SGLT2 inhibitors in the treatment of type 2 diabetes

DIAB-6018; No. of Pages 26 diabetes research and clinical practice xxx (2014) xxx–xxx

Contents available at ScienceDirect

Diabetes Research and Clinical Practice journ al h ome pa ge : www .elsevier.co m/lo cate/diabres

Invited review

SGLT2 inhibitors in the treatment of type 2 diabetes Farhad M. Hasan a,*, Mazen Alsahli b, John E. Gerich c a

University of Virginia School of Medicine, Charlottesville, VA, USA University of Toronto Faculty of Medicine, Toronto, Ontario, Canada c University of Rochester School of Medicine, Rochester, NY, USA b

article info

abstract

Article history:

The kidney plays an important role in glucose homeostasis via its production, utilization,

Received 27 January 2014

and, most importantly, reabsorption of glucose from glomerular filtrate which is largely

Received in revised form

mediated via the sodium glucose co-transporter 2 (SGLT2). Pharmacological inhibition of

6 February 2014

SGLT2 increases urinary glucose excretion and decreases plasma glucose levels in an

Accepted 19 February 2014

insulin-independent manner. Agents that inhibit SGLT2 represent a novel class of drugs,

Available online xxx

which has recently become available for treatment of type 2 diabetes. This article summarizes the rationale for use of these agents and reviews available clinical data on their

Keywords:

efficacy, safety, and risks/benefits. # 2014 Elsevier Ireland Ltd. All rights reserved.

Type 2 diabetes Glucose reabsorption SGLT2 inhibitors Dapagliflozin Canagliflozin Empagliflozin

Contents 1. 2.

3.

4. 5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . The kidneys and normal glucose homeostasis . 2.1. Renal gluconeogenesis. . . . . . . . . . . . . . . 2.2. Renal glucose utilization . . . . . . . . . . . . . 2.3. Renal glucose reabsorption . . . . . . . . . . . Role of the kidney in diabetes . . . . . . . . . . . . . . 3.1. Renal gluconeogenesis. . . . . . . . . . . . . . . 3.2. Renal glucose utilization . . . . . . . . . . . . . 3.3. Renal glucose reabsorption . . . . . . . . . . . Therapeutic implications of SGLTs inhibition. . SGLT2 in clinical practice . . . . . . . . . . . . . . . . .

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* Corresponding author at: 403 Woodcrest Road Wayne, PA 19087, USA. Tel.: +1 585 752 2860. E-mail address: [email protected] (J.E. Gerich). Abbreviations: HbA1c, hemoglobin A1c; FRG, familial renal glucosuria; GLUT, glucose transporter; eGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; SGLT, sodium–glucose co-transporter; T2DM, type 2 diabetes mellitus; UGE, urinary glucose excretion. http://dx.doi.org/10.1016/j.diabres.2014.02.014 0168-8227/# 2014 Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: Hasan FM, et al. SGLT2 inhibitors in the treatment of type 2 diabetes. Diabetes Res Clin Pract (2014), http:// dx.doi.org/10.1016/j.diabres.2014.02.014

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5.1.

6.

7.

1.

Dapagliflozin . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.1. Efficacy in monotherapy trials . . . . . 5.1.2. Efficacy in add-on trials . . . . . . . . . . 5.1.3. Effects on weight . . . . . . . . . . . . . . . 5.1.4. Effects on blood pressure . . . . . . . . . 5.1.5. Effects on lipids . . . . . . . . . . . . . . . . 5.1.6. Safety . . . . . . . . . . . . . . . . . . . . . . . . 5.1.7. Dosing recommendations. . . . . . . . . 5.1.8. Use in special populations . . . . . . . . 5.2. Canagliflozin . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.1. Efficacy in monotherapy trials . . . . . 5.2.2. Efficacy in add-on trials . . . . . . . . . . 5.2.3. Effects on weight . . . . . . . . . . . . . . . 5.2.4. Effects on blood pressure . . . . . . . . . 5.2.5. Effects on lipids . . . . . . . . . . . . . . . . 5.2.6. Safety . . . . . . . . . . . . . . . . . . . . . . . . 5.2.7. Dosing recommendations. . . . . . . . . 5.2.8. Use in special populations . . . . . . . . 5.3. Other considerations . . . . . . . . . . . . . . . . . . . Selected SGLT2 inhibitors in clinical development . 6.1. Empagliflozin . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Ipragliflozin . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. LX4211 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Introduction

Management of type 2 diabetes (T2DM) continues to be challenging despite the numerous therapeutic options available. Metformin is currently recommended as the first choice agent [1–3]. However side effects, primarily gastrointestinal, are common and approximately 10% of patients cannot tolerate it at any dose [4]. T2DM is a progressive disease so that as b cell function deteriorates, most patients will require additional therapy [5]. Alternatives and additions to metformin also have problems, which limit their usefulness. Sulfonylureas, meglitinides, and insulin are associated with weight gain and risk of hypoglycemia [5,6]. Thiazolidinediones are associated with risk of weight gain, edema, heart failure, and fractures [6,7]. Dipeptidyl peptidase 4 (DPP-4) inhibitors have only modest glucose lowering effect and their long-term safety remains to be established [6,8]. Similarly, the long-term safety of glucagon-like peptide-1 (GLP-1) analogs is unknown, and their use is often associated with significant gastrointestinal side effects [6,8]. The use of alpha glucosidase inhibitors outside the orient and Germany is generally low due to their common gastrointestinal side effects and frequent dosing schedule [6,9]. Additionally, renal insufficiency places major restrictions on many of the above agents (e.g. metformin, sulfonylureas, GLP-1 analogs, and alpha glucosidase inhibitors) [10]. Thus there is a need for additional treatment options. The ideal antidiabetes drug would be one associated with a robust and sustained HbA1c reduction, is well tolerated, can be administered easily, has low or no risk of hypoglycemia, has good long term safety, and has added benefit such as a favorable impact on b cell function, blood pressure, weight, albuminuria etc.

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The kidney plays an important role in glucose homeostasis and has recently become a target for treatment of diabetes. The majority of glucose reabsorption from glomerular filtrate is mediated via a transporter protein called sodium glucose cotransporter 2 (SGLT2) [11]. Pharmacological inhibition of SGLT2 increases urinary glucose excretion (UGE) and decreases plasma glucose levels in an insulin-independent manner [11]. SGLT2 inhibitors represent a novel class of drugs that has recently become available for treatment of T2DM. This article summarizes the rationale for use of these agents and reviews available clinical data on their efficacy, safety, and risks/benefits.

2. The kidneys and normal glucose homeostasis The kidney is involved in the regulation of glucose homeostasis via three different mechanisms: release of glucose into the circulation (gluconeogenesis), uptake of glucose from the circulation for its energy needs, and most importantly, glucose reabsorption from glomerular filtrate.

2.1.

Renal gluconeogenesis

After a 14–16 h overnight fast, approximately half of the glucose released into the circulation is from the breakdown of liver glycogen (glycogenolysis) stored in the liver and the other half is from the production of new glucose molecules (gluconeogenesis) by liver and kidneys [12–14]. In humans, only the liver and kidney contain significant amounts of the enzyme glucose-6-phosphatase and therefore are the only

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Table 1 – The sodium glucose co-transporter family. Co-transporter SGLT1 SGLT2 SGLT4 SGLT5 SGLT6 SMIT1

Gene

Substrate

Tissue distribution

SLC5A1 SLC5A2 SLC5A9 SLC5A10 SMIT2/SLC5A11 SLC5A3

Glucose, galactose Glucose Glucose, mannose Not known Glucose, myo-inositol Glucose, myo-inositol

Intestine, trachea, kidney, heart, brain, testis, prostate Kidney, brain, liver, thyroid, muscle and heart Intestine, kidney, liver, brain, lung, trachea, uterus, pancreas Kidney Brain, kidney, intestine Brain, heart, kidney, lung

Adapted from Wright et al. [23].

organs that are able to perform gluconeogenesis. The human liver and kidneys provide about equal amounts of glucose via gluconeogenesis in the postabsorptive state (i.e. 12–16 h after the last meal). Consequently, after an overnight fast, 75–80% of glucose released into the circulation derives from the liver and the remaining 20–25% derives from the kidneys. As the duration of fasting increases, glycogen stores in the liver become further depleted until, after 48 h, virtually all the glucose released into the circulation is derived from gluconeogenesis. Consequently, as the length of fast increases, the proportion of overall glucose release accounted for by renal gluconeogenesis increases [13,15] After meal ingestion, overall endogenous glucose release decreases by 61%, with hepatic glycogenolysis virtually ceasing in the 4–6-h period [16]. Hepatic gluconeogenesis also decreases by 82% and glucose molecules generated through this pathway are not generally released in the circulation, but are largely directed into hepatic glycogen. Perhaps surprisingly, renal gluconeogenesis actually increases by approximately twofold and accounts for 60% of endogenous glucose release in the postprandial period [16]. This has been hypothesized to facilitate efficient repletion of glycogen stores in the liver [16]. These differences in regulation and reciprocal change in renal and hepatic glucose release have led to the concept of hepatorenal glucose reciprocity [17]. This concept refers to the situations in which a physiological or pathological decrease in glucose release by kidney or liver is associated with a compensatory increase in glucose release by liver or kidney so as to prevent hypoglycemia or to optimize homeostasis. Examples of this include the anhepatic phase after liver transplantation, prolonged fasting, acidosis, meal ingestion and insulin overdoses in diabetes mellitus [17,18]. With respect to hormonal influences, insulin suppresses glucose release by both organs with roughly comparable efficacy [19], whereas glucagon normally stimulates hepatic glucose release only, mainly via an early action on glycogenolysis [20]. Catecholamines normally exert a direct effect on renal glucose release only [21,22], although they may indirectly affect both hepatic and renal glucose release by increasing availability of gluconeogenic substrates and by suppressing insulin secretion. Cortisol, growth hormone and thyroid hormones have long-term stimulatory influences on hepatic glucose release (over a period of days) [12]. Their effects on renal glucose release in humans have yet to be determined.

2.2.

Renal glucose utilization

In the post-absorptive setting after an overnight fast, the kidneys utilize approximately 10% of all glucose utilized by the

body for its own energy needs [16]. Postprandially, renal glucose uptake increases approximately threefold; however, the proportion of overall systemic glucose disposal due to the kidney changes very little [16].

2.3.

Renal glucose reabsorption

Normally, the kidneys filter approximately 180 L of plasma each day. Since the average plasma glucose concentration throughout a 24-h period is 5.5 mmol/l (100 mg/dl), 180 g of glucose is filtered by the kidneys each day. In healthy individuals, virtually all of this is reabsorbed into the circulation and the urine is essentially free from glucose. To put this into perspective, in a typical day, the kidneys produce 15–55 g glucose via gluconeogenesis and metabolize 25–35 g glucose [11]. Therefore, in terms of glucose economy, it is clear that renal reabsorption (180 g) is the primary mechanism by which the kidney influences glucose homeostasis. Alterations in renal tubular glucose reabsorption may therefore be expected to have a considerable impact on glucose homeostasis. Reabsorption of glucose from glomerular filtrate occurs by means of sodium–glucose co-transporters (SGLT1 and SGLT2) in the proximal convoluted tubules. There are six members of this family (Table 1) [23]. In animal models, approximately 90% of glucose is reabsorbed by SGLT2, a high-capacity low-affinity glucose transporter thought to be located exclusively on the luminal surface of the epithelial cells lining the S1 and S2 segments of the proximal tubule [24,25]. Transport of sodium and glucose by SGLT2 occurs in a 1:1 ratio [24,26]. The remaining approximately 10% of glucose reabsorption is mediated by SGLT1, a high-affinity, low-capacity glucose/ galactose transporter located on the luminal surface of epithelial cells lining the S3 segment of the proximal tubule [26,27]. SGLT1 is also extensively expressed in the small intestine and in other tissues [26]. Glucose reabsorbed from the proximal tubules by SGLTs is then released into the circulation through the action of facilitative glucose transporters (GLUTs) at the basolateral membrane of the epithelial cells lining the proximal tubules (Fig. 1) [28]. Fig. 2 describes the renal handling of filtered glucose [29]. Glucose is freely filtered in the glomerulus, so that, as plasma glucose levels increase, the amount of glucose in the glomerular filtrate increases linearly. Reabsorption of filtered glucose also increases linearly until the maximal reabsorptive capacity (Tm) is exceeded. The plasma glucose concentration at which this occurs is often referred to as the renal threshold, which is approximately 11.0 mmol/l (200 mg/dl) in healthy adults and equates to a filtration rate of 260–350 mg/min/

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Fig. 1 – Glucose reabsorption from the glomerular filtrate through a proximal tubular epithelial cell into the blood. GLUT, glucose transporter; SGLT, sodium–glucose co-transporter. Modified from Bakris et al. [28]. 1.73 m2 [30]. Once plasma glucose concentrations exceed this threshold, the percentage of filtered glucose that is reabsorbed decreases and the percentage of the filtered load of glucose that is excreted in the urine increases, resulting in glucosuria. The ‘rounding’ of the titration curve seen around the transition from complete reabsorption to urinary excretion of excess glucose (shown in Fig. 2 as ‘splay’) can be accounted for by heterogeneity in the glomerular filtration rate and glucose reabsorptive capacity of different individual nephrons [29]. The renal threshold for glucose is decreased in individuals with a rare condition known as familial renal glucosuria (FRG), caused by a range of mutations to the SLC5A2 gene, which encodes SGLT2 [31]. Depending on the nature of the mutations, these individuals have varying degrees of glucosuria, but in the most severe form (so-called ‘Type 0’ disease) they can lose > 100 g glucose per day to the urine [31]. Interestingly, the large majority of patients exhibit no symptoms and their condition is only identified incidentally. Typically, they do not become hypoglycemic or dehydrated and have no electrolyte imbalance or increased risk of urinary tract infections [31].

3.

Role of the kidney in diabetes

All of the ways in which the kidney normally affects glucose homeostasis are altered in patients with diabetes mellitus.

3.1.

Renal gluconeogenesis

Patients with T2DM have an increased release of glucose into the circulation by the kidney in the fasting state [32]. Although the liver is commonly viewed as being largely responsible for increased release of glucose into the circulation in T2DM, the absolute increase in renal glucose release is comparable in magnitude (2.60 and 2.21 mmol/(kg min) for liver and kidneys, respectively) [32]. Postprandially, renal glucose release also increases to a greater extent in people with T2DM than in people with normal glucose tolerance [33]. Much of this difference is as a result of an increase in endogenous glucose release of which 40% is due to increased renal glucose release [33].

3.2.

Renal glucose utilization

Meyer et al. showed that, in the post-absorptive state, renal glucose uptake is significantly greater in patients with T2DM than in normal individuals (353 mmol/min vs. 103 mmol/min), actually exceeding increased glucose production to result in a net glucose uptake of 92 mmol/min. This contrasts with a net output of 21 mmol/min in non-diabetic individuals [32]. In the postprandial state, uptake of glucose by tissues is increased in patients with T2DM and its distribution and fate are altered [33]. Glucose uptake by the kidneys is raised by more than twofold in diabetic vs. non-diabetic individuals [33], whereas glucose uptake in muscle is not significantly altered. Moreover, less glucose is oxidized [33].

3.3. Fig. 2 – Renal glucose handling. Tm, transport maximum. Adapted from Silverman and Turner [29].

Renal glucose reabsorption

Glucosuria in diabetic patients does not occur at plasma glucose levels that would normally produce glucosuria in

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non-diabetic individuals [34]. This is the result of increased glucose reabsorption from glomerular filtrate due to increased transport maximum (Tm) for glucose. This was shown in 1951 when Farber at al. demonstrated that Tm value for glucose is above mean normal in 10 out of 12 patients with diabetes (type 1 or 2). The administration of insulin decreased the Tm in each of the 12 patients [35]. In another study twenty years later in patients with type 1 diabetes mellitus (T1DM), Mogensen demonstrated that Tm for glucose increased from approximately 350 mg/min in normal individuals to approximately 420 mg/min in those with T1DM [34]. The responsible mechanism appears to involve increased expression of glucose transporter genes as studies of renal proximal tubular cells isolated from the urine of people with T2DM as well as cells from several experimental animal models have demonstrated enhanced expression of SGLT2 and GLUT2 transporters [36,37]. The up-regulation of SGLT2 in T2DM appears to be acquired and possibly secondary to hyperglycemia although the exact mechanism is unknown [36].

4. Therapeutic implications of SGLTs inhibition Phlorizin, a non-specific SGLT1 and SGLT2 inhibitor first isolated from the root bark of the apple tree in 1835 [38], was found to increase glucosuria, reduce hyperglycemia, and normalize insulin sensitivity in a partial pancreatectomized animal model of T2DM [39]. However, it was not developed as a treatment for diabetes because of a number of practical shortcomings. It is non-selective and inhibits SGLT1 at the intestinal brush border, which is responsible for absorption of dietary glucose [23]. Inhibition of SGLT1, therefore, has the potential to result in glucose–galactose malabsorption and thus diarrhea, as occurs in naturally occurring SGLT1 deficiency [40]. Furthermore, phlorizin is poorly absorbed in the intestine and is readily hydrolyzed to phloretin, a compound that blocks the facilitative glucose transporter, GLUT1. This might lead to interference with glucose uptake in a number of tissues [41]. To overcome phlorizin shortcomings, highly specific inhibitors of SGLT2 were developed (Fig. 3) [42]. Early SGLT2 inhibitor candidates, remogliflozin [43] and sergliflozin [44], were selective for SGLT2 versus SGLT1 (296- and 395-fold, respectively) but remained susceptible to glucosidase cleavage in the gut [45] and had relatively short half-lives [46–48]. The discovery of C-arylglucoside SGLT2 inhibitors, which are resistant to gastrointestinal tract b-glucosidases, followed. Initial C-arylglucoside compounds had lower affinities for SGLT2, but further modifications produced the more potent dapagliflozin [45]. In preclinical studies dapagliflozin had a longer half-life (13.8 h following a single oral 50-mg dose) than the earlier SGLT2 inhibitors [49]. The longer half-life allowed for once daily administration to achieve continuous controlled glucosuria. In addition, dapagliflozin is highly selective toward SGLT2, compared with SGLT1. Early in vitro studies with dapagliflozin determined that it was 3000-fold more selective for human SGLT2 versus SGLT1 [50]. In addition, dapagliflozin is 32-fold more potent than phlorizin in SGLT2 inhibition [51]. Dapagliflozin produces a dose-dependent increase in renal glucose excretion in

5

humans though SGLT2 inhibition [51–53]. For example, in a Phase IIa dose-ranging study, patients with T2DM (n = 47) were randomized to receive oral doses of dapagliflozin 5, 25 or 100 mg, or placebo, once daily for 14 days [52]. Dosedependent increases in renal glucose excretion occurred in patients with T2DM who received dapagliflozin. On day 1, renal glucose excretion of 45.2, 75.3 or 81.3 g/day occurred with dapagliflozin 5, 25 and 100 mg, respectively; after 14 days of dosing, renal glucose excretion was 36.6, 70.1 and 69.9 g/ day, corresponding to 20, 41 and 44% inhibition of glucose reabsorption. Fasting and postprandial glucose values decreased with treatment as well, and longer-term studies documented reduction in HbA1c as will be discussed later in this review. Dapagliflozin became recently available for clinical use. Canagliflozin, a similar stable, competitive, reversible, and highly selective SGLT2 inhibitor shortly followed. Currently, multiple agents in this class are being developed for the treatment of T2DM [42]. This approach to lowering hyperglycemia in T2DM is appealing for a number of reasons. Unlike the insulin secretagogues and insulin sensitizers, the action of SGLT2 inhibitors is independent of pancreatic b-cell function, which deteriorates over time. The insulin independence of their action plus the fact that they only lower the threshold without completely blocking renal glucose reabsorption means that hypoglycemic episodes are less likely. In fact, no major increase in hypoglycemic events was noted in clinical trials of SGLT2 inhibitors as will be discussed later. Furthermore, the glucosuric effects of these drugs translate into caloric loss and decrease in bodyweight. For example, the glucosuria induced by dapagliflozin monotherapy in patients with T2DM has been reported in one study to be associated with weight reduction of 2.5–3.4 kg in 12 weeks and a net loss of 200– 300 kcal/day [53]. Modest blood pressure reduction is consistently noted in clinical trials of SGLT2 inhibitors [54,55]. The mechanism of that is not entirely clear. The natriuretic effect of SGLT2 inhibitors, due to sodium-dependent co-transport mechanism of SGLT2, in addition to glucose-induced osmotic diuresis may be contributing. There is also a suggestion that some inhibition of the renin–angiotensin–aldosterone system, secondary to increased sodium delivery to the juxtaglomerular apparatus, may be present with SGLT2 inhibitors use [56,57]. As mentioned earlier, SGLT2 reabsorbs approximately 90% of the filtered glucose load in healthy individuals [24,25]. Unexpectedly, available SGLT inhibitors are incapable of completely blocking this in humans. The maximum effect noted is 80 g/day of urinary glucose excretion (UGE), which is less than 50% of the filtered glucose load. Increasing SGLT2 inhibitor dose after the 50% inhibition is achieved does not result in higher inhibition rate [58,59]. Dapagliflozin for example induced approximately 60 g/d of UGE when used at 20 mg/day or at the much higher dose of 500 mg/day in one study [59]. The reason for this incomplete inhibition is not known. Liu et al. has explored and proposed several potential explanations such as an inability of SGLT2 inhibitor to reach and interact with some SGLT2 transporters, or that SGLT2 could be in fact responsible for less than the previously reported 90% glucose reabsorption fraction [58].

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Fig. 3 – The structure of selected SGLT2 and SGLT2/SGLT1 inhibitors. Modified from Tahrani et al. [42].

5.

SGLT2 in clinical practice

5.1.

Dapagliflozin

In January 2014 the US Food and Drug Administration (FDA) approved the use of dapagliflozin for adult patients with T2DM [60]. It is the second SGLT2 inhibitor approved by the FDA following the approval of canagliflozin. Dapagliflozin has been in use in Europe since 2012 when the European Medicines Agency approved its use for the treatment of T2DM as an adjunct to diet and exercise, in combination with other antidiabetes agents, including insulin, and as a monotherapy in metformin intolerant patients [61]. Currently, dapagliflozin is the SGLT2 inhibitor with the most published trials. Its efficacy and safety were evaluated in 14 clinical trials both as monotherapy [53,62–64] and in combination with other antidiabetes agents. Dapagliflozin trials involved more than 9000 patients with T2DM. Efficacy end points in major phase 3 trials are summarized in Tables 2 and 3.

5.1.1.

Efficacy in monotherapy trials

Four trials have evaluated the use of dapagliflozin as monotherapy for T2DM. In two separate 12-week trials including a total of 668 drug-naı¨ve patients with poorly controlled T2DM, dapagliflozin led to a significant reduction in HbA1c relative to placebo (0.7% by Kaku et al. [62], and 0.56% by List et al. [53]). List et al. also included a metformin arm that achieved a mean reduction in HbA1c of 0.55% relative to placebo, suggesting that dapagliflozin is as effective as metformin monotherpy in lowering HbA1c. Additionally, two

separate 24-week trials involving a total of 878 subjects with uncontrolled T2DM concluded there was a significant decrement in glycemic targets with dapagliflozin relative to placebo (0.52% by Ferrannini et al. [63], and 0.8% by Ji et al. [64]). Furthermore, fasting plasma glucose (FPG) was significantly reduced in all dapagliflozin monotherapy trials (mean decrement of 27 mg/dl, relative to placebo) [53,62–64]. In a double blind, active controlled trial, dapagliflozin 10 mg/day was as effective as extended release metformin (titrated to 2000 mg once daily) in reducing HbA1c (dapagliflozin, 1.45%; metformin, 1.4%) and superior to metformin in reducing FPG (dapagliflozin, 46.4 mg/dl; metformin 34 mg/dl) [65].

5.1.2.

Efficacy in add-on trials

In two phase-3 trials involving 728 subjects, dapagliflozin as an add-on to metformin significantly decreased HbA1c levels at 24 weeks compared to placebo (0.54% and 0.3%, placebo subtracted) without serious adverse effects [66,67]. In a 52week trial on 801 patients, dapagliflozin 20 mg/day was as affective as glipizide 20 mg/day in reducing HbA1c when added to metformin monotherapy (0.52% from baseline in both groups) [68], and both led to comparable reductions in fasting plasma glucose. Compared to placebo, dapagliflozin add-on to metformin led to a significant reduction in fasting plasma glucose (difference vs. placebo, 18 and 17 mg/dl) [66,67]. Dapagliflozin has also been studied as add-on therapy to glimepiride [69], pioglitazone [70], sitagliptin [71], and insulin [72–74]. At a dose of 10 mg/day, the reduction vs. placebo in HbA1c by dapagliflozin add-on to above agents ranged between 0.5% and 0.7%. Across the same studies FPG was reduced from baseline by 17 mg/dl to 33 mg/dl

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Author (year)

n Patients

Monotherapy, placebo controlled Kaku (2013) 279

Duration (wk)

Initial HbA1c %

Initial FBG (md/dl)

Drug and dose

12

8.1

162

Background treatment Drug naı¨ve

DAP DAP DAP DAP PBO DAP DAP DAP DAP DAP PBO DAP DAP DAP PBO DAP DAP PBO

1 mg 2.5 mg 5 mg 10 mg

0.12 0.11 0.37 0.44 0.37 0.71 0.72 0.85 0.55 0.9 0.18 0.58 0.77 0.89 0.23 1.04 1.11 0.29

DHbA1c vs. comparator (%)

0.49 0.48 0.74 0.8

DFBG from baseline (mg/dl) 15.6 19.8 23.5 31.9 11.2 16 19 21 24 31 6 15.2 24.1 28.8 4.1 25.1 31.6 2.5

DFBG vs. comparator (mg/dl) 26.8 31 34.7 43.1

List (2009)

389

12

7.8

148.7

Drug naı¨ve

Ferrannini (2010)

485

24

8.3

172.4

Drug naı¨ve

Ji (2013)

393

24

8.3

161.2

Drug naı¨ve

Monotherapy, active-comparator controlled Henry (2012) 422

24

9.1

193.1

Drug naı¨ve

DAP 5 mg DAP 10 mg MET

1.19 1.45 1.4

0.21 0.1

41.5 46.4 34

7.5 12.4

Add-on to MET, placebo controlled Bailey (2010) 546

24

8

162.9

Metformin

148

Metformin

17.8 21.4 23.4 6.0 14.7 2.4

11.9 15.5 17.5

7.2

0.67 0.7 0.84 0.3 0.39 0.1

0.37 0.4 0.54

24

DAP DAP DAP PBO DAP PBO

Add-on to metformin trials, active-comparator controlled Nauck (2011) 801 52 7.7

NR

Metformin

22.3 18.7

3.6

Add-on to other AHAs, placebo controlled Strojek (2011) 597

172.6

Bolinder (2012)

182

24

8.1

2.5 mg 5 mg 10 mg 20 mg 50 mg

DHbA1c from baseline (%)

2.5 mg 5 mg 10 mg 5 mg 10 mg

2.5 mg 5 mg 10 mg 10 mg

0.53 0.54 0.67 0.37 0.72  0.35 0.54 0.66 0.75 0.82

0.28

27.6 34.1

17.1

DAP 10 mg GLIP 20 mg

0.52 0.52

Trial regimen Add-on to GLIM vs. PBO

DAP 2.5 mg

0.58

0.45

16.8

18.7

DAP DAP PBO DAP DAP PBO DAP

0.63 0.82 0.13 0.95 1.21 0.54 0.5

0.5 0.69

21.2 28.4 2.0 22.8 33.1 13.1 24.1

23.2 30.4

Rosenstock (2012)

420

48

8.4

164.8

Add-on to PIO vs. PBO

Jabbour (2013)

432

24

8

162.6

Add-on to SIT  MET vs. PBO

5 mg 10 mg 5 mg 10 mg 10 mg

0 vs. GLIP

10 13 15 18 25  11.1 20.1 24.4

0.41 0.67 0.5

diabetes research and clinical practice xxx (2014) xxx–xxx

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Table 2 – Dapagliflozin in major clinical trials.

9.7 20.0 27.9

7

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DAP, dapagliflozin; PBO, placebo; MET, metformin; GLIP, glipizide; GLIM, glimepiride; PIO, pioglitazone; INS, insulin; SIT, sitagliptin; n, number; wk, weeks; FPG, fasting plasma glucose; vs., versus; D, change in; LDL, low density lipoprotein cholesterol; NR, not reported.

16.1 5.4 34.1 23.4 18.0 0.82 0.78 0.43

179.0 808 Wilding (2013)

104

8.6

Add-on to INS vs. PBO

DAP 5 mg DAP 10 mg PBO

0.39 0.35

2.5 0.21

16.2 16.9 NR 20.5 0.96 1.01 0.47 0.64

177.5 800 Wilding (2012)

48

8.6

Add-on to INS vs. PBO

DAP 5 mg DAP 10 mg PBO DAP 2.5 mg

0.49 0.54

– 0.32

27.4

9.6 17.8 12.4 0.69 0.09 0.79 DAP 20 mg PBO DAP 2.5 mg

0.78

15.4 3.8 2.4 0.7 0 0.61 PBO DAP 10 mg 161.2 8.4 71 Wilding (2009)

12

Initial FBG (md/dl) Author (year)

Table 2 (Continued )

n Patients

Duration (wk)

Initial HbA1c %

Add-on to INS vs. PBO

DHbA1c from baseline (%) Drug and dose

DHbA1c vs. comparator (%)

DFBG from baseline (mg/dl)

DFBG vs. comparator (mg/dl)

diabetes research and clinical practice xxx (2014) xxx–xxx

compared with changes of +18 mg/dl to 13 mg/dl in placebo groups [69–73]. Additionally, dapagliflozin add-on to glimepiride [69], and add-on to pioglitazone [70] led to a significant reduction in postprandial glucose (PPG). Dapagliflozin has also been studied in combination with metformin in treatmentnaı¨ve patients with T2DM [65]. This combination was more effective than either drug alone in reducing HbA1c (dapagliflozin 10 mg/day, 1.5%; metformin, 1.4%; dapagliflozin 10 mg/dl plus metformin, 2%) and FPG (dapagliflozin 10 mg/day, 46 mg/dl; metformin, 35 mg/dl; dapagliflozin 10 mg/dl plus metformin, 60 mg/dl).

5.1.3.

Effects on weight

Dapagliflozin monotherapy for 12 weeks resulted in a loss of 2.5 kg body weight compared with a loss of 1.2 kg and 1.7 kg in the placebo and metformin arms respectively [53]. In a 12week study of Japanese patients with T2DM, dapagliflozin monotherapy was associated with a significant weight reduction (1.9 kg) relative to placebo [62]. In a head-to-head comparison with metformin, dapagliflozin, both at 5 mg and 10 mg, led to a greater weight reduction (2.6 and 2.7 kg respectively) compared with metformin (1.4 kg) [65]. Ferrannini et al. [63], however, found no significant difference in body weight with dapagliflozin vs. placebo after 24-week treatment (3.2 kg vs. 2.2 kg). The authors attributed this to a high placebo effect likely due to improved adherence to diet and exercise. Yet, consistent with other studies, dapagliflozin produced a loss of 200–300 kcal/day. When used in combination or as add-on to other antidiabetes agents, dapagliflozin therapy resulted in a similar favorable effect on weight. The combination of dapagliflozin and metformin was more effective in reducing body weight than metformin alone (3.3 kg with dapagliflozin 10 mg/day plus metformin, vs. 1.4 kg with metformin alone) [65]. The weight reduction observed in dapagliflozin treated patients was predominantly attributable to reductions in body fat mass [67]. Dapagliflozin add-on to pioglitazone mitigated the weight gain associated with the latter, and the beneficial effects on body weight were sustained at 48 weeks of therapy [70]. When compared to glipizide in patients whose diabetes was inadequately controlled with metformin, dapagliflozin achieved significant reduction from baseline in body weight after 52 weeks (3.2 kg) compared with a weight gain of 1.4 kg with glipizide [68].

5.1.4.

Effects on blood pressure

Dapagliflozin monotherapy over 12–24 weeks was associated with a significant placebo-subtracted reduction in systolic blood pressure in the range of 2–9 mmHg. There was no significant change in heart rate or increase in syncopal episodes [53,62–64]. In a pooled analysis of 12 placebocontrolled studies, treatment with dapagliflozin 10 mg/day resulted in a systolic blood pressure change from baseline of 4.4 mmHg and diastolic blood pressure of 2.1 mmHg vs. 0.9 mmHg systolic and 0.5 mmHg diastolic blood pressure for placebo group at week 24 [54].

5.1.5.

Effects on lipids

An analysis addressing cardiovascular risk factors in the dapagliflozin trials concluded that dapagliflozin had an insignificant effect on lipid levels in individual studies [75].

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Table 3 – Important seconday outcomes in dapagliflozin clinical trials. Author (year)

Drug and dose

DWeight from baseline (kg)

DWeight vs. comparator (kg)

DSBP from baseline (mmHg)

DSBP vs. comparator (mmHg)

DLDL from baseline (mg/dl)

DLDL vs. comparator (mg/dl)

Kaku (2013)

DAP 5 mg DAP 10 mg PBO

2.1 1.9 0.1

2.0 1.8

1.8 2.1 0.6

2.4 2.7

3.5 0.7 1.5

2 0.8

List (2009)

DAP DAP DAP DAP DAP PBO

2.5 mg 5 mg 10 mg 20 mg 50 mg

2.7 2.5 2.7 3.4 3.4 1.2

1.5 1.3 1.5 2.2 2.2

3.1 2.9 6.4 4.3 2.6 2.4

5.5 5.3 8.8 6.7 5

NR

–

Ferrannini (2010)

DAP 2.5 mg DAP 5 mg DAP 10 mg PBO

3.3 2.8 3.2 2.2

1.1 0.8 1.0

4.6 2.3 3.6 0.9

3.7 1.4 2.7

NR

–

Ji (2013)

DAP 5 mg DAP 10 mg PBO

1.6 2.3 0.3

1.4 2.0

1.2 2.3 0.8

2 3.1

3 7.4 1.7

1.3 9.1

Henry (2012)

DAP 5 mg DAP 10 mg MET

2.6 2.7 1.4

1.2 1.3

4.2 4 1.5

2.7 2.5

NR

–

Bailey (2010)

DAP 2.5 mg DAP 5 mg DAP 10 mg PBO

2.2 3 2.9 0.9

1.3 2.1 2

2.1 4.3 5.1 0.2

1.9 4.1 4.9

5 3.2 9.9 3.5

1.5 0.3 6.4

Bolinder (2012)

DAP 10 mg PBO

3 0.9

2.1

2.7 0.1

2.8

NR

–

Nauck (2011)

DAP 10 mg GLIP 20 mg

3.22 1.44

4.65

4.3 0.8

5.1

NR

–

Strojek (2011)

DAP 2.5 mg DAP 5 mg DAP 10 mg PBO

1.18 1.56 2.26 0.72

0.46 0.84 1.54

4.7 4 5 1.2

3.5 2.8 3.8

7.2 1 2.8 0.9

6.3 0.1 1.9

Rosenstock (2012)

DAP 5 mg DAP 10 mg PBO

0.09 0.14 1.64

1.55 1.78

0.8 3.4 1.3

2.1 4.7

NR

–

Jabbour (2013)

DAP 10 mg PBO

2.1 0.3

1.9

6 5.1

0.9

NR

–

Wilding (2009)

DAP 10 mg DAP 20 mg PBO

4.5 4.3 1.9

2.6 2.4

0.7 5.5 2.1

2.8 7.6

4.2 15.4 3

7.2 12.4

Wilding (2012)

DAP 2.5 mg DAP 5 mg DAP 10 mg PBO

1 1 1.6 0.8

1.8 1.8 2.4

5.3 4.3 4.1 1.5

3.8 2.8 2.6

NR

–

Wilding (2013)

DAP 2.5 mg DAP 5 mg DAP 10 mg PBO

1 1 1.5 1.8

2.8 2.9 3.3

NR 2.6 7.5 0.5

 2.1 7

10.3 5.2 1.8 3.5

6.8 8.7 5.3

DAP, dapagliflozin; PBO, placebo; MET, metformin; GLIP, glipizide; vs., versus; D, change in; SBP, systolic blood pressure; LDL, low density lipoprotein cholesterol; NR, not reported.

Small changes in HDL-C (+2.1% to +9.3%), triglyceride (0.9% to 10.6%) and LDL-C (0.5% to +9.5%) were observed overall in patients receiving dapagliflozin therapy. Mean percent placebo-adjusted changes from baseline for dapagliflozin 10 mg were: total cholesterol +1%; HDL-C +1.7%; LDL-C +0.8%; and triglycerides 4.7% [75]. Table 3 summarizes relevant data on

the effect of dapagliflozin on body weight, systolic blood pressure, and LDL-C.

5.1.6.

Safety

Dapagliflozin was well tolerated both as monotherapy and as an add-on to other antidiabetes agents. The most frequent

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adverse events were headache, diarrhea, back pain, and upper respiratory tract infections and there was no difference in their frequency across treatment arms [53,62,63,66]. Dropouts due to adverse events were rare. Hypoglycemic events were infrequent and not significantly different from placebo in patients treated with dapagliflozin monotherapy (0–3%) [62– 64] or as add-on metformin [66,67], pioglitazone [70], or sitagliptin (3% each) [71]. Hypoglycemic events, however, were significantly more frequent when dapagliflozin was used as add-on to insulin (27% vs. 13% in the placebo group at 48 weeks and 66% vs. 62% in the placebo group at 104 weeks) [72,73] or glimepiride therapy (8% vs. 5% in the placebo arm at 24 weeks) [69]. Consistent with several trials on SGLT2 inhibitors, dapagliflozin was associated with an increased incidence of genital infections, predominantly in females, and a modest increase in urinary tract infections when compared to placebo (Table 8). In an analysis, pooled data from 12 phase 2b and phase 3 clinical trials of dapagliflozin as monotherapy or as add-on to other antidiabetes agents, a higher incidence of genital infections, e.g. vulvovagnitis and balanitis, was observed in the dapagliflozin groups (4–6%) than placebo groups (1%) [76]. Another analysis of the same data observed an equivalent rate of urinary tract infections in the dapagliflozin groups (4–6%), but this was not significantly different from the placebo group (4%) [77]. Most of these events were reported to be mild to moderate in intensity and responded to a course of standard antimicrobial treatment. The analysis also demonstrated that higher doses of dapagliflozin were associated with a higher degree of glucosuria but there was no clear dose–response relationship between dapagliflozin and genital or urinary tract infections [76,77]. When added to standard care, dapagliflozin was shown to be effective and safe in older patients (mean age 63–64 years) with T2DM and history of cardiovascular disease [78]. Dapagliflozin therapy is associated with a mild but noticeable increase in hematocrit (Table 8). Mean placebo-adjusted changes from baseline in hematocrit were +1.7% for dapagliflozin 10 mg/day [79]. Despite no evidence of increased teratogenicity in animal studies, an increased number of breast and bladder cancers were reported among dapagliflozin users in clinical trials [80]. Breast cancer was reported in ten patients in the dapagliflozin group and three patients in the placebo group [81]. Also, there were 9 cases of bladder cancer in the treatment arm vs. one case in the control group. Most of the cases of bladder cancer, however, had hematuria at baseline suggesting a possible preexisting cancer [81]. Also, when considering all types of cancers, there is no increased risk with the use of dapagliflozin compared to placebo or comparator [82]. Currently, dapagliflozin is not recommended for patients with bladder cancer [79].

5.1.7.

Dosing recommendations

The manufacturers, Bristol–Myers Squibb and AstraZeneca, market dapagliflozin as Farxiga1. It is available as 10 mg tablets taken orally once daily at any time of day with or without food [79].

5.1.8. Use in special populations 5.1.8.1. Renal impairment. Dapagliflozin is not recommended for patients with T2DM and moderate to severe renal

impairment, end stage renal disease, or patients on dialysis [79]. In a 24-week study on type 2 diabetics who have moderate renal impairment (eGFR = 30–59 ml/min/1.73 m2] the mean reduction in HbA1c from baseline was not significantly different between dapagliflozin (0.43%) and placebo (0.32%) as expected since the efficacy of SGLT2 inhibitors requires adequate filtered load of glucose [83]. No dosage adjustment is indicated in patients with mild renal impairment [79]. Dapagliflozin is not recommended for use in patients receiving loop diuretics or who are volume depleted [79].

5.1.8.2. Hepatic impairment. There is limited experience in clinical trials in patients with hepatic impairment. No dosage adjustment is necessary for patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment, a starting dose of 5 mg is recommended. If well tolerated, the dose may be increased to 10 mg [79]. 5.1.8.3. Older patients. Due to the limited experience in patients 75 years and older, initiation of dapagliflozin therapy is not recommended [79]. 5.1.8.4. Pregnancy and breastfeeding. Dapagliflozin therapy is not recommended in this population. No data are available [79]. 5.2.

Canagliflozin

In March 2013, canagliflozin became the first SGLT2 inhibitor to be approved in the United States [84]. It was similarly approved recently in the European Union [85]. Canagliflozin has been studied extensively in adult patients with T2DM as monotherapy [86,87], and as add-on to metformin therapy [88– 90], metformin plus sulfonylurea [91,92], metformin plus pioglitazone [93], and insulin [94]. The efficacy and safety of canagliflozin were also examined in vulnerable populations such as those with renal impairment [95] and the elderly [96]. Canagliflozin at 100 mg and 300 mg daily doses achieved significant HbA1c reductions compared to placebo and selected active comparators, with slightly greater reductions with canagliflozin 300 mg once daily (Table 4).

5.2.1.

Efficacy in monotherapy trials

Two published trials examined canagliflozin as monotherapy. The first trial studied 584 patients with T2DM who were drug naı¨ve [86]. At 26 weeks, canagliflozin resulted in a significant placebo-corrected reduction from baseline in HbA1c (canagliflozin 100 mg/day, 0.91%; canagliflozin 300 mg/day, 1.17%). In a separate study, Inagaki et al. [87] compared canagliflozin monotherapy with placebo in 383 Japanese patients with T2DM who were treatment naı¨ve over 12 weeks. Relative to placebo, significant reductions in HbA1c were observed in all canagliflozin groups relative to placebo (e.g. 0.91% and 0.99% with canagliflozin 100 mg and 300 mg/day, respectively). In both studies, canagliflozin achieved significant reductions in FPG and postprandial glycemic parameters. The beneficial effect on postprandial glucose is likely mediated through delaying intestinal glucose absorption via SGLT1 inhibition in addition to increasing UGE via SGLT2 inhibition [97].

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DIAB-6018; No. of Pages 26

Author (year)

n Patients

Monotherapy trials, placebo controlled Stenlof (2013) 584

Inagaki (2013)

383

Duration (wk)

Initial HbA1c %

26

8.0

173

12

8.1

165.6

Add-on to metformin trials, placebo and active comparator controlled Rosenstock (2012) 451 12 7.8

Initial FBG (md/dl)

Drug and dosea Background treatment Drug naı¨ve

Drug naı¨ve or washed out

162

PBO and SIT

7.9

169.2

PBO and SIT

Add-on to metformin trials, active-comparator controlled Cefalu (2013) 1450 52

7.8

NR

GLIM

Add-on to other AHAs trials, placebo controlled Wilding (2013) 469

8.1

NR

Trial regimen Add-on to MET + SU vs. PBO

Lavalle Gonzalez (2013)

Matthews (2013)

Yale (2013)

Bode (2013)

1020

1718

269

714

52

26

18

26

26

8.3

8

7.7

169.2

164.3

156.8

Add-on to INS vs. PBO

Add-on to different AHAs vs. PBO

Add-on to different AHAs vs. PBO

DHbA1c from baseline (%)

DHbA1c vs. comparator (%)

DFBG from baseline (mg/dl)

DFBG vs. comparator (mg/dl)

CAN 100 mg CAN 300 mg PBO CAN 50 mg

0.77 1.03 0.14 0.61

CAN 100 mg CAN 200 mg CAN 300 mg PBO

0.8 0.79 0.88 0.11

0.69 0.68 0.77

33.1 36.1 38.3 3

30.1 33.1 35.3

CAN 50 mg CAN 100 mg CAN 200 mg CAN 300 mg CAN 300 mg BID SIT PBO CAN 100 mg CAN 300 mg SIT 100 mg PBO

0.79 0.76 0.7 0.92 0.95 0.74 0.22 0.73 0.88 0.73 0.6

0.57 0.54 0.48 0.7 0.73 0.52 vs. PBO

16.2 25.2 27 25.2 23.4 12.6 3.6 26.2 35.2 17.7 17.8

19.8 28.8 30.6 28.8 27 16.2 vs. PBO

CAN 100 mg CAN 300 mg GLIM

0.82 0.93 0.81

0.01 0.12

25.2 27 18

7.2 9

CAN 100 mg

0.85

0.71

18.0

15.0

CAN 300 mg PBO CAN 100 mg

1.06 0.13 0.63

0.92

30.6 3.6 18.0

27.6

CAN 300 mg PBO CAN 100 mg

0.72 0.01 0.33

0.73

CAN 300 mg PBO CAN 100 mg

0.44 0.03 0.6

0.4

CAN 300 mg PBO

0.73 0.03

0.7

0.91 1.16 0.50

0.13 0.28 0.13 vs. PBO

0.65

0.3

0.57

27 34.2 9 24.7

27.4 39.1 21.7

8.4 17.4 0.1 vs. PBO

22.0

25.0 4.0 14.9

29.0

11.7 0.5 18.1

12.2

20.3 7.4

27.7

diabetes research and clinical practice xxx (2014) xxx–xxx

15.4

25.5

11

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Table 4 – Canagliflozin in major clinical trials.

DIAB-6018; No. of Pages 26

12

5.4 0.66 SIT 100 mg

Once a day unless specified; CAN, canagliflozin; PBO, placebo; MET, metformin; GLIP, glipizide; GLIM, glimepiride; SU, sulfonylureas; PIO, pioglitazone; INS, insulin; SIT, sitagliptin; AHAs, antihyperglycemic agents; n, number; BID, twice daily; wk, weeks; FPG, fasting plasma glucose; vs., versus; D, change in; NR, not reported.

a

25.2 vs. SIT 1.03 CAN 300 mg Add-on to MET + SU vs. SIT 167.4 8.1 Add-on to other AHAs trials, active comparator controlled Schernthaner (2013) 755 52

0.77 1.03 0.26 CAN 300 mg PBO

0.37 vs. SIT

30.6

– NR 0.63 0.89 CAN 100 mg NR 7.9 26 342 Forst (2012)

Duration (wk) n Patients Author (year)

Table 4 (Continued )

Initial HbA1c %

Initial FBG (md/dl)

Add-on to MET + PIO vs. PBO

Drug and dosea

DHbA1c from baseline (%)

DHbA1c vs. comparator (%)

DFBG from baseline (mg/dl)

DFBG vs. comparator (mg/dl)

diabetes research and clinical practice xxx (2014) xxx–xxx

5.2.2.

Efficacy in add-on trials

In add-on to metformin studies, canagliflozin was superior to placebo and sitagliptin, and non-inferior to glimepiride in achieving glycemic targets [88–90]. In a phase 3 trial, 1020 patients with T2DM who were being treated with metformin were randomized to receive canagliflozin 100 mg, 300 mg, sitagliptin 100 mg, or placebo [89]. At week 26, daily canagliflozin at 100 mg and 300 mg significantly reduced HbA1c relative to placebo (0.62% and 0.77%, respectively). At week 52, canagliflozin 100 mg and 300 mg demonstrated noninferiority, and canagliflozin 300 mg demonstrated superiority, to sitagliptin in lowering HbA1c (0.73%, 0.88%, and 0.73%, respectively). Both canagliflozin doses significantly reduced FPG vs. placebo (week 26) and sitagliptin (week 52). In a separate study, canagliflozin add-on to metformin was noninferior to glimepiride and metformin combination [90]; and at 300 mg/day canagliflozin provided greater HbA1c reductions compared to glimepiride (0.93% vs. 0.81%). Additionally, a more favorable FPG profile was observed after 52 weeks with canagliflozin 100 mg/day and 300 mg/day compared to glimepiride (24.3 mg/dl to 27.5 mg/dl vs. 18.4 mg/dl). Canagliflozin add-on was shown to be beneficial and safe in patients inadequately controlled with insulin with or without additional oral agents [94]. Canagliflozin 100 mg and 300 mg daily for 18 weeks achieved significant placebo-adjusted reductions in HbA1c (0.64% and 0.73%) and FPG (22 and 29 mg/dl). The efficacy of canagliflozin was sustained when used as a third agent in patients with T2DM. In a study by Wilding et al. [91] canagliflozin add-on to a background treatment with metformin plus sulfonylurea significantly reduced HbA1c and FPG. Placebo-adjusted changes from baseline in HbA1c were 0.72% for canagliflozin 100 mg/day and 0.93% for 300 mg/ day. These reductions were sustained at week 52 (0.75% and 0.97%). Schernthaner et al. [92] compared canagliflozin 300 mg/day with sitagliptin 100 mg/day in patients inadequately controlled with metformin plus sulfonyurea. At 52 weeks, canagliflozin 300 mg was superior to sitagliptin 100 mg in reducing HbA1C (1.03% and 0.66%, respectively) [92]. In patients inadequately controlled with a combination therapy of metformin and pioglitazone, the addition of canagliflozin resulted in significant placebo corrected reductions in HbA1c (0.63% and 0.77% with canagliflozin 100 mg and 300 mg, respectively) [93]. In a study of 269 patients with T2DM and stage-3 chronic kidney disease (an eGFR  30 and <50 ml/min/ 1.73 m2), canagliflozin at 100 mg and 300 mg/day was generally well tolerated and led to a lower, but still significant, reduction in HbA1c relative to placebo (0.30% and 0.41%) [95]. Compared to placebo group, more patients treated with canagliflozin had increases in serum creatinine (9% and 10% vs. 4%) and blood urea nitrogen (9% and 6% vs. 2%). The changes in renal function occurred more rapidly in the first three weeks of treatment, but trended back towards baseline over time.

5.2.3.

Effects on weight

Canagliflozin monotherapy, both at 100 and 300 mg doses, was associated with a significant reduction in body weight from baseline compared to placebo (2.2% and 3.3%, respectively) [86]. When added to metformin, canagliflozin was superior to glimepiride in reducing body weight at 52 weeks (3.7 kg with 100 mg and 4.0 kg with 300 mg daily, vs. +0.7 kg with

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DIAB-6018; No. of Pages 26 diabetes research and clinical practice xxx (2014) xxx–xxx

glimepiride) [90]. Compared with sitagliptin 100 mg, canagliflozin 300 mg add-on to metformin plus sulfonylurea was superior in achieving weight reduction (2.3 kg vs. +0.1 kg) [92]. Furthermore, weight reduction was an additional benefit when canagliflozin was added to insulin with or without additional oral agents (1.9 kg with 100 mg and 2.4 kg with 300 mg of canagliflozin, both placebo-corrected) [94].

5.2.4.

Effects on blood pressure

Across the placebo-controlled phase 3 studies, the placebosubtracted mean changes from baseline in systolic blood pressure ranged from 2.2 to 5.7 mmHg with canagliflozin 100 mg/day and from 1.6 to 7.9 mmHg with canagliflozin 300 mg/day [55]. At 300 mg/day, canagliflozin achieved a significant reduction (5.1 mmHg) in systolic blood pressure compared to sitagliptin 100 mg/day (+0.9 mmHg) over 52 weeks [92]. Mean changes from baseline in heart rate were 0.1 and 0.7 beats/min with canagliflozin and sitagliptin, respectively. Additionally, treatment with canagliflozin was associated with larger mean decreases from baseline in systolic blood pressure compared to glimepiride (mean differences relative to glimepiride = 3.48 and 4.76 mmHg with canagliflozin 100 mg and 300 mg doses, respectively) [90]. The reductions in SBP were sustained over the 26-week treatment periods in the placebo-controlled studies and the 52-week treatment periods in the active controlled studies [55].

5.2.5.

Effects on lipids

Mean percent increases in HDL-C were observed in the canagliflozin 100 mg and 300 mg groups relative to placebo (ranging from 0.8 to 6.8% with the 100 mg dose and 0.9 to 8.4% with the 300 mg dose) in phase 3 studies, and were significantly greater than those observed with placebo in most studies [55]. While larger mean percent reductions in fasting triglycerides with the canagliflozin groups compared with placebo group were seen in most studies, the treatment difference was generally small and often not statistically significant for individual studies. In a pooled analysis of the placebo-controlled studies, the placebo-subtracted mean percent changes from baseline for LDL-C were 4.5% and 8.0%, for the canagliflozin 100 mg and 300 mg groups, respectively. In 52-week studies, no consistent further increases in LDL-C were observed from weeks 26 to 52 [55]. With regard to the clinical implications of the increase in LDL-C observed with canagliflozin, data from the Cholesterol Treatment Trialists Collaboration [98] suggest that a population mean increase of 8.15 mg/dl in LDL-C for 5 years (the extent of increase observed with the canagliflozin 300 mg group) could translate into a 4% to 5% increase in the incidence of major adverse cardiovascular events over that same time period [55]. This estimated change in cardiovascular risk assumes no change in other cardiovascular risk factors. However, canagliflozin treatment is proven to improve other cardiovascular risk surrogates such as blood pressure, weight, HDL-C, and glycemic control, which may counterbalance the slight rise in LDL-C. Table 5 summarizes relevant data on the effect of canagliflozin on body weight, systolic blood pressure, and LDL-C.

5.2.6.

13

Safety

Canagliflozin was generally well tolerated in the published trials, and the incidence of serious adverse events was comparable to control. Consistent with dapagliflozin trials, hypoglycemia was rare with canagliflozin monotherapy and with combination therapy that did not include insulin or an insulin secretagogue [55,99]. When added to metformin, canagliflozin therapy over 2 years was associated with a significantly lower risk of hypoglycemia compared with glimepiride (6.8% and 8.2% with canagliflozin 100 mg and 300 mg per day respectively, vs. 40.9% with glimepiride) [90]. Furthermore, rates of severe hypoglycemia were lower with canagliflozin 100 and 300 mg relative to glimepiride (0.6%, 0.2%, and 3.3%, respectively). When added to a background therapy of metformin plus sulfonylurea, both canagliflozin 300 mg/day and sitagliptin 100 mg/day had a similar rate of documented hypoglycemia (43.2% vs. 40.7%) and severe hypoglycemia (4% and 3.4%, respectively) [92]. Severe hypoglycemia was defined as events requiring the assistance of another person, or with loss of consciousness or a seizure regardless of whether biochemically documented. Like dapagliflozin, two of the most common adverse events in patients treated with canagliflozin were female genital mycotic infections and urinary tract infections (Table 8) [100,101]. Male genital mycotic infections were less common (2%) and occurred predominantly in uncircumcised males and males with a prior history of balanitis or balanoposthitis [99]. In analysis of canagliflozin trials, the incidence of urinary tract infections in the broad population (n = 9439) was 5.5% with canagliflozin 100 mg, 5.7% with canagliflozin 300 mg, and 4.3% with placebo or active comparator [55]. Upper urinary tract infections were rare (0.2% across all groups). A recent safety meta-analysis of SGLT2 inhibitors and DPP-4 inhibitors, concluded there were no statistically significant differences in the incidence of urinary tract infections in the comparison of both, DPP-4 inhibitors (RR = 1.15, 95% CI: 0.80–1.65) and SGLT2 inhibitors (RR = 1.02, 95% CI: 0.54–1.91) with the placebo [102]. However, the analysis concluded that treatment with SGLT2 inhibitors resulted in a significantly increased risk of genital infection compared with placebo (RR = 2.36, 95% CI: 1.17–4.74). Patients developing genital mycotic infections responded well to a standard course of antimicrobial therapy, usually without discontinuation of canagliflozin during clinical trials [55]. Table 8 summarizes the rates of adverse events of special interest. Owing to its mild diuretic effect, several adverse events related to reductions in intravascular volume were observed in canagliflozin trials, such as orthostatic hypotension, postural dizziness, thirst, increased urination, and dehydration [99]. Factors associated with volume-related adverse effects were older age (75 years), concomitant use of loop diuretics, and moderate renal impairment (eGFR between 30 and 59 ml/min/ 1.73 m2). The incidence rates of adverse effects related to reduced intravascular volume in the broad population (n = 9439) were 2.3%, 3.4%, and 1.5% with canagliflozin 100 mg, 300 mg, and placebo or comparator, respectively [55]. Small, transient, and reversible decreases in eGFR were observed with canagliflozin therapy consistent with its hemodynamic effect [55]

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Table 5 – Important seconday outcomes in canagliflozin clinical trials. Author (year)

Drug and dosea

Stenlof (2013)

CAN 100 mg CAN 300 mg PBO

2.5 3.6 0.3

2.2 3.3

3.3 5.0 0.4

3.7 5.4

8.5 4.6 6.2

2.3 1.6

Inagaki (2013)

CAN 100 mg CAN 300 mg PBO

2.5 3.2 0.8

1.7 2.4

7.1 8.7 1.2

5.9 7.5

4.9 5.5 0.9

5.8 6.4

Rosenstock (2012)

CAN CAN CAN CAN SIT PBO

2.3 2.4 3.0 2.9 0.5 0.9

1.4 1.5 2.1 2.0 0.4 vs. PBO

1.0 2.1 4.9 3.6 0.8 1.3

0.3 0.8 3.6 2.3 0.5 vs. PBO

4.9 3.2 1.1 7.8 8 NR

–

Lavalle Gonzalez (2013)

CAN 100 mg CAN 300 mg SIT 100 mg PBO

3.3 3.7 1.2 NR

Cefalu (2013)

CAN 100 mg CAN 300 mg GLIM

3.7 4.0 0.7

4.4 4.7

3.3 4.6 0.2

3.5 4.8

NR

–

Wilding (2013)

CAN 100 mg CAN 300 mg PBO

2.0 2.6 0.6

1.4 2.0

4.9 4.3 2.7

2.2 1.6

0.8 4.3 0

0.8 4.3

Matthews (2013)

CAN 100 mg CAN 300 mg PBO

1.8 2.3 0.1

1.9 2.4



2.6 4.4



6.3 6.6

Yale (2013)

CAN 100 mg CAN 300 mg PBO

1.2 1.4 0.2

1.4 1.6

6.1 6.4 0.3

5.7 6.1

3.5 3.1 3.4

0.1 7

Bode (2013)

CAN 100 mg CAN 300 mg PBO

2.4 3.1 0.1

2.3 3.0

3.5 6.8 1.1

4.6 7.9

13.2 13 6.2

7 6.8

Forst (2012)

CAN 100 mg CAN 300 mg PBO

NR

2.7 3.7

NR

4.1 3.5

NR

–

Schernthaner (2013)

CAN 300 mg SIT 100 mg

2.3 0.1

2.4 vs. SIT

5.1 0.9

5.9 vs. SIT

6.3 0.4

5.9 vs. SIT

100 mg 200 mg 300 mg 300 mg BID

DWeight from baseline (kg)

DWeight vs. comparator (kg)

DSBP from baseline (mmHg)

DSBP vs. comparator (mmHg)

DLDL from baseline (mg/dl)

DLDL vs. comparator (mg/dl)

4.3 4.3 3.1 NR

3.5 4.7 0.7 NR

a Once a day unless specified; CAN, canagliflozin; PBO, placebo; MET, metformin; GLIM, glimepiride; SIT, sitagliptin; SBP, systolic blood pressure; LDL, low density lipoprotein cholesterol; BID, twice daily; vs., versus; D, change in; NR, not reported.

Effects of canagliflozin on the macrovascular complications of T2DM remain to be determined. The CANagliflozin Cardiovascular Assessment Study (CANVAS) is an ongoing prospective placebo-controlled trial to evaluate the effects of canagliflozin on the risk of cardiovascular disease and to assess safety and tolerability in patients with inadequately controlled T2DM and increased cardiovascular risk [103]. Intermittent data (CANVAS sub-study) have been released and, so far, have been reassuring [104,105]. However, final results are not expected until 2015. Small reductions in bone density and numerical increases in the number of low-trauma upper extremity fractures were observed in older patients receiving canagliflozin therapy relative to placebo [55,106]. The reduction in bone density is likely explained by the associated weight loss. Yet, there were

no meaningful changes in serum or urine calcium excretion, and there were variable, but overall no meaningful changes in 1,25-dihydroxy vitamin D levels. There was a transient increase in PTH at week 3 with no substantive changes at week 12 (phase 2), or at weeks 26 or 52 (phase 3). The FDA has required the manufacturer to conduct a study to assess the effects of canagliflozin on bone health [106].

5.2.7.

Dosing recommendations

Janssen Pharmaceuticals markets canagliflozin as Invokana1. It is administered once daily before the first meal of the day [99]. The recommended starting dose is 100 mg once daily, but can be increased to the maximum dose of 300 mg in patients with an eGFR  60 ml/min/1.73 m2 who require additional glucose control.

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5.2.8. Use in special populations 5.2.8.1. Renal impairment. Canagliflozin has not been studied in advanced chronic kidney disease (eGFR < 30 ml/min/ 1.73 m2), end stage renal disease or dialysis patients [99]. Based on its pharmacological properties, canagliflozin is likely not effective in these patients. Patients with stage 3 chronic kidney disease who received canagliflozin achieved less glycemic efficacy compared to patients with normal renal function and had a higher incidence of renal-related adverse effects such as hypovolemia and hyperkalemia [55,99]. Canagliflozin therapy was also associated with transient decreases in eGFR and increases in blood urea nitrogen in such patients [95]. However, similar, but smaller changes were also observed in patients receiving placebo, suggesting that these changes might be attributable to the underlying diabetic nephropathy rather than to the intervention. Current prescription guidelines for canagliflozin recommend a maximum daily dose of 100 mg for patients with an eGFR between 46 and 59 ml/min/m2, and do not recommend it for eGFR < 45 ml/ min/m2 [99].

5.2.8.2. Hepatic impairment. No dosage adjustments are necessary in patients with mild to moderate hepatic impairment [99]. Canagliflozin has not been studied in patients with severe hepatic impairment and is not recommended in this patient population. 5.2.8.3. Older patients. In clinical trials, 2034 patients aged  65 years were treated with canagliflozin [99]. Older patients had a higher incidence of volume related adverse events such as hypotension, syncope and postural dizziness. These effects were more common with the 300 mg daily dose relative to 100 mg doses [96]. Thus, 100 mg maximum doses may be considered in older patients unless the benefits outweigh the risks of using the higher dose [99]. 5.2.8.4. Pregnancy and breastfeeding. Canagliflozin has not been studied extensively in this population and is therefore considered a category C agent [99]. The extent of canagliflozin excretion in human milk is unknown. 5.3.

Other considerations

The reduction in body weight associated with SGLT2 inhibitors is noteworthy given that over 80% of patients with T2DM are overweight or obese [6,107], weight loss is difficult for patients with T2DM to achieve [6], and many antidiabetes treatments (including pioglitazone) are associated with weight gain. Owing to the mechanism of action of SGLT2 inhibitors, involving glucosuria and the associated osmotic duiresis, there is a concern of developing side effects such as dehydration, electrolytes disturbance, and renal dysfunction. Fortunately, this is generally not supported by the results of the studies discussed above. Further reassurance comes from the evidence that subjects with familial renal glucosuria (FRG), a rare condition caused by a mutation in SGLT2 gene and a disease model of SGLT2 inhibition, do not develop dehydration, electrolytes disturbance, or hypoglycemia [108]. Given the novelty of these agents it is premature to describe their long-term effect on important end points such as cancer

15

risk and cardiovascular outcomes, including myocardial infarction and stroke. Time and further evidence from postmarketing studies are required to quantify any potential associations.

6. Selected SGLT2 inhibitors in clinical development 6.1.

Empagliflozin

Empagliflozin (BI 10773) is a potent and selective SGLT2 inhibitor being developed by Boehringer Ingelheim and Eli Lilly pharmaceuticals as a treatment for T2DM [109]. In a preclinical study, empagliflozin had the highest selectivity for SGLT2 over SGLT1 (>2500-fold), followed by tofogliflozin (>1875-fold), dapagliflozin (>1200 fold), ipragliflozin (>550-fold) and canagliflozin (>250-fold) [110]. Empagliflozin has been shown to induce UGE both in healthy volunteers [111] and in patients with T2DM [112]. A New Drug Application (NDA) has been submitted to the US FDA for empagliflozin [113]. To date, 8 major clinical trials (phases 2b and 3) addressing the efficacy and safety of empagliflozin in patients with T2DM have been published (Tables 6 and 7). Empagliflozin has been studied as monotherapy [114,115], and as add-on to metformin [116,117], two oral agents [118,119] and insulin [120]. Empagliflozin at 25 mg for 12 weeks significantly decreased HbA1c (0.72%), FPG (31.9 mg/dl), and body weight (1.2 kg vs.) relative to placebo in patients with T2DM [114]. In a placebo and active comparator controlled trial, 899 patients were randomized to empagliflozin 10 mg, empagliflozin 25 mg, sitagliptin, and placebo [115]. Compared with placebo, mean differences in change from baseline HbA1c at week 24 were 0.74% for empagliflozin 10 mg, 0.85% for empagliflozin 25 mg, and 0.73% for sitagliptin. Empagliflozin was beneficial when used as an add-on therapy. In a 12-week study in patients with T2DM inadequately controlled with metformin, empagliflozin add-on at 25 mg resulted in HbA1c reduction by up to 0.69% relative to placebo [117]. Additionally it led to significant reductions in FPG (up to 32.7 mg/dl vs. placebo) and weight (up to 1.7 kg vs. placebo). Sustained glycemic control and weight reduction were observed with empagliflozin therapy in a 78-week, openlabel extension of this trial [121]. In a separate trial, 666 patients inadequately controlled on metformin and sulfonylureas were randomized to once-daily empagliflozin 10 mg, empagliflozin 25 mg, or placebo [118]. At week 24, placebosubtracted changes from baseline in HbA1c were 0.65% and 0.60% for empagliflozin 10 mg and 25 mg doses, respectively. Additionally, empagliflozin significantly reduced mean daily glucose levels, weight, and systolic (but not diastolic) blood pressure vs. placebo. In a 78-week phase 3 clinical trial of empagliflozin as add-on to basal insulin in adults with T2DM, placebo-adjusted changes in HbA1c for empagliflozin 10 mg and 25 mg were 0.6% and 0.7% ( p < 0.001), respectively, at week 18, and 0.5% and 0.6%, respectively, at week 78 ( p < 0.001) [120]. The study included an 18-week fixed insulin dose period, after which the dose was adjusted at investigator’s discretion. At week 78, empagliflozin therapy resulted in significant reduction in the required daily insulin dose.

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Author (year)

n, Patients

Duration (wk)

Initial HbA1c %

Initial FBG (md/dl)

Empagliflozin Monotherapy trials, placebo and active comparator controlled Ferrannini (2013) 408 12 7.9

899

24

Monotherapy trials, active comparator controlled Ferrannini (2013) 659 78

Add-on to metformin trials, placebo controlled Ha¨ring (2013) 637 24

D HbA1c vs. comparator (%)

DFBG from baseline (mg/dl)

DFBG vs. comparator (mg/dl)

Background treatment Drug naı¨ve or a single OADs

EMP 10 mg

0.48

0.58

28.9

29.7

EMP 25 mg MET PBO EMP 10 mg EMP 25 mg SIT 100 mg PBO

0.63 0.75 0.1 0.66 0.78 0.66 0.08

0.73 0.85 vs. PBO

31.1 29.7 0.8 19.4 24.5 6.8 11.7

31.9 30.5 vs. PBO

EMP 10 mg

0.34

0.22

30.4

4.4

EMP 25 mg MET

0.47 0.56

0.09

27.7 26

1.7

7.9

151.6

Drug naı¨ve

7.9

178

12-wk prior therapy with EMP

NR

D HbA1c from baseline (%)

0.74 0.85 0.73 vs. PBO

31.1 36.2 18.7 vs. PBO

NR

MET

EMP 10 mg EMP 25 mg PBO

0.7 0.77 0.13

0.57 0.64

20.0 22.3 6.4

26.0 28.6

Add-on to metformin trials, placebo and active comparator controlled Rosenstock (2013) 495 12 7.9

NR

MET

EMP 10 mg EMP 25 mg EMP 50 mg SIT PBO

0.56 0.55 0.49 0.45 0.14

0.7 0.69 0.63 0.59 vs. PBO

22.1 26.8 27.9 12.2 5.0

27.2 31.9 32.9 17.2 vs. PBO

Add-on to metformin trials, active-comparator controlled Ferrannini (2013) 166 78 7.9

178

SIT

EMP 10 mg EMP 25 mg SIT

0.34 0.63 0.4

0.06 0.23

21.3 31.8 16.0

5.3 15.8

Add-on to other AHAs trials, placebo controlled Ha¨ring (2013) 666 24

8.1

152.8

Trial regimen Add-on to MET + SU vs. PBO

EMP EMP PBO EMP EMP PBO EMP EMP PBO

0.82 0.77 0.17 0.59 0.72 0.11 0.48 0.64 0.02

0.64 0.59

23.2 23.2 5.6 16.9 22.0 6.5 10.0 15.0 3.0

28.8 20.9

0.76 0.47

1.23

39.9 5.9

45.8

Kovacs (2013)

498

24

8.1

151.7

Add-on to PIO  MET vs. PBO

Rosenstock (2013)

494

78

8.2

142.1

Add-on to basal INS vs. PBO

16

8.3

175

Background treatment Drug naı¨ve or washout

Ipragliflozin Monotherapy trials, placebo controlled Kashiwagi (2011) 129

10 mg 25 mg 10 mg 25 mg 10 mg 25 mg

IPR 50 mg PBO

0.48 0.61 0.46 0.62

23.4 28.4 13.0 18.0

diabetes research and clinical practice xxx (2014) xxx–xxx

Roden (2013)

NR

Drug and dosea

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16

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Table 6 – Selected SGLT2 inhibitors in clinical trials.

Wilding (2013)

343

12

Add-on to other AHAs trials, placebo controlled Kashiwagi (2012) 242 24 Kashiwagi (2012)

Schwartz (2011)

151

61

LX4211 Monotherapy trials, placebo controlled Zambrowicz (2012) 36

24

Drug naı¨ve or washout

8.32

168.1

MET

7.8

154.8

MET

8.36

178

SU

8.32

171.5

PIO

4

NR

NR

Trial regimen Mono and add-on to OADs vs. PBO

4

8.3

185

Background treatment NR

8.1

172

MET

Add-on to metformin trials, placebo controlled Rosenstock (2012) 299 12

IPR 50 mg IPR 150 mg IPR 300 mg PBO MET

0.39 0.47 0.55 0.26

IPR 50 mg PBO IPR 50 mg IPR 150 mg IPR 300 mg PBO

0.87 0.38 0.65 0.72 0.79 0.31

1.29

IPR 50 mg PBO IPR 50 mg PBO

NR

1.14

NR

38

NR

0.88

NR

41

IPR 50 mg IPR 100 mg IPR 200 mg IPR 300 mg PBO

0.73 0.61 0.84 0.73 0.1

0.63 0.51 0.74 0.63

60.3 49.0 70.6 65.0 10.4

50.0 38.5 60.1 54.5

LX 150 mg LX 300 mg PBO

1.15 1.25 0.49

0.66 0.76

52 68 12

40 56

LX 75 mg LX 200 mg LX 200 mg BID LX 400 mg PBO

0.41 0.53 0.8 0.92 0.08

0.49 0.61 0.88 1

NR



0.65 0.73 0.81

19.8 23.4 30.2

0.72 vs. PBO

21.2 vs. PBO

0.34 -0.4 0.48

22 11 14.2 24.3 27.7 1.1

DIAB-6018; No. of Pages 26

Add-on to metformin trials, placebo controlled Goto (2012) 168 24

165

39.4 13.1 23.2 26.6

a Once a day unless specified; EMP, empagliflozin; IPR, ipragliflozin; LX, LX4211; PBO, placebo; mono, monotherapy; MET, metformin; SU, sulfonylureas; PIO, pioglitazone; INS, insulin; SIT, sitagliptin; OADs, oral antihyperglycemic drugs; AHAs, antihyperglycemic agents; n, number; BID, twice daily; wk, weeks; FPG, fasting plasma glucose; vs., versus; D, change in; NR, not reported.

diabetes research and clinical practice xxx (2014) xxx–xxx

17

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Monotherapy trials, placebo and active comparator controlled Fonseca (2013) 412 12 7.9

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diabetes research and clinical practice xxx (2014) xxx–xxx

Table 7 – Important secondary outcomes in empagliflozin, ipragliflozin, and LX4211 trials. Author (year)

Empagliflozin Ferrannini (2013)

Roden (2013)

Ferranini (2013)

Ha¨ring (2013)

Rosenstock (2013)

Ferrannini (2013)

Ha¨ring (2013)

Kovacs (2013)

Rosenstock (2013)

Ipragliflozin Kashiwagi (2011) Fonseca (2013)

Goto (2012) Wilding (2013)

Kashiwagi (2012) Kashiwagi (2012) LX4211 Zambrowicz (2012)

Rosenstock (2012)

Drug and dosea

DWeight from baseline (kg)

DWeight vs. comparator (kg)

DSBP from baseline (mmHg)

DSBP vs. comparator (mmHg)

DLDL from baseline (mg/dl)

DLDL vs. comparator (mg/dl)

EMP 10 mg EMP 25 mg MET PBO EMP 10 mg EMP 25 mg PBO EMP 10 mg EMP 25 mg MET EMP 10 mg EMP 25 mg PBO EMP 10 mg EMP 25 mg EMP 50 mg SIT PBO EMP 10 mg EMP 25 mg SIT EMP 10 mg EMP 25 mg PBO EMP 10 mg EMP 25 mg PBO EMP 10 mg EMP 25 mg PBO

2.3 2.0 1.3 0.8 2.3 2.5 0.3 2.2 2.6 1.3 2.08 2.46 NR 2.7 2.6 2.9 0.8 1.2 3.1 4.0 0.4 2.2 2.4 0.4 1.6 1.5 0.3 2.2 2.0 0.7

1.6 1.3 0.5 vs. PBO

NR

–

0 0 9.6 vs. PBO

1.9 2.2

2.9 3.7 0.3 0.1 1.7 2 4.5 5.2 NR 4.4 8.5 3.2 2.2 1.8 3.3 3 1.8 4.1 3.5 1.4 3.1 4 0.7 4.1 2.4 0.1

2.6 3.4

1.2 1.2 10.8 1.2 NR

1.9 3.7

NR

–

–

NR

–

2.6 6.7 1.4 0.4 vs. PBO

10 5 8.9 7 1.2 NR

8.8 3.8 7.7 5.8 vs. PBO

1.5 3.9 0.8 3.5 1.6 0 NR

0.4 3.1

IPR 50 mg PBO IPR 50 mg IPR 150 mg IPR 300 mg MET IPR 50 mg PBO IPR 50 mg IPR 150 mg IPR 300 mg IPR PBO IPR 50 mg PBO IPR 50 mg PBO

NR

1.5

NR

3.2

NR

–

1.6 2.0 2.6 0.78 2.3 0.6 2.1 2.0 2.2 0.5 NR

0.7 1.1 1.7 0.12 vs. PBO 2.7

2.6 3 2.6 3.1 NR

NR

–

3.6

NR

1.6 1.5 1.7

3.3 2.2 4.3

NR

4.2

NR

–

NR

2.8

3.8 2.7 4.8 0.5 5.5 1.3 5.9 2.5

3.4

NR

–

LX 150 mg LX 300 mg PBO LX 75 mg LX 200 mg LX 200 mg BID LX 400 mg PBO

3 4 2.0 1.0 1.9 1.8 2.5 0.4

1 2

10 13 4 0.2 3.9 4.5 5.7 0.5

6 9

6 15 22 NR

16 7

0.9 1.3 1.6 2.0 1.5 1.4 1.7 0.4 vs. PBO 2.7 3.6 1.8 2.0 2.0 1.8 2.9 2.7

1.3

0.6 1.5 1.4 2.1

5.1 4.8 2.7 2.1 3.9 4.7 4.2 2.5

0.3 3.4 4 5.2

–

–

3.5 1.6 –

–

–

a Once a day unless specified; EMP, empagliflozin; IPR, ipragliflozin; LX, LX4211; PBO, placebo; MET, metformin; SIT, sitagliptin; SBP, systolic blood pressure; LDL, low density lipoprotein cholesterol; BID, twice daily; vs., versus; D, change in; NR, not reported.

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DIAB-6018; No. of Pages 26 diabetes research and clinical practice xxx (2014) xxx–xxx

Hypoglycemic events were not increased with empagliflozin therapy compared to placebo. A pooled analysis of data obtained from two phase 2b trials examined the effect of empagliflozin on blood pressure [122]. At week 12, significant reductions in mean SBP of 2.6 mmHg and 3.3 mmHg were observed with empagliflozin 10 mg and 25 mg, respectively, relative to placebo, and more pronounced reductions were seen in patients with higher SBP (>140 mmHg at baseline). There was no associated increase in heart rate, and the authors observed that changes in SBP from baseline to week 12 were not correlated with change in body weight or change in HbA1c, suggesting that the antihypertensive effects of empagliflozin are independent of its ability to reduce plasma glucose and body weight [122]. Empagliflozin was superior to metformin and sitagliptin in achieving weight reduction [123]. Adjusted mean reductions in body weight were 2.1 kg and 1.9 kg for empagliflozin 10 mg and 25 mg, respectively, vs. a reduction of 0.9 kg with metformin monotherapy. As add-on to metformin, empagliflozin 10 mg and 25 mg produced mean weight reductions of 2.9 and 3.8 kg, respectively, compared with a negligible change in weight (0.6 kg) with sitagliptin (Table 7). In a separate study, empagliflozin was well tolerated when used as add-on to pioglitazone alone or pioglitazone plus metformin for 24 weeks [119], and it led to significant improvements in glycemic control, body weight, and blood pressure (Tables 6 and 7). Significantly more patients receiving empagliflozin achieved >5% reduction from baseline in body weight at week 24 (14– 19%), compared with placebo (6%). Hypoglycemia was rare with this add-on and comparable to placebo, and there was no increase in the risk of side effects associated with pioglitazone. Hypoglycemia was infrequent and comparable to placebo with empagliflozin therapy [114–120,123]. Yet, the incidence of genital mycotic infections and female urinary tract infections was higher with empagliflozin therapy compared to placebo or active comparator (Table 8). But there was no increased incidence of male urinary tract infections with empagliflozin therapy compared to other groups. A single 50 mg dose of empagliflozin was well tolerated in patients with different stages of renal or hepatic impairment [124,125], and the authors concluded that no dose adjustment of empagliflozin is required for such patients. However, consistent with other SGLT2 inhibitors, UGE produced by empagliflozin decreased with increasing renal impairment and correlated with decreased eGFR [124]. In severe renal impairment or renal failure, empagliflozin therapy showed little to no effect on UGE. A large, 4-year, ongoing head-to-head trial is comparing empagliflozin with glimepiride as add-on to metformin in T2DM with insufficient glycemic control [126]. In addition to determining the effects of these treatments on glycemic control over the long term, this study will investigate their effects on beta-cell function, cardiovascular risk and renal function.

6.2.

Ipragliflozin

Ipragliflozin (ASP1941) is another selective SGLT2 inhibitor that is co-developed by Astellas and Kotobuki Pharmaceuticals [127]. It was recently approved in Japan for the treatment

19

of T2DM [128]. In healthy human subjects [129] and T2DM patients [130], ipragliflozin once daily was associated with a dose dependent UGE. In patients with T2DM, ipragliflozin therapy was associated with UGE of up to 90 g/day, and the amount of UGE positively correlated with plasma glucose levels and the eGFR [130]. In healthy subjects, ipragliflozin did not affect the pharmacokinetics of sitagliptin, pioglitazone, or glimepiride, and vice versa, suggesting that ipragliflozin can be safely co-administered with other oral antidiabetes agents [131]. Published clinical trials have examined ipragliflozin as monotherapy [132,133] and as add-on to metformin [134,135], SU or pioglitazone [136], and other antihyperglycemic agents [130] in patients with T2DM (Tables 6 and 7). In a 12-week dosefinding study, ipragliflozin doses 50 mg/day were comparable to metformin (1500 mg/day) in lowering HbA1c and FPG [133]. Similarly, in a 16-week, placebo-controlled, monotherapy trial in Japanese patients with T2DM, ipragliflozin (50 mg/ day) resulted in significant reductions from baseline in HbA1c (1.23%), FPG (46 mg/dl) and body weight (1.47 kg), compared with placebo [132]. Ipragliflozin was beneficial as an add-on to monotherapy in T2DM patients with inadequate glycemic control. In a 24-week metformin add-on trial, ipragliflozin (50 mg/day) significantly reduced HbA1c (1.29%), FPG (39.4 mg/dl), and body weight (1.69 kg) compared with placebo [134]. Ipragliflozin was generally well tolerated and was not associated with increased risk of hypoglycemia relative to placebo. However, it was associated with increased incidence of genital infections but not urinary tract infections [132,134]. A separate add-on study concluded that ipragliflozin (12.5–300 mg/day) and metformin (1500 mg/day) combination treatment for 12 weeks was well tolerated in patients with T2DM and that dose-dependent reduction in the HbA1c (up to 0.50%, vs. placebo) was observed in more patients treated with ipragliflozin than with placebo [135]. Treatment with ipragliflozin (50 mg/day) added to either an SU or pioglitazone for 24 weeks was well tolerated and significantly reduced HbA1c, body weight, and blood pressure, relative to placebo [136]. Similar to other SGLT2 inhibitors, more patients on ipragliflozin therapy reported diuresis-related adverse effects, such as polyuria and pollakauria, than placebo [136] (see Table 8).

6.3.

LX4211

LX4211 is a novel dual inhibitor of SGLT1 and SGLT2 glucose transporters that is being developed by Lexicon Pharmaceuticals for the treatment of T2DM [137]. In addition to inducing glucosuria through blocking glucose reabsorption by the kidney, LX4211 may also block glucose reabsorption in the small intestine via inhibiting SGLT1 [138]. Hence it may have enhanced benefits in patients with T2DM through its dual mechanism of action. The combination of LX4211 and DPP-4 inhibitors is hypothetically promising and has been tested in preclinical and clinical studies [139]. LX4211 plus sitagliptin was well tolerated and produced significant reductions in glucose levels throughout the day and decreases in insulin levels relative to sitagliptin monotherapy. Additionally, the combination led to synergistic increases in active GLP-1, with no reported GI adverse effects [139].

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Reference (year)

a

Hypoglycemic events, %

Genital tract infections, %

Urinary tract infections, %

SGL2-i agent

PBO or comparator

SGL2-i agent (femalejmale)

PBO or comparator (femaljmale)

SGL2-i agent (femalejmale)

PBO or comparator (femalejmale)

Mono Mono vs. PBO vs. MET Mono Mono vs. MET Add-on to MET Add-on to MET Add-on to MET vs. GLIP Add-on to GLIM Add-on to PIO Add-on to INS Add-on to INS Add-on to INS Add-on to MET vs. Add-on to SIT  MET vs. PBO

3 6–10 1 0–2 1 2–4 2 3 8 2 27 60 61–70 3 3

3 4 2 2 3 3 3 40 5 0 13 52 62 3 2

13 2–7 3–5 0–2 13 8–13 5j2 15 7 8–9 21 11 10–21j3–13 9 10

1 0 1 0 2 5 0 3 1 3 4 3 6j0 2 1

13 5–12 4–5 0–4 11 8 12j2 7 7 5–9 4 11 10–20j7 8 7

4 6 3 2 4 8 2 4 6 8 0 5 7j4 4 6

26 12 12 52 52 26 18 26 26 52

Mono Mono Add-on to Add-on to Add-on to Add-on to Add-on to Add-on to Add-on to vs. SITA

4 1–4 2–6 NR 6 35 49 52 6 43

3 0 2 – 34 18 37 36 3 41

7–9j3–6 2 3–8 10–11j2–5 11–14j7–8 19j7 10–12j4–8 3j2 13j5 12

4j0 0 2 1 1j2 5j1 2j1 0 2j0 2

5–7 0 3–9 5–8 6 8 3 6–8 7 4

4 0 6 7 5 8 2 6 5 6

12 24 24 12 24 24 78 78 78

Mono vs. MET vs. PBO Mono vs. PBO vs. SIT Add-on to MET Add-on to MET vs. SIT vs. PBO Add-on to MET + SU Add-on to PIO  MET Add-on to INS Mono vs. MET Add-on to MET vs. SIT

NR <1 1–2 0–4 14 2 36 1–2 2

– <1 1 0 8 2 35 4 4

0–4 4–9j1–3 4–5 1–10 1–5j1 6–10j1–7 5–8 5–6j4–5 4j2–3

0 0 0 0 1 3j1 2 4j0 0

1–3 13–15j1–2 5–6 3–6 13–18j0–3 22–31j2–4 NR 6–7j0–7 16–23j2–3

1 9 5 3 3 23j1 7j0 15j10

16 12 24 12 24 24

Mono Mono Add-on Add-on Add-on Add-on

MET MET SU PIO

<1 1 0 0–6 1 1

0 0 0 3 1 0

3 0–12 5 0–4 7j2 9j0

0 1 0 2 2j0 0

0 2–13 2 1–7 10j0 14j0

<1 9 4 6 0j2 6j0

4 12

Mono Add-on to MET

0 NR

0 –

NR 3–5

– 0

8 2

0 2

24 12 24 12 24 24 24 104 24 24 12 48 104 24 24

to to to to

MET vs. SIT vs. PBO MET MET vs. GLIM MET + SU INS different AHAs different AHAs

vs. placebo unless specified; PBO, placebo; mono, monotherapy; MET, metformin; GLIP, glipizide; GLIM, glimepiride; SU, sulfonylureas; PIO, pioglitazone; INS, insulin; SIT, sitagliptin; AHAs, antihyperglycemic agents; n, number; BID, twice daily; wk, weeks; FPG, fasting plasma glucose; vs., versus; D, change in; NR, not reported.

diabetes research and clinical practice xxx (2014) xxx–xxx

Dapagliflozin Ferrannini (2010) List (2009) Ji (2013) Kaku (2013) Henry (2012) Bailey (2010) Bolinder (2012) Nauck (2011) Strojek (2011) Rosenstock (2012) Wilding (2009) Wilding (2012) Wilding (2013) Henry (2012) Jabbour (2013) Canagliflozin Stenlof (2013) Inagaki (2013) Rosenstock (2012) Lavalle Gonzalez (2013) Cefalu (2013) Wilding (2012) Matthews (2013) Yale (2013) Bode (2013) Schernthaner (2013) Empagliflozin Ferrannini (2013) Roden (2013) Ha¨ring (2013) Rosenstock (2013) Ha¨ring (2013) Kovacs (2013) Rosenstock (2013) Ferrannini (2013) Ferrannini (2013) Ipragliflozin Kashiwagi (2011) Fonseca (2013) Goto (2012) Wilding (2013) Kashiwagi (2012) Kashiwagi (2012) LX4211 Zambrowicz (2012) Rosenstock (2012)

Regimena

Duration (wk)

DIAB-6018; No. of Pages 26

20

Please cite this article in press as: Hasan FM, et al. SGLT2 inhibitors in the treatment of type 2 diabetes. Diabetes Res Clin Pract (2014), http:// dx.doi.org/10.1016/j.diabres.2014.02.014

Table 8 – Adverse events of special interest in SGLT2 inhibitors trials.

DIAB-6018; No. of Pages 26 diabetes research and clinical practice xxx (2014) xxx–xxx

In a 4-week, phase 2 trial, LX4211 (300 mg/day) produced significant reductions in HbA1c (0.76%) and FPG (56 mg/dl) relative to placebo [138]. In a 12-week metformin add-on trial in 299 patients with T2DM, LX4211 maximized UGE at 200 mg daily dose [140]; and it produced a dose-dependent decrease in HbA1c levels, up to 1% at 400 mg daily dose. Additionally, LX4211 add-on produced significant reductions in body weight (up to 2.1 kg) and systolic blood pressure (up to 5.2 mmHg), relative to placebo. LX4211 treatment significantly reduced triglyceride concentrations in all but the group receiving 200 mg LX4211 per day [140]. A phase 1 study is assessing the drug properties, safety, and tolerability of LX4211 in patients with T2DM and moderate to severe renal impairment [141], and a phase-2 study is examining the safety and efficacy of LX4211 in patients with T1DM [142].

7.

Conclusion

Current therapeutic agents for T2DM have not achieved the desired glycemic goals or have been associated with adverse effects that limit their efficacy. Newer agents with different or complementary mechanisms of action, and better safety profile, are needed. SGLT2 inhibitors are novel agents that improve glycemic targets in addition to ameliorating comorbidities commonly associated with T2DM, such as obesity and hypertension. Their unique, insulin-independent, mechanism of action makes them advantageous where other agents may fail as a result of the disease progression. This article reviews the currently approved SGLT2 inhibitors for the treatment of T2DM and other agents within the class that are in advanced stages of clinical development. The major disadvantage of SGLT2 therapy, perhaps, is the increased risk of genital mycotic infections, and to a lesser extent, urinary tract infections, in small percentage of patients, particularly in women. Additionally, since the efficacy of SGLT2 inhibitors requires adequate filtered load of glucose in the kidney, their efficacy diminishes in renal impairment. Yet, in the absence of moderate or severe renal impairment, SGLT2 inhibitors are associated with significant and sustained HbA1c reduction when used as monotherapy or in combination with other antidiabetes agents, with low incidence of hypoglycemia. Furthermore, they are simple to administer with once daily oral dosing, and they improve beta cell function, promote weight loss, and reduce blood pressure. Data so far are reassuring regarding the effect of SGLT2 inhibitors on important outcomes such as cardiovascular disease and cancer risk; however, longer duration of therapy is needed to study the effect of SGLT2 inhibitors on these outcomes. Dapagliflozin and canagliflozin are two competitive, reversible, and highly selective SGLT2 inhibitors recently became available for clinical use in management of T2DM. Clinical trials to date on these two agents have been well conducted and have shown significant and sustained HbA1c reduction when used as monotherapy or in combination with other antidiabetes agents. Multiple other SGLT2 inhibitors are currently undergoing preclinical testing.

21

Conflict of interest JEG is a consultant/member of the speaker bureau for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Janssen Pharmaceuticals, MannKind, Merck, and Sanofi. FMH and MA have no conflicts.

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