Functional and Clinical Importance of SGLT2-inhibitors in Frailty: From the Kidney to the Heart
Abstract
SGLT2 (sodium-glucose cotransporter 2) enables glucose and sodium reabsorption in the kidney. SGLT2-inhibitors (also known as gliflozins, which include canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin) act by increasing glycosuria, thereby reducing glycemia. These drugs are critical to reach and keep glycemic control, a crucial feature, especially in patients with comorbidities, like frail individuals. Several studies evaluated the effects of SGLT2-inhibitors in different settings beyond diabetes, revealing that they are actually pleiotropic drugs. We recently evidenced the favorable effects of SGLT2-inhibition on physical and cognitive impairment in frail older adults with diabetes and hypertension. In the present overview, we summarize the latest clinical and preclinical studies exploring the main effects of SGLT2-inhibitors on kidney and heart, emphasizing their potential beneficial actions in frailty.
SGLT2 (sodium-glucose cotransporter 2) inhibitors (also known as gliflozins) are oral antidiabetic drugs that have emerged as a cornerstone to reach and keep glycemic control,1–4 particularly in older adults.5–7 SGLT2 is a cotransporter that induces glucose and sodium (Na+) reabsorption in the kidney; hence, SGLT2-inhibitors act interfering with this process, reducing glycemia.8,9
The first SGLT2 inhibitor to be approved by the Food and Drug Administration as antihyperglycemic agent for patients with type 2 diabetes (T2D) was canagliflozin in 2013, followed by dapagliflozin and empagliflozin in 2014, and ertugliflozin in 2017.10 The effects of SGLT2-inhibitors in T2D have been evaluated by a plethora of studies, leading to groundbreaking results in cardiovascular disease and chronic kidney disease (CKD); SGLT2-inhibitors have been extensively studied beyond diabetes and are now considered pleiotropic drugs (Figure 1)11–13 having shown favorable effects in nondiabetic patients with heart failure (HF) with reduced ejection fraction and preserved ejection fraction.
FRAILTY AND SGLT2-INHIBITORS
Frailty is a condition of vulnerability to stressors, which increases the risk of adverse health outcomes such as falls, disability, and hospitalization.
Our group has recently demonstrated the beneficial effects of the SGLT2 inhibitor empagliflozin on cognitive and physical impairment in frail older adults with diabetes and hypertension, highlighting how SGLT2-inhibition could attenuate mitochondrial oxidative stress in human endothelial cells.14 Consistent with our findings, the efficacy and safety of SGLT2-inhibitors has been confirmed in frail elderly subjects by several investigators,15–18 underscoring the large absolute benefits of treatment in these vulnerable patients, who are often needlessly denied therapy.19,20 Besides, a clinical trial known as EMPA-ELDERLY (Empagliflozin in Elderly T2DM Patients; https://www.clinicaltrials.gov; Unique identifier: NCT04531462), which includes 128 elderly Japanese patients with T2D receiving empagliflozin (10 mg) for 52 weeks, has been completed in August 2022 but has yet to publish their findings.21
CLINICAL RELEVANCE OF SGLT2-INHIBITORS IN PATIENTS WITH COMORBIDITIES
Cardiovascular and renal disorders, including atherosclerotic cardiovascular disease, HF, and CKD, represent leading causes of death in patients with diabetes, and are prevailing comorbidities in frail patients.22,23 Analyses conducted by the US Diabetes Collaborative Registry found that among individuals with T2D, 94% have at least one comorbidity of which the most common are cardiovascular (32%) and renal (20%) diseases.24 Likewise, over half of all patients living with HF have CKD, a decisive aspect, since the severity of renal dysfunction is associated with a graded increased risk of death.25
PHARMACOLOGY OF SGLT2-INHIBITORS: MAIN EFFECTS ON THE KIDNEY
SGLT2 and Glucose Reabsorption
The kidney plays indispensable roles in the regulation of glucose level in the blood (Figure 2). It serves as the second largest producer of glucose in the organism after the liver, accounting for 20% of gluconeogenesis. No less important is glucose filtration in the renal glomeruli and further reabsorption in the proximal tubule of the nephron. Glucose freely passes through the glomerular filter and without reabsorption glucose excretion is estimated to reach 180 g/day, which is roughly equal to its daily consumption. However, virtually all glucose is later reabsorbed, and a key role in this process is played by the 2 glucose transporters SGLT1 and SGLT2, which decrease glycemia by reducing renal glucose reabsorption and promoting glucosuria. Their mechanism of action primarily relies on the inhibition of SGLT2, a glucose transporter that allows increased glucose and Na+ excretion alongside a mild osmotic diuresis. Approximately 90% of the glucose filtered by the glomerulus is estimated to be reabsorbed via this mechanism.
SGLT2 is mainly localized at the apical membrane in the S1 and S2 segments of the proximal tubule while SGLT1 is in the S3 segment, both in humans and rodents. Remarkably, a higher expression of SGLT2 in females than in males has been described in rats, whereas no sex differences in this sense seem to be present in humans.26,27
SGLT2 plays a major role in glucose reabsorption. Analysis of glomerular ultrafiltrate composition at different levels of nephron revealed that 93% to 97% of glucose is reabsorbed by SGLT2 and only 3% by SGLT1.28 However, in absence of SGLT2, SGLT1 can reabsorb a significant amount of glucose. Sglt2−/− mice develop glucosuria but maintain normal plasma glucose concentrations.29 To achieve hypoglycemia in nondiabetic animals, the knockout of both transporters is required. Indeed, pharmacological inhibition of SGLT2 in euglycemic mice failed to induce hypoglycemia in wild-type but not in Sglt1−/− mice.30 This partial backup of SGLT2 function by SGLT1 plays a vital role in the safety of SGLT2-inhibitors.
Glucose-lowering effects of SGLT2-inhibitors can be partly attributed to the increased demand for glucose reabsorption observed in diabetes. As noted earlier, glucose passively flows through glomerular capillaries barrier, which means that hyperglycemia results in an increased amount of glucose filtered. To prevent glycosuria, SGLT2 expression in the kidneys is upregulated, thus enhancing glucose reabsorption.31 Intriguingly, in diabetic kidneys, mainly SGLT2 expression is increased; the preferential overexpression of SGLT2 over SGLT1 is essentially explained by the fact that SGLT2 uses 1 Na+ ion to transport 1 glucose molecule, whereas SGLT1 uses 2 Na+ ions, making SGLT2 energetic favorable.
SGLT2 upregulation allows to prevent glycosuria in the majority of diabetic patients. However, when SGLT2 is pharmacologically inhibited in diabetes, SGLT1 is no longer capable of coping with the augmented reabsorption demand; hence, moderate glucosuria develops together with lowering glucose levels, but without significant risks of hypoglycemia.31
SGLT2 Regulates GFR
SGLT2-inhibition exerts many effects on kidney function in diabetes and these effects are independent of lowering blood glucose level. First, SGLT2-inhibitors decrease Na+ reabsorption in proximal tubule. This action results in increased delivery of Na+ to the macula densa with subsequent normalization of the tubule-glomerular feedback,32,33 which is activated in diabetes due to augmented reabsorption of Na+, that is, falsely sensed as a decrease in circulating blood volume. Low levels of Na+ at the macula densa level trigger adenosine-dependent relaxation of afferent arterioles and constriction of efferent arterioles, resulting in increased blood pressure in glomerular capillaries, ensuring increased filtration.34 Inhibition of SGLT2 may counteract this pathological loop, also acting on the reactive oxygen species (ROS)–induced quenching of bioavailable nitric oxide.35–38 In fact, treatment with SGLT2-inhibitors acutely decreases glomerular filtration rate (GFR), but this effect is reversible. Moreover, during the progression of diabetes, the initial increase of GFR is superseded by a decrease of GFR, as a result of CKD development. However, treatment with SGLT2-inhibitors prevents GFR decline in the long term.39
Hyperfiltration is considered to be detrimental due to increased tensile stress applied to the capillary wall structures and heightened shear stress on the podocyte foot processes and body surface. These forces compromise the architecture of the glomerular filtration barrier, including but not limited to stretching the glomerular basement membrane, leading to a mismatch of the areas of glomerular basement membrane and podocyte foot processes, hypertrophy, and subsequent dysfunction of different types of cells in the glomeruli. Preclinical studies revealed that SGLT2-inhibitors are able to preserve normal architecture and function of the glomerular barrier in diabetes.40
Reduction of Na+ reabsorption by SGLT2-inhibitors is not limited to the decreased activity of the transporter per se. The inhibition of SGLT2 is coupled with a decreased activity of the NHE (Na+/H+ exchanger).41 This protein is expressed in various cell types, and is present on the apical membrane of renal epithelial cells, transporting Na+ inside and H+ outside the cell. The exact mechanism of NHE inhibition by gliflozins is not fully understood. NHE upregulation seems to be triggered by the enhancement of glycolysis and SGLT2-inhibitors diminish glucose influx. Nonetheless, microperfusion studies demonstrated the ability of SGLT2-inhibitors to inhibit NHE even in the absence of glucose.42 A possible explanation for glucose-independent NHE with SGLT2-inhibitors may be the physical coupling of NHE and SGLT2 via scaffolding proteins, including PDZK1IP1(PDZ domain containing 1 - interacting protein 1).43
SGLT2 and Renal Oxygen Consumption
Inhibition of SGLT2 exerts dual effects on tubule oxygen consumption. The vast majority of ATP produced by oxidative phosphorylation in the renal tubular epithelium is consumed by the Na+/K+-ATPase, localized in the basal membrane, which uses ATP energy to pump Na+ out of the cell to allow Na+ to enter the cell via the apical membrane; in this manner, Na+ reabsorption is achieved. Inhibition of SGLT2 significantly decreases the amount of Na+ entering the cell, decreasing the energetic demand. This effect becomes even more meaningful in diabetes when hyperperfusion augments the amount of Na+ in the ultrafiltrate.44
A marked accumulation of HIF1 (hypoxia-inducible factor 1) has been observed in the diabetic kidney, which was prevented by SGLT2-inhibition.45 A direct measurement of oxygen tension in the kidney corroborated these results.44 Interestingly, SGLT2-inhibitors were also capable of reducing hypoxic signaling in vitro,45 a finding that may be explained by a reduced oxygen consumption by glycolysis. Yet, gliflozins evoke an increased energy demand in the lower segments of the nephron. An increased amount of glucose due to the SGLT2-inhibition upstream of the nephron results in manifold augmented Na+ influx. Additionally, oxygen tension in peritubular capillaries is falling along the length of the nephron. Collectively, these processes eventually result in the activation of hypoxic signaling in distal parts of proximal tubule and the loop of Henle.46
Effects of SGLT2-Inhibition on Nutrient Sensing and Renal Mitochondria
Inhibition of SGLT2 diminishes glucose influx into the renal epithelium cells, thus mimicking the effects of caloric restriction, triggering akin protective signaling pathways. Several studies demonstrated that gliflozins can inhibit the mTOR (mammalian target of rapamycin).47,48 Because the inhibition of SGLT2 cannot directly modify the availability of amino acids, a direct regulator of mTOR,49 SGLT2-inhibitors are thought to inactivate mTOR utilizing upstream kinases, plausibly via AMPK (AMP-activated protein kinase), whose activation was demonstrated on SGLT2-inhibition.47,50 Inhibition of mTOR is known to activate autophagy and indeed SGLT2-inhibitors have been shown to stimulate the autophagosome flux in renal epithelium.47,51
Mitochondrial fragmentation accompanies renal injury of different causes and its prevention by pharmacological inhibition or genetic ablation of fission protein DRP1 (dynamin-related protein 1) is considered nephroprotective.52 Pharmacological inhibition of SGLT2 has been shown to preserve an elongated mitochondrial architecture, mostly due to the downregulation of mitochondrial DRP1 and upregulation of the fusion protein MFN1 (mitofusin1).47,48 Another positive effect of SGLT2-inhibitors on mitochondria relates to the upregulation of NRF2 (nuclear factor erythroid 2-related factor 2),50 a transcriptional factor that induces the expression of a variety of enzymes controlling the redox status of the cell, ultimately preventing oxidative stress.53 Indeed, gliflozins were shown to reduce the generation of ROS in several models of kidney disease.47,50 Inhibition of SGLT2 was found to ameliorate mitochondrial fatty acid metabolism and prevent lipid accumulation in the kidney.48 Finally, treating rodents with SGLT2-inhibitors diminished mitochondrial apoptosis by downregulating BAX (bcl-2-like protein 4) and upregulating BCL-2 (B-cell lymphoma 2) expression.45,47,51
SGLT2-INHIBITORS AND THE KIDNEY: CLINICAL EVIDENCE
Diabetic nephropathy, the leading cause of CKD worldwide, exacerbates the progression of atherosclerotic cardiovascular disease, systemic hypertension, and cardiac dysfunction.54 In addition to demonstrating decisive findings regarding cardiovascular outcomes, the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in T2D Patients–Removing Excess Glucose) was also the first major trial to demonstrate the valuable effects of an SGLT2 inhibitor on kidney function. The investigators reported a reduction of incident or worsening nephropathy, defined as the development of macroalbuminuria (urinary albumin-to-creatinine ratio >300 mg/g), a 2-fold increase in serum creatinine levels accompanied by an estimated GFR of ≤45 mL/(min·1.73m2), initiation of renal replacement therapy, or death resulting from renal disease. They found that patients in the experimental group were at significantly lower risk for incident or worsening nephropathy.39 A meta-analysis totaling 38 723 participants, revealed that SGLT2-inhibitors significantly reduce the risk of dialysis, transplantation, or death due to kidney disease.55 This benefit was evident in each of the 4 trials and across a wide range of baseline albuminuria and GFR. Follow-up studies by the investigators of other trials—DAPA-CKD (Dapagliflozin in Patients With CKD) and EMPA-KIDNEY (Empagliflozin in Patients With CKD), which was stopped early for efficacy—confirmed that patients with and without T2D benefit from the reno-protective effects of dapagliflozin and empagliflozin.56,57 It should be noted that these studies reported statistically similar differences in safety outcomes between groups, which had initially been a concern in several of the trials assessing cardiovascular outcomes that reported an increased incidence of lower-limb amputation, diabetic ketoacidosis, and genital mycotic infections in SGLT2-inhibitor treated groups.58,59 Although some patients with type 1 diabetes were included in some of these trials (eg, EMPA-KIDNEY), focused analyses of these drugs in this population remain limited.
Dapagliflozin and canagliflozin have been approved by the Food and Drug Administration for reducing the risk of end-stage kidney disease in patients with GFR ≥25 mL/(min·1.73 m2). Dapagliflozin is not limited to patients with diabetic nephropathy as it is also indicated for those with CKD secondary to ischemic nephropathy, focal segmental glomerulosclerosis, IgA nephropathy, and chronic interstitial nephritis. Although SGLT2-inhibitors have shown benefits in treating IgA nephropathy and focal segmental glomerulosclerosis, we want to underscore that these drugs should not be considered a replacement for immunosuppression in cases where it is medically necessary.
The effects of dapagliflozin on kidney outcomes were similar in both diabetic and nondiabetic patients. This finding could imply that the protective effects of SGLT2-inhibitors on the kidney are mediated by mechanisms beyond systemic or tubulointerstitial glycemic control. Indeed, renovascular hemodynamics are thought to play a central role in the reno-protective effects of SGLT2-inhibitors. The drug class acts by reducing glomerular pressure through the above-mentioned glomerulo-tubular feedback pathways. The macula densa/adenosine-mediated reduction in filtration pressure in patients treated with SGLT2-inhibitors accounts for an early drop in GFR, reaching a nadir within the first 2 weeks of treatment, an event consistent across all major trials.
SGLT2-inhibitors have been proven effective not only in controlling glycemia, showing insulin-independent glucose-lowering effects (with low hypoglycemia rates) but also in protecting heart and kidneys. Patients with diabetes have an increased risk of developing cardiovascular and renal disorders, and SGLT2-inhibitors offer significant protective effects. Several large-scale clinical outcome trials have demonstrated that these agents reduce the risk of hospitalizations due to HF and CKD progression. In addition to their established cardiovascular benefits, randomized data examined by Colin Baigent and collaborators in a recent meta-analysis, support the use of SGLT2-inhibitors for modifying risk of kidney disease progression and acute kidney injury, not only in patients with T2D at high cardiovascular risk but also in patients with CKD or HF, irrespective of diabetes status and kidney function.60 Although the underlying mechanisms behind these effects are not fully understood, the benefits of SGLT2-inhibitors are clear, making them a mainstay of modern treatment paradigms for patients with diabetes, HF, and—more recently—CKD.
Gliflozins Increase Hemoglobin and Hematocrit Levels
Mounting evidence suggests a link between SGLT2-inhibitors and increased hematocrit/hemoglobin/erythropoietin levels. Indeed, in the DAPA-HF trial, anemia was more frequently corrected by dapagliflozin than placebo; similarly, dapagliflozin and empagliflozin were associated with increased hematocrit in the DECLARE-TIMI 58 (Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events) and in the EMPA-REG OUTCOME, respectively.61
Whether this phenomenon reflects hemoconcentration due to diuretic effects, expansion of red blood cell mass due to increased EPO (erythropoietin), a modulation of the sympathetic hyperactivity, or other mechanisms remains unclear. Notwithstanding, it may be functionally linked to a reduced CKD progression, a lower risk of HF hospitalization, lower mortality, and potentially advantageous effects in frail populations.
EPO is synthesized in the renal cortex by EPO-producing fibroblasts. As mentioned above, patients with diabetes have increased glucose filtration, resulting in the upregulation of SGLT1 and SGLT2 to increase glucose resorption capacity. However, this process is energy-consuming: the resulting relative cortical hypoxia and increased oxidative stress from higher energy demands of these transporters in the renal cortex cause the cortical fibroblasts to transform into myofibroblasts, which no longer produce EPO. By blocking these transporters, SGLT2-inhibitors reduce energy demands: henceforth, the cortical injury is reduced, the transformation reverses, and EPO production capacity is restored. Additionally, SGLT2-inhibition increases Na+ delivery to the distal portions of the nephron, which evokes the upregulation of medullary Na+ transporters in the loop of Henle and terminal nephron eventually resulting in relative medullary hypoxia, which stimulates erythropoiesis.
SGLT2-INHIBITORS AND CARDIOVASCULAR DISEASE
Main Clinical Trials Assessing the Effects of SGLT2-Inhibitors on Cardiovascular Outcomes
One of the first large placebo-controlled trials assessing the effects of an SGLT2 inhibitor specifically on cardiovascular outcomes was the EMPA-REG OUTCOME trial. It paired 4687 patients with T2D at high risk for cardiovascular events taking 10 mg or 25 mg of empagliflozin once daily with 2333 in the placebo group. The primary end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, which was found to be significantly lower in the empagliflozin group. As adverse events, an increased rate of genital infection was observed in the empagliflozin group, but no increase in other side effects was reported.62
In 2017, with the CANVAS Program (Canagliflozin Cardiovascular Assessment Study), data from 2 trials, the CANVAS and the CANVAS-R (CANVAS-Renal),63 were integrated, totaling 10 142 participants with T2D and high cardiovascular risk, who were randomized to receive canagliflozin or placebo. The risk of the primary outcome, a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, was higher in the placebo than in the treated group. Adverse reactions observed were genitourinary infections, volume depletion, diuresis, and increased risk of amputation; the highest absolute risk of amputation was observed in patients with a previous history of peripheral artery disease.64 Over the following decade, these findings would have been validated by several other trials drawing from populations with distinct risk factors. The most prominent examples include the CREDENCE trial (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation),65 the DECLARE-TIMI 58,66 the VERTIS-CV trial (Design and Baseline Characteristics of the Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes),13 and the SCORED trial (Effect of Sotagliflozin on Cardiovascular and Renal Events in Participants with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk).67 A meta-analysis of some of these studies, except the SCORED, has shown that SGLT2-inhibitors significantly reduce the hazard for major adverse cardiovascular events (MACE; hazard ratio, 0.90 [95% CI, 0.85–0.95]). Furthermore, the presence of atherosclerotic cardiovascular disease did not modify the treatment outcome on MACE.68 There was a marked variability in MACE among each of the 4 gliflozins studied, which still needs further exploration. However, the predominant cardiovascular benefit across all these trials was noted to be a reduction in HF hospitalizations.
The cardiovascular safety profile of dapagliflozin was assessed by Wiviott and collaborators: 17 160 patients with T2D were randomly assigned to dapagliflozin or placebo. The primary safety outcome was a composite of MACE, for which dapagliflozin resulted noninferior to placebo (P<0.001). The primary efficacy outcomes were MACE plus a composite of cardiovascular death or hospitalization for HF; patients in dapagliflozin group had a lower rate of cardiovascular death or hospitalization for HF versus placebo group. Thus treatment with dapagliflozin resulted in a lower rate of hospitalization for HF.66
The main clinical trials substantiating the cardioprotective effects of SGLT2-inhibitors in HF are summarized in the Table. These trials also confirmed that the main adverse effects of gliflozins were infections of the genitourinary tract and volume depletion, without an increased risk of hypoglycemia.73–75
| Trial name | Regimen | No. of patients | Primary outcome(s) | Results |
|---|---|---|---|---|
| CANVAS63 | Canagliflozin 100 or 300 mg | 10 142 | Composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke | HR, 0.86 [95% CI, 0.75–0.97]; P<0.001 for noninferiority; P=0.02 for superiority |
| CREDENCE65,69 | Canagliflozin 100 mg | 4401 | Composite of end-stage kidney disease, a doubling of the serum creatinine level, or death from renal or cardiovascular causes | HR, 0.70 [95% CI, 0.59–0.82]; P=0.00001 |
| DAPA-CKD56 | Dapagliflozin 10 mg | 4304 | Composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes | HR, 0.61 [95% CI, 0.51–0.72]; P<0.001 |
| DAPA-HF70 | Dapagliflozin 10 mg | 4744 | Composite of cardiovascular death or episode of worsening HF | HR, 0.74 [95% CI, 0.65–0.85]; P<0.001 |
| DECLARE-TIMI 5866 | Dapagliflozin 10 mg | 17 160 | Composite of MACE and cardiovascular death or hospitalization for HF | HR, 0.83 [95% CI, 0.73–0.95]; P=0.005 |
| DECLARE TIMI 58 - AFIB71 | Empagliflozin 10 mg | 17 160 | Incidence of episodes of atrial fibrillation or atrial flutter | HR, 0.81 [95% CI, 0.68–0.95]; P=0.009 |
| EMPA-REG OUTCOME reported62 | Empagliflozin 10 or 25 mg | 7020 | Composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke | HR, 0.86 [95.02% CI, 0.74–0.99]; P=0.04 |
| EMPEROR-REDUCED72 | Empagliflozin 10 mg | 3730 | Composite of adjudicated cardiovascular death or hospitalization for HF | HR, 0.76 [95% CI, 0.67–0.87]; P<0.0001 |
| VERTIS-CV13 | Ertugliflozin 5 or 15 mg | 8246 | Composite of MACE | HR, 0.97 [95.6% CI, 0.85–1.11]; P<0.001 |
AFIB indicates atrial fibrillation; CREDENCE, Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation; DAPA-CKD, Dapagliflozin in Patients With CKD; DAPA-HF, Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; DECLARE-TIMI 58, Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events; EMPA-REG OUTCOME, Empagliflozin Cardiovascular Outcome Event Trial in T2D Patients–Removing Excess Glucose; EMPEROR-REDUCED, Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction; GFR, glomerular filtration rate; HF, heart failure; HR, hazard ratio; MACE, major adverse cardiovascular events; MI, myocardial infarction.; T2D, type 2 diabetes; and VERTIS-CV, Design and Baseline Characteristics of the Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes.
Potential Mechanisms Underlying the Cardioprotective Effects of SGLT2-Inhibitors
Numerous theories exist regarding the cardiovascular benefits of SGLT2-inhibitors, which are attributed to both direct and indirect mechanisms (Figure 2). The results of the DAPA-HF trial were among the first to imply that the advantages observed in HF cannot be attributed solely to the blood glucose-lowering effects. However, the most significant impact of this innovative drug class on heart and vascular function has yet to be established. Currently, the primary pathways thought to be involved are the reduction of blood pressure (also via increased diuresis and natriuresis), weight loss (more so in patients with T2D), decreased insulin resistance, improved cardiomyocyte Ca2+ handling, induction of autophagy and lysosomal degradation, reduced epicardial fat, suppression of adipokine and cytokine-mediated inflammation, promotion of autophagy/mitophagy, prevention of adverse cardiac remodeling, inhibition of NHE, reduction of ROS production and NLRP3 (NLR family pyrin domain-containing 3)-inflammasome activity, and improved cardiac mitochondrial bioenergetics—partly through an increase of circulating ketone bodies, which have been shown to play a positive adaptive role in H.9,41,76–79
We demonstrated that empagliflozin significantly reduces mitochondrial calcium overload through many of these pathways in human vascular endothelium; of note, ROS production triggered by high glucose in endothelial cells was ameliorated by empagliflozin, improving cell viability in response to oxidative stress.14,80 Additionally, the relationship between weight redistribution and local inflammation cannot be overlooked. In many patients with T2D, excessive epicardial adipose tissue surrounds the aorta, coronary arteries, and ventricles, leading to the release of proinflammatory mediators (including leptin, tumor necrosis factor-α, resistin, interleukin-1β, and interleukin-6) that can impair ventricular function and lead to myocardial fibrosis.81–83 A 2021 meta-analysis reported that SGLT2-inhibitors markedly decrease epicardial adipose tissue in patients with T2D (standardized mean difference, 0.82 [95% CI, 0.15–1.49]).84 Larger studies are warranted to confirm these aspects.
The cardiovascular benefit of SGLT2-inhibitors may also be tied to their effects on renovascular hemodynamics. By increasing Na+ delivery to the macula densa, SGLT2-inhibitors increase the vasoconstriction of the afferent renal arterioles, thereby reducing hyperfiltration-mediated inflammatory pathways and renal tubule oxygen requirements.82 Enhancing renal function or mitigating renal stress can indirectly slow the progression of HF through multiple canonical pathways, such as decreasing afferent sympathetic nervous system activation, alleviating inflammation, and further minimizing ROS production.85
CONCLUSIONS
Several major clinical trials have spotlighted the cardiac and renal protective effects of gliflozins. Nowadays, SGLT2-inhibitors are well-known not only for their efficacy in glycemic control but are also proven to decrease atherosclerotic events, hospitalizations for HF, cardiovascular mortality, and the advancement of CKD. Given the correlation between diabetes, CKD, and cardiovascular disease, including HF with reduced ejection fraction and preserved ejection fraction, these agents already play a crucial role in modern treatment paradigms. In conclusion, we envision that SGLT2-inhibitors may be considered novel anti-frailty drugs.
Footnote
Nonstandard Abbreviations and Acronyms
- AMPK
- AMP-activated protein kinase
- BAX
- bcl-2-like protein 4
- BCL-2
- B-cell lymphoma 2
- CANVAS-R
- Canagliflozin Cardiovascular Assessment Study-Renal
- CKD
- chronic kidney disease
- CREDENCE
- Canagliflozin and Renal Events in Diabetes with Establish Nephropathy Clinical Evaluation
- DAPA CKD
- Dapagliflozin in Patients with CKD
- DECALRE TIMI 58
- Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events
- EMPA-KIDNEY
- Empagliflozin in Patients With CKD
- EMPA-REG
- Empagliflozin Cardiovascular
- OUTCOME
- Outcome Event Trial in T2D Patients–Removing Excess Glucose
- EPO
- erythropoietin
- GFR
- glomerular filtration rate
- HF
- heart failure
- HIF1
- hypoxia-inducible factor 1
- MFN1
- mitofusin1
- mTOR
- mammalian target of rapamycin
- NHE
- Na+/H+ exchanger
- NLRP3
- NLR family pyrin domain-containing 3
- NRF2
- nuclear factor erythroid 2-related factor 2
- ROS
- reactive oxygen species
- SCORED
- Effect of Sotagliflozin on Cardiovascular and Renal Events in Participants With Type 2 Diabetes and Moderate Renal Impairment Who are at Cardiovascular Risk
- SGLT2
- sodium-glucose cotransporter 2
- T2D
- type 2 diabetes
- VERTIS-CV
- Design and Baseline Characteristics of the Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes
REFERENCES
1.
ElSayed NA, Aleppo G, Aroda VR, Bannuru RR, Brown FM, Bruemmer D, Collins BS, Hilliard ME, Isaacs D, Johnson EL, et al; on behalf of the American Diabetes Association. Pharmacologic approaches to glycemic treatment: standards of care in diabetes-2023. Diabetes Care. 2023;46:S140–S157. doi: 10.2337/dc23-S009
2.
Yuan S, Song C, He J, Zhang R, Bian X, Song W, Dou K. Trends in cardiovascular risk factors control among US adults by glycemic statuses, 2007-2018. Eur J Prev Cardiol. 2023; in press. doi: 10.1093/eurjpc/zwad080
3.
Salmen T, Serbanoiu LI, Bica IC, Serafinceanu C, Muzurović E, Janez A, Busnatu S, Banach M, Rizvi AA, Rizzo M, et al. A critical view over the newest antidiabetic molecules in light of efficacy-a systematic review and meta-analysis. Int J Mol Sci. 2023;24:9760. doi: 10.3390/ijms24119760
4.
Samson SL, Vellanki P, Blonde L, Christofides EA, Galindo RJ, Hirsch IB, Isaacs SD, Izuora KE, Low Wang CC, Twining CL, et al. American Association of Clinical Endocrinology Consensus statement: comprehensive type 2 diabetes management algorithm - 2023 update. Endocr Pract. 2023;29:305–340. doi: 10.1016/j.eprac.2023.02.001
5.
ElSayed NA, Aleppo G, Aroda VR, Bannuru RR, Brown FM, Bruemmer D, Collins BS, Hilliard ME, Isaacs D, Johnson EL, et al; on behalf of the American Diabetes Association. Older adults: standards of care in diabetes-2023. Diabetes Care. 2023;46:S216–S229. doi: 10.2337/dc23-S013
6.
Lunati ME, Cimino V, Gandolfi A, Trevisan M, Montefusco L, Pastore I, Pace C, Betella N, Favacchio G, Bulgheroni M, et al. SGLT2-inhibitors are effective and safe in the elderly: the SOLD study. Pharmacol Res. 2022;183:106396. doi: 10.1016/j.phrs.2022.106396
7.
Hias J, Hellemans L, Walgraeve K, Tournoy J, Van der Linden L. SGLT2 inhibitors in older adults with heart failure with preserved ejection fraction. Drugs Aging. 2022;39:185–190. doi: 10.1007/s40266-022-00920-7
8.
Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi J, Verma S, Tsutsui H, Brueckmann M, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. NEJM. 2020;383:1413–1424. doi: 10.1056/NEJMoa2022190
9.
Varzideh F, Kansakar U, Santulli G. SGLT2 inhibitors in cardiovascular medicine. Eur Heart J Cardiovasc Pharmacother. 2021;7:e67–e68. doi: 10.1093/ehjcvp/pvab039
10.
Teo YN, Ting AZH, Teo YH, Chong EY, Tan JTA, Syn NL, Chia AZQ, Ong HT, Cheong AJY, Li TY, et al. Effects of sodium/glucose cotransporter 2 (SGLT2) inhibitors and combined SGLT1/2 inhibitors on cardiovascular, metabolic, renal, and safety outcomes in patients with diabetes: a network meta-analysis of 111 randomized controlled trials. Am J Cardiovasc Drugs. 2022;22:299–323. doi: 10.1007/s40256-022-00528-7
11.
Solomon SD, McMurray JJV, Claggett B, de Boer RA, DeMets D, Hernandez AF, Inzucchi SE, Kosiborod MN, Lam CSP, Martinez F, et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. NEJM. 2022;387:1089–1098. doi: 10.1056/NEJMoa2206286
12.
Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Böhm M, Brunner-La Rocca HP, Choi DJ, Chopra V, Chuquiure-Valenzuela E, et al. Empagliflozin in heart failure with a preserved ejection fraction. NEJM. 2021;385:1451–1461. doi: 10.1056/NEJMoa2107038
13.
Cannon CP, Pratley R, Dagogo-Jack S, Mancuso J, Huyck S, Masiukiewicz U, Charbonnel B, Frederich R, Gallo S, Cosentino F, et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. NEJM. 2020;383:1425–1435. doi: 10.1056/NEJMoa2004967
14.
Mone P, Varzideh F, Jankauskas SS, Pansini A, Lombardi A, Frullone S, Santulli G. SGLT2 inhibition via empagliflozin improves endothelial function and reduces mitochondrial oxidative stress: insights from frail hypertensive and diabetic patients. Hypertension. 2022;79:1633–1643. doi: 10.1161/HYPERTENSIONAHA.122.19586
15.
Abdelhafiz AH, Sinclair AJ. Cardio-renal protection in older people with diabetes with frailty and medical comorbidities - A focus on the new hypoglycaemic therapy. J Diabetes Complications. 2020;34:107639. doi: 10.1016/j.jdiacomp.2020.107639
16.
Sasaki T. Sarcopenia, frailty circle and treatment with sodium-glucose cotransporter 2 inhibitors. J Diabetes Investig. 2019;10:193–195. doi: 10.1111/jdi.12966
17.
Sinclair AJ, Pennells D, Abdelhafiz AH. Hypoglycaemic therapy in frail older people with type 2 diabetes mellitus-a choice determined by metabolic phenotype. Aging Clin Exp Res. 2022;34:1949–1967. doi: 10.1007/s40520-022-02142-8
18.
Villarreal D, Ramírez H, Sierra V, Amarís JS, Lopez-Salazar AM, González-Robledo G. Sodium-glucose cotransporter 2 inhibitors in frail patients with heart failure: clinical experience of a heart failure unit. Drugs Aging. 2023;40:293–299. doi: 10.1007/s40266-022-01004-2
19.
Butt JH, Dewan P, Merkely B, Belohlávek J, Drożdż J, Kitakaze M, Inzucchi SE, Kosiborod MN, Martinez FA, Tereshchenko S, et al. Efficacy and safety of dapagliflozin according to frailty in heart failure with reduced ejection fraction: a post hoc analysis of the DAPA-HF trial. Ann Intern Med. 2022;175:820–830. doi: 10.7326/M21-4776
20.
Pollack R, Cahn A. SGLT2 inhibitors and safety in older patients. Heart Fail Clin. 2022;18:635–643. doi: 10.1016/j.hfc.2022.03.002
21.
Yabe D, Shiki K, Suzaki K, Meinicke T, Kotobuki Y, Nishida K, Clark D, Yasui A, Seino Y. Rationale and design of the EMPA-ELDERLY trial: a randomised, double-blind, placebo-controlled, 52-week clinical trial of the efficacy and safety of the sodium-glucose cotransporter-2 inhibitor empagliflozin in elderly Japanese patients with type 2 diabetes. BMJ Open. 2021;11:e045844. doi: 10.1136/bmjopen-2020-045844
22.
Raghavan S, Vassy JL, Ho Y-L, Song RJ, Gagnon DR, Cho K, Wilson PWF, Phillips LS. Diabetes mellitus-related all-cause and cardiovascular mortality in a national cohort of adults. J Am Heart Assoc. 2019;8:e011295. doi: 10.1161/JAHA.118.011295
23.
Jankauskas SS, Kansakar U, Varzideh F, Wilson S, Mone P, Lombardi A, Gambardella J, Santulli G. Heart failure in diabetes. Metab Clin Exp. 2021;125:154910. doi: 10.1016/j.metabol.2021.154910
24.
Arnold SV, Kosiborod M, Wang J, Fenici P, Gannedahl G, LoCasale RJ. Burden of cardio-renal-metabolic conditions in adults with type 2 diabetes within the Diabetes Collaborative Registry. Diabetes Obes Metab. 2018;20:2000–2003. doi: 10.1111/dom.13303
25.
Damman K, Valente MAE, Voors AA, O’Connor CM, van Veldhuisen DJ, Hillege HL. Renal impairment, worsening renal function, and outcome in patients with heart failure: an updated meta-analysis. Eur Heart J. 2014;35:455–469. doi: 10.1093/eurheartj/eht386
26.
Vrhovac I, Balen Eror D, Klessen D, Burger C, Breljak D, Kraus O, Radović N, Jadrijević S, Aleksic I, Walles T, et al. Localizations of Na(+)-D-glucose cotransporters SGLT1 and SGLT2 in human kidney and of SGLT1 in human small intestine, liver, lung, and heart. Pflugers Arch. 2015;467:1881–1898. doi: 10.1007/s00424-014-1619-7
27.
Sabolic I, Vrhovac I, Eror DB, Gerasimova M, Rose M, Breljak D, Ljubojevic M, Brzica H, Sebastiani A, Thal SC, et al. Expression of Na+-D-glucose cotransporter SGLT2 in rodents is kidney-specific and exhibits sex and species differences. Am J Physiol Cell Physiol. 2012;302:C1174–C1188. doi: 10.1152/ajpcell.00450.2011
28.
Gorboulev V, Schürmann A, Vallon V, Kipp H, Jaschke A, Klessen D, Friedrich A, Scherneck S, Rieg T, Cunard R, et al. Na(+)-D-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion. Diabetes. 2012;61:187–196. doi: 10.2337/db11-1029
29.
Vallon V, Platt KA, Cunard R, Schroth J, Whaley J, Thomson SC, Koepsell H, Rieg T. SGLT2 mediates glucose reabsorption in the early proximal tubule. J Am Soc Nephrol. 2011;22:104–112. doi: 10.1681/ASN.2010030246
30.
Rieg T, Masuda T, Gerasimova M, Mayoux E, Platt K, Powell DR, Thomson SC, Koepsell H, Vallon V. Increase in SGLT1-mediated transport explains renal glucose reabsorption during genetic and pharmacological SGLT2 inhibition in euglycemia. Am J Physiol Renal Physiol. 2014;306:F188–F193. doi: 10.1152/ajprenal.00518.2013
31.
Umino H, Hasegawa K, Minakuchi H, Muraoka H, Kawaguchi T, Kanda T, Tokuyama H, Wakino S, Itoh H. High basolateral glucose increases sodium-glucose cotransporter 2 and reduces Sirtuin-1 in renal tubules through glucose transporter-2 detection. Sci Rep. 2018;8:6791. doi: 10.1038/s41598-018-25054-y
32.
Vallon V, Richter K, Blantz RC, Thomson S, Osswald H. Glomerular hyperfiltration in experimental diabetes mellitus: potential role of tubular reabsorption. J Am Soc Nephrol. 1999;10:2569–2576. doi: 10.1681/ASN.V10122569
33.
Thomson SC, Rieg T, Miracle C, Mansoury H, Whaley J, Vallon V, Singh P. Acute and chronic effects of SGLT2 blockade on glomerular and tubular function in the early diabetic rat. Am J Physiol Regul Integr Comp Physiol. 2012;302:R75–R83. doi: 10.1152/ajpregu.00357.2011
34.
Kidokoro K, Cherney DZI, Bozovic A, Nagasu H, Satoh M, Kanda E, Sasaki T, Kashihara N. Evaluation of glomerular hemodynamic function by empagliflozin in diabetic mice using in vivo imaging. Circulation. 2019;140:303–315. doi: 10.1161/CIRCULATIONAHA.118.037418
35.
Song P, Huang W, Onishi A, Patel R, Kim YC, van Ginkel C, Fu Y, Freeman B, Koepsell H, Thomson S, et al. Knockout of Na(+)-glucose cotransporter SGLT1 mitigates diabetes-induced upregulation of nitric oxide synthase NOS1 in the macula densa and glomerular hyperfiltration. Am J Physiol Renal Physiol. 2019;317:F207–F217. doi: 10.1152/ajprenal.00120.2019
36.
Vallon V, Gerasimova M, Rose MA, Masuda T, Satriano J, Mayoux E, Koepsell H, Thomson SC, Rieg T. SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice. Am J Physiol Renal Physiol. 2014;306:F194–F204. doi: 10.1152/ajprenal.00520.2013
37.
Paolocci N, Biondi R, Bettini M, Lee CI, Berlowitz CO, Rossi R, Xia Y, Ambrosio G, L’Abbate A, Kass DA, et al. Oxygen radical-mediated reduction in basal and agonist-evoked NO release in isolated rat heart. J Mol Cell Cardiol. 2001;33:671–679. doi: 10.1006/jmcc.2000.1334
38.
Fujita H, Otomo H, Takahashi Y, Yamada Y. Dual inhibition of SGLT2 and DPP-4 promotes natriuresis and improves glomerular hemodynamic abnormalities in KK/Ta-Ins2(Akita) mice with progressive diabetic kidney disease. Biochem Biophys Res Commun. 2022;635:84–91. doi: 10.1016/j.bbrc.2022.10.034
39.
Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, Johansen OE, Woerle HJ, Broedl UC, Zinman B; EMPA-REG OUTCOME Investigators. Empagliflozin and progression of kidney disease in type 2 diabetes. NEJM. 2016;375:323–334. doi: 10.1056/NEJMoa1515920
40.
Locatelli M, Zoja C, Conti S, Cerullo D, Corna D, Rottoli D, Zanchi C, Tomasoni S, Remuzzi G, Benigni A. Empagliflozin protects glomerular endothelial cell architecture in experimental diabetes through the VEGF-A/caveolin-1/PV-1 signaling pathway. J Pathol. 2022;256:468–479. doi: 10.1002/path.5862
41.
Onishi A, Fu Y, Patel R, Darshi M, Crespo-Masip M, Huang W, Song P, Freeman B, Kim YC, Soleimani M, et al. A role for tubular Na(+)/H(+) exchanger NHE3 in the natriuretic effect of the SGLT2 inhibitor empagliflozin. Am J Physiol Renal Physiol. 2020;319:F712–F728. doi: 10.1152/ajprenal.00264.2020
42.
Pessoa TD, Campos LCG, Carraro-Lacroix L, Girardi ACC, Malnic G. Functional role of glucose metabolism, osmotic stress, and sodium-glucose cotransporter isoform-mediated transport on Na+/H+ exchanger isoform 3 activity in the renal proximal tubule. J Am Soc Nephrol. 2014;25:2028–2039. doi: 10.1681/ASN.2013060588
43.
Coady MJ, El Tarazi A, Santer R, Bissonnette P, Sasseville LJ, Calado J, Lussier Y, Dumayne C, Bichet DG, Lapointe J-Y. MAP17 is a necessary activator of renal Na+/glucose cotransporter SGLT2. J Am Soc Nephrol. 2017;28:85–93. doi: 10.1681/ASN.2015111282
44.
O’Neill J, Fasching A, Pihl L, Patinha D, Franzén S, Palm F. Acute SGLT inhibition normalizes O2 tension in the renal cortex but causes hypoxia in the renal medulla in anaesthetized control and diabetic rats. Am J Physiol Renal Physiol. 2015;309:F227–F234. doi: 10.1152/ajprenal.00689.2014
45.
Huang X, Guo X, Yan G, Zhang Y, Yao Y, Qiao Y, Wang D, Chen G, Zhang W, Tang C, et al. Dapagliflozin attenuates contrast-induced acute kidney injury by regulating the HIF-1alpha/HE4/NF-kappaB pathway. J Cardiovasc Pharmacol. 2022;79:904–913. doi: 10.1097/FJC.0000000000001268
46.
Layton AT, Vallon V. SGLT2 inhibition in a kidney with reduced nephron number: modeling and analysis of solute transport and metabolism. Am J Physiol Renal Physiol. 2018;314:F969–F984. doi: 10.1152/ajprenal.00551.2017
47.
Lee YH, Kim SH, Kang JM, Heo JH, Kim D-J, Park SH, Sung MJ, Kim J, Oh J, Yang DH, et al. Empagliflozin attenuates diabetic tubulopathy by improving mitochondrial fragmentation and autophagy. Am J Physiol Renal Physiol. 2019;317:F767–F780. doi: 10.1152/ajprenal.00565.2018
48.
Ke Q, Shi C, Lv Y, Wang L, Luo J, Jiang L, Yang J, Zhou Y. SGLT2 inhibitor counteracts NLRP3 inflammasome via tubular metabolite itaconate in fibrosis kidney. FASEB J. 2022;36:e22078. doi: 10.1096/fj.202100909RR
49.
Al-Bari MA, Xu P. Molecular regulation of autophagy machinery by mTOR-dependent and -independent pathways. Ann N Y Acad Sci. 2020;1467:3–20. doi: 10.1111/nyas.14305
50.
Chi P-J, Lee C-J, Hsieh Y-J, Lu C-W, Hsu B-G. Dapagliflozin ameliorates lipopolysaccharide related acute kidney injury in mice with streptozotocin-induced diabetes mellitus. Int J Med Sci. 2022;19:729–739. doi: 10.7150/ijms.69031
51.
Ala M, Khoshdel MRF, Dehpour AR. Empagliflozin enhances autophagy, mitochondrial biogenesis, and antioxidant defense and ameliorates renal ischemia/reperfusion in nondiabetic rats. Oxid Med Cell Longev. 2022;2022:1197061. doi: 10.1155/2022/1197061
52.
Perry HM, Huang L, Wilson RJ, Bajwa A, Sesaki H, Yan Z, Rosin DL, Kashatus DF, Okusa MD. Dynamin-related protein 1 deficiency promotes recovery from AKI. J Am Soc Nephrol. 2018;29:194–206. doi: 10.1681/ASN.2017060659
53.
Chen QM, Maltagliati AJ. Nrf2 at the heart of oxidative stress and cardiac protection. Physiol Genomics. 2018;50:77–97. doi: 10.1152/physiolgenomics.00041.2017
54.
Yamaguchi S, Hamano T, Oka T, Doi Y, Kajimoto S, Sakaguchi Y, Suzuki A, Isaka Y. Low-grade proteinuria and atherosclerotic cardiovascular disease: a transition study of patients with diabetic kidney disease. PLoS One. 2022;17:e0264568. doi: 10.1371/journal.pone.0264568
55.
Neuen BL, Young T, Heerspink HJL, Neal B, Perkovic V, Billot L, Mahaffey KW, Charytan DM, Wheeler DC, Arnott C, et al. SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2019;7:845–854. doi: 10.1016/S2213-8587(19)30256-6
56.
Heerspink HJL, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, Mann JFE, McMurray JJV, Lindberg M, Rossing P, et al. Dapagliflozin in patients with chronic kidney disease. NEJM. 2020;383:1436–1446. doi: 10.1056/NEJMoa2024816
57.
Herrington WG, Staplin N, Wanner C, Green JB, Hauske SJ, Emberson JR, Preiss D, Judge P, Mayne KJ, Ng SYA, et al. Empagliflozin in patients with chronic kidney disease. NEJM. 2023;388:117–127. doi: 10.1056/NEJMoa2204233
58.
Matthews DR, Li Q, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Desai M, Hiatt WR, Nehler M, Fabbrini E, et al. Effects of canagliflozin on amputation risk in type 2 diabetes: the CANVAS Program. Diabetologia. 2019;62:926–938. doi: 10.1007/s00125-019-4839-8
59.
Yau K, Dharia A, Alrowiyti I, Cherney DZI. Prescribing SGLT2 inhibitors in patients with CKD: expanding indications and practical considerations. Kidney Int Rep. 2022;7:1463–1476. doi: 10.1016/j.ekir.2022.04.094
60.
Nuffield Department of Population Health Renal Studies. Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials. Lancet. 2022;400:1788–1801.
61.
Kolkailah AA, Wiviott SD, Raz I, Murphy SA, Mosenzon O, Bhatt DL, Leiter LA, Wilding JPH, Gause-Nilsson I, Sabatine MS, et al. Effect of dapagliflozin on hematocrit in patients with type 2 diabetes at high cardiovascular risk: observations from DECLARE-TIMI 58. Diabetes Care. 2022;45:e27–e29. doi: 10.2337/dc21-1668
62.
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. NEJM. 2015;373:2117–2128. doi: 10.1056/NEJMoa1504720
63.
Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. NEJM. 2017;377:644–657. doi: 10.1056/NEJMoa1611925
64.
Mahaffey KW, Neal B, Perkovic V, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Fabbrini E, Sun T, Li Q, et al; CANVAS Program Collaborative Group. Canagliflozin for primary and secondary prevention of cardiovascular events: results from the CANVAS program (Canagliflozin Cardiovascular Assessment Study). Circulation. 2018;137:323–334. doi: 10.1161/CIRCULATIONAHA.117.032038
65.
Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. NEJM. 2019;380:2295–2306. doi: 10.1056/NEJMoa1811744
66.
Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Zelniker TA, Kuder JF, Murphy SA, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. NEJM. 2019;380:347–357. doi: 10.1056/NEJMoa1812389
67.
Bhatt DL, Szarek M, Pitt B, Cannon CP, Leiter LA, McGuire DK, Lewis JB, Riddle MC, Inzucchi SE, Kosiborod MN, et al. Sotagliflozin in patients with diabetes and chronic kidney disease. NEJM. 2020;384:129–139. doi: 10.1056/NEJMoa2030186
68.
McGuire DK, Shih WJ, Cosentino F, Charbonnel B, Cherney DZI, Dagogo-Jack S, Pratley R, Greenberg M, Wang S, Huyck S, et al. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis. JAMA Cardiol. 2021;6:148–158. doi: 10.1001/jamacardio.2020.4511
69.
Sarraju A, Li JW, Cannon CP, Chang TI, Agarwal R, Bakris G, Charytan DM, de Zeeuw D, Greene T, Heerspink HJL, et al. Effects of canagliflozin on cardiovascular, renal, and safety outcomes in participants with type 2 diabetes and chronic kidney disease according to history of heart failure: results from the CREDENCE trial. Am Heart J. 2021;233:141–148. doi: 10.1016/j.ahj.2020.12.008
70.
McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Bělohlávek J, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. NEJM. 2019;381:1995–2008. doi: 10.1056/NEJMoa1911303
71.
Zelniker TA, Bonaca MP, Furtado RHM, Mosenzon O, Kuder JF, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, et al. Effect of dapagliflozin on atrial fibrillation in patients with type 2 diabetes mellitus: insights from the DECLARE-TIMI 58 trial. Circulation. 2020;141:1227–1234. doi: 10.1161/CIRCULATIONAHA.119.044183
72.
Packer M, Anker SD, Butler J, Filippatos G, Ferreira JP, Pocock SJ, Carson P, Anand I, Doehner W, Haass M, et al. Effect of empagliflozin on the clinical stability of patients with heart failure and a reduced ejection fraction: the EMPEROR-Reduced trial. Circulation. 2021;143:326–336. doi: 10.1161/CIRCULATIONAHA.120.051783
73.
Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Furtado RHM, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019;393:31–39. doi: 10.1016/S0140-6736(18)32590-X
74.
Requena-Ibanez JA, Santos-Gallego CG, Rodriguez-Cordero A, Vargas-Delgado AP, Mancini D, Sartori S, Atallah-Lajam F, Giannarelli C, Macaluso F, Lala A, et al. Mechanistic insights of empagliflozin in nondiabetic patients with HFrEF: from the EMPA-TROPISM study. JACC Heart Fail. 2021;9:578–589. doi: 10.1016/j.jchf.2021.04.014
75.
Anker SD, Butler J, Filippatos G, Khan MS, Marx N, Lam CSP, Schnaidt S, Ofstad AP, Brueckmann M, Jamal W, et al. Effect of empagliflozin on cardiovascular and renal outcomes in patients with heart failure by baseline diabetes status: results from the EMPEROR-Reduced trial. Circulation. 2021;143:337–349. doi: 10.1161/CIRCULATIONAHA.120.051824
76.
Kalyani RR. Glucose-lowering drugs to reduce cardiovascular risk in type 2 diabetes. NEJM. 2021;384:1248–1260. doi: 10.1056/NEJMcp2000280
77.
Mazidi M, Rezaie P, Gao H-K, Kengne AP. Effect of sodium-glucose cotransport-2 inhibitors on blood pressure in people with type 2 diabetes mellitus: a systematic review and meta-analysis of 43 randomized control trials with 22 528 patients. J Am Heart Assoc. 2017;6:e004007. doi: 10.1161/JAHA.116.004007
78.
Al Jobori H, Daniele G, Adams J, Cersosimo E, Triplitt C, DeFronzo RA, Abdul-Ghani M. Determinants of the increase in ketone concentration during SGLT2 inhibition in NGT, IFG and T2DM patients. Diabetes Obes Metab. 2017;19:809–813. doi: 10.1111/dom.12881
79.
Ferrannini E, Baldi S, Frascerra S, Astiarraga B, Heise T, Bizzotto R, Mari A, Pieber TR, Muscelli E. Shift to fatty substrate utilization in response to sodium–glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes. 2016;65:1190–1195. doi: 10.2337/db15-1356
80.
Mone P, Lombardi A, Kansakar U, Varzideh F, Jankauskas SS, Pansini A, Marzocco S, De Gennaro S, Famiglietti M, Macina G, et al. Empagliflozin improves the MicroRNA signature of endothelial dysfunction in patients with heart failure with preserved ejection fraction and diabetes. J Pharmacol Exp Ther. 2023;384:116–122. doi: 10.1124/jpet.121.001251
81.
Christensen RH, Hansen CS, von Scholten BJ, Jensen MT, Pedersen BK, Schnohr P, Vilsbøll T, Rossing P, Jørgensen PG. Epicardial and pericardial adipose tissues are associated with reduced diastolic and systolic function in type 2 diabetes. Diabetes Obes Metab. 2019;21:2006–2011. doi: 10.1111/dom.13758
82.
Thomson SC, Vallon V. Renal effects of sodium-glucose co-transporter inhibitors. Am J Cardiol. 2019;124(Suppl 1):S28–S35. doi: 10.1016/j.amjcard.2019.10.027
83.
Gruzdeva OV, Akbasheva OE, Dyleva YA, Antonova LV, Matveeva VG, Uchasova EG, Fanaskova EV, Karetnikova VN, Ivanov SV, Barbarash OL. Adipokine and cytokine profiles of epicardial and subcutaneous adipose tissue in patients with coronary heart disease. Bull Exp Biol Med. 2017;163:608–611. doi: 10.1007/s10517-017-3860-5
84.
Masson W, Lavalle-Cobo A, Nogueira JP. Effect of SGLT2-Inhibitors on epicardial adipose tissue: a meta-analysis. Cells. 2021;10:2150. doi: 10.3390/cells10082150
85.
Lopaschuk GD, Verma S. Mechanisms of cardiovascular benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors: a state-of-the-art review. JACC Basic Transl Sci. 2020;5:632–644. doi: 10.1016/j.jacbts.2020.02.004
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Published online: 5 July 2023
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The Santulli’s Lab is currently supported in part by the National Institutes of Health (NIH): National Heart, Lung, and Blood Institute (NHLBI: R01-HL164772, R01-HL159062, R01-HL146691, T32-HL144456), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK: R01-DK123259, R01-DK033823), National Center for Advancing Translational Sciences (NCATS: UL1-TR002556-06, UM1-TR004400) to G.S., by the Diabetes Action Research and Education Foundation (to G.S.), and by the Monique Weill-Caulier and Irma T. Hirschl Trusts (to G.S.). F.V. is supported in part by a postdoctoral fellowship of the American Heart Association (AHA-22POST915561); S.S.J. is supported in part by a postdoctoral fellowship of the American Heart Association (AHA-21POST836407); U.K. is supported in part by a postdoctoral fellowship of the American Heart Association (AHA-23POST1026190).
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- Amyloid-β and heart failure in Alzheimer’s disease: the new vistas, Frontiers in Medicine, 12, (2025).https://doi.org/10.3389/fmed.2025.1494101
- Mitochondria and the Repurposing of Diabetes Drugs for Off-Label Health Benefits, International Journal of Molecular Sciences, 26, 1, (364), (2025).https://doi.org/10.3390/ijms26010364
- A STUDY ON THE PREVALENCE OF ADVERSE EFFECTS ASSOCIATED WITH SODIUM-GLUCOSE COTRANSPORTER 2 INHIBITOR DAPAGLIFLOZIN IN A TERTIARY CARE CENTRE, Asian Journal of Pharmaceutical and Clinical Research, (147-150), (2024).https://doi.org/10.22159/ajpcr.2024v17i12.52456
- Exogenous Ketones in Cardiovascular Disease and Diabetes: From Bench to Bedside, Journal of Clinical Medicine, 13, 23, (7391), (2024).https://doi.org/10.3390/jcm13237391
- GLP-1 receptor agonists and SGLT2 inhibitors: new anti-aging tools?, Future Cardiology, 21, 1, (5-8), (2024).https://doi.org/10.1080/14796678.2024.2433381
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