BP lowering in type 2 diabetes beyond guideline recommendations possibly beneficial

Emdin CA, Rahimi K, Neal B
JAMA. 2015 Feb 10;313(6):603-615. doi: 10.1001/jama.2014.18574

Background

Type 2 diabetes (T2DM) is associated with a higher risk of macrovascular events, including myocardial infarction (MI) and stroke [1] and it also affects the microvasculature, which can lead to blindness and end-stage kidney disease [2,3]. Blood pressure (BP) is commonly higher in individuals with diabetes, and is a well-established risk factor in this population [4,5].
In general adult populations, BP shows a continuous positive correlation with disease outcomes and the risk of macrovascular [8] and microvascular [9] disease in T2DM, from as low as 115 mmHg for systolic and 75 mmHg for diastolic BP [6,7].
Some recent guidelines recommend target levels for BP lowering in individuals with diabetes and diagnosed hypertension that are less aggressive than previous recommendations. It is uncertain whether the entire evidence base on BP lowering in T2DM patients has been used to establish these guidelines.
This study therefore conducted a comprehensive overview of the effects of BP lowering treatment in patients with diabetes, irrespective of absence or presence of diagnosed hypertension, focussing on macrovascular and microvascular outcomes. In this meta-analysis, data of 40 trials involving 100354 participants were used for the primary analysis, with an additional 5 trials (with unclear or high risk of bias) on 4232 participants in secondary analyses.

Main results

• Inverse variance weighted fixed-effects analyses showed that a 10 mmHg reduction in systolic BP was associated with a lower risk of CVD events (RR: 0.89, 95%CI: 0.83-0.95), CHD events (RR: 0.88, 95%CI: 0.80-0.98), stroke events (RR: 0.73, 95%CI: 0.64-0.83), retinopathy (RR: 0.87, 95%CI: 0.76-0.99), and albuminuria (RR: 0.83, 95%CI: 0.79-0.87).
• Lower relative risks were seen for the associations between mean initial systolic BP and CHD, CVD and heart failure, in trials with mean baseline systolic BP of >140 mmHg. The effect of treatment on stroke and albuminuria was not affected by initial systolic BP level.
• When considering systolic BP achieved in the treatment group (>130 or <130 mmHg), a lower risk was seen in the >130 mmHg trials for CHD, CVD, heart failure and albuminuria. No significant interaction was seen for stroke or retinopathy.
• Stratifying the data based on different classes of medication used did not reveal striking differences, with the exception of lower risk of heart failure seen with use of diuretics (RR: 0.83, 95CI: 0.72-0.95) as compared with all other forms of medication.
  CCBs were associated with a higher risk of heart failure, and possibly a lower risk of stroke. Beta-blockers were associated with a higher risk of stroke.

Conclusion

BP-lowering treatment was associated with a reduced risk of CVD, CHD and stroke events in patients with type 2 diabetes, as well as a lower risk of retinopathy and albuminuria. In trials with patients with initial BP level of >140 mmHg, a lower risk of outcomes was seen, except for stroke, albuminuria and retinopathy, the risk of which was lower with <140 mmHg at baseline. Lower risks of stroke and albuminuria were seen in trials were achieved systolic BP was <130 mmHg. Risks of other outcomes were lower at >130 mmHg.
The current findings may lead to recommendations different from those recently published in several guidelines, in that initiation of BP-lowering therapy below systolic BP of 140 mmHg and treatment to a systolic target of 130 mmHg should be considered, in individuals at high risk of stroke, retinopathy or progression of albuminuria.

Editorial comment [10]

The increased susceptibility to BP-mediated injury in diabetes is the consequence of disturbed BP circadian rhythms, impaired blood flow autoregulation and stiffening of large arteries. This makes BP both quantitatively and qualitatively different in people with diabetes. Recognition thereof, in combination the with associated increased CVD risk, has prompted a ‘lower is better’ philosophy for BP treatment thresholds and targets in diabetes.Although this concept was uncritically adopted by many guideline developers, the evidence testing the lower is better hypothesis in type 2 diabetes was limited.
In this study, “although all outcomes, including death, were reduced when systolic BP was lowered from the conventionally adopted elevated baseline systolic BP of 140 mm Hg or greater to a systolic BP range of 130 to 140mmHg, even more benefit in reducing the risk stroke and albuminuria was observed with further BP lowering to less than 130 mm Hg, and from a lower baseline of less than140mmHg.” (…)
“Clinical trials of hypertension therapies often recruit aging populations who often have complex multisystem disease and high risk of death or major events, and these trials are usually conducted over a relatively short duration”(…) “it would seem reasonable to consider a bolder approach toBP treatment in younger patients with diabetes and especially those with albuminuria or other early manifestations of microvascular or macrovascular disease than currently advocated in guidelines. However, this is based on extrapolation, but then so is the routine translation of evidence from older to younger patients and to lower-risk patients, and that translation may leave many patients undertreated and underprotected because of concerns about adverse effects they may never experience.”

Find this article online at JAMA

References

1. WoodwardM, Zhang X, Barzi F, et al. The effects of diabetes on the risks of major cardiovascular diseases and death in the Asia-Pacific region. Diabetes Care. 2003;26(2):360-366.
2. Ciulla TA, Amador AG, Zinman B. Diabetic retinopathy and diabetic macular edema. Diabetes Care. 2003;26(9):2653-2664.
3. Jha V, Garcia-Garcia G, Iseki K, et al. Chronic kidney disease: global dimension and perspectives. Lancet. 2013;382(9888):260-272.
4. Hypertension in Diabetes Study (HDS). Prevalence of hypertension in newly presenting type 2 diabetic patients and the association with risk factors for cardiovascular and diabetic complications. J Hypertens. 1993;11(3):309-317.
5. Pechere-Bertschi A, Greminger P, Hess L, et al. Swiss Hypertension and Risk Factor Program (SHARP): cardiovascular risk factors management in patients with type 2 diabetes in Switzerland. Blood Press. 2005;14(6):337-344.
6. Lewington S, Clarke R, Qizilbash N, et al; Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality. Lancet. 2002;360(9349):1903-1913.
7. Rapsomaniki E, Timmis A, George J, et al. Blood pressure and incidence of twelve cardiovascular diseases. Lancet. 2014;383(9932):1899-1911.
8. Kengne AP, Patel A, Barzi F, et al. Systolic blood pressure, diabetes and the risk of cardiovascular diseases in the Asia-Pacific region. J Hypertens. 2007;25(6):1205-1213.
9. Adler AI, Stratton IM, Neil HA, et al Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabete
10. Williams B. Treating Hypertension in Patients With Diabetes. When to Start and How Low to Go? JAMA. 2015;313(6):573-574