Fixed-dose combination of ertugliflozin and metformin hydrochloride for the treatment of type 2 diabetes

Juan Pablo Frias

To cite this article: Juan Pablo Frias (2019): Fixed-dose combination of ertugliflozin and metformin hydrochloride for the treatment of type 2 diabetes, Expert Review of Endocrinology & Metabolism, DOI: 10.1080/17446651.2019.1571908
To link to this article: https://doi.org/10.1080/17446651.2019.1571908

Accepted author version posted online: 22 Jan 2019.
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EXPERT REVIEW OF ENDOCRINOLOGY & METABOLISM https://doi.org/10.1080/17446651.2019.1571908

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Fixed-dose combination of ertugliflozin and metformin hydrochloride for the treatment of type 2 diabetes
Juan Pablo Frias
Department of Clinical Research, National Research Institute, Los Angeles, CA, USA

ABSTRACT
Introduction: Combining antihyperglycemic agents in order to rapidly and safely achieve the best possible glycemic control is the standard of care today for the management of type 2 diabetes. Agents should ideally have mechanisms of actions that are complementary and that improve glycemic control without unacceptable gain in body weight or hypoglycemia.
Areas covered: Ertugliflozin and metformin hydrochloride (ertugliflozin/metformin, SEGLUROMET) is a recently approved fixed-dose combination tablet containing the sodium-glucose co-transporter 2 (SGLT-2) inhibitor ertugliflozin and metformin. This review summarizes key characteristics of ertugli- flozin and metformin, as well as the efficacy and safety results of co-administration of these agents in the ertugliflozin clinical development program. This information comes from the ertugliflozin/metfor- min prescribing information as well as published clinical trials obtained through a PubMed search. Expert commentary: SGLT-2 inhibitors are an important class of antihyperglycemic agents that are efficacious as monotherapy and in combination with other antihyperglycemic agents. Given their favorable effects on glycemia control as well as ‘extra-glycemic’ parameters such as body weight and blood pressure, they are ideal agents for appropriate patients with type 2 diabetes. The fixed-dose combination of ertugliflozin with metformin is an effective combination that is conveniently adminis- tered and may improve medication adherence and persistence.
ARTICLE HISTORY Received 17 October 2018 Accepted 16 January 2019
KEYWORDS
Type 2 diabetes; fixed-dose combination; ertugliflozin; metformin

1.Introduction and overview of the market
Type 2 diabetes is a chronic and progressive disease character- ized by hyperglycemia due to defects in multiple tissues and organs [1,2]. Persons with type 2 diabetes are generally obese, and the disease is commonly accompanied by comorbidities, including hypertension and dyslipidemia [3]. These, along with chronic hyperglycemia, increase the risk of long-term diabetes- related micro- and macrovascular complications [3].
We are fortunate today to have a variety of anti-diabetic medications with distinct mechanisms of action that help address the complex pathophysiology of the disease [4]. The overarching goal of glycemic management in patients with type 2 diabetes is to attain the best possible glucose control while avoiding side effects, particularly hypoglycemia and weight gain [3,5,6]. Additionally, modifiable cardiovascular risk factors (e.g., hypertension, dyslipidemia, smoking) should be aggressively addressed to reduce the risk of cardiovascular dis- ease, the leading cause of death in this patient population [3,5,6].
Treatment guidelines for the management of hyperglyce- mia in type 2 diabetes call for lifestyle intervention (healthy diet and physical activity) and education as the cornerstones of therapy [3,5,6]. Metformin is recommended at the time of initial diagnosis in all patients without contraindications. Individualized hemoglobin A1c (A1C) targets should be estab- lished and followed closely. If a patient’s target is not achieved after approximately 3 months of a therapeutic intervention, treatment should be intensified with the addition of oral

antihyperglycemic medication(s) and/or injectable agent(s), such as basal insulin or glucagon-like peptide 1 receptor agonists (GLP-1 RAs) [3,5,6].
Traditionally, the combination of agents for the treatment of type 2 diabetes has been accomplished in a sequential manner, beginning with oral agent monotherapy and, if needed, adding single agents to existing therapy. Recently, treatment guidelines have recommended consideration of simultaneous initiation of 2 antihyperglycemic agents at diagnosis (initial combination ther- apy) in patients with very poor glucose control (i.e., A1C greater than 9% or greater than 1.5% above the individualized A1C target) [3,5]. At this level of dysglycemia, it is unlikely that monotherapy will sufficiently improve glycemic control. Whether using a sequential approach or a simultaneous approach of combining medications at diagnosis or when intensifying existing regimens, the ultimate goal of glucose management is to safely and quickly achieve individualized glycemic targets by combining medica- tions with complementary mechanisms of action. As patient con- venience can play an important role in medication adherence and persistence – particularly in those with chronic diseases like type 2 diabetes, who are often on multiple medications – formulations that combine antidiabetic agents into one tablet or injection play an important role in the management of the disease [7,8].
Fixed-dose combination tablets of various classes of oral agents, in a variety of doses, have been commercially available for many years [9]. The present review will focus on the recently approved fixed-dose combination of the sodium-glucose co-

CONTACT Juan Pablo Frias [email protected] National Research Institute, Los Angeles, CA, USA
© 2019 Informa UK Limited, trading as Taylor & Francis Group

transporter 2 (SGLT-2) inhibitor ertugliflozin with metformin (SEGLUROMET). The 3 other currently available SGLT-2 inhibitors in the US – canagliflozin, dapagliflozin and empagliflozin – are also currently available as a fixed-dose combination tablet with metformin.

2.Chemistry, pharmacokinetics, and pharmacodynamics of ertugliflozin with metformin hydrochloride
Neither the properties of ertugliflozin nor metformin are altered by having them in a fixed-dose combination. Given the long-standing availability of metformin and extensive lit- erature on its properties, the reader is referred to recent reviews and the metformin product information for additional metformin-related information [10,11]. This section will focus on the SGLT-2 inhibitor ertugliflozin.

2.1.Chemistry of ertugliflozin
Ertugliflozin L-pyroglutamic acid’s chemical name is (1S,2S,3S, 4R,5S)-5-(4-chloro-3-(4ethoxybenzyl)phenyl)-1-(hydroxymethyl)- 6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol, compound with (2S)- 5-oxopyrrolidine-2-carboylic acid [12]. The molecular formula is C27H32CINO10 and its molecular weight is 566.00. It is a white to off-white powder, soluble in ethyl alcohol and acetone, slightly soluble in ethyl acetate and acetonitrile, and very slightly soluble in water [12].

2.2.Pharmacokinetics of ertugliflozin
Coadministration of ertugliflozin (15 mg) and metformin (1,000 mg) in healthy subjects did not result in meaningful alterations of the pharmacokinetics of either agent [12,13]. Additionally, the effects of a high-fat meal on the pharmaco- kinetics of ertugliflozin and metformin (administered as the fixed-dose combination) were comparable to those reported for the individual tablets [12].
The absolute oral bioavailability of a 15 mg dose of ertugli- flozin is approximately 100%. Under fasting conditions, peak plasma concentrations (Cmax) of ertugliflozin (5 mg and 15 mg) occur 1 hour post-dose (median Tmax). Administration with food decreases Cmax by approximately 30% and prolongs Tmax by 1 hour, but does not alter the plasma area under the curve (AUC). Given this, the effects of food on the pharmacokinetics of ertugliflozin are not considered to be clinically significant, and it can be administered with or without food. With once daily dosing, steady-state plasma ertugliflozin concentrations are reached in 4–6 days [12,14].
Plasma protein binding of ertugliflozin is 93.6%, is indepen- dent of ertugliflozin plasma concentrations, and is not mean- ingfully altered in patients with renal or hepatic impairment [12,15].
Metabolism is the primary clearance mechanism for ertugli- flozin and its major metabolic pathway is UGT1A9 and UGT2B7-mediated O-glucuronidation to two glucuronides that are pharmacologically inactive at clinically relevant con- centrations. CYP-mediated (oxidative) metabolism is minimal (12%) [12,16].

The mean half-life in patients with normal renal function is approximately 16.6 hours and following administration of an oral [14C]-ertugliflozin solution to healthy subjects, approxi- mately 40.9% and 50.2% of the drug-related radioactivity was eliminated in feces and urine, respectively [12,13].
A population pharmacokinetic analysis of ertugliflozin deter- mined that age, body weight, gender, and race did not have clinically meaningful effects on its pharmacokinetics. Additionally, based on drug interaction studies, the ertugliflo- zin/metformin label states that no dose adjustment is needed when administered with commonly prescribed medications [12].

2.3.Pharmacodynamics of ertugliflozin
Dose-dependent increases in the urinary glucose excretion were observed in healthy subjects and in patients with type 2 diabetes mellitus following single- and multiple-dose admin- istration of ertugliflozin. Dose-response modeling indicates that ertugliflozin 5 mg and 15 mg result in near maximal urinary glucose excretion. Enhanced urinary glucose excretion is maintained after multiple-dose administration and results in increases in urinary volume [12].
The effect of ertugliflozin/metformin on QTc interval was evaluated in a Phase 1 study in 42 healthy subjects. At 6.7 times the therapeutic exposures with maximum recommended dose, ertugliflozin/metformin did not prolong QTc to any clini- cally relevant extent [17].
3.Mechanism of action of ertugliflozin and metformin hydrochloride
The components of this fixed-dose combination have comple- mentary mechanisms of action that address important defects in the pathogenesis of type 2 diabetes.

3.1.Mechanism of action of ertugliflozin
Normally, approximately 180 gm of glucose is filtered by the kidneys daily and it is all reabsorbed into the bloodstream at the level of the proximal tubule via SGLT-2 (90%) and, to a lesser extent, SGLT-1 (10%). Thus, under normal conditions, there is no glucose in the urine. Ertugliflozin is a selective SGLT-2 inhibitor. As such, it inhibits renal glucose reabsorption and increases urinary glucose excretion, thereby reducing plasma glucose concentrations [18].

3.2.Mechanism of action of metformin
Metformin, a biguanide, has a complex mechanism of action which has not been fully elucidated. It acts at the level of the liver to reduce hepatic glucose production and, amongst other proposed mechanisms, is thought to increase glucagon like peptide-1 (GLP-1) secretion [11]. These effects, which are dis- tinct from the mechanism of action of the SGLT-2 inhibitors, result in improvements in plasma glucose concentrations.

4.Clinical efficacy of ertugliflozin co-administered with metformin
Although there are no published long-term studies specifically assessing the fixed-dose combination of ertugliflozin with

metformin, the efficacy and safety of the two agents co- administered as separate tablets was studied extensively as part of the ertugliflozin clinical development program [19–23]. Efficacy results of these studies, which form the basis for the regulatory approval of the fixed-dose combination, are sum- marized below.

4.1.Phase 2 studies
A phase 2 dose-ranging study was conducted in patients with type 2 diabetes suboptimally controlled on metformin to assess the efficacy and safety of ertugliflozin [19]. In this 12-week, 6-arm, double-blind, placebo-controlled study, 328 patients were rando- mized to ertugliflozin (1 mg, 5 mg, 10 mg, or 25 mg), sitagliptin (100 mg) or placebo. Metformin therapy was continued through- out the treatment period and the primary endpoint was the change in A1C from baseline to week 12. From a mean baseline A1C of approximately 8.0–8.3%, the placebo-corrected change in A1C ranged from -0.45 to -0.72% for the ertugliflozin doses (p < 0.002) and was -0.76% for sitagliptin (p < 0.0001). At week 26, a greater proportion of patients achieved an A1C less than 7.0% with ertugliflozin (1 mg, 44%; 5 mg, 42.9%; 10 mg, 38.6%; 25 mg, 36.2%) and sitagliptin (43.1%) compared with placebo (15.6%). In addition to improvements in glycemic control, ertugliflozin ther- apyresultedinsignificant reductionsinbodyweight, withabsolute weight loss after 12 weeks of therapy of -1.90, -2.50, -2.90 and
-2.66 kg in the 1 mg, 5 mg, 10 mg, and 25 mg doses, respectively (placebo, -0.75 kg; sitagliptin -0.30 kg). Modest increases in both LDL and HDL cholesterol, and decreases in triglycerides were seen with ertugliflozin therapy.

4.2.Phase 3 studies
The efficacy and safety of ertugliflozin co-administered with metformin was assessed in 4 placebo- or active-comparator phase 3 trials involving 3,643 patients with type 2 diabetes [20–23].

4.2.1.Ertugliflozin as add-on combination therapy with metformin
In this double-blind, placebo-controlled trial, 621 patients with type 2 diabetes inadequately controlled on metformin mono- therapy (baseline A1C 7.0% – 10.5%) were randomized in a 1:1:1 fashion to ertugliflozin 5 mg or 15 mg daily or placebo (added to ongoing metformin therapy) [20]. The primary endpoint was the change in A1C from baseline after 26 weeks of treatment. From a mean baseline A1C of 8.1%, the placebo corrected change in A1C at week 26 for the ertugliflozin 5 mg and 15 mg dose was
-0.7% and -0.9%, respectively (both p < 0.001). An A1C level of less than 7.0% at week 26 was reached by 35% of patients treated with ertugliflozin 5 mg and 40% of those treated with ertugliflozin 15 mg daily, compared with approximately 16% of placebo-treated patients. Significant reductions in fasting plasma glucose were seen with ertugliflozin versus placebo (ertugliflozin 5 mg, -27.0 mg/dL; ertugliflozin 15 mg, -39.6 mg/dL; placebo,
-1.8 mg/dL, both p < 0.001 vs placebo). At both doses, ertugli- flozin-treated patients experienced a reduction in body weight of approximately 3 kg at week 26, compared with a 1.3 kg reduc- tion in the placebo group (both p < 0.001 vs placebo).

Additionally, ertugliflozin-treated patients had significant reduc- tions in both systolic (ertugliflozin 5 mg, -4.4 mm Hg; ertugli- flozin 15 mg, -5.2 mm Hg; placebo, -0.7 mm Hg) and diastolic blood pressure (ertugliflozin 5 mg, -1.6 mm Hg; ertugliflozin 15 mg, -2.2 mm Hg; placebo, 0.2 mm Hg). As in the phase 2 study, there were modest increases in LDL cholesterol (2.0–2.6%) and HDL cholesterol (approximately 4.5%) in the ertugliflozin- treated patients after 26 weeks of therapy.

4.2.2.Ertugliflozin in combination with sitagliptin versus ertugliflozin alone and sitagliptin alone, as add-on to metformin
This was a 52-week, randomized, double-blind, active- comparator trial in 1,233 patients with type 2 diabetes inade- quately controlled on metformin monotherapy (baseline A1C 7.5% to 11.0%) [21]. Patients were randomized in a 1:1:1:1:1 fashion to one of 5 study arms (ertugliflozin 5 mg, ertugliflozin 10 mg, sitagliptin 100 mg, ertugliflozin 5 mg + sitagliptin 100 mg, or ertugliflozin 15 mg + sitagliptin 100 mg). Metformin therapy was continued at a stable dose throughout the 26-week treatment period. The primary endpoint was the change in A1C from baseline to week 26. Long-term efficacy and safety were assessed through 52 weeks of therapy. On a background of metformin, reduction in A1C after 26 weeks of treatment was greatest for the combination of ertugliflozin and sitagliptin (-1.5% with both the 5 mg and 15 mg ertugli- flozin doses in combination with sitagliptin 100 mg, p < 0.001 for all comparisons). The A1C reductions with ertugliflozin 5 mg, 15 mg, and sitagliptin 100 mg were -1.0%, -1.1% and
-1.1%, respectively. The proportion of patients achieving an A1C of less than 7.0% was 52.3% and 49.2% in the ertugliflozin 5 mg + sitagliptin 100 mg and the ertugliflozin 15 mg + sitagliptin 100 mg groups, respectively. This A1C target was achieved by 26.4%, 31.9%, and 32.8% of patients in the ertu- gliflozin 5 mg, ertugliflozin 15 mg, and sitagliptin 100 mg groups, respectively. Reduction in fasting plasma glucose was also greater with the combination of ertugliflozin and sitagliptin, compared with ertugliflozin or sitagliptin alone. Significant reductions in body weight (-2.5 to -3.7 kg) and systolic blood pressure (-3.4 to -3.9 mm Hg) were seen in the 4 study arms with ertugliflozin-treated patients after 26 weeks of treatment and were generally maintained at week 52. With respect to lipids, after 52 weeks of therapy, mean increases in LDL cholesterol (9.9%, 9.5%, 10.9% and 10.1%) and HDL cho- lesterol (6.3%, 7.2%, 0.8%, 6.3%, and 9.2%) and median reduc- tions in triglycerides (5.8%, 5.3%, 3.5%, 5.7%, and 2.3%) were seen in the ertugliflozin 5 mg, ertugliflozin 10 mg, sitagliptin 100 mg, ertugliflozin 5 mg + sitagliptin 100 mg, or ertugliflozin 15 mg + sitagliptin 100 mg groups, respectively.

4.2.3.Ertugliflozin as add-on combination therapy with metformin and sitagliptin
In this 52-week randomized, placebo-controlled trial, 464 patients with suboptimal glycemic control on metformin (≥1,500 mg daily) and sitagliptin 100 mg daily (baseline A1C 7.0% to 10.5%) were randomized in a 1:1:1 fashion to ertugliflozin 5 mg, ertugliflozin 15 mg, or placebo [22]. The primary endpoint was the change in A1C from baseline to week 26. From a baseline

A1C of 8.0%, the placebo-adjusted reduction in A1C at week 26 was -0.7% with ertugliflozin 5 mg daily and -0.8% with ertugli- flozin 15 mg daily (both p < 0.001). An A1C level of less than 7% at week 26 was reached by 32.1% and 39.9% of patients treated with ertugliflozin 5 mg and 15 mg, respectively, compared with 17.0% of placebo-treated patients. The placebo-corrected reduc- tion in fasting plasma glucose at week 26 was -25.2 mg/dL and
-31.3 mg/dL with ertugliflozin 5 mg and 15 mg, respectively (both p < 0.001). The improvement in A1C and fasting glucose was maintained after 52 weeks of treatment. Reductions in body weight at week 26 were -3.4, -3.0, and -1.3 kg and reductions in systolic blood pressure were -3.8, -4.8, and -0.9 mm Hg with ertugliflozin 5 mg, ertugliflozin 15 mg, and placebo, respectively. As with glycemic parameters, the improvements in body weight and blood pressure were also maintained at week 52. There was an increase in both LDL and HDL cholesterol in ertugliflozin- treated patients, with placebo-adjusted increases at week 52 in LDL cholesterol of 4.5% and 2.9% and HDL cholesterol of 5.0% and 5.7% for ertugliflozin 5 mg and 15 mg, respectively.

4.2.4.Ertugliflozin versus glimepiride as add-on combination therapy with metformin
This was a randomized, double-blind, active-comparator trial in 1,326 patients with type 2 diabetes inadequately controlled on metformin monotherapy (≥1,500 mg daily, baseline A1C 7.0 to 9.0%) [23]. Patients were randomized in a 1:1:1 fashion to ertugli- flozin 5 mg or 15 mg once daily, or glimepiride (titrated from 1 mg up to 6 or 8 mg once daily). The primary endpoint was the change from baseline in A1C after 52 weeks of treatment, with a hypoth- esis that the ertugliflozin 15 mg dose was non-inferior with respect to change in A1C (non-inferiority margin of 0.3%). The mean and median doses of glimepiride were 3.0 mg daily. After 52 weeks of treatment, from a baseline A1C of 7.8%, the changes in A1C were
-0.6%, -0.6%, and -0.7% for ertugliflozin 5 mg, ertugliflozin 15 mg, and glimepiride, respectively, with non-inferiority to glime- piride met for the ertugliflozin 15 mg group. The percent of patients reaching an A1C level of less than 7.0% after 52 weeks of treatment was 34.4% for ertugliflozin 5 mg, 38.0% for ertugli- flozin 15 mg, and 43.5% for glimepiride. Fasting plasma glucose was reduced in the 3 treatment arms, with greater reductions seen with ertugliflozin 15 mg versus glimepiride (-23.4 mg/dL versus
-16.2 mg/dL, p < 0.001). Ertugliflozin-treated patients experienced a significant reduction in body weight at week 52 (-3.0 kg and
-3.4 kg for the 5 mg and 15 mg doses, respectively, both p < 0.001 vs glimepiride) compared to an increase in body weight in the glimepiride group (+0.9 kg). Improvements in systolic and diastolic blood pressure were also seen with ertugliflozin compared with glimepiride (systolic blood pressure: -2.2 mmHg, -3.8 mmHg, and +1.0 mmHg; diastolic blood pressure: -0.9 mmHg, -1.2 mmHg, and +0.3 mmHg, for ertugliflozin 5 mg, ertugliflozin 15 mg, and glimepiride, respectively).

5.Safety and tolerability of ertugliflozin with metformin
The safety profile of the fixed-dose combination of ertugliflo- zin with metformin reflects the safety and tolerability of the individual components.

5.1.Metformin safety and tolerability
The most important safety precaution related to metformin therapy is the rare, but clinically important risk of lactic acido- sis [24]. The ertugliflozin/metformin label contains a boxed warning based on this risk [12]. Risk factors for metformin- related lactic acidosis include renal impairment, concomitant use of certain medications (e.g., topiramate), age over 65 years, having a radiological study with contrast, surgery and other procedures, hypoxic states such as congestive heart failure, excessive alcohol intake, and hepatic impairment [24]. Due to this risk, as well as ertugliflozin-related risks (see below), the fixed-dose combination of ertugliflozin with met- formin is contraindicated in patients with an estimated glo- merular filtration (eGFR) less than 30 mL/minute/1.73 m2 [12]. Common side effects of metformin, with an incidence of 5% or greater, include the gastrointestinal side effects nausea, vomit- ing, flatulence, abdominal discomfort, and indigestion. Gradual dose escalation of metformin has been shown to mitigate the risk of and the severity of these side effects. In addition, long-term metformin therapy has been associated with decreases in vitamin B12 absorption, which can rarely result in clinically significant vitamin B12 deficiency [24].

5.2.Ertugliflozin safety and tolerability
Pooled safety data in the ertugliflozin prescribing information is derived from three 26-week clinical trials (ertugliflozin as monotherapy, in combination with metformin, and in combi- nation with metformin + sitagliptin) [12]. In these studies, patients received ertugliflozin 5 mg, 15 mg or placebo. These included 1,029 ertugliflozin-treated patients with an average drug exposure of approximately 25 weeks. Key safety findings from this pooled analysis and more recent precautions related to SGLT-2 inhibitors based on post-market surveillance are discussed below.
The most common side effect seen in the clinical trial program was genital mycotic infection in women (incidence of approximately 9–12% with ertugliflozin and 3% with pla- cebo). This was also increased in male patients, with an inci- dence of approximately 4% in ertugliflozin-treated patients and 0.4% with placebo. The risk was increased in patients with previous genital mycotic infections and in uncircumcised males. These are generally easily treated with standard topical or oral antifungals and the withdraw rate in clinical trials due to this adverse event was low (females, 0.6%; males, 0.2%).
Urinary tract infections, including pyelonephritis, have been reported with SGTL-2 inhibitor treatment, including treatment with ertugliflozin. In the pooled ertugliflozin safety data, urin- ary tract infections were reported in 4.0%, 4.1%, and 3.9% of patients treated with ertugliflozin 5 mg, ertugliflozin 15 mg, and placebo, respectively.
More recently (29 August 2018), the FDA issued a warning related to rare, but serious cases of necrotizing fasciitis of the perineum (Fournier’s gangrene) in patients treated with SGLT- 2 inhibitors. They identified 12 cases in the 5 years between March 2013 and May 2018, one resulting in death. Based on this finding, a new warning has been added to the Prescribing Information of SGLT-2 inhibitors [25].

Based on the mechanism of action of SGLT-2 inhibitors, they cause an osmotic diuresis (as well as natriuresis) which can result in hypotension, signs and symptoms of volume depletion (e.g., presyncope, syncope), and impairment of renal function. Patients most prone to these side effects include the elderly, patients with pre-existing renal impair- ment, and patients on concomitant diuretics. The Prescribing Information recommends assessing renal function and volume status prior to initiation of therapy, correcting volume status as needed, and carefully monitoring renal function and signs/
symptoms of volume depletion during therapy. If acute kidney injury occurs, ertugliflozin should be discontinued and appro- priate therapy should be instituted [12,26].
Diabetic ketoacidosis has been reported in patients with type 2 diabetes treated with SGLT-2 inhibitors [12,27]. Across the ertugliflozin clinical development program, 3 of 3,409 (0.1%) of ertugliflozin-treated patients experienced ketoacidosis (versus 0% in comparator-treated patients) [12]. It is significant to note that given the insulin-independent mechanism of action of SGLT-2 inhibitors, DKA can occur with blood glucose concentra- tions that are less than 250 mg/dL. Although the typical signs and symptoms of metabolic acidosis are present, in reported cases of SGLT-2 inhibitor-associated DKA, the relatively low plasma glucose has led to delay in diagnosis and treatment [12,27]. If DKA is suspected, ertugliflozin should be discontinued and standard therapy for DKA should be instituted.
Increased risk of lower limb amputation, primarily of the toes, was observed with canagliflozin in a long-term cardio- vascular outcome trial (CANVAS) [28]. Across seven Phase 3 trials with ertugliflozin, non-traumatic lower limb amputations were reported in 3 (0.2%), 8 (0.5%), and 1 (0.1%) of patients in the ertugliflozin 5 mg, ertugliflozin 15 mg and the comparator group (active comparator or placebo), respectively. Patients at increased risk are those with prior amputations, significant neuropathy or peripheral vascular disease, and ongoing foot ulcers [12].
As described in the efficacy section above, LDL cholesterol increases with ertugliflozin treatment. This is a class effect seen with other SGLT-2 inhibitors and is of uncertain clinical signifi- cance, given the parallel increase in HDL cholesterol, decrease in triglycerides, and improvements in other cardiovascular risk fac- tors [29]. In the pooled safety data for ertugliflozin, placebo- adjusted increases in LDL cholesterol were 2.6% and 5.4% with ertugliflozin 5 mg and 15 mg, respectively [12].
As with other SGLT-2 inhibitors, ertugliflozin as monotherapy or in combination with agents that do not cause hypoglycemia (such as metformin), should not result in significant hypoglyce- mia. As add-on therapy to in patients on metformin monother- apy, the overall incidence of hypoglycemia (plasma or capillary glucose less than or equal to 70 mg/dL) was 7.2%, 7.8%, and 4.3% with ertugliflozin 5 mg, ertugliflozin 15 mg, and placebo, respec- tively. Severe hypoglycemia, requiring the assistance of a third party, occurred in 1 patient treated with ertugliflozin 5 mg (0.5%) and 1 placebo-treated patient (0.5%). There was no severe hypo- glycemia in the ertugliflozin 15 mg group. In combination with metformin and sitagliptin, the incidence of overall and severe hypoglycemia was also very low when ertugliflozin was added to this therapeutic regimen (overall: 4.5%, 2.0%, and 3.3%; severe: 0.6%, 0.0%, and 0.7%, for ertugliflozin 5 mg, ertugliflozin 15 mg,

and placebo, respectively) [12]. Importantly, when ertugliflozin is added to insulin or insulin secretagogue (e.g., sulfonylurea) ther- apy, it can enhance the risk of hypoglycemia induced by these agents, so consideration should be given to proactive insulin or insulin secretagogue dose reduction.

6.Regulatory affairs and dosing and administration of ertugliflozin with metformin
Ertugliflozin as well as the fixed-dose combinations ertugliflozin with metformin and ertugliflozin with sitagliptin were approved for the treatment of adults with type 2 diabetes in the US in December 2017, in the European Union in February 2018, and in Canada and Australia in May 2018 [30–33].
The fixed-dose combination of ertugliflozin with metformin is indicated for adults with type 2 diabetes who are not adequately controlled on a therapeutic regimen containing ertugliflozin or metformin, or in patients who are already receiving both ertugliflozin and metformin [12].
It is contraindicated in patients with severe renal impair- ment (eGFR less than 30 mL/minute/1.73 m2) and not recom- mended for patients with an eGFR between 30 to less than 60 mL/minute/1.73 m2. It is also contraindicated in patients with acute or chronic metabolic acidosis (including diabetic ketoacidosis) and those with history of serious hypersensitivity reaction to either component of the combination [12].
It is available in 4 different dose combinations: ertugliflozin 2.5 mg and metformin 500 mg, ertugliflozin 2.5 mg and metfor- min 1,000 mg, ertugliflozin 7.5 mg and metformin 500 mg, and ertugliflozin 7.5 mg and metformin 1,000 mg [12].
The initial dose should be individualized, based on the patient’s current antidiabetic regimen. Patients who are already on metfor- min, should be switched to the combination tablet containing 2.5 mg of ertugliflozin (taken twice daily, for an initial total daily ertugliflozin dose of 5 mg), with a similar total daily dose of metformin. Patients who are already on ertugliflozin, should be switched to the combination tablet containing 500 mg of metfor- min, with a similar total daily dose of ertugliflozin. And, patients already treated with both components (ertugliflozin and metfor- min) should switch to the combination tablet containing the same total daily dose of ertugliflozin and a similar daily dose of metfor- min. The maximum recommended daily dose is 15 mg of ertugli- flozin and 2,000 mg of metformin (i.e., the 7.5 ertugliflozin and 1,000 mg metformin tablet twice daily.) [12]
It is recommended to be taken twice daily with meals and for patients not previously on metformin, the dose should be gradually escalated to reduce metformin-related gastrointest- inal side effects. In patients not previously treated with ertu- gliflozin, volume status should be assessed prior to initiation of the fixed-dose combination and volume depletion, if pre- sent, should be corrected [12].

7.Conclusion
Ertugliflozin, a SGLT-2 inhibitor, and metformin, a biguanide, are both oral agents that are approved for the treatment of type 2 diabetes. They have complementary mechanisms of action that ameliorate different pathophysiologic defects of this disorder. As such, their use in combination has been shown to significantly

improve fasting and postprandial glucose and overall glycemic control as measured by A1C. In patients not achieving A1C target of less than 7.0% with metformin alone or in combination with other glucose-lowering agents, the addition of ertugliflozin resulted in an average A1C reduction after 6 months of treatment in the order of 0.7% to 0.9% [20–23]. Importantly, this reduction was sustained in trials with extensions beyond 6 months and was accompanied by weight reduction and favorable effects on blood pressure. Compared with the sulfonylurea glimepiride, similar A1C control was achieved after 1 year of ertugliflozin treatment, but with less hypoglycemia, with weight loss (as opposed to weight gain with the sulfonylurea) and improve- ments in blood pressure [23]. These are clearly very favorable effects of the SGLT-2 inhibitor class and make them an ideal adjunct to metformin therapy in appropriate patients. The added convenience of having this combination as a fixed-dose tablet, may improve adherence and persistence over taking the individual components separately and, depending on insurance coverage, may provide a financial advantage to the patient.
As with any medication, these positive effects must be balanced with patient safety and potential side effects. Critically important for this combination, given contraindications related to renal function for both metformin and ertugliflozin, is the assess- ment of renal function prior to its initiation. It is contraindicated in patients with an eGFR less than 30 mL/minute/1.73 m2 and is not recommended in patients with an eGFR between 30 and 60 mL/
minute/1.73 m2. This is in part due to metformin prescribing information, which does not recommend its use in patients with eGFR between 30 and 45 mL/minute/1.73 m2 and is also based on findings of an ertugliflozin clinical trial in type 2 diabetes patients with impaired renal function (eGFR 30 to 60 mL/minute/1.73 m2; mean baseline eGFR 46 mL/minute/1.73 m2) in which ertugliflozin was not found to improve A1C compared with placebo and was associated with a higher incidence of side effects, particularly those related to worsening of renal function and volume deple- tion [24,34].
In view of its most frequent and clinically important side effects, prior to initiation of this fixed-dose combination patients should be counselled regarding the importance of remaining well hydrated, the signs and symptoms of genital mycotic and urinary tract infections, the importance of preventive foot care, and the importance of informing other healthcare providers, especially in the emergency room, a hospitalization or before a medical procedure, that they are taking a SGLT-2 inhibitor and metformin. Additionally, for patients taking medications that can result in hypoglycemia (e.g., insulin, sulfonylurea, meglitinide), they should be re-educated about recognition and treatment of hypoglycemia, and dose adjustment of these medications should be considered upon initiation of the SGLT-2 inhibitor.
In the appropriate patient, the combination of ertugliflozin and metformin can safely and effectively improve glycemic control and does so with important benefits beyond the A1C, such as weight loss, improved blood pressure, and very low risk of hypoglycemia.

8.Expert commentary
The overarching goal in the management of hyperglycemia in type 2 diabetes is to achieve the best possible glycemic

control with the least potential side effects, thereby reducing the risk of long-term complications and helping improve qual- ity of life [3,5,6]. Unfortunately, despite significant advances in pharmacotherapy and diabetes-related devices, many patients with this disorder do not achieve adequate glycemic control and are at increased risk of long-term complications [35]. The reasons for frequent sub-optimal control are complex, but in part associated to common drug-related side effects such as hypoglycemia and weight gain, and also to therapeutic inertia, the delay in intensification of therapy despite not achieving targets. Large-scale retrospective analyses have demonstrated that patients spend several years with suboptimal glycemic control before intensification with oral antihyperglycemic agents or insulin, and that further intensification of therapy in patients treated with insulin is also significantly delayed [36,37]. Treatment guidelines from major diabetes associations call for early and aggressive intensification of therapy via combination therapy until individualized glycemic targets are reached. Notably, given recent positive cardiovascular findings with both SGLT-2 inhibitors (empagliflozin and canagliflozin) and GLP-1 RAs (liraglutide and semaglutide), guidelines also state that consideration should be given to agents that have positive cardiovascular benefits when intensifying therapy in patients with known cardiovascular disease [3,5,6,28,38–40].
The SGLT-2 inhibitors have several characteristics that address barriers to intensification of therapy. They result in clinically important and sustained improvement in glycemic control, can be used in combination with any of the currently available antihyperglycemic agents, do not cause significant hypoglycemia (although caution must be used when com- bined with insulin or insulin secretagogues, as they may increase the risk of hypoglycemia caused by these agents), lead to reductions in body weight and blood pressure, and have been shown to reduce the risk of cardiovascular events in high-risk patients. It remains to be seen if this cardiopro- tective effect is a class effect or a unique effect of specific drugs in this class.
Recent studies have assessed the combination of SGLT-2 inhibitors and metformin with other antihyperglycemic agents [41]. One particularly promising combination of agents is the triple combination of metformin, a SGLT-2 inhibitor, and a once weekly GLP-1 RA [42–44]. This combination has demonstrated excellent glycemic control with additive posi- tive effects of the SGLT-2 inhibitor and GLP-1 RA on body weight and blood pressure. Therapeutic regimens such as this, which combine medications with complementary mechanisms of action, not only improve glycemic control but do so with limited hypoglycemia and favorable effects on body weight and cardiovascular risk factors, should become more common place as additional data are generated with existing agents and potential new agents with important benefits beyond glycemic control.
From a patient’s perspective, the ease of administration of the SGLT-2 inhibitors and the fixed-dose combination tablets containing SGLT-2 inhibitors is very important. These are orally administered medications that, depending on the combina- tion, are taken once or twice daily, making them very conve- nient for patients to administer. This, in addition to favorable characteristics described above, should aid in medication

adherence and persistence. Studies specifically assessing fixed- dose combination tablets have generally demonstrated improved medication adherence with these formulations ver- sus taking the individual components separately [7,8].
The favorable characteristics of the SGLT-2 inhibitor class may be accompanied by relatively infrequent, but clinically important, side effects. Appropriate patient selection, counsel- ing, and monitoring are therefore critical in maximizing their benefit-to-risk profile.

9.Five-year view
One of the critical clinical questions that currently remains unanswered for ertugliflozin relates to its effects on cardiovas- cular outcomes. The VERTIS CV Study (NCT01986881) is an ongoing long-term, placebo-controlled cardiovascular out- comes trial in high risk patients (established vascular disease) with type 2 diabetes. The primary endpoint is time to first occurrence of the composite 3-point MACE (major adverse cardiovascular event), consisting of cardiovascular death, non- fatal myocardial infarction, or non-fatal stroke. This trial was initiated in November 2013 and is expected to be completed in 2019 [45,46]. In addition, we will continue to learn more about the SGLT-2 inhibitor class, and ertugliflozin, over the next several years. Not only extraglycemic effects in patients with diabetes, but their potential utility in other disease states. These will include their effect on long-term renal health, effects in patients with congestive heart failure, potential as blood pressure lowering agents, and the treatment of nonal- coholic fatty liver disease [47,48]. Their use in the treatment of type 1 diabetes has also been assessed extensively and is currently under regulatory review for some agents in this class, including the dual SGLT-1/SGLT-2 inhibitor sotagliflozin [49]. Importantly, through continued long-term clinical trials and post-marketing pharmacovigilance, we will also continue to learn about the safety of these agents and how best to select and counsel patients.
With respect to combination antihyperglycemic therapy in type 2 diabetes, the important trend to combine therapeutic agents with complementary mechanisms of action early in the course of therapy, avoiding therapeutic inertia and the poten- tial for long periods of unacceptable hyperglycemia before therapeutic interventions, should continue. To this end, having fixed-dose combination agents available, which enhance patient convenience and potentially adherence and persis- tence, will become increasingly valuable.

Key issues
● Ertugliflozin/metformin is a fixed-dose combination of the SGLT-2 inhibitor ertugliflozin and the biguanide metformin.
● It was approved in the US in December 2017, in the European Union in February 2018, and in Canada and Australia in May 2018.
● Ertugliflozin and metformin have complementary mechan- isms of actions, with ertugliflozin inhibiting SGLT-2 at the level of the proximal renal tubule, thereby increasing urin- ary glucose excretion and metformin having its primary

effect at the level of the liver to reduce hepatic glucose production.
● In randomized controlled trials versus placebo or active comparators, ertugliflozin in combination with metformin (and other oral agents, such as the DPP-4 inhibitor sitaglip- tin), significantly reduced A1C from baseline after 26 weeks of treatment. This effect was sustained in trials that assessed 52 weeks of treatment.
● Improvements in A1C in ertugliflozin-treated patients were accompanied by a significant reduction in mean body weight and blood pressure.
● The side effect profile of the fixed-dose combination of ertugliflozin with metformin is consistent with the safety profile of the individual components.
● Renal function and volume status must be assessed prior to initiation of therapy with ertugliflozin/metformin. It is con- traindicated in patients with eGFR less than 30 mL/minute/
1.73 m2 and is not recommended for patients with eGFR between 30 and 60 mL/minute/1.73 m2. If patients are volume depleted, this should be corrected before initiation of treatment.
● The most common side effect with ertugliflozin use (and thereby ertugliflozin/metformin) is genital mycotic infec- tions in women. This was also more commonly seen in men compared with placebo. These infections are more common in patients with previous genital mycotic infec- tions and in uncircumcised men.
● Other less common, but clinically important, side effects include risk of lactic acidosis (based on the metformin component of the fixed-dose combination), diabetic ketoa- cidosis, non-traumatic lower extremity amputation, urinary tract infections, and adverse events related to volume depletion (e.g., hypotension, pre-syncope, decline in renal function)
● Ertugliflozin/metformin is indicated for adults with type 2 diabetes who are not adequately controlled on a therapeutic regimen containing ertugliflozin or metfor- min, or in patients who are already receiving both ertugli- flozin and metformin.
● The starting dose is based on the patient’s prior antidiabetic regimen and the maximum recommended daily dose is 15 mg of ertugliflozin and 2,000 mg of metformin (i.e., the 7.5 ertugliflozin and 1,000 mg metformin tablet twice daily.)

Information resources
The reader is encouraged to review important prescribing information as well as the Medication Guide and patient resources at https://www.merck connect.com/segluromet/overview.html

Funding

This paper was not funded.

Declaration of interest
JP Frías conducts clinical research supported by AbbVie, Allergan, AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, Genentech, IONIS, Janssen, Johnson and Johnson, Lexicon, Ligand, Merck, Mylan, Novartis, Novo Nordisk, Pfizer, Sanofi, and Theracos. JP Frías is a consultant for and

on the advisory boards of AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, Johnson and Johnson, Novo Nordisk, Sanofi. JP Frías is on the speak- er’s bureau for Merck and Sanofi. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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