Canagliflozin

Localization and Physiological Role of SGLT2 in Renal Glucose Reabsorption

Sodium-glucose cotransporter 2 (SGLT2) is a protein primarily expressed in the S1 and S2 segments of the proximal renal tubules in the kidneys. nih.govahdbonline.com Under normal physiological conditions, the kidneys filter approximately 180 grams of glucose from the blood daily. nih.gov SGLT2 is responsible for the reabsorption of the vast majority, about 90%, of this filtered glucose. nih.gov This process of reabsorbing glucose back into the bloodstream is crucial for the body's energy conservation and maintenance of glucose homeostasis. nih.gov The remaining 10% of glucose is reabsorbed by the sodium-glucose cotransporter 1 (SGLT1), which is located more distally in the proximal tubules. jnjmedicalconnect.com

Canagliflozin's Affinity and Potency for Human SGLT2 versus SGLT1

This compound functions as a competitive and reversible inhibitor of SGLT2. It exhibits a high degree of selectivity and potency for human SGLT2 compared to SGLT1. jnjmedicalconnect.com In vitro studies have determined that this compound has a half-maximal inhibitory concentration (IC50) for SGLT2 in the range of 2.2 to 4.2 nM. jocmr.orgmdpi.com In contrast, its IC50 for SGLT1 is significantly higher, approximately 663 to 910 nM. jocmr.orgmdpi.com This demonstrates that this compound is about 150 to over 400 times more selective for SGLT2 than for SGLT1. jnjmedicalconnect.commdpi.com This selectivity ensures that its primary action is targeted at the main site of renal glucose reabsorption.

Table 1: Comparative Inhibitory Potency of this compound

Data sourced from in vitro studies. jocmr.orgmdpi.com

Consequences of SGLT2 Inhibition: Glucosuria and Lowered Renal Threshold for Glucose (RTG)

By inhibiting SGLT2, this compound reduces the reabsorption of filtered glucose in the kidneys, leading to an increase in urinary glucose excretion (UGE), a condition known as glucosuria. jnjmedicalconnect.comuspharmacist.com A primary consequence of this action is the lowering of the renal threshold for glucose (RTG), which is the plasma glucose concentration at which glucose starts to be excreted in the urine. jnjmedicalconnect.com In individuals without diabetes, the typical RTG is around 180 mg/dL. uspharmacist.com this compound lowers this threshold in a dose-dependent manner, with maximal suppression reducing the RTG to a range of approximately 70 to 90 mg/dL. jnjmedicalconnect.com This lowered threshold results in the excretion of glucose at much lower blood concentrations than normal, leading to a caloric loss and a reduction in plasma glucose levels. jnjmedicalconnect.compatsnap.com

Impact on Fasting and Postprandial Plasma Glucose Levels

A key feature of this compound's mechanism is that it is independent of insulin action or secretion. nih.govdovepress.com This allows it to be effective in managing blood glucose levels across different stages of type 2 diabetes. nih.gov The inhibition of SGLT2 and subsequent glucosuria directly results in a decrease in both fasting plasma glucose (FPG) and postprandial plasma glucose (PPG). mdpi.com The reduction in FPG is a result of the continuous excretion of glucose in the urine, while the lowering of PPG is enhanced by both increased UGE and a delay in intestinal glucose absorption, which is likely due to transient inhibition of intestinal SGLT1. jnjmedicalconnect.comnih.govdiabetesjournals.org

Improvements in Beta-Cell Function and Insulin Sensitivity

Studies suggest that this compound can lead to improvements in the function of beta-cells, the cells in the pancreas that produce insulin. plos.orgbjd-abcd.com This beneficial effect is thought to be an indirect result of reducing glucotoxicity, the harmful effect of high glucose levels on beta-cells. bjd-abcd.comdovepress.com By lowering blood glucose through increased urinary excretion, this compound lessens the demand on beta-cells to produce insulin. plos.org

In preclinical studies involving rodent models of type 2 diabetes, this compound treatment improved beta-cell function, as evidenced by an increased insulin-to-glucose ratio during an oral glucose tolerance test. plos.org Furthermore, in a polygenic mouse model of type 2 diabetes, this compound helped preserve beta-cell mass and function. diabetesjournals.org Clinical trials have also pointed to this compound's positive impact on beta-cell function and insulin sensitivity. clinicaltrials.gov One study showed that six months of this compound use improved HOMA-B, a measure of beta-cell function. bjd-abcd.com Another investigation revealed that adding this compound to existing therapy improved beta-cell function by 18%, although this finding was not statistically significant. dovepress.com

While insulin resistance is not a direct pharmacological target of this compound, some research indicates potential benefits. jnjmedicalconnect.com A pooled analysis of four phase 3 studies showed that this compound treatment was associated with improvements in the triglyceride/high-density lipoprotein-C (TG/HDL-C) ratio, a marker of insulin resistance. jnjmedicalconnect.com

Dose-Dependent Intestinal SGLT1 Inhibition and Delayed Oral Glucose Absorption

The inhibitory effect of this compound on intestinal SGLT1 is dose-dependent. jnjmedicalconnect.comeuropa.eu While systemic concentrations of this compound may not be sufficient to significantly inhibit SGLT1 throughout the body, transiently high concentrations within the intestinal lumen following oral administration can lead to local inhibition of SGLT1. diabetesjournals.orgdiabetesjournals.orgeuropa.eu This is particularly observed with higher doses, such as 300 mg. nih.govspringermedizin.deresearchgate.net

This localized and temporary inhibition of intestinal SGLT1 delays the absorption of glucose from the gut. nih.govnih.govdiabetesjournals.org A study using a dual-tracer method in healthy individuals demonstrated that a single 300 mg dose of this compound slowed the rate at which orally administered glucose appeared in the bloodstream during a mixed-meal tolerance test. nih.gov Specifically, the rate of oral glucose absorption was reduced by 31% in the first hour and 20% over the first two hours compared to placebo. jnjmedicalconnect.com This delay in glucose absorption is a key non-renal mechanism contributing to this compound's glucose-lowering effect. nih.govresearchgate.net

Contribution to Postprandial Glucose Lowering

The delayed intestinal glucose absorption resulting from SGLT1 inhibition directly contributes to the reduction of postprandial glucose (PPG), or blood sugar levels after a meal. nih.govspringermedizin.denih.gov By slowing the entry of glucose into the circulation, this compound helps to blunt the sharp spike in blood sugar that can occur after eating. diabetesjournals.orgnih.gov

Multiple studies have confirmed this effect. In healthy subjects, a 300 mg dose of this compound significantly reduced postprandial plasma glucose excursions. nih.gov The mean postprandial plasma glucose incremental area under the curve (ΔAUC) was lower by approximately 44% in the first hour, 35% in the first two hours, and 26% over six hours compared to placebo. nih.gov This effect on postprandial glucose is a distinct mechanism from the increased urinary glucose excretion caused by SGLT2 inhibition, providing an additional pathway for glycemic control. europa.eunih.gov

Renal Hemodynamic Alterations

This compound has been shown to induce changes in the hemodynamics of the kidneys, which are thought to contribute to its long-term renal protective effects. tandfonline.comphysiology.org

A key hemodynamic effect of this compound is the reduction of pressure within the glomeruli, the filtering units of the kidneys. tandfonline.comnih.gov This is achieved through a mechanism involving the restoration of tubuloglomerular feedback. e-dmj.org By inhibiting SGLT2 in the proximal tubules, this compound increases the delivery of sodium to the macula densa, a specialized group of cells in the distal tubule. physiology.orge-dmj.org This signals the afferent arteriole, the small artery that supplies blood to the glomerulus, to constrict. physiology.orge-dmj.org This vasoconstriction of the afferent arteriole leads to a decrease in blood flow into the glomerulus, thereby lowering the intraglomerular pressure. physiology.orgnih.gove-dmj.org

This reduction in intraglomerular pressure is believed to be a major factor in the renoprotective effects observed with this compound and other SGLT2 inhibitors. tandfonline.comnih.govahajournals.org By alleviating the hyperfiltration and pressure that can damage the glomeruli over time, particularly in individuals with diabetes, this compound may help to slow the progression of kidney disease. nih.govjacc.org

Table of Research Findings on this compound's Mechanisms

Table of Mentioned Chemical Compounds

Effects on Renal Tubular Glucose Reabsorption and Glomerular Filtration Rate (GFR) Loss

This compound is an inhibitor of the sodium-glucose co-transporter 2 (SGLT2), which is found in the proximal renal tubules and is responsible for reabsorbing the majority of glucose filtered by the kidneys. nih.govspringermedizin.de By inhibiting SGLT2, this compound reduces the reabsorption of filtered glucose, lowers the renal threshold for glucose, and consequently increases the excretion of glucose in the urine. jnjmedicalconnect.comtandfonline.com This mechanism is independent of insulin secretion. nih.gov The glucose-lowering efficacy of this compound is related to the glomerular filtration rate (GFR), as the amount of urinary glucose excretion depends on the GFR. springermedizin.detandfonline.com

In patients with type 2 diabetes, this compound has been shown to cause an initial, temporary reduction in the estimated GFR (eGFR). tandfonline.comnih.gov However, these changes tend to stabilize or lessen over time and are reversible after stopping the treatment, which suggests the absence of renal damage. tandfonline.com In the long term, this compound has been demonstrated to slow the decline of eGFR. nih.gov The mechanism for this is believed to be the increased delivery of sodium to the juxtaglomerular apparatus, which leads to vasoconstriction of the afferent arteriole, reducing intraglomerular pressure and hyperfiltration. nih.govphysiology.org

Cardiovascular Systemic Effects

Blood Pressure Reduction Mechanisms (e.g., osmotic diuresis, natriuresis)

This compound has been shown to lower both systolic and diastolic blood pressure. nih.gov The primary mechanisms behind this blood pressure reduction are thought to be osmotic diuresis and natriuresis. nih.govnih.gov By increasing urinary glucose excretion, this compound induces an osmotic diuretic effect, leading to a reduction in plasma volume. nih.govtandfonline.com It also promotes natriuresis, the excretion of sodium in the urine, by inhibiting sodium reabsorption in the proximal tubules. physiology.orgtandfonline.com

Other potential contributing factors to blood pressure reduction include weight loss and a possible reduction in arterial stiffness. nih.govtandfonline.com Some research also suggests a local inhibition of the renin-angiotensin-aldosterone system due to increased sodium delivery to the juxtaglomerular apparatus. nih.gov

Influence on Plasma Volume

This compound has a notable effect on plasma volume. Studies have shown that treatment with this compound leads to a reduction in plasma volume. nih.govucl.ac.uk This effect is a result of the osmotic diuresis caused by increased urinary glucose excretion. ucl.ac.uk One study observed a transient decrease in plasma volume at the beginning of treatment, which was largely attenuated by week 12. nih.gov Another study involving patients with type 2 diabetes and chronic heart failure found that this compound significantly reduced estimated plasma volume over 24 weeks, irrespective of whether patients were also taking conventional diuretics. researchgate.net This reduction in intravascular volume is considered a key contributor to the cardiovascular benefits of this compound. ahajournals.org

Impact on Serum Lipids (e.g., total cholesterol, LDL-C, HDL-C, triglycerides)

The effects of this compound on serum lipids have been a subject of various studies, with some reporting mixed results. Generally, this compound has been associated with an increase in both low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C). mdpi.comlipid.org

A meta-analysis of 48 randomized controlled trials indicated that this compound showed the largest effect in increasing LDL-C among the SGLT2 inhibitors studied. lipid.org The CANVAS trial also reported a slight increase in both HDL-C and LDL-C in patients treated with this compound compared to placebo. mdpi.com

Regarding triglycerides, some studies have shown a trend towards a decrease with this compound treatment. nih.govresearchgate.net A meta-analysis found that this compound significantly reduced triglycerides. lipid.org

One study suggested that the increase in HDL-C may be related to a reduction in angiopoietin-like protein 3 (ANGPTL3) expression. nih.gov The mechanisms behind the changes in LDL-C are thought to involve reduced clearance of circulating LDL and increased lipolysis of triglyceride-rich lipoproteins. mdpi.com

Table 1: Effect of this compound on Serum Lipids (Select Studies)

Neuroprotective Properties and Brain Aging

Recent research has begun to explore the neuroprotective potential of this compound and its effects on brain aging.

Modulation of Central Insulin Sensitivity

Studies in animal models suggest that this compound may have beneficial effects on the brain, including improved central insulin responsiveness. nih.govresearchgate.net In aged male mice, this compound treatment has been shown to enhance hypothalamic insulin sensitivity. researchgate.net This is significant because brain insulin resistance is implicated in cognitive decline and neurodegenerative diseases. mdpi.com By improving central insulin signaling, this compound may help to mitigate some of the age-related changes in the brain. nih.govresearchgate.net Furthermore, research in mouse models of Alzheimer's disease has indicated that this compound treatment can improve cognition and reduce neuroinflammation. biorxiv.orgmdpi.com

Effects on mTOR Signaling

This compound has been shown to influence the mammalian target of rapamycin (mTOR) signaling pathway, a crucial regulator of cellular growth and metabolism. jst.go.jpnih.gov In studies on glioblastoma cells, this compound demonstrated an ability to inhibit cell growth by enhancing the phosphorylation of AMP-activated protein kinase (AMPK) and suppressing the phosphorylation of S6 protein and p70S6 kinase, which are downstream targets of mTOR. jst.go.jp This suggests that this compound activates AMPK and subsequently inhibits the mTOR pathway, leading to reduced glioblastoma growth both in laboratory settings and in animal models. jst.go.jp

Further research indicates that the reduction in mTORC1 signaling is a common mechanism shared with other treatments that extend lifespan. nih.gov Interestingly, the effect of this compound on mTOR signaling appears to be sex-specific, with a reduction in mTORC1 and ERK1-2 signaling observed only in male mice, which corresponds with the lifespan extension seen exclusively in males. nih.govaging-us.com This modulation of the mTOR pathway is also implicated in the drug's ability to interrupt inflammatory signaling in certain cancer models. nih.gov In renal cells, this compound has been observed to induce autophagy by regulating the AMPK/mTOR signaling pathways. researchgate.net

The mechanism by which this compound inhibits the mTOR pathway may also be linked to its effects on the AKT/mTOR axis. In hepatocellular carcinoma cells, this compound was found to inhibit HIF-1α protein accumulation, a key factor in tumor metastasis and angiogenesis, by targeting the AKT/mTOR pathway. mdpi.com

Reduction of Neuroinflammation

This compound has demonstrated significant neuroprotective effects by reducing neuroinflammation. aging-us.commdpi.com Studies in aged mice have shown that this compound treatment can significantly decrease age-associated hypothalamic gliosis, which is an increase in the number of glial cells in response to central nervous system damage, along with a reduction in the production of inflammatory cytokines by microglia. researchgate.netnih.gov Specifically, in the hypothalamus and hippocampus of aged male mice, this compound treatment led to a notable reduction in neuroinflammation. aging-us.comnih.gov

The anti-inflammatory effects of this compound in the brain appear to be sex-specific. In the hippocampus, this compound reduced both microgliosis and astrogliosis in male mice, but not in females. researchgate.netnih.gov This sex-dimorphic effect aligns with findings that aged male mice tend to have more robust neuroimmune responses than their female counterparts. researchgate.netnih.gov The reduction in microgliosis in males was partially correlated with decreased phosphorylation of S6 kinase in microglia. researchgate.netnih.gov

The mechanisms underlying this compound's anti-inflammatory properties in the central nervous system are multifaceted. They are thought to involve the modulation of inflammatory pathways and nutrient signaling. aging-us.com For instance, some of its neuroprotective effects may be mediated through the inhibition of the NLRP3 inflammasome, a key component of the innate immune system linked to brain aging and degenerative diseases. aging-us.com Furthermore, this compound has been shown to alleviate high glucose-induced inflammatory toxicity in microglia by repressing proinflammatory factors and reducing signaling activities of pathways like NFκB, JNK, and p38. mdpi.com

Improvement in Neuromuscular Function and Locomotor Activity

This compound treatment has been associated with improvements in neuromuscular function and locomotor activity, particularly in aged male mice. aging-us.com Research has demonstrated that this compound treatment improved exploratory and locomotor activity in 30-month-old male mice, an effect not observed in their female counterparts. researchgate.netnih.gov This suggests a sex-specific neuroprotective benefit of the drug on motor function during aging. aging-us.comresearchgate.netnih.gov

In a different experimental model using rats, this compound treatment was found to significantly reduce increased levels of locomotor activity induced by valproic acid. nih.gov While this may seem contradictory, it highlights the context-dependent effects of the drug on motor behavior, potentially by normalizing hyperactivity in certain pathological states. One study noted that this compound treatment increased energy expenditure without affecting ambient locomotor activity in specific mouse models. portlandpress.com

The improvement in neuromuscular function may be linked to the broader neuroprotective effects of this compound, including the reduction of neuroinflammation and improved central insulin sensitivity, which are also predominantly observed in males. aging-us.comresearchgate.netnih.gov

Hepatic Effects, Liver Steatosis, and Fibrosis

This compound has demonstrated beneficial effects on the liver, particularly in the context of non-alcoholic fatty liver disease (NAFLD) and its progression. nih.govjst.go.jp Multiple studies have shown that this compound can improve hepatic steatosis, which is the accumulation of fat in the liver. nih.govjst.go.jp In a six-month prospective study involving patients with type 2 diabetes and NAFLD, this compound significantly reduced hepatic proton density fat fraction (PDFF), a measure of liver fat, from a median of 20.6% to 10.6%. nih.govjst.go.jp

The mechanisms behind the improvement in hepatic steatosis are thought to include reductions in body weight, visceral fat, and improvements in insulin resistance and inflammation. nih.gov A large secondary analysis of the CANVAS and CANVAS-R trials, involving over 10,000 patients with type 2 diabetes, found that this compound treatment resulted in improvements in liver biochemistry. oup.com Specifically, a composite endpoint of a greater than 30% improvement in alanine aminotransferase (ALT) levels or normalization of ALT levels occurred in 35.2% of patients receiving this compound compared to 26.4% in the placebo group. oup.com

Beyond steatosis, this compound may also positively impact liver fibrosis. The same large analysis showed that this compound led to improvements in some noninvasive tests for fibrosis. oup.com In animal models of nonalcoholic steatohepatitis (NASH), this compound inhibited the development of hepatic fibrosis. jofem.org A post hoc analysis of the CREDENCE trial also suggested that this compound reduces biomarkers related to inflammation and fibrosis. springermedizin.de

Table 1: Effects of this compound on Hepatic Parameters

Anti-proliferative Action in Endothelial Cells

This compound exerts a notable anti-proliferative effect on endothelial cells, the cells that line blood vessels. This action has been observed in various studies and appears to be a characteristic that distinguishes it from some other SGLT2 inhibitors. frontiersin.orgnih.gov

Research has consistently shown that this compound inhibits the proliferation of human endothelial cells in a concentration-dependent manner. frontiersin.orgnih.govresearchgate.net For instance, a 10 μM concentration of this compound was found to reduce endothelial cell proliferation by approximately 45%. frontiersin.orgnih.gov This inhibitory effect occurs without causing cell death and is associated with a decrease in DNA synthesis. frontiersin.orgnih.gov

In addition to inhibiting proliferation, this compound markedly attenuates the ability of endothelial cells to form tube-like structures, a critical step in the process of angiogenesis (the formation of new blood vessels). frontiersin.orgnih.gov A high concentration of this compound (50 μM) was shown to reduce tube formation by 65% and endothelial cell sprouting from mouse aortas by 80%. frontiersin.orgnih.gov This robust inhibition of both proliferation and tube formation is a key aspect of this compound's action on the vasculature. frontiersin.orgmdpi.com It has been suggested that this anti-angiogenic property could be beneficial in conditions like proliferative diabetic retinopathy but may also contribute to an increased risk of limb amputation in certain patient populations by impairing vascular repair. mdpi.com

A significant part of this compound's anti-proliferative mechanism in endothelial cells is the blockade of cyclin A expression. frontiersin.orgnih.gov The inhibition of endothelial cell growth by this compound is associated with cell cycle arrest and a striking decrease in the levels of cyclin A. frontiersin.orgnih.gov Cyclins are a family of proteins that control the progression of cells through the cell cycle.

The importance of this blockade is highlighted by experiments where the restoration of cyclin A expression, through adenoviral-mediated gene transfer, partially rescued the proliferative response of endothelial cells treated with this compound. frontiersin.orgnih.gov While the inhibition of cyclin A is a key contributor, it is likely that other unidentified mediators are also involved in the full anti-proliferative effect of this compound. frontiersin.org The mechanism by which this compound suppresses cyclin A expression is not fully understood but may be related to the blockade of mitochondrial metabolism. mdpi.com

Table 2: Effects of this compound on Endothelial Cell Function

Reduction in Hemoglobin A1c (HbA1c)

Clinical trials consistently show that this compound, at recommended doses, significantly reduces HbA1c levels. When used as monotherapy in patients inadequately controlled with diet and exercise, this compound 100 mg and 300 mg resulted in mean HbA1c reductions of -0.77% and -1.03%, respectively, compared to placebo at 26 weeks nih.gov. Over a 52-week period, these reductions were sustained, with mean HbA1c decreases of -0.81% and -1.11% for the 100 mg and 300 mg doses, respectively, compared to placebo/sitagliptin researchgate.net.

As add-on therapy to metformin, this compound 100 mg and 300 mg lowered HbA1c by approximately 0.59%–0.74% compared to placebo dovepress.com. In general, this compound 100 mg and 300 mg doses lower HbA1c by approximately 0.6%–0.8% compared to placebo dovepress.com.

Table 1: Mean HbA1c Reduction with this compound in Clinical Trials

Effects as Monotherapy and Add-on Therapy

This compound has proven effective when used as a standalone treatment or when added to existing antihyperglycemic regimens. As monotherapy, it significantly reduces HbA1c, fasting plasma glucose (FPG), and body weight in patients inadequately controlled by diet and exercise alone nih.govresearchgate.netwjgnet.com. When used as an add-on therapy, particularly to metformin, this compound further improves glycemic control, demonstrating reductions in HbA1c beyond what is achieved with metformin alone dovepress.comdiabetesjournals.org. Studies have also shown its efficacy when added to metformin and sulfonylureas, or metformin and DPP-4 inhibitors, maintaining significant HbA1c reductions dovepress.comnih.gov. In Japanese patients, this compound demonstrated sustained reductions in HbA1c and body weight for up to 52 weeks, whether administered as monotherapy or in combination with other oral antihyperglycemic drugs nih.gov.

Comparative Efficacy with Other Antihyperglycemic Agents

This compound has been directly compared with other classes of antihyperglycemic agents. In head-to-head trials, this compound 300 mg demonstrated superiority over sitagliptin 100 mg in reducing HbA1c levels, with mean reductions of -0.9% compared to -0.7% for sitagliptin when added to metformin nih.gov. Similarly, this compound 300 mg was found to be superior to glimepiride in lowering HbA1c when used as add-on therapy to metformin nih.govdiabetesjournals.org. Network meta-analyses suggest that this compound 300 mg is more effective than sitagliptin in reducing HbA1c and appears superior to sulfonylureas like glimepiride dovepress.comnih.gov. While this compound 100 mg was found to be noninferior to glimepiride and sitagliptin in HbA1c reduction, the 300 mg dose showed superior efficacy in these comparisons diabetesjournals.org.

Reduction in Major Adverse Cardiovascular Events (MACE)

The CANVAS Program, an integrated analysis of the CANVAS and CANVAS-R trials, demonstrated that this compound significantly reduced the risk of major adverse cardiovascular events (MACE), defined as the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke jnj.comahajournals.orgahajournals.orgnih.gov. Across the program, this compound achieved a 14% reduction in the risk of MACE compared to placebo (Hazard Ratio [HR]: 0.86; 95% Confidence Interval [CI]: 0.75–0.97) jnj.comahajournals.orgnih.gov. The event rate was 26.9 per 1000 patient-years with this compound versus 31.5 per 1000 patient-years with placebo ahajournals.orgnih.gov.

The CREDENCE trial, which included patients with type 2 diabetes and chronic kidney disease, also reported significant cardiovascular benefits. This compound reduced the composite endpoint of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke by 20% compared to placebo (HR: 0.80; 95% CI: 0.67–0.95) ahajournals.orgahajournals.org. In this trial, this compound reduced first cardiovascular events by 26% (HR: 0.74) and total cardiovascular events by 29% ahajournals.org.

Table 2: Reduction in Major Adverse Cardiovascular Events (MACE)

Impact on Heart Failure Hospitalization

This compound has demonstrated a significant protective effect against heart failure (HF) hospitalizations. In the CANVAS Program, this compound reduced the risk of hospitalization for heart failure (HHF) by 33% compared to placebo (HR: 0.67; 95% CI: 0.52–0.87) jnj.comacc.orgreliasmedia.com. The trial also showed a 22% reduction in the composite of cardiovascular death or hospitalized HF (HR: 0.78; 95% CI: 0.67–0.91) acc.orgreliasmedia.comnih.gov and a 30% reduction in fatal or hospitalized HF (HR: 0.70) acc.orgnih.gov. Notably, the benefit on cardiovascular death or hospitalized HF appeared greater in patients with a history of HF at baseline, showing a 39% reduction compared to those without HF (HR: 0.61; 95% CI: 0.46–0.80) reliasmedia.comnih.gov.

The CREDENCE trial also reported a significant reduction in heart failure hospitalizations. This compound reduced hospitalization for heart failure by 30% (HR: 0.70) ahajournals.orgahajournals.orgnih.gov2minutemedicine.com and the composite of cardiovascular death or hospitalization for heart failure by 31% (HR: 0.69; 95% CI: 0.57–0.83) ahajournals.org.

Table 3: Impact on Heart Failure Hospitalization

Compound Names Mentioned:

this compound

Sitagliptin

Glimepiride

Metformin

Empagliflozin

Dapagliflozin

Ertugliflozin

Liraglutide

Semaglutide

Albiglutide

Genital Mycotic Infections

This compound is associated with an increased incidence of genital mycotic infections, primarily candidiasis, in both women and men. This is attributed to the increased glucose concentration in the genitourinary tract, which can promote fungal growth.

In a pooled analysis of clinical studies (Population 1), the incidence of genital mycotic infections was significantly higher with this compound compared to placebo. In females, the incidence was 10.4% for the 100 mg dose and 11.4% for the 300 mg dose, compared to 3.2% for placebo. In males, the incidence was 4.2% for the 100 mg dose and 3.7% for the 300 mg dose, versus 0.6% for placebo tandfonline.comnih.govcapes.gov.brresearchgate.net.

In a broader pooled analysis (Population 2), similar trends were observed, with incidences in females of 14.7% (100 mg), 13.9% (300 mg), and 3.1% (control), and in males of 7.3% (100 mg), 9.3% (300 mg), and 1.6% (control) tandfonline.comnih.govcapes.gov.br.

These infections were generally mild to moderate in intensity, rarely serious, and infrequently led to treatment discontinuation tandfonline.comnih.govcapes.gov.brnih.govdovepress.com. Most events responded to standard antifungal therapies tandfonline.comnih.govcapes.gov.br.

The majority of these infections occurred within the first four months of treatment in women and the first year in men tandfonline.comnih.govcapes.gov.brresearchgate.net. Women with a prior history of vulvovaginitis and uncircumcised men were noted to have a higher risk researchgate.net.

Table 1: Incidence of Genital Mycotic Infections in Clinical Studies

Urinary Tract Infections (UTIs)

This compound use has been associated with a small increase in the incidence of urinary tract infections (UTIs). However, studies indicate that these infections were generally similar in severity to those seen with placebo, and there was no increased risk of serious or upper UTIs nih.govdovepress.comnih.govoup.comdiabetesjournals.orgresearchgate.netfrontiersin.org.

In pooled analyses of Phase III studies, this compound 100 mg and 300 mg were linked to small increases in UTI incidence compared to control groups, without a clear dose-dependence nih.govopenaccessjournals.com. For instance, in one pooled dataset, UTI incidence was 4% with this compound 100 mg, 5.9% with 300 mg, and 4% with placebo openaccessjournals.com.

In the CANVAS program, the incidence of UTIs with this compound was comparable to placebo (40 vs. 37 events per 1000 patient-years) oup.com.

The proportion of patients experiencing recurrent UTIs remained low across all groups nih.gov.

Osmotic Diuresis-Related Events

The mechanism of SGLT2 inhibition inherently leads to osmotic diuresis, characterized by increased urine volume and frequency. This can manifest as several related adverse events.

this compound increases urinary glucose excretion, inducing osmotic diuresis which can lead to increased urination (polyuria) and more frequent urination (pollakiuria) dovepress.comdiabetesjournals.orgfda.govnih.govnih.govjnjmedicalconnect.comeuropa.eu.

Other commonly reported terms associated with osmotic diuresis include thirst, dry mouth, dry throat, urgency, and nocturia fda.govnih.govnih.govjnjmedicalconnect.com.

In pooled placebo-controlled phase 3 studies, the incidence of osmotic diuresis-related adverse events was higher with this compound compared to placebo. For example, events such as pollakiuria and polyuria occurred in 6.7% (100 mg) and 5.6% (300 mg) of patients treated with this compound, compared to 0.8% in the placebo group fda.govnih.gov.

These events were generally mild to moderate in intensity and infrequently led to discontinuation nih.govdiabetesjournals.org. The majority of these events with this compound occurred within the first six weeks of treatment nih.gov.

Volume Depletion-Related Events

The osmotic diuresis induced by this compound can lead to a reduction in intravascular volume, potentially causing volume depletion-related adverse events.

These events include hypotension, postural dizziness, orthostatic hypotension, dizziness, syncope, and dehydration dovepress.comresearchgate.netopenaccessjournals.comfda.govnih.govnih.goveuropa.eueuropa.eujnjmedicalconnect.comfda.govmedcentral.com.

In pooled analyses of clinical studies, the incidence of volume depletion-related adverse events was dose-dependent, occurring more frequently with the 300 mg dose compared to the 100 mg dose and placebo europa.eujnjmedicalconnect.comfda.gov. For instance, in one pooled analysis of eight clinical trials, the incidence was 2.3% for this compound 100 mg, 3.4% for 300 mg, and 1.5% for comparator groups openaccessjournals.com. Another pooled analysis of four placebo-controlled studies reported incidences of 1.2% (100 mg), 1.3% (300 mg), and 1.1% (placebo) europa.eu.

Specific patient populations are at higher risk for these events. These include elderly patients (particularly those ≥75 years), patients with moderate renal impairment (eGFR <60 mL/min/1.73 m²), and patients taking concomitant loop diuretics openaccessjournals.comeuropa.eujnjmedicalconnect.comfda.govmedcentral.com.

These events most frequently occurred within the first three months of treatment europa.eu.

Table 2: Incidence of Volume Depletion-Related Adverse Events in Pooled Clinical Trials

Ketoacidosis: Incidence and Contributing Factors

This compound, like other SGLT2 inhibitors, has been associated with an increased risk of diabetic ketoacidosis (DKA), including euglycemic DKA (eDKA), where blood glucose levels may not be significantly elevated.

Studies suggest that this compound may carry a higher risk of DKA compared to other SGLT2 inhibitors, potentially due to its lower selectivity for SGLT2 over SGLT1 ajmc.comresearchgate.netcnodes.ca. This compound's inhibition of SGLT1 in the small intestine can lead to osmotic diarrhea and volume depletion, which are recognized predisposing factors for DKA ajmc.comcnodes.ca.

The SGLT2 inhibition mechanism itself may promote lipid oxidation and ketogenesis, possibly via volume depletion, contributing to the pathophysiological pathway of SGLT2 inhibitor-related DKA ajmc.com.

In a study using the FAERS database, this compound was associated with a higher hazard ratio (HR) for DKA compared to DPP-4 inhibitors (HR: 3.58) cnodes.ca. Another analysis reported an increased risk of DKA from 0.03% (comparator drugs) to 0.11% with this compound 300 mg in type 2 diabetic patients nih.gov.

Other contributing factors for DKA in patients taking this compound include pancreatic insulin deficiency, alcohol abuse, caloric restriction, and history of pancreatitis nih.govnih.gov.

Table 3: Incidence of Diabetic Ketoacidosis (DKA) with SGLT2 Inhibitors

Note: Data from population-based cohort studies comparing SGLT2 inhibitors to DPP-4 inhibitors cnodes.ca. Specific placebo-controlled incidence rates for this compound alone are also noted nih.gov.

Amputation Risk: Observed Incidence and Ongoing Research into Mechanisms

The risk of lower limb amputations has been a significant area of investigation for this compound. Data from major clinical trials have yielded differing results, prompting further research into potential mechanisms.

In the This compound cardioVascular Assessment Study (CANVAS) Program , which included patients with T2DM at high cardiovascular risk, an increased risk of lower extremity amputations was observed. The incidence rate for this compound was 6.3 per 1000 patient-years (PYs), compared to 3.4 per 1000 PYs for placebo, resulting in a hazard ratio (HR) of 1.97 (95% CI, 1.41-2.75) jnjmedicalconnect.comnih.gov. This increased risk was noted for both 100 mg and 300 mg doses, with no clear dose-response relationship identified jnjmedicalconnect.com. The majority of these amputations were minor, predominantly affecting the toes nih.goveuropa.eu. Risk was found to be similar across various subgroups, including those with a history of peripheral vascular disease (PVD), prior amputation, or reduced estimated glomerular filtration rate (eGFR) ukkidney.org.

Conversely, the This compound and Renal Events in Diabetes withీ Atherosclerosis post-stroke Outcome (CREDENCE) trial , which enrolled patients with T2DM and albuminuric chronic kidney disease (CKD), did not demonstrate a statistically significant difference in the risk of atraumatic lower limb amputation between the this compound and placebo arms. The incidence rates were 12.3 per 1000 PYs for this compound and 11.2 per 1000 PYs for placebo, with an HR of 1.11 (95% CI, 0.79-1.56) jnjmedicalconnect.comjnjmedicalconnect.com.

A pooled analysis comparing the CANVAS Program and the CREDENCE trial revealed significant heterogeneity in the effect of this compound on amputation risk between the studies (Pheterogeneity = 0.02) nih.govdoi.org. Despite extensive analysis, no specific participant or trial-level factors were identified to fully explain this discrepancy nih.govdoi.org. While several hypotheses have been proposed, including drug-induced hypovolemia, dehydration, decreased tissue perfusion, increased hematocrit, blood viscosity, or arterial thrombosis, the precise mechanism remains unclear in the published medical literature jnjmedicalconnect.com. It is noteworthy that in August 2020, the U.S. Food and Drug Administration (FDA) removed the Boxed Warning regarding amputation risk from this compound's label, citing subsequent reviews that indicated a lower risk than initially described jnjmedicalconnect.com.

Table 1: Amputation Incidence Rates in Key Clinical Trials

Bone Mineral Density and Fracture Risk

This compound has also been evaluated for its impact on bone mineral density (BMD) and the risk of fractures.

Bone Mineral Density (BMD): Studies have reported that this compound may be associated with modest decreases in BMD. In older patients (aged 55-80 years) with T2DM, this compound treatment (100 mg and 300 mg) resulted in small, statistically significant reductions in total hip BMD over 104 weeks. Placebo-subtracted changes were -0.9% for the 100 mg dose and -1.2% for the 300 mg dose fda.govoup.com. Similar decreases at the total hip were observed after 2 years of treatment nih.gov. These changes in BMD, along with increases in bone turnover markers (such as serum collagen type 1 β-carboxy-telopeptide and osteocalcin), were correlated with weight loss, a known factor influencing bone metabolism oup.com. The mechanisms are thought to involve weight loss and potential reductions in estradiol levels in women oup.com.

Table 2: Fracture Incidence and BMD Changes Associated with this compound

Electrolyte Imbalances

This compound can influence serum electrolyte concentrations, with notable observations concerning potassium, magnesium, and phosphate.

Potassium: Studies have indicated that this compound is generally associated with small changes in serum potassium levels. Pooled analyses from four placebo-controlled trials showed that mean percent changes from baseline in potassium were slightly higher with this compound 100 mg and 300 mg compared to placebo nih.govtandfonline.com. Episodes of potassium elevation (defined as >5.4 mmol/L and >15% increase from baseline) occurred more frequently in patients treated with this compound, particularly the 300 mg dose, and were more prevalent in those with reduced eGFR nih.govtandfonline.comoup.commdpi.comnih.gov. While adverse events of hyperkalemia were uncommon, they were numerically higher in the CANVAS study with this compound compared to placebo oup.com. Transient increases in serum potassium have also been observed shortly after the initiation of this compound treatment openaccessjournals.com.

Table 3: Electrolyte Changes Associated with this compound

Compound Names:

this compound

Impact on Glycemic Efficacy with Declining Renal Function

Glycemic Control and Safety Profile

High-Performance Liquid Chromatography (HPLC)

Numerous reverse-phase HPLC (RP-HPLC) methods have been developed for the routine analysis of this compound. core.ac.ukpharmascholars.com These methods typically utilize a C18 column and a mobile phase consisting of a mixture of an acidic buffer and an organic solvent like acetonitrile or methanol. core.ac.uknih.gov Detection is commonly performed using a UV detector at wavelengths ranging from 214 nm to 290 nm. pharmascholars.comnih.gov

One validated RP-HPLC method employed an Inertsil ODS-3 column with a mobile phase of 0.02% formic acid and acetonitrile (40:60 v/v) at a flow rate of 1.2 ml/min, with detection at 230 nm. core.ac.uk This method demonstrated a linear response for this compound in the concentration range of 10-50 µg/ml. core.ac.uk Another study utilized a Supelcosil C18 column with a mobile phase of 0.2% v/v trifluoroacetic acid in water and acetonitrile (80:20 v/v) at a flow rate of 1.0 mL/min, with detection at 290 nm. nih.gov This method was found to be linear over a concentration range of 12.6–37.9 μg/mL. nih.gov

Ultra-Performance Liquid Chromatography (UPLC)

UPLC methods offer advantages over traditional HPLC, including shorter run times, improved resolution, and lower solvent consumption. afjbs.com A validated UPLC method for the simultaneous determination of this compound and Metformin utilized a Hypersil Gold column with a mobile phase of methanol and 0.03 M phosphate buffer (80:20 v/v) at a flow rate of 0.4 mL/min. afjbs.com Detection was carried out at 240 nm, and the method demonstrated linearity for this compound over a concentration range of 0.1–50 µg/mL. afjbs.com Another UPLC method for this compound employed a C18 column with a mobile phase of water and methanol (70:30) at a flow rate of 1 ml/min, with detection at 286 nm. impactfactor.org This method showed a limit of detection of 0.0039 µg/ml and a limit of quantification of 0.0119 µg/ml. impactfactor.org

Hyphenated Techniques (e.g., LC-MS/MS, UPLC-MS)

Hyphenated techniques, particularly liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS), are highly sensitive and specific methods for quantifying this compound, especially in biological matrices like plasma and urine. scispace.comnih.govirjms.com These methods often employ an internal standard for accurate quantification. innovareacademics.in

An LC-MS/MS method was developed for the quantification of this compound in rabbit plasma using an Inertsil ODS C18 column and a mobile phase of 0.01M ammonium acetate and methanol (30:70 v/v). scispace.com The method was linear over a range of 5 ng/ml to 600 ng/ml. scispace.com Another UPLC-MS/MS method for quantifying this compound and its metabolites in rat plasma utilized a Waters XBridge BEH C18 column with a mobile phase of 0.1% acetonitrile–formic acid (75:15, v/v). nih.gov

UV Spectrophotometry

UV spectrophotometric methods are based on the measurement of the absorbance of this compound at its wavelength of maximum absorbance (λmax). phmethods.net In methanol, this compound exhibits a λmax at approximately 290 nm. phmethods.netajpaonline.com

One study developed a UV spectrophotometric method with a linearity range of 1-25 μg/ml and a correlation coefficient of 0.9998. bamu.ac.in The method was found to be precise with intra-day and inter-day relative standard deviations ranging from 0.34% to 1.44% and 0.072% to 1.44%, respectively. bamu.ac.in Another method established linearity in the concentration range of 5-10 mcg/mL, with a limit of detection (LOD) of 0.084 mcg/ml and a limit of quantification (LOQ) of 0.255 mcg/ml. phmethods.net

Spectrofluorimetry

Spectrofluorimetry is a highly sensitive technique that measures the fluorescence of a compound. This compound exhibits native fluorescence, which can be exploited for its quantification. researchgate.netpharmasm.com A spectrofluorimetric method was developed using methanol as the solvent, with an excitation wavelength of 293 nm and an emission wavelength of 349 nm. researchgate.netpharmasm.com This method demonstrated a linear relationship in the concentration range of 100-500 ng/mL. researchgate.netpharmasm.com The LOD and LOQ were found to be 13.58 ng/mL and 41.15 ng/mL, respectively. researchgate.netpharmasm.com Another study utilized a synchronous spectrofluorimetric method with a Δλ of 50 nm, measuring the fluorescence intensity at a peak maximum of 291.8 nm, with a linearity range of 100–600 ng/mL. researchgate.netoup.com