The role of SGLT2 inhibitors beyond glucose-lowering to cardio-renal protection

People with type 2 diabetes mellitus (T2DM) are at high risk of developing cardiovascular disease (CVD) and kidney disease. This enhanced cardio-renal risk persists despite improvements in care and treatments over the last 20 years. Intensive glucose control alone does not substantially reduce the risk of CVD and end stage kidney disease (ESKD). However, in 2015 the landmark EMPA-REG trial demonstrated for the first time the benefits of Empagliflozin a sodium-glucose co-transporter 2 (SGLT2) inhibitor on CVD events and mortality in people with T2DM. Since this trial several other SGLT2 Inhibitors including Dapagliflozin and Canagliflozin have demonstrated CVD benefits. SGLT2 inhibitors have also demonstrated significant reductions in the risk of hospitalization for heart failure (HHF) and ESKD. As a consequence of this growing evidence, there has been a shift in the focus of care in T2DM from glucose management to preservation of organ function. SGLT2 inhibitors have emerged as key treatment to reduce CVD, HHF and prevent progression of kidney disease. The benefits for reducing HHF and preventing ESKD have been observed in people with and without T2DM in large randomised controlled clinical trials. In T2DM the positive effects of SGLT2 inhibitors occur early and are independent of their glucose lowering effects. It is vital that all clinicians recognise the remarkable benefits of SGLT2 inhibitors and use this important class of drugs promptly and early to prevent CVD, HHF and ESKD. Relationships and Activities: In addition, there was a 38% reduction in risk of CV death, a 35% reduction in risk of hospitalization for HF (HHF) and a 32% reduction in the risk of death from any cause [10]. These findings were supported subsequently by data from CVOTs assessing the other licenced SGLT2is, canagliflozin, dapagliflozin and ertugliflozin (Canagliflozin Cardiovascular Assessment Study (CANVAS) Program, Dapagliflozin Effect on Cardiovascular Events — Thrombolysis in Myocardial Infarction (DECLARE-TIMI 58) respectively) [11-13]. the recent with glucose lowering agents on CVD outcomes including HHF.

osmotic diuresis and mild natriuresis and a corresponding reduction in extracellular fluid and plasma volume [4,5]. Of importance these blood pressure lowering effects are also observed in people without T2DM [4].

Effects of SGLT2 inhibitors on the cardiovascular (CV) system
T2DM is a major CV risk factor, and is associated with a nearly three-fold excess risk of coronary artery disease including angina, myocardial infarction, stroke and heart failure (HF), in patients with and without established CV disease (CVD) [6,7].
The close inter-relationship between T2DM and CVD has been recognized for many decades. However for many years the focus was largely on glucose control on the assumption that hyperglycaemia promotes CVD and thus it was assumed that intensive glucose control would slow the progression of CVD. The United Kingdom Prospective Diabetes Study (UKPDS) demonstrated the benefits of intensive glucose-lowering therapy in newly diagnosed T2DM on microvascular complications but failed to demonstrate a significantly reduced the risk on macrovascular complications or CVD death compared with conventional therapy at the end of the trial [8]. Similar results were observed in people with T2DM and longer duration of diabetes in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial which suggesting that glucose control did not have a beneficial impact on CVD and that intensive glucose lowering may be associated with harm [9].
The paradigm shift in 2015 The entire treatment landscape in T2DM however changed in 2015 when the first of the modern CV outcomes trials (CVOTs) to show superiority of a glucoselowering therapy over placebo was presented in September 2015. The Empaglif lozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG) study reported not only CV safety but also a 14% reduction in the primary composite endpoint of CV death, non-fatal myocardial infarction and non-fatal stroke compared with placebo (the three-point major adverse CV event (MACE) endpoint). In addition, there was a 38% reduction in risk of CV death, a 35% reduction in risk of hospitalization for HF (HHF) and a 32% reduction in the risk of death from any cause [10]. These findings were supported subsequently by data from CVOTs assessing the other licenced SGLT2is, canagliflozin, dapagliflozin and ertuglif lozin (Canaglif lozin Cardiovascular Assessment Study (CANVAS) Program, Dapaglif lozin Effect on Cardiovascular Events -Thrombolysis in Myocardial Infarction (DECLARE-TIMI 58) respectively) [11][12][13]. Table 1 summarises the recent trials with glucose lowering agents on CVD outcomes including HHF.
Importance of HF HF is a major public health issue affecting up to 63 million people worldwide [14], with 1 in 5 people expected to develop HF during their lifetime [15]. T2DM

Introduction
The importance of the kidney to the pathophysiology of type 2 diabetes mellitus (T2DM) has been appreciated for many decades [1]. However, in recent years key role of renal sodium glucose cotransporters (SGLTs) glucose homeostasis led to the development of a new class of glucose lowering drugs, sodium glucose cotransporter 2 (SGLT2) inhibitor. SGLT2 inhibitors prevent proximal renal tubular renal glucose and sodium reabsorption [1]. The resultant glucoretic and natriuretic effect of SGLT2 inhibitors are associated with reductions in glycaemia (HbA 1c ), body weight and systolic blood pressure. Because SGLT2 inhibitors act on the kidney and have no direct effect on beta cells in the pancreas their metabolic effects occur independently of insulin and the risk of hypoglycaemia is very low [1].

Glycaemic effects
In T2DM all SGLT2 inhibitors show very similar reductions in HbA 1c in trials where the agents have been used as monotherapy in drug-naive patients, in combination with other oral agents or insulin. Although the short-term reduction in HbA 1c with SGLT2 inhibitors is comparable to that achieved with metformin, sulphonylureas and DPP-IV inhibitors (0.7-1%), there is evidence that the durability of glycaemic lowering may better with SGLT2 inhibitors compared to these other drug classes [3,4].

Effects on weight
As compared to other effects of anti-diabetic agents on weight such metformin (weight neutral), sulphonylureas (weight gain) and DPP-IV inhibitors (weight neutral) there is weight loss associated with SGLT inhibitors treatment [4]. Weight loss is related to the glucose excretion promoted by these agents (60-100 g of glucose excreted per day in the urine) and the related calorific loss. There is typically around 2-3 kg weight reduction observed after 6 months' treatment and there are positive changes in body composition associated with this weight loss with a reduction in total fat mass, visceral and subcutaneous adipose tissue [4].

Blood pressure reduction
In clinical trials and real-world studies there are consistent sustained reductions in both systolic (~5 mm Hg) and diastolic (~2 mm Hg) blood pressure with all SGLT2 inhibitors. These effects are likely to be related to the coupling of glucose and sodium reabsorption in the proximal tubule. SGLT2 inhibition leads to both an is a major risk factor for the development of HF and also a significant adverse prognostic factor in those with established HF [10,11]. People with T2DM have a 2-4 times increased risk of developing HF, higher rates of HHF and mortality compared to people with T2DM. Chronic HF is the leading cause of hospitalisation in patients over 65 years old [16], with those hospitalised having a 10%, 30-day and 50%, 1-year mortality. There is also significant economic cost of HF with an estimated global cost being more than $100 billion per year with cost of HHF the major contributing factor. In the Great Britain the average cost for per HHF event is nearly £4000 (~$5400) [17].
People with T2DM can develop two distinct phenotypes of HF according to their ejection fraction. Many develop HF with a reduced ejection fraction (EF) <40% (HFrEF), which is often characterised by a loss and stretch of cardiac myocytes, left ventricular enlargement and increased serum natriuretic peptides. Treatment of HFrEF encompasses symptomatic control with diuretic treatment accompanied by key treatments that have demonstrated CVD benefits and reduction in HHF (inhibitors of the renin-angiotensin system (including ACE-inhibitors, angiotensin receptor blockers, angiotensin receptor neprilysin inhibitors), beta-blockers and mineralocorticoid receptor antagonists, MRA) [16].
Many people develop HF with preserved ejection fraction (EF >50%; HFpEF) which is characterised by systemic and adipose tissue inflammation, microvascular dysfunction and myocardial fibrosis. In contrast to HFrEF patients with HFpEF do not have significantly increased LV size or concentrations of serum natriuretic peptides and show little/no response to neurohormonal antagonists [15,18]. Observational studies highlight a shifting pattern of the epidemic with the prevalence of HFpEF increasing relative to HFrEF [19], and over time this HFpEF likely to constitute ~65% of the total HF burden. This increase is related to the growing prevalence of comorbidities such as T2DM, obesity, hypertension [16].

SGLT2 inhibitors and HF
Two recent HF outcomes trials: Dapaglif lozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF); Empaglif lozin Outcome Trial in Patients Table 1 Trials with SGLT2 inhibitors demonstrating major adverse cardiovascular events or hospitalization for HF benefit  with Chronic Heart Failure and a Reduced Ejection Fraction (EMPEROR-Reduced, Table 2) [20,21]. The DAPA-HF trial in 4744 patients with New York Heart Association Class 2, 3 or 4 HF and an ejection fraction 40% or less demonstrated a beneficial effect for dapaglif lozin compared with placebo (26% relative risk reduction) on the primary outcome of a composite of worsening of HF (hospitalization or an urgent visit resulting in intravenous therapy for HF) or cardiovascular death (hazard ratio (HR) 0.74, 95% confidence interval (CI) 0.65-0.85). Dapagliflozin also had beneficial effects for hospitalization for HF (HR 0.70, 95% CI, 0.59-0.83) and deaths from cardiovascular causes (HR 0.82, 95% CI 0.69-0.98). Importantly the beneficial effects on primary outcomes were similar in those with and without T2DM at baseline which was first clear demonstration that SGLT2 inhibitors would have a beneficial impact in people without T2DM [20].
In the recently published EMPEROR-Reduced trial in 3730 patients with New York classification 2, 3 or 4 HF and ejection fraction less than 40% were randomized to receive 10 mg empaglif lozin or placebo [21]. In this trial a 25% reduction in the primary composite outcome of cardiovascular death or hospitalization for HF in the empaglif lozin group compared with the placebo group (HR 0.75, 95% CI 0.65-0.86) was observed [21]. Similar to the DAPA-HF findings the beneficial effect of empaglif lozin on the primary outcome were consistent regardless of presence or absence of T2DM [21].
Both trials have more similarities than differences and conclusively demonstrated benefits in HFrEF that were similar in patients with and without T2DM. Importantly these positive effects were observed on top of standard of care goal-directed medical therapy including RAS inhibition (sacubitril/valsartan, or ACE-I or angiotensin receptor blockers) beta blockers and mineralocorticoid antagonists. This confirms that the mechanism of effect of SGLT2 inhibitors are distinct from these other established treatment for HF and are in indeed complementary [22,23].
A meta-analysis of these two trials comprising 8474 participants demonstrated that SGLT2 inhibitors were associated with a 30% reduction in all-cause death (HR 0.87, 95% CI 0.77-0.98), 14% reduction in cardiovascular death (HR 0.86, 95% CI 0.76-0.98) and a 25% reduction  [22]. These significant treatment effects were consistent for subgroups of patients based on age, sex, T2DM status and baseline estimated glomerular filtration rate [22].

Potential mechanisms of cardiovascular benefit of SGLT2
The mechanism by which SGLT2 inhibitors reduce CV death and HF remains unknown, although many theories have been proposed [5]. What is very apparent is fast speed of onset of the cardio-renal benefits of SGLT2 inhibitors and that the proposed mechanisms are not directly related to glucose lowering effects of these medications. Moreover similar benefits for HHF have been observed in those with or without T2DM. Proposed cardiac mechanisms include cardiac remodelling, improved contractility and a shift in myocardial and renal substrate utilisation from fat and glucose oxidation toward an energy-efficient 'super fuel' like ketone bodies, which improve myocardial/renal work efficiency and function, inhibition of sodium-hydrogen exchange, increases in erythropoietin levels, and reduction in myocardial ischemia or reperfusion injury [5,24]. Figure 1 details the proposed mechanisms by which SGLT2 inhibitors offer cardio-renal protection. What is very clear from the growing literature is that SGLT2 inhibitors are novel neurohormonal antagonists that have remarkable molecular, cellular and clinical mechanism of benefit on the cardiovascular system [24].

Effects of SGLT2 inhibitors on chronic kidney disease (CKD)
As well as HF, T2DM is frequently complicated by CKD (~40% of people with T2DM). T2DM is the leading cause of end-stage kidney disease (ESKD) globally. T2DM, CKD and HF are interconnected and co-exist with nearly 50% of people with HF have moderate-severe CKD. This co-existence of CKD and HF ref lects common pathophysiology such as advancing age, hypertension, coronary artery disease, and type 2 diabetes [25]. Furthermore, the presence of one of these conditions also adversely affect the prognosis of the other. For example, HHF in CKD is associated with a 2-4-fold increased risk of ESKD and the presence of CKD in HF patient is associated with 1-2-fold increased risk increased mortality and 3-4-fold higher rates of HHF [26].
The renoprotective effects of SGLT2 inhibitors in T2DM have been evaluated in five major CV outcomes trials (CVOTs): EMPA-REG OUTCOME (empaglif lozin), CANVAS program, (canagliflozin), DECLARE-TIMI 58 (dapagliflozin), and VERTIS CV (ertugliflozin). In these trials renal endpoints were evaluated as secondary endpoints and all demonstrated SGLT2 inhibitors could prevent the development of CKD and prevent or delay the worsening of CKD in people with T2D at any level of renal risk [27].
Two  renal outcomes and Cardiovascular mortality in patients with chronic kidney disease (Dapa-CKD) [28,29] ( Table 2). The CREDENCE trial was the first dedicated renal outcomes trial with an SGLT2 inhibitor, in people with CKD and T2D. The relative risk of the primary renal composite endpoint (ESKD, doubling of serum creatinine, or renal or CV death) was 30% lower in the canagliflozin group than in the placebo group [28].
Multiple mechanisms are likely to explain the observed benefits for renal protection with SGLT2 inhibitors [30,31]. Figure 1 details the proposed mechanisms by which SGLT2 inhibitors offer cardiorenal protection.

Adverse effects of SGLT2 Inhibitors and how to minimise their impact
The most common adverse effect and how to prevent and manage them if they do occur are listed in Table 3. Genital mycotic infections are common and can be managed with patient education and topical antifungal treatment often [4,32]. In severe infections not respon ding to topical treatment temporary suspension of SGLT2 inhibitor maybe required to enable more effective treatment (e.g. oral anti-fungal medication) for the mycotic infection. Although there also be a slightly increased risk of urinary tract infections this however has not been consistently observed in randomised controlled trials. There have been concerns about Fournier's gangrene, a necrotizing fasciitis of the scrotum from safety reporting databases but this adverse event has not observed in large trials to date. There are no current serious or clinically relevant pharmacokinetic interactions between SGLT2i and other medicinal products. Documented interactions are related to the potential effects of synergistic hypotension or hypoglycaemia. Therefore, patients taking drugs with blood pressure or glucose lowering effects concurrently, should have their blood pressure and blood glucose monitored. SGLT2 in-hibitors alone are very unlikely to cause hypoglycaemia. Hypoglycaemia is mostly caused by insulin or sulfonylureas (e.g. gliclazide, glimepiride). In many patients, SGLT2 inhibitors can be started safely without adjustment to other diabetes therapeutics such as metformin. Hypoglycaemia is also unlikely when eGFR <45 mL/ min/1.73 m 2 as the drug's glucose lowering effect is reduced. Some patients are at higher risk of hypoglycaemia, for example if they have a history of previous frequent hypoglycaemic events or if their glycaemic control (estimated by HbA 1c ) at baseline is very good and they are already on agents that can cause hypoglycaemia (such as insulin, sulfonylureas. In such high-risk patients, liaison with the diabetes specia list team prior to initiation of SGLT2 is recommended as these patients may need cessation or dose adjustment of their other diabetic medications to enable starting SGLT2 inhibitors.
Diabetic ketoacidosis is a known but rare risk with SGLT2 inhibitors and can occur at normal glucose levels [4]. Suspect diabetic ketoacidosis in patients with nonspecific symptoms such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or sleepiness. Patients should be assessed for ketoacidosis immediately if these symptoms occur, regardless of blood glucose level.

Conclusions
In the last 5 years there has been a paradigm shift in the care of patients with T2DM. The growing evidence for treatments such as SGLT2 inhibitors that offer cardiorenal protection has resulted in this major change. International and national guidelines in cardiology, renal medicine and diabetes have adapted to this evidence and now recommend early use of SGLT2 Inhibitors for the prevention of HF, kidney disease and atherosclerotic cardiovascular disease. Put together, this change in approach has major implications not only for primary care, where the majority of these patients with T2DM, HF and CKD are often managed, but also for specialist care physicians, including cardiologists, diabetologists, and nephrologists. SGLT2 inhibitors are a unique class that have multiple uses across different medical specialities and will be an essential medication for future management of people with or without established cardiovascular disease, with or without T2DM, patients with renal disease and those with HF.