Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors vs. Dipeptidyl Peptidase-4 (DPP4) Inhibitors for New-Onset Dementia: A Propensity Score-Matched Population-Based Study With Competing Risk Analysis

Introduction: The effects of sodium-glucose cotransporter 2 inhibitors (SGLT2I) and dipeptidyl peptidase-4 inhibitors (DPP4I) on new-onset cognitive dysfunction in type 2 diabetes mellitus remain unknown. This study aimed to evaluate the effects of the two novel antidiabetic agents on cognitive dysfunction by comparing the rates of dementia between SGLT2I and DPP4I users.Methods: This was a population-based cohort study of type 2 diabetes mellitus patients treated with SGLT2I and DPP4I between January 1, 2015 and December 31, 2019 in Hong Kong. Exclusion criteria were <1-month exposure or exposure to both medication classes, or prior diagnosis of dementia or major neurological/psychiatric diseases. Primary outcomes were new-onset dementia, Alzheimer's, and Parkinson's. Secondary outcomes were all-cause, cardiovascular, and cerebrovascular mortality.Results: A total of 13,276 SGLT2I and 36,544 DPP4I users (total n = 51,460; median age: 66.3 years old [interquartile range (IQR): 58–76], 55.65% men) were studied (follow-up: 472 [120–792] days). After 1:2 matching (SGLT2I: n = 13,283; DPP4I: n = 26,545), SGLT2I users had lower incidences of dementia (0.19 vs. 0.78%, p < 0.0001), Alzheimer's (0.01 vs. 0.1%, p = 0.0047), Parkinson's disease (0.02 vs. 0.14%, p = 0.0006), all-cause (5.48 vs. 12.69%, p < 0.0001), cerebrovascular (0.88 vs. 3.88%, p < 0.0001), and cardiovascular mortality (0.49 vs. 3.75%, p < 0.0001). Cox regression showed that SGLT2I use was associated with lower risks of dementia (hazard ratio [HR]: 0.41, 95% confidence interval [CI]: [0.27–0.61], P < 0.0001), Parkinson's (HR:0.28, 95% CI: [0.09–0.91], P = 0.0349), all-cause (HR:0.84, 95% CI: [0.77–0.91], P < 0.0001), cardiovascular (HR:0.64, 95% CI: [0.49–0.85], P = 0.0017), and cerebrovascular (HR:0.36, 95% CI: [0.3–0.43], P < 0.0001) mortality.Conclusions: The use of SGLT2I is associated with lower risks of dementia, Parkinson's disease, and cerebrovascular mortality compared with DPP4I use after 1:2 ratio propensity score matching.

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The risk of new-onset atrial fibrillation in patients with type 2 diabetes mellitus treated with sodium glucose cotransporter 2 inhibitors versus dipeptidyl peptidase-4 inhibitors

10.21203/rs.3.rs-31689/v2 ◽

2020 ◽

Author(s):

Ann Wan-Chin Ling ◽

Cze-Ci Chan ◽

Shao-Wei Chen ◽

Wei-Yi Kao ◽

Chien-Ying Huang ◽

...

Keyword(s):

Diabetes Mellitus ◽

Atrial Fibrillation ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Lower Risk ◽

Dipeptidyl Peptidase 4 ◽

Sodium Glucose Cotransporter ◽

Onset Atrial Fibrillation ◽

New Onset

Abstract Background: Sodium glucose cotransporter 2 inhibitor (SGLT2i) reduces the risk of hard cardiovascular endpoints in type 2 diabetes mellitus (T2DM) patients with/without established cardiovascular diseases. Whether SGLT2i is associated with a lower risk of new-onset atrial fibrillation (AF) in T2DM patients is unclear. We aimed to evaluate the risk of new-onset AF associated with the use of SGLT2i compared to dipeptidyl peptidase-4 inhibitor (DPP4i) among a longitudinal cohort of diabetic patients. Methods: We used medical data from a multi-center healthcare provider in Taiwan, which included a total of 15,606 and 12,383 patients treated with SGLT2i and DPP4i, respectively, from June 1, 2016 to December 31, 2018. We used propensity-score weighting to balance covariates across study groups. Patients were followed up from the drug index date until the occurrence of new-onset AF, discontinuation of the index drug, or the end of the study period, whichever occurred first. Results: Overall, 55%, 45%, and 0% of the patients were treated with empagliflozin, dapagliflozin, and canagliflozin, respectively. Most patients in the DPP4i group were prescribed with linagliptin (51%), followed by sitagliptin (24%), saxagliptin (13%), vildagliptin (8%) and alogliptin (5%). The use of SGLT2i was associated with a lower risk of new-onset AF compared with DPP4i after propensity-score weighting [hazard ratio: 0.61; 95% confidential interval: 0.50-0.73; P< 0.001]. Subgroup analysis revealed that the use of SGLT2i was associated with a lower risk of new-onset AF compared with DPP4i across several subgroups including old age, female in gender, the presence of cardiovascular disease, hemoglobin A1c 8%, and chronic kidney disease. The advantage of SGLT2i over DPP4i persisted with different SGLT2i (dapagliflozin or empagliflozin) and either low- or standard-dose SGLT2i. Conclusions: SGLT2i was associated with a lower risk of new-onset AF compared with DPP4i among T2DM patients in real-world practice.

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The risk of new-onset atrial fibrillation in patients with type 2 diabetes mellitus treated with sodium glucose cotransporter 2 inhibitors versus dipeptidyl peptidase-4 inhibitors

Cardiovascular Diabetology ◽

10.1186/s12933-020-01162-w ◽

2020 ◽

Vol 19 (1) ◽

Author(s):

Ann Wan-Chin Ling ◽

Cze-Ci Chan ◽

Shao-Wei Chen ◽

Yi-Wei Kao ◽

Chien-Ying Huang ◽

...

Keyword(s):

Diabetes Mellitus ◽

Atrial Fibrillation ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Lower Risk ◽

Dipeptidyl Peptidase 4 ◽

Sodium Glucose Cotransporter ◽

Onset Atrial Fibrillation ◽

New Onset

Abstract Background Sodium glucose cotransporter 2 inhibitor (SGLT2i) reduces the risk of hard cardiovascular endpoints in type 2 diabetes mellitus (T2DM) patients with/without established cardiovascular diseases. Whether SGLT2i is associated with a lower risk of new-onset atrial fibrillation (AF) in T2DM patients is unclear. We aimed to evaluate the risk of new-onset AF associated with the use of SGLT2i compared to dipeptidyl peptidase-4 inhibitor (DPP4i) among a longitudinal cohort of diabetic patients. Methods We used medical data from a multi-center healthcare provider in Taiwan, which included a total of 15,606 and 12,383 patients treated with SGLT2i and DPP4i, respectively, from June 1, 2016 to December 31, 2018. We used propensity-score weighting to balance covariates across study groups. Patients were followed up from the drug index date until the occurrence of new-onset AF, discontinuation of the index drug, or the end of the study period, whichever occurred first. Results Overall, 55%, 45%, and 0% of the patients were treated with empagliflozin, dapagliflozin, and canagliflozin, respectively. Most patients in the DPP4i group were prescribed with linagliptin (51%), followed by sitagliptin (24%), saxagliptin (13%), vildagliptin (8%) and alogliptin (5%). The use of SGLT2i was associated with a lower risk of new-onset AF compared with DPP4i after propensity-score weighting [hazard ratio: 0.61; 95% confidential interval: 0.50–0.73; P < 0.001]. Subgroup analysis revealed that the use of SGLT2i was associated with a lower risk of new-onset AF compared with DPP4i across several subgroups including old age, female in gender, the presence of cardiovascular disease, hemoglobin A1c $$\ge$$ ≥ 8%, and chronic kidney disease. The advantage of SGLT2i over DPP4i persisted with different SGLT2i (dapagliflozin or empagliflozin) and either low- or standard-dose SGLT2i. Conclusions SGLT2i was associated with a lower risk of new-onset AF compared with DPP4i among T2DM patients in real-world practice.

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Effect of sodium-glucose cotransporter 2 inhibitor in patients with non-alcoholic fatty liver disease and type 2 diabetes mellitus: a propensity score-matched analysis of real-world data

Therapeutic Advances in Endocrinology and Metabolism ◽

10.1177/20420188211000243 ◽

2021 ◽

Vol 12 ◽

pp. 204201882110002

Author(s):

Taeang Arai ◽

Masanori Atsukawa ◽

Akihito Tsubota ◽

Shigeru Mikami ◽

Hiroki Ono ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Propensity Score ◽

Fatty Liver Disease ◽

Liver Inflammation ◽

Alcoholic Fatty Liver ◽

Sodium Glucose Cotransporter ◽

Alcoholic Fatty Liver Disease

Background: Although sodium-glucose cotransporter 2 inhibitors (SGLT2-Is) improve not only glycemic control but also liver inflammation and fatty changes in patients with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM), its sustainability and effect on liver fibrosis have remained unclear. The current study aimed to clarify the effects of 48-week SGLT2-I therapy on liver inflammation, fatty changes, and fibrosis in NAFLD patients with T2DM. Methods: This study evaluated the effects of SGLT2-I on NAFLD, including liver fibrosis assessed via transient elastography, in 56 patients with NAFLD who received SGLT2-I for 48 weeks. Moreover, changes in each clinical parameter between patients receiving SGLT2-I (the SGLT2-I group) and those receiving other oral hypoglycemic agents (OHAs) (the non-SGLT2-I group) were compared, using 1:1 propensity score matching to adjust for baseline factors. Results: The SGLT2-I group exhibited a significant decrease in controlled attenuation parameter (312 dB/m at baseline to 280 dB/m at week 48) and liver stiffness measurement (9.1–6.7 kPa) ( p < 0.001 for both). After propensity score matching (44 patients each in the SGLT2-I and non-SGLT2-I groups), no significant difference in HbA1c decrease was observed between the two groups. However, compared with the non-SGLT2-I group, the SGLT2-I group showed a significant decrease in body weight ( p < 0.001), alanine aminotransferase ( p = 0.02), uric acid ( p < 0.001), and Fibrosis-4 (FIB-4) index ( p = 0.01) at week 48. The improvement in FIB-4 index, defined as a ⩾10% decline from baseline at week 48, was 56.8% (25/44) in the SGLT2-I group and 20.5% (9/44) in the non-SGLT2-I group ( p < 0.001). Conclusion: SGLT2-Is improved not only glycemic control but also liver fatty infiltration and fibrosis in patients with NAFLD and T2DM, suggesting their possible superiority to other OHAs concerning these effects.

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Risk of morbidity and mortality in patients with type 2 diabetes treated with sodium-glucose cotransporter-2 inhibitor and/or dipeptidyl peptidase-4 inhibitor: a nationwide study

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-001765 ◽

2021 ◽

Vol 9 (1) ◽

pp. e001765

Author(s):

Gábor Sütő ◽

Gergő A Molnár ◽

Gyorgy Rokszin ◽

Ibolya Fábián ◽

Zoltan Kiss ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Propensity Score ◽

Propensity Score Matching ◽

Dipeptidyl Peptidase ◽

Dipeptidyl Peptidase 4 ◽

Sodium Glucose Cotransporter ◽

Dipeptidyl Peptidase 4 Inhibitor ◽

All Cause Mortality

IntroductionMortality and disability in diabetes mellitus are determined mostly by cardiovascular complications and cancer. The impact of dipeptidyl peptidase-4 inhibitor (DPP-4i) and sodium-glucose cotransporter-2 inhibitor (SGLT2i) monotherapy or combination on long-term complications of type 2 diabetes mellitus was studied.Research design and methodsPatients with type 2 diabetes treated with DPP-4i or SGLT2i during a 3-year period were identified in the database of the National Institute of Health Insurance Fund in Hungary. All-cause mortality, acute myocardial infarction, stroke, hospitalization for heart failure (HHF), lower limb amputation (LLA) and cancer were assessed. Outcomes of add-on SGLT2i to DPP-4i treatment in comparison with switching DPP-4i therapy to SGLT2i were also evaluated. After propensity score matching, survival analysis was performed with a Cox proportional hazards model.ResultsAfter propensity score matching, both SGLT2i and DPP-4i groups included 18 583 patients. All-cause mortality (HR, 0.80; 95% CI 0.68 to 0.94; p=0.0057), HHF (HR, 0.81; 95% CI 0.71 to 0.92; p=0.0018), and risk of cancer (HR, 0.75; 95% CI 0.66 to 0.86; p<0.0001) were lower in the SGLT2i population compared with DPP-4i. Risk of LLA was higher in the SGLT2i group (HR, 1.35; 95% CI 1.03 to 1.77; p=0.0315). SGLT2i in combination with DPP-4i results in lower all-cause mortality (HR, 0.46; 95% CI 0.31 to 0.67; p=0.0001), with a lower trend in stroke, LLA, HHF and cancer, but without any statistical difference.ConclusionsSGLT2i treatment leads to a lower risk of overall mortality, HHF and cancer when compared with DPP-4i treatment. Adding SGLT2i to DPP-4i instead of switching from DPP-4i to SGLT2i further lowers the risk of all-cause mortality.

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Comparative effects of sodium glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP4) inhibitors on new-onset atrial fibrillation and stroke outcomes

10.1101/2021.01.04.21249211 ◽

2021 ◽

Author(s):

Sharen Lee ◽

Jiandong Zhou ◽

Carlin Chang ◽

Tong Liu ◽

Dong Chang ◽

...

Keyword(s):

Diabetes Mellitus ◽

Atrial Fibrillation ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Propensity Score ◽

Lower Risk ◽

Sglt2 Inhibitors ◽

All Cause Mortality ◽

New Onset

AbstractBackgroundSGLT2I and DPP4I are medications prescribed for type 2 diabetes mellitus patients. However, there are few population-based studies comparing their effects on incident atrial fibrillation or ischemic stroke.MethodsThis was a territory-wide cohort study of type 2 diabetes mellitus patients prescribed SGLT2I or DPP4I between January 1st, 2015 to December 31st, 2019 in Hong Kong. Patients with both DPP4I and SGLT2I use and patients with drug discontinuation were excluded. Patients with prior AF or stroke were excluded for the respective analysis. 1:2 propensity-score matching was conducted for demographics, past comorbidities and medications using nearest-neighbor matching method. Cox models were used to identify significant predictors for new onset heart failure (HF) or myocardial infarction (MI), cardiovascular and all-cause mortality.ResultsThe AF-free cohort included 49108 patients (mean age: 66.48 years old [SD: 12.89], 55.32% males) and the stroke-free cohort included 49563 patients (27244 males [54.96%], mean baseline age: 66.7 years old [SD: 12.97, max: 104.6 years old]). After propensity score matching, SGLT2i use was associated with a lower risk of new onset AF (HR: 0.43[0.28, 0.66]), cardiovascular mortality (HR: 0.79[0.58, 1.09]) and all-cause mortality (HR: 0.69[0.60, 0.79]) in the AF-free cohort. It was also associated with a lower risk of new onset stroke (0.46[0.33, 0.64]), cardiovascular mortality (HR: 0.74[0.55, 1.00]) and all-cause mortality (HR: 0.64[0.56, 0.74]) in the stroke-free cohort.ConclusionsThe novelty of our work si that SGLT2 inhibitors are protective against atrial fibrillation and stroke development for the first time. These findings should be validated in other cohorts.

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Effect of Dipeptidyl-Peptidase 4 Inhibitors on Circulating Oxidative Stress Biomarkers in Patients with Type 2 Diabetes Mellitus

Antioxidants ◽

10.3390/antiox9030233 ◽

2020 ◽

Vol 9 (3) ◽

pp. 233

Author(s):

Elisabetta Bigagli ◽

Cristina Luceri ◽

Ilaria Dicembrini ◽

Lorenzo Tatti ◽

Francesca Scavone ◽

...

Keyword(s):

Oxidative Stress ◽

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Propensity Score ◽

Oxidative Damage ◽

Dipeptidyl Peptidase ◽

Dipeptidyl Peptidase 4 ◽

Dipeptidyl Peptidase 4 Inhibitors

Pre-clinical studies suggested potential cardiovascular benefits of dipeptidyl peptidase-4 inhibitors (DPP4i), however, clinical trials showed neither beneficial nor detrimental effects in patients with type 2 diabetes mellitus (T2DM). We examined the effects of DPP4i on several circulating oxidative stress markers in a cohort of 32 T2DM patients (21 males and 11 post-menopausal females), who were already on routine antidiabetic treatment. Propensity score matching was used to adjust demographic and clinical characteristics between patients who received and who did not receive DPP4i. Whole-blood reactive oxygen species (ROS), plasma advanced glycation end products (AGEs), advanced oxidation protein products (AOPP), carbonyl residues, as well as ferric reducing ability of plasma (FRAP) and leukocyte DNA oxidative damage (Fpg sites), were evaluated. With the exception of Fpg sites, that showed a borderline increase in DPP4i users compared to non-users (p = 0.0507), none of the biomarkers measured was affected by DPP4i treatment. An inverse correlation between estimated glomerular filtration rate and AGEs (p < 0.0001) and Fpg sites (p < 0.05) was also observed. This study does not show any major effect of DPP4i on oxidative stress, assessed by several circulating biomarkers of oxidative damage, in propensity score-matched cohorts of T2DM patients.

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The risk of new-onset atrial fibrillation in patients with type 2 diabetes mellitus treated with sodium glucose cotransporter 2 inhibitors versus dipeptidyl peptidase-4 inhibitors

10.21203/rs.3.rs-31689/v1 ◽

2020 ◽

Author(s):

Ann Wan-Chin Ling ◽

Cze-Ci Chan ◽

Shao-Wei Chen ◽

Wei-Yi Kao ◽

Chien-Ying Huang ◽

...

Keyword(s):

Diabetes Mellitus ◽

Atrial Fibrillation ◽

Type 2 Diabetes ◽

Lower Risk ◽

Dipeptidyl Peptidase 4 ◽

Sodium Glucose Cotransporter ◽

Dipeptidyl Peptidase 4 Inhibitors ◽

Onset Atrial Fibrillation ◽

New Onset

Abstract Purpose: Sodium glucose cotransporter 2 inhibitor (SGLT2i) reduced the risk of hard cardiovascular endpoints in type 2 diabetes mellitus (T2DM) patients with/without established cardiovascular diseases. Whether SGLT2i is associated with a lower risk of new-onset atrial fibrillation (AF) in T2DM patients is unclear. We aimed to evaluate the risk of new-onset AF associated with the use of SGLT2i compared to dipeptidyl peptidase-4 inhibitors (DPP4i) among a longitudinal cohort of diabetic patients. Methods: We used medical data from a multi-center healthcare provider in Taiwan, which included a total of 21,480 and 22,989 patients treated with SGLT2i and DPP4i, respectively, from June 1, 2016 to December 31, 2018. We used propensity-score weighting to balance covariates across study groups. Patients were followed up from the drug index date until the occurrence of new-onset AF, discontinuation of the index drug, or the end of the study period, whichever occurred first. Results: Overall, 56%, 42%, and 2% of the patients were treated with empagliflozin, dapagliflozin, and canagliflozin, respectively. Most patients in the DPP4i group were prescribed with linagliptin (51%), followed by sitagliptin (24%), saxagliptin (13%), vildagliptin (8%) and alogliptin (4%). The use of SGLT2i was associated with a lower risk of new-onset AF compared with DPP4i after propensity-score weighting [adjusted hazard ratio: 0.69; 95% confidential interval: 0.64-0.74; P < 0.001]. Subgroup analysis revealed that the use of SGLT2i was associated with a lower risk of new-onset AF compared with DPP4i across several subgroups including old age, the presence of congestive heart failure, cardiovascular disease, overweight patients, hemoglobin A1c 8%, and chronic kidney disease. The advantage of SGLT2i over DPP4i persisted with different SGLT2i (dapagliflozin or empagliflozin) and either low- or standard-dose SGLT2i. Conclusions: SGLT2i was associated with a lower risk of new-onset AF compared with DPP4i among T2DM patients in real-world practice.

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