1. بسم االله الرحمن الرحيم

3. Use of Beta-Blockers In patients With Diabetes Mellitus
Professor Taalat Abd El-Aatty
Diabetes & Metabolism
Alexandria University

4. Questions? Are β-blockers contraindicated in diabetes mellitus?
Are β-blockers still considered as first line treatment of hypertension?
Are β-blockers the first line treatment for control of hypertension in patients with diabetes?

5. Diabetes mellitus: A Cardiovascular Disease
Diabetes alone, without co morbid coronary heart disease (CHD), exposes individuals to the same high risk (>20%) as does prior CHD for a major cardiovascular event (cardiovascular risk equivalent).
Diabetes doubles the risk of CVD in men and triples the risk in women.

6. Diabetes mellitus: A Cardiovascular Disease
CVD is a major cause of morbidity, mortality for those with diabetes.
Common conditions coexisting with T2DM (e.g., hypertension, dyslipidemia) are clear risk factors for CVD.
Diabetes itself confers independent risk.

7. Diabetes mellitus & Hypertension
Hypertension is twice as common in persons with diabetes as it is in the general populations.
At age 45, approximately 40% of patients with type 2 diabetes also have hypertension, increasing to 60% by age 75.

8. Diabetes mellitus & Hypertension
Truncal obesity, hypertension,, insulin resistance, and dyslipidemia are among the components of the metabolic syndrome, which has been associated with an increased risk of coronary heart disease.

9. "The Goal is to Get to Goal!”
Hypertension
-PLUS-
Diabetes or Renal Disease
< 140/90 mmHg
< 130/80 mmHg
In diabetics blood pressure goals are lower, and thus more difficult to achieve.

10. 3/31/2017 2:34:36 PM
UKPDS
In diabetic hypertensives: every 10 mmHg ↓ in mean SBP above was associated with
44%
56%
21%
Heart Failure
Stroke
Myocardial
infarction 10

11. Beta-blocker

13. Beta 2 – on bronchial and vascular smooth muscle - relaxation
Increased in heart failure
Beta 3 – mediate vasodilatation by release of nitric oxide

14. Antihypertensive effect –
1.Inhibition of prejunctional beta receptors on the terminal neurons
2.Reduction of central adrenergic outflow
3.Decreased Renin-angiotensin system –beta receptors mediate renin release
Thus decreases after load and wall stress

19. Beta-Blockers: Side Effects
Dizziness, fatigue.
Intermittent claudication,
Airway obstruction in asthma.
Heart block.
Raynaud’s phenomenon.
Erectile dysfunction (ED)
Hypoglycaemia.
Increase in insulin resistance or new-onset diabetes.

23. BB with VD Properties

26. 26

29. Beta-Blockers: Contraindications
Asthma.
Atrioventricular block.
Diabetes PER SE is Not a Contraindication for use of β.blocker

30. Beta-Blockers
Increased insulin resistance and a higher incidence of new-onset diabetes mellitus were reported in early trials with beta-blockers.
However, more modern agents such as bisoprolol and carvedilol appear to have no detrimental effect on glucose metabolism.

31. Beta-Blockers
Existing diabetes mellitus is not a contra- indication to beta-blockade, although b1- selective agents are preferable in insulin- dependent patients, to avoid masking hypoglycaemia.

32. Beta-Blockers
Patients with diabetes and concomitant CHF or CAD are among those who can benefit most from beta-blockers.
European guidelines recommend β-blockers for all diabetic patients with acute cardiac syndrome, post-MI, and in CHF.
Post-MI beta-blockade reduces mortality by 23% in diabetic patients.
In CHF studies, β-blockers have consistently shown a significant benefit in patients with diabetes.

33. Meta-analysis by Haas et al
Meta-analysis by Haas et al. showed that compared with placebo, β-blockers for CHF significantly reduces all-cause mortality by 16% in patients with DM.

34. COPERNICUS Study
In the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) study of carvedilol, in patients with advanced HF, all- cause mortality was reduced equivalently in diabetic and nondiabetic patients.

35. Now back to the 1st question
Are β-blockers contraindicated in diabetes mellitus?
β-blockers are not contraindicated in patients with diabetes mellitus.
β-blockers are highly indicated in diabetics with CAD or CHF.

38. Questions? Are β-blockers contraindicated in diabetes mellitus?
Are β-blockers still considered as first line treatment of hypertension?
Are β-blockers the first life treatment for control of hypertension in patients with diabetes?

39. JNC 7: β-blockers 1st line anti-hypertensive
Compelling Indication*
Recommended Drugs
DIURETIC BB
ACEI
ARB
CCB
Aldo ANT
Heart failure •
Post-MI
Diabetes
Chronic kidney disease
Patients with prehypertension or hypertension who have compelling indications (specific high-risk conditions) require therapy with specific antihypertensive agents (ACEIs, ARBs, β-blockers, CCBs). Compelling indications include heart failure, post-MI, high CHD risk, diabetes, chronic kidney disease, and prevention of recurrent stroke.
The selections of agents for patients with these high-risk conditions are based on favorable outcome data from clinical trials.
Also in these patients, however, a combination of agents may be required to lower BP.
Other management considerations include medications already being taken by the patient, tolerability, and desired BP targets.   
National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Bethesda, Md: National Heart, Lung, and Blood Institute; NIH Publication No
Partners in Healthcare Education, LLC 2009

40. NICE/BHS 2006: removed β-blockers

41. BMJ 2008; (including LIFE and ASCOT) A meta-analysis favour the use of β-blockers

42. Largest Meta-analysis
Conclusions: With the exception of the extra protective effect of β blockers given shortly after a myocardial infarction and the minor additional effect of calcium channel blockers in preventing stroke, all the classes of blood pressure lowering drugs have a similar effect in reducing CHD events and stroke for a given reduction in blood pressure so excluding material pleiotropic effects.
BMJ May 19

43. Law et al BMJ 2009

44. Conclusions of meta-analysis
Beta-blockers are vital in treatment of hypertension.
it’s the level of blood pressure reduction that counts.
don’t ‘trust’ drug leaflets (and out-dated side-effect warnings).
be sensitive and treat macro-economically cost-effectively

45. 3/31/2017 2:34:36 PM
Recent Guidelines 2009

46. Large-scale meta-analyses of available data confirm that major antihypertensive drug classes, (diuretics, ACE inhibitors, calcium antagonists, angiotensin receptor antagonists, and b-blockers) do not differ significantly for their overall ability to reduce BP in hypertension.

47. There is also no evidence that major drug classes differ in their ability to protect against overall cardiovascular risk or cause-specific cardiovascular events, such as stroke and myocardial infarction.
Diuretics, ACE inhibitors, calcium antagonists, angiotensin receptor antagonists and b-blockers can all be considered suitable for initiation of antihypertensive treatment, as well as for its maintenance.

48. 3/31/2017 2:34:36 PM
Keeping the number of drug options large increases the chance of BP control in a larger fraction of hypertensives.
Cardiovascular protection by antihypertensive treatment substantially depends on BP lowering per se, regardless of how it is obtained.
The traditional ranking of drugs into first, second, third and subsequent choice, has now little scientific justification and should be avoided.

49. In the absence of compiling indications  Use any anti-hypertensive from the 5 major classes.

50. To answer our 2nd question
Are β-blockers contraindicated in diabetes mellitus?
Are β-blockers still considered as first line treatment of hypertension?
The answer is yes according to large recent meta-analysis and the revised European guidelines in 2009.

51. Questions? Are β-blockers contraindicated in diabetes mellitus?
Are β-blockers still considered as first line treatment of hypertension?
Are β-blockers the first life treatment for control of hypertension in patients with diabetes?

52. United Kingdom Prospective Diabetes Study (UKPDS)
Design: Randomized, controlled trial comparing an ACE inhibitor with a b-blocker in preventing complications of type 2 diabetes.
Population: 1148 patients with hypertension and type 2 diabetes.
Treatment: 758 patients allocated to tight control of BP:
Captopril (n=400)
Atenolol (n=358)

53. Patients With Events (%) Years from Randomization
UKPDS 50
Less tight blood pressure control
Captopril
Atenolol 40
P=0.43 30
Patients With Events (%) 20 10 1 2 3 4 5 6 7 8 9
Years from Randomization
No. of patients at risk:
Captopril Atenolol
UKPDS Group. BMJ. 1998;317:

54. UKPDS
Conclusion:
Captopril and atenolol produced similar reductions in BP in hypertensive diabetics.
Both drugs were equally effective in reducing risk of:
Fatal and non-fatal diabetic complications
Death related to diabetes
Heart failure
Progression of retinopathy

55. JNC 7: β-blockers can be used in diabetics
Compelling Indication*
Recommended Drugs
DIURETIC BB
ACEI
ARB
CCB
Aldo ANT
Heart failure •
Post-MI
Diabetes
Chronic kidney disease
Patients with prehypertension or hypertension who have compelling indications (specific high-risk conditions) require therapy with specific antihypertensive agents (ACEIs, ARBs, β-blockers, CCBs). Compelling indications include heart failure, post-MI, high CHD risk, diabetes, chronic kidney disease, and prevention of recurrent stroke.
The selections of agents for patients with these high-risk conditions are based on favorable outcome data from clinical trials.
Also in these patients, however, a combination of agents may be required to lower BP.
Other management considerations include medications already being taken by the patient, tolerability, and desired BP targets.   
National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Bethesda, Md: National Heart, Lung, and Blood Institute; NIH Publication No
Partners in Healthcare Education, LLC 2009

56. ADA

57. (C) 2011 ADA Recommendation Level of evidence C
Pharmacologic therapy for patients with diabetes and hypertension should include either an ACE inhibitor or ARB.
If needed to achieve blood pressure targets, a thiazide diuretic should be added to those with an estimatedGRF ≥30 mL/min and a loop diuretic for those with an estimated GFR <30.
Slide Summary
The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) acknowledges the evidence from recent clinical trials (eg the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial [ALLHAT]) that most patients with hypertension will require two or more drugs to reach target blood pressure (BP) levels. Further, JNC 7 recommends that combination therapy be considered as initial therapy where BP is greater than 20/10 mm Hg above goal.
Background
JNC 7 notes the increased cardiovascular risk due to hypertension, and in its recommendations has set out guidelines aimed at effective and timely ways of achieving goal BP in hypertensive patients. The JNC authors recommend that initial combination therapy be considered as optimal therapy in patients who are greater than 20/10 mm Hg from goal BP.
JNC 7. JAMA. 2003;289:
ALLHAT Investigators. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor, or calcium channel blocker vs diuretic. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:

58. Level of evidence C:
Supportive evidence from poorly controlled or uncontrolled studies.
Evidence from RCTS with ≥ 1 major or ≥ 3 minor methodological flaws that could invalidate results.
Evidence from observational studies with high potential for bias.
Evidence from case series or case reports.
Conflicting evidence with the weight of evidence supporting the recommendation.

59. If Blood Pressure >130/80 mm Hg in Diabetes + Albuminuria
START with ACEI or ARB ± diuretic)
If BP Still Not at Goal (130/80 mm Hg)
Add CCB or b blocker
If BP Still Not at Goal (130/80 mm Hg)
Consider low dose aldosterone antagonists#
If BP Still Not at Goal (130/80 mm Hg)
Add Vasodilator (hydralazine, minoxidil)
© American College of Physicians. All Rights Reserved.

60. 3/31/2017 2:34:36 PM
European Guidelines
Meta-analyses of available trials show that in diabetes all major antihypertensive drug classes protect against cardiovascular complications, probably because of the protective effect of BP lowering per se.
They can thus all be considered for treatment.

61. Questions? Are β-blockers contraindicated in diabetes mellitus?
Are β-blockers still considered as first line treatment of hypertension?
Are β-blockers the first life treatment for control of hypertension in patients with diabetes?
Definitely not to start with in diabetics with micro-abluminuria in which ACE.I or ARBs are proved to have more benfit.

62. Conclusion Are β-blockers contraindicated in diabetes mellitus? NO
Are β-blockers still considered as first line treatment of hypertension? YES
Are β-blockers the first life treatment for control of hypertension in patients with diabetes? NO

63. Thank YOU