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Effects of reducing blood pressure on renal outcomes in patients with type 2 diabetes: Focus on SGLT2 inhibitors and EMPA-REG OUTCOME.

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Effects of reducing blood pressure on renal outcomes in patients with type 2

diabetes: Focus on SGLT2 inhibitors and EMPA-REG OUTCOME

A.J. Scheena,b, P. Delanayec

a Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, Liège,

Belgium

b Clinical Pharmacology Unit, CHU Liège, Center for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium

c Division of Nephrology, Dialysis, Transplantation and Hypertension, Department of Medicine, CHU Liège (ULg-CHU), Liège, Belgium

ABSTRACT

Empagliflozin, a sodium-glucose cotransporter type 2 (SGLT2) inhibitor, has enabled remarkable reductions in cardiovascular and all-cause mortality as well as in renal outcomes in patients with type 2 diabetes (T2D) and a history of cardiovascular disease in the EMPA-REG OUTCOME. These results have been attributed to haemodynamic rather than metabolic effects, in part due to the osmotic/diuretic action of empagliflozin and the reduction in arterial blood pressure (BP). The present narrative review includes the results of meta-analyses of trials evaluating the effects on renal outcomes of lowering BP in patients with T2D, with a special focus on the influence of baseline and achieved systolic BP, and compares the renal outcome results of the EMPA-REG OUTCOME with those of other major trials with inhibitors of the renin-angiotensin system in patients with T2D and the preliminary findings with other SGLT2 inhibitors, and also evaluates post hoc analyses from the EMPA-REG OUTCOME of special interest as regards the BP-lowering hypothesis and renal function. While systemic BP reduction associated to empagliflozin therapy may have contributed to the renal benefits reported in EMPA-REG OUTCOME, other local mechanisms related to kidney homoeostasis most probably also played a role in the overall protection observed in the trial.

Keywords: Blood pressure; Empagliflozin; Hypertension; Kidney; SGLT2 inhibitor; Type 2 diabetes Introduction

Arterial hypertension is frequently associated with type 2 diabetes (T2D). These two adverse companions markedly increase not only the risk of cardiovascular (CV) disease, but also the risk of chronic kidney disease (CKD), both of which lead to premature death [1,2]. In a large survey performed in the US, there was a substantial decline in rates of diabetic complications over the past two decades, with the largest relative decrease being in acute myocardial infarctions followed by stroke and amputations, and the smallest decrease being in end-stage renal disease (ESRD), such that the relative contribution of CKD is progressively increasing [3]. Although much progress has been made in slowing the progression of diabetic nephropathy, renal dysfunction and the development of ESRD remain major concerns in T2D. In the observational part of United Kingdom Prospective Diabetes Study (UKPDS), the risk of complications in T2D was shown to be associated independently and additively with hyperglycaemia and hypertension, meaning that intensive treatment of both these risk factors is required to minimize the incidence of complications [4]. In the interventional part of the UKPDS, the positive impact of lowering high blood pressure (BP) [5] appeared to be stronger than just controlling hyperglycaemia [6] in patients with newly diagnosed T2D. In the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) study, the effects of routine BP-lowering and intensive glucose control were independent of each another, such that, when combined, they produced additional reductions in clinically relevant outcomes [7]. However, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study, none of the CV or renal outcomes was significantly reduced by simultaneous intensive treatment of both glycaemia and BP, signifying the lack of any additional beneficial effect from combined therapy [8].

BP-lowering therapy is likely to prevent major cardiovascular events (MACEs) and deaths even in patients with uncomplicated mild hypertension, including patients with T2D [9]. However, despite the well-demonstrated benefits of lowering BP in the general population with hypertension [10] and in patients with diabetes [11,12], BP targets in patients with T2D [13] as well as in patients with high CV risk [14] remain controversial and may vary across guidelines [15]. While lowering diastolic BP was considered a potential target in T2D patients following the Hypertension Optimal Treatment (HOT) Study [16] and the Appropriate Blood Pressure Control in Diabetes (ABCD) Trial [17], more recent

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studies have instead focused on systolic BP [13,18]. Interestingly, some data suggest that these BP targets may differ when comparing their effects on renal vs CV outcomes, with possibly lower systolic BP targets to optimalize renal prognoses, especially in patients who already have signs of early or advanced CKD [19-21]. Overall, the achieved systolic BP appears to play a greater role than the type of antihypertensive agent(s) used to reach the target [22, 23], although blocking the renin-angiotensin-aldosterone system (RAAS) has been shown to be associated with remarkable renal protection in diabetic patients with proteinuria [24, 25].

Nevertheless, the potential nephroprotection of the classic antihyperglycaemic drugs beyond the control of hyperglycaemia remains largely unknown [26]. Positive results were recently reported with two glucagon-like peptide-1 (GLP-1) receptor agonists—liraglutide in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial [27] and semaglutide in the trial to evaluate cardiovascular and other long-term outcomes with semaglutide in subjects with type 2 diabetes (SUSTAIN-6 Trial) [28]-two agents that not only reduce hyperglycaemia, but also systolic BP and body weight. In addition, sodium-glucose cotransporter type 2 (SGLT2) inhibitors are novel glucose-lowering agents indicated for the treatment of patients with T2D [29]. These compounds have a distinct mechanism of action in the renal proximal tubule involving blocking the reabsorption of glucose. Among several pleiotropic effects [30-32], a reduction in arterial BP has been consistently reported with all SGLT2 inhibitors [33-36], as recently reviewed [37]. Although not approved as antihypertensive agents, the ability of this new class of antihyperglycaemic agents to lower BP is not trivial and, while not used primarily for this indication, they can help T2D patients attain the currently recommended BP targets, thereby potentially improving clinical outcomes while providing renal protection [37-39].

In patients with a history of T2D and CV enrolled in the placebo-controlled landmark trial, the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME), the addition of empagliflozin, a selective SGLT2 inhibitor, to standard care was associated with significant reductions in the primary endpoint (a composite of CV mortality, non-fatal myocardial infarction and non-fatal stroke), CV and all-cause mortality, and hospitalizations for heart failure [40]. Furthermore, a prespecified analysis showed that, in those patients with T2D at high CV risk, empagliflozin was associated with slower progression of kidney disease and lower rates of clinically relevant renal events vs a placebo when added to standard care [41]. Also, as the positive CV effects happened within the first few months of treatment, haemodynamic rather than antiatherogenic effects have been suspected [42, 43]. These effects may be attributed to the diuretic (natriuretic/osmotic) actions of SGLT2 inhibitors that accompany the glucuretic effect [44-47], although this so-called 'diuretic hypothesis' has also been challenged [48, 49].

In addition to lowering systemic BP, preclinical and exploratory human studies have suggested that SGLT2 inhibitors may also lower intraglomerular pressure through preglomerular vasoconstriction [50-52]. While this effect might explain the transient decline in both measured and estimated glomerular filtration rates (eGFRs) [53, 54], it could also have a potentially beneficial impact in the long run by reducing the rate of eGFR decline in patients with diabetic nephropathy [55, 56]. Recent attention has been directed at alterations in the proximal tubule and resulting changes in GFR [50-52]. Hyperglycaemia causes an increase in proximal tubular reabsorption of glucose, with associated increases in sodium-glucose cotransport. This tubular effect leads to a decrease in solute load to the macula densa, deactivation of tubuloglomerular feedback and increases in GFR. As glomerular hyperfiltration is a recognized risk factor for progression of CKD in diabetic patients, limiting proximal tubular reabsorption, an effect shared by all SGLT2 inhibitors, constitutes a potential target for reducing hyperfiltration and, consequently, for retarding the decline of renal function [55,57]. While numerous recent papers have carefully analyzed the CV endpoints reported in the EMPA-REG OUTCOME [42-47], the interest in renal outcomes is rather new [58], but should rapidly increase after the remarkable results recently published [41].

To analyze the potential contribution of BP reduction to the diminution of renal events reported in EMPA-REG OUTCOME [40], the literature has been carefully gleaned for randomized controlled trials (RCTs) and meta-analyses investigating the effects of lowering BP with different antihypertensive agents, especially RAAS blockers, on renal outcomes in patients with T2D. Specific focus was placed on the influence of baseline and achieved systolic BP on renal outcomes, and the results were compared with those recently reported in the EMPA-REG OUTCOME with empagliflozin [41] and other, limited trials of other SGLT2 inhibitors. To identify the relevant studies, an extensive literature search of MEDLINE was performed from January 1990 to September 2016, using the following Medical Subject Headings (MeSH) terms: 'T2D', 'BP', 'hypertension', 'diuretic' and 'SGLT2 inhibitor' on

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the one hand, and 'CKD', 'renal outcome', 'albuminuria', 'GFR and 'mortality' on the other. No language restrictions were imposed. Reference lists of original studies, narrative reviews, and previous systematic reviews and meta-analyses were also carefully examined.

Meta-analyses of RCTs evaluating the effects of antihypertensive therapy in T2D patients according to baseline systolic BP

Several recent meta-analyses have investigated the effects of lowering BP with different antihypertensive agents on renal outcomes in patients with T2D (Table 1) [59-61]. Results are expressed as standardized effects of a 10-mmHg reduction in systolic BP. All meta-analyses showed significant reductions in a composite endpoint of MACEs, CV mortality and all-cause mortality, as recently reviewed [37]. Similarly, a reduction of albuminuria [urinary albumin-to-creatinine ratio (UACR)] and of renal events (worsening of renal function as detected by a decline in GFR or doubling of serum creatinine) has also been reported (Table 1). However, these events may be considered surrogate endpoints. Lowering BP failed to show any significant reduction in renal failure (including progression to ESRD requiring dialysis or renal transplantation; Table 1 ), possibly due to a too-low event rate and a too-short follow-up.

While some trials of antihypertensive agents were performed in T2D patients with high BP at baseline, especially the landmark UKPDS [5], the benefits of lowering BP have also been evidenced in diabetic patients with mild uncomplicated hypertension [9]. Baseline BP of T2D patients in the EMPA-REG OUTCOME was relatively well controlled at <140/90 mmHg on average [40]. Therefore, it is of interest to analyze the influence of baseline BP on the effects of lowering BP on renal outcomes in such T2D patients (Table 1). While the reduction in albuminuria was greater in patients with higher systolic BP at baseline [59], no significant trend according to baseline systolic BP was observed as far as renal failure is concerned, again perhaps due to too-few events of special interest resulting from a rather short-term follow-up [59-61].

When trials included in a meta-analysis [60] were stratified by baseline CKD, a significant interaction was seen for MACEs (P interaction = 0.012), with larger proportional (relative risk; RR) reductions in populations without CKD [RR: 0.68; 95% confidence interval (CI): 0.62-0.75] than with CKD (RR: 0.84; 95% CI: 0.73-0.96). A significant interaction was also observed for heart-failure events, with a larger and statistically significant risk reduction of 52% (RR: 0.48; 95% CI: 0.38-0.62) for every 10-mmHg systolic BP reduction in the subgroup without CKD compared with a nonsignificant reduction in those with CKD (RR: 0.95; 95% CI: 0.70-1.29; P interaction = 0.0008) [60].

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Table 1: Randomized controlled trials of the effects of blood pressure (BP)-lowering (all antihypertensive agents combined) on cardiovascular (CV) outcomes (primary

composite endpoint of major CV adverse events), all-cause mortality and renal outcomes in patients with hypertension and type 2 diabetes, and the influence of baseline systolic BP.

Meta-analyses Baseline systolic BP (mmHg) CV outcomes All-cause mortality Albuminuriaa Renal failureb

Emdin et al., 2015 [59] Pooled data (any BP level) 0.89 (0.83-0.95) 0.87 (0.78-0.96) 0.83 (0.79-0.87) 0.91 (0.74-1.12) >140 0.74 (0.65-0.85) 0.73 (0.64-0.84) 0.71 (0.63-0.79) 0.75 (0.52-1.08) <140 0.96 (0.88-1.05) 1.07 (0.92-1.26) 0.86 (0.81-0.90) 1.00 (0.77-1.29)

P = 0.001 P<0.001 P = 0.002 P = 0.21

Ettehad et al., 2016 [60] Pooled data (any BP level) 0.80 (0.77-0.83) 0.87 (0.84-0.91) NA 0.95 (0.84-1.07)

130-139 0.87 (0.82-0.92) 0.89 (0.82-0.98) NA 1.02 (0.82-1.26) 140-149 0.79 (0.72-0.87) 0.99 (0.89-1.09) NA 3.23 (0.73-14.30) 150-159 0.80(0.71-0.91) 0.78 (0.69-0.90) NA 0.90 (0.76-1.05) >160 0.74 (0.69-0.79) P = 0.22 0.86 (0.80-0.92) P = 0.79 NA 0.94 (0.56-1.56) P = 0.52

Brunstrom and Carlberg, 2016 [61] Pooled data (any BP level) NA 0.92 (0.87 to 0.96) NA 0.88 (0.80-0.97)

>150 NA 0.89 (0.80-0.99) NA 0.82 (0.71-0.94) 140-150 NA 0.87 (0.78-0.98) NA 0.91 (0.74-1.12) <140 NA 1.05 (0.95-1.16) P = 0.019 NA 0.97 (0.80-1.17) P = 0.359

Results are expressed as the standardized effect of a 10-mmHg reduction in systolic BP (mean hazard ratio with 95% confidence interval); P values are between-group comparisons according to baseline systolic BP and all are for trend.

a Development of microalbuminuria as well as the composite of new or worsening albuminuria.

b End-stage renal disease requiring dialysis or transplantation or death due to renal disease. NA: not available.

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composite endpoint of major CV adverse events), all-cause mortality and renal outcomes in patients with hypertension and type 2 diabetes, and the influence of achieved systolic BP.

Meta-analyses Achieved systolic BP (mmHg)

CV outcomes All-cause mortality Albuminuriaa Renal failureb

Bangalore et al., 2011 [62] Overall NA 0.90 (0.83-0.98) NA 0.73 (0.64-0.84)

<135 NA 0.87 (0.79-0.95) NA 0.83 (0.68-1.00)

<130 NA 1.04 (0.86-1.25) NA 0.64 (0.53-0.78)

P = 0.09 P = 0.06

Emdin et al., 2015 [59] Overall 0.89 (0.83-0.96) 0.87 (0.78-0.96) 0.83 (0.79-0.87) 0.91 (0.74-1.12) >130 0.74 (0.64-0.85) 0.75 (0.65-0.86) 0.71 (0.64-0.79) 0.74 (0.52-1.06) <130 0.96 (0.88-1.05) 1.06 (0.90-1.25) 0.86 (0.81-0.90) 1.01 (0.78-1.32)

P = 0.002 P = 0.001 P = 0.002 P =0.16

Brunstrom and Carlberg, 2016

[61] Overall NA 0.93 (0.87-0.98) NA 0.88 (0.80-0.97)

>140 NA 0.96 (0.86-1.06) NA 0.88 (0.76-1.03)

130-140 NA 0.86 (0.79-0.93) NA 0.84 (0.66-1.07)

<130 NA 1.10 (0.91-1.33) P=

NA NA 1.01 (0.71-1.43) P = NA

Results are expressed as the standardized effect of a 10-mmHg reduction in systolic BP (mean hazard ratio with 95% confidence interval); P values are between-group comparisons according to achieved systolic BP and all are for trend.

a Development of microalbuminuria and composite of new or worsening albuminuria.

b End-stage renal disease requiring dialysis or transplantation, or death due to renal disease, except in Bangalore et al., where overt nephropathy was not

precisely defined. NA: not available.

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Trials Intervention Patients (n): intensive vs

less intensive

Systolic BP

(mmHg) Composite CVevents All-causemortality Albuminuria Renal failure Compositerenal outcomeb

ACCORD [77] Systolic BP 2362 vs

2371 Baseline: 139/76 0.88 (0.73-1.06) 1.07 (0.85-1.35) Micro: 0.93 (NA) P = 0.13 1.04 (NA) NA Original publication <120 vs <140 mmHg Achieved:

119.3/64.4 P = 0.20 P = 0.55 Macro: 0.76 (NA) P = 0.93

a

Follow-up (years): 4.7 vs 133.5/70.5 P = 0.009

ACCORD [8] Systolic BP Micro: 0.84

(0.72-0.97)

1.0 (0.71-1.43) NA

Post hoc analysis <120 vs <140 mmHg P = 0.019 P = 0.991a

Follow-up (years): 4.7 Macro: 0.81

(0.63-1.03) P = 0.087

SPRINT [78] Systolic BP 4678 vs

4683 Baseline: 140/78 0.75 (0.64-0.89) 0.73 (0.60-0.90) Follow-up (years): 3.3 <120 vs <140 mmHg Achieved:

121.5/68.7 vs 134.6/76.3 P< 0.001 P = 0.003 With CKD at baseline: <120 vs <140 mmHg 1330 vs 1316 NA NA NA Incident: 0.72 (0.48-1.07) P = 0.11 0.87 (0.36-1.07)P = 0.75c 0.89 (0.42-1.87) P=0.76 Without CKD at baseline: <120 vs <140 mmHg 3332 vs 3345 NA NA NA Incident: 0.81 (0.63-1.04) P = 0.10 3.49 (2.44-5.10)P<0.001d NA

Results are mean hazard ratios (lower vs higher target) with 95% confidence intervals; P values are between-group comparisons according to target systolic BP.

a For end-stage renal disease or need for dialysis.

b For participants with chronic kidney disease (CKD) at baseline with first occurrence of a reduction in estimated glomerular filtration rate (eGFR) >50%,

long-term dialysis [0.57 (0.19-1.54); P = 0.27] or kidney transplantation.

c >50% reduction in eGFR (confirmed).

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Trials with different systolic BP targets or achieved levels in T2D patients

BP targets in patients with T2D are controversial mainly because results from RCTs have been heterogeneous [13]. Besides the influence of baseline BP, the achieved BP throughout follow-up may also play a major role in renal outcomes. There are two ways to test this hypothesis: (i) compare renal outcomes in meta-analyses (Table 2) and RCTs (Table S1; see supplementary material associated with this article online) investigating the influence of achieved BP in post hoc analyses; and (ii) compare renal outcomes in RCTs with a prespecified primary goal to test intensified vs standard BP-lowering (Table 3).

Thus far, three meta-analyses have investigated the influence of achieved systolic BP on renal outcomes in patients with T2D [59,61,62]. However, no significant trend could be found when comparing albuminuria or renal failure in patients achieving systolic BP levels either < or >130mmHg (Table 2). Meta-regression analyses testing whether the protective effect was proportional to the magnitude of BP reduction achieved showed non-significant RR reductions for renal failure (P = 0.09) [60].

Results were somewhat different when the influence of achieved systolic BP was also specifically investigated in post hoc analyses of several large RCTs: the Reduction of Endpoints in Non-Insulin-Dependent Diabetes with the Angiotensin II Antagonist Losartan(RENAAL) study [63]; the OngoingTelmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTAR-GET) [64]; Veterans Affairs Diabetes Trial (VADT) [65]; VeteransAffairs Nephropathy in Diabetes Study (NEPHRON-D) [66]; Avoiding Cardiovascular Events Through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) [67]; and Olmesartan Reducing Incidence of End Stage Renal Disease in Diabetic Nephropathy Trial (ORIENT) [68,69]. Overall, these results showed better renal outcomes in patients achieving lower systolic BP, with less albuminuria, less worsening of GFR and less renal failure (Table S1).

These results were confirmed in a post hoc analysis of the Irbesartan Type II Diabetic Nephropathy Trial (IDNT) [70]. In patients with overt proteinuria and mild-to-moderate CKD, the best renal outcome (fewer patients reaching a doubling of serum creatinine or ESRD) was observed in patients who achieved a systolic BP < 134 mmHg. On the other hand, the risk of a renal endpoint was 2.2-fold higher among patients with follow-up systolic BP levels >149 mmHg [70]. This trend was even more pronounced in ADVANCE [71]. In age- and gender-adjusted analyses, there was an approximately log-linear relationship (P < 0.0001) between the rate of any renal event and the achieved systolic BP during follow-up. The lowest risk for a renal event was observed among patients with a median achieved systolic BP of 106 mmHg [71].

These better renal outcomes with lower systolic BP observed in RCTs have also been confirmed by real-life data from various studies performed in the US [72], Italy [73] and Japan [74]. However, the results can vary according to the characteristics of the studied population. For instance, in a cohort of diabetic patients with CKD and a mean BP < 140/80 mmHg, BP was not independently associated with CKD progression [75]. In the general non-diabetic middle-aged population, an elevated BP was not associated with accelerated GFR decline when GFR was measured with a reference method [76]. Two studies specifically compared intensified (<120 mmHg) vs standard (<140mmHg) systolic BP-lowering strategies: the ACCORD in T2D patients [8,77]; and the Systolic Blood Pressure Intervention Trial (SPRINT) [78] in non-diabetic patients at high CV risk (Table 3). In the ACCORD, the intensified-treatment group showed a reduction in the occurrence of macroproteinuria, but not microalbuminuria, and there was no difference in the incidence of renal failure compared with the less-intensified group [8,77]. Thus, renal outcomes did not differ from those reported for composite CV outcomes or all-cause mortality, which also did not significantly differ between the two groups (only significantly fewer strokes were reported in the intensified group; Table 3). In SPRINT, while a remarkable reduction in composite CV endpoints and all-cause mortality was observed in the intensified BP group compared with the less-intensified BP group, only a trend towards a reduction in albuminuria was observed, while no protection of renal function could be detected (in contrast, a >30% reduction in eGFR to <60 mL/min/1.73 m2 was seen significantly more frequently in the intensified BP group without CKD at

baseline; Table 3) [78].

In general, while renal outcomes seem to arise less frequently when lower targets are reached for systolic BP in patients with T2D with or without CKD, heterogeneity is evident when analyzing all the available data in the literature. Such heterogeneity may possibly be due to marked differences in clinical (age, diabetes duration) and biological (baseline albuminuria and GFR) characteristics of the

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studied patients. Furthermore, differences in life expectancy and baseline risk between trial subjects and real-world populations of older adults with CKD may also diminish the somewhat marginal benefit of preventing ESRD [79]. Moreover, it is still not clear whether lower systolic BP targets should be recommended to reduce renal outcomes compared with those proposed to reduce CV outcomes or whether targets in patients with T2D should be lower than those in non-diabetic populations. In 2012, the Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group recommended BP targets <140/ 90 mmHg in diabetic patients without microalbuminuria and < 130/80 mmHg in diabetic patients with micro- or macro-albuminuria [21]. According to the European Society of Hypertension (ESH) and European Society of Cardiology (ESC) guidelines published in 2013, systolic BP should be lowered to <140 mmHg in patients with diabetic renal disease, but when overt proteinuria is present, then values <130 mmHg may be targeted, provided that changes in eGFR are monitored and diastolic BP is <85 mmHg [20].

Renal outcomes in EMPA-REG OUTCOME vs other major RCTs with RAAS blockers in T2D patients

The EMPA-REG OUTCOME population included patients who had T2D, established CV disease and an eGFR of at least 30 mL/min/ 1.73 m2, according to the four-variable Modification of Diet in Renal

Disease (MDRD) formula [41]. Prespecified renal outcomes included incident or worsening nephropathy [progression to macroalbuminuria, doubling of serum creatinine (sCr), initiation of renal replacement therapy (RRT), death from renal disease] and incident albuminuria. Incident or worsening nephropathy was noted in 525 of 4124 patients (12.7%) in the empagliflozin group and in 388 of 2061 (18.8%) in the placebo group [empagliflozin hazard ratio (HR): 0.61; 95% CI: 0.53-0.70; P< 0.001]. This corresponds to a number-needed-to-treat (NNT) of 16 to avoid one case of incident or worsening nephropathy. Doubling of sCr was reduced by 44% (1.5% in the empagliflozin group vs 2.6% in the placebo group) and, although the number of events was limited, it must be emphasized that the most relevant renal endpoint — requirement of RRT— was also significantly reduced by 55% (0.3% vs 0.6%, respectively). Progression to macroalbuminuria was reduced by 38% (11.2% vs 16.2%, respectively) but, rather surprisingly, there was no significant between-group difference in the rate of incident albuminuria (Table 4) [41].

The first landmark study in patients with T2D and hypertension (UKPDS) recruited patients with newly diagnosed T2D. BP was rather high at baseline, and patients were randomly assigned to either antihypertensive therapy (captopril or atenolol) or a placebo [5]. The average BP reductions were somewhat large at 10 mmHg for systolic and 5 mmHg for diastolic BP. This was associated with a significant reduction in microvascular endpoints (P = 0.0092), predominantly due to a reduced risk of retinal photocoagulation and a reduction of albuminuria [80]. The number of renal events was low in both groups despite the rather long follow-up, although a trend towards lower rates was observed in the group receiving intensified BP therapy (Table 4) [5,80].

Since the UKPDS, numerous studies have investigated the effects of antihypertensive agents on CV and renal outcomes in T2D patients with or without markers of CKD, focusing mainly on RAAS inhibitors [22] such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) [8,81-88]. Findings are rather consistent with significant reductions in microalbuminuria or proteinuria and at least a trend (significant in some trials) towards a reduction of renal outcomes (deterioration of eGFR or progression to ESRD; Table 4). However, significant slowing of nephropathy progression was only observed in those with proteinuria at >300 mg/day [24,25,63,84]. Yet, in a post hoc analysis of ADVANCE-BP, the treatment benefits for renal outcomes (as well as for CV outcomes and deaths) with routine administration of a fixed combination of perindopril-indapamide were consistent across all stages of CKD at baseline, eGFR levels and levels of UACR [not significant (NS) for trend] [89].

The results of these large trials with either ACEIs or ARBs confirm those obtained in a meta-analysis of smaller groups of patients (mostly post hoc subgroup analyses) published in 2004 [90] : progression from microalbuminuria to macroalbumiuria, HR: 0.45 (0.28-0.71), P = 0.0007 with ACEIs, and HR: 0.49 (0.32-0.75), P = 0.001 with ARBs; doubling of sCr, HR: 0.60 (0.34-1.05), P = 0.08 with ACEIs and 0.79 (0.67-0.93), P = 0.004 with ARBs; and progression to ESRD, HR: 0.64 (0.40-1.03), P = 0.07 with ACEIs and HR: 0.78 (0.67-0.91), P = 0.001 with ARBs.

Globally, the renal results of EMPA-REG OUTCOME are rather impressive, especially the reduction of a hard endpoint such as the requirement of RRT. Such a result was not observed with RAAS blockers in trials of T2D patients where the most reported beneficial effect was a reduction in

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micro-/macroalbuminuria, which is only a surrogate endpoint (Table 4). However, it is not easy to compare renal outcomes with empagliflozin and with RAAS blockers. Indeed, in the EMPA-REG OUTCOME, most of the patients in both groups had already been treated with either ACEIs or ARBs whereas, by definition, no patients in the placebo groups of trials testing RAAS blockers had received such treatment. Attempts to better inhibit RAAS through dual blockade failed to show positive results with either a telmisartan-ramipril combination, as in ONTARGET [91 ], or the addition of the renin inhibitor aliskiren to either an ACEI or ARB in the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) [92].

Of potential interest, favourable results with a reduction in systolic BP, albuminuria and progression of CKD were reported with the addition of a mineralocorticoid receptor antagonist (spironolactone) to standardized antihypertensive therapy, including ACEIs and ARBs [93-95]. However, the risk of hyperkalemia was increased with mineralocorticoid receptor antagonists, whereas no deleterious changes in serum potassium levels were observed with the addition of empagliflozin in the EMPA-REG OUTCOME [40,41]. Other alternatives have recently been evaluated, with positive effects for dual inhibition of RAAS and endothelin-1 in the treatment of CKD, but this approach remains to be tested in patients with T2D and diabetic nephropathy [96].

Renal outcomes of EMPA-REG OUTCOME vs other trials with SGLT2 inhibitors

In one of the first meta-analyses published of SGLT2 inhibitors [97], the incidence of kidney-related adverse events was increased with dapagliflozin and canagliflozin compared with placebos in patients with moderate renal impairment, and similar findings were reported with the highest dose of canagliflozin in patients with normal or mildly impaired renal function. In this respect, the data from EMPA-REG OUTCOME with empagliflozin 10 mg and 25 mg are reassuring [41].

Renal endpoints from the trial [41] also confirm previous preliminary results obtained in shorter-term trials of the three SGLT2 inhibitors available in Europe and the US, specifically, canagliflozin [98], dapagliflozin [99-101] and empagliflozin [102]. However, these trials only had useful results for relatively soft endpoints, such as incipiens microalbuminuria, progression to macroproteinuria and changes in eGFR (Table 5). In most trials, SGLT2 inhibitors reduced the level of albuminuria and proportion of patients progressing to a higher category of albuminuria (from no albuminuria to microalbuminuria or from microalbuminuria to macroproteinuria), while increasing the proportion of patients with albuminuria at baseline who showed no progression of albuminuria at the final visit. Yet, in the EMPA-REG OUTCOME, the fact that the rate of de novo microalbuminuria was not reduced in patients treated with empagliflozin compared with those receiving a placebo is astonishing and remains inexplicable [41].

As far as eGFR is concerned, an initial transient reduction is commonly observed during the first few weeks in all trials of SGLT2 inhibitors. For instance, during the initial 4 weeks of therapy, the EMPA-REG OUTCOME reported decreases of 0.62 mL/min/1.73 m2 in the empagliflozin 10-mg group and of

0.82 mL/min/1.73 m2 in the 25-mg group compared with a small increase (+0.01 mL/min/ 1.73 m2) in

the placebo group (P< 0.001 for both vs placebo). Thereafter, during long-term administration (from week 4 to the final week of treatment), the eGFR remained stable in both empagliflozin groups, but declined steadily in the placebo group (P < 0.001 for both vs placebo; Table 5). After stopping the study drug (between the last week of treatment and the follow-up), eGFR increased with both doses of empagliflozin compared with almost no change in the placebo group (P < 0.001 for both vs placebo) [41]. Nevertheless, a limitation of this type of analysis is that the GFR was indirectly estimated and not directly measured. However, previous smaller and shorter studies that directly measured GFR using a reference method in patients treated with SGLT2 inhibitors showed a very similar GFR pattern in both type 1 diabetes [55] and T2D [53,54] patients. Interestingly, this biphasic change with an initial GFR reduction followed by secondary renal protection is closely similar to what is observed in T2D patients treated with RAAS blockers [24,25].

In a recent secondary analysis of a large clinical trial of 1450 patients with T2D treated with metformin and randomly assigned to receive once daily either canagliflozin (100 mg or 300 mg) or glimepiride, a sulphonylurea used as a glucose-lowering active reference, the objective was to determine whether the SGLT2 inhibitor decreases albuminuria and renal function decline independently of its glycaemic effects [103]. Overall, the results showed renal protection with canagliflozin comparable to that reported in EMPA-REG OUTCOME, with a smaller decline in eGFR and greater reduction in UACR in patients treated with canagliflozin compared with patients treated with glimepiride. However, as the between-group differences in glucose control were modest, it was concluded that canagliflozin might

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confer renoprotective effects independently of its glycaemic effects. Nevertheless, an effect due to the greater systolic BP reduction with canagliflozin (100 mg and 300 mg) than with glimepiride (at 2 years: -2.0 and -3.1 vs +1.7mmHg, respectively) cannot be excluded, although adjusting for changes in HbA1c, BP and body weight did not alter the results [103].

This conclusion was also confirmed by a post hoc pooled analysis of five RCTs with empagliflozin in patients with T2D and either micro- or macroalbuminuria [104], wherein empagliflozin reduced UACR by a clinically meaningful amount. Intriguingly, in regression models, most of this UACR-lowering effect was not explained by SGLT2 inhibition-related improvements in either HbAlc, systolic BP or body

weight. It was concluded that the renal effect of empagliflozin was largely independent of the known metabolic or systemic haemodynamic effects of this drug class, further supporting a direct effect of SGLT2 inhibitors within the kidneys [104].

Post hoc analyses of EMPA-REG OUTCOME

As previously reported for CV protection [40], the renoprotective effect of empagliflozin in the EMPA-REG OUTCOME was observed independently of baseline BP levels (Table S2; see supplementary material associated with this article online). Considering incident or worsening nephropathy, the P value for interaction was 0.56 when patients with systolic BP > 140 mmHg and/or diastolic BP > 90 mmHg were compared with patients with systolic BP < 140 mmHg and/or diastolic BP < 90 mmHg at baseline [41]. Thus, subgroup analyses comparing renal outcomes in T2D patients achieving (or not) low systolic BPs (for instance, <130 mmHg) with empagliflozin therapy would be of great value to further determine the role of BP-lowering in overall renal protection, although such information is not yet available.

Subgroup analyses suggest that the background antihypertensive therapy does not significantly alter the effect of empagliflozin on renal outcomes (Table S2). The presence or absence of diuretic therapy at baseline also did not influence the risk of incident or worsening nephropathy (P = 0.95 for

interaction). As already stated, the vast majority of participants in the EMPA-REG OUTCOME had already been treated with drugs inhibiting RAAS, and a trend towards better protection against incident or worsening nephropathy was observed in patients treated with an antihypertensive agent (P = 0.13), especially an RAAS blocker (ACEIs and/or ARBs; P = 0.06). For this reason, it has been postulated that, in patients treated with RAAS blockers, empagliflozin might have additional cardioprotective effects through activation of the non-classic RAAS pathways, such as activation of the angiotensin II type 2 (AT2) receptor and the AT1-7 pathway, with antiproliferative, anti-inflammatory, antiarrhythmic vasodi-latory effects [105]. Whether these potential mechanisms might also help to explain the reduction in renal outcomes with empagliflozin remains to be proven.

Prespecified subgroup analyses for incident or worsening nephropathy showed no significant

interaction when patients were divided according to UACR at baseline (<30 vs >30 mg/g; P = 0.87 for interaction). As already mentioned, this may differ from results previously reported with RAAS

blockers, which showed better efficacy on renal outcomes in patients with proteinuria [24,25]. However, no significant interaction was found when patients were divided according to eGFR at baseline (>90, 60 to <90, 45 to <60 and <45 mL/min/1.73 m2; P = 0.40 for interaction; Table S2).

Nearly one-third of patients in EMPA-REG OUTCOME had impaired renal function at baseline with an eGFR < 60mL/min/1.73m2 (mean: 48.4 mL/min/1.73 m2), while a prespecified analysis compared the

outcomes of these patients with those of patients with normal kidney function at baseline (eGFR=83.1 mL/min/1.73 m2) [40,41]. Patients with renal impairment had somewhat similar baseline BP control as

patients with normal kidney function (136.1/74.5 mmHg vs 135.0/ 77.4 mmHg, respectively), but used more antihypertensive agents, especially diuretics (58.6% vs 38.5% of patients, respectively). Incident or worsening nephropathy was significantly reduced in patients with prevalent kidney disease, defined as an eGFR < 60 mL/min/1.73 m2 and/or macroalbuminuria at baseline (HR: 0.58; 95% CI: 0.47-0.71;

P< 0.001) [40,41]. These results are closely comparable to those obtained for the whole study population (HR: 0.61; 95% CI: 0.53-0.70; P < 0.001) [40].

It is also noteworthy that the EMPA-REG OUTCOME recruited T2D patients with established CV disease and eGFRs >30 mL/min/ 1.73 m2, which means that their results for renal outcomes may not

necessarily be extrapolated to all T2D patients. Furthermore, no frail elderly patients were included in most, if not all, of the RCTs of SGLT2 inhibitors. Thus, caution is recommended for real-life patients who are more exposed to acute renal insufficiency, especially in cases of dehydration [79].

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Conclusion

Treating hypertension is associated with significant reductions in microalbuminuria, macroproteinuria and worsening of kidney function, including progression to ESRD, in patients with T2D. However, while small improvements in BP can at least affect albuminuria, a validated surrogate endpoint of diabetic nephropathy, benefits for hard renal outcomes, especially the slowing or avoidance of ESRD, require longer patient follow-up to become more evident. In general, limited BP reductions have resulted in rather small reductions in renal outcomes. However, the bulk of data concerns agents that block the RAAS, where even the use of ACEIs and ARBs failed to markedly improve renal outcomes in T2D patients with relatively well controlled BP at baseline, despite further small reductions in BP. Thus, BP targets for positive renal outcomes remain controversial, and analyses of the available data remain rather confusing in this respect. Guidelines published in 2012 (KDIGO) and 2013 (ESH/ESC) should probably be updated according to recent and incoming data.

SGLT2 inhibitors consistently reduce BP by 3-4 mmHg on average for systolic BP, an effect that is commonly explained by their diuretic/natriuretic effects and perhaps by other mechanisms, such as a reduction of arterial stiffness. The EMPA-REG OUTCOME is the first to demonstrate marked reductions in CV and all-cause mortality rates with the SGLT2 inhibitor empagliflozin, together with a significant reduction in hospitalizations for heart failure, in T2D patients with antecedents of CV disease. In another recent paper, a significant reduction in renal outcomes was reported and, clearly, such results cannot be explained by the modest improvements in glucose control or the rather limited BP reduction in patients with already adequate BP control at baseline. In fact, the effects are even more impressive than those previously reported with RAAS blockers, and it is noteworthy that they were obtained with the SGLT2 inhibitor empagliflozin in patients who had previously received an ACEI or ARB. Indeed, an interesting study would be one comparing empagliflozin with a diuretic that induces a similar reduction in systolic BP in T2D patients already treated with an RAAS blocker. In general, our present analysis of the literature supports a local intrarenal positive effect of the SGLT2 inhibitor empagliflozin rather than a systemic (BP-lowering) effect to explain the better renal outcomes in EMPA-REG OUTCOME. Although several hypotheses have already been proposed, further studies are nonetheless required to better understand the underlying mechanisms. Furthermore, there is no doubt that more physiological studies with measured GFRs using a reference method (not eGFR based on creatinine) would help to clarify the renal effects of SGLT2 inhibitors in T2D patients in the long term. Finally, the results of the EMPA-REG OUTCOME now need to be confirmed by the ongoing prospective trials of other SGLT2 inhibitors, such as the Effects of Canagliflozin on Renal Endpoints in Adult Participants with Type 2 Diabetes Mellitus (CANVAS-R) and Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants with Diabetic Nephropathy (CREDENCE), and the Dapagliflozin Effect on Cardiovascular Events (DECLARE). However, in any event, the present results with empagliflozin in the EMPA-REG OUTCOME and preliminary findings with other SGLT2 inhibitors still raise new hopes for improving the renal prognosis in T2D patients.

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Table 4 : Comparison of cardiovascular (CV) outcomes in EMPA-REG OUTCOME and other major placebo-controlled trials of antihypertensive therapy targeting the

renin-angiotensin-aldosterone system (RAAS) in patients with type 2 diabetes (T2D).

Intervention Type of patients Patients (n) active vs placebo/control Follow-up (years) Baseline BP (mmHg) ΔBP VS placebo (mmHg) Composite CV events All-cause mortality

Albuminuria Renal failure Composite renal

outcomesd EMPA-REG OUTCOME [40] Empagliflozin CVD 4687 vs 2333 3.1 135.3/76.6 -4/1 0.86 (0.74-0.99) P = 0.04 0.68 (0.57-0.82) P < 0.001 → Micro: 0.95 (0.87-1.04) P = 0.25 → Macro: 0.62 (0.54-0.72) P< 0.001 0.45 (0.21-0.97) P = 0.04c 0.61 (0.53-0.70) P< 0.001 UKPDS [5] Captopril

(or atenolol) New-onset T2D 758 vs 390 8.4 159/94 10/5 0.66 (NA) P = 0.019 0.82 (0.63-1.08) P=0.17 Death from renal failure: 0.35 (0.03-3.66) P=NS At 6 yearsa: → Micro: 0.71 (0.51-0.99) P = 0.00085 → Macro: 0.61 (0.31-1.21) P = 0.061 0.58 (0.15- 2.21) P = NS NA MICRO-HOPE [81] Enalapril CVD or CVRF 1808 vs 1769 4.5 142/80 ~2.5/1 0.75 (0.64-0.88) P = 0.0004 0.76 (0.63-0.92) P = 0.004 0.76 (0.60-0.97) P = 0.027 0.80 (-2.0, -1.53) P = 0.70b NA

RENAAL [82] Losartan Neph 751 vs 762 3.4 152/82 4/2 (at 1 year) 0.90 (NA)

P = 0.26 NA ~0.65 (NA) P< 0.001 0.72 (0.58-0.89) P = 0.002 0.84 (0.72-0.98) P = 0.02 Collaborative Study

Group [83] Irbesartan Neph 579 vs 569 2.6 160/87 4/3 0.91 (0.72-1.14)

P = 0.40

0.92 (0.69-1.23)

P = 0.57 0.77 (NA) 0.77 (0.57-1.03) P = 0.07 0.80 (0.66-0.97) P = 0.02

DIABHYCAR [84] Ramipril Alb 2443 vs 2469 4.0 146/82 2.43/1.06

(at 2 years) 1.54/0.30 (final) 0.97 (0.85-1.11) P = 0.66 1.01 (0.90-1.20) P = 0.57 0.86 (0.72-1.04) P = 0.07 (subgroup only) 0.40 (0.13-1.30) P = 0.18 Doubled sCr: 0.81 (0.56-1.12) P = 0.27 TRANSCEND [85] Telmisartan CVD or end-organ damage 2954 vs 2972 4.7 141/82 3-5/1.5-2.5 0.87 (0.76-1.00) P = 0.048 1.02 (0.91-1.22) P = 0.49 0.77 (0.67-0.88) P = 0.001 0.67 (0.19-2.38) P =0.54 1.29 (0.87-1.89) P = 0.20) Plus death: 1.10 (0.95-1.26) P = 0.193)

ROADMAP [86] Olmesartan Normo-alb 2232 vs 2215 3.2 137/81 3.0/1.9 1.00

(0.75-1.33) P = 0.99 1.70 (0.90-3.22) P = 0.10 0.77 (0.63-0.94) P = 0.01 NA Doubled sCr: 1.00 (NA) P = 1.00

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ADVANCE [8,87,88] Perindopril/ indapamide CVD or CVRF 5569 vs 5571 5.3 145/81 5.6/2.2 0.92 (0.81-1.04) P = 0.16 0.86 (0.75-0.98) P = 0.02e → Micro: 0.79 (0.73-0.86) P< 0.0001 → Micro: 0.84 (0.72-0.97) P< 0.019 → Macro: 0.81 (0.63-1.03) P< 0.087 1.01 (0.71-1.43)' P = NS ESRD: 1.61 (0.67-3.89) P = 0.29 0.82 (0.68-1.01) P = 0.055

Results are mean hazard ratios of RAAS inhibitor vs placebo with 95% confidence interval; P values are comparisons of active vs placebo/control groups.

a Data at 9 years: 0.87 (0.60-1.26), P=NS, Micro: NS, Macro: NS. b Dialysis.

c Initiation of renal replacement therapy (RRT).

d New or worsening nephropathy [development of macroalbuminuria, doubling of serum creatinine (sCr) to at least 200 µmol/L, need for RRT or death due to

renal disease).

e Death from renal causes: 1.14 (0.54-2.40), P=0.72.

f Development of renal failure (initiation of dialysis, end-stage renal disease or renal transplantation, or sCr 4292 mmol/L with no acute reversible cause). CVD:

cardiovascular disease; CVRF: cardiovascular risk factor; neph: nephropathy; NA: not available; alb: albuminuria.

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Table 5 : Comparison of renal outcomes in EMPA-REG OUTCOME and other trials of sodium-glucose cotransporter type 2 (SGLT2) inhibitors in patients with type 2 diabetes (T2D) and different stages of chronic kidney disease (CKD).

Type of patients Follow-up

(weeks) Intervention Patients(n) BP (mmHg)Baseline ΔBP (mmHg) Albuminuria (UACR) Progression of albuminuria(% patients) eGFR(mL/min/1.73m

2)

EMPA-REG

OUTCOME [40] CVD 37 Empagliflozin 10-25 mg 4687 135.3/76.6 ~-4/-2 NA No →Micro: 51.5% NS vs placebo → Macro: 11.2% P < 0.001 vs

placebo

-0.19 (annual decrease) P< 0.001 vs placebo

Placebo 2333 135.8/76.8 ~0/-1.5 NA No →Micro: 51.2% → Macro:

16.2% -1.67 (annual decrease)

Yale et al. [98] CKD 26 Canagliflozin 100mg 90 135.9/73.5 -6.1/-2.6 -29.9% Progression to higher category:

5.1% -3.6

Canagliflozin 300 mg 89 136.7/75.7 -6.4/-3.5 -20.9% 8.3% -3.9

Placebo 90 132.1/73.9 -0.3/-1.4 -7.5% 11.8% -1.4

Heerspink et al. [103] T2D on metformin 104 Canagliflozin 100mg 483 130.0/78.8 -2.0 -5.7% vs glimepiride NA -2.7

Canagliflozin 300mg 485 129.9/79.1 -3.1 P = 0.16

-11.2% vs glimepiride

NA -3.9

Glimepiride 482 129.5/78.9 +1.7 P < 0.01 NA NA -5.4

Heerspink et al. [99] ANTIHYP + RAAS 12 Dapagliflozin 10mg 167 151.9/91.3 -3.5 vs

placebo

-33.2% vs placebo NA -2.8 vs placebo

blockers Placebo 189 151.4/91.5 NA NA NA NA

Kohan et al. [100] Stages 1-2 CKD 104 Dapagliflozin 5 mg 767 130.5/79.5 -2.0/-2.0 NA Progression to higher category

(24 weeks): 10.4% +2.52

Dapagliflozin 10mg 859 131.1/79.1 -1.7/-1.6 NA 6.0% +1.38

Placebo 785 130.8/79.6 +0.7/-1.0 NA 6.0% +1.31

Fioretto et al. [101] Stage 3 CKD 104 Dapagliflozin 5 mg 53 135.7/74.3 0.1 -43.8% vs placebo Progression to higher category:

14.7% -1.4

Dapagliflozin 10mg 56 137.3/75.1 -7.6 -57.2% vs placebo 4.3% -4.2

Placebo 57 133.3/74.6 +0.6 NA 27.3% -3.5

Barnett et al. [102] Stage 2 CKD 52 Empagliflozin 10mg 98 137.4/76.5 -2.9/-1.4 -185U vs placebo P

= 0.0831 No → Micro: 10.6% Micro → macro: 11.1% ~-2.5 Empagliflozin 25 mg 97 133.7/76.7 -4.5/-2.2 -236 U vs placebo P = 0.0257 No → Micro: 6.3% Micro →macro: 5.0% ~-3 Placebo 95 134.7/77.5 +0.7/+1.1 NA No → Micro: 14.5% Micro → macro: 5.3% ~-1

Stage 3 CKD Empagliflozin 25 mg 187 137.4/76.5 -3.9/-1.7 -184U P = 0.0031 No → Micro: 12.2%

Micro →macro: 2.0% ~-3

Placebo 187 134.7/77.5 +0.4/+0.2 NA No → Micro: 22.2%

Micro → macro: 11.4% ~-1

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Funding

No sources of funding were used to assist in the preparation of this manuscript.

Disclosure of interest

A.J. Scheen has received lecture/advisor fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk and Sanofi, and has worked as a clinical investigator in the EMPA-REG OUTCOME.

P. Delanaye declares that he has no competing interest.

Appendix A. Supplementary data

Supplementary data (Tables S1 and S2) associated with this article can be found, in the online version, at http://dx.doi.org/10. 1016/j.diabet.2016.12.010.

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Figure

Table 1: Randomized controlled trials of the effects of blood pressure (BP)-lowering (all antihypertensive agents combined) on cardiovascular (CV) outcomes (primary  composite endpoint of major CV adverse events), all-cause mortality and renal outcomes in
Table 3: Cardiovascular (CV) and renal outcomes in clinical trials with different systolic blood pressure (BP) targets in patients with and without type 2 diabetes.
Table 4 : Comparison of cardiovascular (CV) outcomes in EMPA-REG OUTCOME and other major placebo-controlled trials of antihypertensive therapy targeting the  renin-angiotensin-aldosterone system (RAAS) in patients with type 2 diabetes (T2D).
Table 5 :  Comparison of renal outcomes in EMPA-REG OUTCOME and other trials of sodium-glucose cotransporter type 2 (SGLT2) inhibitors in patients with type 2  diabetes (T2D) and different stages of chronic kidney disease (CKD).

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