NIHR Signal Choice of blood pressure medication for people with diabetes may not be as important as treating blood pressure well

Published on 3 May 2016

This review found that a selection of different blood pressure medications were equally effective as the commonest group of medication prescribed (called renin angiotensin system blockers) for preventing cardiovascular disease and renal outcomes in people with type 2 diabetes. Results mainly apply to people without kidney disease.

Currently renin angiotensin system blocker drugs are recommended as the first-line medication for treating high blood pressure in people with diabetes in the UK. The findings of this review suggest that there may be a case for rethinking this, and that a choice of other blood pressure drugs could be considered.

There are some limitations to the wider interpretation of this study, for example, separate data for people with kidney disease or with type 1 diabetes was not available. So the findings may not necessarily apply to them. There was also no economic evaluation, so it is not clear how the choice of medication might affect overall cost or the balance of benefits and costs. Most medication for blood pressure control is relatively low in cost, however, so choice of medication is usually determined by effictiveness, side effects or drug interactions as many people need more than one drug to control their blood pressure.

Choice of blood pressure medication for people with diabetes may not be as important as treating blood pressure well

Why was this study needed?

In 2014, around 5% of the UK population, that’s 3.5 million people, had diabetes. This number is expected to rise to 5 million by 2025. Diabetes affects blood glucose control, which causes various vascular health complications. Many people with diabetes also take treatments for blood pressure.

People with diabetes are at an increased risk of cardiovascular disease and high blood pressure. Diabetes also is associated with progressive damage to small blood vessels in other parts of the body, such as the eyes and kidneys. Therefore, people with diabetes require extensive monitoring and treatment.

Renin angiotensin system blocking drugs act on one of the systems that regulate blood pressure and kidney function. The two main types of renin angiotensin system blockers are angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB).

Various guidelines recommend renin angiotensin system blockers as first line treatment for people with diabetes, predominantly based on placebo controlled trials done 20 years ago. Other guidelines - based on more recent trials comparing these drugs versus active comparators - suggest renin angiotensin system blockers are similar in effectiveness to other blood pressure lowering drugs.

This systematic review investigated whether, in people with diabetes, renin angiotensin system blockers are better than other anti-hypertensive drugs for preventing cardiovascular and kidney problems in direct comparative trials.

What did this study do?

This systematic review included 19 randomised controlled trials comparing the effectiveness of renin angiotensin system blockers against other anti-hypertensive drugs in people with diabetes or impaired fasting glucose – sometimes called pre-diabetes. To be included, trials had to include 100 or more participants and not include participants who also had heart failure.

ACE inhibitor was used in 14 of the trials and six trials used an ARB. Fifteen of the included trials compared renin angiotensin system blockers with a calcium channel blocker, three with a thiazide diuretic and two with a beta blocker. All trials included people with type 2 diabetes only. There were several main outcomes that the trials set out to examine, but the focus was on important outcomes such as death, heart disease, stroke, drug withdrawal or renal disease.

What did it find?

  • There was no significant difference in outcomes whether participants received renin angiotensin system blockers or other antihypertensive drugs. The outcomes studied were death (relative risk [RR] 0.99, 95% confidence interval [CI] 0.93 to 1.05), cardiovascular death (RR 1.02, 95% CI 0.83 to 1.24), myocardial infarction (RR 0.87, 95% CI 0.64 to 1.18), angina (RR 0.80, 95% CI 0.58 to 1.11), stroke (RR 1.04, 95% CI 0.92 to 1.17), heart failure (RR 0.90, 95% CI 0.76 to 1.07), revascularisation (RR 0.97, 95% CI 0.77 to 1.22), end-stage kidney disease (RR 0.99, 95% CI 0.78 to 1.28), major adverse cardiovascular events (RR 0.97, 95% CI 0.89 to 1.06) or drug withdrawal due to adverse events (RR 0.80, 95% CI 0.61 to 1.05).
  • Comparing renin angiotensin system blockers with the individual classes of calcium channel blockers, thiazide diuretics or beta blockers also showed no significant differences. However, there is less confidence in the results of the comparison with a thiazide diuretic or a beta blocker due to the small number of studies studying these drugs (three and two trials respectively).
  • An additional analysis indicated that the proportion of people with kidney disease in each group did not affect the overall results. An analysis including only participants with kidney disease was not possible because trials did not report outcomes separately for this group.

What does current guidance say on this issue?

For adults with Type 1 or 2 diabetes, 2015 NICE guidance recommends renin angiotensin system blocking drugs as the first‑line therapy for high blood pressure. An ACE inhibitor is usually the first choice drug, switching to an ARB if an ACE is not tolerated, does not resolve high blood pressure, or their kidney function deteriorates.

In adults with Type 2 diabetes of African or Caribbean family origin NICE specifically recommend giving an ACE inhibitor in combination with a diuretic or calcium-channel blocker.

NICE do not recommend giving an ACE inhibitor combined with an ARB.

What are the implications?

This review suggests that renin angiotensin system blockers and alternative anti-hypertensive drugs are equally effective for preventing cardiovascular disease outcomes in people with type 2 diabetes. There did not appear to be a difference for people with kidney disease. Participants with kidney disease or type 1 diabetes were included in the studies but not specifically identified so we do not know whether they respond differently.

An economic evaluation was not included; therefore it is not possible to say which anti-hypertensive was good value for money.

These results suggest that there may be a case for allowing a choice of antihypertensive in the first-line treatment of hypertension in the UK. The choice of renin angiotensin system blocker or other drugs could be based on side effect profiles and the need to treat blood pressure to a target level, rather than a preference for one drug over another. The conclusions of this study do not apply to people with existing kidney disease, for whom the renin angiotensin system blockers may be indicated. Further investigation – particularly focusing on people with kidney disease and comparing cost-effectiveness – is required before practice can be changed.

Citation and Funding

Bangalore S, Fakheri R, Toklu B, Messerli FH. Diabetes mellitus as a compelling indication for use of renin angiotensin system blockers: systematic review and meta-analysis of randomized trials. BMJ. 2016;352:i438.

No funding information was provided for this study.

Bibliography

Diabetes UK. Facts and stats [Internet]; 2015.

NICE. Diabetes (type 1 and type 2) in children and young people: diagnosis and management. NG18. London: National Institute for Health and Care Excellence; 2015.

NICE. Type 1 diabetes in adults: diagnosis and management. NG17. London: National Institute for Health and Care Excellence; 2015.

NICE. Type 2 diabetes in adults: management. NG28. London: National Institute for Health and Care Excellence; 2015.

NICE.  Renin-angiotensin system drugs: dual therapy. KTT2. London: National Institute for Health and Care Excellence; 2015.

Why was this study needed?

In 2014, around 5% of the UK population, that’s 3.5 million people, had diabetes. This number is expected to rise to 5 million by 2025. Diabetes affects blood glucose control, which causes various vascular health complications. Many people with diabetes also take treatments for blood pressure.

People with diabetes are at an increased risk of cardiovascular disease and high blood pressure. Diabetes also is associated with progressive damage to small blood vessels in other parts of the body, such as the eyes and kidneys. Therefore, people with diabetes require extensive monitoring and treatment.

Renin angiotensin system blocking drugs act on one of the systems that regulate blood pressure and kidney function. The two main types of renin angiotensin system blockers are angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB).

Various guidelines recommend renin angiotensin system blockers as first line treatment for people with diabetes, predominantly based on placebo controlled trials done 20 years ago. Other guidelines - based on more recent trials comparing these drugs versus active comparators - suggest renin angiotensin system blockers are similar in effectiveness to other blood pressure lowering drugs.

This systematic review investigated whether, in people with diabetes, renin angiotensin system blockers are better than other anti-hypertensive drugs for preventing cardiovascular and kidney problems in direct comparative trials.

What did this study do?

This systematic review included 19 randomised controlled trials comparing the effectiveness of renin angiotensin system blockers against other anti-hypertensive drugs in people with diabetes or impaired fasting glucose – sometimes called pre-diabetes. To be included, trials had to include 100 or more participants and not include participants who also had heart failure.

ACE inhibitor was used in 14 of the trials and six trials used an ARB. Fifteen of the included trials compared renin angiotensin system blockers with a calcium channel blocker, three with a thiazide diuretic and two with a beta blocker. All trials included people with type 2 diabetes only. There were several main outcomes that the trials set out to examine, but the focus was on important outcomes such as death, heart disease, stroke, drug withdrawal or renal disease.

What did it find?

  • There was no significant difference in outcomes whether participants received renin angiotensin system blockers or other antihypertensive drugs. The outcomes studied were death (relative risk [RR] 0.99, 95% confidence interval [CI] 0.93 to 1.05), cardiovascular death (RR 1.02, 95% CI 0.83 to 1.24), myocardial infarction (RR 0.87, 95% CI 0.64 to 1.18), angina (RR 0.80, 95% CI 0.58 to 1.11), stroke (RR 1.04, 95% CI 0.92 to 1.17), heart failure (RR 0.90, 95% CI 0.76 to 1.07), revascularisation (RR 0.97, 95% CI 0.77 to 1.22), end-stage kidney disease (RR 0.99, 95% CI 0.78 to 1.28), major adverse cardiovascular events (RR 0.97, 95% CI 0.89 to 1.06) or drug withdrawal due to adverse events (RR 0.80, 95% CI 0.61 to 1.05).
  • Comparing renin angiotensin system blockers with the individual classes of calcium channel blockers, thiazide diuretics or beta blockers also showed no significant differences. However, there is less confidence in the results of the comparison with a thiazide diuretic or a beta blocker due to the small number of studies studying these drugs (three and two trials respectively).
  • An additional analysis indicated that the proportion of people with kidney disease in each group did not affect the overall results. An analysis including only participants with kidney disease was not possible because trials did not report outcomes separately for this group.

What does current guidance say on this issue?

For adults with Type 1 or 2 diabetes, 2015 NICE guidance recommends renin angiotensin system blocking drugs as the first‑line therapy for high blood pressure. An ACE inhibitor is usually the first choice drug, switching to an ARB if an ACE is not tolerated, does not resolve high blood pressure, or their kidney function deteriorates.

In adults with Type 2 diabetes of African or Caribbean family origin NICE specifically recommend giving an ACE inhibitor in combination with a diuretic or calcium-channel blocker.

NICE do not recommend giving an ACE inhibitor combined with an ARB.

What are the implications?

This review suggests that renin angiotensin system blockers and alternative anti-hypertensive drugs are equally effective for preventing cardiovascular disease outcomes in people with type 2 diabetes. There did not appear to be a difference for people with kidney disease. Participants with kidney disease or type 1 diabetes were included in the studies but not specifically identified so we do not know whether they respond differently.

An economic evaluation was not included; therefore it is not possible to say which anti-hypertensive was good value for money.

These results suggest that there may be a case for allowing a choice of antihypertensive in the first-line treatment of hypertension in the UK. The choice of renin angiotensin system blocker or other drugs could be based on side effect profiles and the need to treat blood pressure to a target level, rather than a preference for one drug over another. The conclusions of this study do not apply to people with existing kidney disease, for whom the renin angiotensin system blockers may be indicated. Further investigation – particularly focusing on people with kidney disease and comparing cost-effectiveness – is required before practice can be changed.

Citation and Funding

Bangalore S, Fakheri R, Toklu B, Messerli FH. Diabetes mellitus as a compelling indication for use of renin angiotensin system blockers: systematic review and meta-analysis of randomized trials. BMJ. 2016;352:i438.

No funding information was provided for this study.

Bibliography

Diabetes UK. Facts and stats [Internet]; 2015.

NICE. Diabetes (type 1 and type 2) in children and young people: diagnosis and management. NG18. London: National Institute for Health and Care Excellence; 2015.

NICE. Type 1 diabetes in adults: diagnosis and management. NG17. London: National Institute for Health and Care Excellence; 2015.

NICE. Type 2 diabetes in adults: management. NG28. London: National Institute for Health and Care Excellence; 2015.

NICE.  Renin-angiotensin system drugs: dual therapy. KTT2. London: National Institute for Health and Care Excellence; 2015.

Diabetes mellitus as a compelling indication for use of renin angiotensin system blockers: systematic review and meta-analysis of randomized trials

Published on 13 February 2016

Bangalore, S.,Fakheri, R.,Toklu, B.,Messerli, F. H.

Bmj Volume 352 , 2016

OBJECTIVE: To evaluate the outcomes with use of renin angiotensin system (RAS) blockers compared with other antihypertensive agents in people with diabetes. DESIGN: Meta-analysis. DATA SOURCES AND STUDY SELECTION: PubMed, Embase, and the Cochrane central register of controlled trials databases for randomized trials of RAS blockers versus other antihypertensive agents in people with diabetes mellitus. Outcomes were death, cardiovascular death, myocardial infarction, angina, stroke, heart failure, revascularization, and end stage renal disease. RESULTS: The search yielded 19 randomized controlled trials that enrolled 25 414 participants with diabetes for a total of 95 910 patient years of follow-up. When compared with other antihypertensive agents, RAS blockers were associated with a similar risk of death (relative risk 0.99, 95% confidence interval 0.93 to 1.05), cardiovascular death (1.02, 0.83 to 1.24), myocardial infarction (0.87, 0.64 to 1.18), angina pectoris (0.80, 0.58 to 1.11), stroke (1.04, 0.92 to 1.17), heart failure (0.90, 0.76 to 1.07), and revascularization (0.97, 0.77 to 1.22). There was also no difference in the hard renal outcome of end stage renal disease (0.99, 0.78 to 1.28) (power of 94% to show a 23% reduction in end stage renal disease). CONCLUSIONS: In people with diabetes, RAS blockers are not superior to other antihypertensive drug classes such as thiazides, calcium channel blockers, and beta blockers at reducing the risk of hard cardiovascular and renal endpoints. These findings support the recommendations of the guidelines of the European Society of Cardiology/European Society of Hypertension and eighth Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure to also use other antihypertensive agents in people with diabetes but without kidney disease.

Expert commentary

There have been conflicting recommendations of the use of renin angiotensin system blockers in people with diabetes with hypertension in terms of cardiovascular and renal benefits. In this review renin angiotensin system blockers were associated with a similar risk of death, cardiovascular mortality, myocardial infarction, angina pectoris, stroke, heart failure and coronary revascularisation. The review suggests these blockers are not superior to other antihypertensive agents in people with diabetes. The most important recommendation should be to detect hypertension and control blood pressure using any antihypertensive agent in people with diabetes without kidney disease.

Professor Kamlesh Khunti, Professor of Primary Care Diabetes & Vascular Medicine, University of Leicester

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  •   Cardiovascular system disorders, Diabetes, Medicines, Renal and urogenital disorders