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Drug Forecast

Ertugliflozin (Steglatro): A New Option for SGLT2 Inhibition

Nikolas Kovacich PharmD Candidate
Benjamin Chavez PharmD, BCPP, BCACP

INTRODUCTION

A 2017 Centers for Disease Control Statistics Report estimated that 9.4% of the U.S. population suffers from diabetes, with an additional 33.9% having prediabetes.1 Increasing medication options that are safe and effective treatments for diabetes is imperative. In 2013, a unique class of medications—sodium-glucose cotransporter 2 (SGLT2) inhibitors—entered the market. By inhibiting SGLT2, these medications block the reabsorption of glucose in the proximal renal tubule. This mechanism of action allows SGLT2 inhibitors to lower glucose independent of insulin. There are now four SGLT2 inhibitors available, with the most recent being ertugliflozin.

According to the 2018 American Diabetes Association (ADA) Standards of Care, SGLT2 inhibitors are an adequate agent to add on to metformin for combination therapy.2 The SGLT2 inhibitors are placed on a par with sulfonylureas, thiazelinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) inhibitors, and basal insulin. The ADA recommends selecting a drug class based on specific effects and patient factors. Table 1 summarizes the commercially available SGLT2 inhibitors, and some relevant differences between them. Two SGLT2 inhibitors, canagliflozin and empagliflozin, have data showing a reduction in cardiovascular risk. While it is not known if the reduction is a class effect, these SGLT2 inhibitors are being pushed to the forefront of clinicians’ minds. This article focuses on the efficacy and safety of ertugliflozin and highlights its place in treatment.

INDICATION

Ertugliflozin (Steglatro, Merck & Co.) is indicated as an adjunct therapy to diet and exercise to improve glycemic control in adults with type-2 diabetes mellitus (T2DM). Steglatro contains ertugliflozin L-pyroglutamic acid in film-coated oral tablets.3

PHARMACOLOGY

Mechanism of Action

Ertugliflozin inhibits SGLT2 that is found in the kidneys. SGLT2 is the predominant transporter responsible for the resorption of glucose back into circulation from glomerular filtrate. Ertugliflozin inhibits the reabsorption of glucose mediated by this specific transporter, which increases the renal excretion of glucose and helps decrease glucose levels in circulation.3

Pharmacodynamics

The dose-dependent nature of the increases in urinary glucose excretion was observed in healthy subjects and in subjects with T2DM. Observations from these dose-dependent models indicate that ertugliflozin 5-mg and ertugliflozin 15-mg doses produce near-maximal urinary glucose excretion, and this effect is maintained after multiple-dose administration. This increase in urinary glucose excretion is consequently accompanied by an increase in total urinary volume.3

Pharmacokinetics

The pharmacokinetics of ertugliflozin are similar in healthy subjects and in those with T2DM. Steady-state concentrations are reached after 4 to 6 days of once-daily dosing. The maximum concentration (Cmax) and total area under the plasma drug concentration-time curve (AUC) at steady-state for ertugliflozin 5-mg tablets are 81.3 ng/mL and 398 ng·hr/mL, respectively. The Cmax and AUC at steady-state for ertugliflozin 15-mg tablets are 268 ng/mL and 1,193 ng·hr/mL, respectively. Ertugliflozin exhibits dose-proportional pharmacokinetics in both single- and multiple-dose administrations.3

Absorption

The time to peak plasma concentrations (median Tmax) is approximately one hour after administration in the fasted state. In the post-prandial state (high-fat, high-calorie meal), Tmax is doubled to approximately two hours and Cmax is decreased by 29%; however, AUC is not significantly altered. Manufacturer labeling indicates that ertugliflozin may be administered without respect to food.3

Distribution

Steady-state volume of distribution for ertugliflozin is 85.5 L. Ertugliflozin is 93.6% protein-bound in plasma independent of ertugliflozin plasma concentrations. This protein-binding profile is not significantly altered in subjects with impaired renal or hepatic function.3

Metabolism

The primary route of ertugliflozin metabolism is via UGT1A9- and UGT2B7-mediated glucuronidation, and this is the primary mechanism of ertugliflozin clearance. The resulting metabolites are pharmacologically inactive at clinically relevant concentrations. Ertugliflozin undergoes minimal cytochrome P450 enzyme-mediated metabolism.3

Excretion

About 41% and 50% of ertugliflozin metabolites are eliminated in the urine and feces, respectively. Less than 2% of ertugliflozin is eliminated in the urine as unchanged drug; however, about 34% of ertugliflozin is eliminated as unchanged drug in the feces. The estimated half-life of ertugliflozin in patients with T2DM with normal renal function is 16.6 hours. Clearance is estimated as 11.2 L/hr.3

CLINICAL EFFICACY

Clinical efficacy for ertugliflozin was evaluated in a series of clinical trials led by the eValuation of ERTugliflozin effIcacy and Safety (VERTIS) study group. Ertugliflozin has been studied as monotherapy (VERTIS MONO and VERTIS MONO extension) as well as in adjunct to metformin (VERTIS MET), with both scenarios keeping diet and exercise as priority lifestyle adjustments.79 The findings of these studies largely contributed to ertugliflozin’s FDA approval for T2DM and will be discussed in this article.

VERTIS MONO (Phase A)

The objective of the multi-centered, randomized, double-blind, double-dummy VERTIS MONO trial was to assess the efficacy and safety of ertugliflozin monotherapy in participants with T2DM and inadequate glycemic control despite diet and exercise.7 Any patients on prior antihyperglycemic therapy, including metformin, underwent an eight-week washout period to avoid confounding the results from this study. This trial consisted of an initial 26-week, placebo-controlled treatment period (phase A), followed by a 26-week, active-controlled treatment period (phase B, VERTIS MONO extension).7,8

Four hundred sixty-one participants were randomized into phase A in a 1:1:1 ratio to receive daily placebo, ertugliflozin 5 mg, or ertugliflozin 15 mg (n = 153, 156, and 152, respectively). All participants were counseled on dietary and exercise habits and asked to maintain these habits throughout the study.

The study’s primary endpoint was change in glycated hemoglobin (A1C) from baseline after 26 weeks. Changes from baseline in fasting plasma glucose (FPG), 2-hour post-prandial glucose (2H-PPBG), body weight (BW), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were prespecified secondary endpoints. The proportion of patients in each treatment group who achieved an A1C of < 7% and those patients identified as needing hyperglycemic rescue therapy (HRT) were also reported. HRT was provided via open-label metformin initiation. Participants who were deemed to require HRT met the following predetermined criteria: FPG > 270 mg/dL through week six, FPG > 240 mg/dL after week six and through week 12, and FPG > 200 mg/dL after week 12 through week 26. Participants were predominantly male (56.6%) and Caucasian (83.7%). At baseline, the participants averaged a 5-year history of T2DM, a BW of 92.9 kg, a body mass index (BMI) of 33.0 kg/m2, an A1C of 8.2%, and an estimated glomerular filtration rate (eGFR) of 87.7 mL/min/m2. No participants with an eGFR < 55 mL/min/m2 were included in the study.

Efficacy Results

The average A1C reduction in the ertugliflozin treatment arms was reported as placebo-adjusted least-squares (LS) mean (95% confidence interval [CI]) change from baseline after week 26. Daily ertugliflozin 5 mg and 15 mg reduced the A1C significantly more than placebo, by −0.99% and −1.16%, respectively (P < 0.001 for both comparisons). Significant reductions were maintained across all analyzed subgroups. Subjects who began the study with greater A1C values at baseline experienced incrementally greater mean reductions in A1C. For example, those whose A1C was greater than or equal to 8% experienced a mean reduction in A1C of −1.11% and −1.52% in the ertugliflozin 5-mg and 15-mg groups, respectively. A total of 35.8%, 28.2%. and 13.1% of participants achieved an A1C of < 7% in the ertugliflozin 15-mg, ertugliflozin 5-mg, and placebo groups, respectively. Other key efficacy outcomes of the VERTIS MONO phase A trial included:

  • Significantly greater odds of achieving A1C of < 7% compared to placebo in the ertugliflozin 5-mg group (odds ratio [OR], 3.59 [1.85, 6.95]) and the ertugliflozin 15-mg group (OR, 6.77 [3.46, 13.24]; both P < 0.001);
  • Significantly greater reductions in FPG LS mean change from baseline in both ertugliflozin groups compared to placebo (−34 mg/dL and −44 mg/dL for ertugliflozin 5 mg and 15 mg, respectively; P < 0.001 for both comparisons);
  • Significantly greater reductions in BW LS mean change from baseline in both ertugliflozin groups compared to placebo (−1.76 kg and −2.16 kg for ertugliflozin 5 mg and 15 mg, respectively; P < 0.001 for both comparisons);
  • A larger proportion of subjects in the placebo group (25.5%) requiring metformin HRT than in the ertugliflozin groups (both < 3%); and
  • Non-significant reductions in SBP LS mean change from baseline in the ertugliflozin 15-mg group compared to placebo. Because of a lack of significance in this comparison, all further statistical analysis of blood pressure differences was halted per protocol.

VERTIS MONO Extension Study (Phase B)

Patients who did not receive metformin HRT in VERTIS MONO were eligible to enroll in the additional 26-week VERTIS MONO extension study.8 The objective of this study was to evaluate the long-term efficacy and safety of ertugliflozin monotherapy in T2DM patients who were inadequately controlled on diet and exercise alone. Eligible placebo-group participants from phase A had blinded-metformin therapy added in a titration schedule over the course of four weeks (500 mg twice daily for 2 weeks, 1,000 mg in the morning and 500 mg in the evening for 2 weeks, and 1,000 mg twice daily thereafter). Participants in the ertugliflozin treatment arms did not receive metformin.

The primary endpoints of phase B were all related to the safety and tolerability of ertugliflozin monotherapy over 52 weeks and will be discussed later in this article. Because the extension period was active-controlled, no formal hypothesis tests were conducted for efficacy outcomes in comparing the three treatment groups; however, this study descriptively assessed changes from baseline in A1C, FPG, BW, SBP, and diastolic blood pressure (DBP) after 52 weeks of treatment. The proportions of patients achieving A1c < 7%, patients achieving A1C < 6.5%, and patients requiring glimepiride HRT were also assessed. In phase B, patients were pre-determined as requiring glimepiride HRT if they experienced a FPG > 200 mg/dL or an A1C > 8% at any time during the extension study.

Three hundred eighty-four eligible participants were enrolled into phase B (n = 153, 156, 152 for the placebo/metformin, ertugliflozin 5-mg, and ertugliflozin 15-mg groups, respectively). Participants who entered phase B were predominantly men (56.3%). The average age of participants was 56.8 years, and the average baseline A1C was 8.2%. Average A1C at the beginning of phase B was 7.8% for the placebo/metformin group and 7.3% for both ertugliflozin groups.

Reductions in A1C observed at week 26 for the ertugliflozin arms were maintained through the end of week 52. Other key efficacy outcomes of the VERTIS MONO extension trial included:

  • Mean (standard error [SE]) changes in A1C from baseline (week 0): −1.0% (0.1), −0.9% (0.1), and −1.0% (0.1) in the metformin/placebo, ertugliflozin 5-mg, and ertugliflozin 15-mg groups, respectively;
  • Proportion of patients achieving A1C < 7% at week 52: 27.5%, 25.6%, 28.5% in the metformin/placebo, ertugliflozin 5-mg, and ertugliflozin 15-mg groups, respectively;
  • Proportion of patients achieving A1C < 6.5% at week 52: 18.3%, 9.0%, 9.9% in the metformin/placebo, ertugliflozin 5-mg, and ertugliflozin 15-mg groups, respectively;
  • Percentage of patients receiving HRT by week 52: 31.4%, 19.9%, 15.1% in the metformin/placebo, ertugliflozin 5-mg, and ertugliflozin 15-mg groups, respectively;
  • Mean (SE) changes in FPG from baseline to week 52: −29 mg/dL (3.6), −29 mg/dL (3.6), and −32 mg/dL (3.6) in the metformin/placebo, ertugliflozin 5-mg, and ertugliflozin 15-mg groups, respectively;
  • Mean (SE) changes in BW from baseline to week 52: −3.3 kg (0.5), −3.6 kg (0.4), and −3.7 kg (0.4) in the metformin/placebo, ertugliflozin 5-mg, and ertugliflozin 15-mg groups, respectively; and
  • Mean (SE) changes in SBP from baseline to week 52: −2.4 (1.3), −3.7 (1.3), and −1.8 (1.2) mmHg in the metformin/placebo, ertugliflozin 5-mg, and ertugliflozin 15-mg groups, respectively.

VERTIS MET Trial

The objective of the multi-centered, randomized, double-blind, placebo-controlled VERTIS MET trial was to assess the efficacy and safety of ertugliflozin in T2DM patients lacking glycemic control despite active therapy with metformin, diet, and exercise, and to assess the effects of ertugliflozin on bone mineral density (BMD).9 Perimenopausal and postmenopausal women augmented the study population to provide additional insight into ertugliflozin effects in patients who are at particularly high risk for osteoporosis. VERTIS MET was scheduled as a two-phase trial: phase A, consisting of the first 26 weeks of treatment, and phase B, a 78-week extension trial. Phase B has been completed, but results are not yet published. We discuss the published findings of phase A here.

A total of 621 patients were randomized in a 1:1:1 ratio to receive once-daily placebo, ertugliflozin 5 mg, or ertugliflozin 15 mg (n = 209, 207, and 205, respectively) as an adjunct to current metformin and lifestyle therapies. Randomization was further stratified into four groups: men, premenopausal women, perimenopausal women (< 3 years since last menstrual period), and postmenopausal women (3 or more years since last menstrual period). All participants were counseled on dietary and exercise habits and asked to maintain these habits throughout the study.

The primary endpoint was change in A1C from baseline after 26 weeks. Changes from baseline in FPG, BW, SBP, and DBP were prespecified secondary endpoints. The proportion of patients in each treatment group who achieved an A1C of < 7% and those identified as needing HRT were also reported. Participants who were deemed to require HRT met the same predetermined criteria as discussed in phase A of the VERTIS MONO trial above. HRT in this trial was provided via open-label glimepiride. Changes in BMD were measured at baseline and at week 26 via dual energy X-ray absorptiometry scans (DEXA). Sites measured via DEXA included the lumbar spine, femoral neck, total hip, and distal forearm.

Participants were predominantly female (53.6%) and Caucasian (66%), and postmenopausal women made up 76% of the study population. At baseline, the participants averaged an eight-year history of T2DM, a BW of 84.9 kg, an A1C of 8.1%, and an eGFR of 90.5 mL/min/m2. No participants with an eGFR < 55 mL/min/m2 were included in the study.

Efficacy Results

A1C reduction in the ertugliflozin treatment arms was reported as placebo-adjusted LS mean (95% CI) change from baseline after week 26. Daily ertugliflozin 5 mg and 15 mg reduced A1C significantly more than placebo—by −0.7% and −0.9%, respectively (P < 0.001 for both comparisons). Participants who began the study with greater A1C values at baseline experienced incrementally greater mean reductions in A1C. For example, those who began the trial with an A1C of 9% or greater experienced a mean (standard deviation [SD]) reduction in A1C of −1.7% (1.1) and −1.8% (0.8) in the ertugliflozin 5-mg and 15-mg groups, respectively. A total of 40%, 35%, and 16% of participants achieved an A1C of < 7% in the ertugliflozin 15-mg, ertugliflozin 5-mg, and placebo groups, respectively. Other key efficacy outcomes of the VERTIS MET trial included:

  • Significantly greater odds of achieving an A1C of < 7% compared to placebo in the ertugliflozin 5-mg group (OR, 3.0 [1.8, 5.1]) and 15-mg group (OR, 4.5 [2.6, 7.6]; both P < 0.001);
  • Significantly greater reductions in FPG LS mean change from baseline in both ertugliflozin groups compared to placebo (−27 and −40 mg/dL for ertugliflozin 5 mg and 15 mg, respectively; P < 0.001 for both comparisons);
  • Significantly greater reductions in BW LS mean change from baseline in both ertugliflozin groups compared to placebo (−3.0 and −2.9 kg for ertugliflozin 5 mg and 15 mg, respectively; P < 0.001 for both comparisons);
  • Significantly greater reductions in SBP LS mean change from baseline in both ertugliflozin groups compared to placebo (−4.4 and −5.2 mmHg for ertugliflozin 5 mg and 15 mg, respectively; P = 0.002 and 0.001, respectively);
  • Significantly greater reductions in DBP LS mean change from baseline in both ertugliflozin groups compared to placebo (−1.6 and −2.2 mmHg for ertugliflozin 5 mg and 15 mg, respectively; P = 0.013 and 0.001, respectively);
  • A larger proportion of subjects in the placebo group requiring glimepiride HRT (17%) than in the ertugliflozin groups (both < 3%); and
  • No significant differences in BMD between baseline and week 26 in the placebo or ertugliflozin arms at any of the sites measured by DEXA.

SAFETY PROFILE

Genital Mycotic Infections

Ertugliflozin has repeatedly been shown to increase incidence of genital mycotic infections (GMI). GMI in women (genital candidiasis, vaginal infection, vulvitis, vulvovaginal candidiasis, vulvovaginal mycotic infection, vulvovaginitis, etc.) occurred in 4.4%, 13.6%, and 14.3% of female participants in the placebo, ertugliflozin 5-mg, and ertugliflozin 15-mg groups, respectively, in the pooled participants from the VERTIS MET, VERTIS MONO, and VERTIS MONO extension trials (see Table 2). GMI in men (balanitis candida, balanoposthitis, genital infection, etc.) occurred in 0.6%, 3.2%, and 5.5% of male participants, respectively, in the same trials.79 Package labeling indicates that the patients at highest risk for GMI while taking ertugliflozin are those who have a history of GMI, women, and uncircumcised men.3

Urinary Tract Infections

The incidence of urinary tract infections (UTIs) was found to be generally similar among the treatment groups across the trials discussed. Coincidentally, UTIs were found to be significantly greater in the placebo/metformin group compared to the ertugliflozin 15-mg group in the VERTIS MONO extension trial (13.7% vs. 6.6 %, respectively; P = 0.039).79 In general, diabetes patients have significantly greater odds of contracting a UTI compared to non-diabetic patients.10 Diabetic patients at especially high risk for UTI contraction include those with poor glycemic control (e.g., A1C > 8.5%), those of advanced age, those who are female, and those with a history of UTI within the previous two years.11 While only minor cases have been reported in ertugliflozin, UTIs should be monitored carefully and treated promptly.

Ketoacidosis

There were no confirmed cases of ketoacidosis in the trials discussed here; however, in another analysis that included 3,409 patients treated with ertugliflozin, three (0.1%) cases were identified.3 Ketoacidosis has occurred in patients treated with SGLT2 inhibitors without the presence of profound hyperglycemia.12 This complication is potentially life-threatening and should be treated promptly once recognized. Risk factors that may predispose patients to ketoacidosis while taking ertugliflozin include type-1 diabetes mellitus, insulin dose reduction, pancreatic disorders that limit insulin production (including acute or chronic pancreatitis), caloric restriction, and alcohol abuse.3

Lower-Limb Amputations

There were no confirmed cases of amputations of any kind in the trials discussed here. A recent disproportionality analysis found that in patients receiving antihyperglycemic agents, lower-limb amputations (LLAs) were more likely to have occurred in those receiving SGLT2 inhibitors than in other classes.13 Indeed, the CANVAS trial found a significantly increased risk of toe and metatarsal amputations in patients receiving canagliflozin compared to placebo.14 To date, there has been no causal association identified between ertugliflozin and amputations; however, in light of these recent publications, caution should be taken before implementing ertugliflozin in those patients with risk factors for amputations (e.g., history of amputation, established peripheral vascular disease, recurrent hypovolemia, etc.).3,13,14 Recall that the study population of the CANVAS trial included only patients with established cardiovascular disease (CVD), and those without CVD but who had at least two risk factors.14 A recent observational retrospective cohort involving more than 118,000 diabetic patients found no difference in risk of below-knee lower extremity (BKLE) amputations between patients taking SGLT2 inhibitors and those taking other antihyperglycemics in the general population. This real-world population included a lower proportion of patients with established CVD, those who had generally better glycemic control, and those who were generally younger than the population in the CANVAS trial.14,15 More studies are needed to evaluate the risk of LLAs that stratify specific patient populations receiving SGLT2 inhibitors to clarify the most prevalent risk factors for amputation.

Hypoglycemia

There was no significant difference in the incidence of symptomatic hypoglycemia between the treatment and control groups in the trials discussed here (see Table 2). Ertugliflozin alone is unlikely to increase the risk for symptomatic hypoglycemia, but an increased incidence has been reported when it is taken in conjunction with insulin or insulin secretagogues.3 Added caution and adequate patient counseling should be considered when combining ertugliflozin with these medications.

Hypovolemia

There was no significant difference in the incidence of symptomatic hypovolemia between the treatment and control groups in the trials discussed here (see Table 2). Package labeling for ertugliflozin indicates that patients most likely to experience symptomatic hypovolemia are those with impaired renal function, which may explain why no significant increase was found in the analyses above. Monitoring for hypovolemia symptoms (e.g., dehydration, dizziness, syncope, hypotension, and orthostatic hypotension) should be increased in patients with an eGFR < 60 mL/min/m2.3

Hypotension

The ertugliflozin trials discussed here found no significant difference in the incidence of hypotension.79 Package labeling indicates that increased incidence has been reported when used in certain populations, including: older patients (≥ 65 years), patients with impaired renal function (eGFR < 60 mL/min/m2), patients with low SBP at baseline, and patients on diuretics.3 Blood pressure should be closely monitored in these patients to prevent symptomatic hypotension and orthostasis.

Renal Impairment

Studies evaluating ertugliflozin’s safety and efficacy in renal disease have stratified their patient populations in terms of eGFR; therefore, clinical decisions should be based on eGFR rather than on estimated creatinine clearance (CrCL). Ertugliflozin is contraindicated in patients with an eGFR < 30 mL/min/m2, and should not be initiated in patients with an eGFR of 30 to < 60 mL/min/m2. If patients with normal or mild renal impairment are initiated on ertugliflozin, then develop a persistent eGFR of 30 to < 60 mL/min/m2, continuing the drug is not recommended. Ertugliflozin may cause an increase in serum creatinine and collateral decrease in eGFR, especially in patients with an eGFR < 60 mL/min/m2. From a mechanistic standpoint, the antihyperglycemic effects of ertugliflozin are substantially compromised in patients with moderate-to-severe kidney impairment. The risks of therapy may outweigh its benefits in these populations.3

Hepatic Impairment

No dosage adjustments are necessary in patients with mild-to-moderate hepatic impairment (i.e., Child Pugh Class A and Class B, respectively). Currently, no data are published that evaluate the safety and efficacy of ertugliflozin in patients with severe hepatic impairment (Child Pugh Class C). Ertugliflozin should not be administered in patients with severe hepatic impairment until further studies are published to evaluate its use in this population.3

Pregnancy

Ertugliflozin has not been extensively studied in human pregnancy; however, data have been extrapolated from animal studies with juvenile rats and rabbits. Renal tubule dilatation, malformation, and mineralization occurred when ertugliflozin was administered in gestational periods that correspond to the late second and third trimesters of human pregnancy. Consequently, package labeling indicates that ertugliflozin is not recommended in the second and third trimesters of pregnancy.3 It should be noted that uncontrolled diabetes is a significant cause of neonatal abnormalities and miscarriages.16 Clinicians should evaluate the risks and benefits of therapy on a case-by-case basis.

Lactation

There is a dearth of data on the presence of ertugliflozin in human breast milk, but the drug is present in the breast milk of nursing rats. Human renal development continues from the latter stages of neonatal development and through the first two years of life. Given that renal abnormalities have been found in gestational animal studies, it is not unreasonable to assume that exposing human infants to ertugliflozin may pose a threat to normal renal development. With this in mind, it is not advisable to administer ertugliflozin to nursing mothers.3

Pediatrics

The safety and efficacy of ertugliflozin have not been established in pediatric populations. It should not be administered to any patient younger than 18 years of age.3

P&T COMMITTEE CONSIDERATIONS

The comparative average wholesale price (AWP) per tablet and wholesale acquisition cost (WAC) for commercially available SGLT2 inhibitors are outlined in Table 3. At the time of writing this article, Steglatro tablets had more than a 40% reduction in WAC for a month’s supply of medication compared to its competitors in the same class.1720 This cost decrease does not come with a decrease in antihyperglycemic efficacy (see Table 1).

Current ADA guidelines do not recommend the use of any antihyperglycemic agent for the management of T2DM without prior initiation of metformin; however, situations often arise in clinical practice that cause clinicians to stray from strictly guideline-directed therapy.2 A significant number of patients may not be able to tolerate metformin due to its frequent gastrointestinal side effects. The VERTIS MONO and subsequent extension studies presented earlier provide evidence that ertugliflozin is generally safe and efficacious as monotherapy in adult T2DM patients with adequate renal function for at least 52 weeks of therapy.7,8 Other SGLT2 inhibitors have been studied in similar clinical scenarios and have demonstrated comparable results.21

Ertugliflozin does come with limitations compared to other SGLT2 inhibitors. As of late, improvements in macrovascular outcomes have become a primary consideration with antihyperglycemic medications. The EMPA-REG and CANVAS trials have each demonstrated macrovascular benefits in empagliflozinand canagliflozin-treated patients, respectively. 14,22 Trials evaluating the potential macrovascular benefits of ertugliflozin are ongoing; therefore, one should not assume that ertugliflozin will provide the same benefits until data are published.

Ertugliflozin’s safety profile is similar to that of other SGLT2 inhibitors. GMIs are significantly increased in patients treated with ertugliflozin, especially in females and uncircumcised males.3,79 Lower-limb amputations and euglycemic ketoacidosis remain a primary concern with all SGLT2 inhibitors. Although no causal relationship has been established between ertugliflozin and these adverse events, the drug should not be considered a safer alternative in high-risk populations.

CONCLUSION

Ertugliflozin is the newest SGLT2 inhibitor to receive FDA approval. The VERTIS MONO and VERTIS MONO extension trials found that ertugliflozin greatly reduced A1C compared to placebo and was generally safe as monotherapy for at least 52 weeks of therapy. The VERTIS MET trial demonstrated that when added to metformin, ertugliflozin significantly reduces A1C compared to placebo. All three trials demonstrated significant benefits in the reduction of BW, FPG, and odds of achieving A1C < 7% compared to placebo. Substantial reductions in SBP and DBP were inconclusive, but general reductions were observed compared to placebo. GMIs were the only significantly greater adverse effect consistently demonstrated, and women and uncircumcised men are at particularly high risk.

Ertugliflozin is available to wholesalers for a substantially reduced cost compared to the other FDA-approved SGLT2 inhibitors. This, along with data indicating safety and efficacy as monotherapy, are positive considerations for P&T committees to review; however, this must also be weighed against the current paucity of macrovascular data available for ertugliflozin, and the contrasting available data for other agents in the same class.

Tables

Summary of Commercially Available SGLT2 Inhibitors36

Drug Name Dosage Forms Available Dosing Frequency Renal Dosing Reduction in A1C*
Canagliflozin (Invokana) 100 mg, 300 mg Once daily Not recommended in eGFR < 45 100 mg = −0.7%
300 mg = −1.03%
Empagliflozin (Jardiance) 10 mg, 25 mg Once daily eGFR > 45 and < 60, max dose 100 mg; not recommended in eGFR < 45 10 mg = −0.7%
25 mg = −0.8%
Dapagliflozin (Farxiga) 5 mg, 10 mg Once daily Not recommended in eGFR < 60 ml/min/1.73 m2 5 mg = −0.8%
10 mg = −0.9%
Ertugliflozin (Steglatro) 5 mg, 15 mg Once daily Not recommended in eGFR < 60 ml/min/1.73 m2 5 mg = −0.7%
15 mg = −0.8%

*Based on trials as monotherapy vs. placebo.

eGFR = estimated glomerular filtration rate

Summary of Incidence of Drug-Related Adverse Events Reported in VERTIS MET, VERTIS MONO, and VERTIS MONO Extension Trials79

Reported Adverse Events Placebo +/− Metformin (N = 362) Ertugliflozin 5 mg (N = 363) Ertugliflozin 15 mg (N = 357)
Genital Mycotic Infections (Women) 4.4% (n = 182) 13.6%a (n = 177) 14.3%a,b (n = 174)
Genital Mycotic Infections (Men) 0.6% (n = 180) 3.2% (n = 186) 5.5%a (n = 183)
Urinary Tract Infections 6.4%c 6.3% 4.8%
Symptomatic Hypoglycemia 3.0% 2.5% 3.1%
Hypovolemia 2.2% 1.1% 1.4%
Pollakiuria 0.8% 2.2% 1.7%
Drug discontinued due to drug-related adverse event 3.6% 2.8% 2.5%
Dizzinessd 0.5% 1.4% 0.5%
Polyuriae 0% 1.9% 1.3%
Nocturiae 2.0% 0.6% 0%

aSignificantly greater incidence compared to placebo/metformin (VERTIS MONO extension);

bSignificantly greater incidence compared to placebo (VERTIS MET);

cSignificantly greater incidence compared to ertugliflozin 15 mg (VERTIS MONO extension);

dFindings only reported in VERTIS MET;

eFindings only reported in VERTIS MONO.

Drug Acquisition Costs for FDA-Approved SGLT2 Inhibitors1720

Medication (Manufacturer/Distributer) AWP Unit Price WAC for 30-Count Package WAC Percent Change From Reference
Jardiance (Empagliflozin) (Boehringer Ingelheim Pharma.) $18.60 $464.95 -
Invokana (Canagliflozin) (Janssen Pharmaceuticals) $18.58 $464.58 −0.08%
Farxiga (Dapagliflozin) (AstraZeneca Pharmaceuticals) $18.58 $464.54 −0.09%
Steglatro (Ertugliflozin) (Merck Sharp & Dohme Corp.) $10.73 $268.20 −42.32%

Prices do not change between dose strengths in each of the medications included. All prices are based upon Red Book data (accessed via Micromedex online, November 16, 2018).

AWP = average wholesale price; WAC = wholesale acquisition cost.

Author bio: 
Mr. Kovacich is a PharmD Candidate at the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, in Aurora, Colorado. Dr. Chavez is an Associate Professor with the Department of Clinical Pharmacy at the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, and also practices as a clinical pharmacist at Salud Family Health Centers in Aurora. Drug Forecast is a regular column coordinated by Alan Caspi, PhD, PharmD, MBA, President of Caspi and Associates in New York, New York.

References

  1. Centers for Disease Control and Prevention. National diabetes statistics report, 2017 Atlanta, GA: Centers for Disease Control and Prevention, U.S. Dept of Health and Human Services. 2017;
  2. American Diabetes Association. Pharmacological approach to glycemic treatment: standards of medical care in diabetes. Diabetes Care 2018;41;(suppl 1):S73–S85.
  3. Steglatro (ertugliflozin) tablets [package insert] Whitehouse Station, NJ: Merck Sharp & Dohme Corp. 2017;
  4. Invokana (canagliflozin) tablets [package insert] Titusville, NJ: Janssen Pharmaceuticals, Inc. 2016;
  5. Jardiance (empagliflozin) tablets [package insert] Ridgfield, CT: Boehringer Ingelheim Pharmaceuticals. 2016;
  6. Farxiga (dapagliflozin) tablets [package insert] Wilmington, DE: AstraZeneca Pharmaceuticals LP. 2017;
  7. Terra SG, Focht K, Davies M, et al. Phase III, efficacy and safety study of ertugliflozin monotherapy in people with type 2 diabetes mellitus inadequately controlled with diet and exercise alone. Diabetes Obes Metab 2017;19:721–728.10.1111/dom.12888
  8. Aronson R, Frias J, Goldman A, et al. Long-term efficacy and safety of ertugliflozin monotherapy in patients with inadequately controlled T2DM despite diet and exercise: VERTIS MONO extension study. Diabetes Obes Metab 2018;1–8.10.1111/dom.13251
  9. Rosenstock J, Frias J, Páll D, et al. Effect of ertugliflozin on glucose control, body weight, blood pressure and bone density in type 2 diabetes mellitus inadequately controlled on metformin monotherapy (VERTIS MET). Diabetes Obes Metab 2018;20:520–529.10.1111/dom.13103
  10. Hirji I, Guo Z, Andersson SW, et al. Incidence of urinary tract infection among patients with type 2 diabetes in the UK General Practice Research Database (GPRD) [published online August 11, 2016]. J Diabetes Complications 2012;26;(6):513–516.10.1016/j.jdiacomp.2012.06.008
  11. Wilke T, Boettger B, Berg B, et al. Epidemiology of urinary tract infections in type 2 diabetes mellitus patients: an analysis based on a large sample of 456,586 German T2DM patients [published online September 1, 2015]. J Diabetes Complications 2015;29;(8):1015–1023.10.1016/j.jdiacomp.2015.08.021
  12. Chacko B, Whitley M, Beckmann U, et al. Postoperative euglycaemic diabetic ketoacidosis associated with sodium-glucose cotransporter-2 inhibitors (gliflozins): a report of two cases and review of the literature. Anaesth Intensive Care 2018;46;(2):215–219.
  13. Khouri C, Cracowski JL, Roustit M. SGLT-2 inhibitors and the risk of lower-limb amputation: is this a class effect [published online March 12, 2018]?. Diabetes Obes Metab 2018;20;(6):1531–1534.10.1111/dom.13255
  14. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes [published online June 12, 2017]. N Engl J Med 2017;377;(7):644–657.10.1056/NEJMoa1611925
  15. Yuan Z, DeFalco FJ, Ryan PB, et al. Risk of lower extremity amputations in people with type 2 diabetes mellitus treated with sodium-glucose co-transporter-2 inhibitors in the USA: a retrospective cohort study [published online October 11, 2017]. Diabetes Obes Metab 2018;20;(3):582–589.10.1111/dom.13115
  16. Greene MF. Spontaneous abortions and major malformations in women with diabetes mellitus. Semin Reprod Endocrinol 1999;17;(2):127–136.
  17. Active ingredient: Empagliflozin. Red Book online Micromedex Healthcare SeriesGreenwood Village, CO: Truven Health Analytics. Available at: http://www.micromedexsolutions.com. Accessed November 16, 2018
  18. Active ingredient: Canagliflozin. Red Book online Micromedex Healthcare Series [database online]Truven Health Analytics. Greenwood Village, CO: Available at: http://www.micromedexsolutions.com. Accessed November 16, 2018
  19. Active ingredient: Dapagliflozin. Red Book online Micromedex Healthcare Series [database online]Truven Health Analytics. Greenwood Village, CO: Available at: http://www.micromedexsolutions.com. Accessed November 16, 2018
  20. Active ingredient: Ertugliflozin. Red Book online Micromedex Healthcare Series [database online]Truven Health Analytics. Greenwood Village, CO: Available at: http://www.micromedexsolutions.com. Accessed November 16, 2018
  21. Johnston R, Uthman O, Cummins E, et al. Canagliflozin, dapagliflozin and empagliflozin monotherapy for treating type 2 diabetes: systematic review and economic evaluation. Health Technol Assess 2017;21;(2):1–218.10.3310/hta21020
  22. Zinman B, Wanner C, Lachin D, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes [published online September 17, 2015]. N Engl J Med 2015;373;(22):2117–2128.10.1056/NEJMoa1504720