Efficacy and safety of initial combination therapy with alogliptin plus metformin versus either as monotherapy in drug‐naïve patients with type 2 diabetes: a randomized, double‐blind, 6‐month study

Pratley, Richard E.; Fleck, Penny; Wilson, Craig

doi:10.1111/dom.12258

Cited by 49 publications

(62 citation statements)

References 22 publications

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“…Of note, subadditive HbA 1c lowering was observed with the combinations of SGLT2 inhibitors and dipeptidyl peptidase 4 inhibitors (i.e., dapagliflozin/ saxagliptin, empagliflozin/linagliptin), even though dipeptidyl peptidase 4 inhibition might be expected to attenuate SGLT2 inhibition-mediated glucagon increases, thereby preventing endogenous glucose production (EGP) (27,29). Less than additive HbA 1c -lowering effects were also observed in the current study with the CANA/MET combinations and have been observed in studies of other combination treatments (27)(28)(29)(30)(31)(32)(33)(34)(35), with few exceptions (36), even when the individual agents have complementary mechanisms. The less than additive efficacy commonly observed with combination treatments may be at least partly due to a "floor effect," as the efficacy of each individual agent depends on baseline HbA 1c .…”

Section: Discussionsupporting

confidence: 44%

Initial Combination Therapy With Canagliflozin Plus Metformin Versus Each Component as Monotherapy for Drug-Naïve Type 2 Diabetes

et al. 2016

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OBJECTIVE This study assessed the efficacy/safety of canagliflozin (CANA), a sodium–glucose cotransporter 2 (SGLT2) inhibitor, plus metformin extended-release (MET) initial therapy in drug-naïve type 2 diabetes. RESEARCH DESIGN AND METHODS This 26-week, double-blind, phase 3 study randomized 1,186 patients to CANA 100 mg (CANA100)/MET, CANA 300 mg (CANA300)/MET, CANA100, CANA300, or MET. Primary end point was change in HbA1c at week 26 for combinations versus monotherapies. Secondary end points included noninferiority in HbA1c lowering with CANA monotherapy versus MET; changes in fasting plasma glucose, body weight, and blood pressure; and proportion of patients achieving HbA1c <7.0% (<53 mmol/mol). RESULTS From mean baseline HbA1c of 8.8% (73 mmol/mol), CANA100/MET and CANA300/MET significantly lowered HbA1c versus MET (median dose, 2,000 mg/day) by –1.77%, –1.78%, and –1.30% (–19.3, –19.5, and –14.2 mmol/mol; differences of −0.46% and –0.48% [–5.0 and –5.2 mmol/mol]; P = 0.001) and versus CANA100 and CANA300 by –1.37% and –1.42% (–15.0 and –15.5 mmol/mol; differences of –0.40% and –0.36% [–4.4 and –3.9 mmol/mol]; P = 0.001). CANA100 and CANA300 monotherapy met noninferiority for HbA1c lowering and had significantly more weight loss versus MET (–2.8, –3.7, and –1.9 kg [–3.0%, –3.9%, and –2.1%]; P = 0.016 and P = 0.002). Greater attainment of HbA1c <7.0% (50%, 57%, and 43%) and significantly more weight loss (–3.2, –3.9, and –1.9 kg [–3.5%, –4.2%, and –2.1%]; P = 0.001) occurred with CANA100/MET and CANA300/MET versus MET. The incidence of adverse events (AEs) related to SGLT2 inhibition (genital mycotic infections, osmotic diuresis– and volume depletion–related AEs) was higher in the CANA arms (0.4–4.4%) versus MET (0–0.8%). AE-related discontinuation rates were 1.3–3.0% across groups. The incidence of hypoglycemia was 3.0–5.5% in the CANA arms and 4.6% with MET. CONCLUSIONS Initial therapy with CANA plus MET was more effective and generally well tolerated versus each monotherapy in drug-naïve type 2 diabetes. CANA monotherapy demonstrated noninferior HbA1c lowering versus MET.

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Section: Discussionsupporting

confidence: 44%

Initial Combination Therapy With Canagliflozin Plus Metformin Versus Each Component as Monotherapy for Drug-Naïve Type 2 Diabetes

et al. 2016

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“…52 The mean HbA 1C reduction from baseline (8.45%) was À1.22% and À1.55% for alogliptin 12.5 mg twice daily plus metformin 500 mg or 1000 twice daily groups versus À0.56%, À0.65%, and À1.11% for alogliptin 12.5 mg, metformin 500 mg and 1000 mg twice daily groups, respectively (P < 0.001). FPG reduction was À1.76 and À2.55 mmol/L for alogliptin 12.5 mg twice daily plus metformin 500 mg or 1000 twice daily groups versus À0.54, À0.64 and À1.78 mmol/L for alogliptin 12.5 mg, metformin 500 mg and 1000 mg twice daily groups, respectively (P < 0.05).…”

Section: Combination Therapymentioning

confidence: 92%

“…FPG reduction was À1.76 and À2.55 mmol/L for alogliptin 12.5 mg twice daily plus metformin 500 mg or 1000 twice daily groups versus À0.54, À0.64 and À1.78 mmol/L for alogliptin 12.5 mg, metformin 500 mg and 1000 mg twice daily groups, respectively (P < 0.05). 52 Alogliptin plus metformin caused only mild to moderate hypoglycaemia (1.9-5.3%) and weight loss (0.6-1.2 kg). These data demonstrate that alogliptin plus metformin initial combination therapy was more efficacious in controlling glycaemia in drug-na€ ıve T2DM patients than either as monotherapy and well tolerated.…”

Section: Combination Therapymentioning

confidence: 93%

“…For detailed clinical pharmacology of alogliptin, please read recent reviews about this drug. 38,[41][42][43][44][45][46][47][48][49] Alogliptin as monotherapy or added to metformin, [50][51][52] pioglitazone, [53][54][55][56] glipizide, 57,58 glyburide/glibenclamide, 59 voglibose, [60][61][62] miglitol, 62 acarbose, 63 or insulin 64,65 significantly improves glycaemic control compared with placebo or active comparators in adult or elderly patients with inadequately controlled T2DM. This is associated with good gastrointestinal tolerability and a low incidence of hypoglycaemia.…”

Section: Dpp-4 Inhibitors In Diabetes Treatmentmentioning

confidence: 99%

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Clinical pharmacology of dipeptidyl peptidase 4 inhibitors indicated for the treatment of type 2 diabetes mellitus

Chen

Zhou

et al. 2015

Clin Exp Pharma Physio

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SUMMARYDipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral antidiabetic drugs that improve glycaemic control without causing weight gain or increasing hypoglycaemic risk in patients with type 2 diabetes mellitus (T2DM). The eight available DPP-4 inhibitors, including alogliptin, anagliptin, gemigliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin, and vildagliptin, are small molecules used orally with identical mechanism of action and similar safety profiles in patients with T2DM. DPP-4 inhibitors may be used as monotherapy or in double or triple combination with other oral glucoselowering agents such as metformin, thiazolidinediones, or sulfonylureas. Although DPP-4 inhibitors have the same mode of action, they differ by some important pharmacokinetic and pharmacodynamic properties that may be clinically relevant in some patients. The main differences between the eight gliptins include: potency, target selectivity, oral bioavailability, elimination half-life, binding to plasma proteins, metabolic pathways, formation of active metabolite(s), main excretion routes, dosage adjustment for renal and liver insufficiency, and potential drug-drug interactions. The off-target inhibition of selective DPP-4 inhibitors is responsible for multiorgan toxicities such as immune dysfunction, impaired healing, and skin reactions. As a drug class, the DPP-4 inhibitors have become accepted in clinical practice due to their excellent tolerability profile, with a low risk of hypoglycaemia, a neutral effect on body weight, and once-daily dosing. It is unknown if DPP-4 inhibitors can prevent disease progression. More clinical studies are needed to validate the optimal regimens of DPP-4 inhibitors for the management of T2DM when their potential toxicities are closely monitored.

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“…However, some studies have shown weight loss in patients with type 2 diabetes mellitus who received alogliptin [128,129]. A meta-analysis of randomized, doubleblind, controlled trials conducted by Berhan and Berhan [130] showed that the effect of alogliptin on body weight change was not conclusive and needs further investigation.…”

Section: Cardioprotective Effects Referencesmentioning

confidence: 99%

Incretin-based therapies for obesity treatment

Mello¹,

Prá²,

Cardoso³

et al. 2015

Metabolism

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Efficacy and safety of initial combination therapy with alogliptin plus metformin versus either as monotherapy in drug‐naïve patients with type 2 diabetes: a randomized, double‐blind, 6‐month study

Abstract: Alogliptin plus metformin initial combination therapy was well tolerated yet more efficacious in controlling glycaemia in drug-naïve T2DM patients than either as monotherapy.

Cited by 49 publications

References 22 publications

Initial Combination Therapy With Canagliflozin Plus Metformin Versus Each Component as Monotherapy for Drug-Naïve Type 2 Diabetes

Initial Combination Therapy With Canagliflozin Plus Metformin Versus Each Component as Monotherapy for Drug-Naïve Type 2 Diabetes

Clinical pharmacology of dipeptidyl peptidase 4 inhibitors indicated for the treatment of type 2 diabetes mellitus

Incretin-based therapies for obesity treatment

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