Sodiumglucose Cotransporter 2 Inhibitors For Type 2 Diabetes Mellitus: An Overview For The Primary Care Physician
International Journal of Clinical Practice Sodiumglucose cotransporter 2 inhibitors for type 2 diabetes mellitus: An overview for the primary care physician Department of Medicine, State University of New York at Buffalo, Buffalo, NY, USA Paresh Dandona, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, State University of New York at Buffalo, Buffalo, NY, USA. Department of Medicine, State University of New York at Buffalo, Buffalo, NY, USA Paresh Dandona, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, State University of New York at Buffalo, Buffalo, NY, USA. Please review our Terms and Conditions of Use and check box below to share full-text version of article. I have read and accept the Wiley Online Library Terms and Conditions of Use Use the link below to share a full-text version of this article with your friends and colleagues. Learn more. Sodiumglucose cotransporter type 2 (SGLT2) inhibitors are a new class of antihyperglycaemic agents in type 2 diabetes mellitus (T2DM). This review examines their mechanism of action and provides an overview of safety and efficacy from the main studies of SGLT2 inhibitors marketed in the United States and Europe, namely, canagliflozin, dapagliflozin and empagliflozin. We searched the PubMed database to identify relevant publications on the mechanism of action of SGLT2 inhibitors and clinical trial reports. Clinical trials in patients with T2DM have shown significant improvements in glycaemic control vs placebo with canagliflozin, dapagliflozin and empagliflozin: patients were more likely to reach target glycated haemoglobin levels compared with patients receiving placebo. All SGLT2 inhibitors also led to modest reductions in body weight and blood pressure vs placebo. Genera Continue reading >>
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Euglycemic Diabetic Ketoacidosis With Sglt2 Inhibitors In Lean Type 2 Diabetes
Mi-kyung KIM Abstract We experienced a case of euglycemic diabetic ketoacidosis after adding SGLT2 inhibitor to current medications in type 2 diabetes. She was 57 years old and DM duration was 3 years. She had low body mass index (< 18 mg/m2) which may mean relative insulin deficiency state. Her ketone body levels and fasting serum glucagon levels were higher with SGLT2 inhibitors and decreased after stopping them. Their DKA were improved by stopping SGLT2 inhibitors, hydration with insulin treatment. Key words Type 2 diabetes, Euglycemic diabetic ketoacidosis Introduction Sodium-glucose cotransporter 2 (SGLT2) inhibitors are novel anti-hyperglycemic agents showed surprisingly significant reductions in cardiovascular mortality and all-cause mortality [1]. While the exact mechanisms why SGLT2 inhibitors dramatically improved CV outcome are not clear, one of explanations for them is that they lower not only glucose but also weight and blood pressure [2]. In terms of weight loss, SGLT2 inhibitors produce weight loss of ∼2–3 kg, secondary to the 280–320 kcal/day loss because 70-80 g of glucose is excreted in the urine [3,4]. Since type 2 diabetes are usually more obese than non-diabetes, SGLT2 inhibitors may be the first medication after metformin for obese diabetic patients. But, weight loss could be a concern for patients with low body weight after SGLT2 inhibitors treatment. We recently experienced a case of euglycemic diabetic ketoacidosis with SGLT2 inhibitors in lean type 2 diabetes. Case reports A 57-year-old woman was diagnosed with diabetes at the age of 54 years. Her height was 163 cm, body weight was 47 kg and body mass index was 17.7 kg/m2. She had family history of diabetes. She did not have history of diabetic ketoacidosis. She received glimepiride (4 mg Continue reading >>
Sglt2 Inhibitors For The Treatment Of Diabetes
SGLT2 Inhibitors for the Treatment of Diabetes This activity is intended for endocrinologists, diabetologists, primary care physicians, physician assistants, nurse practitioners, and nurses who care for patients with type 1 and type 2 diabetes. The goal of this activity is to review the latest data on emerging treatments for hyperglycemia. Upon completion of this activity, participants will be able to: Discuss the mode of action, side effects, and potential clinical uses of the SGLT2 inhibitors in the treatment of diabetes Review emerging treatments for hyperglycemia in type 2 diabetes, including glucokinase activators, glucagon antagonists, and sirtuins As an organization accredited by the ACCME, Medscape, LLC requires everyone who is in a position to control the content of an education activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines "relevant financial relationships" as financial relationships in any amount, occurring within the past 12 months, including financial relationships of a spouse or life partner, that could create a conflict of interest. Medscape, LLC encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content. Professor of Medicine & Honorary Consultant Physician, Head of Diabetes and Endocrinology Clinical Research Unit, Clinical Sciences Centre, University Hospital Aintree, Liverpool, United Kingdom Disclosure: John P.H. Wilding, DM, FRCP, has disclosed that he has served as an advisor or consultant to AstraZeneca, Bristol-Myers Squibb, and GlaxoSmithKline. Dr. Wilding has also disclosed that he has received grants for clinical research from AstraZeneca and Bristol-Myer Continue reading >>
Where Do Sglt2 Inhibitors Fit In Diabetes Care?
Where Do SGLT2 Inhibitors Fit in Diabetes Care? New Class of Drugs 'Turns Glucosuria on Its Head' This feature requires the newest version of Flash. You can download it here . Do We Need New Treatments for Type 2 Diabetes? Hello. I am Cliff Bailey, Professor of Clinical Science at Aston University in Birmingham, United Kingdom. It is my pleasure to be able to say a few words about sodium glucose co-transporter 2 (SGLT2) inhibitors as a new type of treatment for type 2 diabetes to control hyperglycemia. You might reasonably ask why we want new treatments for type 2 diabetes, bearing in mind the selection that we have already, so I would like to preface these words with some words about type 2 diabetes as a heterogeneous and progressive disease. It has a multivariable etiopathology, meaning that essentially there are many different factors that contribute to type 2 diabetes to different extents in different individuals, and these play out to a greater or lesser extent as the disease progresses. Therefore, we need different treatments and different combinations of treatments to focus on these different factors at different times as the disease progresses. Glycemic control is an important issue in type 2 diabetes. Blood pressure control is very important and lipid control is very important. We now have very good evidence that good glycemic control, especially at the very beginning of type 2 diabetes, after diagnosis, is also very important in the long term to reduce the onset and severity of the complications of type 2 diabetes and to reduce macrovascular risk. Therefore, there is very good rationale for using as many therapies as we need at different times to control hyperglycemia. Continue reading >>
Euglycemic Diabetic Ketoacidosis: The Clinical Concern Of Sglt2 Inhibitors
Euglycemic diabetic ketoacidosis is a post market warning in patients with type 1 diabetes and type 2 diabetes treated with SGLT-2 inhibitors. We report a case of a 39-year-old obese female with presumed type 2 diabetes for seven years who presented to the emergency department with three days of nausea, vomiting, and abdominal pain. Due to previous total non-adherence with a prescribed insulin regimen, she was recently started on canagliflozin and liraglutide. The diagnosis of euDKA was missed in the initial evaluation as the blood glucose level was only 167 mg/dL. Further work up showed severe metabolic acidosis with an anion gap of 25 and positive ketones in the urine. She was treated successfully with dextrose water 5%/half normal saline and an insulin drip. As part of the work up, she tested positive for glutamic acid decarboxylase autoantibodies. Given the increasing utilization of SGLT-2 inhibitors and the fact that patients can present with near-normal glycemia, the diagnosis can be missed. Vigilance with the use of SGLT-2 inhibitors is necessary to decrease morbidity and potentially mortality particularly in patients with long-standing type 2 diabetes associated with marked β-cell insufficiency, type 1 diabetes mellitus, or latent autoimmune diabetes of adult onset. Continue reading >>
Sglt2 Inhibitors And The Diabetic Kidney.
Diabetes Care. 2016 Aug;39 Suppl 2:S165-71. doi: 10.2337/dcS15-3006. SGLT2 Inhibitors and the Diabetic Kidney. Department of Medicine, University of Padua, Padua, Italy [email protected] Department of Medicine, University of Padua, Padua, Italy. Diabetic nephropathy (DN) is the most common cause of end-stage renal disease worldwide. Blood glucose and blood pressure control reduce the risk of developing this complication; however, once DN is established, it is only possible to slow progression. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, the most recent glucose-lowering oral agents, may have the potential to exert nephroprotection not only through improving glycemic control but also through glucose-independent effects, such as blood pressure-lowering and direct renal effects. It is important to consider, however, that in patients with impaired renal function, given their mode of action, SGLT2 inhibitors are less effective in lowering blood glucose. In patients with high cardiovascular risk, the SGLT2 inhibitor empagliflozin lowered the rate of cardiovascular events, especially cardiovascular death, and substantially reduced important renal outcomes. Such benefits on DN could derive from effects beyond glycemia. Glomerular hyperfiltration is a potential risk factor for DN. In addition to the activation of the renin-angiotensin-aldosterone system, renal tubular factors, including SGLT2, contribute to glomerular hyperfiltration in diabetes. SGLT2 inhibitors reduce sodium reabsorption in the proximal tubule, causing, through tubuloglomerular feedback, afferent arteriole vasoconstriction and reduction in hyperfiltration. Experimental studies showed that SGLT2 inhibitors reduced hyperfiltration and decreased inflammatory and fibrotic responses of proximal tubula Continue reading >>
Sglt2 Inhibitor/dpp-4 Inhibitor Combination Therapy Complementary Mechanisms Of Action For Management Of Type 2 Diabetes Mellitus
SGLT2 inhibitor/DPP-4 inhibitor combination therapy complementary mechanisms of action for management of type 2 diabetes mellitus Accepted author version posted online: 21 Mar 2017 Get access/doi/full/10.1080/00325481.2017.1307081?needAccess=true Type 2 diabetes mellitus is a progressive disease with multiple underlying pathophysiologic defects. Monotherapy alone cannot maintain glycemic control and leads to treatment failure. Ideally, a combination of glucose-lowering agents should have complementary mechanisms of action that address multiple pathophysiologic pathways, can be used at all stages of the disease, and be generally well tolerated with no increased risk of hypoglycemia, cardiovascular events, or weight gain. The combination should also provide conveniences for patients, such as oral dosing, single-pill formulations, and once-daily administration, potentially translating to improved adherence. Two classes of glucose-lowering agents that meet these criteria are the sodium glucose cotransporter-2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors. This article reviews the rationale for combination therapy with these agents, and evidence from clinical trials with empagliflozin and linagliptin or dapagliflozin and saxagliptin in the management of type 2 diabetes mellitus. Both combinations have been approved as single-pill formulations. Continue reading >>
The Efficacy And Safety Of Sglt2 Inhibitors For Adjunctive Treatment Of Type 1 Diabetes: A Systematic Review And Meta-analysis
The efficacy and safety of SGLT2 inhibitors for adjunctive treatment of type 1 diabetes: a systematic review and meta-analysis Scientific Reports volume 7, Articlenumber:44128 (2017) To assess the efficacy and safety of the SGLT-2 inhibitors as adjunct therapy to insulin in T1DM, clinical trials indexed in PubMed, Cochrane Library, EMbase from inception through April 5, 2016. A meta-analysis was conducted on trials of SGLT-2 inhibitors in patients with T1DM on insulin therapy using RevMan 5.3 software. Of the 371 articles identified, ten met eligibility criteria. Seven clinical trials including four randomized controlled trials and 581 patients were included. Compared with the control group, SGLT-2 inhibitors group had significantly reduced fasting plasma glucose by 0.69 mmol/L [1.32; 0.07], glycosylated hemoglobin A1C by 0.37% [0.54; 0.20], body weight by 2.54 kg [3.48; 1.60] and total daily insulin dose by 6.22 IU [8.04; 4.40]. The total incidence of adverse events (AEs), hypoglycemia, and genital and urinary infections were also similar to placebo, while an increased incidence of diabetic ketoacidosis (DKA) (n = 16) was seen in SGLT-2 inhibitors group. The present study demonstrates that SGLT-2 inhibitors are effective as adjunct therapy to insulin in T1DM, heralding improved glycemic control, reduced body weight and total daily insulin dose without an increase in total AEs, hypoglycemia, or genital and urinary infections. However, the risk of DKA should be carefully monitored in future clinical trials. Diabetes mellitus (DM) is the seventh leading cause of mortality worldwide, with a continually increasing prevalence and incidence 1 . Globally, in 2015 the disease prevalence was 415 million adults, with an estimated 318 million people at risk for development of DM, Continue reading >>
Sglt2 Inhibitors: An Effective Option For Diabetes Management
SGLT2 Inhibitors: An Effective Option for Diabetes Management The most recent class of diabetes medications to be approved by the Food and Drug Administration (FDA) is called Sodium Glucose Co-Transporter 2 Inhibitors, also known as SGLT2 inhibitors. SGLT2 inhibitors work in the kidneys by preventing glucose (sugar) from being reabsorbed into the blood stream. Instead, the sugar is eliminated in urine. By eliminating sugar this way, you lower your blood sugar levels and your A1C levels. There are now three SGLT2 inhibitors available in the United States, and they arecanagliflozin (Invokana), empagliflozin (Jardiance), and dapagliflozin (Farxiga). Each of these medications are also available as a combination product mixed with other diabetes medications. SGLT2 inhibitors are currently approved for use in patients with type 2 diabetes. They are taken once a day in the morning. These medications may lower your blood pressure; so your blood pressure should be monitored. Sometimes the doses of your blood pressure medications can be decreased.When you urinate out sugar you are losing calories, which can lead to some weight loss. Because you may urinate more frequently when taking this drug, especially when first taking it, make sure you stay well hydrated. Like all medications, SGLT2 inhibitors can cause some side effects. The most commonly reported in both men and women are urinary tract infections (UTI), genital fungal infections (yeast infection), and increased urination. If any of these happen, they are usually mild, easily treated, and do not reoccur. Rare side effects are diabetic ketoacidosis (DKA) and kidney infections.These medications have been prescribed world-wide to over 5 million people and the incidence of these side effects is very rare. For example, as of Ma Continue reading >>
Sglt2 Inhibitors: A New Treatment Option For Type 2 Diabetes
Introduction Diabetes mellitus is a chronic disease often requiring complex treatment regimens to prevent long-term complications.1 In 2010, it was estimated that 18.8 million adults and children in the United States were diagnosed with diabetes and another 7 million went undiagnosed, with the prevalence of diabetes expected to increase significantly by 2050.2,3 Various classes of medications have been approved by the FDA for the treatment of diabetes; however, few highly effective options are available with minimal adverse effects.1 Thus, the search continues for improved diabetes therapies. The FDA recently approved 2 medications from a novel class called sodium- glucose cotransporter 2 (SGLT2) inhibitors. This article will detail the characteristics of these agents, summarize the evidence leading to their approval, describe their current place in therapy, and discuss ongoing research involving this novel class. SGLT2 Inhibition Each day, approximately 180 g of glucose are filtered from the glomeruli of a healthy adult, and almost all of the filtered glucose is reabsorbed from the glomerular filtrate and returned to the circulation.4 Of the filtered glucose, 90% is reabsorbed in the bloodstream by the SGLT2, located primarily in the luminal membrane of the proximal renal tubules.5 The cotransportation of glucose and sodium from the filtrate is driven by the active transport of sodium out of the basolateral cells by the Na/K-ATPase pump.4 Glucose is also transferred out of the cell with the concentration gradient and subsequently returned to the bloodstream by glucose transporters. In type 2 diabetes mellitus (T2DM), renal glucose handling and transport is increased, likely due to upregulation of SGLT2. As a result, glucose excretion in the urine occurs only at higher Continue reading >>
Practical Approach To Initiating Sglt2 Inhibitors In Type 2 Diabetes
, Volume 8, Issue5 , pp 953962 | Cite as Practical Approach to Initiating SGLT2 Inhibitors in Type 2 Diabetes Sodium-glucose co-transporter 2 (SGLT2) inhibitors are an attractive novel therapeutic option for the treatment of type 2 diabetes. They block the reabsorption of filtered glucose in kidneys, mainly in proximal renal tubules, resulting in increased urinary glucose excretion and correction of the diabetes-related hyperglycemia. Beyond improving glucose control, SGLT2 inhibitors offer potential benefits by reducing body weight and blood pressure. On the basis of the efficacy demonstrated in clinical trials, SGLT2 inhibitors are recommended as second- or third-line agents for the management of patients with type 2 diabetes. Beneficial effects on kidney disease progression, cardiovascular and all-cause mortality, and hospitalization for heart failure have also been demonstrated with one SGLT2 inhibitor (empagliflozin). Potential adverse events resulting from their mechanism of action or related to concomitant therapies are reviewed. A treatment algorithm for the adjustment of concomitant therapies after initiating SGLT2 inhibitors is also proposed. ConcomitantInitiationManagementSGLT2 inhibitorsType 2 diabetes This article has associated CME accreditation, valid until July 2018. Please follow this link to access the activity: . To view enhanced content for this article go to . An erratum to this article is available at . Type 2 diabetes mellitus (T2DM) is a chronic metabolic condition characterized by a hyperglycemic state due to impaired insulin secretion and diminished insulin action in peripheral tissues [ 1 ]. Diabetes is the leading cause of blindness, non-traumatic limb amputations, and chronic kidney disease. It is strongly associated with an increased risk Continue reading >>
Is An Sglt2 Inhibitor Right For Your Patient With Type 2 Diabetes?
Is an SGLT2 inhibitor right for your patient with type 2 diabetes? J Fam Pract. 2016 September;65(9):587-593 Department of Pharmacy Practice, Auburn University, Harrison School of Pharmacy, Alabama The authors reported no potential conflict of interest relevant to this article. Metformin isnt quite doing the job or is contraindicated? Heres a look at the patients who may benefit from these agents and the monitoring required. 1. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach. Update to a position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2015;38:140-149. 2. Canagliflozin, dapagliflozin, empagliflozin. Lexicomp, Inc. (Lexi-Drugs). Accessed October 12, 2015. 3. Stenlf K, Cefalu WT, Kim KA, et al. Long-term efficacy and safety of canagliflozin monotherapy in patients with type 2 diabetes mellitus inadequately controlled with diet and exercise: findings from the 52-week CANTATA-M study. Curr Med Res Opin. 2014;30:163-175. 4. Ferrannini E, Ramos SJ, Salsali A, et al. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care. 2010:33:2217-2224. 5. Roden M, Weng J, Eilbracht J, et al. Empagliozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol. 2013;1:208-219. 6. Ferrannini E, Berk A, Hantel S, et al. Long-term safety and efficacy of empagliflozin, sitagliptin, and metformin: an active-controlled, parallel-group, randomized, 78-week open-label extension study Continue reading >>
Nsaids With Sglt2 Inhibitors In Diabetes May Cause Renal Injury
NSAIDs With SGLT2 Inhibitors in Diabetes May Cause Renal Injury Use of sodiumglucose cotransporter 2 (SGLT2) inhibitors for treatment of type 2 diabetes could potentially lead to hypoxic acute renal injury in the setting of dehydration and/or during use of nonsteroidal anti-inflammatory agents (NSAIDs) or radiocontrast studies, according to an Israeli research team. Hence, those circumstances should be avoided while people are taking the SGLT2 inhibitor class of glucose-lowering agents, Samuel N Heyman, MD, of Hadassah Hebrew University Hospitals, Jerusalem, Israel, and colleagues advise in an observation piece, published online January 27 in Diabetes Care. SGLT2 inhibitors, such as canagliflozin canagliflozin (Invokana, Janssen) and dapagliflozin (Farxiga/Forxiga, AstraZeneca), carry US Food and Drug Administration (FDA) label warnings about acute kidney injury. At the same time, empagliflozin (Jardiance, Boehringer Ingelheim), also an SGLT2 inhibitor, has been associated with long-term renoprotection in the EMPA-REG Outcome Study . And canagliflozin is being specifically tested in a diabetic kidney-disease population in the large multicenter randomized Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE) trial. Although one issue is acute renal injury and the other long-term renal protection, these observations have caused some confusion among physicians. Urine Biomarkers Needed to Assess Occurrence of Renal Injury Now, in their new publication, Dr Heyman and colleagues say "there might be a few explanations for this troubling news other than mere chance and publication bias." They note that "while an initial reduction in glomerular filtration rate, related to transglomerular pressure red Continue reading >>
Sodium-glucose Co-transporter 2 Inhibitors For The Treatment Of Type 2 Diabetes Mellitus
INTRODUCTION Current treatments for type 2 diabetes have centered on increasing insulin availability (either through direct insulin administration or through agents that promote insulin secretion), improving sensitivity to insulin, delaying the delivery and absorption of carbohydrate from the gastrointestinal tract, or increasing urinary glucose excretion. Sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce blood glucose by increasing urinary glucose excretion. This topic will review the mechanism of action and therapeutic utility of SGLT2 inhibitors for the treatment of type 2 diabetes mellitus. A general discussion of the initial management of blood glucose and the management of persistent hyperglycemia in adults with type 2 diabetes is presented separately. (See "Initial management of blood glucose in adults with type 2 diabetes mellitus" and "Management of persistent hyperglycemia in type 2 diabetes mellitus".) MECHANISM OF ACTION The SGLT2 is expressed in the proximal tubule and mediates reabsorption of approximately 90 percent of the filtered glucose load. SGLT2 inhibitors promote the renal excretion of glucose and thereby modestly lower elevated blood glucose levels in patients with type 2 diabetes. The ability to lower blood glucose and glycated hemoglobin (A1C) levels is limited by the filtered load of glucose and the osmotic diuresis that is caused by this therapy. Moreover, although the currently developed SGLT2 inhibitors almost completely block proximal tubular glucose reabsorption, the measured inhibition is less than 50 percent based on urine glucose excretion. The glucose-lowering effect is independent of insulin (beta cell function and insulin sensitivity). Thus, they do not usually cause hypoglycemia in the absence of therapies that otherwise cau Continue reading >>
The Emerging Role Of Sglt2 Inhibitors In The Treatment Of Type 2 Diabetes. Focus On Dapagliflozin
The Emerging Role of SGLT2 Inhibitors in the Treatment of Type 2 Diabetes. Focus on Dapagliflozin The Emerging Role of SGLT2 Inhibitors in the Treatment of Type 2 Diabetes. Focus on Dapagliflozin Department of Functional Sciences, Victor Babe University of Medicine and Pharmacy, Timioara, Romania Department of Diabetes Nutrition and Metabolic Diseases, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania 2nd Department of Internal Medicine, Victor Babe University of Medicine and Pharmacy, Timioara, Romania Published Online: 2016-03-19 | DOI: An erratum for this article can be found here: Type 2 diabetes is a progressive metabolic disorder, accounting for more than 90% of all cases of diabetes. Treatment strategies target blood glucose reduction and non-glycemic effects that can reduce long-term complications, such as cardiovascular disease. Although metformin is often initially effective as monotherapy, the progressive nature of diabetes frequently requires additional therapies. Sodium-glucose transporter 2 (SGLT2) became a very attractive therapeutic target in diabetes management. The mechanism of action of SGLT2 inhibitors is not dependent on insulin, thus making them attractive options anytime over the course of the disease. Dapagliflozin is a stable and highly selective inhibitor of SGLT2. The reductions in fasting plasma glucose concentration and bodyweight recorded during the first week of treatment in the dapagliflozin groups continued over weeks and years of treatment. Early weight loss with dapagliflozin might be partly due to a mild osmotic diuresis, while the gradual progressive reduction in bodyweight is consistent with a reduction of fat mass. Although dapagliflozin is well tolerated, signs and symptoms suggestive for urinary and/or genital Continue reading >>
