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Clinical utility in the treatment of type 2 diabetes with the saxagliptin/metformin fixed combination.

ABSTRACT: Fixed-dose combination (FDC) products represent a widely accepted approach to type 2 diabetes treatment, given that monotherapies sometimes fail to meet the treatment targets - obtaining a sustained reduction in micro- and macrovascular complications. Saxagliptin (SAXA)/metformin (MET) FDC tablets can be used either alone or in combination with glyburide, thiazolidinediones, or insulin. It has been proven that the SAXA/MET combination leads to a significant improvement in glycemic control compared to placebo in patients with type 2 diabetes that is inadequately controlled with MET alone. In addition, this FDC has been proven to be safe for people with diabetes mellitus and established cardiovascular disease, elderly patients, and patients with impaired renal function (>30 mL/minute), with dosage modification. Patient compliance, adherence, and persistence to the therapeutic regimen has been shown to be very good, while the titration of each compound according to the patient's profile is easy, given the availability of different formulations. The SAXA/MET FDC is a patient-friendly, dosage-flexible, and hypoglycemia-safe regimen with very few adverse events and a neutral or even favorable effect on body weight. It achieves significant glycosylated hemoglobin A1c reduction helping the patient to achieve his/her individual glycemic goals.

SUBMITTER: Panagoulias GS

PROVIDER: S-EPMC3931578 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Clinical utility in the treatment of type 2 diabetes with the saxagliptin/metformin fixed combination.

Panagoulias George S GS Doupis John J

Patient preference and adherence 20140215

Fixed-dose combination (FDC) products represent a widely accepted approach to type 2 diabetes treatment, given that monotherapies sometimes fail to meet the treatment targets - obtaining a sustained reduction in micro- and macrovascular complications. Saxagliptin (SAXA)/metformin (MET) FDC tablets can be used either alone or in combination with glyburide, thiazolidinediones, or insulin. It has been proven that the SAXA/MET combination leads to a significant improvement in glycemic control compar ...[more]

PMID: 24627627

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Project description:Metformin is recommended as a first-line therapy for patients with type 2 diabetes mellitus (T2DM). However, many patients do not achieve glycemic goals with metformin monotherapy and require subsequent combination therapy with other antihyperglycemic agents (AHAs). For newly diagnosed patients with high blood glucose, initial combination therapy may be required to achieve glycemic control. The American Association for Clinical Endocrinologists algorithm for the treatment of T2DM recommends metformin plus a sodium glucose co-transporter 2 (SGLT2) inhibitor as the first oral combination in patients who present with HbA1c ≥7.5%. Canagliflozin, an SGLT2 inhibitor, lowers the renal threshold for glucose and increases urinary glucose excretion leading to a mild osmotic diuresis and a net caloric loss. The effect of canagliflozin is insulin-independent and complementary to other AHAs, including metformin. A fixed-dose combination (FDC) of canagliflozin and metformin is also available with variable dosing, which may be attractive to some patients owing to the potential for reduced pill burden and costs. This article reviews the efficacy and safety of canagliflozin in combination with metformin based on data from the canagliflozin phase 3 clinical program. As initial combination therapy in drug-naïve patients or as dual therapy with metformin or triple therapy in combination with metformin and other AHAs, canagliflozin 100 and 300 mg improved glycemic control and provided reductions in body weight and systolic blood pressure that were sustained for up to 104 weeks. Canagliflozin was generally well tolerated across studies in combination with metformin. An increased incidence of adverse events (AEs) related to the mechanism of SGLT2 inhibition (i.e., genital mycotic infections, urinary tract infections, osmotic diuresis-related AEs) was observed with canagliflozin. Canagliflozin was associated with a low incidence of hypoglycemia when not used in conjunction with AHAs associated with hypoglycemia (i.e., insulin or sulfonylurea). Together, these results support the use of a canagliflozin and metformin FDC as a treatment approach for a broad range of patients with T2DM.FundingJanssen Scientific Affairs, LLC.

Project description:IntroductionType 2 diabetes mellitus (T2DM) is a complex disease in which multiple organs and hormones contribute to the pathogenesis of disease. The intestinal hormone, glucagon-like peptide-1 (GLP-1), secreted in response to nutrient ingestion, increases insulin secretion from pancreatic β-cells and reduces glucagon secretion from pancreatic α-cells. GLP-1 is inactivated by the dipeptidyl peptidase-4 (DPP-4) enzyme. Saxagliptin is a DPP-4 inhibitor that prevents the degradation of endogenous GLP-1 and prolongs its actions on insulin and glucagon secretion. This article reviews the efficacy and safety of saxagliptin in patients with T2DM.MethodsA PubMed literature search was conducted to identify relevant, peer-reviewed saxagliptin clinical trial articles published between January 2008 and June 2015. Search terms included "saxagliptin" and "DPP-4 inhibitors".ResultsIn clinical trials, saxagliptin significantly improved glycemic control when used as monotherapy or as add-on therapy to other antidiabetes agents and was associated with a low risk of hypoglycemia. In a large cardiovascular (CV) outcomes trial (SAVOR) in patients with T2DM and with established CV disease or multiple CV risk factors, saxagliptin neither increased nor decreased CV risk compared with placebo as assessed by the composite end point of death from CV causes, nonfatal myocardial infarction, or nonfatal stroke. Unexpectedly, more patients in the saxagliptin (3.5%) than in the placebo group (2.8%) were hospitalized for heart failure.ConclusionSaxagliptin demonstrated statistically significant and clinically meaningful improvements in glycemic control and a low risk of hypoglycemia in patients with T2DM. However, this positive profile needs to be tempered by the observation of an increased risk of hospitalization for heart failure in the SAVOR trial. Results from ongoing CV outcome trials with other DPP-4 inhibitors may provide additional data on how best to manage patients with T2DM who are at risk for heart failure.FundingAstraZeneca LP.

Project description:BackgroundTo compare the safety and efficacy of saxagliptin 2.5 mg twice daily (BID) versus placebo add-on therapy to metformin immediate release (IR) in patients with type 2 diabetes and inadequate glycemic control with metformin alone.MethodsThis multicenter, 12-week, double-blind, parallel-group trial enrolled adult outpatients with type 2 diabetes (glycated hemoglobin [HbA1c] 7.0%-10.0%) on stable metformin IR monotherapy (≥1500 mg, BID for ≥8 weeks). Patients were randomized to double-blind saxagliptin 2.5 mg BID or placebo added on to metformin IR following a 2-week, single-blind, placebo add-on therapy lead-in period. The primary end point was the change from baseline to week 12 in HbA1c. Key secondary end points included change from baseline to week 12 in fasting plasma glucose (FPG) and the proportion of patients achieving HbA1c <7.0% or HbA1c ≤ 6.5% at week 12. Efficacy was analyzed in all patients who received randomized study drug with ≥1 postbaseline assessment. Safety was assessed in all treated patients.ResultsIn total, 74 patients were randomized to double-blind saxagliptin add-on therapy and 86 to placebo add-on therapy. At week 12, least-squares mean changes (95% CI) from baseline HbA1c (adjusted for baseline HbA1c) were significantly greater (P = 0.006) in the saxagliptin + metformin group -0.56% (-0.74% to -0.38%) versus the placebo + metformin group -0.22% (-0.39% to -0.06%). Adjusted mean changes from baseline in FPG were numerically greater with saxagliptin versus placebo; the difference (95% CI) -9.5 mg/dL (-21.7 to 2.7) was not statistically significant (P = 0.12). A numerically greater proportion of patients in the saxagliptin group than the placebo group achieved HbA1c < 7.0% (37.5% vs 24.2%) or HbA1c ≤6.5% (24.6% vs 10.7%). There were no unexpected safety findings. Hypoglycemia occurred in 4 patients (5.4%) in the saxagliptin group and 1 patient (1.2%) in the placebo group; confirmed hypoglycemia (symptoms plus fingerstick glucose ≤50 mg/dL) occurred in 1 patient in the placebo group.ConclusionsAddition of saxagliptin 2.5 mg BID to metformin therapy in patients with type 2 diabetes and inadequate glycemic control on metformin monotherapy reduced HbA1c compared with placebo added to metformin, with an adverse events profile similar to placebo and no unexpected safety findings.Trial registrationClinicalTrials.gov NCT00885378.

Project description:AimsType 2 diabetes is associated with endothelial dysfunction leading to cardiovascular disease. CD34+ endothelial Progenitor Cells (EPCs) are responsible for endothelial repair and neo-angiogenesis and can be used as a cardiovascular disease risk biomarker. This study investigated whether the addition of saxagliptin, a DPP-IV inhibitor, to metformin, may reduce cardiovascular disease risk in addition to improving glycemic control in Type 2 diabetes patients.MethodsIn 12 week, double-blind, randomized placebo-controlled trial, 42 subjects already taking metformin 1-2 grams/day were randomized to placebo or saxagliptin 5 mg. Subjects aged 40-70 years with diabetes for < 10 years, with no known cardiovascular disease, BMI 25-39.9, HbA1C 6-9% were included. We evaluated EPCs number, function, surface markers and gene expression, in addition to arterial stiffness, blood biochemistries, resting energy expenditure, and body composition parameters. A mixed model regression to examine saxagliptin vs placebo, accounting for within-subject autocorrelation, was done with SAS (p < 0.05).ResultsAlthough there was no significant increase in CD34+ cell number, CD31+ cells percentage increased. Saxagliptin increased migration (in response to SDF1α) with a trend of higher colony formation count. MNCs cytometry showed higher percentage of CXCR4 double positivity for both CD34 and CD31 positive cells, indicating a functional improvement. Gene expression analysis showed an upregulation in CD34+ cells for antioxidant SOD1 (p < 0.05) and a downregulation in CD34- cells for IL-6 (p < 0.01). For arterial stiffness, both augmentation index and systolic blood pressure measures went down in saxagliptin subjects (p < 0.05).ConclusionSaxagliptin, in combination with metformin, can help improve endothelial dysfunction in early diabetes before macrovascular complications appear. Trial registration Trial is registered under clinicaltrials.gov, NCT02024477.

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Clinical utility in the treatment of type 2 diabetes with the saxagliptin/metformin fixed combination.

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Clinical utility in the treatment of type 2 diabetes with the saxagliptin/metformin fixed combination.

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