Efficacy and Safety of Ertugliflozin in Patients With Type 2 Diabetes Mellitus and Established Cardiovascular Disease Using Insulin

Abstract Introduction: Ertugliflozin (ERTU), a sodium-glucose cotransporter 2 inhibitor, is approved as an adjunct to diet and exercise to improve glycemic control in patients (pts) with type 2 diabetes mellitus (T2DM). Aim: As part of the VERTIS CV trial (NCT01986881), the efficacy and safety of ERTU were assessed in pts with T2DM and established atherosclerotic cardiovascular disease (ASCVD) inadequately controlled by insulin. Methods: Pts were randomly assigned to placebo (PBO), ERTU 5 mg or 15 mg once daily. A pre-specified sub-study was conducted in pts on a stable dose of insulin ≥20 units/day (± metformin). The primary endpoint was HbA1c change from baseline at 18 weeks. Key secondary endpoints included proportion of patients achieving HbA1c <7%, fasting plasma glucose (FPG), body weight (BW), and systolic blood pressure (SBP). Changes from baseline at Week 18 for continuous efficacy endpoints were assessed using a constrained longitudinal data analysis model. HbA1c reduction was also assessed in subgroups based on baseline HbA1c, age, sex, race, ethnicity, and use of metformin. Results: Of 8246 pts randomized in VERTIS CV, 1065 pts (ERTU 5 mg: 348; ERTU 15 mg: 370; PBO: 347) with T2DM and ASCVD were included in the sub-study. Mean baseline characteristics were similar across treatment groups; age 64.8 years, T2DM duration 16.7 years, HbA1c 8.4%, and eGFR 73.7 mL/min/1.73 m2. At baseline, 40.6% of pts were on insulin alone, 59.4% were receiving insulin + metformin; median (range) insulin dose was 58.0 (20–350) units/day. At Week 18, least squares mean change (95% confidence interval) from baseline in HbA1c was significantly greater with ERTU 5 mg and 15 mg vs PBO. PBO-adjusted differences were −0.6% (−0.7, −0.4) and −0.7% (−0.8, −0.5), for ERTU 5 mg and 15 mg, respectively (P<0.001 for both). HbA1c reductions were greater with ERTU vs PBO for all subgroups including by use of metformin. At Week 18, 10.7%, 20.7%, and 21.1% of pts with PBO, ERTU 5 mg and 15 mg, respectively, achieved HbA1c <7.0%. ERTU 5 mg and 15 mg significantly reduced FPG, BW, SBP, and ERTU 15 mg led to a small reduction in total daily insulin dose. The overall incidence of adverse events and serious adverse events was similar across treatment groups. In women, the incidences of genital mycotic infections was higher with ERTU 5 mg (3.4%; P=0.05) and ERTU 15 mg (3.6%; P=0.04) vs PBO (0.0%). The incidences of urinary tract infections (3.2–4.1%), symptomatic hypoglycemia (26.4–28.5%), and severe hypoglycemia (3.5–5.1%) were similar across treatment groups. The incidences of hypovolemia were low (1.4–2.4%) and similar across treatment groups. Conclusion: ERTU added to insulin (± metformin) led to greater reductions from baseline in HbA1c, FPG, BW, and SBP, and a higher proportion of pts achieving HbA1c <7.0%, vs PBO at 18 weeks in pts with T2DM and ASCVD, without increasing the risk of hypoglycemia.

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Efficacy and Safety of Ertugliflozin in Patients With Type 2 Diabetes Mellitus and Established Cardiovascular Disease Treated With Metformin and Sulfonylurea

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.676 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A331-A331

Author(s):

Matthew J Budoff ◽

Timothy M E Davis ◽

Alexandra G Palmer ◽

Robert Frederich ◽

David E Lawrence ◽

...

Keyword(s):

Diabetes Mellitus ◽

Blood Pressure ◽

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Type 2 Diabetes Mellitus ◽

Body Weight ◽

Glycemic Control ◽

Sglt2 Inhibitor ◽

Efficacy And Safety

Abstract Introduction: Ertugliflozin (ERTU), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is approved as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus (T2DM). Aim: As a pre-specified sub-study of the Phase 3 VERTIS CV trial (NCT01986881), the efficacy and safety of ERTU were assessed in patients with T2DM and established atherosclerotic cardiovascular disease (ASCVD) inadequately controlled with metformin and sulfonylurea (SU). Methods: Patients with T2DM, established ASCVD, and HbA1c 7.0–10.5% on stable metformin (≥1500 mg/day) and SU doses as defined per protocol were randomized to once-daily ERTU (5 mg or 15 mg) or placebo. The primary sub-study objectives were to assess the effect of ERTU on HbA1c compared with placebo and to evaluate safety and tolerability during 18-week follow-up. Key secondary endpoints included proportion of patients achieving HbA1c <7%, fasting plasma glucose (FPG), body weight, and systolic blood pressure. Changes from baseline at Week 18 for continuous efficacy endpoints were assessed using a constrained longitudinal data analysis model. Results: Of the 8246 patients enrolled in the VERTIS CV trial, 330 patients were eligible for this sub-study (ERTU 5 mg, n=100; ERTU 15 mg, n=113; placebo, n=117). Patients had a mean (SD) age of 63.2 (8.4) years, T2DM duration 11.4 (7.4) years, estimated glomerular filtration rate 83.5 (17.8) mL/min/1.73 m2, and HbA1c 8.3% (1.0) (67.4 [10.6] mmol/mol). At Week 18, ERTU 5 mg and 15 mg were each associated with a significantly greater least squares mean (95% CI) HbA1c reduction from baseline versus placebo; the placebo-adjusted differences for ERTU 5 mg and 15 mg were –0.7% (–0.9, –0.4) and –0.8% (–1.0, –0.5), respectively (P<0.001). A higher proportion of patients in each ERTU group achieved HbA1c <7% relative to placebo (P<0.001). ERTU significantly reduced FPG and body weight (P<0.001, for each dose versus placebo), but not systolic blood pressure. Adverse events were reported in 48.0%, 54.9%, and 47.0% of patients in the ERTU 5 mg, 15 mg, and placebo groups, respectively. Genital mycotic infections were experienced by significantly higher proportions of male patients who received ERTU 5 mg and 15 mg (4.2% and 4.8%, respectively) versus placebo (0.0%; P≤0.05) and by a numerically, but not significantly, higher proportion of female patients who received ERTU 15 mg (10.3%) compared with placebo (3.8%) (P=0.36). The incidences of symptomatic hypoglycemia were 11.0% (5 mg), 12.4% (15 mg), and 7.7% (placebo), and of severe hypoglycemia 2.0% (5 mg), 1.8% (15 mg), and 0.9% (placebo). Conclusion: Among patients with T2DM and ASCVD, ERTU (5 mg and 15 mg) added to metformin and SU for 18 weeks improved glycemic control (HbA1c and FPG) and reduced body weight, and was generally well tolerated with a safety profile consistent with the SGLT2 inhibitor class.

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Efficacy and Safety of Imarikiren in Patients with Type 2 Diabetes and Microalbuminuria

Clinical Journal of the American Society of Nephrology ◽

10.2215/cjn.07720618 ◽

2019 ◽

Vol 14 (3) ◽

pp. 354-363 ◽

Cited By ~ 1

Author(s):

Sadayoshi Ito ◽

Tomoya Kagawa ◽

Takuya Saiki ◽

Kohei Shimizu ◽

Shingo Kuroda ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Adverse Events ◽

Candesartan Cilexetil ◽

Creatinine Ratio ◽

Efficacy And Safety ◽

Urine Albumin ◽

End Of Treatment

Background and objectivesImarikiren is a novel, potent, and selective direct renin inhibitor that has shown high oral availability during clinical development for the treatment of diabetic nephropathy. We evaluated the efficacy and safety of imarikiren in patients with type 2 diabetes mellitus and microalbuminuria.Design, setting, participants, & measurementsThis was a randomized, multicenter, placebo-controlled, double-blind, phase 2, dose-finding trial. A total of 415 patients were randomized to imarikiren 5, 20, 40, or 80 mg; placebo; or candesartan cilexetil 8 mg treatment for 12 weeks. The primary end point was change in log-transformed urine albumin-to-creatinine ratio from baseline to the end of treatment analyzed using analysis of covariance and a fixed sequence testing procedure. Secondary efficacy end points included urine albumin-to-creatinine ratio at each assessment point and remission and progression rates. Exploratory efficacy end points included eGFR and sitting BP before dosing.ResultsChanges in the urine albumin-to-creatinine ratio from baseline to the end of treatment were 16% (placebo), −16% (imarikiren 5 mg), −27% (imarikiren 20 mg), −38% (imarikiren 40 mg), −39% (imarikiren 80 mg), and −31% (candesartan cilexetil 8 mg). Urine albumin-to-creatinine ratio reductions from baseline were statistically significant in all imarikiren groups versus placebo (P<0.001 each) as well as for candesartan cilexetil 8 mg versus placebo (P<0.001). Remission rates (urine albumin-to-creatinine ratio <30 mg/g creatinine and decreased ≥30% from baseline) were higher in all imarikiren groups versus the placebo group. Incidence of adverse events was higher in the imarikiren 80-mg group (52%) versus placebo (42%) and candesartan cilexetil (43%) groups. Incidence of adverse events for the other imarikiren groups ranged from 33% to 42%. Adverse events were mild or moderate in severity. All imarikiren doses were well tolerated.ConclusionsImarikiren resulted in a dose-dependent improvement in albuminuria compared with placebo, and it was well tolerated in patients with type 2 diabetes mellitus and microalbuminuria.

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Efficacy and safety of GP40021 insulin lispro biphasic compared with Humalog Mix 25 in Type 2 diabetes mellitus patients

Journal of Comparative Effectiveness Research ◽

10.2217/cer-2020-0064 ◽

2020 ◽

Author(s):

Alexandr Y Mayorov ◽

Anna A Mosikian ◽

Diana N Alpenidze ◽

Igor E Makarenko ◽

Valeria L Orlova ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Immune Response ◽

Type 2 Diabetes Mellitus ◽

Insulin Dose ◽

Efficacy And Safety ◽

Open Label ◽

The Difference ◽

Noninferiority Margin

Aim: To compare safety (immunogenicity) and efficacy of a biosimilar insulin GP-Lis25 and a reference insulin Ly-Lis25 (Humalog Mix 25) in Type 2 diabetes mellitus (T2D) patients. Materials & methods: This randomized open-label, 26-week clinical trial enrolled 210 T2D patients, randomized 1:1 to twice-daily GP-Lis25 or Ly-Lis25. The primary end point was immune response at 26th week. Noninferiority margin for HbA1c was 0.4%. Results: Immune response frequency was similar in GP-Lis25 and Ly-Lis25 groups both at week 12 (p = 0.651) and 26 (p = 0.164). The difference of HbA1c change at week 26 was (95% CI) 0.01 (-0.27–0.28)%. Fasting plasma glucose, seven-point glucose profile and insulin dose were similar between groups. Safety did not differ between groups. Conclusion: GP-Lis25 and Ly-Lis25 demonstrated similar safety and efficacy. ClincalTrials.gov identifier: NCT04023344 .

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