SGLT2 (Table
1) is the major transporter responsible for the reabsorption of glucose from the glomerular filtrate back into the circulation, is characterized by low affinity, high volume, as well as is predominantly expressed in the proximal tubules [
19,
20]. By inhibiting SGLT2, SGLT2 inhibitors lower renal reabsorption of filtered glucose and reduce the renal threshold for glucose, thereby increasing urinary glucose excretion [
19,
21‐
27]. This reduces HbA1c by approximately 0.6–1.0% [
8,
28]. SGLT2 inhibitors increase sodium delivery to distal tubules through blocking SGLT2-dependent glucose and sodium reabsorption, which is thought to increase tube-ball feedback and decrease intraglomerular pressure. This may affect a variety of physiological functions, comprising reducing cardiac preload and afterload and downregulating sympathetic nerve activity [
4,
19,
21‐
28]. Metabolism is shifted to gluconeogenesis and ketosis, which are thought to have protective effects on the heart and kidneys [
28]. SGLT2 inhibitors can reduce glucotoxicity in renal tubular cells by reducing mitochondrial dysfunction and inflammation, and also reduce renal hypoxia by reducing tubular energy and oxygen demand [
28].
Table 1
Clinical effects and risks of SGLT2 inhibitors
1. Effect on glycemic |
A.The value of HbA1c level reduced approximately 0.7–1.0% |
B.Lower fasting plasma glucose, about 1.2 mmol/L |
C.Improved beta cell function |
D.Improve glucotoxicity |
E.Improved insulin sensitivity |
F.Increased endogenous glucose production |
G.Reduced insulin resistance |
2. Effects on lipids |
A.Increased HDL, LDL and apolipoprotein |
B.Does not alter the concentration of LDL-C, but decreases small, dense LDL-C and increases large buoyant LDL-C |
C.Increased total cholesterol |
D.Lower triglyceride levels |
E.Lead to increased adiponectin |
3. Weight |
A.Decreased waist circumference, subcutaneous adipose tissue, and visceral adipose tissue |
B.Increased glucagon secretion |
C.Weight loss of about 2–4 kg |
4. Cardiovascular effects |
A.Reduced systolic blood pressure |
B.Improve inflammation and oxidative stress |
C.Improve vascular function |
D.Reduce cardiac preload |
E.Decreased left ventricular mass index |
F.Decreased NT-proBNP concentration |
G.Improve natriuresis |
H.Reduces pathological cardiomyocyte stiffness |
I.Lead to osmotic diuresis |
J.Increase hematocrit |
K.Lung fluid volume improved |
L.Improves diastolic function |
M.Improve cardiac remodeling |
N.Reduce ischemia–reperfusion injury |
5. Effects on fibrosis markers |
A.Decreased Mac-2 binding protein |
B.FIB-4 index decreased |
C.Significantly lower NAFIC scores |
6. Liver function improvement |
A.Reduced fatty liver index |
B.Decreased serum alanine aminotransferase, aspartate aminotransferase and gamma-glutamyltransferase levels |
C.Proton density fat fraction decreased |
7. Effects on the kidneys |
A.Reducing vascular volume |
B.Reduce blood uric acid levels |
C.Reduced proteinuria |
D.Stabilize eGFR |
E.Improve urinary albumin/creatinine ratio |
F.Reduced kidney disease progression |
G.Improve natriuresis |
8. SGLT2 inhibitors may reduce bone density |
9. Effects on inflammatory factors |
A.Decreses soluble dipeptidyl peptidase levels |
B.Decreases ICAM-1, VCAM-1, TNF-α and IL-6 |
10. Oxidative stress |
A.Reduce H2O2, GSH, lipid peroxide |
B.Prevent PKGIα oxidation |
11. Effect on anemia |
A.Decrease hepcidin levels |
B.Improve erythropoiesis |
C.Increase hemoglobin levels |
Cardiovascular: heart failure and hospitalization for heart failure, cardiovascular death, atrial fibrillation | Hypoglycemia |
Hypotension |
All-cause mortality | Sarcopenia |
Anemia | Acute kidney injury |
Nonalcoholic fatty liver | Diabetic ketoacidosis |
Renal protection: diabetic kidney disease, chronic kidney disease, end-stage renal disease, kidney failure, kidney death | Genital or urinary tract infection |
Dehydration |
Hypovolemia |
Indeterminate ameliorated events | Osmotic diuresis |
Nonfatal myocardial infarction | Amputation |
Non-fatal stroke | Fracture |
The expression of
SLC5A2 was higher in islets of non-T2DM patients than in islets of T2DM individuals or normal islets exposed to chronic hyperglycemia, with lower glucagon gene expression [
4]. Glucagon secretion can be achieved by inhibiting
SLC5A2 by siRNA-induced gene silencing or by inhibiting SGLT2 activation through K
ATP channels by dapagliflozin [
4]. Glucagon secretion and hepatic gluconeogenesis were improved in normal mice treated with dapagliflozin, and fasting-induced hypoglycemia was limited [
4,
29]. The effect of SGLT1 on glucagon secretion depends on glucose transport, not glucose metabolism. Canagliflozin inhibits glucagon secretion by inhibiting SGLT1 in alpha cells [
29].
SGLT2 inhibitors can induce transforms in IL-6, adiponectin, and serum leptin and improve adipose tissue function, which have favorable effects on insulin sensitivity and cardiovascular disease risk [
30,
31]. SGLT2 inhibitors also increase HDL, LDL levels and reduce triglyceride levels [
32,
33]. SGLT2 inhibitors are able to obviously reduce systolic blood pressure (SBP) and lead to weight loss (Table
2). Additionally, a meta-analysis of 58 studies reported favorable effects of SGLT2 inhibitors on HbA1c levels (mean difference (MD) from placebo − 0.66%; active comparator − 0.06%). SGLT2 inhibitors decreased body weight (− 1.80 kg) and SBP (− 4.45 mm Hg) compared to other drugs [
34].
Table 2
Effects of SGLT-2 on change from baseline HbA1c (%), FPG (mmol/L), body weight (kg) and SBP (mmHg) in patients with T2DM, changes from baseline results of randomized controlled trials
| T2DM patients with 7.0–9.5% HbA1c | Canagliflozin 100 mg | 483 | − 1.35 | − 0.82 | − 3.7 | − 3.3 |
Canagliflozin 300 mg | 485 | − 1.52 | − 0.93 | − 4.0 | − 4.6 |
Glimepiride | 482 | − 1.02 | − 0.81 | 0.7 | 0.2 |
Lavalle-González et al. [ 100] | Patients with T2DM had inadequate glycaemic control | Sitagliptin | 366 | − 1.0 | − 0.73 | − 1.3 | − 0.7 |
Canagliflozin 100 mg | 368 | − 1.5 | − 0.73 | − 3.8 | − 3.5 |
Canagliflozin 300 mg | 367 | − 2.0 | − 0.88 | − 4.2 | − 4.7 |
Placebo/sitagliptin | 183 | | − 0.17c | − 1.2c | |
| Patients with 7.0% ≤ HbA1c ≤ 10.0% | Placebo | 237 | 0.4 | − 0.03 | − 0.1 | 1.1 |
Canagliflozin 100 mg | 241 | − 1.0 | − 0.60 | − 2.2 | − 3.5 |
Canagliflozin 300 mg | 236 | − 1.1 | − 0.73 | − 2.8 | − 6.8 |
Michael Roden et al. [ 108] | Adults had no treatment in the previous 12 weeks | Placebo | 228 | 0.65 | 0.08 | − 0.33 | − 0.3 |
Empagliflozin 10 mg | 224 | − 1.08 | − 0.66 | − 2.26 | − 2.9 |
Empagliflozin 25 mg | 224 | − 1.36 | − 0.78 | − 2.48 | − 3.7 |
Sitagliptin | 223 | − 0.38 | − 0.66 | 0.18 | 0.5 |
| Patients with T2DM | Empagliflozin 10 mg | 80 | − 30b | − 0.34 | − 2.2 | 0.1 |
Empagliflozin 25 mg | 88 | − 28b | − 0.47 | − 2.6 | − 1.7 |
Metformin | 56 | − 26b | −
0.56 | − 1.3 | 2.0 |
| Patients with T2DM inadequately controlled by metformin | Exenatide plus dapagliflozin | 228 | − 3.66 | − 2.0 | − 3.55 | − 4.3 |
Exenatide | 227 | − 2.54 | − 1.6 | − 1.56 | − 1.2 |
Dapagliflozin | 230 | − 2.73 | − 1.4 | − 2.22 | − 1.8 |
| Patients with inadequately controlled T2DM and hypertension | Placebo | 224 | 0.2 | − 0.02 | − 0.59 | − 7.62 |
Dapagliflozin | 225 | − 1.0 | − 0.63 | − 1.44 | − 11.90 |
| Patients with T2DM inadequately controlled on metformin | Placebo | 167 | − 6.7b | − 0.2 | − 1.2 | 0.2 |
Ertugliflozin 5 mg | 170 | − 37.1b | − 1.0 | − 3.0 | − 5.1 |
Ertugliflozin 15 mg | 169 | − 34.5b | − 0.9 | − 3.2 | − 3.9 |
| Adults with T2DM inadequately controlled on metformin | Placebo/glimepiride | 209 | − 0.6 | − 0.6 | − 0.18 | 0.05 |
Ertugliflozin 5 mg | 207 | − 1.0 | − 0.6 | − 3.77 | − 3.61 |
Ertugliflozin 15 mg | 205 | − 1.6 | − 0.9 | − 3.63 | − 3.13 |
| Patients with HbA1c ≥ 7.5% and ≤ 11.0% | Ertugliflozin 5 mg | 250 | − 28.7 | − 1.0 | − 2.4 | − 2.7 |
Ertugliflozin 15 mg | 248 | − 30.8 | − 0.9 | − 3.2 | − 1.6 |
Sitagliptin | 247 | − 15.2 | − 0.8 | − 0.1 | − 0.2 |
Ertugliflozin 5 mg/sitagliptin | 243 | − 39.3 | − 1.4 | − 2.4 | − 2.3 |
Ertugliflozin 15 mg/sitagliptin | 244 | − 41.8 | − 1.4 | − 2.8 | − 2.2 |
Effect on liver
Nonalcoholic fatty liver disease (NAFLD), which often coexists with T2DM, is the most prevalent chronic liver disease worldwide [
38‐
40]. Clinically, SGLT2 inhibitors have shown benefit for NAFLD.
In the E-LIFT trial, SGLT2 inhibitors were obviously better at decreasing liver fat than standard therapy [MRI-Proton Density Fat Fraction (PDFF) difference − 4.0%; P < 0.0001]. MRI-PDFF was notably lower in the SGLT2 inhibitor group (P < 0.0001) compared with baseline. Two groups displayed a significant difference in serum alanine aminotransferase (ALT) levels (P = 0.005) [
38]. Two meta-analyses results showed that SGLT-2 inhibitors significantly reduced serum ALT, aspartate aminotransferase and γ-glutamyltransferase levels compared with controls, and the absolute percentage of liver fat content based on magnetic resonance technology, and body composition, glycemic control, lipid parameters, and markers of inflammation were significantly improved, and there was a trend for improvement in markers of fibrosis [
41,
42].
In NAFLD patients, dapagliflozin significantly reduced the fatty liver index (P < 0.01) compared with pioglitazone, and changes in the fatty liver index were significantly positively correlated with changes in insulin (P < 0.01) and HbA1c (P = 0.03) levels [
43].
Cardiovascular benefits
The investigators concluded that the cardioprotective effects of SGLT2 inhibitors can be attributed to (Table
1): blood pressure control, increased plasma erythrocytes levels, decreased inflammation and oxidative stress, decreased uric acid, prevention of ischemia/reperfusion injury and improved cardiac and vascular function [
8,
30,
32,
44]. The effects of SGLT2 inhibitors in the early stages, in addition to direct improvements in peripheral endothelial function, are responsible for the clinical benefit found in the Cardiovascular Outcomes Trial [
45]. SGLT2 inhibitors lead to acute and chronic reductions in SBP, reductions in vasoconstrictors and increases in vasodilators. These changes may contribute to its antihypertensive effect and its benefit in congestive HF [
46]. Early pathogenesis of human diabetic cardiomyopathy is associated with JunD/PPAR-γ overexpression and lipid accumulation after heart transplantation in diabetic patients. This phenomenon was decreased by therapy with SGLT2 inhibitors that act directly on the heart of diabetic patients [
47].
EMPA-HEART CardioLink-6 was designed to determine whether empagliflozin causes decreased left ventricular mass in coronary artery disease patients with T2DM [
48]. For patients assigned to empagliflozin and placebo, mean body surface area-related left ventricular mass regressions over 6 months was 2.6 g/m
2 and 0.01 g/m
2, respectively (P = 0.01) [
48]. SGLT2 inhibitors was related to obviously lower extracellular volume, left ventricular mass index, and indexed extracellular compartment volume, which may be partly responsible for the beneficial cardiovascular outcomes [
48,
49].
An analysis of the results of the CANVAS program (Canagliflozin Cardiovascular Assessment Study) indicated that patients with a previous cardiovascular event had higher absolute rates of cardiovascular, renal and death outcomes compared with participants without a previous cardiovascular event. Canagliflozin reduced cardiovascular outcomes overall [
50]. Data from the DIVERSITY-CVR trial demonstrated that SGLT2 inhibitors were obviously more effective than sitagliptin in improving cardiometabolic risk factors [
51]. Results of an exploratory analysis of EMPA-REG OUTCOME indicated that changes in hemoglobin and hematocrit mediated 48.9% and 51.8%, respectively, of the effect of empagliflozin vs. placebo on the risk of cardiovascular death, while HbA1c, fasting plasma glucose (FPG) and uric acid were less regulated (29.3%) [
52]. Ertugliflozin was noninferior to placebo in terms of major adverse cardiovascular events (MACE) in patients with atherosclerotic cardiovascular disease and T2DM [
11].
In a retrospective cohort study, patients administered SGLT2 inhibitors experienced a lower risk of developing HHF [hazard ratio (HR) = 0.86], all-cause mortality (HR = 0.85), and stroke (HR = 0.86) compared with DPP-4 inhibitors [
53]. A multi-database retrospective cohort study also identified that SGLT2 inhibitors were related to a reduced risk of HF (0.43), cardiovascular death (0.60), MACE (HR = 0.76) and myocardial infarction (0.82) compared with DPP-4 inhibitors. Canagliflozin (HR = 0.79), dapagliflozin (0.73), and empagliflozin (0.77) had similar benefits for MACE [
54].
Multiple meta-analyses have reported that SGLT2 inhibitors were related to fewer cardiovascular events, especially HHF and cardiovascular mortality. However, for non-fatal stroke and myocardial infarction differ [
12,
55‐
60]. SGLT2 inhibitors reduced MACE by 11% (P = 0.0014), with benefit only in atherosclerotic cardiovascular disease patients (HR = 0.86) [
61]. A meta-analysis of 764 studies (n = 421,346) reported that SGLT-2 inhibitors reduced non-fatal myocardial infarction, and cardiovascular death. Importantly, SGLT-2 inhibitors decreased HHF more than GLP-1 [
55]. Results of a network meta-analysis of 453 studies showed that oral SGLT-2 inhibitors decreased HHF in patients at increased cardiovascular risk who had prior metformin-based therapy [
12]. Another meta-analysis included data from 57 trials (n = 33,385) and 6 regulatory submissions (n = 37,525), providing data on seven SGLT2 inhibitors [
60]. SGLT2 inhibitors prevented the risk of MACE (relative risk 0.84; P = 0.006), all-cause death (0.71; P < 0.0001), HF (0.65; P = 0.002), and cardiovascular death (0.63; P < 0.0001). There was no significant effect on angina (0.95; P = 0.70) or non-fatal myocardial infarction (0.88; P = 0.18) [
60].
Benefits of SGLT2 inhibitors in HF, HFrEF and HHF
SGLT2 inhibitors reduce left ventricular volume in T2DM or prediabetic patients with HFrEF. Favorable reverse left ventricular remodeling may be a mechanism by which SGLT2 reduces HHF and mortality in patients with HFrEF [
62]. The partial of patients receiving SGLT2 inhibitors improved significantly in lung fluid volume [
63]. Elevated concentrations of N-terminal pre-B-type natriuretic peptide (NT-proBNP) are related to HF diagnosis and prediction of cardiovascular risk [
64]. A significant proportion of patients in the CANVAS trial had increased NT-proBNP values. Canagliflozin reduced NT-proBNP concentrations compared with placebo. However, the reduction in NT-proBNP explains only a small fraction of the benefit of canagliflozin on HF events [
64]. A meta-analysis showed that SGLT2 inhibitors was related to obviously improved diastolic function and NT-proBNP levels in T2DM patients with or without chronic HF, while it did not significantly affect the structural parameters of the heart based on body surface area. Left ventricular ejection fraction levels improved only in patients with HFrEF [
65]. SGLT2 inhibitors reduce inflammation and oxidative stress in HF with preserved ejection fraction, improve NO-sGC-cGMP-cascade and PKGIα activity by reducing PKGIα oxidation and aggregation, thereby reducing pathological cardiomyocyte stiffness [
66]. Results from the large multinational study CVD-REAL demonstrated that SGLT-2 inhibitors were related to lower HHF and mortality compared with other antidiabetic agents [
67].
Some randomized controlled trials have also conformed the benefit of SGLT2 inhibitors in HF or HHF (Table
3) [
13,
68‐
72]. In the CANVAS program, canagliflozin significantly reduced severe HF or HHF (P = 0.003) and HHF (P = 0.002) compared with placebo. Canagliflozin had a greater benefit of cardiovascular death or HHF in patients with a prior history of HF (HR 0.61 vs. 0.87; P = 0.021) compared patients without HF at baseline [
72]. Empagliflozin was related to a 35 percent decrease in the relative risk of HHF compared with placebo in EMPA-REG OUTCOME [
69]. In EMPEROR-Reduced, the incidence of HHF was obviously lower in empagliflozin compared to placebo in adults with or without T2DM with HFrEF (HR = 0.69). And the overall number of people with HHF was less (21.0% vs. 30.0; P < 0.001) [
68]. In DAPA-HF, the risk of HHF was lower in the dapagliflozin group for patients with (12.8% vs. 16.2%; P = 0.017) or without (7.2% vs. 11.2%; P < 0.001) T2DM [
71]. Approximately 12.3% patients with HFrEF accompany by COPD, and these patients were at higher risk for the primary outcome. The benefit of dapagliflozin on prespecified outcomes was consistent regardless of COPD [
73]. Ertugliflozin was also able to decrease the risk of HHF to some extent compared with placebo in the VERTIS CV trial [
11,
74]. The risk reduction for first HHF was similar in patients with ejection fraction ≤ 45% or preserved ejection fraction > 45% or unknown [
74].
Table 3
The clinical cardiovascular events occurrence (%) of SGLT2 inhibitors, results from major randomized controlled trials
| Patients with T2DM and albuminuric CKD | 2.62 years | Canagliflozin | 2202 | 12.4 | 4.0 | 5.0 | | |
Placebo | 2199 | 16.4 | 6.4 | 6.4 | | |
P value | | | < 0.001 | 0.05 | | |
| T2DM patients | 3.1 years | Empagliflozin | 4687 | 10.5 | 2.7 | 3.7 | 4.5 | 3.2 |
Placebo | 2333 | 12.1 | 4.1 | 5.9 | 5.2 | 2.6 |
P value | | < 0.001 | 0.002 | < 0.001 | 0.22 | 0.16 |
| Patients with HF and an EF of 40% or less | 16 months | Empagliflozin | 1863 | 19.4 | 13.2 | 10.0 | | |
Placebo | 1867 | 24.7 | 18.3 | 10.8 | | |
P value | | < 0.001 | | | | |
| T2DM patients and/or atherosclerotic CV disease | 4.2 years | Dapagliflozin | 8582 | 8.8 | 2.5 | 2.9 | 4.6b | 2.7 |
Placebo | 8578 | 9.4 | 3.3 | 2.9 | 5.1b | 2.7 |
P value | | 0.17 | | | | |
| Patients with HF and an EF of 40% or less | 18.2 months | Dapagliflozin | 2373 | 16.3 | 9.7 | 9.6 | | |
Placebo | 2371 | 21.2 | 13.4 | 11.5 | | |
P value | | < 0.001 | | | | |
| Patients with Chronic Kidney Disease | 2.4 years | Dapagliflozin | 2152 | 4.6 | | 3.0 | | |
Placebo | 2152 | 6.4 | | 3.7 | | |
P value | | 0.009 | | | | |
| T2DM patients with atherosclerotic CV disease | 3.5 years | Ertugliflozin | 5499 | 11.9 | 2.5 | 6.2 | 5.6 | 2.9 |
| Placebo | 2747 | 11.9 | 3.6 | 6.7 | 5.4 | 2.8 |
| P value | | < 0.001 | | | | |
| T2DM patients with high CV risk | | Canagliflozin | 5795 | 26.9 | 5.5 | 11.6 | 9.7 | 7.1 |
| Placebo | 4347 | 31.5 | 8.7 | 12.8 | 11.6 | 8.4 |
| P valued | | 0.5980 | 0.2359 | 0.9387 | 0.9777 | 0.4978 |
Several meta-analyses have indicated that SGLT-2 inhibitors reduce HHF and are related to lower HF compared with placebo or active control group [
12,
55,
56,
59,
61,
75‐
77]. SGLT-2 inhibitors were notably related to a lower incidence of HF events (HR = 0.62) [
75]. SGLT2 inhibitors decreased the risk of cardiovascular death or HHF by 23% (P < 0.0001) and HHF by 31% (P < 0.0001), similar benefits were seen in patients with or without a history of HF or atherosclerotic cardiovascular disease [
61]. Canagliflozin (HR = 0.69, 0.68, 0.67, 0.58) or empagliflozin (HR = 0.70, 0.69, 0.68, 0.59) notably decreased HHF compared with duraglutide, exenatide, lixisenatide, and subcutaneous injection [
56]. In a real-world meta-analysis OBSERVE-4D, the HR estimate for canagliflozin vs. a non-SGLT2 inhibitor for HHF was 0.39 [
76]. In a network meta-analysis of 23 studies, compared to DPP-4 inhibitors, SGLT2 inhibitors reduced the risk of HHF [
77].
SGLT2 inhibitors (all four SGLT2 inhibitors) were able to reduce the risk of HF or HHF compared with control group (such as placebo or other antidiabetic drugs), regardless of cardiovascular disease. This view is supported by the combined results of clinical trials and meta-analyses.
Cardiovascular death
The beneficial effect of SGLT2 inhibitors on cardiovascular death now appears indisputable, whether meta-analyses, retrospective studies, or large clinical trials (Table
3) showed similar data that SGLT2 inhibitors lowered the risk of cardiovascular death. All four SGLT2 inhibitors are able to achieve this and are superior to DPP-4 inhibitors [
12,
54,
55,
60,
75,
77]. In CANVAS, canagliflozin was slightly related to a lower risk of cardiovascular death compared with placebo (HR = 0.87) [
78]. In EMPA-REG OUTCOME, the relative risk of cardiovascular death was decreased by 38% in the empagliflozin group [
69]. Interestingly, dapagliflozin in the DAPA-HF and DECLARE–TIMI 58 studies achieved different cardiovascular mortality outcomes [
13,
79]. Ertugliflozin does not appear to significantly reduce cardiovascular death compared with placebo (HR = 0.92) [
11]. Outcomes from a large meta-analysis showed that SGLT2 inhibitors prevented cardiovascular death (P < 0.0001). Evidence that individual agents had different effects on cardiovascular outcomes or death was not evident (all I
2 < 43%) [
60]. SGLT-2 inhibitors obviously decreased cardiovascular death compared to DPP-4 inhibitors (RR = 0.88), in contrast to GLP-1 receptor agonists, there was no difference [
77].
Arrhythmia
Several meta-analyses have showed that SGLT2 inhibitors decreased the risk of atrial fibrillation [
58,
80]. A meta-analysis of 22 trials reported SGLT2 inhibitors were related to a lower risk of atrial fibrillation (RR = 0.82), atrial fibrillation/flutter (RR = 0.82), and ventricular tachycardia (RR = 0.73). The risk reduction for atrial flutter (RR = 0.83) and cardiac arrest (RR = 0.83) did not reach statistical significance [
58]. Another meta-analysis indicated that the incidence of atrial fibrillation was 0.9% in subjects who received SGLT2 inhibitors and 1.1% in subjects who received placebo. The incidence of atrial fibrillation was significantly reduced (RR = 0.79) in both T2DM and non-T2DM patients receiving SGLT2 inhibitors [
80].
Although current evidence supports that SGLT2 inhibitors reduce the risk of ventricular tachycardia, and atrial fibrillation in patients with or without T2DM, this is limited to meta-analyses, while the mechanisms are not well elucidated. More clinical trials are required to support the benefit of SGLT2 inhibitors in cardiac arrhythmias.
Nonfatal myocardial infarction
Although several meta-analyses have reported reductions in non-fatal myocardial infarction with SGLT-2 inhibitors, most have shown no apparent effect [
55,
59,
60,
75]. Data from representative clinical trials (Table
3) showed that SGLT-2 inhibitors did not notably reduce the risk of non-fatal myocardial infarction. In CANVAS only, canagliflozin reduced the risk of non-fatal myocardial infarction to some extent compared with placebo (HR = 0.85) [
78]. When compared with GLP-1 receptor agonists, the risk of non-fatal myocardial infarction was similar for both [
77]. Based on the results of the current clinical trials and meta-analyses, it can be speculated that the effect of SGLT2 inhibitors on non-fatal myocardial infarction may be neutral. Potent evidence is now needed to support this.
Stroke
Results from some randomized controlled trials indicated that only canagliflozin among SGLT-2 inhibitors (Table
3) decreased the risk of stroke to a certain extent. In the CANVAS, canagliflozin had a similar effect to placebo on fatal or non-fatal stroke in patients with (HR = 0.84) and patients without a history of HF (HR = 0.88) [
72]. In EMPA-REG OUTCOME, empagliflozin slightly increased the risk of fatal or non-fatal stroke (HR = 1.18; P = 0.26), and only for non-fatal stroke (HR = 1.24) [
69].
Large meta-analyses displayed that SGLT-2 inhibitors barely reduced the risk of non-fatal stroke and even increased the risk (relative risk 1.30; P = 0.049) [
55,
60]. This was also the case in a large retrospective study showing that SGLT2 inhibitors were less beneficial for ischemic stroke (HR = 0.85) [
54]. Notably, a meta-analysis reported that SGLT2 was related to a lower risk of embolic stroke (RR = 0.32) [
58]. Interestingly, the risk of non-fatal stroke was similar between GLP-1 receptor agonists and SGLT2 inhibitors, while only GLP-1 receptor agonists decreased the risk of non-fatal stroke when compared to placebo [
77].
CKD with decreased estimated glomerular filtration rate (eGFR) or increased proteinuria increases the risk of hemorrhagic and ischemic stroke [
81]. Outcomes from the CREDENCE trial and meta-analysis showed that 142 patients had a stroke (HR = 0.77). Effects on stroke subtypes were: ischemic (HR = 0.88), hemorrhagic (HR = 0.50), and indeterminate (HR = 0.54) [
81]. There was evidence that the effect of SGLT2 inhibitors on total stroke varies by baseline eGFR (P = 0.01), with protection in the lowest eGFR (< 45 mL/min/1.73 m
2) subgroup (HR = 0.50) [
81].
SGLT2 inhibitors generally do not increase the risk of non-fatal stroke, and different results are reflected between different SGLT2 inhibitors, such as canagliflozin and empagliflozin. Several meta-analyses have also shown that SGLT2 inhibitors may lower the risk of certain types of stroke, such as embolic stroke. SGLT2 inhibitors on stroke risk may vary in different populations, such as depending on the level of renal function.
Renal protection
Diabetes is the most common cause of CKD, accounting for approximately 50% renal failure cases requiring replacement therapy [
82]. DKD develops in 30–50% of diabetic patients [
83]. SGLT-2 inhibitors have been clearly shown in multiple studies to improve renal outcomes in patients with CKD or DKD (Table
4), and glomerular hemodynamic function, significantly reduces the risk of proteinuria and renal failure [
5,
78,
82,
84‐
86].
Table 4
Associated renoprotective effects of SGLT2 inhibitors, results from randomized controlled trials
| Canagliflozin | 5.5 | 89.4 | 1.2 | | 0.4 | 5.3 |
Placebo | 9.0 | 128.7 | 2.4 | | 0.6 | 8.7 |
P value | 0.3868 | 0.0184 | | | | |
| Canagliflozin | 11.1 | | 5.4 | 0.1 | 5.3 | 3.5 |
Placebo | 15.5 | | 8.5 | 0.2 | 7.5 | 5.7 |
P value | 0.00001 | | < 0.001 | | 0.002 | |
| Dapagliflozin | 1.5 | | | 0.1 | 0.1 | 1.4 |
Placebo | 2.6 | | | 0.1 | 0.2 | 2.5 |
P value | < 0.0001 | | | 0.32 | 0.013 | < 0.0001 |
| Dapagliflozin | 6.6 | | | < 0.1 | 5.1 | 5.2 |
Placebo | 11.3 | | | 0.3 | 7.5 | 9.3 |
P value | < 0.001 | | | | | |
| Empagliflozin | 1.6 | | | | | |
Placebo | 3.1 | | | | | |
P value | | | | | | < 0.001 |
| Empagliflozin | 1.7 | 11.2 | 1.5 | | | |
Placebo | 3.1 | 16.2 | 2.6 | | | |
P value | < 0.001 | < 0.001 | < 0.001 | | | |
| Ertugliflozin | 3.2 | | 3.1 | 0 | | |
Placebo | 3.9 | | 3.8 | 0 | | |
SGLT2 inhibition was related to an acute, dose-dependent decrease in eGFR of about 5 mL/min/1.73 m
2 and a reduction in albuminuria of approximately 30–40%. These effects reflect preclinical observations showing that proximal tubular sodium excretion activates tubulo-glomerular feedback by increasing the delivery of sodium and chloride, subsequently causing afferent vasoconstriction [
87]. Due to reduced glomerular filtration, CKD patients have attenuated glucosuria and weight loss (eGFR < 60 mL/min/1.73 m
2) [
87]. A potential mechanism for the renoprotective effect of SGLT2 inhibitors may also involve uric acid reduction [
88,
89]. In T2DM patients with stage 2 or 3 CKD, SGLT2 inhibitors improved HbA1c and urinary albumin/creatinine ratios without increasing serious adverse renal events [
90,
91].
The National Kidney Foundation convened a scientific symposium of an international panel of more than 80 experts to elucidate and support the role of SGLT2 inhibitors in T2DM and CKD [
82]. The notion that the benefits of SGLT2 inhibitors are mediated by non-glycemic mechanisms at the meeting is supported by a number of observations that CKD and cardiovascular disease risk reductions in clinical trials of these drugs have not been associated with glycemic control or the use of other antidiabetic drugs [
82].
Dapagliflozin and canagliflozin are approved for CKD or DKD. In the CANVAS program, canagliflozin was related to a lower incidence of the composite of sustained doubling of serum creatinine (dSCr), ESKD, and renal death compared with placebo (HR = 0.53) [
78,
85]. Canagliflozin may be beneficial for the progression of albuminuria (HR = 0.73) and the composite outcome of sustained 40% decrease in eGFR, requirement for renal replacement therapy, or renal death (HR = 0.60) [
78,
85]. In CREDENCE, the risk of renal failure was lower in the canagliflozin group compared with the placebo group [
70]. Results from CANTATA-SU secondary analysis showed that compared with glimepiride, canagliflozin slowed the progression of renal disease over 2 years, and that it may confer renoprotective effects independent of its glycemic effects [
92]. Dapagliflozin had a reduced incidence of renal events in the DECLARE–TIMI 58 trial (4.3% vs. 5.6%) [
13]. The cardio-renal secondary composite outcome was obviously lower with dapagliflozin (P < 0.0001). The sustained decline in eGFR was reduced by 46% (P < 0.0001). Compared with placebo, dapagliflozin was associated with a lower risk of renal death or ESKD (0.1% vs. 0.3%; P = 0.012) [
93]. A prespecified analysis from DAPA-CKD showed that when added to ACEI or ARB therapy, dapagliflozin decreased the risk of several clinical outcomes (such as ≥50% eGFR decline and ESKD) in patients with CKD [
94].
Empagliflozin demonstrated renal protection in T2DM patients, as demonstrated in EMPA-REG OUTCOME, where empagliflozin was related to slower renal disease progression and a lower incidence of clinically relevant renal events compared with placebo (Table
4) [
86]. Additionally, compared with placebo, empagliflozin improved uric acid levels with a lower risk of serious renal outcomes [
68,
86,
88]. A sub-analysis of EMBODY trial reported that empagliflozin prevented the decline of renal function in T2DM patients with acute myocardial infarction, especially those with a baseline eGFR ≥ 60 mL/min/1.73 m
2 [
88]. Uric acid reduced about 0.9 mg/dL in the empagliflozin group (P < 0.001) [
88].
SGLT-2 inhibitors decrease renal failure risk in multiple meta-analyses [
12,
55‐
57]. SGLT2 inhibitors reduced the risk of kidney disease progression by 45% (P < 0.0001), including in some patients, regardless of atherosclerotic cardiovascular disease. The magnitude of the benefit of SGLT2 inhibitors varies with baseline renal function [
61]. A meta-analysis including 32,949 patients showed that SGLT-2 inhibitors reduced the risk of renal events (RR = 0.68) [
57]. Compared with GLP-1, SGLT-2 inhibitors were related to a lower risk of renal events (RR = 0.79) [
57]. Moreover, dapagliflozin (HR = 0.62, 0.60, 0.68 and 0.63) and empagliflozin (HR = 0.64, 0.61, 0.69 and 0.64) notably decreased renal function progression compared with duraglutide, exenatide, liraglutide, and lixisenatide [
56].
All-cause mortality
Results from several SGLT-2 inhibitor cardiovascular outcomes investigation trials indicated that SGLT-2 inhibitors decreased the risk of all-cause mortality compared with placebo. In the CANVAS program, compared with placebo, canagliflozin displayed a greater benefit on all-cause mortality in patients with a history of HF (HR = 0.70) than in patients without HF history (HR = 0.93) [
72]. In EMPA-REG OUTCOME, empagliflozin reduced the risk of all-cause mortality by 32% (P < 0.001) [
69]. In contrast, dapagliflozin did not notably lower the risk of all-cause mortality compared with placebo in DECLARE–TIMI 58 (HR = 0.93) [
13]. In DAPA-HF, dapagliflozin reduced cardiovascular mortality to some extent (HR = 0.83) in subjects with HFrEF regardless of a previous history of diabetes [
79]. There was a similar all-cause mortality between ertugliflozin and placebo (HR = 0.93) [
11].
Several meta-analyses have showed that SGLT-2 inhibitors lower the risk of all-cause mortality [
12,
55,
59,
60,
95]. A network meta-analysis of 236 trials showed that SGLT-2 inhibitors (HR = 0.80) were obviously reduced all-cause mortality than controls. SGLT-2 inhibitors (HR = 0.78) were associated with lower mortality compared to DPP-4 inhibitors [
75]. SGLT-2 inhibitors reduced deaths by 5–48 per 1000 patients over 5 years [
55].
Overall, all SGLT2 inhibitors, except ertugliflozin, were able to significantly reduce all-cause mortality, and the corresponding meta-analyses showed results consistent with clinical trials.
Anemia
SGLT-2 inhibitors also reduce hepcidin levels, improve erythropoiesis, increase hemoglobin levels, and reduce the incidence of anemia [
28,
96‐
98]. A post hoc analysis from CREDENCE displayed that 13% of the 4401 participants developed anemia or started treatment for anemia. Mean hemoglobin concentrations were 7.1 g/L higher and hematocrit was 2.4% higher in
canagliflozin compared to placebo. The risk of the composite outcome of anemia or initiation of anemia treatment was lower in the canagliflozin group compared to the placebo group (HR = 0.6; P < 0.0001). Subjects received canagliflozin had a lower risk of anemia events (0.58; P < 0.0001) alone, initiation of iron preparations (0.64; P < 0.0001), and need for erythropoiesis-stimulating agents (0.65; P = 0.012) [
96].
Results of a retrospective cohort study indicated that SGLT2 inhibitors usage was related to an obviously lower prevalence of anemia [odds ratio (OR) = 0.35]. The adjusted MD for hemoglobin levels between SGLT2 inhibitor subjects and non-users was 7.0 g/L [
97]. A corresponding meta-analysis reported that SGLT2 inhibitors significantly increased hemoglobin levels compared with placebo (P < 0.00001), and each SGLT2 inhibitor resulted in a notable increase in hematocrit levels (P < 0.00001) [
98].