Sodium-glucose cotransporter-2 inhibitors in type 2 diabetes
This themed collection focuses on the newest class of glucose-lowering agents to enter the type 2 diabetes management arena, sodium-glucose cotransporter-2 (SGLT2) inhibitors. These agents reduce hyperglycemia in an insulin-independent manner by increasing urinary excretion of glucose and also exert favorable effects beyond glucose control, including consistent reductions in body weight and blood pressure. Notably, a large cardiovascular outcome trial recently reported that the use of a specific SGLT2 inhibitor, empagliflozin, is associated with a reduction in major cardiovascular events. There is consequently growing interest in empagliflozin and the entire SGLT2 inhibitor class as drugs that could potentially change the way in which hyperglycemia is managed in patients with type 2 diabetes.
This collection comprises a selection of recent full-text articles and chapters from the Springer Nature portfolio that discuss the mode of action of SGLT2 inhibitors, their effects on glucose and other parameters in patients with type 2 diabetes, and their clinical use. Over time this collection will be enhanced by the addition of specially commissioned articles and resources that provide further guidance to healthcare practitioners regarding the use of these agents, as well as selected full-text articles sourced from other prominent publishers.
This review provides an overview of the current concerns and misconceptions on the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors for the treatment of type 2 diabetes and provides an overview of their place within the diabetes management pathway.
Based on the evidence for SGLT2 inhibitors summarized in the review, the authors developed a benefit/risk tool that can be used as a quick reference for clinicians in routine practice.
SGLT2 inhibitors reduce the reabsorption of glucose in the kidney in an insulin-independent manner, thereby increasing glucose excretion via urine.
Three SGLT2 inhibitors are approved in the UK: canagliflozin, dapagliflozin and empagliflozin. National Institute for Health and Care Excellence (NICE) and Scottish Intercollegiate Guidelines Network (SIGN) guidelines recommend the use of SGLT2 inhibitors for first intensification of type 2 diabetes treatment after metformin failure.
Guidelines also note that SGLT2 inhibitors can be administered in combination with other anti-diabetic drugs, such as insulin and glucagon-like peptide-1 receptor antagonists.
Randomized controlled trials and real-world evidence have shown that SGLT2 inhibitors achieve and maintain glucose levels, are associated with weight loss (reduce visceral fat), and have cardio- and renoprotective effects.
SGLT2 inhibitors are generally well tolerated; however, there are some patient populations that may be at increased risk of adverse events.
Genital infections are a common adverse event with SGLT2 inhibitors. To achieve optimum treatment benefit, education on the risk of these and practical hygiene advice at the start of treatment are recommended.
There is conflicting evidence for the risk of lower limb amputation and bone fractures with SGLT2 inhibitors; however, high-risk individuals should avoid SGLT2 inhibitors. Preventative footcare advice and ongoing monitoring is recommended.
Patients receiving SGLT2 inhibitors may experience diabetic ketoacidosis, although this is rare. Diabetic ketoacidosis monitoring should be implemented when administering SGLT2 inhibitors.
SGLT2 inhibitors should be discontinued immediately in patients with acute illness or planned surgical procedures, but can be resumed following full recovery.
Wilding J et al. Diabetes Ther 2018. doi: 10.1007/s13300-018-0471-8
Sodium-glucose cotransporter-2 (SGLT2) inhibitors are recommended in type 2 diabetes. This review describes their actions, adverse events, and a treatment algorithm.
SGLT2 inhibitors reduce plasma glucose, body weight, and blood pressure, and are recommended as second/third-line treatments for patients with type 2 diabetes.
In the key EMPA-REG OUTCOME TRIAL, empagliflozin had cardio- and renal protective effects in patients with type 2 diabetes.
Hemodynamic effects may underlie its rapid onset of action; other benefits include weight loss, improved cardiac function and metabolic effects.
The overall incidence of adverse events is similar to those for other antidiabetic drugs; the most common is genitourinary tract infection.
Risks of dehydration and postural hypotension are higher in patients also receiving diuretics or drugs with gastrointestinal adverse events.
Regulatory agencies have issued warnings for increased risks of ketoacidosis and lower limb amputation for SGLT2 inhibitors.
Patients that may benefit with SGLT2 inhibitors have younger age, unimpaired renal function, cardiovascular disease, no genitourinary infection, overweight/obese, and/or hypertension.
Lower doses of SGLT2 inhibitors are recommended when starting treatment.
In patients with glycated hemoglobin (HbA1c) <8.5%, daily insulin doses should be reduced by 20% and sulfonylureas should be reduced or stopped; in those with HbA1c >8.5%, the insulin dose should be maintained.
Patients with symptoms of ketoacidosis should be monitored.
Concomitant diuretic treatment should be monitored and reconsidered according to the clinical situation.
Gomez-Peralta F et al. Diabetes Ther 2017; 8: 953–962. doi: 10.1007/s13300-017-0277-0
Sodium-glucose cotransporter-2 (SGLT2) inhibitors are frequently prescribed for outpatients. This review describes potential hospital usage, and the risks of euglycemic ketoacidosis in this setting.
Meta-analysis data indicated no risk of hypoglycemia unless given with insulin or an insulin secretagogue. SGLT2 inhibitors could therefore be prescribed in hospital to patients not receiving these concomitant treatments.
SGLT2 inhibitors tend to have synergistic effects with other blood pressure treatments.
The US Food and Drug Administration issued a warning for ketoacidosis during SGLT2 inhibitor use.
Euglycemic ketoacidosis can result if patients have decreased glucose for energy expenditure and insulin deficiency, and can be difficult to diagnose.
Patients admitted to hospital have risk factors for SGLT2 inhibitor-associated ketoacidosis.
Worsening renal function without adjusted doses of SGLT2 inhibitors could increase the risk of ketoacidosis.
Other risks include genitourinary infection, and postural hypotension, which may be exacerbated by reduced oral intake.
Levine JA, Karam SL, Aleppo G. Curr Diab Rep 2017; 17: 54. doi: 10.1007/s11892-017-0874-3
An overview of sodium-glucose cotransporter-2 (SGLT2) inhibitors, their potential benefits and risks, and their effects on glucose and other metabolic parameters in patients with type 2 diabetes.
SGLT2 inhibitors reduce glycated hemoglobin (HbA1c) concentrations by increasing urinary excretion of glucose and have been shown to cause a mild reduction in blood pressure and body weight.
The most recent American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) position statement recommends SGLT2 inhibitors as a reasonable drug option if additional glucose-lowering effect is needed beyond metformin monotherapy.
The most common adverse effects with their use include an increase in urine volumes and voiding frequency, and genital mycotic infections, as well as reported cases of diabetic ketoacidosis.
SGLT2 inhibitors (specifically empagliflozin) are the first antidiabetic drug class linked to a reduction in major cardiovascular events.
It remains to be determined whether SGLT2 inhibitors should be considered preferred agents after metformin monotherapy in those with established cardiovascular disease.
Future investigations are needed to determine whether these agents should be used as initial monotherapy (instead of the standard approach using metformin), for diabetes prevention, and even in non-diabetic patients with cardiovascular disease or heart failure.
Because this class of drugs reduces albumin excretion, there is also some interest in their potential to improve renal outcomes in non-diabetic individuals with chronic kidney disease.
Results from this retrospective cohort study show that combination therapy of glucagon-like peptide-1 (GLP-1) agonists and sodium-glucose cotransporter-2 (SGLT2) inhibitors is a promising option for patients with diabesity.
‘Diabesity’ is a term describing obesity that leads to the development of type 2 diabetes.
Many conventional antidiabetic medications (eg, sulphonylureas, thiazolidinediones, meglitinides and insulin) are associated with considerable weight gain and are thus less suitable for overweight and obese patients.
GLP-1 agonists and SGLT2 inhibitors may be preferable in these patients because of their association with weight loss.
A small retrospective patient cohort study (n=37) demonstrated statistically significant reductions in glycated hemoglobin (HbA1c), body weight, body mass index, and total daily insulin requirements in patients with type 2 diabetes receiving combination treatment with a GLP-1 agonist and a SGLT2 inhibitor.
Combination therapy with GLP-1 and SGLT2 inhibitors is a promising option for patients with diabesity but randomised double-blind controlled trials are needed.
Deol H et al. Endocrine 2017; 55: 173–178. doi: 10.1007/s12020-016-1125-0
Sodium-glucose cotransporter-2 (SGLT2) inhibitors are cardioprotective in patients with type 2 diabetes. This review discusses their use as a potential treatment for heart failure.
Increased renal glucose excretion caused by SGLT2 blockade is associated with chronic weight loss, reduced blood volume and a diuretic-like reduction in blood pressure.
In the key EMPA-REG OUTCOME trial, compared with placebo empagliflozin reduced the risk of cardiovascular death by 38% and heart failure hospitalization by 35% in patients with type 2 diabetes mellitus.
These results were supported by real-world data from the international CVD-Real Study, and by the CANVAS PROGRAM, indicating a class cardiovascular protective effect for SGLT2 inhibitors in T2DM.
These cardiovascular effects occur early, possibly due to hemodynamic activity.
Other putative actions include (1) increased ketone production and metabolism, which may have anti-arrhythmogenic effects, (2) interaction with the cardiac cell Na+/H+ exchanger, reducing cytoplasmic sodium and increasing mitochondrial calcium, ultimately mitigating systolic dysfunction, (3) reduced visceral adiposity, (4) improved lipid profile, and (5) decreased uric acid levels.
Clinical data also support reduced progression of renal disease in type 2 diabetes, and delayed rises in cardiovascular risk biomarkers.
The most common adverse event has been polyuria.
Regulatory agencies have issued warnings for increased risks of unexplained leg/foot amputations and ketoacidosis for SGLT2 inhibitors.
Sodium-glucose cotransporter-2 (SGLT2) inhibitors may have direct, cardioprotective effects, independent of SGLT2 expression, countering the toxic effects of raised glucose levels in stressed cells.
Effect 1: Inhibition of the cardiac cell Na+/H+ exchanger. The subsequent decrease in cytosolic calcium and increase in mitochondrial calcium prevents heart failure and is cardioprotective in the context of ischaemia-reperfusion injury.
Effect 2: Suppression of gp91phox NADPH oxidase activity, a cause of myocardial injury, via inhibition of SGLT1/sodium-myoinositol co-transporter-1. SGLT2 inhibitors may block SGLT1 directly through mixed SGLT2 and SGLT1 inhibition or indirectly via improved glycemic control and a consequent reduction in SGLT1 activation following ischemia.
Effect 3: Inhibition of SGLT-induced intracellular sodium and calcium accumulation secondary to raised extracellular glucose levels. Improved glucose control with mixed SGLT1/SGLT2 inhibitors may limit SGLT1-mediated glucotoxicity in acutely injured cells.
Effect 4: Increasing the availability of ketones for metabolism. SGLT2 inhibitors lead to mild ketogenesis, thereby providing challenged organs with an advantageous energy substrate.
Sodium-glucose cotransporter-2 (SGLT2) inhibitors have beneficial effects in type 2 diabetes. This review explores mechanisms by which they may directly influence the cardiovascular system.
Decreasing Na+/H+ exchanger activity decreases intracellular sodium levels, subsequently causing decreased cytosolic calcium levels in a cardioprotective manner.
Protective metabolic effects may include direct reductions of plasma glucose levels, lowering myocardial fatty acid storage, and shifting myocardial metabolism to fatty acids and ketones.
Reduction in plasma glucose concentrations, improvements in cardiac insulin sensitivity and glucose usage, plus lowering triglyceride accumulation in cardiac tissue may facilitate the cardioprotective actions of ketones at the same time as limiting the toxic effects of glucose and lipids.
SGLT2 inhibition may also reduce oxidative stress and inflammation in the myocardium and vasculature.
Reductions in body weight, blood pressure, arterial stiffness and vascular resistance may improve cardiac output in patients with type 2 diabetes.
Kaplan A et al. Heart Fail Rev 2018; 23: 419–437. doi: 10.1007/s10741-017-9665-9
This review summarizes known and postulated effects of sodium-glucose cotransporter-2 (SGLT2) inhibition on the cardiovascular system and discusses the role of SGLT2 inhibition for the treatment of high-risk patients with type 2 diabetes and cardiovascular disease.
Patients with type 2 diabetes exhibit an increased risk for cardiovascular cardiovascular events.
Glucose-lowering strategies studied to date have had little to no impact on reducing cardiovascular risk, especially in patients with a long duration of type 2 diabetes and prevalent cardiovascular disease.
SGLT2 inhibitors increase urinary glucose excretion, thus improving glycemic control independent of insulin.
The cardiovascular outcome trial, EMPA-REG OUTCOME, demonstrated that the SGLT2 inhibitor empagliflozin significantly reduced the combined cardiovascular endpoint of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke vs placebo in a population of patients with type 2 diabetes and prevalent atherosclerotic cardiovascular disease.
Empagliflozin also significantly and robustly reduced the individual endpoints of cardiovascular death, overall mortality, and hospitalization for heart failure in this high-risk population.
Various factors beyond glucose control such as weight loss, blood pressure lowering and sodium depletion, among others may contribute to these beneficial effects of SGLT2 inhibition.
This review article discusses the potential of the sodium-glucose cotransporter-2 (SGLT2) inhibitor drug class to reduce blood pressure and protect from diabetic nephropathy.
Sodium-glucose cotransporter-2 (SGLT2) inhibitors act as osmotic diuretics to lower blood pressure in addition to reducing plasma glucose and assisting with weight loss.
Although not approved as antihypertensive agents, the ability of this new class of antihyperglycemic agents to lower blood pressure may well assist diabetic patients in reaching recommended blood pressure targets.
However, given the frequent lack of a nocturnal blood pressure dip among diabetic subjects, the association of nocturnal hypertension with cardiovascular events and emerging evidence regarding the benefits of specifically targeting night time blood pressure, it would seem premature to use SGLT2 inhibitors as primarily antihypertensive agents.
Results from dedicated cardiovascular and renal outcome studies reports are anticipated shortly to further understanding in this area.
Sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) agonists reduce body weight and promote metabolic benefits. This paper reviews treatment in combination.
GLP-1 receptor agonists may improve cardiac function by decreasing inflammation, improving endothelial function and slowing atheroma formation.
Evidence from two prospective clinical studies and four retrospective analyses in patients with type 2 diabetes indicates that SGLT2 inhibitors and GLP-1 agonists have additive effects with respect to lowering glycated hemoglobin, blood pressure and body weight.
Similar effects on body weight and blood pressure were also observed in obese adults without diabetes.
This combination treatment may reduce major cardiovascular events and slow the progression of renal disease beyond that seen with either class of agent alone or in combination with other hypoglycemic treatments.
The risk of ketoacidosis with SGLT2 inhibitor treatment may be lessened by coadministration with a GLP-1 agonist.
Goncalves E, Bell DSH. Diabetes Ther 2018; 9: 919–926. doi: 10.1007/s13300-018-0420-6
This pooled analysis of trial data shows that empagliflozin reduces albuminuria by a clinically meaningful amount in patients with type 2 diabetes and either micro- or macroalbuminuria.
This pooled analysis examined the effect of sodium-glucose co-transporter 2 (SGLT2) inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes.
SGLT2 inhibition lowers HbA1c, systolic BP (SBP) and weight in patients with type 2 diabetes and reduces renal hyperfiltration associated with type 1 diabetes, suggesting decreased intraglomerular hypertension.
As lowering HbA1c, SBP, weight and intraglomerular pressure is associated with anti-albuminuric effects in diabetes, the authors hypothesized that SGLT2 inhibition would reduce the urine albumin-to-creatinine ratio (UACR) to a clinically meaningful extent.
The authors examined the effect of the SGLT2 inhibitor empagliflozin on UACR by pooling data from patients with type 2 diabetes and prevalent microalbuminuria (UACR = 30–300 mg/g; n = 636) or macroalbuminuria (UACR > 300 mg/g; n = 215) who participated in one of five phase III randomized clinical trials.
In patients with type 2 diabetes and either micro- or macroalbuminuria, empagliflozin reduced UACR by a clinically meaningful amount.
This effect was largely independent of the known metabolic or systemic hemodynamic effects of this drug class.
Cherney D et al. Diabetologia 2016; 59: 1860–1870. doi: 10.1007/s00125-016-4008-2
Pooled data suggest that reductions in glycated hemoglobin (HbA1c) and systolic blood pressure with canagliflozin occur by both weight-loss-independent and weight-loss-associated mechanisms.
This pooled analysis investigated the contribution of weight loss resulting from treatment with the sodium-glucose cotransporter-2 inhibitor canagliflozin to HbA1c and systolic BP (SBP) reductions in patients with type 2 diabetes.
Canagliflozin 100 and 300 mg reduced mean body weight, HbA1c and SBP compared with placebo (p < 0.001 for each), and more patients had body-weight reductions >0%, ≥5% and ≥10% with canagliflozin treatment than with placebo.
Weight-loss-independent and weight-loss-associated mechanisms contributed to HbA1c and SBP lowering with canagliflozin: ~85% of HbA1c lowering and ~60% of SBP lowering was independent of weight loss.
In patients with type 2 diabetes, canagliflozin provided clinically meaningful body-weight reductions, and the weight loss contributed to reductions in HbA1c and SBP.
Cefalu WT et al. Diabetologia 2015; 58: 1183–1187. doi: 10.1007/s00125-015-3547-2
Sodium-glucose co-transporter (SGLT)-2 inhibitors are cardio- and renal protective in type 2 diabetes mellitus (T2DM). Clinical data indicate these benefits may extend to type 1 DM (T1DM).
SGLT2 inhibitors improve blood glucose control in T1DM as well as in T2DM.
There is low risk of hypoglycaemia due to the compensatory activity of SGLT1 and the body’s metabolic counter-regulation, both of which persist during SGLT2 inhibition.
In the key EMPA-REG OUTCOME trial in patients with T2DM, empagliflozin reduced the risks of nephropathy by 39%, progression to end-stage renal disease by 55%, cardiovascular (CV) death by 38%, all-cause death by 32%, and heart failure hospitalization by 35% versus placebo.
Similar effects were observed for canaglifozin in the CANVAS Program.
CV and renal protective actions also relevant in T1DM patients include reduced glomerular filtration, blood pressure, volume overload, body weight, and blood glucose; and mild ketosis which may be organ protective.
Three double-blind, randomized, double-blind trials have showed SGLT2 inhibitors to reduce HbA1c, body weight and daily insulin doses in patients with T1DM.
Ketoacidosis is an especial risk in T1DM patients.
Fattah H, Vallon, V. Drugs 2018; 78: 717–726. doi: 10.1007/s40265-018-0901-y
Sodium-glucose cotransporter-2 inhibitors reduce hyperglycemia by increasing urinary glucose excretion independently of insulin secretion or action. This review describes their biological rationale, mode of action, and clinical pharmacology.
Sodium-glucose cotransporter-2 (SGLT2) inhibitors prevent reabsorption of glucose in the kidney and facilitate its excretion in urine. As glucose is excreted, its plasma levels fall leading to an improvement in all glycemic parameters.
Three of these agents, canagliflozin, dapagliflozin and empagliflozin, are available in the USA and Europe.
They are associated with a variety of non-glycemic benefits, including reductions in body weight and blood pressure.
Potential adverse effects include genitourinary infections, symptoms of volume depletion, and deleterious effects on the skeleton.
SGLT2 inhibitors do not exhibit any clinically relevant drug–drug interactions, including with other anti-diabetic drugs and diuretics.
The efficacy of SGLT2 may be suboptimal in individuals with advance renal disease.
SGLT2 inhibitors are a reasonable treatment option if an additional glucose-lowering effect is needed beyond metformin monotherapy, and can be used as initial monotherapy in persons in whom metformin is not indicated, or not tolerated.
Kalra S. Diabetes Ther 2014;5:355–366. doi:10.1007/s13300-014-0089-4
Bonner et al. demonstrate that sodium-glucose cotransporter-2 inhibitors increase the secretion of glucagon by means of a direct effect on pancreatic alpha cells, which may, at least in part, offset their effect on glucose reabsorption in the kidney.
Treatment with sodium-glucose cotransporter-2 (SGLT2) inhibitors in subjects with type 2 diabetes increases both plasma glucagon and endogenous glucose production (EGP) by unknown mechanisms; increased EGP is the main cause of fasting hyperglycemia in type 2 diabetes (T2D).
Data from this study reveal that SGLT2 is expressed in glucagon-secreting alpha cells of the pancreatic islets, and suggest that sodium-glucose co-transport by SGTL2 is essential for the appropriate regulation of glucagon secretion.
Inhibition of SGLT2 via dapagliflozin treatment in human islets increases glucagon secretion through KATP channel activation, explaining the hyperglucagonemia previously reported in T2D individuals treated with dapagliflozin.
These results identify a heretofore unknown role of SGLT2. The effect of SGLT2 inhibitors on alpha cells may counter their effect on glucose reabsorption in the kidney.
Bonner C et al. Nat Med 2015; 21: 512–517. doi: 10.1038/nm.3828