Emerging use of combination therapies for the management of type 2 diabetes - focus on saxagliptin and dapagliflozin.
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ABSTRACT:
SUBMITTER: Yu H
PROVIDER: S-EPMC5533573 | biostudies-literature | 2017
REPOSITORIES: biostudies-literature
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Emerging use of combination therapies for the management of type 2 diabetes - focus on saxagliptin and dapagliflozin.
Diabetes, metabolic syndrome and obesity : targets and therapy 20170721
<h4>Aims</h4>The aim of this article is to review the safety and efficacy data of dapagliflozin, saxagliptin, and their combination in the management of patients with type 2 diabetes. Evidence for the use of the single-tablet combination formulation is also presented.<h4>Methods</h4>A nonsystematic literature review was performed using the Ovid, PubMed, and Google Scholar databases.<h4>Results</h4>The addition of dapagliflozin/saxagliptin to metformin can lower mean hemoglobin A1c by as much as ...[more]
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Project description:ObjectiveTo compare the efficacy and safety of dapagliflozin and dapagliflozin plus saxagliptin vs glimepiride as add-on to metformin in patients with type 2 diabetes.Research design and methodsThis 52-week, multicentre, double-blind, active-controlled study (NCT02471404) randomized (1:1:1) patients (n = 939; HbA1c 7.5%-10.5%) on metformin monotherapy (≥1500 mg/day) to add-on dapagliflozin 10 mg, dapagliflozin 10 mg plus saxagliptin 5 mg, or glimepiride 1 to 6 mg (titrated). The primary efficacy end point was change in HbA1c from baseline to Week 52.ResultsBaseline mean age, diabetes duration and HbA1c were 58.4 years, 7.0 years and 8.3%, respectively. Adjusted mean HbA1c change from baseline was -1.20% with dapagliflozin plus saxagliptin and -0.82% with dapagliflozin, vs -0.99% with glimepiride (mean dose at Week 52, 4.6 mg). Changes in body weight (-3.2 kg and -3.5 kg vs +1.8 kg) and systolic blood pressure (SBP; -6.4 mm Hg and -5.6 mm Hg vs -1.6 mm Hg) were significantly greater with dapagliflozin plus saxagliptin and dapagliflozin than with glimepiride. FPG decreased significantly with dapagliflozin plus saxagliptin compared with glimepiride (-2.1 mmol/L vs -1.5 mmol/L) and was similar with dapagliflozin (-1.6 mmol/L) compared with glimepiride. Confirmed incidence of hypoglycaemia was lower with dapagliflozin regimens than with glimepiride (0 and 1 vs 13 patients) and fewer patients required rescue. Genital infections were more frequent with dapagliflozin; other AE profiles were similar.ConclusionsDapagliflozin, saxagliptin and metformin improved glycaemic control compared with glimepiride plus metformin; add-on of dapagliflozin alone showed efficacy similar to that of glimepiride. Both dapagliflozin regimens decreased body weight and SBP, with a lower incidence of hypoglycaemia compared with glimepiride.
| S-EPMC6220756 | biostudies-literature
Project description:Saxagliptin is a selective and potent dipeptidyl peptidase (DPP)-4 inhibitor, approved as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus (T2DM) in the USA on July 2009, and had been launched globally in over 86 countries by September 2013. In patients with T2DM, once-daily administration of saxagliptin before breakfast achieves sustained inhibition of plasma DPP-4 activity and reduction of postprandial hyperglycemia, including after dinner, associated with an increase in plasma glucagon-like peptide-1 levels. This paper reviews the safety and efficacy of saxagliptin in Japanese patients with T2DM. The clinical development study in Japan supported its usefulness for the disease. Saxagliptin 1, 2.5, and 5 mg led to significant improvements in glycated hemoglobin (HbA1c), and was generally well tolerated. Treatment with saxagliptin 5 mg induced a sustained reduction in HbA1c over 52 weeks. Long-term combination therapy with saxagliptin and other oral hypoglycemic agents also provided sustained glycemic control and was well tolerated for up to 52 weeks. Saxagliptin as add-on to sulfonylureas or glinides has a tendency to increase hypoglycemia, but not with other oral antidiabetic agents, such as α-glucosidase inhibitors, metformin, or thiazolidinediones. The results of clinical trials have confirmed the long-term efficacy and safety of saxagliptin monotherapy as well as its use as add-on combination therapy, and support its usefulness as a therapeutic agent for T2DM. Saxagliptin has less concern for hypoglycemia and weight gain, which often becomes problematic in routine care of T2DM. Meta-analysis of clinical trials in the USA showed no evidence of increased risk of cardiovascular events associated with saxagliptin, suggesting the superior of saxagliptin in terms of safety. Recently, investigators in the SAVOR-TIMI (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction) 53 study suggested that DPP-4 inhibition with saxagliptin did not increase or decrease the rate of ischemic events, although the rate of hospitalization for heart failure was increased. Although saxagliptin improves glycemic control, other approaches are necessary to reduce cardiovascular risk in patients with diabetes. Saxagliptin is applicable for various pathological conditions, and is considered to be clinically significant as a new therapeutic option for Japanese patients with T2DM.
| S-EPMC4103926 | biostudies-literature
Project description:ObjectiveTo examine the mechanisms responsible for improved glycemia with combined sodium-glucose cotransporter 2 inhibitor (SGLT2i) plus dipeptidyl peptidase 4 inhibitor therapy in type 2 diabetes.Research design and methodsFifty-six patients (HbA1c 8.9 ± 0.2% [74 ± 2 mmol/mol]) were randomized to dapagliflozin (DAPA) 10 mg, DAPA/saxagliptin (SAXA) 10/5 mg, or placebo (PCB) for 16 weeks. Basal endogenous glucose production (EGP) (3-3H-glucose), urinary glucose excretion, glucose/lipid oxidation, HbA1c, and substrate/hormone levels were determined before treatment (Pre-Tx) and after treatment (Post-Tx).ResultsAt week 16, HbA1c decrease was greater (P < 0.05) in DAPA/SAXA (-2.0 ± 0.3%) vs. DAPA (-1.4 ± 0.2%) and greater than PCB (0.2 ± 0.2%). Day 1 of drug administration, EGP (∼2.40 mg/kg/min) decreased by -0.44 ± 0.09 mg/kg/min in PCB (P < 0.05) but only by -0.21 ± 0.02 mg/kg/min in DAPA and DAPA/SAXA (P < 0.05 vs. PCB). At week 16, EGP increased to 2.67 ± 0.09 mg/kg/min (DAPA) and 2.61 ± 0.08 mg/kg/min (DAPA/SAXA), despite reductions in fasting plasma glucose by 47 and 77 mg/dL, respectively, and no changes in PCB. Baseline plasma free fatty acids rose by 40 µmol/L with DAPA but declined by -110 with PCB and -90 µmol/L with DAPA/SAXA (P < 0.05, Pre-Tx vs. Post-Tx). In DAPA, carbohydrate oxidation rates decreased from 1.1 ± 0.1 to 0.7 ± 0.1 mg/kg/min, whereas lipid oxidation rates increased from 0.6 ± 0.1 to 0.8 ± 0.1 mg/kg/min (P < 0.01). In DAPA/SAXA, the shift in carbohydrate (1.1 ± 0.1 to 0.9 ± 0.1 mg/kg/min) and lipid (0.6 ± 0.1 to 0.7 ± 0.1 mg/kg/min) oxidation was attenuated (P < 0.05).ConclusionsThe addition of SAXA to DAPA resulted in superior glycemic control compared with DAPA monotherapy partly because of increased glucose utilization and oxidation. Although the decrease in insulin/glucagon ratio was prevented by SAXA, EGP paradoxical elevation persisted, indicating that other factors mediate EGP changes in response to SGLT2i-induced glucosuria.
| S-EPMC7510028 | biostudies-literature
Project description:Saxagliptin (Onglyza™) is a potent, selective, once-daily dipeptidyl peptidase-4 (DPP-4) inhibitor indicated for improving glycemic control in patients with type 2 diabetes (T2D). By blocking DPP-4, saxagliptin increases and prolongs the effects of incretins, a group of peptide hormones released by intestinal cells after meals, which stimulate glucose-dependent insulin secretion to lower blood glucose. In controlled clinical trials, saxagliptin administered as monotherapy or in combination with metformin, glyburide, or a thiazolidinedione improved glycemic control in a clinically significant manner, reflected by significant decreases in glycated hemoglobin (monotherapy, -0.5%; add-on to metformin, thiazolidinedione, or sulfonylurea, -0.6% to 0.9%; initial combination with metformin, -2.5%), fasting plasma glucose, and postprandial glucose compared with controls. Additionally, saxagliptin improved ?-cell function, reflected as increases in homeostasis model assessment (HOMA)-2?. Saxagliptin was generally well tolerated; it did not increase hypoglycemia compared with controls, and was weight neutral. A meta-analysis of Phase II and III trials showed that saxagliptin did not increase the risk of major cardiovascular events. Professional organizations have updated their guidelines for T2D to include a DPP-4 inhibitor as an early treatment option-either as initial therapy in combination with metformin, or as add-on therapy for patients whose glycemia is inadequately controlled by a single oral antidiabetic drug.
| S-EPMC3047974 | biostudies-other
Project description:Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disorder, which affects more than 300 million people globally. The common effect of uncontrolled diabetes is the state of hyperglycemia, which results from beta-cell dysfunction as well as insulin resistance, which is accompanied with microvascular and macrovascular complications. As hyperglycemia defines diabetes, glycemic control is fundamental to the management of diabetes. Sodium glucose co-transporter 2 inhibitors (SGLT2) are a new group of oral antidiabetic medications that act by blocking the reabsorption of glucose, causing it to be excreted in the urine. Canagliflozin was the first SGLT2 inhibitor to be approved in the US by the Food and Drug Administration for the treatment and control of T2DM and on September 19, 2013, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Invokana(®). Canagliflozin is a SGLT2 inhibitor, which acts upon the proximal tubules of the kidneys and reduces the renal threshold for glucose. It is highly selective, binding 250 times more potently to SGLT2 than sodium glucose co-transporter 1 inhibitor. This action allows a higher amount of glucose to be excreted within the urine, causing the patient's plasma glucose level to be decreased and indirectly causing weight loss. Among the most common adverse events are hypoglycemia, headache, nausea, female genital and urinary tract infections, nasopharyngitis, and transient postural dizziness. Given its high efficacy in reducing hyperglycemia and good safety profile as either monotherapy or an add-on treatment to metformin, sulfonylureas, or insulin, canagliflozin seems to be a promising antihyperglycemic drug. Nevertheless, further large-scale and long-term studies should be conducted to evaluate the impact of canagliflozin on cardiovascular risk in T2DM patients.
| S-EPMC4149387 | biostudies-literature
Project description:In type 2 diabetes (T2D), early combination therapy using agents that target a number of the underlying pathophysiologic defects contributing to hyperglycemia may improve patient outcomes. For many patients, the combination of metformin with a sodium-glucose cotransporter-2 (SGLT-2) inhibitor may be a good option because these agents have complementary mechanisms of action, neutral-to-positive effects on body weight, and a low risk of hypoglycemia. This review focuses on the combination of metformin with dapagliflozin, a member of the SGLT-2 inhibitor class of antidiabetes agents. In clinical trials, the combination of dapagliflozin with metformin produced significant and sustained reductions in glycated hemoglobin and body weight in a broad range of adult patients with T2D, including those initiating pharmacotherapy and those with more advanced disease. These reductions were accompanied by modest decreases in blood pressure. Dapagliflozin as add-on therapy to metformin was well tolerated and associated with low rates of hypoglycemia. Genital infections and, in some studies, urinary tract infections were more frequent with dapagliflozin than with placebo. Early combination therapy with dapagliflozin and metformin may be a safe and appropriate treatment option that enables patients with T2D to achieve individualized glycemic goals as either initial combination therapy in treatment-naïve patients or as dapagliflozin add-on in patients inadequately controlled with metformin therapy.
| S-EPMC4801192 | biostudies-other
Project description:PurposeThe purpose of this review article is to provide guidance to health care providers regarding the use of dapagliflozin-metformin XR (extended release) as a therapeutic option for the treatment of patients with type 2 diabetes mellitus (T2DM).MethodsThe PubMed database was searched through August 2015 to identify clinical trials and meta-analyses evaluating the use of the sodium-glucose cotransporter type 2 inhibitor dapagliflozin administered as monotherapy or in combination with metformin.ResultsFourteen studies were included for this review, six of which evaluated dapagliflozin in combination with metformin, one of which evaluated dapagliflozin monotherapy, and four of which evaluated dapagliflozin as an add-on therapy to other antidiabetic agents. The combination of dapagliflozin and metformin resulted in an A1C decrease of up to 2%, weight loss of 2-3 kg, and modest systolic blood pressure decrease of 3-5 mmHg. However, long-term effects on cancer and cardiovascular health are still being investigated. Providing patients with a fixed-dose combination therapy such as dapagliflozin-metformin XR can increase medication adherence and patient satisfaction, and improve glycemic control. Dapagliflozin-metformin XR is ideal because it can be administered orally once a day, is associated with a low risk of hypoglycemia, and provides the added benefit of weight reduction and modest blood pressure lowering.ConclusionThe unique combined mechanism of action and favorable efficacy and safety profile of dapagliflozin-metformin XR support consideration of this fixed-dose combination as a treatment option for patients with T2DM.
| S-EPMC4770010 | biostudies-literature
Project description:AimTo assess the effects of dapagliflozin plus saxagliptin plus metformin versus glimepiride plus metformin on liver fat (proton density fat fraction) and visceral and subcutaneous adipose tissue volumes over 52 weeks of treatment.Materials and methodsThis was a magnetic resonance imaging substudy of a 52-week, multicentre, randomized, double-blind, parallel-group trial that evaluated the efficacy and safety of dapagliflozin 10 mg/day plus saxagliptin 5 mg/day versus titrated glimepiride 1-6 mg (1, 2, 3, 4 or 6 mg) in 82 patients with type 2 diabetes (HbA1c 7.5%-10.5%) on metformin ≥1500 mg/day background. Analyses were exploratory and not controlled for multiplicity; P-values are nominal.ResultsMagnetic resonance imaging was performed on 59 patients; liver fat and adipose tissue volumes were analysed for 59 and 57 patients, respectively. There was a significant >30% reduction from baseline in liver fat (P = 0.007) and >10% reduction in adipose tissue volumes (P < 0.01) with dapagliflozin plus saxagliptin plus metformin at week 52 versus glimepiride plus metformin. In the full-study population, dapagliflozin plus saxagliptin plus metformin decreased body weight and serum alanine aminotransferase and aspartate aminotransferase levels over 52 weeks.ConclusionsDapagliflozin plus saxagliptin significantly decreased liver fat and adipose tissue volume versus glimepiride, and reduced serum liver enzyme levels, indicating a favourable metabolic profile of dapagliflozin plus saxagliptin in patients with type 2 diabetes on metformin therapy.
| S-EPMC7318158 | biostudies-literature
Project description:The present study sought to evaluate the cost-effectiveness of first-line (immediate) versus delayed use of combination dapagliflozin and metformin in patients with type 2 diabetes, from the perspective of the Australian healthcare system. We developed a Markov model to simulate the progress of subjects with type 2 diabetes. Decision analysis was applied to assess the cost-effectiveness of first-line combination dapagliflozin and metformin versus first-line metformin monotherapy followed by gradual addition of dapagliflozin over time. Transition probabilities, costs (in Australian dollars) and utility data were derived from published sources. All costs, years of life lived and quality adjusted life years (QALYs) lived were discounted at an annual rate of 5%. Over a 20-year model period, first-line use of combination dapagliflozin and metformin was predicted to reduce the onset of hospitalisation of heart failure, cardiovascular deaths and all cause deaths by 5.5%, 57.6% and 29.6%, respectively. An additional 2.5 years of life (discounted) and 1.9 QALYs (discounted) would be gained per patient, at a cost of AUD $23,367 (discounted) per person. These figures equated to AUD $9,535 per years of life saved (YoLS) and AUD $12,477 per QALYs saved. Sensitivity analyses indicated the results to be robust. Compared to first-line metformin monotherapy followed by gradual addition of dapagliflozin, first-line use of combination dapagliflozin and metformin is likely to be a cost-effective approach to the management of Australians with type 2 diabetes mellitus.
| S-EPMC6397228 | biostudies-literature
Project description: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.
| S-EPMC3931578 | biostudies-literature