Giugliano et al. Cardiovasc Diabetol (2021) 20:17 https://doi.org/10.1186/s12933-021-01213-w Cardiovascular Diabetology

REVIEW Open Access Sodium–‑2 inhibitors for prevention and treatment of cardiorenal complications of type 2 Dario Giugliano1* , Miriam Longo1, Lorenzo Scappaticcio1, Paola Caruso2 and Katherine Esposito3

Abstract Hospitalization for major diabetes complications, including myocardial infarction, stroke, lower-extremity amputation, and end-stage kidney disease, is on the rise and represents a great health burden for patients with (T2D), in particular for older people. Newer glucose-lowering have generated some optimism on the possibility to infuence the natural history of cardiorenal complications of T2D. This review summarizes work in the area of sodium–glucose cotransporter 2 inhibitors (SGLT-2i) treatment and prevention of cardiorenal complications in patients with T2D (major adverse cardiovascular events, hospitalization for heart failure, kidney outcomes), with a particular emphasis on the efect of age, the role of primary versus secondary prevention and the possible extension of their cardiorenal benefts to the entire class of SGLT-2i. Keywords: SGLT-2 inhibitors, Type 2 diabetes, MACE, Heart failure, Diabetic kidney disease, Age, Primary and secondary prevention, Class efect

Introduction both Swedish [5] and UK [6] data indicating that patients In the frst half of the past decade, hospitalization for with T2D who obtained the control of fve variables to major diabetes complications, including myocardial optimal values (hemoglobin A1c [A1C], total cholesterol infarction (MI), stroke, lower-extremity amputation, and or LDL-cholesterol, blood pressure, absence of albumi- end-stage kidney disease (ESKD), has increased substan- nuria or triglycerides, and abstinence from smoking) tially, subtracting much of the benefts obtained during were at higher risk (31 to 45% higher risk) of hospitaliza- the years between 1990 and 2010 [1]. Te future of dia- tion for HF. Te natural history of HF in T2D seems to be betes care may be darkened by this apparent resurgence unafected by the optimal control of major metabolic and of vascular complications, as well as by the evidence that cardiovascular (CV) risk factors. heart failure (HF), once a neglected complication, may Life expectancy in the U.S. has declined since 2014 be as common as coronary heart disease in patients with [7], which has been attributed, in part, to increased T2D [2, 3]. Accordingly, there has been a paradoxical prevalence of underlying cardiometabolic risk factors, increase of 11% in the rates of HF in young adults with including obesity and diabetes. Moreover, the estimated diabetes participating in the National Health Interview number of people over 65 years of age with diabetes was Survey 1985–2014 [4]. Tese US data are consistent with 111 million in 2019 and will reach 276 million by 2045 [8]. Older people with T2D are especially vulnerable to cardiovascular disease (CVD) which remains the leading *Correspondence: [email protected] cause of death globally [9]. Consequently, prevention and 1 Division of Endocrinology and Metabolic Diseases, Department of Advanced Medical and Surgical Sciences, University of Campania Luigi optimal treatment of CVD in this population will be a Vanvitelli, Naples, Italy major worldwide health policy challenge during the next Full list of author information is available at the end of the article decades.

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Glycemic control is not enough ertuglifozin are the SGLT-2i that have been investigated Only 9% of the risk of MACE (major adverse cardio- in cardiovascular outcomes trials (CVOTS) and are avail- vascular events) is eliminated after achievement of the able in both US and EU. Other SGLT-2i are ipraglifozin, best possible glycemic control in patients with T2D and luseoglifozin, and tofoglifozin, all launched in Japan, the risk of HF is not infuenced at all [2]. Tis evidence sotaglifozin, approved in UE for certain patients with has generated the concept of residual vascular risk, i.e. type 1 diabetes, and remoglifozin approved in India [19]. the risk of vascular event that persists high to very high SGLT-2i have a unique mechanism of action, as they after intensive glucose control despite the attainment of mediate the reabsorption of about 90% of the fltered near‐to‐normal A1C targets [10, 11]. Moreover, among glucose (approximately 200 g), because the overall pro- adults with T2D and pre-existing CVD, there is no difer- cess has a high capacity [17]. As a consequence, inhibi- ence in the risk of CV events in those allocated to inten- tion of glucose reabsorption at the level of the proximal sive glucose control compared with those in the standard tubule results in enhanced glycosuria, osmotic diuresis care arm (hazard ratio = 0.98, 95% confdence interval, and natriuresis, thereby improving glucose control, with 0.87–1.09) [12]. Paradoxically, tight glycemic control is a limited risk of hypoglycemia. Moreover, SGLT-2i exert inefective on CV risk in those T2D patients who are at additional positive efects on overall CV risk by lower- their maximum risk for future CV events. Finally, tight ing body weight and blood pressure. Tey are oral drugs, glycemic control, especially in older patients with mul- which may also ft with the exhortation by the American tiple medical conditions, is associated with an increased Diabetes Association (ADA) to limit complex therapies, risk of hypoglycemia [13, 14], which may further increase especially for older adults with diabetes [20]. Simplifca- CV risk [15]. tion of therapy at every level could contribute to increase Te evidence so far accumulated seems in con- the adherence to antidiabetic therapy, which may range trast with the old paradigm that therapeutic eforts for from 38.5 to 93.1% [21]. For instance, Gordon et al. [22] patients with T2D should be devoted to the control of used the real-world data from 33,849 patients with T2D hyperglycemia for preventing the development of micro- in UK and found that antihyperglycemic drugs associated and macrovascular complications. However, the contrast with weight loss and lower incidence of hypoglycemia can only be apparent, as the CV risk in T2D can only be were generally associated with better adher- cleared of by the simultaneous control of the multiple ence, which in turn was related to improved glycemic factors at play, including glucose, lipids, blood pressure, control. Medication non-adherence may also contribute albuminuria, and smoking. As detailed before, HF is a for up to 75% to the gap between clinical efcacy from pathological condition that is not afected by the control randomized controlled trials and real world results in of major CV risk factors. Furthermore, chronic kidney lowering A1C levels [23, 24]. disease (CKD) has an independent role in dictating the CV prognosis of patients with T2D [16]. Te cornerstone Cardiorenal efects of therapy to prevent diabetic kidney disease (DKD) is Cardiovascular events the strict control of blood pressure with the renin–angio- Overall, CVD afects approximately about 32% of all per- tensin–aldosterone system blockade and blood glucose sons with T2D [25] in whom CV risk is mitigated primar- levels [17]. However, many patients with T2D progress ily with statins and aspirin [26]. Recent meta-analyses of to DKD despite standard treatment. Tere is an unmet CVOTs with empaglifozin, canaglifozin or dapaglifozin clinical need to prevent or delay DKD progression; as a reported a statistically signifcant 11–12% reduction in logical consequence, the optimal anti-hyperglycemic MACE [27, 28], with beneft only seen in patients with drug should be the one that also improves the cardiorenal atherosclerotic cardiovascular disease (14% reduction) outlook of patients with T2D. and not in those without (0% reduction, P for interac- tion = 0.0501) [27]. Most patients assessed in the trials (EMPA-REG [29], CANVAS [30], DECLARE [31], CRE- SGLT‑2 inhibitors DENCE [32]) had preserved kidney function (estimated Sodium-glucose cotransporter 2 inhibitors (SGLT-2i) 2 glomerular fltration rate [eGFR] ≥ 60 ml/min/1.73 m ), are a new class of orally active drugs approved for the with 7754 participants (20%) presenting a baseline management of T2D [18]. Tey are also known as gli- eGFR < 60 ml/min/1.73 m2. Patients with reduced kidney fozins, by the founder which was shown to function achieved greater proportional risk reductions cause glycosuria in 1886. However, inadequate pharma- for MACE (23% reduction) than patients with preserved cokinetic characteristics, such as low oral availability and kidney function (9% reduction), although the difer- short half-life, hampered phlorizin use as a therapeutic ence was of borderline signifcance (P for heterogeneity agent. Dapaglifozin, canaglifozin, empaglifozin and between subgroups = 0.053) (Fig. 1) [33]. Giugliano et al. Cardiovasc Diabetol (2021) 20:17 Page 3 of 10

Fig. 1 Meta-analysis evaluating the efcacy of SGLT-2i (empaglifozin, canaglifozin and dapaglifozin) on MACE according to basal eGFR values in four trials (EMPA-REG, CANVAS, DECLARE and CREDENCE)

Te data suggest that the CV benefts of SGLT-2i may Fig. 2 Random efect meta-analysis of nine trials with fve SGLT-21 (empaglifozin, canaglifozin, dapaglifozin, eurtuglifozin, sotaglifozin) even be greater in patients with T2D and DKD. Tis on hospitalization for heart failure (HF) in patients with or without interpretation has recently found a support from the T2D, and with or without HF at baseline. Overall hazard ratio (HF) is results of the SCORED trial [34] which randomized 0.67 (95% Confdence Intervals 0.60–0.74) 10,584 patients with T2D and DKD (eGFR values between 25 and 60 ml/min/1.73 m­ 2), with or without albuminuria, to sotaglifozin or placebo: compared to worsening HF randomized to sotaglifozin or placebo placebo, sotaglifozin resulted in a lower risk of MACE and followed for 9 months). Te primary outcome (16%, P = 0.035), associated with a robust and signifcant varied across trials: MACE (EMPA-REG, CANVAS, reduction of 32% total MI and 34% total stroke. Sotagli- DECLARE, VERTIS-CV), composite of end-stage kid- fozin not only inhibits SGLT-2 but also SGTL-1, which ney disease, doubling of the serum creatinine level, primarily resides in the gastrointestinal tract and is the or death from renal or cardiovascular causes (CRE- main route for gut absorption of glucose. Te activity of DENCE), composite of worsening heart failure or car- sotaglifozin against the SGLT-1 protein likely explains diovascular death (DAPA-HF, EMPEROR-Reduced), its ability to cut A1C levels in patients with severe renal deaths from cardiovascular causes, hospitalizations dysfunction, a condition that opposes glucose lowering for heart failure, and urgent visits for heart failure by SGLT-2i. (SCORED, SOLOIST-WHF). We did a random efect meta-analysis including Heart failure all the nine trials that evaluated the efect of the fve SGLT-2i (empaglifozin, canaglifozin, dapaglifozin, Hospitalization for HF was signifcantly reduced by ertuglifozin, sotaglifozin) in 67,190 patients with or 31–32% with SGLT-2i [27, 28], whether the meta-analy- without T2D, and with or without HF at baseline, on ses included three (EMPA-REG, CANVAS, DECLARE) hospitalization for HF. Pooled summary estimates were or four ( CREDENCE) trials. Since then, other out- + calculated according to the random efects model, using come trials have been published: specifcally, the VER- the empirical Bayes method [40]. Te overall efect TIS-CV trial [35] with ertuglifozin (8246 patients with showed a 32% reduction of the risk of hospitalization T2D randomized to ertuglifozin or placebo and fol- for HF in those taking the SGLT-2i than those taking lowed for a mean of 3.5 years), the DAPA-HF trial [36, placebo (Fig. 2). Te absence of heterogeneity and the 37] with dapaglifozin (4744 patients with or without strict range of 95% confdence intervals allow to predict T2D and with HF randomized to dapaglifozin or pla- an estimate of the true mean of HR likely to be within cebo and followed for a median of 18.2 months), the 0.60 and 0.74, indicating a reduction of the risk ranging EMPEROR-Reduced trial [38] with empaglifozin (3730 from 40 to 26%. patients with or without T2D and with HF randomized An indirect support for this estimate comes from the to empaglifozin or placebo and followed for a median results of the DAPA-CKD trial [41] evaluating 4304 of 16 months), the SCORED trial [34] with sotaglifo- patients with or without T2D, and with CKD rand- zin (10 584 patients with T2D and DKD randomized omized to dapaglifozin or placebo and followed for to sotaglifozin or placebo and followed for 16 months) a median period of 2.4 years: the hazard ratio for the and the SOLOIST-WHF trials [39] with sotaglifo- composite endpoint of CV death and hospitalization zin (1222 patients with T2D recently hospitalized for Giugliano et al. Cardiovasc Diabetol (2021) 20:17 Page 4 of 10

for HF was 0.71 (95% CI 0.55–0.92), but that for HF At the present, SGLT2-i, at least empaglifozin, canagli- alone, although not presented in the results, should fozin and dapaglifozin, are the glucose-lowering agents even be lower, as the HR for CV death alone was 0.81 that are associated with the most impressive overall renal (0.58–1.12). protection, with a positive combined efect on albumi- Te results of the present meta-analysis gives further nuria, eGFR decline and progression to ESKD within support for the use of SGLT-2i to provide symptomatic the context of renin–angiotensin–aldosterone system improvement in HF symptoms and hospital presenta- (RAAS) blockade therapy. Treatment with these SGLT- tions, as well as deaths, in subjects both with and without 2i could be useful for early [47] as well as late [48] pre- T2D [42]. Te benefts of SGLT-2i on HF occur early after vention of DKD. On the other hand, both VERTIS-CV randomization, are independent of the glycemic status trial [35] with ertuglifozin and SCORED trial [34] with of patients and unrelated to glycemic control in patients sotaglifozin failed to show any signifcant efect on kid- with T2D [43]. Moreover, both SCORED [34] and SOLO- ney endpoints, casting some doubt about a class efect of IST-WHF [39] trials included a percentage of diabetic SGLT-2i for renal protection. patients with HF and preserved ejection fraction (left ventricular ejection fraction of at least 50%); both trials Proposed mechanisms found that sotaglifozin was efective in reducing hospi- Several hypotheses have been postulated to explain the talization for HF, which may remove some hesitation to beneft on cardiorenal outcomes observed with SLGT- use SGLT-2i in T2D patients with HF and preserved ejec- 2i. Te fuel hypothesis [49] postulates that SGLT-2i tion fraction. Moreover, SOLOIST-WHF was the frst cause a mild but persistent increase in the production of trial that evaluated patients with T2D recently hospital- ketone bodies, in particular beta-hydroxybutyrate, which ized for worsening HF, although in stable conditions. becomes, along with free fatty acids, the main substrates Te combination of β-blockers, renin angiotensin sys- for ATP production in the myocardium, in detriment of tem blockers with neprilysin inhibitors, and mineralo- glucose. Te sodium-hydrogen exchanger hypothesis [50] corticoid receptor antagonists reduces mortality among claims that SLGT-2i may directly bind to and inhibit the patients with HF and reduced ejection fraction by an sodium-hydrogen exchangers in the heart and kidney. estimated 63% vs placebo, to which it can be added a fur- Te smart diuretic hypothesis [51] suggests that the car- ther 2.3% absolute risk reduction in all-cause mortality diorenal benefts observed with SGLT-2i are in part due at 18 months from SGLT-2i. A combination of these four to their more selective diuretic efects, leading to osmotic medicines represents one of the most cost-efective inter- diuresis. Te tubule-centered hypothesis [52] asserts that vention in reducing the risk of death in patients with HF tubular growth is associated with the development of a [44]. For instance, it has been calculated that about 80% senescence-like molecular signature that sets the stage of patients with HF and reduced ejection fraction would for infammation and fbrosis; by attenuating the proxi- be potentially eligible for initiation of dapaglifozin based mal reabsorption of sodium and glucose, SGLT-2i miti- on the US Food and Drug Administration label, and inde- gate hyperfltration and normalize tubule-glomerular pendent of the presence of T2D [45]. feedback signals. Moreover, the list of their cardiorenal protective efects is expanding and includes, among oth- Kidney disease ers, preventing adverse cardiac remodeling and ischemia/ Up to 40% of individuals of the US adult diabetic popula- reperfusion injury, increasing circulating hematopoietic tion have some form of kidney disease [32]. In 4 outcome progenitor cells, decreasing epicardial fat mass, decreas- trials (EMPA-REG, CANVAS, DECLARE and CRE- ing oxidative stress and infammation, increasing eryth- DENCE), SGLT-2i reduced by 33% the risk of dialysis, ropoietin levels and inhibiting the sympathetic nervous transplantation or death due to kidney disease, reduced system [53, 54]. by 35% ESKD and by 25% acute kidney injury. Te ben- Attractive these hypotheses may be, they must com- efts were consistent across studies and for all eGFR pare with the results of mechanistic studies. For exam- subgroups, including participants with a baseline eGFR ple, dapaglifozin did not produce a meaningful decline 30–45 ml/min/1.73 m2 [46]. Moreover, in the DAPA- in natriuretic peptides in a smaller mechanistic study in CKD trial [41], which assessed the efect of dapaglifozin patients with HF with reduced ejection fraction [55], sug- in patients with CKD, with or without T2D, the primary gesting that enhanced diuresis and decongestion may not outcome (a composite of a sustained decline in the eGFR be a primary driver of the reduced risk of outcomes seen of at least 50%, ESKD, or death from renal or CV causes) in DAPA-HF trial [36]. Further research will be needed was reduced by 39% (HR = 0.61; 95% CI 0.51 to 0.72, to identify the mechanisms of action of dapaglifozin and P < 0.001). other SGLT-2i in patients with HF. Giugliano et al. Cardiovasc Diabetol (2021) 20:17 Page 5 of 10

The efect of age a broad spectrum of age (< 55 to ≥ 75 years), without Nearly 50% of patients with T2D are 65 years old or older safety concerns even in older individuals. Similarly, in [8]. In older patients, treatment with SGLT-2i is efec- the DAPA-CKD trial [41], the reduction of the primary tive at lowering glucose, body weight and systolic blood endpoint (a composite of a sustained decline in the eGFR pressure, as shown in a meta-analysis of post-hoc studies of ≥ 50%, ESKD, or death from renal or cardiovascular in which the median age of patients was > 60 years [56]. causes) with dapaglifozin was of the same magnitude On the other hand, specifc trials that evaluated both the in both patients aged < 65 and ≥ 65 years. Overall, the efcacy and safety of SGLT-2i in older patients with T2D, results are reassuring, as they confrm that the efcacy especially in those > 75 years, are still lacking and only profle of SGLT-2i is unchanged by age. very limited data are available from observational studies [57]. Te post-hoc analysis of both EMPA-REG [58] and Class efect of SGLT‑2i DECLARE [59] trials confrms that the efcacy/safety Te defnition of class efect for a drug may be based profle of these two SGLT-2i is unchanged by age, even on three concepts: a similar chemical structure, a simi- with some signal of greater efcacy in patients older than lar mechanism of action and similar pharmacological 65 years of age. In particular, a signifcant interaction efects [62]. SGLT-2i are considered a class as they share (P = 0.01) was reported in EMPA-REG trial [58] regard- a similar chemical structure derived from the ancestor ing the primary cardiovascular composite end point phlorizin, a similar mechanism of action related to the with better results in patients with T2D aged ≥ 65 years inhibition of SGLT-2 located on the luminal membrane versus < 65 years. of proximal tubular cells (brush border), and similar Figure 3 shows the results of a meta-analysis [60] on pharmacological efects at the level of kidney, resulting the efects of three SGLT-2i of the risk of MACE strati- in glycosuria and osmotic diuresis. In order to make the fed by age (< 65 years vs ≥ 65 years). Te percentage of concept of a class more stringent, we have assumed that diabetic patients ≥ 65 years ranged from 44.5% (EMPA- a class efect is paramount when an efect on a particular REG), to 46% (DECLARE), to 60% (CANVAS). Te haz- outcome is present and is signifcant for each drug within ard ratio for MACE was 0.95 in people < 65 years and 0.83 the class of SGLT-2i [19]. for people ≥ 65 years, and the efect on MACE was only Figure 4 shows the efects of the fve SGLT-2i (empa- signifcant in people of 65 years of age or older. However, glifozin, canaglifozin, dapaglifozin, ertuglifozin and the absence of interaction between subgroups (P = 0.15) sotaglifozin) tested in outcome trials according to the suggests that the efect of intervention on MACE was more stringent defnition of class efect, as detailed above. similar in participants of both age groups. Te outcomes considered include MACE (with its three In the SCORED trial [34] with sotaglifozin, the primary components of nonfatal MI, CV mortality and nonfatal efcacy endpoint of total occurrences of cardiovascular stroke), which was the primary outcome in EMPA-REG deaths, HF hospitalizations, and urgent visits for HF was [29], CANVAS [30], DECLARE [31], VERTIS-CV [35] not signifcantly diferent in the 3224 (30.5%) patients and SCORED [34], hospitalization for HF and progres- aged < 65 years (HR = 0.60, 95% CI 0.43–0.83) vs the 7360 sion of DKD, which were secondary outcomes. Because (69.5%) patients aged ≥ 65 years (HR = 0.79, 0.66–0.95). of the early closing of the SCORED trial and the fewer Furthermore, according to a post- hoc analysis of the than planned number of events, the primary end point data of DAPA-HF [61], dapaglifozin reduced the risk of was changed during the trial to the composite of the total death and worsening HF and improved symptoms across number of deaths from CV causes, hospitalizations and urgent visits for HF. For MACE, there seems to be no class efect, as both DECLARE and VERTIS-CV failed to reduce it signif- cantly: on the other hand, a class efect is evident for hos- pitalization for HF, which at present remains the more striking therapeutic efect of SGLT-2i. Unfortunately, both VERTIS-CV and SCORED trials were unable to show any signifcant efect on DKD progression, a renal composite outcome of death from renal causes, kidney replacement therapy, or doubling of the serum creatinine level. Although comparison between trials should always Fig. 3 Meta-analysis evaluating the efcacy of SGLT-2i on MACE be done with caution, the fve trials are generally consist- according to the age at entry in three trials (EMPA-REG, CANVAS and DECLARE) ent with each other, showing reliable cardiorenal ben- efts (with the exception of VERTIS-CV and SCORED Giugliano et al. Cardiovasc Diabetol (2021) 20:17 Page 6 of 10

Fig. 4 Scenario of cardiorenal efects SGLT-2i in patients with T2D participating in CVOTs. MACE, major adverse cardiovascular events; DKD, diabetic kidney disease. : modest beneft (the hazard ratio -HR- for a given endpoint during treatment with a glifozin is > 0.85 and < 1.0, as compared with placebo). : moderate beneft (HR 0.85 and > 0.75). : large beneft (HR 0.75) ≤ ≤

for DKD progression) and comparable expected adverse Data from 57 articles including a population of efects. 4,549,481 persons with T2D suggest a prevalence of CVD of 32.2%, i.e. about one third of T2D population may have Primary vs secondary prevention established CV disease [24]; however, this epidemiologi- cal fgure is overturned in CVOTs, in which the percent- Te defnition of secondary prevention usually refers to age of participating with established CVD at baseline was patients who sufered a previous acute ischemic event, 65% (Table 1). In order to ensure a sufcient number of whereas all other patients are categorized as requiring events in the shortest possible time, drug companies and primary prevention. Te distinction between primary investigators included most patients with experience of a and secondary prevention risk categories in diabetes is previous CV event and/or with established CVD. no longer reported in European Society of Cardiology Table 2 shows the cardiorenal efects of SGLT-2i in pri- guidelines on diabetes, pre-diabetes, and CVD devel- mary and secondary prevention. Both EMPA-REG and oped in collaboration with the European Association VERTIS-CV trials included patients in secondary pre- for the Study of Diabetes [63]. Accordingly, the CV risk vention only, and therefore an estimate of their efect in in patients with T2D may range from the highest risk primary prevention of T2D is at present not possible. All in patients who experienced a previous CV event, to a mild risk in patients with the main risk factors within target ranges, a very small category of about 5%-6% of patients [5, 6, 63, 64]. Te CVOTs used to distinguish Table 1 Separation of T2D patients participating in CVOTs T2D patients with established CVD (secondary preven- according to the presence (secondary prevention) tion), that is, those having experienced a previous event or absence (primary prevention) of established CVD or with evidence of more than 50% stenosis in an epi- Trial Drug Primary prevention Secondary cardial coronary artery, and patients without established prevention CVD (primary prevention), i.e. those with many risk fac- EMPA-REG Empaglifozin 56 (0.8%) 6964 (99.2%) tors for CVD. However, defnitions of established CVD CANVAS Canaglifozin 2819 (27.8%) 7323 (72.2%) varied across trials; although most patients had experi- DECLARE Dapaglifozin 10 193 (59.4%) 6967 (40.6%) enced a previous event at the level of coronary, cerebral VERTIS-CV Ertuglifozin 82 (1%) 8155 (99%) or peripheral arteries, patients without events, but with SCORED Sotaglifozin 5440 (51.4%) 5144 (48.6%) clinical or instrumental evidence of the presence of CVD, Total 18 590 (35.0%) 34 553 (65.0%) were also included. Giugliano et al. Cardiovasc Diabetol (2021) 20:17 Page 7 of 10

Table 2 Cardiorenal efects of SGLT-2i in primary and secondary prevention in T2D SGLT-2 inhibitors EMPA-REGa CANVAS DECLARE VERTIS-CVa SCORED

MACE Primary – Neutral Neutral – Reduced Secondary Reduced Reduced Neutral Neutral Reduced Heart failure Primary – Reduced Reduced – Reduced Secondary Reduced Reduced Reduced Reduced Reduced DKD Primary – Reduced Reduced – Neutral Secondary Reduced Reduced Reduced Neutral Neutral a Included T2D patients in secondary prevention only fve trials are consistent with a similar efect of the fve Te results of post-hoc analyses [58, 59] or real-world SGLT-2i on HF, both in primary and secondary preven- databases [71] are reassuring about both the efcacy and tion, pointing to an important therapeutic role in this safety of SGLT-2i in older patients with T2D, for whom condition, whatever its genesis. the choice of the optimal drug is often limited by subjec- tive (health state of patient) and objective (side efects of What’s the road ahead? the antihyperglycemic drug) considerations. SGLT-2is Despite treatment for T2D changed markedly in the last can be used as an add-on therapy in selected and healthy two decades, including the use of new medications and older patients with T2D, especially those who are over- combined therapies, overall glycemic control has not weight and have uncontrolled hypertension. For instance, improved as much as expected [65]. Among the SGLT-2i in a multinational observational study [72] including approved in the US and in Europe, dapaglifozin has been 1,006,577 new users of SGLT-2i or dipeptidyl pepti- approved for the treatment of HF, canaglifozin to reduce dase-4 inhibitors (DPP-4i), the use of SGLT-2i was asso- the risk of ESKD and worsening kidney function in adults ciated with a lower risk of HF and CKD versus DPP-4i in with DKD. It is anticipated that novel indications may patients with T2D otherwise free from both cardiovascu- be issued in the near future as the results of ongoing tri- lar and renal disease. als become available. Te accumulated evidence sug- More research is needed to better delineate the main gests that SGLT-2i should be considered for control of mechanisms involved in the cardiorenal protection of hyperglycemia in patients with T2D, particularly in those SGLT-2i (for example focusing more on the cell types tar- with established CVD, given that they reduce the risk of get of SGLT-2 inhibition), in order to explain some dif- MACE, hospitalization for HF and progression of DKD, ferences observed in CVOTs. Hopefully, this may lead to regardless of whether patients are receiving or not met- new treatment targets in patients with CV risk factors. formin [66]. Te remarkable reduction in risk of HF seen across Balancing benefts and harms CVOTs, as well as other intervention trials (Fig. 2) and Te demonstration of cardiorenal benefts in patients observational data [67] is one major benefts of therapy with T2D has been the main breakthrough emerged with SGLT-2i in patients with T2D. Accordingly, the last from SGLT-2i trials and observational studies worldwide updated clinical recommendations by ADA exhort cli- in the last fve years. However, SGLT-2i have also been nicians to consider the use of SGLT-2i in patients with associated with a variety of adverse efects [73], induc- T2D and established HF with reduced ejection fraction ing both the FDA and EMA to publish specifc warnings to reduce the risk of worsening HF and CV death [68]. regarding an increased risk of lower-limb amputation, SGLT-2i have already been included in the frst-level pre- diabetic ketoacidosis, bone fracture, acute renal injury vention guidelines of the 2019 American College Cardi- and Fournier gangrene. In the SCORED trial [33], diar- ology/American Heart Association for cardiovascular rhea, genital mycotic infections, volume depletion, and disease [69]. Moreover, evidence from completed trials diabetic ketoacidosis occurred more with sotaglifozin also indicates that patients with T2D and with lower lev- than placebo. Terefore, these medications should be els of eGFR and higher levels of albuminuria are among considered with particular attention, and probably bet- those who stand to gain the greatest absolute benefts ter avoided in frail diabetic patients, especially if treated [70]. with loop diuretics (due to increased risk of dehydration Giugliano et al. Cardiovasc Diabetol (2021) 20:17 Page 8 of 10

and orthostatic hypotension) [74], or those with previous in patients with diabetes and recent worsening heart failure; DAPA-CKD: Dapaglifozin in patients with chronic kidney disease; DPP-4i: Dipeptidyl limb ulcers or history of amputation. However, a recent peptidase-4 inhibitors. meta-analysis [75] of six trials (EMPA-REG, CANVAS, CREDENCE, DECLARE, DAPA-HF, VERTIS-CV) show Acknowledgements Not applicable. that SGLT-2i were not signifcantly associated with an increased risk of amputation, including subgroups with Authors’ contributions or without established peripheral artery disease. Moreo- DG wrote the manuscript. DG, ML and KE did the meta-analysis. ML, LS, PC and KE critically reviewed the manuscript. All authors read and approved the fnal ver, the results of a large population-based cohort study manuscript. [76] indicate that use of SGLT-2i is not associated with an overall increased risk of breast cancer compared with Funding This study was funded in part by the “Associazione Salute con Stile”, Naples, DPP-4 inhibitors, at least in the short term (median fol- Italy. low-up 2.6 years). Availability of data and materials All data generated or analyzed during this study are included in this published Conclusions article. Te cardiorenal benefts demonstrated by SGLT-2i Ethics approval and consent to participate are not only limited to patients with T2D, as a mount- Not applicable. ing evidence indicates that they can also be extended to Consent for publication patients without T2D who have CVD, HF, or CKD [36– Not applicable. 38, 48]. Intuitively, the use of these agents will presum- Competing interests ably be extended to other medical fgures that cooperate DG received honoraria for speaking at meetings from Novartis, Sanof, Lilly, in the management of T2D, including cardiologists and Astrazeneca, and NovoNordisk. K.E. received honoraria for speaking at meet- nephrologists, within the frame of a multidisciplinary ings from Novartis, Sanof-Aventis, Lilly, AstraZeneca, Boehringer Ingelheim, and NovoNordisk. No other potential confict of interest relevant to this article approach, with the paramount aim to improve glyce- was reported. mic control and reduce the risk of cardiorenal events. It seems important that cardiologists and nephrologists Author details 1 Division of Endocrinology and Metabolic Diseases, Department of Advanced become more knowledgeable about T2D and its man- Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, agement, while diabetologists do the same with cardiac Italy. 2 Ph.D. of Translational Medicine, Chair of Endocrinology and Metabolic and kidney disease, especially those that are prevalent in Diseases, Department of Advanced Medical and Surgical Sciences, Univer- sity of Campania Luigi Vanvitelli, Naples, Italy. 3 Diabetes Unit, Department T2D. At present, only the robust reduction in the risk of of Advanced Medical and Surgical Sciences, University of Campania Luigi hospitalization for HF should be considered a class efect, Vanvitelli, Naples, Italy. i.e. embracing the fve components of SGLT-2i (empa- Received: 5 December 2020 Accepted: 5 January 2021 glifozin, canaglifozin, dapaglifozin, ertuglifozin and sotaglifozin), as emerged by outcome trials. It is sad to acknowledge that, despite the continuing accumulation of data regarding the benefts of SGLT- References 2i which are incorporated in newly updated guidelines, 1. Gregg EW, Hora I, Benoit SR. Resurgence in diabetes-related complica- many eligible patients with T2D are still not receiving tions. JAMA. 2019;321:1867–8. 2. Giugliano D, Meier JJ, Esposito K. Heart failure and type 2 diabetes: these agents, depriving them of protection against the from cardiovascular outcome trials, with hope. 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