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 >>
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 >>
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 >>
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 >>
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 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 . 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 . 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 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 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 >>
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 >>
Acute Kidney Injury In Patients On Sglt2 Inhibitors: A Propensity-matched Analysis.
Diabetes Care. 2017 Nov;40(11):1479-1485. doi: 10.2337/dc17-1011. Epub 2017 Aug 21. Acute Kidney Injury in Patients on SGLT2 Inhibitors: A Propensity-Matched Analysis. Department of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY [email protected] [email protected] Icahn School of Medicine at Mount Sinai, New York, NY. Division of Nephrology, Geisinger Medical Center, Danville, PA. Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD. Department of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY. Institute for Healthcare Delivery Science, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are new medications that improve cardiovascular and renal outcomes in patients with type 2 diabetes (T2D). However, the Food and Drug Administration has issued alerts regarding increased acute kidney injury (AKI) risk with canagliflozin and dapagliflozin. We aimed to assess the real-world risk of AKI in new SGLT2 inhibitor users in two large health care utilization cohorts of patients with T2D. We used longitudinal data from the Mount Sinai chronic kidney disease registry and the Geisinger Health System cohort. We selected SGLT inhibitor users and nonusers (patients with T2D without SGLT2 inhibitor prescription). We determined AKI by the KDIGO (Kidney Disease: Improving Global Outcomes) definition (AKIKDIGO). We performed 1:1 nearest-neighbor propensity matching and calculated unadjusted hazard ratios (HRs) and adjusted HRs (aHRs; accounting for covariates poorly balanced) for AKI in primary and sensitivity analyses. We identified 377 SGLT2 inhibitor users and 377 nonusers in the Mount Sinai cohort, 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 >>
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 >>
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 (gliflozins)
SGLT2 inhibitors help the kidneys lower blood glucose levels Sodium-glucose co-transporter-2 (SGLT2) inhibitors are a new group of oral medications used for treating type 2 diabetes . The drugs work by helping the kidneys to lower blood glucose levels . SGLT2 inhibitors have been approved for use as a treatment for diabetes since 2013. They are taken once a day with or without food. SGLT2 inhibitors work by preventing the kidneys from reabsorbing glucose back into the blood. This allows the kidneys to lower blood glucose levels and the excess glucose in the blood is removed from the body via urine. The kidneys work by filtering glucose out of the blood and then reabsorbing glucose back into the blood. The proteins that reabsorb glucose are called sodium-glucose transport proteins. SGLT2 inhibitors block these proteins which means less glucose gets reabsorbed back into the blood and gets passed out of the body via the urine. SGLT2 inhibitors may be suitable for people with type 2 diabetes that have high blood glucose levels despite being on a medication regimen such as metformin and insulin. SGLT2 inhibitors are not recommended for prescribing to people with kidney disease (nephropathy) as kidney disease prevents the drug from working sufficiently well. What are the benefits of SGLT2 inhibitors? SGLT2 inhibitors help to remove glucose from the blood and therefore help to lower blood glucose levels. By removing glucose from the body, SGLT2 inhibitors can also have benefits for weight loss . As the drugs cause more glucose to be excreted in the urine, there is a higher chance of getting genital and urinary tract infections . These side effects are more common in women than in men. Taking SGLT2 inhibitors with insulin, sulphonylureas or glinides may increase the risk of hy Continue reading >>
Sglt2 Inhibitors: A New Class Of Diabetes Medications
Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of diabetic medications indicated only for the treatment of type 2 diabetes. In conjunction with exercise and a healthy diet, they can improve glycemic control. They have been studied alone and with other medications including metformin, sulfonylureas, nizagara 100, pioglitazone, and insulin. Editor’s Note: Since we first looked at this new drug class in April 2013, numerous studies have been done on the benefits and risks of the SGLT2 inhibitors. See below for a roundup of the new information, including the latest investigational drug in this class, Ertugliflozin. How SGLT2 Inhibitors Work SGLT2 is a protein in humans that facilitates glucose reabsorption in the kidney. SGLT2 inhibitors block the reabsorption of glucose in the kidney, increase glucose excretion, and lower blood glucose levels. SGLT2 is a low-affinity, high capacity glucose transporter located in the proximal tubule in the kidneys. It is responsible for 90% of glucose reabsorption. Inhibition of SGLT2 leads to the decrease in blood glucose due to the increase in renal glucose excretion. The mechanism of action of this new class of drugs also offers further glucose control by allowing increased insulin sensitivity and uptake of glucose in the muscle cells, decreased gluconeogenesis and improved first phase insulin release from the beta cells. It is proposed that in prehistoric times, we developed an elegant system for maximizing energy conservation and storage, due to lack of consistent food supplies. This system included reducing the activity of our neurological endocrine system to slow metabolism and conserve the stored energy in our bodies, as well as a method to increase reabsorption of excess glucose that was removed by the kidneys Continue reading >>