The blood pressure target for patients with type 2 diabetes with and without chronic kidney disease remains controversial. A recent article by Beddhu et al.¹ reported that intensive lowering of systolic blood pressure to <120 mm Hg versus standard lowering to <140 mm Hg increased the risk of incident chronic kidney disease in people with and without type 2 diabetes after a 3 year follow-up period. For the analysis, the authors used combined data from the Systolic Blood Pressure Intervention Trial (SPRINT) and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies. These studies have some similarities, but also notable differences. In addition to not having diabetes, as compared to ACCORD, SPRINT subjects were older, less likely to have cardiovascular disease at baseline and had lower body mass index, glomerular filtration rate (GFR) and albuminuria at baseline. Authors found that the difference in incident chronic kidney disease (CKD) between intensive and standard interventions was especially pronounced in the patients with type 2 diabetes.

CKD is associated with increasing risk of death and cardiovascular events.² The presence of CKD in persons with type 2 diabetes is highly correlated with increased mortality, with a nearly three-fold higher relative risk of mortality than in persons with type 2 diabetes without CKD.³ For these reasons, it is expected that identifying CKD early is important in order to establish early therapy to slow further GFR loss.

It is known that use of renin-angiotensin-aldosterone system (RAAS) blockade has an initial decline in GFR but over time an improved slope and delays end stage renal disease in patients with diabetes. RAAS blockade slows progression to macroalbuminuria. In the ACCORD study macroalbuminuria was lower in the intensively treated group compared to the standard group (6.6 vs. 8.7%), while there was no difference in the development of end stage renal disease (2.5 vs. 2.4%).⁴ The use of RAAS blockade was higher in ACCORD than in SPRINT participants (73% vs. 66 %) and may account for some of the differences noted between these two studies. In contrast to the findings in the ACCORD study, in the Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) study, which also enrolled individuals with type 2 diabetes, blood pressure treatment with a combination of perindopril and indapamide reduced risk of renal events by 21% and a threshold below which renal benefit was lost was not identified.⁵

The rate of incident CKD depends on the definition used and varies accordingly by race, gender and comorbidities, particularly diabetes.⁶ Women are at increased risk for incident CKD.⁷ The authors defined incident CKD as reduction in GFR of 30% or higher with a second confirmed eGFR below 60 mL/min per 1.73 m². While this is an important epidemiological definition, clinicians are particularly interested in identifying who is at risk for faster GFR decline, delaying end-stage kidney disease and decreasing mortality. Interestingly, cardiovascular benefit is reported with intensive blood pressure control in the subgroup of ACCORD participants in the standard glycemic control arm.⁸

The findings of Beddhu et al. are in the context of individuals in their mid 60s with longstanding diabetes who are already at high risk for CKD and should not be generalized to other populations. As a counter example, in a large community-based registry of patients with hypertension, time-varying SBP was associated with incident CKD with a steady increase in risk of incident CKD above an SBP of 120 mmHg.⁹

There remains conflicting data as to the appropriate blood pressure goals. As individuals with type 2 diabetes are at particularly high risk for renal disease and cardiovascular disease there is much interest in identifying optimal goals for these patients. The analysis by Beddhu et al. adds to our understanding of blood pressure cutoffs at which a higher degree of incident CKD may be seen in a subset of persons with type 2 diabetes. Differences in study findings point towards underlying differences in study populations and particular treatment agents which should be contemplated when considering applicability to a particular patient. What is clear is that renal function should be carefully monitored during antihypertensive drug treatment, particularly in individuals with type 2 diabetes. Blood pressure control is an important risk factor for cardiovascular and kidney outcomes. BP goals should be individualized depending on age, comorbidities and proteinuria.

References

1. Beddhu S, Greene T, Boucher R, et al. Intensive systolic blood pressure control and incident chronic kidney disease in people with and without diabetes mellitus: secondary analyses of two randomised controlled trials. Lancet Diabetes Endocrinol 2018;6:555-63.
2. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351:1296-305.
3. Afkarian M, Sachs MC, Kestenbaum B, et al. Kidney disease and increased mortality risk in type 2 diabetes. J Am Soc Nephrol 2013;24:302-8.
4. ACCORD Study Group, Cushman WC, Evans GW, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362:1575-85.
5. de Galan BE, Perkovic V, Ninomiya T, et al. Lowering blood pressure reduces renal events in type 2 diabetes. J Am Soc Nephrol 2009;20:883-92.
6. Bash LD, Coresh J, Kottgen A, et al. Defining incident chronic kidney disease in the research setting: the ARIC study. Am J Epidemiol 2009;170:414-24.
7. Yu MK, Katon W, Young BA. Associations between sex and incident chronic kidney disease in a prospective diabetic cohort. Nephrology 2015;20:451-8.
8. Tsujimoto T, Kajio H. Benefits of intensive blood pressure treatment in patients with type 2 diabetes mellitus receiving standard but not intensive glycemic control. Hypertension 2018;72:323-30.
9. Hanratty R, Chonchol M, Havranek EP, et al. Relationship between blood pressure and incident chronic kidney disease in hypertensive patients. Clin J Am Soc Nephrol 2011;6:2605-11.

Clinical Topics: Heart Failure and Cardiomyopathies, Prevention, Statins, Hypertension

Keywords: Diabetes Mellitus, Type 2, Indapamide, Perindopril, Antihypertensive Agents, Glomerular Filtration Rate, Blood Pressure, Gliclazide, Albuminuria, Renin-Angiotensin System, Risk Factors, Cardiovascular Diseases, Secondary Prevention, Body Mass Index, Follow-Up Studies, Renal Insufficiency, Chronic, Hypertension, Kidney Failure, Chronic, Drug Combinations, Registries, Comorbidity

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