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1.
Cardiorenal outcomes with sodium/glucose cotransporter-2 inhibitors in patients with type 2 diabetes and low kidney risk: real world evidence.
Schechter, M, Melzer-Cohen, C, Rozenberg, A, Yanuv, I, Chodick, G, Karasik, A, Kosiborod, M, Mosenzon, O
Cardiovascular diabetology. 2021;(1):169
Abstract
BACKGROUND Randomized controlled trials showed that sodium/glucose cotransporter-2 inhibitors (SGLT2i) protect the heart and kidney in an array of populations with type 2 diabetes (T2D) and increased cardiorenal risk. However, the extent of these benefits also in lower kidney-risk T2D populations needs further investigation. METHODS Members of Maccabi Healthcare Systems listed in their T2D registry who initiated new glucose lowering agents (GLA), were divided into SGLT2i initiators and other GLAs (oGLAs). Groups were propensity score-matched by baseline demographic and medical characteristics. Two composite cardiovascular outcomes were defined: all-cause mortality (ACM) or hospitalization for heart failure (hHF); and ACM, myocardial infraction (MI) or stroke. The cardiorenal outcome was: ACM, new end-stage kidney disease (ESKD) or ≥ 40% reduction from baseline estimated glomerular filtration rate (eGFR). Renal-specific outcome was new ESKD or ≥ 40% eGFR reduction. Single components of cardiovascular and kidney outcomes were also assessed. Three subgroup definitions of low baseline kidney-risk were used: eGFR > 90 ml/min/1.73 m2; urinary albumin below detectable levels; and low risk according to Kidney Disease: Improving Global Outcomes (KDIGO) classification. Analyses were performed utilizing an unadjusted model, and a model adjusted to baseline eGFR and urinary albumin-to-creatinine ratio. RESULTS Between April 1, 2015 and June 30, 2018; 68,187 patients initiated new GLAs - 11,321 SGLT2i initiators and 42,077 oGLAs initiators were eligible. Propensity score-matching yielded two comparable cohorts; each included 9219 participants. Median follow-up was 1.7 years. Compared to oGLAs, SGLT2i initiators had lower incidence of ACM or hHF [HR95%CI = 0.62(0.51-0.75)]; ACM, MI or stroke [0.67(0.57-0.80)]; the cardiorenal outcome [0.65(0.56-0.76)]; and the renal-specific outcome [0.70(0.57-0.85)]. SGLT2i initiators also had lower risk for ACM, hHF and ≥ 30%, ≥ 40%, ≥ 50%, ≥ 57% eGFR reduction. No difference between groups was observed for MI or stroke. In the low baseline kidney-risk subgroups, SGLT2i initiation was generally associated with lower risk of the cardiovascular and cardiorenal outcomes, driven mainly by lower ACM incidence. CONCLUSIONS Our findings in the general population of patients with T2D demonstrates lower risk of cardiorenal outcomes associated with initiation of SGLT2i compared with oGLAs, including specifically in patients with low baseline kidney-risk.
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2.
Safety and effectiveness of tofogliflozin in Japanese patients with type 2 diabetes mellitus treated in real-world clinical practice: Results of a 36-month post-marketing surveillance study (J-STEP/LT).
Utsunomiya, K, Koshida, R, Kakiuchi, S, Senda, M, Fujii, S, Kurihara, Y, Gunji, R, Kaku, K
Journal of diabetes investigation. 2021;(2):184-199
Abstract
AIMS/INTRODUCTION Tofogliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that lowers plasma glucose levels by enhancing urinary glucose excretion. After its approval in Japan in 2014 for the treatment of type 2 diabetes mellitus, we carried out a 3-year prospective observational post-marketing surveillance study in Japanese patients (Japanese Study of Tofogliflozin with Type 2 Diabetes Mellitus Patients/Long Term [J-STEP/LT]). MATERIALS AND METHODS This surveillance was carried out between September 2014 and February 2019, and recorded safety in terms of adverse drug reactions (ADRs) and ADRs of special interest, and effectiveness in terms of changes in glycated hemoglobin and bodyweight from baseline to last observation carried forward. RESULTS Of 6,897 patients with type 2 diabetes mellitus registered, 6,711 and 6,451 were analyzed for safety and effectiveness, respectively. ADRs were reported in 846 patients (12.61%), with serious ADRs in 101 patients (1.5%). ADRs of special interest included hypoglycemia (62 patients [0.9%]), polyuria/pollakiuria (90 [1.3%]), volume depletion-related disorders (135 [2.0%]), urinary tract infections (91 [1.4%]), genital infections (117 [1.7%]) and skin diseases (53 [0.8%]). One case of diabetic ketoacidosis was reported. The mean ± standard deviation changes from baseline to last observation carried forward in glycated hemoglobin and bodyweight were -0.68 ± 1.34% (n = 6,158, P < 0.0001) and -3.13 ± 4.67 kg (n = 5,213, P < 0.0001), respectively. CONCLUSIONS J-STEP/LT, a 3-year, prospective, observational, post-marketing study in Japan, found no unprecedented ADRs, and consistent reductions from baseline in glycated hemoglobin and bodyweight over the observation period. The present results provide further evidence regarding the safety and tolerability of tofogliflozin in Japanese patients with type 2 diabetes mellitus.
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3.
Prescribing in Type 2 Diabetes Patients With and Without Cardiovascular Disease History: A Descriptive Analysis in the UK CPRD.
Farmer, RE, Beard, I, Raza, SI, Gollop, ND, Patel, N, Tebboth, A, McGovern, AP, Kanumilli, N, Ternouth, A
Clinical therapeutics. 2021;(2):320-335
Abstract
PURPOSE Some classes of glucose-lowering medications, including sodium-glucose co-transporter 2 inhibitors (SGLT2is) and glucagon-like peptide 1-receptor agonists (GLP1-RAs) have cardio-protective benefit, but it is unclear whether this influences prescribing in the United Kingdom (UK). This study aims to describe class-level prescribing in adults with type 2 diabetes mellitus (T2DM) by cardiovascular disease (CVD) history using the Clinical Practice Research Datalink (CPRD). METHODS Four cross-sections of people with T2DM aged 18-90 and registered with their general practice for >1 year on 1st January 2017 (n = 166,012), 1st January 2018 (n = 155,290), 1st January 2019 (n = 152,602) and 31st December 2019 (n = 143,373) were identified. Age-standardised proportions for class use through time were calculated separately in those with and without CVD history and by total number of medications prescribed (one, two, three, four+). An analysis by UK country was also performed. FINDINGS Around 31% of patients had CVD history at each cross-section. Metformin was the most common treatment (>70% of those with and without CVD had prescriptions across all treatment lines). Overall use of SGLT2is and GLP1-RAs was low, with slightly less use in patients with CVD (SGLT2i: 9.8% and 13.8% in those with and without CVD respectively; GLP1-RA: 4.3% and 4.9%, December 2019). Use of SGLT2is as part of dual therapy was low but rose throughout the study. In January 2017, estimated use was 8.0% (95% CI 6.9-9.1%) and 8.9% (8.6-9.3%) in those with and without CVD. By December 2019 this reached 18.3% (17.0-19.5%) and 21.2% (20.6-21.7%) for those with and without CVD respectively. SGLT2i use as triple therapy increased: 22.7% (21.0-24.4%) and 25.9% (25.2-26.6%) in January 2017 to 41.3% (39.5-43.0%) and 45.5% (44.7-46.3%) in December 2019. GLP1-RA use also increased, but observed usage remained lower than SGLT2 inhibitors. Insulin use remained stable throughout, with higher use observed in those with CVD (16% vs 9.7% Dec 2019). Time trends in England, Wales, Scotland and Northern Ireland were similar, although class prevalence varied. IMPLICATIONS Although use of SGLT2is and GLP1-RAs has increased, overall usage remains low with slightly lower use in those with CVD history, suggesting there is opportunity to optimise use of these medicines in T2DM patients to manage CVD risk. Insulin use was substantially more prevalent in those with CVD despite no evidence of CVD benefit. Further investigation of factors influencing this finding may highlight strategies to improve patient access to the most appropriate treatments, including those with evidence of cardiovascular benefit.
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4.
Glucose-dependent diuresis in relation to improvements in renal-tubular markers of sodium-glucose cotransporter-2 inhibitors in hospitalized heart failure patients with diabetes.
Ikeda, Y, Ishii, S, Maemura, K, Oki, T, Yazaki, M, Fujita, T, Nabeta, T, Maekawa, E, Koitabashi, T, Ako, J
Heart and vessels. 2021;(7):978-985
Abstract
Clinical parameters with correlation to diuretic effects after initiation of sodium-glucose cotransporter-2 (SGLT2) inhibitors are unclear. We aimed to identify the factors associated with the diuretic effect observed following the initiation of SGLT2 inhibitors in patients with diabetes having an acute heart failure (HF). Fifty-six patients included were hospitalized for acute HF with diabetes and started on SGLT2 inhibitors. Changes in urine volume (ΔUV) and blood/urine laboratory parameters before and during the first 4 days of therapy were evaluated. Data were prospectively obtained under clinically stable conditions after initial HF treatment. UV increased following the initiation of SGLT2 inhibitors [UV at baseline (BL): 1383 ± 479 mL/day; ΔUV over 4 days: + 189 ± 358 mL/day]. Multivariate analysis revealed no association between BL-hemoglobin A1c or BL-estimated glomerular filtration rate and ΔUV. Conversely, higher BL-fasting plasma glucose (FPG) and higher BL-urine N-acetyl-β-D-glucosaminidase (NAG) were associated with a higher ΔUV. ΔUV was inversely associated with ΔFPG and ΔNAG, and positively associated with Δurinary sodium excretion. Elevated FPG and NAG both improved over 4 days of treatment. In conclusion, the diuretic effect of SGLT2 inhibitors was glycemia-dependent, and was associated with a reduction in elevated renal-tubular markers in hospitalized HF complicated with diabetes.
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5.
Initiation of SGLT2 Inhibitors and the Risk of Lower Extremity Minor and Major Amputation in Patients with Type 2 Diabetes and Peripheral Arterial Disease: A Health Claims Data Analysis.
Rodionov, RN, Peters, F, Marschall, U, L'Hoest, H, Jarzebska, N, Behrendt, CA
European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery. 2021;(6):981-990
Abstract
OBJECTIVE To assess the association between long term risk of hospitalisation for heart failure (HHF) and lower extremity minor and major amputation (LEA) in patients initiating sodium glucose cotransporter 2 inhibitors (SGLT2i) suffering from type 2 diabetes and peripheral arterial disease (PAD). Outcomes were compared with patients without PAD and evaluated separately for the time periods before and after the official warning of the European Medicines Agency (EMA) in early 2017. METHODS This study used BARMER German health claims data including all patients suffering from type 2 diabetes initiating SGLT2i therapy between 1 January 2013 and 31 December 2019 with follow up until the end of 2020. New users of glucagon like peptide 1 receptor agonists (GLP1-RAs) were used as active comparators. Inverse probability weighting with truncated stabilised weights was used to adjust for confounding, and five year risks of HHF and LEA were estimated using Cox regression. Periods before and after the EMA warning were analysed separately and stratified by presence of concomitant PAD. RESULTS In total, 44 284 (13.6% PAD) and 56 878 (16.3% PAD) patients initiated SGLT2i or GLP1-RA, respectively. Before the EMA warning, initiation of SGLT2i was associated with a lower risk of HHF in patients with PAD (hazard ratio, HR, 0.85, 95% confidence interval, CI, 0.73 - 0.99) and a higher risk of LEA in patients without PAD (HR 1.79, 95% CI 1.04 - 2.92). After the EMA warning, the efficacy and safety endpoints were no longer statistically different between groups. CONCLUSION The results from this large nationwide real world study highlight that PAD patients exhibit generally high amputation risks. This study refutes the idea that the presence of PAD explains the excess LEA risk associated with initiation of SGLT2i. The fact that differentials among study groups diminished after the EMA warning in early 2017 emphasises that regulatory surveillance measures worked in everyday clinical practice.
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6.
The impact of weight loss related to risk of new-onset atrial fibrillation in patients with type 2 diabetes mellitus treated with sodium-glucose cotransporter 2 inhibitor.
Chan, YH, Chen, SW, Chao, TF, Kao, YW, Huang, CY, Chu, PH
Cardiovascular diabetology. 2021;(1):93
Abstract
BACKGROUND Sodium-glucose cotransporter 2 inhibitor (SGLT2i) use reduces body weight (BW) in patients with type 2 diabetes mellitus (T2DM). Obesity and T2DM are strong risk factors of new-onset atrial fibrillation (AF). However, whether BW loss following SGLT2i treatment reduces AF risk in patients with T2DM remains unclear. METHODS We used a medical database from a multicenter health care provider in Taiwan, which included 10,237 patients with T2DM, from June 1, 2016 to December 31, 2018, whose BW data at baseline and at 12 weeks of SGLT2i treatment were available. Patients were followed up from the drug index date until the occurrence of new-onset AF, discontinuation of the SGLT2i, or the end of the study period, whichever occurred first. RESULTS The patients' baseline body mass index (BMI) was 28.08 [Formula: see text] 4.88 kg/m2. SGLT2i treatment was associated with a BW loss of 1.35 [Formula: see text] 3.28 kg (1.78%[Formula: see text] 4.47%). There were 37.4%, 47.0%, and 15.6% of patients experienced no-BW loss (n = 3832), BW loss 0.0-4.9% (n = 4814), and [Formula: see text] 5.0% (n = 1591) following SGLT2i treatment, respectively. Compared with patients with baseline BMI < 23 kg/m2, AF risk significantly increased in patients with baseline BMI [Formula: see text] 27.5 kg/m2 (P for trend = 0.015). Compared with those without BW loss after SGLT2i treatment, AF risk significantly decreased with a BW loss of [Formula: see text] 5.0% (adjusted hazard ratios [95% confidence intervals]: 0.39[0.22-0.68]). Use of diuretics, old age, high-dose SGLT2i, higher estimated glomerular filtration rate, and baseline BMI were independent factors associated with a BW loss of [Formula: see text] 5.0% following SGLT2i initiation. By contrast, neither baseline BMI nor BW loss after SGLT2i treatment predicted major cardiovascular adverse events or heart failure hospitalization risk (P for trend > 0.05). CONCLUSION BW loss of ≥ 5.0% following SGLT2i treatment was associated with a lower risk of new-onset AF in patients with T2DM in real-world practice.
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7.
The risk of consequent nephropathy following initial weight loss in diabetic patients treated with sodium glucose cotransporter 2 inhibitors.
Chan, YH, Chen, SW, Chao, TF, Kao, YW, Huang, CY, Chu, PH
Cardiovascular diabetology. 2021;(1):167
Abstract
BACKGROUND There is a controversy over the association between obesity and the risk of renal events in patients with type 2 diabetes mellitus (T2DM). Furthermore, whether body weight (BW) loss following sodium glucose cotransporter 2 inhibitor (SGLT2i) treatment associated with risk of adverse renal events is unknown. METHODS We used medical data from a multi-center healthcare provider in Taiwan, enrolling 8992 T2DM patients with a baseline/following-up BW data available after around 12 weeks of SGLT2i treatment, from June 1, 2016 to December 31, 2018. Patients were followed up until the occurrence of composite renal outcome (estimated glomerular filtration rate decline > 40% or end-stage kidney disease) or the end of study period, whichever occurred first. RESULTS Participants were divided into six baseline BMI categories: < 18.5 (n = 55); 18.5-22.9 (n = 985); 23.0-24.9 (n = 1389); 25.0-29.9 (n = 3941); 30.0-34.9 (n = 1973); and ≥ 35.0 kg/m2 (n = 649). There were 38.9%, 23.5%, 24.7%, 8.4%, 2.7%, and 1.8% of patients experienced no-BW loss, initial BW loss of 0.0-2.4%, 2.5-4.9%, 5.0-7.4%, 7.5-9.9%, and ≥ 10.0%, associated with SGLT2i treatment, respectively. Compared with patients with normal BMI (BMI: 18.5-22.9 kg/m2), underweight (BMI: < 18.5 kg/m2) was associated with a higher risk of composite renal outcome (adjusted hazard ratio (aHR) [95% confidence intervals (CI)]: 2.17; [1.16-4.04]), whereas pre-obese (BMI: 25.0-29.9 kg/m2) associated with the lowest risk of composite renal outcome (0.52; [0.40-0.68]) after multivariate adjustment. Compared with those without BW loss after SGLT2i treatment, BW loss of 0.0-2.4% (0.55; [0.43-0.70]) and 2.5-4.9% (0.78; [0.63-0.98]) were associated with a lower risk, whereas BW loss ≥ 10.0% associated with a higher risk of composite renal outcome (1.61; [1.06-2.46]) after multivariate adjustment. CONCLUSION A modest BW loss of 0-5% associated with SGLT2i treatment was associated with a favorable renal outcome. Caution should be taken for whom are underweight at baseline or have a pronounced BW loss ≥ 10.0% associated with SGLT2i treatment, which was associated with a worse renal outcome.
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8.
On-label use of sodium-glucose cotransporter 2 inhibitors might increase the risk of diabetic ketoacidosis in patients with type 1 diabetes.
Horii, T, Oikawa, Y, Atsuda, K, Shimada, A
Journal of diabetes investigation. 2021;(9):1586-1593
Abstract
AIMS/INTRODUCTION This study aimed to investigate the risk of diabetic ketoacidosis (DKA) in insulin-treated type 1 diabetes patients administered sodium-glucose cotransporter 2 (SGLT2) inhibitors in real-world clinical practice. MATERIALS AND METHODS We carried out a real-world, retrospective, observational cohort study using Japanese Medical Data Vision, a diagnosis procedure combination database. We identified insulin-treated adult type 1 diabetes patients enrolled from December 2018 to October 2019. We assessed the incidence and risk of DKA in type 1 diabetes patients using SGLT2 inhibitors in an 'on-label' manner. Cox multivariate regression analyses were carried out to determine clinical factors linked to SGLT2 inhibitor-associated DKA. RESULTS Of 11,475 type 1 diabetes patients, 1,898 (16.5%) were prescribed SGLT2 inhibitors. DKA occurred in 139 (7.3%) of these patients, with 20.2 incidences per 100 person-years. These patients also showed significantly higher DKA rates than did those not receiving SGLT2 inhibitors (hazard ratio 1.66, 95% confidence interval 1.33-2.06; P < 0.001). The mean time until DKA onset in SGLT2 inhibitor-treated type 1 diabetes patients was 30.6 ± 30.1 days. The risk of SGLT2 inhibitor-associated DKA increased in type 1 diabetes patients irrespective of sex, age or body mass index. However, the risk did not increase in type 1 diabetes patients receiving continuous subcutaneous insulin infusion, which warrants further investigation because of the small number of type 1 diabetes patients receiving continuous subcutaneous insulin infusion. CONCLUSIONS 'On-label' SGLT2 inhibitor use might increase DKA risk among insulin-treated type 1 diabetes patients irrespective of sex, age or body mass index. Both type 1 diabetes patients and healthcare providers should be wary of DKA, especially during the first month of initiating SGLT2 inhibitors.
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9.
Do sodium-glucose cotransporter 2 inhibitors lead to fracture risk? A pharmacovigilance real-world study.
Zhao, B, Shen, J, Zhao, J, Pan, H
Journal of diabetes investigation. 2021;(8):1400-1407
Abstract
AIMS/INTRODUCTION Given the mechanism of action of sodium-glucose cotransporter 2 inhibitors (SGLT2is), these drugs can also reduce bone density and increase fracture risk. We aimed to identify and characterize fracture-related adverse events that are associated with SGLT2is. MATERIALS AND METHODS In this observational, retrospective, pharmacovigilance, real-world study, we used disproportionality and Bayesian analyses to compare fracture-related adverse event reporting in patients who received SGLT2is from the first quarter in 2004 to the fourth quarter in 2019 in the Food and Drug Administration Adverse Event Reporting System. We also compared the effect on combined therapy with SGLT2is and other glucose-lowering medications (GLMs), and compared their onset times and outcomes. RESULTS A total of 317 SGLT2is-associated fractures were identified. Affected patients tended to be aged >45 years (68.76%) and were more often male than female (58.04% vs 34.07%). SGLT2is-associated fracture is most commonly reported with canagliflozin (51.10%), dapagliflozin (24.60%) and empagliflozin (23.66%). SGLT2is or SGLT2is combined with GLMs do not show an association with fracture risk under disproportionality and Bayesian analyses. SGLT2i-associated fractures result in hospitalization in 66.64% of patients and death in 9.38% of patients. GLMs show an increased hospitalization rate compared with SGLT2is (69.72% vs 55.14%, P < 0.0001) and GLMs plus SGLT2is (69.72% vs 61.20%, P = 0.0197). CONCLUSIONS Based on the Food and Drug Administration Adverse Event Reporting System database, no association is noted between fracture risk and SGLT2is, or SGLT2is combined with GLMs. Long-term follow up and high-quality studies need to further verify and explore the relationship between SGLT2is and fractures.
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10.
Empagliflozin and left ventricular diastolic function following an acute coronary syndrome in patients with type 2 diabetes.
Lan, NSR, Yeap, BB, Fegan, PG, Green, G, Rankin, JM, Dwivedi, G
The international journal of cardiovascular imaging. 2021;(2):517-527
Abstract
Sodium-glucose cotransporter 2 inhibitors can improve heart failure outcomes, however, the effects on left ventricular (LV) function remain unclear. This prospective observational study aimed to investigate whether initiating empagliflozin therapy was associated with improved LV diastolic function following an acute coronary syndrome (ACS) in patients with type 2 diabetes (T2D). Patients with ACS and T2D were identified during hospitalisation in a cardiology unit. Empagliflozin was initiated at discharge in eligible patients (i.e. HbA1c > 7%) without contraindications or precautions. Transthoracic echocardiography was performed during admission and after 3-6 months. Changes in echocardiographic parameters were compared between patients initiated on empagliflozin versus not initiated on empagliflozin (control). There were 22 patients in each group (n = 44). Baseline characteristics, medications and echocardiographic parameters were similar except HbA1c (empagliflozin: 9.8 ± 1.6% versus control: 6.6 ± 0.7%, p < 0.001). Baseline LV global longitudinal strain (GLS) (empagliflozin: - 12.4 ± 2.8 versus control: - 13.0 ± 3.6%) and ejection fraction (51.1 ± 11.3 versus 54.9 ± 10.8%) were similar. The difference in change from baseline to follow-up was significant for LV mass index (empagliflozin: - 14.1 ± 21.6 versus control: 3.6 ± 18.7 g/m2, p = 0.006), left atrial volume index (- 2.1 ± 8.1 versus 3.4 ± 9.5 ml/m2, p = 0.045), mitral valve E-wave velocity (- 0.14 ± 0.23 versus 0.03 ± 0.16 m/s, p = 0.007) and average E/e' (- 2.1 ± 2.6 versus 0.9 ± 3.4, p = 0.002). There were no significant between-group differences in change for LV GLS, ejection fraction and volume. In patients with ACS and T2D, addition of empagliflozin to ACS therapy at discharge was associated with a reduction in LV mass and favourable changes in diastolic function parameters. Further studies are warranted to investigate these findings.