mg/day
Follow-up
4 years
30% reduction in LDL
116 mg/dl 81 mg/dl
Lancet 2004;364:685-696
CARDS: Primary endpoint-Major CVE
Relative Risk Reduction 37%
(95% CI: 17-52 , P=0.001)
Cumulative Hazard (%)
15
Acute coronary events =36%
CVA= 48%
Placebo
127 events
10
Atorvastatin
83 events
5
0
0
Placebo 1410
Atorva
1428
1
2
3
4
4.75
1351
1392
1306
1361
1022
1074
651
694
305
328
Years
HPS :
Heart Protection Study
Lancet 2002;360:7-22
T2DM
n=2838
Simvastatin
Placebo
40mg/day
Follow-up
5 years
31% reduction in LDL
123 mg/dl 85 mg/dl
Heart Protection Study
40
37.8%
RR=24%
33.4%
p<0.0001
% of patients
30
Placebo
Simvastatin
25.1%
20.2%
18.6%
20
13.8%
10
0
n=2985 n=2978
All patients
with diabetes
n=1009
n=972
With diabetes,
with prior CHD
n=1976 n=2006
With diabetes,
without prior CHD
Simvastatin significantly decreased the relative risk of
major vascular events by 24% among all patients
Heart Protection Study
Lancet 2002;360:7-22;
Simvastatin
better
Baseline level*
Placebo
better
LDL-C (mg/dl)
<100 (2.6 mmol/L)
100 <130
130 (3.4 mmol/L)
ALL PATIENTS
24% risk reduction
p <0.0001
0.4
0.6
0.8
1.0
1.2
1.4
Risk ratio and 95% CI
*
•Similar reductions were observed regardless of baseline LDL-C,
even in patients with the lowest levels (<100 mg/dl).
•Moreover, there was no lower LDL-C limit at which benefits of
simvastatin were not observed.
HPS :
Heart Protection Study
Microvascular events in diabetics
ALLHAT :
Antihypertensive and Lipid-Lowering Treatment of Prevent Heart Attack Trial
n=10,353
35% T2DM
Pravastatin
Usual care
40 mg/day
Follow-up
4.8 years
Pravastatin did
not reduce the
primary end point
>30% started taking
a lipid-lowering drug
during the trial
Major Coronary Events in 4S:
(Scandinavian Simvastatin Survival Study)
Diabetics and Non-Diabetics
% of patients without events
100
Diabetes (n=202)
90
80
24 %
70
60
Diabetes , Simva
Diabetes , Placebo
50
No Diabetes , Simva
No Diabetes , Placebo
55%
p = 0.002
risk reduction
p = 0.0001
0
0
1
2
3
4
5
Years Since Randomization
6
Diabetes Care 1997; 20:614-620
ASPEN :
Atorvastatin Study for Prevention of CHD
Endpoint in NIDDM Diabetes Care. 2006;29:1478-1485
T2DM
n=2410
Atorvastatin
Placebo
40mg/day
Follow-up 4 years
27% concomitantly
taking a lipid lowering
medication
Atorva. Therapy failed to produce a
statistically significant risk reduction
FIELD :
Fenofibrate Intervention and Event Lowering in Diabetes
T2DM ,n=9795
63 center, 3 countries
Aust. , New Zealand , Finland
Fenofibrate
Placebo
200 mg/day
19% taking a Statin
by the end of study
Follow-up 5 years
36% taking a Statin
By the end of study
CHD death
Nonfatal MI
Non significant
Lancet. 2005;366:1849-1861
ASCOT :
Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm
n=10,305
25% T2DM
Atorvastatin
Placebo
10mg/day
Follow-up
3.3 years
Atorva. Therapy was with
35% relative risk reduction in
non-fatal MI and fatal CHD
ASCOT :
Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm
Fatal and non fatal stroke
CARE :
Cholesterol And Recurrent Events
n=4159
Post MI patients
14% T2DM
Average baseline
LDL= 139 mg/dl
Pravastatin
Placebo
40 mg/day
Follow-up
5 years
30% reduction
In LDL
25% RR reduction in
incidence of
coronary events
TNT :
Treating to New Target
n= 10,001
15% T2DM
Atorvastatin
Atorvastatin
10mg/day
Mean LDL
101 mg/dl
80mg/day
5
years
Mean LDL
77 mg/dl