Active comparator restricted disproportionality analysis for pharmacovigilance signal detection studies of chronic disease medications: An example using sodium/glucose cotransporter 2 (SGLT2) inhibitors

: Type 2 diabetes mellitus is one of the most common forms of the disease worldwide. Hyperglycemia and insulin resistance play key roles in type 2 diabetes mellitus. Renal glucose reabsorption is an essential feature in glycaemic control. Kidneys filter 160 g of glucose daily in healthy subjects under euglycaemic conditions. The expanding epidemic of diabetes leads to a prevalence of diabetes-related cardiovascular disorders, in particular, heart failure and renal dysfunction. Cellular glucose uptake is a fundamental process for homeostasis, growth, and metabolism. In humans, three families of glucose transporters have been identified, including the glucose facilitators GLUTs, the sodium-glucose cotransporter SGLTs, and the recently identified SWEETs. Structures of the major isoforms of all three families were studied. Sodium-glucose cotransporter (SGLT2) provides most of the capacity for renal glucose reabsorption in the early proximal tubule. A number of cardiovascular outcome trials in patients with type 2 diabetes have been studied with SGLT2 inhibitors reducing cardiovascular morbidity and mortality. : The current review article summarises these aspects and discusses possible mechanisms with SGLT2 inhibitors in protecting heart failure and renal dysfunction in diabetic patients. Through glucosuria, SGLT2 inhibitors reduce body weight and body fat, and shift substrate utilisation from carbohydrates to lipids and, possibly, ketone bodies. These pleiotropic effects of SGLT2 inhibitors are likely to have contributed to the results of the EMPA-REG OUTCOME trial in which the SGLT2 inhibitor, empagliflozin, slowed down the progression of chronic kidney disease and reduced major adverse cardiovascular events in high-risk individuals with type 2 diabetes. This review discusses the role of SGLT2 in the physiology and pathophysiology of renal glucose reabsorption and outlines the unexpected logic of inhibiting SGLT2 in the diabetic kidney.

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Efficacy and cardiovascular safety of SGLT2 Inhibitors

Current Drug Safety ◽

10.2174/1574886315666201002154640 ◽

2020 ◽

Vol 15 ◽

Author(s):

Cornelius James Fernandez ◽

Abisha Graciano Nevins ◽

Shasta Nawaz ◽

Tahir Nazir ◽

Fahmy W F Hanna

Keyword(s):

Decision Process ◽

Cardiovascular Events ◽

Unmet Need ◽

Clinical Decision ◽

Sglt2 Inhibitors ◽

Renal Protection ◽

Sodium Glucose Cotransporter ◽

Patients With Diabetes ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

: Patients with diabetes continued to exhibit a high risk for cardiovascular and renal events despite achieving satisfactory glycemic, blood pressure and lipid targets. Studies evaluating new diabetes medications focused on cardiovascular events, largely overlooking heart failure (HF). The latter has recently been recognised as a major cause of morbidity and mortality in patients with diabetes mellitus. There had been an unmet need for drugs with cardiovascular (including HF) and renal protection, with an expectation that an ideal diabetic drug should improve these end points. Moreover, an ideal drug should have weight lowering benefits. Recently published outcome trials have shown that sodium glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1RAs) can reduce cardiovascular and renal events, together with statistically significant weight reduction. As a result, many recently published international guidelines have recommended SGLT2 inhibitors and GLP-1RAs in patients with diabetes and pre-existing cardiovascular disease (CVD). In this review we will critically analyse the efficacy and cardiovascular (CV) safety of SGLT2 inhibitors, based on the available literature to help position them in the clinical decision process.

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Central administration of sodium-glucose cotransporter-2 inhibitors increases food intake involving adenosine monophosphate-activated protein kinase phosphorylation in the lateral hypothalamus in healthy rats

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-002104 ◽

2021 ◽

Vol 9 (1) ◽

pp. e002104

Author(s):

Kenji Takeda ◽

Hiraku Ono ◽

Ko Ishikawa ◽

Tomohiro Ohno ◽

Jin Kumagai ◽

...

Keyword(s):

Food Intake ◽

Lateral Hypothalamus ◽

Molecular Mechanisms ◽

Intraperitoneal Administration ◽

Adenosine Monophosphate ◽

Sglt2 Inhibitors ◽

Central Administration ◽

Hypothalamic Area ◽

Sodium Glucose Cotransporter ◽

Increase Food Intake

IntroductionSodium glucose cotransporter-2 (SGLT2) inhibitors are widely used for diabetes treatment. Although SGLT2 inhibitors have been clinically observed to increase food intake, roles or even the presence of SGLT2 in the central nervous system (CNS) has not been established. We aimed to elucidate potential functions of SGLT2 in the CNS, and the effects of CNS-targeted SGLT2 inhibitors on food intake.Research design and methodsWe administered three kinds of SGLT2 inhibitors, tofogliflozin, dapagliflozin, and empagliflozin, into the lateral ventricle (LV) in rats and evaluated their effects on food intake. We also evaluated the effects of tofogliflozin administration in the third (3V) and fourth ventricle (4V). Intraperitoneal administration of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist known to suppress food intake, was combined with central tofogliflozin to elucidate whether GLP-1 signaling antagonizes the effect of central SGLT2 inhibitors on food intake. To elucidate potential molecular mechanisms mediating changes in feeding, hypothalamic areas associated with food intake regulation were harvested and analyzed after intracerebroventricular administration (ICV) of tofogliflozin.ResultsBolus ICV injection of tofogliflozin induced a robust increase in food intake starting at 1.5 hours postinjection, and lasting for 5 days. No effect was observed when the same dose of tofogliflozin was administered intraperitoneally. ICV dapagliflozin and empagliflozin significantly enhanced food intake, although the strength of these effects varied among drugs. Food intake was most markedly enhanced when tofogliflozin was infused into the LV. Fewer or no effects were observed with infusion into the 3V or 4V, respectively. Systemic administration of liraglutide suppressed the effect of ICV tofogliflozin on food intake. ICV tofogliflozin increased phosphorylation of AMPK and c-fos expression in the lateral hypothalamus.ConclusionsSGLT2 inhibitors in the CNS increase food intake. SGLT2 activity in the CNS may regulate food intake through AMPK phosphorylation in the lateral hypothalamic area.

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Pleiotropic Effects of Sodium-Glucose Cotransporter-2 Inhibitors: Renoprotective Mechanisms beyond Glycemic Control

International Journal of Molecular Sciences ◽

10.3390/ijms22094374 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4374

Author(s):

Tomoaki Takata ◽

Hajime Isomoto

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Glycemic Control ◽

Kidney Injury ◽

Sglt2 Inhibitors ◽

Pleiotropic Effects ◽

Future Research ◽

Diabetic Patients ◽

Sodium Glucose Cotransporter ◽

Stage Renal Disease

Diabetes mellitus is a major cause of chronic kidney disease and end-stage renal disease. However, the management of chronic kidney disease, particularly diabetes, requires vast improvements. Recently, sodium-glucose cotransporter-2 (SGLT2) inhibitors, originally developed for the treatment of diabetes, have been shown to protect against kidney injury via glycemic control, as well as various other mechanisms, including blood pressure and hemodynamic regulation, protection from lipotoxicity, and uric acid control. As such, regulation of these mechanisms is recommended as an effective multidisciplinary approach for the treatment of diabetic patients with kidney disease. Thus, SGLT2 inhibitors are expected to become key drugs for treating diabetic kidney disease. This review summarizes the recent clinical evidence pertaining to SGLT2 inhibitors as well as the mechanisms underlying their renoprotective effects. Hence, the information contained herein will advance the current understanding regarding the pleiotropic effects of SGLT2 inhibitors, while promoting future research in the field.

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Pharmacovigilance of Sodium-Glucose Cotransporter-2 Inhibitors for Genital Fungal Infections and Urinary Tract Infections: A Review of the Food and Drug Administration Adverse Event Reporting System Database

Journal of Pharmacy Technology ◽

10.1177/8755122518760984 ◽

2018 ◽

Vol 34 (4) ◽

pp. 144-148

Author(s):

Hannah Mohammad ◽

Nancy Borja-Hart

Keyword(s):

Urinary Tract ◽

Tract Infection ◽

Adverse Events ◽

Fungal Infections ◽

Adverse Event Reporting System ◽

Adverse Event Reporting ◽

Sglt2 Inhibitors ◽

Postmarketing Surveillance ◽

Sodium Glucose Cotransporter ◽

Tract Infections

Background: Postmarketing surveillance had previously identified the need for revisions in the labeling of the sodium-glucose cotransporter-2 (SGLT2) inhibitors drug class related to the risk of diabetic ketoacidosis. Other adverse events have been reported. Objective: To examine postmarketing surveillance data of the SGLT2 inhibitors, using the Food and Drug Administration Adverse Event Reporting System (FAERS) database, specifically to assess prevalence of urinary tract infections (UTIs) and genital fungal infections. Methods: FAERS case reports submitted between March 2013 and November 2015 were reviewed for 6 SGLT2 inhibitors (mono and combo therapies). The Medical Dictionary for Regulatory Activities (MedDRA) was used to define preferred terms (genital fungal infections: vulvovaginal mycotic infection, vulvovaginal candidiasis, urinary tract infection fungal, and genital candidiasis; UTI: urinary tract infection, genitourinary tract infection, kidney infection, cystitis, and pyelonephritis). Word frequencies were queried using the qualitative data analysis software NVivo 11 (QSR International), and results were then individually reviewed. Results: A total of 12 581 cases were received, but 466 were excluded (total n = 12 115). A total of 348 cases related to genital fungal infections were reported (2.9% of reports submitted): dapagliflozin = 53, empagliflozin/linagliptin = 6, canagliflozin = 267, canagliflozin/metformin = 3, empagliflozin = 17, and dapagliflozin/metformin HCl ER = 2. A total of 727 cases related to UTIs were reported (6% of reports submitted): dapagliflozin = 168, empagliflozin/linagliptin = 5, canagliflozin/metformin = 8, canagliflozin = 503, empagliflozin = 38, and dapagliflozin/metformin HCl ER = 5. Conclusions: A causal relationship between SGLT2 inhibitors and the adverse events reported cannot be established due to the nature of postmarketing surveillance. However, health care providers should counsel patients about these potential adverse events.

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The Efficacy of Sodium-Glucose Cotransporter 2 (SGLT2) inhibitors for the treatment of chronic diabetic macular oedema in vitrectomised eyes: a retrospective study

BMJ Open Ophthalmology ◽

10.1136/bmjophth-2017-000130 ◽

2018 ◽

Vol 3 (1) ◽

pp. e000130 ◽

Cited By ~ 4

Author(s):

Hiroki Mieno ◽

Kazuhito Yoneda ◽

Masahiro Yamazaki ◽

Ryosuke Sakai ◽

Chie Sotozono ◽

...

Keyword(s):

Macular Oedema ◽

Sglt2 Inhibitor ◽

Diabetic Macular Oedema ◽

Sglt2 Inhibitors ◽

Rank Test ◽

Sodium Glucose Cotransporter ◽

Signed Rank ◽

Before And After ◽

Patients With Diabetes ◽

Signed Rank Test

ObjectiveTo investigate the change of chronic diabetic macular oedema (DMO) in vitrectomised eyes when the administration of sodium–glucose cotransporter 2 (SGLT2) inhibitors is initiated as a systemic medical treatment.Methods and analysisThis study involved 10 eyes of five patients with chronic DMO lasting more than 6 months who had previously undergone vitrectomy and whose systemic medical treatments were newly changed to SGLT2 inhibitors. In this study, chronic DMO was defined as persistent diffuse macular oedema despite ophthalmic treatment in patients with diabetes. Patients who received antivascular endothelial growth factor therapy or steroids administration, or change of eye-drop medication from at 3 months before and after the initiation of SGLT2 inhibitors, were excluded. In this study, visual acuity (VA) and central retinal thickness (CRT, μm) prior to and at 3, 6 and 12 months after the initiation of SGLT2 inhibitors were retrospectively compared. The Wilcoxon signed-rank test was used for statistical analysis.ResultsIn the 10 treated eyes, from at baseline to at 3, 6 and 12 months after the initiation of SGLT2 inhibitor, median VA (logMAR) improved from 0.35 to 0.15 (p=0.038), 0.2 (p=0.157) and 0.2 (p=0.096), respectively, and median CRT significantly reduced from 500.5 µm to 410 µm (p<0.01), 378 µm (p<0.01) and 339 µm (p<0.01), respectively.ConclusionAlthough this study involved only five patients, our findings indicate that SGLT2 inhibitors might have structural efficacy for chronic DMO in vitrectomised eyes.

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Mitigation of the Adverse Consequences of Nutrient Excess on the Kidney: A Unified Hypothesis to Explain the Renoprotective Effects of Sodium-Glucose Cotransporter 2 Inhibitors

American Journal of Nephrology ◽

10.1159/000506534 ◽

2020 ◽

Vol 51 (4) ◽

pp. 289-293 ◽

Cited By ~ 2

Author(s):

Milton Packer

Keyword(s):

Type 2 Diabetes ◽

Adipose Tissue ◽

Renin Angiotensin System ◽

Tissue Expansion ◽

Adenosine Monophosphate ◽

Sglt2 Inhibitors ◽

Sirtuin 1 ◽

Glomerular Hyperfiltration ◽

Sodium Glucose Cotransporter

The 2 most common causes of chronic kidney disease worldwide (type 2 diabetes and obesity) are states of nutrient excess, suggesting that fuel overabundance leads to deleterious effects on the structure and function of the kidneys. Three pathophysiological pathways may potentially explain this linkage. First, both obesity and type 2 diabetes are characterized by glomerular hyperfiltration, which may result from increased proximal tubular reabsorption of sodium (due to enhanced glucose and sodium transport) coupled with activation of the renin-angiotensin system. Second, both obesity and type 2 diabetes are characterized by adipose tissue expansion and inflammation, followed by the augmented synthesis and release of lipid intermediates and proinflammatory adipocytokines that can have deleterious effects on the kidney. Third, states of nutrient excess cause a diminution in the activation of the energy sensors, sirtuin-1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK). The result is a suppression of autophagy, a lysosomal degradative pathway that is responsible for the clearance of damaged organelles that are an important source of oxidative and endoplasmic reticulum stress and inflammation. Sodium-glucose cotransporter 2 (SGLT2) inhibitors induces a transcriptional paradigm that mimics fasting, which leads to the amelioration of glomerular hyperfiltration and adipose tissue inflammation as well as augmentation of AMPK/SIRT1 signaling and autophagy, thereby acting to mute organellar and cellular stress in the kidney. Therefore, SGLT2 inhibitors are positioned to antagonize all 3 pathways by which nutrient excess can lead to nephropathy.

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How and why SGLT2 inhibitors should be explored as potential treatment option in diabetic retinopathy: clinical concept and methodology

Therapeutic Advances in Endocrinology and Metabolism ◽

10.1177/2042018819891886 ◽

2019 ◽

Vol 10 ◽

pp. 204201881989188 ◽

Cited By ~ 2

Author(s):

Marcus May ◽

Theodor Framke ◽

Bernd Junker ◽

Carsten Framme ◽

Amelie Pielen* ◽

...

Keyword(s):

Treatment Option ◽

Microvascular Complications ◽

Treatment Options ◽

Sglt2 Inhibitors ◽

Diabetic Microangiopathy ◽

Potential Treatment ◽

Treatment And Prevention ◽

Clinical Complications ◽

Sodium Glucose Cotransporter ◽

Increased Risk

Patients suffering from type 2 diabetes are at an increased risk of developing classical microvascular complications such as retinopathy, neuropathy, and nephropathy, which represent a significant health burden. Tight control of blood glucose, blood pressure, and serum cholesterol reduce the risk of microvascular complications but effective pharmacologically targeted treatment options for the treatment and prevention of diabetic microangiopathy are still lacking. Pharmacological inhibition of sodium glucose cotransporter 2 (SGLT2) might have the potential to directly protect against microvascular complications and could represent a potential treatment option. Randomized controlled clinical proof of concept trials are needed to investigate a potential central role of SGLT2 inhibitors in the prevention of diabetic microangiopathy and its classical clinical complications of retinopathy, neuropathy, and nephropathy.

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Antidiabetic Therapy in the Treatment of Nonalcoholic Steatohepatitis

International Journal of Molecular Sciences ◽

10.3390/ijms21061907 ◽

2020 ◽

Vol 21 (6) ◽

pp. 1907 ◽

Cited By ~ 10

Author(s):

Yoshio Sumida ◽

Masashi Yoneda ◽

Katsutoshi Tokushige ◽

Miwa Kawanaka ◽

Hideki Fujii ◽

...

Keyword(s):

Liver Disease ◽

Nonalcoholic Steatohepatitis ◽

Body Weight Gain ◽

Severe Form ◽

Sglt2 Inhibitors ◽

Glucagon Receptor ◽

Nonalcoholic Fatty Liver ◽

Antidiabetic Therapy ◽

Sodium Glucose Cotransporter ◽

Glucagon Like Peptide 1

Liver-related diseases are the third-leading causes (9.3%) of mortality in type 2 diabetes (T2D) in Japan. T2D is closely associated with nonalcoholic fatty liver disease (NAFLD), which is the most prevalent chronic liver disease worldwide. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can lead to hepatocellular carcinoma (HCC) and hepatic failure. No pharmacotherapies are established for NASH patients with T2D. Though vitamin E is established as a first-line agent for NASH without T2D, its efficacy for NASH with T2D recently failed to be proven. The effects of pioglitazone on NASH histology with T2D have extensively been established, but several concerns exist, such as body weight gain, fluid retention, cancer incidence, and bone fracture. Glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors are expected to ameliorate NASH and NAFLD (LEAN study, LEAD trial, and E-LIFT study). Among a variety of SGLT2 inhibitors, dapagliflozin has already entered the phase 3 trial (DEAN study). A key clinical need is to determine the kinds of antidiabetic drugs that are the most appropriate for the treatment of NASH to prevent the progression of hepatic fibrosis, resulting in HCC or liver-related mortality without increasing the risk of cardiovascular or renal events. Combination therapies, such as glucagon receptor agonist/GLP-1 or gastrointestinal peptide/GLP-1, are under development. This review focused on antidiabetic agents and future perspectives on the view of the treatment of NAFLD with T2D.

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