Postprandial Dynamics of Plasma Glucose, Insulin, and Glucagon in Patients with Type 2 Diabetes Treated with Saxagliptin Plus Dapagliflozin Add-On to Metformin Therapy

Hansen, Lars; Iqbal, Nayyar; Ekholm, Ella; Cook, William J.; Hirshberg, Boaz

doi:10.4158/ep14489.or

Cited by 60 publications

(50 citation statements)

References 21 publications

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“…Changes in plasma insulin and glucose but not glucagon AUC0-180 min correlated with change in HbA1c [26].…”

Section: Pharmacodynamicsmentioning

confidence: 95%

“…A study analyzed changes in plasma glucose, insulin, and glucagon in relation to glycaemic response after a liquid meal tolerance test during treatment with dual add-on of saxagliptin plus dapagliflozin to metformin extended release compared with saxagliptin addon or dapagliflozin add-on alone in patients with T2D poorly controlled with metformin [26].…”

Section: Pharmacodynamicsmentioning

confidence: 99%

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DPP-4 inhibitor plus SGLT-2 inhibitor as combination therapy for type 2 diabetes: from rationale to clinical aspects

Scheen

2016

Expert Opinion on Drug Metabolism & Toxicology

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SUMMARYIntroduction : Type 2 diabetes (T2D) is a complex disease with multiple defects, which generally require a combination of several pharmacological approaches to control hyperglycemia. Combining a dipeptidyl peptidase-4 inhibitor (DPP-4i) and a sodium-glucose cotransporter type 2 inhibitor (SGT2i) appears to be an attractive approach.Area covered: An extensive literature search was performed to analyze the pharmacokinetics, pharmacodynamics and clinical experience of different gliptin-gliflozin combinations.Expert opinion: There is a strong rationale for combining a DPP-4i and a SGLT2i in patients with T2D because the two drugs exert different and complementary glucose-lowering effects.Dual therapy (initial combination or stepwise approach) is more potent than either monotherapy in patients treated with diet and exercise or already treated with metformin.Combining the two pharmacological options is safe and does not induce hypoglycemia. The additional glucose-lowering effect is more marked when a gliflozin is added to a gliptin than when a gliptin is added to a gliflozin. Two fixed-dose combinations (FDCs) are already available (saxagliptin-dapagliflozin and linagliptin-empagliflozin) and others are in current development. Bioequivalence of the two compounds given as FDC tablets was demonstrated when compared with coadministration of the individual tablets. FDCs could simplify the antihyperglycaemic therapy and improve drug compliance. Article highlights box -Type 2 diabetes (T2D) often requires the combination of several medications with complementary actions to reach glucose control targets while limiting side effects -The combination of a dipeptidyl peptidase-4 inhibitor (DPP-4i) and a sodium-glucose cotransporter type 2 inhibitor (SGLT2i) is an attractive approach for the management of T2D. Keywords-Both saxagliptin plus dapagliflozin and linagliptin plus empagliflozin combined therapies have been tested as separate tablets (no clinically relevant pharmacokinetic drug-drug interactions) and as fixed-dose combination (FDC : bioequivalence studies).-DPP-4i -SGLT2i combined therapies are more efficacious than either monotherapy to control blood glucose, without worsening of the safety profile.-Initial DPP-4i -SGLT2i combination may be considered or one compound may the added to the other. However, which one should be used in first place remains an open question.

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“…Changes in plasma insulin and glucose but not glucagon AUC0-180 min correlated with change in HbA1c [26].…”

Section: Pharmacodynamicsmentioning

confidence: 95%

Section: Pharmacodynamicsmentioning

confidence: 99%

DPP-4 inhibitor plus SGLT-2 inhibitor as combination therapy for type 2 diabetes: from rationale to clinical aspects

Scheen

2016

Expert Opinion on Drug Metabolism & Toxicology

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“…The combination of dapagliflozin plus saxagliptin provided additional reductions in glucose AUC 0-180 min and HbA1c, without the increase in plasma insulin seen with saxagliptin alone and without the increase in plasma glucagon seen with dapagliflozin alone [46] . The absence of plasma insulin increase with the addition of saxagliptin may probably be explained by the concomitant reduction in hyperglycaemia, mainly due to the amount of glucose lost in the urine.…”

Section: Clinical Efficacymentioning

confidence: 98%

“…Changes in plasma glucose, insulin, and glucagon in relation to glycaemic response after a liquid meal tolerance test were analyzed during treatment with dual add-on of dapagliflozin plus saxagliptin to metformin extended release compared with dapagliflozin add-on alone or saxagliptin add-on alone in patients with T2D poorly controlled with metformin [46] . The combination of dapagliflozin plus saxagliptin provided additional reductions in glucose AUC 0-180 min and HbA1c, without the increase in plasma insulin seen with saxagliptin alone and without the increase in plasma glucagon seen with dapagliflozin alone [46] .…”

Section: Clinical Efficacymentioning

confidence: 99%

Pharmacokinetic Characteristics and Clinical Efficacy of an SGLT2 Inhibitor Plus DPP-4 Inhibitor Combination Therapy in Type 2 Diabetes

Scheen

2016

Clin Pharmacokinet

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SUMMARYType 2 diabetes (T2D) generally requires a combination of several pharmacological approaches to control hyperglycaemia. Combining a sodium-glucose cotransporter type 2 inhibitor (SGLT2i, known as gliflozin) and a dipeptidyl peptidase-4 inhibitor known as gliptin) appears to be an attractive strategy because of complementary modes of action.This narrative review analyzes the pharmacokinetics and clinical efficacy of different combined therapies with a SGLT2i (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, tofogliflozin) and a DPP-4i (linagliptin, saxagliptin, sitagliptin, teneligliptin). Drug-drug pharmacokinetic interaction studies do not show any significant changes in peak concentrations (C max ) and total exposure (area under the curve of plasma concentrations or AUC) of either drug when they were given orally together compared to corresponding values when each of them was absorbed alone. Some fixed-dose combinations (FDC) are already available (dapagliflozin-saxagliptin, empagliflozin-linagliptin) or in development (ertugliflozin-sitagliptin), and preliminary results showed bioequivalence of the two medications given as FDC tablets when compared with co-administration of the individual tablets. Dual therapy is more potent than either monotherapy in patients treated with diet and exercise or already treated with metformin. SGLT2i and DPP-4i could be used as initial combination or in a stepwise approach. The additional glucose-lowering effect appears to be more marked when a gliflozin is added to a gliptin than when a gliptin is added to a gliflozin. Combining the two pharmacological options is safe and does not induce hypoglycaemia. Key-words : Combined therapy -DPP-4 inhibitor -Fixed-dose combination -SGLT2 inhibitor -Type 2 diabetesKey points -The combination of a sodium-glucose cotransporter type 2 inhibitor (SGLT2i), which promotes glycosuria and improves glucose tolerance independently of insulin, and a dipeptidyl peptidase-4 inhibitor (DPP-4i), an incretin-based therapy that corrects islet dysfunction, is an attractive approach for the management of type 2 diabetes.-Both dapagliflozin plus saxagliptin and empagliflozin plus linagliptin combined therapies have been tested as separate tablets (no clinically relevant pharmacokinetic drug-drug interactions) and as fixed-dose combination (FDC: bioequivalence studies); such combined therapies are more efficacious than either monotherapy to control blood glucose, without worsening of the safety profile.-Other combinations of a SGLT2i and a DPP-4i have been evaluated in studies that also showed the absence of drug-drug pharmacokinetic interactions and better glucose control compared to either therapy alone. An ertugliflozin-sitagliptin FDC is in current development.-Initial SGLT2i -DPP-4i combination may be considered or one medication may be added to the other, with apparently better results when the SGLT2i was added to the DPP-4i compared with the reverse sequence. However, which glucose-lowering agent sh...

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“…Another study showed that saxagliptin reduced the mealinduced increase in glucagon levels obtained by the sodiumglucose transport protein-2 inhibitor dapagliflozin [61]. In contrast, DPP-4 inhibition seems to have no effect on glucagon levels either in healthy individuals with a mean FPG of approximately 4.5 mmol/l [45] or in individuals with IFG and a mean FPG of approximately 6.0 mmol/l [31].…”

Section: Effects On Alpha Cellsmentioning

confidence: 99%

Improved glucose regulation in type 2 diabetic patients with DPP-4 inhibitors: focus on alpha and beta cell function and lipid metabolism

Åhrén

Foley²

2016

Diabetologia

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Inhibition of dipeptidyl peptidase-4 (DPP-4) is an established glucose-lowering strategy for the management of type 2 diabetes mellitus. DPP-4 inhibitors reduce both fasting and postprandial plasma glucose levels, resulting in reduced HbA 1c with low risk for hypoglycaemia and weight gain. They act primarily by preventing inactivation of the incretin hormones glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, thereby prolonging the enhanced endogenous levels of these hormones after meal ingestion. This in turn causes islet and extrapancreatic effects, including increased glucose sensing in islet alpha and beta cells. These effects result in increased insulin secretion and decreased glucagon secretion being more effective in hyperglycaemic states and reduced insulin secretion and increased glucagon secretion being more effective during hypoglycaemia. Other secondary pharmacological actions of DPP-4 inhibitors include mobilisation and burning of fat during meals, decrease in fat extraction from the gut, reduction of fasting lipolysis and liver fat and increase in LDL particle size. These actions contribute to the clinical effects of DPP-4 inhibition, and the reduced demand for insulin could also lead to a durability benefit. This review summarises the current knowledge of the secondary pharmacological actions of DPP-4 inhibitors that lead to improved glucose regulation in patients with type 2 diabetes, focusing on alpha and beta cell function and lipid metabolism.

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Postprandial Dynamics of Plasma Glucose, Insulin, and Glucagon in Patients with Type 2 Diabetes Treated with Saxagliptin Plus Dapagliflozin Add-On to Metformin Therapy

Cited by 60 publications

References 21 publications

DPP-4 inhibitor plus SGLT-2 inhibitor as combination therapy for type 2 diabetes: from rationale to clinical aspects

DPP-4 inhibitor plus SGLT-2 inhibitor as combination therapy for type 2 diabetes: from rationale to clinical aspects

Pharmacokinetic Characteristics and Clinical Efficacy of an SGLT2 Inhibitor Plus DPP-4 Inhibitor Combination Therapy in Type 2 Diabetes

Improved glucose regulation in type 2 diabetic patients with DPP-4 inhibitors: focus on alpha and beta cell function and lipid metabolism

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