CHAPTER SGLT2 Inhibitors

173 Vijay Negalur

INTRODUCTION high doses of phlorizin caused glycosuria. Since then, Type 2 diabetes mellitus (T2DM) is a chronic progressive phlorizin has been shown to normalise blood glucose disease characterized by hyperglycemia that results from levels in pancreatectomised diabetic rat models. But it has insulin resistance, diminished or absent insulin secretion, not been developed as a glucose-lowering drug due to a or both. Morbidity and mortality associated with diabetes combination of its poor bioavailability, poor side-effect is high, resulting from a spectrum of complications, profile, which is likely to be a result of its non-selective primarily cardiovascular disease and nephropathy. action (its metabolite, phloretin, inhibits SGLT-1 in the intestinal mucosa causing malabsorption of glucose and Glucose-lowering therapies with insulin-dependent galactose). Hence, selective SGLT2 inhibitor was the need mechanisms of action, lose efficacy over time as both of the hour. endogenous insulin secretion and insulin sensitivity decrease. Side effects such as hypoglycaemia and weight MECHANISM OF ACTION OF SGLT2I gain are significant issues in management, especially in the The mechanism of action of SGLT2i is based on the role context of high prevalence of obesity and cardiovascular of kidneys in glucose metabolism and homeostasis. The diseases in this patient population. kidney plays a significant role in glucose homeostasis The sodium-glucose co-transporter 2 inhibitors (SGLT2i) through gluconeogenesis and glomerular filtration and are a new class of medications for the treatment of type reabsorption of glucose in the proximal convoluted 2 diabetes which improve glucose control by increasing tubules. Nearly all of the glucose filtered by the glomeruli urinary glucose excretion. These agents are efficacious as (>99%) is reabsorbed in a healthy adult and returned monotherapy and add-on therapy for patients with type to the circulation (~90% reabsorption take place from 2 diabetes uncontrolled on metformin, sulfonylureas, S1 segment of proximal convoluted tubule while ~10% insulin, and other antihyperglycemic combinations. reabsorption take place from S2/S3 segment of proximal convoluted tubule) (Figure 1). At plasma glucose HISTORY AND DEVELOPMENT OF SGLT2I concentrations beyond the resorptive threshold (~180 Phlorizin is a bitter white glycoside which acts asa g/d), glucose begins to appear in the urine. non-selective inhibitor of SGLT-1 and SGLT-2, and was Glucose reabsorption occurs primarily within the isolated from the root bark of the apple tree by French proximal renal tubule. This occurs through carrier proteins chemists in 1835. In the late 19th century, phlorizin due - sodium-glucose transporter 1 (SGLT1) and SGLT2 which to its bitter taste was used as an anti-malarial and other catalyze the active transport of glucose across the luminal infectious diseases. During its use it was noted that membrane.

~10% reabsorption The SGLT2 transporter is found primarily in the S1 segment from S2/S3 PCT of the proximal tubule and accounts for approximately 90% of reabsorbed glucose, with expression limited to within the kidney. Glucose SGLT1 is a low-capacity transporter found more distal in the S2/S3 segment of the proximal tubule and is involved with reabsorption of the remaining glucose load. It is primarily involved with glucose absorption within the ~90% reabsorption gastrointestinal tract. from S1 PCT SGLT2 couples glucose with the transport of sodium and actively pumps it against a concentration gradient across the luminal membrane. Glucose passively diffuses out of the cell via facilitative glucose transporters (GLUT) 1 and 2. The filtered glucose load is the product of the plasma glucose concentration and the glomerular filtration rate Fig. 1: Renal handling of glucose transport. PCT, proximal (GFR). As the plasma glucose concentration increases, the Figure 1. Renal handling of glucose transport.convoluted PCT, tubule proximal convoluted tubule

Glucose reabsorption occurs primarily within the proximal renal tubule. This occurs through carrier proteins - sodium-glucose transporter 1 (SGLT1) and SGLT2 which catalyse the active transport of glucose across the luminal membrane.

The SGLT2 transporter is found primarily in the S1 segment of the proximal tubule and accounts for approximately 90% of reabsorbed glucose, with expression limited to within the kidney.

SGLT1 is a low-capacity transporter found more distal in the S2/S3 segment of the proximal tubule and is involved with reabsorption of the remaining glucose load. It is primarily involved with glucose absorption within the gastrointestinal tract.

SGLT2 couples glucose with the transport of sodium and actively pumps it against a concentration gradient across the luminal membrane. Glucose passively diffuses out of the cell via facilitative glucose transporters (GLUT) 1 and 2.

The filtered glucose load is the product of the plasma glucose concentration and the glomerular filtration rate (GFR). As the plasma glucose concentration increases, the filtered glucose load also increases in a linear manner. When the reabsorption capacity of the

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792 filtered glucose load also increases in a linear manner. As an add on to metformin, canagliflozin 100 and 300 mg When the reabsorption capacity of the proximal tubule was associated with significant glycemic improvements is surpassed, as occurs during hyperglycemia, glucose and body weight reductions and also found to be well appears in the urine. This maximum reabsorption capacity tolerated compared with metformin alone in drug-naive is called as ‘the maximum transport rate (Tm)’. patients with T2DM over 26 weeks. Combination therapy provided statistically significant greater reductions in In healthy individuals without diabetes, Tm for glucose is HbA1c and body weight with a significantly higher reached at blood glucose concentrations of approximately proportion of patients achieving their glycemic goals. 200 mg/dL. On the other hand the mean Tm for glucose has been reported to be higher – approximately 20% or Dapagliflozin 2.5 or 5 mg twice daily added to metformin more compared with healthy individuals. was also effective in reducing glycaemic levels in patients with type 2 diabetes inadequately controlled with Consequently, suppressing renal glucose reabsorption metformin alone as assessed through reduction in HbA c and effectively increasing urinary glucose excretion via 1 and FBG. SGLT2 inhibition is a logical approach to glycemic control. Since SGLT2 is only expressed in the kidney, the effects of SGLT2i as an add on to dual or triple therapy regimens DIABETES SGLT2 i are limited to glycosuria and associated salt and The efficacy and safety of canagliflozin as an add-on to water losses. metformin plus sulphonylurea in patients with T2DM Several SGLT2i including canagliflozin, dapagliflozin, was evaluated in a randomised, double-blind, placebo- ipragliflozin, empagliflozin, and ertugliflozin have been controlled, Phase 3 study. developed or are currently undergoing clinical trials. HbA1c was significantly reduced with canagliflozin 100 Dapagliflozin, canagliflozin and empagliflozin have now and 300 mg vs. placebo at week 26 (-0.85%, -1.06%, and been approved for clinical use in patients with T2DM in -0.13%; p < 0.001); these reductions were maintained at several countries. week 52 (-0.74%, -0.96%, and 0.01%). Both canagliflozin The available SGLT2 inhibitors share similar doses reduced FPG and body weight vs. placebo at week pharmacokinetic characteristics, with a rapid oral 26 (p < 0.001) and week 52. absorption, a long elimination half-life allowing once- The efficacy and safety of canagliflozin, has also been daily administration, an extensive hepatic metabolism similarly evaluated in patients with T2DM inadequately mainly via glucuronidation to inactive metabolites, the controlled with metformin and pioglitazone and was absence of clinically relevant drug-drug interactions found to improve glycaemic control, reduced body weight and a low renal elimination as parent drug. SGLT2 co- and systolic BP, and also found to be well tolerated. transporters are responsible for reabsorption of most (90 %) of the glucose filtered by the kidneys. Canagliflozin significantly improved health related quality of life, a benefit attributed to the additional weight CLINICAL EFFICACY OF SGLT2 INHIBITORS loss benefits of the drug. Glycemic benefits SGLT2i improves beta cell function Results of numerous placebo-controlled randomised Canagliflozin has been shown to increase beta cell glucose clinical trials of 12-104 weeks duration have shown sensitivity compared with placebo. Three separate phase significant reductions in glycated haemoglobin (HbA1c), 3 studies demonstrate that sustained treatment with resulting in a significant increase in the proportion of canagiflozin for 6 to 12 months improved measures of patients reaching HbA1c targets. Significant lowering of beta cell function fasting plasma glucose is observed when SGLT2i were administered as monotherapy or in addition to other Experience in Indian patients glucose-lowering therapies including insulin in patients Several Indian studies have shown canagliflozin to with T2DM. In head-to-head comparison trials of up to 2 provide glycaemic control, body weight reduction, and years, SGLT2 inhibitors exerted similar glucose-lowering good tolerability in Indian patients with T2DM similar to activity compared to metformin, sulphonylureas or that seen in patient populations across the world. sitagliptin. The durability of the glucose-lowering effect Findings from this analysis support canagliflozin as an of SGLT2 inhibitors has been shown to be good in clinical effective therapeutic option for patients with T2DM in trials. India who may be on a range of background therapies. The 52 week CANTATA-M study assessed the long- term efficacy and safety of canagliflozin monotherapy in EXTRA-GLYCEMIC BENEFITS patients with T2DM inadequately controlled with diet SGLT2i and blood pressure reduction and exercise. Emerging data suggests that the SGLT2 inhibitors provide a meaningful reduction in blood pressure (BP), although This study showed that canagliflozin monotherapy the precise mechanism of the blood pressure drop remains provided sustained improvement in glycemic control and incompletely elucidated. It has been suggested that the body weight reduction, and was generally well tolerated blood pressure reduction is partially due to a combination in patients with T2DM over 52 weeks compared to of diuresis, nephron remodelling, reduction in arterial sitagliptin. stiffness, and weight loss. CHAPTER 173 793 Cardiovascular safety of SGLT2i safety Cardiovascular (CV) mortality is the principal Although cardiovascular cause of death in individuals with T2DM, reduction of significantly not does alone concentration glucose plasma exert multiple CV disease (CVD) risk. SGLT2i lower metabolic benefits, and the risk factors beyond glucose with these positively potentially be modulated that can adiposity, visceral weight, pressure, agents include blood Genital infections and urinary tract infections the risk raise by SGLT2i induced glycosuria of High levels and candidiasis) (mostly genital infections developing of lesser extent, urinary tract infections (UTIs) to a relatively in treated patients. The most frequently reported adverse are female genital mycotic infections, while events and observed commonly urinary tract infections are less generally benign. Both infections respond to appropriate agents. anti-infective SGLT2i and diabetic ketoacidosis diabetic ketoacidosis and SGLT2i SGLT- into postmarketing reports of Investigations diabetic ketoacidosis (DKA), 2 inhibitor–associated in type 1 diabetes and to occur which has been reported less than expected hyperglycemia T2DM patients with after a are on-going. However , (euglycemic DKA) during an October thorough review of the evidence of Clinical Association American 2015 meeting, an of American College Endocrinologists (AACE) and Endocrinology (ACE) Scientificexpert group found that consensus the incidence of DKA and Clinical Review SGLT-2 in changes no recommended infrequent and is inhibitor labelling. DKA, the associated of SGLT2i the risk minimize To at least 24 hours to stop SGLT2i recommend –ACE AACE procedures, invasive planned surgery, prior to elective activity such stressful physical or anticipated severe of an emergency as running a marathon. In the event the drug should surgery or any extreme stress event, clinical care be stopped immediately and appropriate should be also suggest provided. The recommendations inhibitors should avoid excess that patients taking SGLT2 alcohol intake and very-low-carbohydrate/ketogenic ketones blood of routine measurement However diets. urine ketone measurement because is not recommended ketones is blood of measurement and be misleading, can patients. preferred for diagnosis of DKA in symptomatic lowering, lowering, eGFR and albuminuric effects are preserved, in CKD. perhaps exaggerated and inhibitors to SGLT2 response The pharmacodynamics impairment, of renal severity with increasing declines information that the prescribing recommended it is and dosage regarding should be consulted SGLT2i for each renal severe to restrictions in moderate or adjustments in the elderly recommended Caution is also dysfunction. of a higher risk of renal impairment, population because if and dehydration, even orthostatic hypotension represents an obvious the absence of hypoglycaemia in this population. advantage SGLT2i in patients with renal impairment with renal in patients SGLT2i with an acute, dose-dependent associated is SGLT2i reduction in glomerular filtrationml/min/1.73m2 and ~30-40% reduction in albuminuria. rate (eGFR )These by ~5 effects suggest that proximaltubular renal tubuloglomerular feedback through activates natriuresis increased macula densa sodium and chloride delivery, leading to afferent vasoconstriction. reduced glomerular filtration, glycosuric andweight loss On the basiseffects of are attenuated in patients(CKD, eGFR <60 ml/min/1.73m2). In contrast, BP disease with kidney chronic Renoprotective effects of SGLT2i effectsRenoprotective of SGLT2i renoprotective additional offer SGLT2i that suggest Studies effects. Canagliflozin 100 or 300 the progression of renal disease over glimepiride, slowed mg/d, compared with 2 years in patients glycemic its with of independently effects T2DM, renoprotective confer and canagliflozin may risk, cardiovascular high at T2DM with patients In effects. empagliflozinwas associated with slower progression of renal rates of clinically relevant and lower kidney disease than placebo when added to standard care. events SGLT2i and risk of hypoglycaemia and risk of hypoglycaemia SGLT2i risk of hypoglycemia trials, the lower clinical In various to compared of SGLT2i with the usage is observed similarly low as that reported and was sulphonylureas with metformin, pioglitazone or sitagliptin. SGLT2i and weight loss and weight SGLT2i also assists weight Increased renal glucose elimination consistent across been very loss and these results have for advantages additional and they represent the trials inhibitors when compared with other oral glucose- SGLT2 lowering agents. In a 104 week study of evaluating canagliflozin effect on bodyweight and body composition, more patients on canagliflozin experienced ≥5% weight loss with canagliflozin with significant reduction in BMI it is also found that Moreover, circumference. and waist inhibitors is majorly with loss occurring SGLT2 the weight due to loss of fat mass. Since the main reason for reduction in BP has been been in BP has for reduction reason the main Since attributed to decrease in intravascular volume associated of the events natriuresis, and diuresis osmotic with particularly in patients more common were, hypotension as elderly patients, such depletion, volume at risk of diuretics. or those on loop renal impairment patients with BP of 3.6–6.7 in systolic (from baseline) Mean reductions mmHg with dapagliflozinwere noted across studies up incidence of with no notable increases in the to 52 weeks, Sustained, although somewhat orthostatic hypotension. noted with were BP in systolic decreases smaller, years. 1–4 over dapagliflozin 10mg 4.3–6.9mmHg of 3.3–5.4 and BP in systolic Reductions with canagliflozin 100and noted 300mg, across studies respectively, up to were 52 weeks. CanagliflozinSBP ABPM-assessed reduce 24 hour shown to rapidly has risk important predictors of clinical CV both of which are and future events. 794 hyperinsulinemia, arterial stiffness, albuminuria, background metformin therapy or background SU plus circulating uric acid levels and oxidative stress. metformin therapy. There was no significant difference among these agents in A1c reduction but SGLT2i were In a recent CV safety study on empagliflozin in T2DM associated with consistent weight loss and BP reduction patients with high CVD risk empagliflozin reduced the compared to DPP4i. primary major adverse cardiac event end point (CV death, nonfatal myocardial infarction, nonfatal stroke) by Place of SGLT2 inhibitors in therapy 14%. This beneficial effect was driven by a 38% reduction The Update to the Position Statement of the American in CV mortality with no significant decrease in nonfatal Diabetes Association and the European Association for myocardial infarction or stroke. Empagliflozin also the Study of Diabetes recommends the use of SGLT2 caused a 35% reduction in hospitalization for heart failure inhibitors as one of the second line therapy when without affecting hospitalization for unstable angina. monotherapy with metformin fails. A recently published meta-analysis substantiated this The AACE/ACE 2016 guidelines state that SGLT2 i as benefit as a class effect providing clear evidence that one of the acceptable alternatives to metformin as initial SGLT2 inhibition protects against major cardiovascular therapy. DIABETES events, cardiovascular death, heart failure, and death from any cause. The most recent guidance document from the National Institute of Health and Care Excellence (NICE), UK, on The reasons for this benefit have been hypothesised in SGLT2i recommends canagliflozin, dapagliflozin or the “thrifty substrate hypothesis”. It has been suggested empagliflozin as a monotherapy options for treating that under conditions of mild, persistent hyperketonemia, T2DM in adults for whom metformin is contraindicated such as those that prevail during treatment with SGLT2 or not tolerated and when diet and exercise alone do not i, b-hydroxybutyrate is freely taken up by the heart provide adequate glycaemic control, only if: (among other organs) and oxidized in preference to fatty acids. This substrate selection improves the • a dipeptidyl peptidase-4 (DPP-4) inhibitor would transduction of oxygen consumption into work efficiency otherwise be prescribed and in the endangered myocardium (and also improves • a sulfonylurea or pioglitazone is not appropriate. metabolic status and function of other organs, mainly the kidney). These mechanisms in addition to enhanced CONCLUSIONS diuresis and reduced blood pressure probably results in The kidney plays a key role in glucose homeostasis cardioprotection. and the pathophysiology of T2DM. SGLT2 inhibitors, canagliflozin, dapagliflozin and empagliflozin area Possible factors contributing to CV effects of SGLT2i new class of antihyperglycemic agents for the treatment • Glycemic control of T2DM with a novel insulin-independent mechanism • Decrease in body weight and visceral adiposity of action that targets the kidney. The SGLT2 inhibitors decrease renal glucose reabsorption, thereby increasing • Decrease in blood pressure and arterial stiffness urinary glucose excretion and lowering plasma glucose • Decrease in oxidative stress levels in patients with hyperglycemia. • Decrease in uric acid level Modest reductions in body weight and blood pressure have also been observed following treatment with SGLT2 • Decrease in albuminuria inhibitors. SGLT2 inhibitors appear to be generally well Effect of SGLT2i on bone tolerated, and have been used safely when given as Inhibition of tubular glucose reabsorption has the monotherapy or in combination with other oral anti- potential to affect mineral metabolism and possibly diabetes agents and insulin. The risk of hypoglycemia is bone health. On the other hand there is no data relating low with SGLT2 inhibitors. Typical adverse events appear to the expression of SGLT2 in relevant bone-derived cell to be related to the presence of glucose in the urine, types relating to bone homeostasis, such as osteoblasts namely genital mycotic infection and lower urinary tract or osteoclasts suggesting that SGLT2 is unlikely to play infection, and are more often observed in women than in a major functional role within bone tissue. Across clinical men. studies, canagliflozin did not meaningfully affect calcium Data from long-term safety studies with SGLT2 inhibitors homeostasis or hormones regulating calcium homeostasis. and from head-to-head SGLT2 inhibitor comparator A meta-analysis based on available randomised clinical studies are needed to fully determine their benefit- trial data also does not support the harmful effect of risk profile, and to identify any differences between SGLT2 inhibitors on fracture. individual agents. However, given current safety and efficacy data, SGLT2 inhibitors may present an attractive SGLT2i after metformin –comparisons with dipeptidyl option for T2DM patients who are failing with metformin peptidase-4 inhibitors (DPP- 4 inhibitors) monotherapy, especially if weight is part of the underlying There are four head-to-head studies comparing DPP4i treatment consideration. with SGLT2i either in treatment naive patient or on CHAPTER 173 795 2016; 2015; 9:48- 2015; 2016; 32:1375-85. 2016; 4:411-9. 2016. Maliha G, Townsend RR. SGLT2 inhibitors: inhibitors: their potential G, Maliha SGLT2 RR. Townsend Hypertens Am Soc J pressure. in blood reduction 53. of Progression Slows Canagliflozin M. Desai HJ, Heerspink Renal Function Decline Independently of Glycemic Effects. Am Soc Nephrol J Wanner C1, Inzucchi SE1Empagliflozin and 2016; Diabetes. N Engl J Med Disease in Type 2 of Kidney Progression 375:323-34. 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