Elsevier

Diabetes & Metabolism

Volume 42, Issue 4, September 2016, Pages 224-233
Diabetes & Metabolism

Review
Reappraisal of the diuretic effect of empagliflozin in the EMPA-REG OUTCOME trial: Comparison with classic diuretics

https://doi.org/10.1016/j.diabet.2016.05.006Get rights and content

Abstract

Aims

Empagliflozin, a sodium–glucose cotransporter type 2 (SGLT2) inhibitor, has been associated with a remarkable reduction in cardiovascular and all-cause mortality in patients with type 2 diabetes and antecedents of cardiovascular disease. This effect was attributed to a diuretic (haemodynamic) rather than metabolic (antiatherogenic) effect. The aim of this review is to offer arguments that either support or challenge this ‘diuretic hypothesis’.

Methods

The literature was scrutinized to: (1) examine the diuretic effects of SGLT2 inhibitors vs. hydrochlorothiazide as the reference diuretic; (2) analyze the effects of classic diuretics on cardiovascular outcomes and mortality in diabetic patients; and (3) reconsider some of the specific analyses of the EMPA-REG OUTCOME trial possibly related to a diuretic effect.

Results

The diuretic effect of empagliflozin has so far been poorly investigated, although SGLT2 inhibitors have actions distinct from those of classic diuretics. The effects of thiazide-like diuretics on cardiovascular and overall mortality have been limited in diabetic patients with hypertension, whereas the effects of mineralocorticoid receptor antagonists in subgroups of diabetic patients with heart failure were more impressive, but still largely inferior to those reported in EMPA-REG, where relative reductions in mortality with empagliflozin were observed in diabetic patients with or without heart failure, arterial hypertension, renal impairment or diuretic background therapy.

Conclusion

Although the diuretic hypothesis was put forward to explain the remarkable reduction in mortality with empagliflozin in EMPA-REG, the available results do not support a major contribution of this mechanism, unless the specific diuretic effect of SGLT2 inhibitors turns out to be markedly different from those of classic diuretics.

Introduction

Sodium–glucose cotransporter type 2 (SGLT2) inhibitors are novel glucose-lowering agents indicated for the treatment of patients with type 2 diabetes (T2D) [1]. These compounds have a distinctive mechanism of action in the renal proximal tubule by blocking the reabsorption of glucose. Because of this insulin-independent effect, they may be combined with any other antidiabetic agents, including insulin, and are increasingly being used in the management of T2D [2]. Besides promoting glucosuria, they exert pleiotropic effects, which could reduce several cardiovascular (CV) risk factors and potential CV complications [3], [4]. In the placebo-controlled EMPA-REG OUTCOME trial in patients with T2D and CV antecedents, the addition of empagliflozin, a selective SGLT2 inhibitor, to the usual antidiabetic agents and a panel of cardioprotective drugs was associated with a significant reduction (–14%, P = 0.04) in the primary endpoint, a composite of CV mortality, non-fatal myocardial infarction and non-fatal stroke, the so-called ‘triple MACE’ (major adverse cardiovascular events) [5]. Surprisingly, the reductions in CV mortality (–38%, P < 0.001) and all-cause mortality (–32%, P < 0.001) were highly significant, whereas no significant effects were reported for either myocardial infarction or stroke [5].

These impressive results strongly contrast with several disappointing results previously reported with other glucose-lowering agents in T2D [6], and are also more favourable than those reported with metformin in high-risk populations [7]. A recent systematic review and meta-analysis suggested that results for other SGLT2 inhibitors (specifically, canagliflozin and dapagliflozin) may not be clearly different, although results from ongoing studies will be crucial for substantiating these findings across the drug class [8]. Because the reduction in mortality had already occurred within the first few months, a haemodynamic rather than metabolic (antiatherogenic) effect has been put forward [9], [10]. This may be attributed to the diuretic (natriuretic/osmotic) activity of SGLT2 inhibitors that accompanies the glucuretic effect [11], [12]. One major argument in favour of such a ‘diuretic hypothesis’ is the important and significant reduction in hospitalizations for congestive heart failure (CHF; –35%, P = 0.002) [13], as recently pointed out [14], [15]. However, this explanation is probably too simple and open to challenge [16].

Surprisingly, the diuretic activity of SGLT2 inhibitors in general, and of empagliflozin in particular, has not been extensively investigated so far; only a few studies have compared the diuretic effects of SGLT2 inhibitors with those of hydrochlorothiazide (HCTZ), used as reference. Diuretics belong to a heterogeneous family, which means that several classes need to be distinguished: thiazide or thiazide-like agents [17]; loop diuretics; and mineralocorticoid receptor antagonists (MRAs) [18]. These various compounds exert diverse effects on electrolytes and metabolic parameters that could have different effects on CV outcomes (Fig. 1). Yet, no study has specifically investigated the effects of classic diuretics on CV complications and mortality in patients with T2D. Nevertheless, some interesting, albeit limited, data may be derived from post-hoc analyses of subgroups of T2D patients who participated in large CV outcome studies enrolling patients with either arterial hypertension or CHF. Furthermore, the available post-hoc analyses of subgroups of patients who participated in the EMPA-REG trial may provide additional information regarding the potential contribution of the diuretic effect of empagliflozin to reducing CV and all-cause mortality.

The main aims of the present review are to:

  • analyze the available data examining the diuretic effects of SGLT2 inhibitors, especially in comparison to a reference compound such as HCTZ;

  • briefly discuss the limited available results reported with classic diuretics (thiazides and MRAs) regarding CV outcomes in patients with T2D and compare them with those reported in EMPA-REG;

  • reconsider some of the specific analyses of EMPA-REG that focused on changes related to a diuretic effect (haematocrit, electrolytes and uric acid) and changes observed in subgroups of patients of special interest when considering a possible diuretic effect (those with elevated blood pressure, heart failure or impaired renal function, or using diuretic therapy at baseline).

Section snippets

Diuretic effects of SGLT2 inhibitors

Treatment with SGLT2 inhibitors is consistently associated with a lowering of systolic blood pressure (SBP) [19], [20]. This effect is also observed in patients already treated with a combination antihypertensive therapy [21]. The reduction in SBP is commonly attributed to a diuretic/natriuretic effect, although other mechanisms may be considered, such as a reduction in arterial stiffness and vascular resistance [22]. Because of the osmotic effect of SGLT2 inhibitors, a contribution of diuretic

Thiazide-like diuretics in T2D patients with hypertension

New evidence suggests that central SBP is a better predictor of adverse CV outcomes than peripheral SBP [36]. It has also been shown that thiazide diuretics reduce central SBP and peripheral SBP in a similar manner [36], and with results comparable to what is observed with other antihypertensive agents [37].

A meta-analysis of four placebo-controlled randomized controlled trials (RCTs)—the Hypertension Detection and Follow-up Program (HDFP), European Working Party on High Blood Pressure in the

Increased haematocrit

In the EMPA-REG trial, empagliflozin therapy was associated with a sustained increase in haematocrit compared with placebo (maximum adjusted mean difference = 2.9 percentage points), suggesting the persistence of volume depletion in the absence of a direct effect of the SGLT2 inhibitor on bone marrow [5]. In contrast, 4-week therapy with HCTZ failed to significantly modify haematocrit levels in patients with hypertension [52]. These data confirm previous results showing a significant increase in

Conclusion

The early and remarkable reduction of CV and all-cause mortality observed with empagliflozin in the EMPA-REG OUTCOME trial of patients with T2D and antecedents of CV disease has mostly been attributed to a diuretic (haemodynamic) rather than metabolic (antiatherogenic) effect. However, the diuretic effects of SGLT2 inhibitors (especially empagliflozin) have been poorly investigated and appear to be clearly different from those of classic diuretics, although more comparative studies are needed.

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, Sanofi-Aventis and Takeda.

A.J. Scheen served as a clinical investigator in the EMPA-REG OUTCOME trial.

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