Telmisartan combinations

1. ARB + Statin
Evidence from emerging concepts as
the rationale

2. The topics for discussion
• The existing situation and observations
• The rationale for combining ARB & Statin
• The effects of combining ARB & Statin
• The benefits of combining ARB & Statin
• The choice of telmisartan as the ARB in
combination therapy
• The indications for Telmisartan + Statin

3. The exisiting situation
Evidence and observations

4. The observations
• There is strong synergy between hypertension
and hypercholesterolemia in terms of risk factors
for the development of CVD.
• Both hypertension and hypercholesterolemia
result in endothelial dysfunction and
consequently the development of atherosclerosis.

5. CAD risk by associated risk factors

6. CAD mortality in metabolic syndrome
15
Cardiovascular Disease Mortality
Cumulative Hazard (%)
Metabolic
RR (95% CI), 3.55 (1.98–6.43) Syndrome:
10
YES
5
NO
0
0 2 4 6 8 10 12
Follow-up (Years)
Lakka HM et al. JAMA 2002;288:2709-2716.

7. CAD event free survival with CRP
levels in metabolic syndrome
1.00
CV Event–Free Survival Probability
CRP < 3 mg/L,
0.99 No metabolic syndrome
CRP ≥ 3 mg/L,
0.98 No metabolic syndrome
CRP < 3 mg/L,
0.97 Metabolic syndrome
0.96
CRP ≥ 3 mg/L,
0.95 Metabolic syndrome
0 2 4 6 8
Follow-up (Years)
Ridker PM et al. Circulation 2003;107:391-397.

8. Metabolic syndrome
• A syndrome characterized by:
– Hypertension,
– Dyslipidemia and elevated LDL-C
– Elevated triglyceride levels,
– Central obesity
– Insulin resistance
• All these represent a cluster of factors that are
synergistic for CAD.

9. Traditional Treatment Approach
Dyslipidemia Hypertension Type 2 DM
Lipid panels BP Blood sugar
Monitor Lipoprotein Ambulatory BP Glycosylated
subsets hemoglobin
↓ Total fat ↓ Sodium ↓ Sugar
Diet
↓ Cholesterol ↑ K++ Distribute CHO, Pro, Fat
↑ Fiber
Statins ACEI Insulin
Meds Fibrates Sulfonylureas
ARB
Niacin Diuretic TZDs
Resins Ca-channel blockers
Weight
Monitoring? Diet/Exercise? Medications?

10. New Treatment Approach
↑ Adipose Tissue
Reduce BMI and waist circumference
 ↓ Calories, glycemia
 ↑ Daily activity/exercise
 Behavior therapy
 Medication-Current, CB1 Antagonists, others in
development, combinations
Dyslipidemia Hypertension IGT
↑ Omega-3s DASH ↑ Fiber
Diet ↑ MUFA ↓ Na ↓ Glycemic diet
↓ Sat fat ↓ ETOH
↓ Trans fat
↓ Glycemia + ETOH
ATP III guidelines: TLC diet
Statins ACEI Metformin
Meds Fibrate ARB Exenatide

11. Cross talk
• Cross-talk between inflammatory and insulin signaling pathways causes
both endothelial dysfunction and metabolic insulin resistance that
synergize to cardiovascular disorders in Metabolic Syndrome
Kim J, Koh KK, Quon MJ. Arterioscler Thromb Vasc Biol 2005;25:889.

12. Cross talk
• Shared and Interacting mechanisms underlie the reciprocal relationships
between Insulin Resistance and Endothelial Dysfunction.
Insulin Resistance Endothelial dysfunction
Diabetes, Obesity, Dyslipidemia CAD, Hypertension, Atherosclerosis
Han SH, Quon MJ, Koh KK. Cur Op Lipidology 2007;18:58 (review)

13. Cross talk and ARBs
• The selective and potent inhibition of angiotensin II
by ARBs can prevent end-organ damage from
hypertension-associated diseases such as CAD,
atherosclerosis, and renal disease,
• These effects appear to be independent of their BP-
lowering effects and in addition, most of the new
trials have revealed that ARB treatment decreases
new-onset diabetes
– AT1 blockade
– AT2 stimulation

14. The big question?
Will ARBs combined with
statins be better than monotherapy in a
defined section of patients?

15. Hypercholesterolaemia &
hypertension
• Hypercholesterolemia, diabetes,
hypertension, and heart failure result
in release of angiotensin II, which acts
on AT1 receptors.
• Activation of AT1 receptors stimulates
NADH oxidase in endothelial cells,
• This leads to oxidative stress resulting
in generation of reactive oxygen
species in vascular cells and
eventually, endothelial dysfunction.
• ROS leads to proinflammatory status
and plays critical roles in initiation and
progression of atherosclerosis,
• All this reduces bioavailability of NO
in vascular wall, which appears to
result from increased breakdown and
decreased NO production.
Nippon Rinsho. 2009 Apr;67(4):812-8.

16. ARB+statin on NO
• Reduced bioavailability of
NO impairs endothelium-
dependent vasodilation
and activates other
mechanisms that play a
role in the pathogenesis of
atherosclerosis.
• ARBs by blocking AT1
receptors ↓oxidative stress
and ↓breakdown of NO,
• Statins increase
production of NO by
activating eNOS.
Nippon Rinsho. 2009 Apr;67(4):812-8.

17. ARB+statin on NO
• ARB increases NO level by ↓ the breakdown.
• Angiotensin II increases lipid uptake in cells and
lipid accumulation in the vessel wall
– ARB prevents this from happening.
• Thus, the combination of ARB with statin seems
to be more effective through:
– Increase in NO levels,
– Reduced possibility of lipid uptake in cell walls.
– Better reduction in inflammation or effects of
oxidative stress,
Nippon Rinsho. 2009 Apr;67(4):812-8.

18. ARB+statin & phospholipase
• This study was done in patients with CAD to evaluate the
impact of a combined treatment of ARB and statin on:
– the secretory phospholipase and
– oxidized low density lipoprotein (oxLDL).
• 60 patients with angiographically documented CAD and a
history of arterial hypertension were randomized in a
double-blinded fashion to statin or statin + ARB for 3
months.
• The findings show that in patients with CAD, the
combined treatment of statin with ARB reduced
– phospholipase-activity,
– phospholipase-protein concentration, and
– oxLDL, suggesting a novel anti-atherogenic effect by
combining ARB with statin treatment.
European Heart Journal 2008 29(16):1956-1965

19. ARB & age-related
hypercholesterolaemia
• Angiotensin II Type 1 (AT1) Receptor Deficiency
Halts the Progression of Age-Related
Atherosclerosis in Hypercholesterolemia
• This study establishes a molecular link between
the AT1 Receptor and hypercholesterolemia and
thus shows that amongst all antihypertensives,
ARBs have the best anticholesterol effect.
Hypertension Research (2008) 31, 1495–1497.

20. ARB+statin and cross talk
• Experimental studies have shown a cross-talk
between hyperlipidemia and renin-angiotensin-
aldosterone system at multiple steps.
• Combined therapy with statins and ARBs show
additive beneficial effects on ED and insulin
resistance (IR) when compared with
monotherapies in patients with CV risk factors by
both distinct and interrelated mechanisms.
• Combined therapy is useful in treating and
preventing atherosclerosis, CHD, and co-morbid
metabolic disorders characterized by ED and IR.

21. ARB+statin on LV remodelling
• Both ARB and statins have been shown to attenuate
cardiomyocyte hypertrophy after myocardial infarction.
• Whether combination treatment may be superior to either
drug alone on cardiomyocyte hypertrophy remains unclear.
• This study showed that dual therapy with a statin and
ARB,
– produced an additive reduction in cardiomyocyte hypertrophy
and cardiac fibrosis after myocardial infarction through
different mechanisms,
– also decreases the propensity of the heart to arrhythmogenesis.
• The statin provided favorable ventricular remodeling,
probably through decreased tissue endothelin-1 level and
the ARB-related attenuated cardiomyocyte hypertrophy is
independent of endothelin-1 pathway.
Am J Physiol Heart Circ Physiol 291: H1281-H1289, 2006.

22. ARBs and EPCs
• Ischemia is a major component of most of end-target damages
of hypertension;
• Thus, treatments aiming to promote neovascularization could
have new and unexpected beneficial effects.
• The formation of new capillaries to provide oxygen supply for
ischemic tissues was believed to be exclusively mediated by the
proliferation and migration of existing endothelial cells.
• However, increasing evidence suggests that circulating cells
home to sites of ischemia and contribute to adult
neovascularization.
• Treatment with ARBs increases the number of regenerative
endothelial progenitor cells (EPCs) in patients with type II
diabetes and this action may be of therapeutic relevance
contributing to their beneficial cardiovascular effects.
Hypertension 2005;45;491-492, 526-529.

23. ARB+statin on plaque size
• The combined treatment with a statin and an
ARB may have additive protective effects on
endothelial function as well as atherosclerotic
change.
• CT and histology of the thoracic aorta revealed
that the plaque area decreased significantly
more with the combination than with the
monotherapy.
Hypertension Research (2008) 31, 1199–1208.

24. Summary
↑ NO
↓ PLAQUE ↓ LIPID
SIZE ACCUMULATION
TELMISARTAN
↓ PHOSPO
↑ EPCs +
LIPASES
sTATIN
↓ LV ↓ OXI.
REMODELLING LDL
↓ CROSS
TALK

25. ARB + Statin
The role

26. Learnings from animal studies
• Ang II-Induced Hypertension accelerates
atherosclerosis in ApoE-deficient mice
Weiss et al, Circulation 2001;103:448

27. Learnings from animal studies
• Hypercholesterolemia & Hypertension have
synergistic deleterious effects on Endothelial
function
Rodriguez-Porcel et al, Arterioscler Thromb Vasc Biol. 2003;23:885.

28. ARB+Statin after stenting
• Statins enhance the inhibitory effects of ARB on vascular neointimal formation
in mice. The present case-control study investigated the efficacy of combined
treatment with statin and ARB for preventing restenosis in patients with
coronary artery disease.
• 210 patients with angina pectoris undergoing elective coronary stenting for de
novo lesions of native coronary arteries were examined. All enrolled patients
received aspirin and ticlopidine. The subjects were in 3 groups:
– no statin
– statin treatment without ARB
– Statin treatment with ARB.
• The rate of restenosis at 6 months after stent implantation in the statin group
(19%) was significantly lower than that in the control group (32%).
• Study findings indicate that combined treatment with statin and ARB after
stenting is a useful strategy for the prevention of coronary restenosis as patients
treated with statins and ARBs were least likely [odds ratio (95% confidence
interval): 0.30(0.12-0.74)] to develop coronary restenosis.
Combined Treatment With Statin and ARB after Stenting for prevention of Coronary Restenosis, NISHIKAWA et al, J Cardiol,

29. ARB after grafting
• 164 patients were divided into the following 2 groups,
– 92 subjects who were orally administered an ARB,
– 72 subjects who were administered an ACE-inhibitor.
• Graft angiography was performed 1 year after surgery and
the RA intima was evaluated using an angioscope.
• The results of evaluation one year after surgery revealed
• no significant difference in effects on the RA endothelium
between ARB and ACE inhibitor.
• ARB reduced cholesterol and its effect was confirmed with
blood examination data and endoscopic findings.
Ann Thorac Cardiovasc Surg 2008; 14: 25–28

30. Statins and kidney disease
• Data from small studies in glomerular disease suggest that
– statins decrease proteinuria.
– statins decrease the loss of glomerular filtration.
• The pleiotropic effects of statins may derive from inhibition of
other downstream targets (isoprenoids) of the mevalonic acid
pathway that are separate from cholesterol synthesis.
• These effects may lead to
1. decreased monocyte/macrophage infiltration in the glomerulus,
2. decreased mesangial proliferation and
3. decreased accumulation of extracellular matrix and fibrosis.
4. inhibition of RhoA and Ras leading to decrease inflammation and
increase eNOS activity.
• These effects could lead to improvement in the progression of
kidney disease.
Kidney Int. 2008 Sep;74(5):571-6.

31. TELMISARTAN + STATIN
Why Telmisartan is the ARB of
choice in the combination of
ARB+Statin?

32. Difference between antihypertensives
• Reduced rates of new onset diabetes in subjects
treated with ARBs versus other agents

33. Mechanisms of ARB action
ARB Glucose Fatty acid
Glucose uptake
Lipoprotein
and utilization ↑
lipase ↑
↑ GLUT4
↓ TNF-α
PPAR γ - RXR
Adipogenesis
lipid accumulation ↓ in
Transcription of Skeletal Muscle
insulin-responsive
genes

34. Metabolic Effects of Telmisartan
Metabolic Effects of Replacing Valsartan or Candesartan by Telmisartan
18 hypertensive patients with type 2 diabetes
Valsartan 80 mg/day
Telmisartan 40 mg/day
Candesartan 8 mg/day
>6 months 12 weeks
Miura Y et al., Diabetes Care 2005 Mar; 28, 757-758

35. Effects of Telmisartan on glucose,
insulin and TG
Metabolic Effects of Replacing Valsartan or Candesartan by Telmisartan
Plasma Glucose Plasma Insulin TG
(mg/dl) (mU/l) ** (mg/dl)
NS *
160 12 160
140 140
10
120 P<0.01 P<0.05
120
8
100 100
80 6 80
60 60
4
40 40
2
20 20
0 0Candesartan/ Telmisartan 0 Candesartan/
Candesartan/ Telmisartan Telmisartan
Valsartan Valsartan Valsartan
Miura Y et al., Diabetes Care 2005 Mar; 28, 757-758

36. Effects of Telmisartan on
Adiponectin and hs-CRP Levels
Metabolic Effects of Replacing Valsartan or Candesartan by Telmisartan
Adiponectin hs-CRP
(mg/dl) (mg/dl)
** *
10 0.2
9
8
P<0.01 0.15
7
6
5 0.1 P<0.05
4
3
0.05
2
1
0 0
Candesartan/ Telmisartan Candesartan/ Telmisartan
Valsartan Valsartan
Miura Y et al., Diabetes Care 2005 Mar; 28, 757-758

37. Effects on Hs-CRP& Insulin resistance
• hs-CRP is closely related to insulin resistance and
development of atherosclerosis. The reduction of
high-sensitivity C-reactive protein (hs-CRP) is
significant in the telmisartan group as compared
to other ARBs
• Telmisartan has additional effects on insulin
sensitivity and antiatherosclerosis, probably via
its effects on PPAR-γ.
Rodriguez-Porcel et al, Arterioscler Thromb Vasc Biol. 2003;23:885.

38. PPAR modulation
Adapted from Tenenbaum A et al. Intl J Cardiol. 2004;97:167-72.

39. Telmisartan
Activates Blocks
PPARγ pathways Angiotensin pathways
Insulin Cell Cell Oxidative
Dyslipidemia inflammation Hypertension stress
resistance proliferation
Atherosclerosis

40. Who would benefit from combined
therapy of ARBs and Statins?
• Combination therapy of an ARB and a statin in:
1. Patients with cardiovascular risk intervention such as
stenting and grafting
2. Patients presenting with 2 or more linked risk factors
for CVD ie,
• Patients with hypertension + ↑ cholesterol levels
• Patients with metabolic syndrome,
• Patients with hypertension and type 2 diabetes,
• Patients with hypertension and a previous cardiovascular
event such as stroke or myocardial infarction).
3. Proactively, in hypertensives without symptomatic
disease but who are ≥55 years old, as age becomes a
risk factor due to age related hypercholesterolaemia.

41. Who would not benefit from
combination of ARBs and Statins?
• Combination therapy of an ARB and a statin
not in:
1. Patients with telmisartan and higher doses of
atorvastatin
2. Patients with hypertension and elevated TG
levels.
3. Hypertensives with myopathy.

42. The target audience
ARB & Statin

43. The target audience
ARB & Statin