Sodium-glucose cotransporter 2 inhibitors combined with dipeptidyl peptidase-4 inhibitors in the management of type 2 diabetes: a review of current clinical evidence and rationale.

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metformin 20 endocrinologydiseasesdrugs
sitagliptin 7 endocrinologydiseasesdrugs
type 1 diabetes mellitus 1 endocrinologydiseases
dapagliflozin 35 endocrinologydiseasesdrugs
hypoglycemia 10 endocrinologydiseases
hyperglycemia 2 endocrinologydiseases
type 2 diabetes mellitus 1 endocrinologydiseases
diabetes mellitus 4 endocrinologydiseases
diabetic ketoacidosis 1 endocrinologydiseases

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dapagliflozin 7467 SGLT2 inhibitor to receive US regulatory approval for use in T2DM, and was followed by US approvals for dapagliflozin and empagliflozin in 2014.[35] Canagliflozin, dapagliflozin, and empagliflozin are based on a C-glucoside
dapagliflozin 7527 T2DM, and was followed by US approvals for dapagliflozin and empagliflozin in 2014.[35] Canagliflozin, dapagliflozin , and empagliflozin are based on a C-glucoside structure (not shown),[36] and have comparable pharmacokinetic
dapagliflozin 9566 (4/5,337), 0.11% (6/5,350), and 0.03% (2/6,909) for 100 mg, 300 mg, and comparator, respectively;[63] dapagliflozin events were <0.1% in >18,000 patients (no further details stated);[64] and DKA events with empagliflozin
dapagliflozin 10287 inhibitors and SGLT2 inhibitors are currently approved in the treatment of T2DM: fixed-dose formulations of dapagliflozin plus saxagliptin (approved by the European Medicines Agency [EMA] in July 2016), and empagliflozin plus
dapagliflozin 11439 duration; post hoc analyses were excluded.In a 24-week, randomized, placebo-controlled study (N=432) of dapagliflozin (10 mg/day) or placebo added to sitagliptin (100 mg/day), given with/without metformin (≥1,500 mg/day),[68]
dapagliflozin 11563 mg/day) or placebo added to sitagliptin (100 mg/day), given with/without metformin (≥1,500 mg/day),[68] dapagliflozin significantly reduced mean HbA1c vs placebo (placebo-corrected change from baseline to week 24: −0.5%;
dapagliflozin 11923 baseline to week 24: −0.8%; 95% CI −1.1, −0.6; P<0.0001).[68] A similar trend was observed for dapagliflozin vs placebo, respectively, for fasting plasma glucose (FPG) (−24.1 vs +3.8 mg/dL) and body weight (−2.1
dapagliflozin 12337 were low.[68] A similar number of patients in both groups reported hypoglycemic events at week 24 ( dapagliflozin : 6/225, 2.7%; placebo 4/226, 1.8%), and none of these events led to treatment discontinuation.[68] At
dapagliflozin 12561 the rate of UTI was balanced between groups (~4%–5%), but genital infection was more common with dapagliflozin vs placebo (8.4% vs 0.4%, respectively), and one patient (dapagliflozin group) discontinued treatment
dapagliflozin 12633 infection was more common with dapagliflozin vs placebo (8.4% vs 0.4%, respectively), and one patient ( dapagliflozin group) discontinued treatment due to vulvovaginal mycotic infection.[68] Both UTI and genital infection
dapagliflozin 12946 the 24-week extension period (ie, at week 48), and occurred in low numbers in both treatment groups ( dapagliflozin : 3/225, 1.3%; placebo 2/226, 0.9%).[68]In a randomized, placebo-controlled study where dapagliflozin
dapagliflozin 13047 (dapagliflozin: 3/225, 1.3%; placebo 2/226, 0.9%).[68]In a randomized, placebo-controlled study where dapagliflozin (10 mg/day) was added to saxagliptin (5 mg/day) – that is, as dual add-on therapy vs each agent administered
dapagliflozin 13301 background of metformin therapy (extended-release formulation, 1,500–2,000 mg/day), patients receiving dapagliflozin plus saxagliptin demonstrated greater improvements in glycemic control (ie, HbA1c and FPG) at week 24
dapagliflozin 13445 greater improvements in glycemic control (ie, HbA1c and FPG) at week 24 than those receiving either dapagliflozin or saxagliptin (Table 5).[69] Furthermore, 41% of patients achieved HbA1c <7% with dapagliflozin plus
dapagliflozin 13542 either dapagliflozin or saxagliptin (Table 5).[69] Furthermore, 41% of patients achieved HbA1c <7% with dapagliflozin plus saxagliptin vs 18% and 22% with saxagliptin or dapagliflozin, respectively.[69] As noted in a separate
dapagliflozin 13608 patients achieved HbA1c <7% with dapagliflozin plus saxagliptin vs 18% and 22% with saxagliptin or dapagliflozin , respectively.[69] As noted in a separate report of these study data by Abdul-Ghani,[6] when patients
dapagliflozin 13891 patients with baseline HbA1c ≥9% (n=190; mean HbA1c ~10%), the mean change in HbA1c was similar for the dapagliflozin plus saxagliptin group and the dapagliflozin group (−2.03% and −1.87%, respectively), whereas the
dapagliflozin 13936 HbA1c ~10%), the mean change in HbA1c was similar for the dapagliflozin plus saxagliptin group and the dapagliflozin group (−2.03% and −1.87%, respectively), whereas the contribution of saxagliptin was lower (−1.32%).[6],[69]
dapagliflozin 14177 higher baseline HbA1c levels were associated with proportionally larger changes in HbA1c following dapagliflozin therapy (eg, increasing baseline mean HbA1c from ~7.5% to ~10% was associated with the following changes
dapagliflozin 14323 mean HbA1c from ~7.5% to ~10% was associated with the following changes in HbA1c at treatment end: dapagliflozin group, −0.45% vs −1.87% [greater than fourfold change]; dapagliflozin plus saxagliptin group, −0.80%
dapagliflozin 14397 in HbA1c at treatment end: dapagliflozin group, −0.45% vs −1.87% [greater than fourfold change]; dapagliflozin plus saxagliptin group, −0.80% vs −2.03% [greater than twofold change]; saxagliptin group, −0.69%
dapagliflozin 14632 than twofold change]).[6],[69] Mean reductions in systolic BP and body weight only occurred in the dapagliflozin plus saxagliptin group and the dapagliflozin group (systolic BP: reductions of 1.9 and 3.5 mmHg, respectively;
dapagliflozin 14677 reductions in systolic BP and body weight only occurred in the dapagliflozin plus saxagliptin group and the dapagliflozin group (systolic BP: reductions of 1.9 and 3.5 mmHg, respectively; and body weight: reductions of 2.1
dapagliflozin 15276 group, and there were no major hypoglycemic events.[69] UTI occurred in ≤1% of patients receiving dapagliflozin plus saxagliptin vs in 5% of patients receiving dapagliflozin or saxagliptin. However, genital infection
dapagliflozin 15338 occurred in ≤1% of patients receiving dapagliflozin plus saxagliptin vs in 5% of patients receiving dapagliflozin or saxagliptin. However, genital infection events were more common in the dapagliflozin group (6%) vs
dapagliflozin 15426 patients receiving dapagliflozin or saxagliptin. However, genital infection events were more common in the dapagliflozin group (6%) vs the saxagliptin group (0.6%) and, interestingly, were not reported in the dapagliflozin
dapagliflozin 15528 dapagliflozin group (6%) vs the saxagliptin group (0.6%) and, interestingly, were not reported in the dapagliflozin plus saxagliptin group (0%).[69]Two further RCTs investigated the triple combination therapy of dapagliflozin
dapagliflozin 15638 dapagliflozin plus saxagliptin group (0%).[69]Two further RCTs investigated the triple combination therapy of dapagliflozin plus saxagliptin plus metformin. In the first study, patients (N=320) received open-label treatment
dapagliflozin 15962 being randomized to a 24-week, double-blind treatment period and receive additional treatment with dapagliflozin (10 mg/day) or placebo.[70] The second study (N=315) followed a similar design and drug dosing, but
dapagliflozin 16115 study (N=315) followed a similar design and drug dosing, but with saxagliptin (or placebo) added to dapagliflozin and metformin.[71] The results from both studies showed a comparable trend to those reported above in
dapagliflozin 16338 dual add-on study, with greater reductions in HbA1c and FPG at week 24 occurring in patients receiving dapagliflozin plus saxagliptin plus metformin (Table 5).[70],[71] Adverse events occurred with a similar frequency
dapagliflozin 16673 add-on to saxagliptin and metformin study, genital infections occurred in 5.0% of patients receiving dapagliflozin vs 0.6% of those receiving placebo,[70] whereas in the add-on to dapagliflozin and metformin study,
dapagliflozin 16752 of patients receiving dapagliflozin vs 0.6% of those receiving placebo,[70] whereas in the add-on to dapagliflozin and metformin study, the proportions were 0% for saxagliptin vs 2.5% for placebo.[71]An RCT evaluated
dapagliflozin 38834 mg/dL where stated (mmol/L value × 18.0182 = mg/dL value).Abbreviations: CANA, canagliflozin; DAPA, dapagliflozin ; EMPA, empagliflozin; FPG, fasting plasma glucose; HbA1c, glycated hemoglobin; PBO, placebo; SBP, systolic
dapagliflozin 43715 single dosage form (ie, single pill containing DPP-4 inhibitor and SGLT2 inhibitor).Abbreviations: DAPA, dapagliflozin ; DPP-4, dipeptidyl pepti dase-4; EMPA, empagliflozin; FPG, fasting plasma glucose; HbA1c, glycated hemoglobin;
metformin 11530 (N=432) of dapagliflozin (10 mg/day) or placebo added to sitagliptin (100 mg/day), given with/without metformin (≥1,500 mg/day),[68] dapagliflozin significantly reduced mean HbA1c vs placebo (placebo-corrected
metformin 13210 – that is, as dual add-on therapy vs each agent administered alone (N=534), all on a background of metformin therapy (extended-release formulation, 1,500–2,000 mg/day), patients receiving dapagliflozin plus
metformin 14934 reduction in either parameter in the saxagliptin group.[69] Thus, an SGLT2 inhibitor given as an add-on to metformin or in combination with saxagliptin plus metformin appears to contribute to both body weight and BP-lowering
metformin 14984 group.[69] Thus, an SGLT2 inhibitor given as an add-on to metformin or in combination with saxagliptin plus metformin appears to contribute to both body weight and BP-lowering potential. The proportion of adverse events
metformin 15674 (0%).[69]Two further RCTs investigated the triple combination therapy of dapagliflozin plus saxagliptin plus metformin . In the first study, patients (N=320) received open-label treatment with saxagliptin (5 mg/day) and
metformin 15784 In the first study, patients (N=320) received open-label treatment with saxagliptin (5 mg/day) and metformin (immediate-release formulation, ≥1,500 mg/day) for 16 weeks before being randomized to a 24-week,
metformin 16133 followed a similar design and drug dosing, but with saxagliptin (or placebo) added to dapagliflozin and metformin .[71] The results from both studies showed a comparable trend to those reported above in the dual add-on
metformin 16374 reductions in HbA1c and FPG at week 24 occurring in patients receiving dapagliflozin plus saxagliptin plus metformin (Table 5).[70],[71] Adverse events occurred with a similar frequency across the treatment groups in
metformin 16598 and the overall risk of hypoglycemia was low (0%–2.5%).[70],[71] In the add-on to saxagliptin and metformin study, genital infections occurred in 5.0% of patients receiving dapagliflozin vs 0.6% of those receiving
metformin 16770 receiving dapagliflozin vs 0.6% of those receiving placebo,[70] whereas in the add-on to dapagliflozin and metformin study, the proportions were 0% for saxagliptin vs 2.5% for placebo.[71]An RCT evaluated single-pill
metformin 17055 weeks, with data reported for treatment-naïve patients,[72] and for those inadequately controlled on metformin .[73] Treatment-naïve patients (N=667) were randomized into five treatment groups (where all study drugs
metformin 19671 10 mg) discontinued study drug as a result of these events.[72]Patients inadequately controlled on metformin (≥1,500 mg/day, maximum tolerated dose, or maximum dose per local label; N=674) were also randomized
metformin 22500 studies.[74],[75] One study (N=333) evaluated empagliflozin vs placebo as add-on therapy to linagliptin and metformin ,[74] and the second study (N=709) evaluated linagliptin vs placebo as add-on therapy to empagliflozin
metformin 22616 and the second study (N=709) evaluated linagliptin vs placebo as add-on therapy to empagliflozin and metformin .[75] Empagliflozin/linagliptin combination therapy (plus metformin) produced greater reductions in HbA1c
metformin 22683 add-on therapy to empagliflozin and metformin.[75] Empagliflozin/linagliptin combination therapy (plus metformin ) produced greater reductions in HbA1c and FPG from baseline than that observed with either linagliptin
metformin 22815 reductions in HbA1c and FPG from baseline than that observed with either linagliptin plus placebo (plus metformin ) or empagliflozin plus placebo (plus metformin).[74],[75] Adverse events were more common in the placebo
metformin 22862 observed with either linagliptin plus placebo (plus metformin) or empagliflozin plus placebo (plus metformin ).[74],[75] Adverse events were more common in the placebo groups in both studies, and the incidence
metformin 23601 consistent with genital infection were reported in more patients receiving empagliflozin plus placebo (plus metformin ) than those receiving combination therapy (plus metformin); 8.0% and 3.1% for empagliflozin 25 and 10
metformin 23659 receiving empagliflozin plus placebo (plus metformin) than those receiving combination therapy (plus metformin ); 8.0% and 3.1% for empagliflozin 25 and 10 mg, respectively, plus placebo, vs 2.7% and 2.4% for combination
metformin 43901 plasma glucose; HbA1c, glycated hemoglobin; IR, immediate release (formulation); LINA, linagliptin; MET, metformin ; MTD, maximum tolerated dose; PBO, placebo; SAXA, saxagliptin; SBP, systolic blood pressure; SITA, sitagliptin;
sitagliptin 4736 concentration.[11] DPP-4 inhibitors first gained US regulatory approval for use in T2DM in 2006, with sitagliptin as the first-in-class.[12] Other US-approved DPP-4 inhibitors are saxagliptin, linagliptin, and alogliptin,
sitagliptin 6196 Postmarketing cardiovascular outcomes trials in patients receiving saxagliptin,[28] alogliptin,[29] and sitagliptin [30] produced conflicting results regarding the risk of hospitalization for heart failure associated
sitagliptin 10736 studies between SGLT2 inhibitors and other glucose-lowering agents, including the DPP-4 inhibitors sitagliptin and linagliptin, did not demonstrate any significant changes in exposure following coadministration,
sitagliptin 11485 24-week, randomized, placebo-controlled study (N=432) of dapagliflozin (10 mg/day) or placebo added to sitagliptin (100 mg/day), given with/without metformin (≥1,500 mg/day),[68] dapagliflozin significantly reduced
sitagliptin 34371 gastrointestinal; HbA1c, glycated hemoglobin; LINA, linagliptin; PBO, placebo; SAXA, saxagliptin; SITA, sitagliptin .Table 3Summary of pharmacokinetic characteristics of SGLT2 inhibitors (US-approved)ParametersCanagliflozin[38],[41]Dapagliflozin[39],[42]Empagliflozin[40],[43]Recommended
sitagliptin 39016 hemoglobin; PBO, placebo; SBP, systolic blood pressure; SGLT2, sodium-glucose cotransporter 2; SITA, sitagliptin ; T2DM, type 2 diabetes mellitus.Table 5Summary of efficacy and safety data from published Phase III
sitagliptin 44010 metformin; MTD, maximum tolerated dose; PBO, placebo; SAXA, saxagliptin; SBP, systolic blood pressure; SITA, sitagliptin ; SGLT2, sodium-glucose cotransporter 2; XR, extended release (formulation)
Select Disease Character Offset Disease Term Instance
diabetes mellitus 430 Hyattsville, MD, USAPublication date (collection): /2017Publication date (epub): 3/2017AbstractType 2 diabetes mellitus (T2DM) is a progressive and multifactorial cardiometabolic disorder. Almost half of adults with diabetes
diabetes mellitus 1273 inhibitors, and considers the possible role of such dual therapy in the management of T2DM.IntroductionType 2 diabetes mellitus (T2DM) is a progressive, multifactorial metabolic and cardiovascular disorder characterized by multiple
diabetes mellitus 9307 euglycemic.[58]–[60] Other cases of DKA were associated with off-label use of SGLT2 inhibitors in patients with type 1 diabetes mellitus .[58],[61],[62] SGLT2 inhibitor clinical trials reported low frequencies of DKA in T2DM: canagliflozin
diabetes mellitus 39042 SBP, systolic blood pressure; SGLT2, sodium-glucose cotransporter 2; SITA, sitagliptin; T2DM, type 2 diabetes mellitus .Table 5Summary of efficacy and safety data from published Phase III clinical trials (≥24 weeks) using
diabetic ketoacidosis 9054 susceptible patients.[41]–[43] More recently, postmarketing cases of urosepsis and pyelonephritis, and diabetic ketoacidosis (DKA) associated with SGLT2 inhibitor therapy have been reported.[57] Some cases of DKA in T2DM patients
hyperglycemia 2670 the current standards of care for diabetes, but the guidance is directed at those with more severe hyperglycemia .[5] The American Diabetes Association/European Association for the Study of Diabetes recommend that
hyperglycemia 7191 inhibitors suppress renal glucose reabsorption and promote urinary glucose excretion (UGE), which decreases hyperglycemia .[33] SGLT2 inhibitors act independently of pancreatic β-cell function and the degree of insulin resistance.[33],[34]
hypoglycemia 5279 T2DM when given as monotherapy or in combination therapy, with no increased risk of weight gain or hypoglycemia [13] (when used without insulin secretagogues or insulin).[16]–[19] DPP-4 inhibitor monotherapy reduced
hypoglycemia 8549 generally favorable safety profile.[45]–[47] These agents are not associated with an increased risk of hypoglycemia , unless combined with insulin secretagogues or insulin.[45]–[47] However, SGLT2 inhibitors are associated
hypoglycemia 16522 occurred with a similar frequency across the treatment groups in both studies, and the overall risk of hypoglycemia was low (0%–2.5%).[70],[71] In the add-on to saxagliptin and metformin study, genital infections occurred
hypoglycemia 18590 events were reported in the two empagliflozin/linagliptin single-pill combination groups; however, hypoglycemia was reported in one subject in each of the empagliflozin 25-mg and linagliptin 5-mg groups, and in four
hypoglycemia 21034 overall proportion and intensity of adverse events were similar for all treatment groups. Confirmed hypoglycemia event rates were low (1.4%–3.6%); no patients discontinued treatment due to hypoglycemia.[73] UTI
hypoglycemia 21125 Confirmed hypoglycemia event rates were low (1.4%–3.6%); no patients discontinued treatment due to hypoglycemia .[73] UTI events were reported in 9.6%–10.2% of patients receiving empagliflozin/linagliptin single-pill
hypoglycemia 27668 adverse effects from the component drugs.[5] Medication-related body weight gain and increased risk of hypoglycemia are particularly important to patients with T2DM,[83],[84] and may affect subsequent adherence to treatment.[83]
hypoglycemia 28004 weight,[45]–[47] and neither of these drug classes is associated with a significantly increased risk of hypoglycemia (unless coadministered with insulin secretagogues, eg, sulfonylureas or insulin).[12],[45]–[47] Therefore,
hypoglycemia 31306 tolerability of this combination, in particular the absence of body weight gain and the low risk of hypoglycemia , may add to its potential viability as an option for early treatment intensification in T2DM.Table 1Summary
hypoglycemia 34044 studies.bUnits converted from mmol/L to mg/dL where stated (mmol/L value × 18.0182 = mg/dL value).cConfirmed hypoglycemia .dReported as “rare (1.5%–3.0%); no hypoglycemic event was considered an AE, or was severe enough
type 1 diabetes mellitus 9300 euglycemic.[58]–[60] Other cases of DKA were associated with off-label use of SGLT2 inhibitors in patients with type 1 diabetes mellitus .[58],[61],[62] SGLT2 inhibitor clinical trials reported low frequencies of DKA in T2DM: canagliflozin
type 2 diabetes mellitus 39035 placebo; SBP, systolic blood pressure; SGLT2, sodium-glucose cotransporter 2; SITA, sitagliptin; T2DM, type 2 diabetes mellitus .Table 5Summary of efficacy and safety data from published Phase III clinical trials (≥24 weeks) using

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