Drugs that selectively target the SGLT2 transporter.

Glucose is freely filtered at the glomerulus and is reabsorbed via active transport mechanisms in the proximal convoluted tubule.

In type two diabetes, the hyperabsorption of glucose and sodium in the proximal renal tubules by SGLT2 causes afferent arteriolar vasodilation, which causes glomerular hyperfiltration, leading to glomerular information, fibrosis, and ultimately diabetic kidney disease.

The reduction of reabsorption of sodium increases the sodium concentration at the macula densa, the specialized cells in the distal renal tubules adjacent to the glomeruli.

SGLT-2 at the cellular level reduces local inflammation and inhibits mediators of maladaptive repair and fibrosis, initiates known protective pathways, reduces oxidative stress and activation of mitochondrial autophagy and biogenesis.

There are two sodium-glucose co-transporters responsible for glucose reabsorption: SGLT1 and SGLT2.

The reabsorption of glucose from the glomerular filtrate is an active process linked to sodium and requires a carrier proteins, referred to as a sodium glucose called transporter (SGLT).

Gliflozin class of agents.

SGLT2 is a high capacity, low-affinity transporter located in the initial portion of the proximal tubule and is responsible for the 90% of glucose reabsorption, whereas SGLT 1 is a low capacity, high affinity transporter at the end of the proximal tubule responsible for approximately 10% of glucose reabsorption.

Patients with diabetes reabsorb more glucose at the proximal tubule compared with individuals without diabetes because of increased qualities quantities of the SGLT 2 receptors.

The daily glomerular filtrate of a healthy person contains about 1 mol of glucose (about 180 g).

If this amount of glucose was excreted into the urine it would constitute a loss of energy equivalent to about 30% of the body’s caloric expenditure: nearly all the filtered glucose is reclaimed by the sodium-glucose cotransporters (SGLT) 1 and 2 in the proximal tubule which has the capacity to reabsorb about 2.5 mol glucose per day.

SGLT 1, reabsorbs 2 sodium per glucose, uses twice as much energy per glucose as SGLT 2, which reabsorbs 1 sodium per glucose.

SGLT 1 is located primarily in the small intestine and has little effect on the renal tubule.

Lowers blood glucose levels in patients with type two diabetes by enhancing urinary glucose excretion through the inhibition of SGLT2 in the proximal convoluted tubule where glucose is reabsorbed.

Essentially all glucose that is filtered by the kidney is reabsorbed in the proximal convoluted tubule.

SGLT2 inhibitions does not interact with insulin, and the risk of hypoglycemia is low when used as monotherapy.

SGLT2 is located in the first segment of the proximal tubule and is responsible for the re-uptake of glucose.

SGLT2 use associate with naturally with natriuresis and diuresis.

Inhibition of the SGLT2 locks glucose reabsorption, leading to increased urinary excretion and reduce blood glucose levels.

In diabetes the increased filtered load of glucose in the kidney promotes avid proximal tubule reabsorption of glucose and sodium, leading to less distal sodium delivery and less sodium reabsorption by the macular densa of the distal convoluted tubule: signaling a vasodilatory response in the neighboring glomerular afferent arteriole, there by causing glomerular hyperfiltration and glomerular Hypertension, both of which are implicated diabetic glomerulopathy.

SGLT2 inhibitors interrupt this sequence of events mitigating glomerular hyperfiltration and Hypertension probably explaining the nephroprotective effects of SGLT2 Inhibitors..

SGLT2 inhibitors reduce the renal threshold of glucose from 180 mg/dL to 40-120 mg/dL thereby effectively lowering blood glucose levels.

Membrane proteins that transport glucose, amino acids, vitamins, ions, and osmolytes that cross the brush border of proximal renal tubules, as well as the intestinal epithelium.

SGLT1 is primarily located in the gastrointestinal tract and is a low capacity, high affinity SGLT.

SGLT1 is the key absorption transporter for glucose in the gastrointestinal tract.

SGLT1 intestinal glucose transport influences GLP-1 levels and therefore glucagon levels.

SGLT1 accounts for 10% of glucose reabsorption in the kidney.

SGLT2 is a high-capacity, low affinity transporter primarily in the kidney.

SGLT2 is the most prevalent and functionally important transporter in the kidney.

SGLT2 a task for approximately 90% of glucose reabsorption in the kidney.

SGLT2 binds sodium and glucose in the tubular filtrate and they are then translocated across the cell membrane.

Renal threshold for glucose reabsorption is typically 180 mg/dL in healthy individuals and 240 mg/dL in patients with type two diabetes, in part due to increased SGLT2 expression.

Pharmacologic SGLT2 inhibition lowers the renal glucose threshold to 70 mg/dL to 90 mg/dL to enhance glycosuria with minimal risk for hypoglycemia.

SGLT2 inhibitors have a renoprotective effect including a reduction in pressure within the glomerular capillaries, with protection of glomerular podocytes, which are the targets of glomeruli injury in most of, if not all proteinuric kidney diseases.

Dysfunctional podocytes cannot sufficiently counteract elevated, gomerular capillary pressure, suggesting that SGLT2 mediated afferent arterial vasoconstriction may be beneficial.

The effect of SGLT2 inhibitors is consistent across all levels of kidney function coming down to an estimated GFR of 30 mLper minute per 1.73 m² of body surface area, whereas glucose lowering effects are directly proportional to glomerulofiltration and are substantially decreased when kidney function declines, underscoring the importance of regulating glomerular hemodynamics in progressive renal disease.

Empagliflozin showed a significant reduction in the development of worsening kidney function, defined as the composite of doubling of the serum creatinine level, an increase in albuminuria, initiation of renal replacement therapy, or death due to kidney disease.

ALL SGLT2 inhibitors provide renal protection.

SGLT2 inhibition reduces glycated hemoglobin-hemoglobin A1C by a mean of 0.5% to 1% over 52 weeks.

SGLT2 inhibition also promotes favorable effects or non-glycemic cardiovascular risk factors by reducing fat mass, inducing total body weight loss, and lowering blood pressure, and these cardioprotective effects are sustained over the long term.

Cardiovascular outcome trials have shown at SGLT2 inhibitors reduce cardiovascular benefits beyond glucose lowering.

SGLT2 inhibitors reduce the hazard ratio in patients with type two diabetes, with a reduction in adverse cardiac events.

SGLT2 inhibitors may reduce heart failure by decreasing heart failure, improving cardiac energetics, sodium-hydrogen exchange, erythropoietin, progenitor cells and Calcium/calmoldulin dependence kinase II.

SGLT2 inhibitors reduce the activity of the sarcolemmal sodium hydrogen exchanger 1, the late inward sodium current, and calcium-calmodulin independent protein kinase II, which impairs cardiomyocytes contraction and relaxation.

SGLT2 inhibitors reduce hospitalization for heart failure in adults with diabetes with or without established cardiovascular disease.

SGLT2 inhibitors reduce the risk of death from cardiovascular causes or hospitalization for worsening heart failure among patients with reduced LVEF and in those with a preserved LVEF.

Inflammation is frequently present in heart failure and can cause cardiac fibrosis and SGLT2 inhibitors attenuate activation of the nucleotide binding domain like protein 3, which stimulates inflammatory responses.

Carotid artery plaques show reduced inflammation and increased collagen content.

SGLT2 inhibitors are more effective in heart failure with reduced ejection fraction than in patients with preserved ejection fraction.

SGLT2 inhibitors reduce free radical formation in cardiomyocytes, enhancing systolic and diastolic function.

SGLT2 inhibits pro-inflammatory pathways and improves coronary endothelial function and enhances low mediated vasodilatation.

In many patients with type two diabetes the aorta, coronary arteries, and ventricles are surrounded by excessive epicardial adipose tissue, which can release pro inflammatory mediators that may impair ventricular function, and SGLT2 inhibitors reduce this adipose tissue, body weight, waist circumference, visceral and central adiposity and extracellular volume, reducing aortic stiffness and myocardial fibrosis.

These agents lower blood pressure, body weight and reduce risk for major adverse cardiovascular events, including cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke.

Reduces the hospitalization rate for congestive heart failure.

Trials show definitive insert protection against a broad range of cardiovascular and kidney complications for patients with heart failure and reduced dejection fraction.

SGLT 2 inhibitors slow the progression of cardiac and renal disease regardless of the cause an independent of the presence or absence of diabetes.

Sodium-glucose co-transporter 2 inhibitors (SGLT2 inhibitors) reduce the risk of incident heart failure for T2D patients.

More recently, 4 large SGLT2 inhibitor cardiovascular outcome trials, EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58 and VERTIS CV, of empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin, respectively, demonstrated a significant reduction in HF hospitalization among T2D patients with and without established CVD.

Metaanalysis of critical end points involving 38,723 patients with type two diabetes showed that as compared with patients receiving placebo, those who receive SGLT2 has significant reduction in the risk of progression to dialysis, transplantation, or death due to kidney disease:benefit was observed itrespective of baseline GFR, across urinary albumin:creatinine ratios and independent of the glycemic effect.

Reductions in HF hospitalization were significant and consistent across each of the trials.

In the DIRECT-TIMI 58, the largest trial with the highest proportion of patients without CVD (10,186 of 17,160), investigators reported a significant reduction in HF hospitalization.

These results suggest that dapagliflozin, and possibly the SGLT2 inhibitors class as a whole, might serve as a disease modifier for patients with pre-clinical CVD/HF.

Dapagliflozin (Farxiga) received FDA approval to reduce the risk of hospitalization for HF in primary prevention patients with T2D.

Clinical Practice Guidelines on Diabetes, Pre-Diabetes and Cardiovascular Diseases recommend starting with an SGLT2 inhibitor or GLP-1RA before metformin in newly diagnosed T2D patients who are treatment naive and either have established CVD or are at high CVD risk.

The 2020 ADA Standards of Medical Care in Diabetes include SGLT2 inhibitors and GLP-1 RAs as second-line therapy after metformin for patients with established CVD or at high CVD risk.

For patients with high ASCVD risk, established chronic kidney disease, or HF, guidelines suggest an SGLT2 inhibitor may be used as part of the glucose-lowering regimen independent of a1c and in consideration of patient-specific factors.

Recommendations suggest an SGLT2 inhibitor for patients with T2D who are at high risk of developing HF, diabetic kidney disease, clinically evident ASCVD, or any combination of these conditions.

The current guidelines provide strong recommendations for the use of SGLT2 inhibitors for the reduction of incident HF among T2D.

Agents can cause genital mycotic infections and urinary tract infections.

Fournier’s gangrene is relatively rare but potentially fatal complication of treatment with sodium-glucose cotransporter-2 (SGLT2) inhibitors.

Agents can have a diuretic affect and lead to dehydration, hypovolemia, and hypotension, particularly in elderly with renal impairment and when treated with loop diuretics.

May increase serum creatinine, decreases GFR, hyperkalemia, hypomagnesemia, hyperphosphatemia, and increased LDL cholesterol can occur.

Increased incidence of fracture can occur and the risk is greater in patients with renal impairment.

Use associated with an increased risk of diabetic ketoacidosis.

Surgery can precipitate ketoacidosis when on SGLT2 inhibitors.

These drugs should be held during Covid-19 infections due to a higher incidence of diabetic ketoacidosis,

Used as an adjunctive therapy in type 1 patients because of its insulin independent mechanism.

Empagliflozin has a cardiovascular mortality benefit.

Patient treated with empagliflozin was significantly less likely to develop the primary composite outcome of cardiovascular death, non-fatal stroke, or non-fatal myocardial infarction, largely driven by a 38% relative reduction in cardiovascular death.

Empagliflozin Cardiovascular Outcome Event Trial indicated reduced risk of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke relative to those who received placebo.

A meta-analysis of randomized controlled trials and adjusted observational studies showed SGLT2 inhibitors significantly reduced the risks of major adverse cardiac events, all-cause mortality, cardiovascular mortality, nonfatal myocardial infarction, hospitalization for heart failure, and progression of albuminuria.

No significant difference in nonfatal stroke was found.

These agents associated with long-term preservation of renal function

In a matched cohort of type two diabetics, SGLT2 inhibitor use was associated with preserved renal function relative to other glucose lowering medications used over 2-4 years.

Trial sequential analysis provided firm evidence of a 20% reduction in major adverse cardiac events, all-cause mortality, and hospitalization for heart failure with SGLT2 inhibitors, but evidence remains inconclusive for cardiovascular mortality.

Empagliflozin in the above trial reduced hospitalization for heart failure.

Agents include canagliflozin, empagliflozin, dapagliflozin and ertugliflozin.

Among agents empagliflozin, associated with a reduction in cardiovascular mortality.

Canaglifozin associated with a relatively increased risk for amputations.

A relatively increase risk for amputations is seen with Canaglifozin.

Canaliflozin Cardiovascular Assessment Study in patients with type two diabetes is the median follow up of 2.4 years sound a relative risk reduction of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke by 14%.

Canaglifozin lowers the risk of kidney failure and cardiovascular events compared with placebo.

Combining SGLT-1 inhibitors with DPP-4 inhibitors or/and GLP-1 receptor agonists can decrease elevations in glucagon.

Sotagliflozin in patients with diabetes and chronic kidney disease results in a lower risk of composite deaths from cardiovascular causes and hospitalizations for heart failure, but has increased adverse events compared to placebo.

Guidelines suggest that in patients who have established atherosclerotic cardiovascular disease, chronic kidney disease, or heart failure should be treated with a sodium glucose code transporter 2 inhibitor or glucagon-like peptide 1 receptor agonist, irrespective of hemoglobin A-1 C

Exceptions to the above include signs of catabolism such as unintentional weight loss, hemoglobin A-1 C higher than 10% or glucose levels higher than 300 mg/dL in which case insulin should be considered.

These agents are helpful in patients with heart failure with or without diabetes (Neal B).

These agents are helpful in patients with heart failure with reduced or preserved ejection fractions.

Study of more than 45k unique patients, found SGLT2 inhibitors were associated with reduced risk of adverse cardiovascular disease events and kidney outcomes

SGLT2 inhibitors in general are associated with favorable CV and kidney outcomes.

Results indicated SGLT2 inhibitors were associated with a reduced risk of major adverse cardiovascular events:hospitalizations for heart failure or cardiovascular death and kidney outcomes.

SGLT 2 inhibitors have a significant reduction in the risk of progression to dialysis, transplantation, or death due to kidney disease.

These findings are across a wide range of urinary albumin to creatinine ratios and is independent of the glycemic affect.

The presence or absence of atherosclerotic cardiovascular disease did not modify the association with outcomes for major adverse cardiovascular events and noted similar absence of association with outcome modification for hospitalization for heart failure/cardiovascular death.

The CV benefits are not attributable to glucose control per se.

Agents include: dapaglizlozin, canagliflozin, empagliflozin, and ertuggliflozin.

Common adverse events: genital infections or volume depletion are generally mild and manageable, and rare events include ketoacidosis.

There is an increased risk of volume depletion related adverse events including hypotension, syncope, and dehydration.

The most common adverse effects are mycotic genital infections related to the glycosuric action of these agents and occur more frequently in women than men.

SGLT2 inhibitors reduce serum uric acid concentration by a mean of 0.6 mg/dL.

Less commonly urinary tract infections, pyelonephritis, and diabetic ketoacidosis may be seen.

Diabetic ketoacidosis in patients with SGLT2 inhibitors is euglycemic ketoacidosis and is not accompanied by markedly elevated blood glucose levels.

Meta-analysis suggest an association with SGL T2 inhibitors with modest but significant reduction in arterial blood pressure of an average 2.5 mmHg systolic at 1.5 mmHg diastolic with no increased heart rate.

The combination of an SGLT2 inhibitor and the glucagon like peptide receptor agonist appears safe and additive in reducing glycated hemoglobin levels.

The use of SGL T2 inhibitors following a myocardial infarction is not superior to placebo in decreasing the risk of heart failure or death.

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