Sodium glucose co-transporter inhibitors for the management of diabetes mellitus: an opinion paper from the Endocrine and Metabolism Practice and Research Network of the American College of Clinical Pharmacy

Type 2 diabetes mellitus (T2DM) carries a high prevalence in the United States and worldwide. Therefore, the number of medication classes being developed and studied has grown. The individualized management of diabetes is accomplished by evaluating a medication’s efficacy, safety, and cost, along with the patient’s preference and tolerance to the medication. Sodium glucose co-transporter 2 inhibitors are a new therapeutic class indicated for the treatment of diabetes and have a unique mechanism of action, independent of beta-cell function. The first agent approved by the Food and Drug Administration (FDA) was canagliflozin in March 2013. Two agents – dapagliflozin and empagliflozin – were FDA-approved in January and July 2014, respectively. A clear understanding of the new class is needed to identify its appropriate use in clinical practice. Members of the American College of Clinical Pharmacy Endocrine and Metabolism Practice and Research Network reviewed available literature regarding this therapeutic class. The article addresses the advantages, disadvantages, emerging role, and patient education for sodium glucose co-transporter 2 inhibitors. Key limitations for this article include limited access to clinical trial data not published by the pharmaceutical company and limited data on products produced outside the United States.     

Empagliflozin/Linagliptin: Combination therapy in patients with type 2 diabetes

Glyxambi^® (empagliflozin/linagliptin) is a fixed-dose, once-daily tablet combining a sodium glucose co-transporter-2 (SGLT2) inhibitor with a dipeptidyl peptidase-4 (DPP-4) inhibitor. Glyxambi^® is served as an adjuvant to diet and exercise to improve glycemic control in adults with type 2 diabetes when both empagliflozin and linagliptin are appropriate treatments. Glyxambi^® combines 10 mg or 25 mg empagliflozin with 5 mg linagliptin, with different, complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes. Empagliflozin removes glucose through the urine by blocking blood glucose re-absorption in the kidney, and linagliptin exerts glucose-lowering activity by increasing hormones that stimulate the pancreas to produce more insulin and decreasing the levels of glucagon in the circulation. In addition, this combination therapy modestly reduces body weight and blood pressure without significant safety issues.     

Fixed-dose combination of empagliflozin and linagliptin for the treatment of patients with type 2 diabetes mellitus: A systematic review and meta-analysis

The present meta-analysis evaluated the efficacy and safety of empagliflozin + linagliptin combination compared with either monotherapy [n=6 randomized controlled trials; 2857 adults with type 2 diabetes (T2DM) on diet + exercise ± metformin; 39.7% women; mean age: 54.6–59.9 years]. The combination of empagliflozin 10 mg + linagliptin 5 mg led to significantly greater reductions in glycated haemoglobin (HbA1c) compared with either drug alone over 24 weeks: weighted mean difference [WMD; −0.72%, 95% confidence interval (CI): −1.04, −0.40], and fasting plasma glucose (−1.60 mmol/L 95% CI: −2.21, −1.00). Similar results were observed when empagliflozin 25 mg + linagliptin 5 mg was compared with linagliptin 5 mg monotherapy or with empagliflozin 10 or 25 mg monotherapy. Patients with T2DM treated with the drug combination had more than three times higher likelihood of achieving HbA1c <7% than those on either monotherapy. Weight reduction was significantly greater in the combination group only when compared with linagliptin monotherapy. Safety profile was similar between combination treatment and monotherapies. Overall, the empagliflozin + linagliptin combination had superior efficacy and similar safety in achieving euglycaemia compared with either monotherapy. This combination, administered once daily, has the potential to reduce regimen complexity, enhance adherence and improve outcomes in clinical practice.     

Early detection of euglycemic ketoacidosis during thoracic surgery associated with empagliflozin in a patient with type 2 diabetes: A case report

We report the first case of intraoperatively detected euglycemic diabetic ketoacidosis (DKA) associated with sodium–glucose cotransporter 2 inhibitors during thoracic surgery. A 59-year-old man had a 12-year history of type 2 diabetes mellitus treated with insulin and empagliflozin. The patient developed bacterial empyema and was initiated with antibiotics at a local hospital. Owing to the persistence of his symptoms, he was transferred to our hospital after the medication of empagliflozin the day before surgery. After overnight fasting, the patient underwent thoracoscopic debridement and intrathoracic lavage surgery. During this surgery, he was noted to have euglycemic ketosis and acidosis, and diagnosed as euglycemic DKA. Immediately after the consultation in our department, the patient underwent treatment for DKA. He awoke from anesthesia normally and showed no symptoms of DKA. DKA gradually resolved over the next 24 h. Early identification and management are critical for rapid recovery from perioperative euglycemic DKA associated with sodium–glucose cotransporter 2 inhibitors, especially during thoracic surgery.     

恩格列净通过抑制细胞焦亡改善糖尿病小鼠肾脏损伤

目的研究恩格列净(empagliflozin)对db/db小鼠肾脏损伤的保护作用及其潜在作用机制。方法db/db小鼠随机分为糖尿病肾病组(db/db组)和恩格列净治疗组(Empa组,恩格列净10 mg·kg-1·d-1灌胃),C57BL/6J小鼠作为正常对照组。干预3个月,检测血清生化、炎症因子等指标;病理染色观察肾脏病理学改变;检测细胞焦亡相关分子NLRP3、Cleaved Caspase-1、GSDMD的蛋白表达水平。结果与db/db组相比,Empa组空腹血糖、HbA1C、血脂、血清IL-1β、IL-18及ACR明显降低(均P<0.05),病理染色显示Empa组肾小球固缩、肾间质纤维化明显改善,Empa组肾脏组织NLRP3、Cleaved Caspase-1、GSDMD蛋白表达下调(P<0.05)。结论恩格列净可能通过抑制NLRP3/Caspase-1/GSDMD细胞焦亡信号通路而改善糖尿病小鼠肾脏损伤。     

A series of diabetic ketoacidosis associated with the use of sodium-glucose co-transporter-2 inhibitors in secondary care

Background and aimsSodium-glucose co-transporter-2 inhibitors (SGLT-2i) are associated with diabetic ketoacidosis (DKA), however limited case series are published.MethodsWe evaluated the characteristics of patients admitted with SGLT-2i associated DKA.ResultsOver 4 months, 22 patients were identified; 45.5% of DKA was not associated with concurrent illness.ConclusionDKA is not uncommonly associated with SGLT2i with no clear patient factors associated with severity.     

Sodium–glucose cotransporter 2 inhibitors: an evidence-based practice approach to their use in the natural history of type 2 diabetes

Objective The sodium–glucose cotransporter 2 (SGLT-2) inhibitors are an important addition to available treatments for patients with type 2 diabetes (T2D) as an adjunct to modifications in diet and exercise. SGLT-2 inhibitors may be prescribed alone or as add-on treatment in patients receiving metformin, sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, and/or insulin across the natural history of the disease. Inhibition of SGLT-2, which is responsible for approximately 90% of renal glucose reabsorption, increases urinary glucose excretion and lowers blood glucose concentrations. The objective of this review is to discuss the pathophysiology of diabetes and the contribution of the kidney to glucose homeostasis and to provide an evidence-based practice approach to clinical applications of SGLT-2 inhibitors in the treatment of T2D.

Methods PubMed and Google Scholar databases were searched to identify literature published from 1990 through September 2015 examining the pathophysiology of T2D, the role of the kidney in regulating glucose concentrations, and clinical evidence for the efficacy and safety of SGLT-2 inhibitors in T2D.

Results There is a need for early treatment in patients with T2D to minimize the risk of cardiovascular complications that increase morbidity and mortality. SGLT-2 inhibitors improve glycemic control, reduce body weight and blood pressure, and are associated with a low risk of hypoglycemia. Adverse events associated with SGLT-2 inhibitors include mild to moderate urinary tract and genital infections and mild dehydration potentially leading to orthostatic hypotension.

Conclusions An evidence-based practice approach to examining the importance of early, proactive treatment of T2D using SGLT-2 inhibitors from initiation of pharmacotherapy to increasingly more complicated combination therapy regimens, including insulin, suggests that this treatment strategy maximizes benefits and minimizes potential side effects. The SGLT-2 inhibitors augment the arsenal of available antidiabetes agents, facilitating the ability of clinicians to design tailored treatment regimens that help patients achieve therapeutic goals.     

消渴清颗粒联合恩格列净治疗2型糖尿病的临床研究

目的探讨消渴清颗粒联合恩格列净治疗2型糖尿病的临床疗效。方法选取2019年7月—2020年7月商丘市第三人民医院收治的150例2型糖尿病患者为研究对象,根据用入院号的奇偶数分成对照组(75例)和治疗组(75例)。对照组口服恩格列净片,10 mg/次,1次/d;治疗组在对照组治疗基础上口服消渴清颗粒,6 g/次,3次/d。两组均经8周治疗后进行效果评价。观察两组的临床疗效,比较两组治疗前后血糖相关指标、血糖波动指标和血清学因子的变化情况。结果经治疗,治疗组的总有效率为98.67%,明显高于对照组(82.67%,P<0.05)。经治疗,治疗组空腹血糖(FPG)、餐后2 h血糖(2 h PG)、糖化血红蛋白(HbAlc)、胰岛素(FINS)水平均较治疗前显著降低(P<0.05);治疗后,治疗组血糖相关指标低于对照组(P<0.05)。经治疗,两组HOMA-β均增高,而HOMA-IR均降低(P<0.05);治疗后,治疗组HOMA-β高于对照组,而HOMA-IR低于对照组(P<0.05)。经治疗,两组患者血糖标准差(SDBG)、平均血糖波动幅度(MAGE)、24h血糖波动次数(NGE)及24h血糖平均绝对差(MODD)均较治疗前显著降低(P<0.05);且治疗后,治疗组血糖波动指标显著低于对照组(P<0.05)。经治疗,两组血清趋化素、生长分化因子-15(GDF-15)、单核细胞趋化蛋白-1(MCP-1)、淀粉样蛋白A(SAA)水平均显著降低,但1-磷酸鞘氨醇(SIP)显著升高(P<0.05);治疗后,治疗组趋化素、GDF-15、MCP-1、SAA水平低于对照组,而SIP高于对照组(P<0.05)。结论消渴清颗粒联合恩格列净治疗2型糖尿病患者具有较好的临床疗效,可有效降低患者血糖水平,改善机体趋化素、GDF-15、MCP-1、SAA、SIP水平,并有效保护胰岛β细胞功能,有着良好的临床应用价值。     

Cardiac and kidney benefits of empagliflozin in heart failure across the spectrum of kidney function: Insights from the EMPEROR-Preserved trial

Aim

In the EMPEROR-Preserved trial, empagliflozin improved clinical outcomes of patients with heart failure (HF) with preserved ejection fraction. In this pre-specified analysis, we aim to study the effect of empagliflozin on cardiovascular and kidney outcomes across the spectrum of kidney function.

Methods and results

Patients were categorized by the presence or absence of chronic kidney disease (CKD) at baseline (CKD defined by an estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m² or urine albumin to creatinine ratio >300 mg/g). The primary and key secondary outcomes were (i) a composite of cardiovascular death or first HF hospitalization (primary outcome); (ii) total number of HF hospitalization, (iii) eGFR slope; and a pre-specified exploratory composite kidney outcome including a sustained ≥40% decline in eGFR, chronic dialysis or renal transplant. The median follow-up was 26.2 months. A total of 5988 patients were randomized to empagliflozin or placebo, of whom 3198 (53.5%) had CKD. Irrespective of CKD status, empagliflozin reduced the primary outcome (with CKD: hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.69–0.94; without CKD: HR 0.75, 95% CI 0.60–0.95; interaction p = 0.67) and total (first and recurrent) hospitalizations for HF (with CKD: HR 0.68, 95% CI 0.54–0.86; without CKD: HR 0.89, 95% CI 0.66–1.21; interaction p = 0.17). Empagliflozin slowed the slope of eGFR decline by 1.43 (1.01–1.85) ml/min/1.73 m²/year in patients with CKD and 1.31 (0.88–1.74) ml/min/1.73 m²/year in patients without CKD (interaction p = 0.70). Empagliflozin did not reduce the pre-specified kidney outcome in patients with or without CKD (with CKD: HR 0.97, 95% CI 0.71–1.34; without CKD: HR 0.92, 95% CI 0.58–1.48; interaction p = 0.86) but slowed progression to macroalbuminuria and reduced the risk of acute kidney injury. The effect of empagliflozin on the primary composite outcome and the key secondary outcomes was consistent across five baseline eGFR categories (all interaction p >0.05). Empagliflozin was well tolerated independent of CKD status.

Conclusions

In EMPEROR-Preserved, empagliflozin had a beneficial effect on the key efficacy outcomes in patients with and without CKD. Overall, the benefit and safety of empagliflozin was consistent across a wide range of kidney function spectrum, down to a baseline eGFR of 20 ml/min/1.73 m².     

Pharmacokinetics,pharmacodynamics, safety and tolerability of 4 weeks' treatment with empagliflozin in Japanese patients with type 2 diabetes mellitus

Introduction

To evaluate the pharmacodynamics, pharmacokinetics, safety and tolerability of empagliflozin in Japanese patients with type 2 diabetes mellitus.

Materials and methods

In this 4‐week, multiple dose, randomized, parallel‐group, double‐blind, placebo‐controlled trial, patients (n = 100) were randomized to receive 1, 5, 10 or 25 mg of empagliflozin, or placebo once daily. Key end‐points were urinary glucose excretion (UGE), fasting plasma glucose (FPG) and eight‐point glucose profile.

Results

Data are presented for 1, 5, 10, 25 mg of empagliflozin and placebo groups, respectively. Adjusted mean changes from baseline to day 27 in UGE were 40.8, 77.1, 80.9, 93.0 and −2.1 g (P < 0.0001 for all empagliflozin groups vs placebo). Adjusted mean changes from baseline to day 28 in FPG were −1.56, −1.96, −2.31, −2.37 and −0.86 mmol/L (P < 0.01 for all empagliflozin groups vs placebo). Adjusted mean changes from baseline to day 27 in eight‐point glucose profile were −1.96, −2.21, −2.42, −2.54 and −0.97 mmol/L (P < 0.01 for all empagliflozin groups vs placebo). Empagliflozin reached peak plasma concentration 1.5–2 h after dosing. Mean steady state terminal elimination half‐lives ranged from 13.2 to 18.0 h. Of 100 patients, 25 experienced an adverse event, occurring more frequently for empagliflozin (29.1%) than placebo (9.5%); frequency was not dose related.

Conclusions

In Japanese patients with type 2 diabetes mellitus, empagliflozin at doses up to 25 mg once daily for 4 weeks was well tolerated and resulted in significant improvements in glycemic control compared with placebo. This trial was registered with ClinicalTrials.gov (no. NCT00885118).