Steglatro Drug Information

Generic name: ERTUGLIFLOZIN

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Uses of Steglatro

® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. STEGLATRO is a sodium glucose co-transporter 2 (SGLT2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use: Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus.

Limitations of Use Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus .

Dosage & Administration of Steglatro

Prior to Initiation of

STEGLATRO Assess renal function before initiating STEGLATRO and as clinically indicated . Assess volume status. In patients with volume depletion, correct this condition before initiating STEGLATRO.

Recommended Dosage

The recommended starting dosage of STEGLATRO is 5 mg orally once daily, taken in the morning, with or without food. For additional glycemic control, the dosage may be increased to 15 mg orally once daily in patients tolerating STEGLATRO. Use of STEGLATRO is not recommended in patients with an estimated glomerular filtration rate (eGFR) less than 45 mL/min/1.73 m 2.

Temporary Interruption for Surgery Withhold

STEGLATRO for at least 4 days, if possible, prior to surgery or procedures associated with prolonged fasting. Resume STEGLATRO when the patient is clinically stable and has resumed oral intake.

Side Effects of Steglatro

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Pool of Placebo-Controlled Trials Evaluating STEGLATRO 5 and 15 mg The data in Table 1 are derived from a pool of three 26-week, placebo-controlled trials. STEGLATRO was used as monotherapy in one trial and as add-on therapy in two trials . These data reflect exposure of 1,029 patients to STEGLATRO with a mean exposure duration of approximately 25 weeks.

Patients received STEGLATRO 5 mg (N=519), STEGLATRO 15 mg (N=510), or placebo (N=515) once daily. The mean age of the population was 57 years and 2% were older than 75 years of age. Fifty-three percent (53%) of the population was male and 73% were White, 15% were Asian, and 7% were Black or African American.

At baseline the population had diabetes for an average of 7.5 years, had a mean HbA1c of 8.1%, and 19.4% had established microvascular complications of diabetes. Baseline renal function (mean eGFR 88.9 mL/min/1.73 m 2 ) was normal or mildly impaired in 97% of patients and moderately impaired in 3% of patients. Table 1 shows common adverse reactions associated with the use of STEGLATRO. These adverse reactions were not present at baseline, occurred more commonly on STEGLATRO than on placebo, and occurred in at least 2% of patients treated with either STEGLATRO 5 mg or STEGLATRO 15 mg.

Table 1: Adverse Reactions Reported in ≥2% of Patients with Type 2 Diabetes Mellitus Treated with STEGLATRO The three placebo-controlled studies included one monotherapy trial and two add-on combination trials with metformin HCl or with metformin HCl and sitagliptin. and Greater than Placebo in Pooled Placebo-Controlled Clinical Studies of STEGLATRO Monotherapy or Combination Therapy Number (%) of Patients Placebo N = 515 STEGLATRO 5 mg N = 519 STEGLATRO 15 mg N = 510 Female genital mycotic infections Includes: genital candidiasis, genital infection fungal, vaginal infection, vulvitis, vulvovaginal candidiasis, vulvovaginal mycotic infection, and vulvovaginitis. Percentages calculated with the number of female patients in each group as denominator: placebo (N=235), STEGLATRO 5 mg (N=252), STEGLATRO 15 mg (N=245). 3.0% 9.1% 12.2% Male genital mycotic infections Includes: balanitis candida, balanoposthitis, genital infection, and genital infection fungal. Percentages calculated with the number of male patients in each group as denominator: placebo (N=280), STEGLATRO 5 mg (N=267), STEGLATRO 15 mg (N=265). 0.4% 3.7% 4.2% Urinary tract infections Includes: cystitis, dysuria, streptococcal urinary tract infection, urethritis, urinary tract infection. 3.9% 4.0% 4.1% Headache 2.3% 3.5% 2.9% Vaginal pruritus Includes: vulvovaginal pruritus and pruritus genital.

Percentages calculated with the number of female patients in each group as denominator: placebo (N=235), ertugliflozin 5 mg (N=252), ertugliflozin 15 mg (N=245). 0.4% 2.8% 2.4% Increased urination Includes: pollakiuria, micturition urgency, polyuria, urine output increased, and nocturia. 1.0% 2.7% 2.4% Nasopharyngitis 2.3% 2.5% 2.0% Back pain 2.3% 1.7% 2.5% Weight decreased 1.0% 1.2% 2.4% Thirst Includes: thirst, dry mouth, polydipsia, and dry throat. 0.6% 2.7% 1.4% Volume Depletion STEGLATRO causes an osmotic diuresis, which may lead to intravascular volume contraction and adverse reactions related to volume depletion, particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m 2 ). In patients with moderate renal impairment, adverse reactions related to volume depletion (e.g., dehydration, dizziness postural, presyncope, syncope, hypotension, and orthostatic hypotension) were reported in 0%, 4.4%, and 1.9% of patients treated with placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively. STEGLATRO may also increase the risk of hypotension in other patients at risk for volume contraction . Hypoglycemia The incidence of hypoglycemia by study is shown in Table 2. Table 2: Incidence of Overall Overall hypoglycemic events: plasma or capillary glucose of less than or equal to 70 mg/dL. and Severe Severe hypoglycemic events: required assistance, lost consciousness, or experienced a seizure regardless of blood glucose. Hypoglycemia in Placebo-Controlled Clinical Studies in Patients with Type 2 Diabetes Mellitus Monotherapy (26 weeks) Placebo (N = 153) STEGLATRO 5 mg (N =156) STEGLATRO 15 mg (N = 152) Overall 1 4 4 Severe 0 0 2 Add-on Combination Therapy with Metformin HCl (26 weeks) Placebo (N = 209) STEGLATRO 5 mg (N = 207) STEGLATRO 15 mg (N = 205) Overall 9 15 16 Severe 1 1 0 Add-on Combination Therapy with Metformin HCl and Sitagliptin (26 weeks) Placebo (N = 153) STEGLATRO 5 mg (N = 156) STEGLATRO 15 mg (N = 153) Overall 5 7 3 Severe 1 1 0 In Combination with Insulin and/or an Insulin Secretagogue in Patients with Moderate Renal Impairment (26 weeks) Placebo (N = 133) STEGLATRO 5 mg (N = 148) STEGLATRO 15 mg (N = 143) Overall 48 53 39 Severe 3 5 3 Add-on Combination with Insulin with or without Metformin HCl (18 weeks) Placebo (N = 347) STEGLATRO 5 mg (N = 348) STEGLATRO 15 mg (N = 370) Overall 130 137 144 Severe 12 13 19 Add-on Combination with a Sulfonylurea (18 weeks) Placebo (N =48) STEGLATRO 5 mg (N =55) STEGLATRO 15 mg (N =54) Overall 2 4 5 Severe 0 0 0 Add-on Combination with Metformin HCl and a Sulfonylurea (18 weeks) Placebo (N = 117) STEGLATRO 5 mg (N = 100) STEGLATRO 15 mg (N = 113) Overall 17 20 30 Severe 1 2 2 Lower Limb Amputation In a long-term cardiovascular outcomes study , in patients with type 2 diabetes mellitus and established cardiovascular disease, the occurrence of non-traumatic lower limb amputations was reported with event rates of 4.7, 5.7, and 6.0 events per 1,000 patient-years in the placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg treatment arms, respectively.

Across seven STEGLATRO clinical trials, non-traumatic lower limb amputations were reported in 1 (0.1%) patient in the comparator group, 3 (0.2%) patients in the STEGLATRO 5 mg group, and 8 (0.5%) patients in the STEGLATRO 15 mg group. Genital Mycotic Infections In the pool of three placebo-controlled clinical trials, the incidence of female genital mycotic infections (e.g., genital candidiasis, genital infection fungal, vaginal infection, vulvitis, vulvovaginal candidiasis, vulvovaginal mycotic infection, vulvovaginitis) occurred in 3%, 9.1%, and 12.2% of females treated with placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively (see Table 1 ). In females, discontinuation due to genital mycotic infections occurred in 0% and 0.6% of patients treated with placebo and STEGLATRO, respectively. In the same pool, male genital mycotic infections (e.g., balanitis candida, balanoposthitis, genital infection, genital infection fungal) occurred in 0.4%, 3.7%, and 4.2% of males treated with placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively (see Table 1 ). Male genital mycotic infections occurred more commonly in uncircumcised males.

In males, discontinuations due to genital mycotic infections occurred in 0% and 0.2% of patients treated with placebo and STEGLATRO, respectively. Phimosis was reported in 8 of 1729 (0.5%) male ertugliflozin-treated patients, of which four required circumcision. Urinary Tract Infections In VERTIS CV, urinary tract infections (e.g., urinary tract infection, cystitis, dysuria) occurred in 10.2%, 12.2% and 12.0% of patients treated with placebo, STEGLATRO 5 mg and STEGLATRO 15 mg, respectively.

The incidences of serious urinary tract infections were 0.8%, 0.9% and 0.4% with placebo, STEGLATRO 5 mg and STEGLATRO 15 mg, respectively. Laboratory Tests Changes in Serum Creatinine and eGFR Initiation of STEGLATRO causes an increase in serum creatinine and decrease in eGFR within weeks of starting therapy and then these changes stabilize. In a study of patients with moderate renal impairment, larger mean changes were observed.

In a long-term cardiovascular outcomes trial, an initial increase in serum creatinine and a decrease in eGFR within weeks of starting therapy was observed (at Week 6 eGFR changes of -2.7, -3.8 and -0.4 mL/min/1.73 m 2 in the STEGLATRO 5 mg, STEGLATRO 15 mg and placebo arms, respectively). The initial decline was followed by a recovery toward baseline to Week 52 (eGFR change from baseline of - 0.4, - 1.1 and - 0.2 mL/min/1.73 m 2 in STEGLATRO 5 mg, STEGLATRO 15 mg, and placebo arms, respectively). Acute hemodynamic changes may play a role in the early renal function changes observed with STEGLATRO since they are reversed after treatment discontinuation. Increases in Low-Density Lipoprotein Cholesterol (LDL-C) In the pool of three placebo-controlled trials, dose-related increases in LDL-C were observed in patients treated with STEGLATRO. Mean percent changes from baseline to Week 26 in LDL-C relative to placebo were 2.6% and 5.4% with STEGLATRO 5 mg and STEGLATRO 15 mg, respectively. The range of mean baseline LDL-C was 96.6 to 97.7 mg/dL across treatment groups.

Increases in Hemoglobin In the pool of three placebo-controlled trials, mean changes (percent changes) from baseline to Week 26 in hemoglobin were -0.21 g/dL (-1.4%) with placebo, 0.46 g/dL (3.5%) with STEGLATRO 5 mg, and 0.48 g/dL (3.5%) with STEGLATRO 15 mg. The range of mean baseline hemoglobin was 13.90 to 14.00 g/dL across treatment groups. At the end of treatment, 0.0%, 0.2%, and 0.4% of patients treated with placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively, had a hemoglobin increase greater than 2 g/dL and above the upper limit of normal.

Increases in Serum Phosphate In the pool of three placebo-controlled trials, mean changes (percent changes) from baseline in serum phosphate were 0.04 mg/dL (1.9%) with placebo, 0.21 mg/dL (6.8%) with STEGLATRO 5 mg, and 0.26 mg/dL (8.5%) with STEGLATRO 15 mg. The range of mean baseline serum phosphate was 3.53 to 3.54 mg/dL across treatment groups. In a clinical trial of patients with moderate renal impairment, mean changes (percent changes) from baseline at Week 26 in serum phosphate were -0.01 mg/dL (0.8%) with placebo, 0.29 mg/dL (9.7%) with STEGLATRO 5 mg, and 0.24 mg/dL (7.8%) with STEGLATRO 15 mg.

Postmarketing Experience Additional adverse reactions have been identified during postapproval use of

STEGLATRO. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Infections: necrotizing fasciitis of the perineum (Fournier's Gangrene) Skin and Subcutaneous Tissue Disorders: angioedema, rash

Warnings & Cautions for Steglatro

Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis

In patients with type 1 diabetes mellitus, STEGLATRO significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received sodium glucose transporter 2 (SGLT2) inhibitors compared to patients who received placebo; this risk may be greater with higher doses. STEGLATRO is not indicated for glycemic control in patients with type 1 diabetes mellitus.

Type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are also risk factors for ketoacidosis. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors. Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under-insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse.

Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists for 4 days after discontinuing STEGLATRO ; however, there have been postmarketing reports of ketoacidosis and/or glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors.

Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation. Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue STEGLATRO, promptly evaluate, and treat ketoacidosis, if confirmed.

Monitor patients for resolution of ketoacidosis before restarting STEGLATRO. Withhold STEGLATRO, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume STEGLATRO when the patient is clinically stable and has resumed oral intake. Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue STEGLATRO and seek medical attention immediately if signs and symptoms occur.

Lower Limb Amputation

In a long-term cardiovascular outcomes study , in patients with type 2 diabetes mellitus and established cardiovascular disease, the occurrence of non-traumatic lower limb amputations was reported with event rates of 4.7, 5.7, and 6.0 events per 1,000 patient-years in the placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg treatment arms, respectively. Amputation of the toe and foot were most frequent (81 out of 109 patients with lower limb amputations). Some patients had multiple amputations, some involving both lower limbs. Lower limb infections, gangrene, and diabetic foot ulcers were the most common precipitating medical events leading to the need for an amputation.

Patients with amputations were more likely to be male, have higher A1C (%) at baseline, have a history of peripheral arterial disease, amputation or peripheral revascularization procedure, diabetic foot, and to have been taking diuretics or insulin. Across seven STEGLATRO clinical trials, non-traumatic lower limb amputations were reported in 1 (0.1%) patient in the comparator group, 3 (0.2%) patients in the STEGLATRO 5 mg group, and 8 (0.5%) patients in the STEGLATRO 15 mg group. Counsel patients about the importance of routine preventative foot care.

Monitor patients receiving STEGLATRO for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue STEGLATRO if these complications occur.

Volume Depletion

STEGLATRO can cause intravascular volume contraction which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine . There have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including STEGLATRO. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m 2 ) , elderly patients, patients with low systolic blood pressure, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating STEGLATRO in patients with one or more of these characteristics, assess volume status and renal function. In patients with volume depletion, correct this condition before initiating STEGLATRO. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy.

Urosepsis and Pyelonephritis

There have been postmarketing reports of serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization in patients receiving SGLT2 inhibitors. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated .

Hypoglycemia with

Concomitant Use with Insulin or Insulin Secretagogues Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. STEGLATRO may increase the risk of hypoglycemia when used in combination with insulin or an insulin secretagogue . The risk of hypoglycemia may be lowered by a reduction in the dose of insulin or sulfonylurea (or other concomitantly administered insulin secretagogues). Inform patients using these medications concomitantly of this risk and educate them on the signs and symptoms of hypoglycemia.

Necrotizing Fasciitis of the Perineum (Fournier's Gangrene) Reports of necrotizing fasciitis of

the perineum (Fournier's Gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including STEGLATRO. Cases have been reported in females and males. Serious outcomes have included hospitalization, multiple surgeries, and death. Patients treated with STEGLATRO presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis.

If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue STEGLATRO, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.

Genital Mycotic Infections

STEGLATRO increases the risk of genital mycotic infections. Patients who have a history of genital mycotic infections or who are uncircumcised are more likely to develop genital mycotic infections . Monitor and treat appropriately.

Drug Interactions with Steglatro

  • Table 3: Clinically Significant Drug Interactions with STEGLATRO Insulin or Insulin Secretagogues Clinical Impact: The risk of hypoglycemia is increased when STEGLATRO is used in combination with insulin or an insulin secretagogue.
  • Intervention: A lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with STEGLATRO.
  • Lithium Clinical Impact: Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations.
  • Intervention: Monitor serum lithium concentration more frequently during STEGLATRO initiation and dosage changes.
  • Positive Urine Glucose Test Clinical Impact: SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests.
  • Intervention: Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control. Interference with 1,5-anhydroglucitol (1,5-AG) Assay Clinical Impact: Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors.
  • Intervention: Monitoring glycemic control with 1,5-AG assay is not recommended. Use alternative methods to monitor glycemic control. See full prescribing information for information on drug interactions and interference of STEGLATRO with laboratory tests.

Pregnancy Safety for Steglatro

Pregnancy Risk Summary Based on animal data showing adverse renal effects, STEGLATRO is not recommended during the second and third trimesters of pregnancy. The limited available data with STEGLATRO in pregnant women are not sufficient to determine a drug-associated risk of adverse developmental outcomes. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations ). In animal studies, adverse renal changes were observed in rats when ertugliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy.

Doses approximately 13 times the maximum clinical dose caused renal pelvic and tubule dilatations and renal mineralization that were not fully reversible. There was no evidence of fetal harm in rats or rabbits at exposures of ertugliflozin approximately 300 times higher than the maximal clinical dose of 15 mg/day when administered during organogenesis (see Data ). The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20-25% in women with HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Animal Data When ertugliflozin was orally administered to juvenile rats from PND 21 to PND 90, increased kidney weight, renal tubule and renal pelvis dilatation, and renal mineralization occurred at doses greater than or equal to 5 mg/kg (13-fold human exposures, based on AUC). These effects occurred with drug exposure during periods of renal development in rats that correspond to the late second and third trimester of human renal development, and did not fully reverse within a 1-month recovery period.

In embryo-fetal development studies, ertugliflozin (50, 100 and 250 mg/kg/day) was administered orally to rats on gestation days 6 to 17 and to rabbits on gestation days 7 to 19. Ertugliflozin did not adversely affect developmental outcomes in rats and rabbits at maternal exposures that were approximately 300 times the human exposure at the maximum clinical dose of 15 mg/day, based on AUC. A maternally toxic dose (250 mg/kg/day) in rats (707 times the clinical dose), was associated with reduced fetal viability, and a higher incidence of a visceral malformation (membranous ventricular septal defect). In the pre- and post-natal development study in pregnant rats, ertugliflozin was administered to the dams from gestation day 6 through lactation day 21 (weaning). Decreased post-natal growth (weight gain) was observed at maternal doses ≥100 mg/kg/day (greater than or equal to 331 times the human exposure at the maximum clinical dose of 15 mg/day, based on AUC).

Pediatric Use of Steglatro

Pediatric Use Safety and effectiveness of STEGLATRO in pediatric patients under 18 years of age have not been established.

Contraindications for Steglatro

is contraindicated in patients with hypersensitivity to ertugliflozin or any excipient in STEGLATRO. Reactions such as angioedema have occurred. Hypersensitivity to ertugliflozin or any of the excipients in STEGLATRO.

Overdosage Information for Steglatro

In the event of an overdose with STEGLATRO, contact the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. Employ the usual supportive measures as dictated by the patient's clinical status. Removal of ertugliflozin by hemodialysis has not been studied.

Clinical Studies of Steglatro

Glycemic Control Trials in Patients with Type 2 Diabetes Mellitus

STEGLATRO has been studied as monotherapy and in combination with metformin HCl, sitagliptin, a sulfonylurea, insulin (with or without metformin HCl), metformin HCl plus sitagliptin, metformin HCl plus a sulfonylurea and compared to a sulfonylurea (glimepiride). STEGLATRO has also been studied in patients with type 2 diabetes mellitus and moderate renal impairment. In patients with type 2 diabetes mellitus treatment with STEGLATRO reduced hemoglobin A1c (HbA1c) compared to placebo. Reduction in HbA1c was generally similar across subgroups defined by age, sex, race, geographic region, baseline body mass index (BMI), and duration of type 2 diabetes mellitus.

Monotherapy A total of 461 patients with type 2 diabetes mellitus inadequately controlled (HbA1c between 7% and 10.5%) on diet and exercise participated in a randomized, double-blind, multi-center, 26-week, placebo-controlled study (NCT01958671) to evaluate the efficacy and safety of STEGLATRO monotherapy. These patients, who were either treatment naïve or not receiving any background antihyperglycemic treatment ≥8 weeks, entered a 2-week, single-blind, placebo run-in period and were randomized to placebo, STEGLATRO 5 mg, or STEGLATRO 15 mg, administered once daily. At Week 26, treatment with STEGLATRO at 5 mg or 15 mg orally once daily provided statistically significant reductions in HbA1c compared to placebo.

STEGLATRO also resulted in a greater proportion of patients achieving an HbA1c <7% compared with placebo (see Table 4 and Figure 3 ). Table 4: Results at Week 26 from a Placebo-Controlled Monotherapy Study of STEGLATRO in Patients with Type 2 Diabetes Mellitus N includes all randomized and treated patients with a baseline measurement of the outcome variable. At Week 26, the primary HbA1c endpoint was missing for 23%, 11%, and 16% of patients, and during the trial, rescue medication was initiated by 25%, 2%, and 3% of patients randomized to placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively. Missing Week 26 measurements were imputed using multiple imputation with a mean equal to the baseline value of the patient.

Results include measurements collected after initiation of rescue medication. For those patients who did not receive rescue medication and had values measured at 26 weeks, the mean changes from baseline for HbA1c were -0.1%, -0.8%, and - 1.0% for placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively. Placebo STEGLATRO 5 mg STEGLATRO 15 mg HbA1c (%) N = 153 N = 155 N = 151 Baseline (mean) 8.1 8.2

Change from baseline (LS mean Intent-to-treat analysis using

ANCOVA adjusted for baseline value, prior antihyperglycemic medication, and baseline eGFR. ) -0.2 -0.7 -

Difference from placebo (LS mean, 95% CI) -0.6 p<0.001 compared to placebo.

(-0.8, -0.4) -0.7 (-0.9, -0.4) Patients with HbA1c <7% 26 47 59 FPG (mg/dL) N = 150 N = 151 N = 149 Baseline (mean) 180.2 180.9

Change from baseline (LS mean ) -11.6 -31.0 -36.4 Difference from placebo

(LS mean, 95% CI) -19.4 (-27.6, -11.2) -24.8 (-33.2, -16.4) The mean baseline body weight was 94.2 kg, 94.0 kg, and 90.6 kg in the placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg groups, respectively. The mean changes from baseline to Week 26 were -1.0 kg, -3.0 kg, and -3.1 kg in the placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg groups, respectively. The difference from placebo (95% CI) for STEGLATRO 5 mg was -2.0 kg (-2.8, -1.2) and for STEGLATRO 15 mg was -2.1 kg (-2.9, -1.3). Figure 3: HbA1c (%) Change Over Time in a 26-Week Placebo-Controlled Monotherapy Study of STEGLATRO in Patients with Type 2 Diabetes Mellitus Data to the left of the vertical line are observed means (non-model-based) excluding values occurring post glycemic rescue.

Data to the right of the vertical line represent the final Week 26 data, including all values regardless of use of glycemic rescue medication and use of study drug, with missing Week 26 values imputed using multiple imputation (26-MI) with a mean equal to the baseline value of the patient (see Table 4 ). Figure 3 Combination Therapy Add-on Combination Therapy with Metformin HCl A total of 621 patients with type 2 diabetes mellitus inadequately controlled (HbA1c between 7% and 10.5%) on metformin HCl monotherapy (≥1,500 mg/day for ≥8 weeks) participated in a randomized, double-blind, multi-center, 26-week, placebo-controlled study (NCT02033889) to evaluate the efficacy and safety of STEGLATRO in combination with metformin HCl. Patients entered a 2-week, single-blind, placebo run-in, and were randomized to placebo, STEGLATRO 5 mg, or STEGLATRO 15 mg administered once daily in addition to continuation of background metformin HCl therapy. At Week 26, treatment with STEGLATRO at 5 mg or 15 mg orally once daily provided statistically significant reductions in HbA1c compared to placebo.

STEGLATRO also resulted in a greater proportion of patients achieving an HbA1c <7% compared to placebo (see Table 5 ). Table 5: Results at Week 26 from a Placebo-Controlled Study for STEGLATRO Used in Combination with Metformin HCl in Patients with Type 2 Diabetes Mellitus N includes all randomized and treated patients with a baseline measurement of the outcome variable. At Week 26, the primary HbA1c endpoint was missing for 12%, 6%, and 9% of patients, and during the trial, rescue medication was initiated by 18%, 3%, and 1% of patients randomized to placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively. Missing Week 26 measurements were imputed using multiple imputation with a mean equal to the baseline value of the patient.

Results include measurements collected after initiation of rescue medication. For those patients who did not receive rescue medication and had values measured at 26 weeks, the mean changes from baseline for HbA1c were -0.2%, -0.7%, and - 1.0% for placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively. Placebo STEGLATRO 5 mg STEGLATRO 15 mg HbA1c (%) N = 207 N = 205 N = 201 Baseline (mean) 8.2 8.1

Change from baseline (LS mean Intent-to-treat analysis using

ANCOVA adjusted for baseline value, prior antihyperglycemic medication, menopausal status and baseline eGFR. ) -0.2 -0.7 -

Difference from placebo (LS mean, 95% CI) -0.5 p<0.001 compared to placebo.

(-0.7, -0.4) -0.7 (-0.9, -0.5) Patients with HbA1c <7% 38 74 87 FPG (mg/dL) N = 202 N = 199 N = 201 Baseline (mean) 169.1 168.1

Change from baseline (LS mean ) -8.7 -30.3 -40.9 Difference from placebo

(LS mean, 95% CI) -21.6 (-27.8, -15.5) -32.3 (-38.5, -26.0) The mean baseline body weight was 84.5 kg, 84.9 kg, and 85.3 kg in the placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg groups, respectively. The mean changes from baseline to Week 26 were - 1.4 kg, -3.2 kg, and -3.0 kg in the placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg groups, respectively. The difference from placebo (95% CI) for STEGLATRO 5 mg was -1.8 kg (-2.4, -1.2) and for STEGLATRO 15 mg was -1.7 kg (-2.2, -1.1). The mean baseline systolic blood pressure was 129.3 mmHg, 130.5 mmHg, and 130.2 mmHg in the placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg groups, respectively.

The mean changes from baseline to Week 26 were -1.8 mmHg, -5.1 mmHg, and -5.7 mmHg in the placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg groups, respectively. The difference from placebo (95% CI) for STEGLATRO 5 mg was -3.3 mmHg (-5.6, -1.1) and for STEGLATRO 15 mg was -3.8 mmHg (-6.1, -1.5). Active Controlled Study versus Glimepiride as Add-on Combination Therapy with Metformin HCl A total of 1,326 patients with type 2 diabetes mellitus inadequately controlled (HbA1c between 7% and 9%) on metformin HCl monotherapy participated in a randomized, double-blind, multi-center, 52-week, active comparator controlled study (NCT01999218) to evaluate the efficacy and safety of STEGLATRO in combination with metformin HCl. These patients, who were receiving metformin HCl monotherapy (≥1,500 mg/day for ≥8 weeks), entered a 2-week, single-blind, placebo run-in period and were randomized to glimepiride, STEGLATRO 5 mg, or STEGLATRO 15 mg administered orally once daily in addition to continuation of background metformin HCl therapy.

Glimepiride was initiated at 1 mg/day and titrated up to a maximum dose of 6 or 8 mg/day (depending on maximum approved dose in each country) or a maximum tolerated dose or down-titrated to avoid or manage hypoglycemia. The mean daily dose of glimepiride was 3.0 mg. STEGLATRO 15 mg was non-inferior to glimepiride after 52 weeks of treatment. (See Table 6.) Table 6: Results at Week 52 from an Active-Controlled Study Comparing STEGLATRO to Glimepiride as Add-on Therapy in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Metformin HCl N includes all randomized and treated patients with a baseline measurement of the outcome variable.

At Week 52, the primary HbA1c endpoint was missing for 15%, 20%, and 16% of patients and during the trial, rescue medication was initiated by 3%, 6%, and 4% of patients randomized to glimepiride, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively. Missing Week 52 measurements were imputed using multiple imputation with a mean equal to the baseline value of the patient. Results include measurements collected after initiation of rescue medication.

For those patients who did not receive rescue medication and had values measured at 52 weeks, the mean changes from baseline for HbA1c were -0.8%, -0.6%, and -0.7% for glimepiride, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively. Glimepiride STEGLATRO 5 mg STEGLATRO 15 mg HbA1c (%) N = 437 N = 447 N = 440 Baseline (mean) 7.8 7.8

Change from baseline (LS mean Intent-to-treat analysis using

ANCOVA adjusted for baseline value, prior antihyperglycemic medication and baseline eGFR. ) -0.6 -0.5 -

Difference from glimepiride (LS mean, 95% CI) 0.2 Non-inferiority is declared when

the upper bound of the two-sided 95% confidence interval (CI) for the mean difference is less than 0.3%. 0.1 (-0.0, 0.2) Patients with HbA1c <7% 208 177 186 The mean baseline body weight was 86.8 kg, 87.9 kg, and 85.6 kg in the glimepiride, STEGLATRO 5 mg, and STEGLATRO 15 mg groups, respectively. The mean changes from baseline to Week 52 were 0.6 kg, -2.6 kg, and -3.0 kg in the glimepiride, STEGLATRO 5 mg, and STEGLATRO 15 mg groups, respectively. The difference from glimepiride (95% CI) for STEGLATRO 5 mg was -3.2 kg (-3.7, -2.7) and for STEGLATRO 15 mg was -3.6 kg (-4.1, -3.1). In Combination with Sitagliptin versus STEGLATRO Alone and Sitagliptin Alone, as Add-on to Metformin HCl A total of 1,233 patients with type 2 diabetes mellitus with inadequate glycemic control (HbA1c between 7.5% and 11%) on metformin HCl monotherapy (≥1,500 mg/day for ≥8 weeks) participated in a randomized, double-blind, 26-week, active controlled study (NCT02099110) to evaluate the efficacy and safety of STEGLATRO 5 mg or 15 mg orally once daily in combination with sitagliptin 100 mg orally once daily compared to the individual components.

Patients were randomized to one of five treatment arms: STEGLATRO 5 mg, STEGLATRO 15 mg, sitagliptin 100 mg, STEGLATRO 5 mg + sitagliptin 100 mg, or STEGLATRO 15 mg + sitagliptin 100 mg. At Week 26, STEGLATRO 5 mg or 15 mg + sitagliptin 100 mg provided statistically significantly greater reductions in HbA1c compared to STEGLATRO (5 mg or 15 mg) alone or sitagliptin 100 mg alone. The mean change from baseline in HbA1c was -1.4% for STEGLATRO 5 mg or 15 mg + sitagliptin 100 mg versus -1.0%, for STEGLATRO 5 mg, STEGLATRO 15 mg, or sitagliptin 100 mg, respectively.

More patients receiving STEGLATRO 5 mg or 15 mg + sitagliptin 100 mg achieved an HbA1c <7% (53.3% and 50.9%, for STEGLATRO 5 mg or 15 mg, respectively, + sitagliptin 100 mg) compared to the individual components (29.3%, 33.7%, and 38.5% for STEGLATRO 5 mg, STEGLATRO 15 mg, or sitagliptin 100 mg, respectively). Add-on Combination Therapy with Metformin HCl and Sitagliptin A total of 463 patients with type 2 diabetes mellitus inadequately controlled (HbA1c between 7% and 10.5%) on metformin HCl (≥1,500 mg/day for ≥8 weeks) and sitagliptin 100 mg once daily participated in a randomized, double-blind, multi-center, 26-week, placebo-controlled study (NCT02036515) to evaluate the efficacy and safety of STEGLATRO. Patients entered a 2-week, single-blind, placebo run-in period and were randomized to placebo, STEGLATRO 5 mg, or STEGLATRO 15 mg orally once daily. At Week 26, treatment with STEGLATRO at 5 mg or 15 mg daily provided statistically significant reductions in HbA1c. STEGLATRO also resulted in a higher proportion of patients achieving an HbA1c <7% compared to placebo (see Table 7 ). Table 7: Results at Week 26 from an Add-on Study of STEGLATRO in Combination with Metformin HCl and Sitagliptin in Patients with Type 2 Diabetes Mellitus N includes all randomized and treated patients with a baseline measurement of the outcome variable.

At Week 26, the primary HbA1c endpoint was missing for 10%, 11%, and 7% of patients and during the trial, rescue medication was initiated by 16%, 1%, and 2% of patients randomized to placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively. Missing Week 26 measurements were imputed using multiple imputation with a mean equal to the baseline value of the patient. Results include measurements collected after initiation of rescue medication.

For those patients who did not receive rescue medication and had values measured at 26 weeks, the mean changes from baseline for HbA1c were -0.2%, -0.8%, and -0.9% for placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively. Placebo STEGLATRO 5 mg STEGLATRO 15 mg HbA1c (%) N = 152 N = 155 N = 152 Baseline (mean) 8.0 8.1

Change from baseline (LS mean Intent-to-treat analysis using

ANCOVA adjusted for baseline value, prior antihyperglycemic medication and baseline eGFR. ) -0.2 -0.7 -

Difference from placebo (LS mean, 95% CI) -0.5 p<0.001 compared to placebo.

(-0.7, -0.3) -0.6 (-0.8, -0.4) Patients with HbA1c <7% 31 54 64 FPG (mg/dL) N = 152 N = 156 N = 152 Baseline (mean) 169.6 167.7

Change from baseline (LS mean ) -6.5 -25.7 -32.1 Difference from placebo

(LS mean, 95% CI) -19.2 (-26.8, -11.6) -25.6 (-33.2, -18.0) The mean baseline body weight was 86.5 kg, 87.6 kg, and 86.6 kg in the placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg groups, respectively. The mean changes from baseline to Week 26 were -1.0 kg, -3.0 kg, and -2.8 kg in the placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg groups, respectively. The difference from placebo (95% CI) for STEGLATRO 5 mg was -1.9 kg (-2.6, -1.3) and for STEGLATRO 15 mg was -1.8 kg (-2.4, -1.2). The mean baseline systolic blood pressure was 130.2 mmHg, 132.1 mmHg, and 131.6 mmHg in the placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg groups, respectively.

The mean changes from baseline to Week 26 were -0.2 mmHg, -3.8 mmHg, and -4.5 mmHg in the placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg groups, respectively. The difference from placebo (95% CI) for STEGLATRO 5 mg was -3.7 mmHg (-6.1, -1.2) and for STEGLATRO 15 mg was -4.3 mmHg (-6.7, -1.9). Initial Combination Therapy with Sitagliptin A total of 291 patients with type 2 diabetes mellitus inadequately controlled (HbA1c between 8% and 10.5%) on diet and exercise participated in a randomized, double-blind, multi-center, placebo-controlled 26-week study (NCT02226003) to evaluate the efficacy and safety of STEGLATRO in combination with sitagliptin. These patients, who were not receiving any background antihyperglycemic treatment for ≥8 weeks, entered a 2-week, single-blind, placebo run-in period and were randomized to placebo, STEGLATRO 5 mg or STEGLATRO 15 mg, in combination with sitagliptin (100 mg) orally once daily.

At Week 26, treatment with STEGLATRO 5 mg and 15 mg in combination with sitagliptin at 100 mg daily provided statistically significant reductions in HbA1c compared to placebo. STEGLATRO 5 mg and 15 mg in combination with sitagliptin at 100 mg daily also resulted in a higher proportion of patients achieving an HbA1c <7% and greater reductions in FPG compared with placebo. Add-on Combination Therapy with Insulin (with or without Metformin HCl) In an 18-week randomized, double-blind, multi-center, placebo-controlled, glycemic sub-study of VERTIS CV (eValuation of ERTugliflozin efficacy and Safety CardioVascular, NCT01986881, study details see 14.2 ), a total of 1,065 patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease with inadequate glycemic control (HbA1c between 7% and 10.5%) on background therapy of insulin ≥20 units/day (59% also on metformin HCl ≥1,500 mg/day) were randomized to placebo, STEGLATRO 5 mg or STEGLATRO 15 mg orally once daily treatment.

At Week 18, treatment with STEGLATRO at 5 mg or 15 mg daily provided statistically significant reductions in HbA1c compared to placebo (see Table 8 ). Table 8: Results at Week 18 from an Add-on Study of STEGLATRO in Combination with Insulin (with or without Metformin HCl) in Patients with Type 2 Diabetes Mellitus N includes all randomized and treated patients with a baseline measurement of the outcome variable. At Week 18, the primary HbA1c endpoint was missing for 10%, 9%, and 12% of patients and during the trial, rescue medication was initiated by 12%, 7%, and 6% of patients randomized to placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively. Results include measurements collected after initiation of rescue medication.

Prior to Week 18, background antidiabetic medication was held stable. Missing Week 18 measurements were imputed using multiple imputation with a mean equal to the baseline value of the patient (Return to Baseline analysis). Placebo STEGLATRO 5 mg STEGLATRO 15 mg SE: standard error. HbA1c (%) N = 346 N = 346 N = 367 Baseline (mean) 8.4 8.4

Change from baseline (LS mean Intent-to-treat analysis using

ANCOVA adjusted for baseline value, insulin stratum, and baseline eGFR., SE) -0.2 -0.7 -

Difference from placebo (LS mean, 95% CI) -0.5 p<0.001 compared to placebo.

(-0.6, -0.4) -0.5 (-0.7, -0.4) Patients with HbA1c <7% Missing values imputed as not meeting the <7% criterion. 37 79 81 FPG (mg/dL) N = 343 N = 346 N = 368 Baseline (mean) 167.4 173.8

Change from baseline (LS mean, SE) -6.3 -25.6 -29.8 Difference from placebo

(LS mean, 95% CI) -19.2 (-26.8, -11.6) -23.4 (-30.9, -16.0) The mean baseline body weights were 93.3 kg, 93.8 kg, and 92.1 kg in the placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg groups, respectively. The mean changes from baseline to Week 18 were - 0.2 kg, -1.6 kg, and -1.9 kg in the placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg groups, respectively. The differences from placebo (95% CI) for STEGLATRO 5 mg were - 1.4 kg (- 1.9, - 0.9) and for STEGLATRO 15 mg was -1.6 kg (-2.1, -1.1). The mean baseline systolic blood pressures were 134.0 mmHg, 135.6 mmHg, and 133.7 mmHg in the placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg groups, respectively.

The mean changes from baseline to Week 18 were 0.7 mmHg, -2.2 mmHg, and -1.7 mmHg in the placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg groups, respectively. The differences from placebo (95% CI) for STEGLATRO 5 mg was – 2.9 mmHg (-4.9, -1.0) and for STEGLATRO 15 mg were -2.5 mmHg (- 4.4, - 0.5). Add-on Combination Therapy with Metformin HCl and Sulfonylurea In an 18-week randomized, double-blind, multi-center, placebo-controlled, glycemic sub-study of VERTIS CV (NCT01986881, study details see 14.2 ), a total of 330 patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease with inadequate glycemic control (HbA1c between 7% and 10.5%) with background therapy of metformin HCl ≥1,500 mg/day and a sulfonylurea (SU) were randomized to placebo, STEGLATRO 5 mg or STEGLATRO 15 mg orally once daily treatment. At Week 18, treatment with STEGLATRO at 5 mg or 15 mg daily provided statistically significant reductions in HbA1c compared to placebo (see Table 9 ). Table 9: Results at Week 18 from an Add-on Study of STEGLATRO in Combination with Metformin HCl and a SU in Patients with Type 2 Diabetes Mellitus N includes all randomized and treated patients with a baseline measurement of the outcome variable.

At Week 18, the primary HbA1c endpoint was missing for 9%, 8%, and 6% of patients and during the trial, rescue medication was initiated by 10%, 7%, and 3% of patients randomized to placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively. Results include measurements collected after initiation of rescue medication. Missing Week 18 measurements were imputed using multiple imputation with a mean equal to the baseline value of the patient (Return to Baseline analysis). Placebo STEGLATRO 5 mg STEGLATRO 15 mg SE: standard error HbA1c (%) N = 116 N = 99 N = 113 Baseline (mean) 8.3 8.4

Change from baseline (LS mean Intent-to-treat analysis using

ANCOVA adjusted for baseline value and baseline eGFR., SE) -0.3 -0.8 -

Difference from placebo (LS mean, 95% CI) -0.6 p<0.001 compared to placebo.

(-0.8, -0.3) -0.7 (-0.9, -0.4) Patients with HbA1c <7% Missing values imputed as not meeting the <7% criterion. 17 39 38 FPG (mg/dL) N = 117 N = 99 N = 113 Baseline (mean) 177.3 183.5

Change from baseline (LS mean, SE) -3.5 -31.3 -33.0 Difference from placebo

(LS mean, 95% CI) -27.9 (-37.8, -17.9) -29.5 (-39.0, -19.9) The mean baseline body weights were 90.5 kg, 92.1 kg, and 92.9 kg in the placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg groups, respectively. The mean changes from baseline to Week 18 were - 0.6 kg, -2.0 kg, and - 2.2 kg in the placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg groups, respectively. The differences from placebo (95% CI) for STEGLATRO 5 mg were - 1.4 kg (- 2.2, - 0.7) and for STEGLATRO 15 mg was - 1.6 kg (- 2.3, - 0.9). Use in Patients with Type 2 Diabetes Mellitus and Moderate Renal Impairment 26-Week Placebo-Controlled Study The efficacy of STEGLATRO was assessed in a multicenter, randomized, double-blind, placebo-controlled study (NCT01986855) of patients with type 2 diabetes mellitus and moderate renal impairment (468 patients with eGFR ≥30 to <60 mL/min/1.73 m 2 ). In this study, 202 patients exposed to STEGLATRO (5 mg or 15 mg) had an eGFR between 45 and 60 mL/min/1.73 m 2 and 111 patients exposed to STEGLATRO (5 mg or 15 mg orally once daily) had an eGFR between 30 and 45 mL/min/1.73 m 2. The mean duration of diabetes for the study population was approximately 14 years, and the majority of patients were receiving background insulin (55.9%) and/or sulfonylurea (40.3%) therapy.

Approximately 50% had a history of cardiovascular disease or heart failure. STEGLATRO did not show efficacy in this study. The HbA1c reductions from baseline to Week 26 were not significantly different between placebo and STEGLATRO 5 mg or 15 mg .

Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus and Established Cardiovascular

Disease The effect of STEGLATRO on cardiovascular risk in adult patients with type 2 diabetes and established atherosclerotic cardiovascular disease was evaluated in the VERTIS CV study (NCT01986881), a multicenter, multi-national, randomized, double-blind, placebo-controlled, event-driven trial. The study compared the risk of experiencing a major adverse cardiovascular event (MACE) between STEGLATRO and placebo when these were added to and used concomitantly with standard of care treatments for diabetes and atherosclerotic cardiovascular disease. A total of 8,246 patients were randomized to placebo (N=2,747), oral once daily STEGLATRO 5 mg (N=2,752) or oral once daily STEGLATRO 15 mg (N=2,747) and followed for a median of 3 years.

Approximately 88% of the study population was White, 6% Asian, and 3% Black or African American. The mean age was 64 years and approximately 70% were male. All patients in the study had inadequately controlled type 2 diabetes mellitus at baseline (HbA1c greater than or equal to 7%). The mean duration of type 2 diabetes mellitus was 13 years, the mean HbA1c at baseline was 8.2% and the mean eGFR was 76 mL/min/1.73 m 2. At baseline, patients were treated with one (32%) or more (67%) antidiabetic medications including biguanides (metformin HCl) (76%), insulin (47%), sulfonylureas (41%) DPP-4 inhibitors (11%) and GLP-1 receptor agonists (3%). Almost all patients (99%) had established atherosclerotic cardiovascular disease at baseline including: a documented history of coronary artery disease (76%), cerebrovascular disease (23%) or peripheral artery disease (19%). Approximately 24% patients had a history of heart failure (HF). At baseline, the mean systolic blood pressure was 133 mmHg, the mean diastolic blood pressure was 77 mmHg, the mean LDL was 89 mg/dL, and the mean HDL was 44 mg/dL. At baseline, approximately 81% of patients were treated with renin angiotensin system inhibitors, 69% with beta-blockers, 43% with diuretics, 82% with statins, 4% with ezetimibe, and 89% with antiplatelet agents.

The primary endpoint in VERTIS CV was the time to first occurrence of MACE. A major adverse cardiovascular event was defined as occurrence of either a cardiovascular death or a nonfatal myocardial infarction (MI) or a nonfatal stroke. The statistical analysis plan pre-specified that the 5 and 15 mg doses would be combined for the analysis. A Cox proportional hazards model was used to test for non-inferiority against the pre-specified risk margin of 1.3 for the hazard ratio of MACE. Type-1 error was controlled across multiple tests using a hierarchical testing strategy.

The incidence rate of MACE was similar between the STEGLATRO-treated and placebo-treated patients. The estimated hazard ratio of MACE associated with STEGLATRO relative to placebo was 0.97 with 95.6% confidence interval. The upper bound of this confidence interval excluded a risk larger than 1.3 ( Table 10 ). Results for the individual 5 mg and 15 mg doses were consistent with results for the combined dose group.

Table 10: Analysis of MACE and its Components from the VERTIS-CV Study Intent-to-treat analysis set. Endpoint MACE was evaluated in subjects who took at least one dose of study medication and, for subjects who discontinued study medication prior to the end of the study, censored events that occurred more than 365 days after the last dose of study medication. Other endpoints were evaluated using all randomized subjects and events that occurred any time after the first dose of study medication until the last contact date.

The total number of first events was analyzed for each endpoint. Placebo (N=2747) STEGLATRO (N=5499) Hazard Ratio vs Placebo (CI) HR and CI are based on Cox proportional hazards regression model, stratified by cohorts. For MACE a 95.6% CI is presented, for other endpoints a 95% CI is presented.

N (%) Event Rate (per 100 person-years) N (%) Event Rate (per 100 person-years) N=Number of patients, CI=Confidence interval, CV=Cardiovascular, MI=Myocardial infarction. MACE (CV death, non-fatal MI, or non-fatal stroke) Composite 327 4.0 653 3.9 0.97 Components of Composite Endpoint Non-fatal MI 148 1.6 310 1.7 1.04 Non-fatal Stroke 78 0.8 157 0.8 1.00 CV death 184 1.9 341 1.8 0.92

Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.

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