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    Reduction in HbA1c with SGLT2 inhibitors vs. DPP-4 inhibitors as add-ons to metformin monotherapy according to baseline HbA1c: A systematic review of randomized controlled trials. Scheen A J Diabetes & metabolism AIMS:This study compared the reduction of glycated haemoglobin (HbA1c) with sodium-glucose cotransporter type-2 inhibitors (SGLT2is) vs. dipeptidyl peptidase-4 inhibitors (DPP-4is) as add-ons to metformin in patients with type 2 diabetes mellitus (T2DM), with a specific focus on HbA1c changes according to baseline HbA1c. MATERIALS AND METHODS:Electronic databases were scrutinized for randomized controlled trials (RCTs) evaluating the reduction of HbA1c from baseline (Δ HbA1c) with an SGLT2i or DPP-4i in patients with T2DM not well controlled by metformin monotherapy. The endpoint was Δ HbA1c using both indirect and direct comparisons. RESULTS:Overall, Δ HbA1c was slightly greater with SGLT2is (-0.80±0.20% from 8.03±0.35%; 44 analyses, 29 RCTs, 15 with two doses, n=9321) than with DPP-4is (-0.71±0.23% from 8.05±0.43%; 61 analyses, 59 RCTs, n=17,914; P=0.0354). When the mean baseline HbA1c was<8% ([64mmol/mol] 7.79±0.15% vs. 7.71±0.23%), Δ HbA1c averaged -0.735±0.17% vs. -0.62±0.16% (P=0.0117) with SGLT2is vs. DPP-4is, respectively. However, this difference vanished when the mean baseline HbA1c was≥8% (-0.87±0.22% from 8.27±0.32% with SGLT2is vs. -0.80±0.24% from 8.35±0.33% with DPP-4is; P=0.2756). The relationship between Δ HbA1c and baseline HbA1c was only slightly stronger with SGLT2is (slope: -0.39, r=-0.43; P<0.0001) than with DPP-4is (slope: -0.26, r=-0.25; P<0.0001). CONCLUSION:Because of the small difference in Δ HbA1c whatever the baseline HbA1c level with SGLT2is vs. DPP-4is as add-ons to metformin, choosing between these glucose-lowering agents in clinical practice should be based on other efficacy criteria (such as weight and blood pressure changes, cardiovascular and renal protection) or on safety profiles rather than on HbA1c levels. 10.1016/j.diabet.2020.01.002
    Comparison of tofogliflozin versus glimepiride as the third oral agent added to metformin plus a dipeptidyl peptidase-4 inhibitor in Japanese patients with type 2 diabetes: A randomized, 24-week, open-label, controlled trial (STOP-OB). Kitazawa Toru,Seino Hiroaki,Ohashi Hiroshi,Inazawa Takeshi,Inoue Masahiro,Ai Masumi,Fujishiro Midori,Kuroda Hisamoto,Yamada Masayo,Anai Motonobu,Ishihara Hisamitsu Diabetes, obesity & metabolism Metformin plus a dipeptidyl peptidase-4 inhibitor (DPP-4i) is the most common therapy for Japanese patients with type 2 diabetes. This 24-week, multicentre, open-label, parallel-group trial randomized patients on dual therapy to add-on tofogliflozin (20 mg/day, n = 33) or glimepiride (0.5 mg/day, n = 31). The primary outcome was change in body fat percentage. The secondary outcomes included changes in HbA1c, fat mass, fat-free mass, liver function variables and uric acid. Tofogliflozin and glimepiride reduced HbA1c to a similar extent. Body fat percentage did not change from baseline in either group. Fat mass was reduced by tofogliflozin but was increased by glimepiride (by -2.0 ± 1.7 kg and +1.6 ± 1.6 kg, P = .002). Fat-free mass was also reduced by tofogliflozin and increased by glimepiride (by -1.3 ± 1.3 kg and +0.9 ± 2.0 kg, P < .001). Alanine aminotransferase and uric acid levels were reduced by tofogliflozin (P = .006 and P < .001, respectively). These data provide novel information useful for selecting the third oral agent for patients whose diabetes is inadequately controlled with metformin plus DPP-4i dual therapy. 10.1111/dom.14059
    Add-on therapy in metformin-treated patients with type 2 diabetes at moderate cardiovascular risk: a nationwide study. Thein David,Christiansen Mia Nielsen,Mogensen Ulrik Madvig,Bundgaard Johan Skov,Rørth Rasmus,Madelaire Christian,Fosbøl Emil Loldrup,Schou Morten,Torp-Pedersen Christian,Gislason Gunnar,Køber Lars,Kristensen Søren Lund Cardiovascular diabetology BACKGROUND:In randomised clinical trials, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter 2 (SGLT-2) inhibitors reduced cardiovascular events in patients with type 2 diabetes (T2D) at high cardiovascular risk, as compared to standard care. However, data comparing these agents in patients with T2D who are at moderate risk is sparse. METHODS:From Danish national registries, we included patients with T2D previously on metformin monotherapy, who started an additional glucose-lowering agent [GLP-1 RA, SGLT-2 inhibitor, dipeptidyl peptidase-4 (DPP-4) inhibitor, sulfonylurea (SU), or insulin] in the period 2010-2016. Patients with a history of cardiovascular events [heart failure (HF), myocardial infarction (MI) or stroke] were excluded. Patients were followed for up to 2 years. Cause-specific adjusted Cox regression models were used to compare the risk of hospitalisation for HF, a composite endpoint of major adverse cardiovascular events (MACE) (MI, stroke or cardiovascular death), and all-cause mortality for each add-on therapy. Patients who initiated DPP-4 inhibitors were used as reference. RESULTS:The study included 46,986 T2D patients with a median age of 61 years and of which 59% were male. The median duration of metformin monotherapy prior to study inclusion was 5.3 years. Add-on therapy was distributed as follows: 13,148 (28%) GLP-1 RAs, 2343 (5%) SGLT-2 inhibitors, 15,426 (33%) DPP-4 inhibitors, 8917 (19%) SUs, and 7152 (15%) insulin. During follow-up, 623 (1.3%, range 0.8-2.1%) patients were hospitalised for HF-hazard ratios (HR) were 1.11 (95% CI 0.89-1.39) for GLP-1 RA, 0.84 (0.52-1.36) for SGLT-2 inhibitors, 0.98 (0.77-1.26) for SU and 1.54 (1.25-1.91) for insulin. The composite MACE endpoint occurred in 1196 (2.5%, range 1.5-3.6%) patients, yielding HRs of 0.82 (0.69-0.97) for GLP-1 RAs, 0.79 (0.56-1.12) for SGLT-2 inhibitors, 1.22 (1.03-1.49) for SU and 1.23 (1.07-1.47) for insulin. 1865 (3.9%, range 1.9-9.0%) died from any cause during follow-up. HRs for all-cause mortality were 0.91 (0.78-1.05) for GLP-1 RAs, 0.79 (0.58-1.07) for SGLT-2 inhibitors, 1.13 (0.99-1.31) for SU and 2.33 (2.08-2.61) for insulin. CONCLUSION:In a nationwide cohort of metformin-treated T2D patients and no history of cardiovascular events, the addition of either GLP-1 RA or SGLT-2 inhibitor to metformin treatment was associated with a similar risk of hospitalisation for HF and death, and a lower risk of MACE for GLP-1 RA when compared with add-on DPP-4 inhibitors. By contrast, initiation of treatment with SU and insulin were associated with a higher risk of MACE. Additionally, insulin was associated with an increased risk of all-cause mortality and hospitalisation for HF. 10.1186/s12933-020-01078-5
    Randomized clinical trial comparing the efficacy and safety of treatment with the once-weekly dipeptidyl peptidase-4 (DPP-4) inhibitor omarigliptin or the once-daily DPP-4 inhibitor sitagliptin in patients with type 2 diabetes inadequately controlled on metformin monotherapy. Goldenberg Ronald,Gantz Ira,Andryuk Paula J,O'Neill Edward A,Kaufman Keith D,Lai Eseng,Wang Yin Na,Suryawanshi Shailaja,Engel Samuel S Diabetes, obesity & metabolism AIM:To compare the efficacy and safety of the once-weekly oral dipeptidyl peptidase-4 (DPP-4) inhibitor omarigliptin or once-daily DPP-4 inhibitor sitagliptin in patients with type 2 diabetes (T2DM) and inadequate glycaemic control on metformin. MATERIALS AND METHODS:Patients with T2DM with a glycated haemoglobin (HbA1c) concentration ≥6.5% to ≤9.0% while on a stable dose of metformin (≥1500 mg/d) were randomized in a double-blind manner to receive omarigliptin 25 mg once weekly (n = 322) or sitagliptin 100 mg once daily (n = 320). The primary analysis assessed whether omarigliptin was non-inferior to sitagliptin in reducing HbA1c at week 24, based on the criterion of having an upper bound of the 95% confidence interval (CI) about the difference less than the non-inferiority bound of 0.3%. RESULTS:The mean baseline HbA1c was 7.5% in both groups. After 24 weeks, the least squares (LS) mean change in HbA1c from baseline was -0.47% in the omarigliptin group and -0.43% in the sitagliptin group, with a between-group difference of -0.03% (95% CI -0.15, 0.08). This result met the prespecified criterion for declaring non-inferiority. The LS mean change from baseline in fasting plasma glucose and the percentage of patients with HbA1c <7.0% or <6.5% at week 24 were similar in the two treatment groups. There were no notable differences in adverse events and the incidence of symptomatic hypoglycaemia was low and similar in the groups. CONCLUSIONS:In patients with T2DM and inadequate glycaemic control on metformin, the addition of omarigliptin 25 mg once weekly or sitagliptin 100 mg once daily led to similar improvements in glycaemic control. Both agents were generally well tolerated with a low incidence of hypoglycaemia. 10.1111/dom.12832
    Glycemic Improvement with a Fixed-dose combination of DPP-4 inhibitor + metformin in patients with Type 2 diabetes (GIFT study). Bajaj Harpreet S,Ye Chenglin,Jain Esha,Venn Karri,Stein Eden,Aronson Ronnie Diabetes, obesity & metabolism This study investigates changes in A1C following a switch from dual therapy of metformin and DPP-4 inhibitor to a fixed-dose combination (FDC) of metformin + DPP-4 inhibitor following the introduction of the FDC in the provincial formulary. The LMC Diabetes Registry was queried retrospectively for patients with type 2 diabetes, aged between 18 and 80 years with at least one A1C recorded prior and ≥3 months post-switch. Five hundred and sixty-eight subjects with mean age 64 ± 12 years and mean A1C 7.7% ± 1.2% met study criteria. Overall, A1C was 0.3% lower post-switch to FDC (P < .01). In stratified analysis, subjects with baseline A1C between 7% and 10% had 0.4% lower A1C (P < .01), with 31% of these subjects reaching target A1C ≤7%, post-switch. A1C reduction was greater among patients with a higher baseline pill burden: 0.4% among those using ≥10 pills/day vs. 0.1% for those with <10 pills/day (P = .02). In this real-world study, switching to FDC of metformin + DPP-4 inhibitor was associated with a significant improvement in A1C. Switching to FDC, especially in patients with high pill burden, can improve A1C goal achievement in clinical practice. 10.1111/dom.13040
    Cost-effectiveness analysis of metformin+dipeptidyl peptidase-4 inhibitors compared to metformin+sulfonylureas for treatment of type 2 diabetes. Kwon Christina S,Seoane-Vazquez Enrique,Rodriguez-Monguio Rosa BMC health services research BACKGROUND:Patients with type 2 diabetes (T2D) typically use several drug treatments during their lifetime. There is a debate about the best second-line therapy after metformin monotherapy failure due to the increasing number of available antidiabetic drugs and the lack of comparative clinical trials of secondary treatment regimens. While prior research compared the cost-effectiveness of two alternative drugs, the literature assessing T2D treatment pathways is scarce. The purpose of this study was to evaluate the long-term cost-effectiveness of dipeptidyl peptidase-4 inhibitors (DPP-4i) compared to sulfonylureas (SU) as second-line therapy in combination with metformin in patients with T2D. METHODS:A Markov model was developed with four health states, 1 year cycle, and a 25-year time horizon. Clinical and cost data were collected from previous studies and other readily available secondary data sources. The incremental cost-effectiveness ratio (ICER) was estimated from the US third party payer perspective. Both, costs and outcomes, were discounted at a 3% annual discount rate. One way and probabilistic sensitivity analyses were performed to evaluate the impact of uncertainty on the base-case results. RESULTS:The discounted incremental cost of metformin+DPP-4i compared to metformin+SU was $11,849 and the incremental life-years gained were 0.61, resulting in an ICER of $19,420 per life-year gained for patients in the metformin+DPP-4i treatment pathway. The ICER estimated in the probabilistic sensitivity analysis was $19,980 per life-year gained. Sensitivity analyses showed that the results of the study were not sensitive to changes in the parameters used in base-case. CONCLUSIONS:The metformin+DPP-4i treatment pathway was cost-effective compared to metformin+SU as a long-term second-line therapy in the treatment of T2D from the US health care payer perspective. Study findings have the potential to provide clinicians and third party payers valuable evidence for the prescription and utilization of cost-effective second-line therapy after metformin monotherapy failure in the treatment of T2D. 10.1186/s12913-018-2860-0
    Impact of metformin use on the cardiovascular effects of dipeptidyl peptidase-4 inhibitors: An analysis of Medicare claims data from 2007 to 2015. Crowley Matthew J,Gokhale Mugdha,Pate Virginia,Stürmer Til,Buse John B Diabetes, obesity & metabolism AIMS:To examine the outcomes of dipeptidyl peptidase-4 (DPP-4) inhibitor initiation with and without concurrent metformin treatment. MATERIALS AND METHODS:We identified Medicare enrollees initiating a DPP-4 inhibitor, a sulphonylurea or a thiazolidinedione. Using propensity-score-weighted Poisson models, we evaluated 1-year cardiovascular (CV) outcome incidence among initiators of DPP-4 inhibitors versus comparators in subgroups with and without concurrent metformin use, and assessed the interaction between initiation drug and metformin. Outcomes included mortality, non-fatal myocardial infarction (MI), stroke, and a composite outcome. RESULTS:For the DPP-4 inhibitor (n = 13 391) versus sulphonylurea (n = 33 206) comparison, rate differences in composite outcome incidence favoured DPP-4 inhibitors: -2.0/100 person-years among metformin users (95% confidence interval [CI] -2.7 to -1.3) and - 1.0/100 person-years (95% CI -1.8 to -0.2) among metformin non-users. Similar rate difference trends among metformin users and non-users were seen for mortality (-1.5/100 person-years [95% CI -2.1 to -0.9] and -0.7/100 person-years [95% CI -1.4 to 0.0]) and non-fatal MI (-0.5/100 person-years [95% CI -0.8, -0.3] and 0.1/100 person-years [95% CI -0.2 to 0.4]). The interaction between DPP-4 inhibitor initiation and metformin was statistically significant for non-fatal MI (P = 0.008). For the DPP-4 inhibitor (n = 22 210) versus thiazolidinedione (n = 9517) comparison, rate differences in composite outcome incidence for DPP-4 inhibitor initiation were -0.6/100 person-years (95% CI -1.5 to 0.2) among metformin users and 1.0 (95% CI 0.0 to 2.0) among metformin non-users. Similar rate difference trends among metformin users and non-users were seen for mortality (-0.5/100 person-years [95% CI -1.3 to 0.1] and 0.8/100 person-years [95% CI -0.0 to 1.7]) and non-fatal MI (-0.1/100 person-years [95% CI -0.4 to 0.2] and 0.2/100 person-years [95% CI -0.1 to 0.6]). The interaction between DPP-4 inhibitor initiation and metformin was statistically significant for the composite outcome (P = 0.024) and mortality (P = 0.023). CONCLUSION:Incidence rate differences in multiple CV outcomes appeared more favourable when DPP-4 inhibitor initiation occurred in the presence of metformin, suggesting a possible interaction between DPP-4 inhibitors and metformin. 10.1111/dom.13589
    Real-world comparison of mono and dual combination therapies of metformin, sulfonylurea, and dipeptidyl peptidase-4 inhibitors using a common data model: A retrospective observational study. Lee Kyung Ae,Jin Heung Yong,Kim Yu Ji,Kim Sang Soo,Cho Eun-Hee,Park Tae Sun Medicine ABSTRACT:The comparative effectiveness of oral hypoglycemic agents on glycemic control and chronic complications in clinical practice is unknown in Korea. This study aimed to compare glycemic control and the incidence of hypoglycemia and chronic complications among adult patients with type 2 diabetes prescribed metformin, dipeptidyl peptidase-4 inhibitors (DPP4I), and sulfonylurea (SU) as monotherapy or dual combination therapy.We retrospectively analyzed propensity-matched cohort data from 3 national university hospitals in Korea. All electronic health records were transformed into a unified Observational Medical Outcomes Partnership Common Data Model and analyzed using ATLAS, an open-source analytical tool, and R software. Glycemic control was assessed as the first observation of a reduction in glycosylated hemoglobin (HbA1c) level below 7% after prescription of the drug. Differences in the incidence of chronic complications were compared based on the first observation of each complication. Glycemic control and chronic complications were evaluated in patients who maintained the same prescription for at least 3 and 12 months, respectively.Patients who received metformin had lower hazard of reaching HbA1c levels below 7% as compared with those who received SU, and had higher hazard compared with those who received DPP4I (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.75-0.98; and HR, 1.68; 95% CI, 1.42-1.99, respectively). The incidence of hypoglycemia was significantly higher in the SU group than in the metformin and DPP4I groups (metformin vs SU; HR, 0.30; 95% CI, 0.21-0.43; SU vs DPP4I; HR, 4.42; 95% CI, 2.35-8.31). Metformin + DPP4I had similar hazard of reaching HbA1c levels below 7% compared with metformin + SU (HR, 1.19; 95% CI, 0.99-1.43) and the incidence of hypoglycemia was significantly lower in the metformin + DPP4I group (HR 0.13; 95% CI 0.05-0.30). There was no significant difference in the analysis of the occurrence of chronic complications.SU followed by metformin was effective, and both drugs showed an increased hazard of reaching HbA1c levels below 7% compared with DPP4I. Metformin + DPP4I is comparatively effective for HbA1c level reduction below 7% compared with metformin + SU. Hypoglycemia was high in the SU-containing therapy. 10.1097/MD.0000000000028823