Cost-utility of empagliflozin in patients with type 2 diabetes at high cardiovascular risk

Aims

In the Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG) trial, empagliflozin reduced cardiovascular and all-cause mortality in type 2 diabetes (T2D) patients at high cardiovascular risk. We sought to estimate the cost-effectiveness of empagliflozin versus standard treatment for the prevention of cardiovascular morbidity and mortality in patients with T2D.

Safety and efficacy of empagliflozin in elderly Japanese patients with type 2 diabetes mellitus: A post hoc analysis of data from the SACRA study

Elderly diabetic patients are likely to have uncontrolled nocturnal hypertension, which confers higher risks of cardiovascular events and heart failure. To investigate the efficacy and safety of empagliflozin in elderly patients with type 2 diabetes (T2DM), a sub‐analysis was performed of data from the SGLT2 inhibitor and Angiotensin receptor blocker Combination theRapy in pAtients with diabetes and uncontrolled nocturnal hypertension (SACRA) study, a multi‐center, double‐blind, randomized, parallel study of T2DM patients who were treated with empagliflozin for 12 weeks. In the present analysis, we compared efficacy and safety outcomes in participants aged <75 and ≥75 years. At baseline, 44 participants were ≥75 years and 87 were <75 years. Nighttime ambulatory systolic blood pressure (SBP) decreased by 4.2 mm Hg in the ≥75‐year‐old group and by 7.9 mm Hg in the <75‐year‐old group (p = .884 for the between‐age group difference in the change between baseline and week 12) [primary endpoint]. Empagliflozin, but not placebo, significantly reduced mean 24‐h SBP (−8.7 mm Hg in ≥75‐year‐olds vs. −11.0 mm Hg in <75‐year‐olds) and daytime SBP (−10.8 mm Hg in ≥ 75‐year‐olds vs. −12.3 mm Hg in <75‐year‐olds) between baseline and week 12, with no significant differences between the groups. In addition, there were significant reductions in glycated hemoglobin, body weight, and uric acid during 12 weeks of empagliflozin treatment in the two age groups. The incidences of hypoglycemic episodes, hypotension, and metabolic adverse events were similar in the two groups. Thus, empagliflozin was effective and well tolerated in elderly diabetic patients with uncontrolled nocturnal hypertension when administered for 12 weeks.     

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.     

The ratio of free triiodothyronine to free thyroxine is regulated differently in patients with type 2 diabetes mellitus treated and not treated with sodium glucose cotransporter 2 inhibitors

Background and aimsTriiodothyronine reduces sodium glucose cotransporter 2 expression in the kidney and increased glucose excretion in urine of alloxan-induced diabetic rats. Free thyroxine is also negatively associated with islet beta-cell function in euthyroid subjects. However, the influence of sodium glucose cotransporter 2 inhibitor on thyroid function in patients with type 2 diabetes mellitus has not been established.MethodsWe investigated thyroid function in patients with type 2 diabetes mellitus in the presence or absence of sodium glucose cotransporter 2 inhibitor in a multicenter retrospective study conducted between 2019 and 2021. All participants visited the hospital monthly for type 2 diabetes mellitus treatment and plasma glucose and glycated hemoglobin level measurements. Furthermore, thyroid-stimulating hormone, free triiodothyronine, and free thyroxine levels were measured annually.ResultsFree triiodothyronine level and the free triiodothyronine:free thyroxine ratio in the group treated with sodium glucose cotransporter 2 inhibitor were significantly higher than the levels in the group not treated with sodium glucose cotransporter 2 inhibitor. Free triiodothyronine levels in the group treated with sodium glucose cotransporter 2 inhibitor were significantly higher than the levels in the group not treated with sodium glucose cotransporter 2 inhibitor (p = 0.040). Free thyroxine levels in the group treated with sodium glucose cotransporter 2 inhibitor were significantly lower than the levels in the group not treated with sodium glucose cotransporter 2 inhibitor (p = 0.002). Thyroid-stimulating hormone levels did not differ significantly between the two groups.ConclusionsOur findings show that sodium glucose cotransporter 2 inhibitor affects free triiodothyronine levels free thyroxine levels, and the free triiodothyronine:free thyroxine ratio.     

Metabolic and hemodynamic effects of sodium‐dependent glucose cotransporter 2 inhibitors on cardio‐renal protection in the treatment of patients with type 2 diabetes mellitus

The specific sodium–glucose cotransporter 2 inhibitors (SGLT2 inhibitors) inhibit glucose reabsorption in proximal renal tubular cells, and both fasting and postprandial glucose significantly decrease because of urinary glucose loss. As a result, pancreatic β‐cell function and peripheral insulin action significantly improve with relief from glucose toxicity. Furthermore, whole‐body energy metabolism changes to relative glucose deficiency and triggers increased lipolysis in fat cells, and fatty acid oxidation and then ketone body production in the liver during treatment with SGLT2 inhibitors. In addition, SGLT2 inhibitors have profound hemodynamic effects including diuresis, dehydration, weight loss and lowering blood pressure. The most recent findings on SGLT2 inhibitors come from results of the Empagliflozin, Cardiovascular Outcomes and Mortality in Type 2 Diabetes trial. SGLT2 inhibitors exert extremely unique and cardio‐renal protection through metabolic and hemodynamic effects, with long‐term durability on the reduction of blood glucose, bodyweight and blood pressure. Although a site of action of SGLT2 inhibitors is highly specific to inhibit renal glucose reabsorption, whole‐body energy metabolism, and hemodynamic and renal functions are profoundly modulated during the treatment of SGLT2 inhibitors. Previous studies suggest multifactorial clinical benefits and safety concerns of SGLT2 inhibitors. Although ambivalent clinical results of this drug are still under active discussion, the present review summarizes promising recent evidence on the cardio‐renal and metabolic benefits of SGLT2 inhibitors in the treatment of type 2 diabetes.     

Efficacy and safety of empagliflozin in people with type 2 diabetes during Ramadan fasting

Background and aimsTo explore efficacy and safety of empagliflozin in people with type2 diabetes during Ramadan fastingMethodsPeople with type2 diabetes (T2DM) who were taking empagliflozin and sulphonylurea with or without a metformin and dipeptidyl peptidase inhibitors (DPP4) recruited a month before Ramadan. Glycated hemoglobin (HbA1c) and estimated glomerular filtration rate (eGFR) were recorded pre- and post-Ramadan. A predesigned diary was given to the participants to keep track of their T2DM status during Ramadan. The proportion of the people who had hypoglycaemia, or any adverse event related to the study drug was assessed after-Ramadan.ResultsA total of 116 participants completed the study. Symptomatic episodes of hypoglycaemia were more common among people who used sulphonylurea (i.e., 8.6%). Genitourinary infections and volume depletion events were recorded more in people on empagliflozin i.e., (6.9% and 5.17%, respectively). A significant reduction in body mass index (BMI), and HbA1c was noted among people on empagliflozin post Ramadan. A significant reduction in eGFR was noted only in people who were taking empagliflozin in combination with metformin.ConclusionEmpagliflozin was found to be safe and effective in fasting people with T2DM. Further large-scale studies are needed to validate our findings.     

Sodium–glucose cotransporter inhibition: therapeutic potential for the treatment of type 2 diabetes mellitus

Results from randomized controlled trials have demonstrated that the risk of microvascular complications can be reduced by intensive glycaemic control in patients with type 2 diabetes mellitus (T2DM). However, only about half of patients with diagnosed diabetes achieve recommended glycaemic goals. New therapies with complementary mechanisms of action that are independent of insulin secretion or action may provide additional therapeutic options to enable patients to achieve glycaemic control. The kidney plays an important role in glucose homeostasis, primarily by the reabsorption of filtered glucose. The sodium–glucose cotransporter 2 (SGLT2), located in the proximal convoluted tubule, is responsible for the majority of glucose reabsorption by the kidney. SGLT2 inhibitors offer a novel approach to treat T2DM and reduce hyperglycaemia by increasing urinary excretion of glucose. Dapagliflozin, an SGLT2 inhibitor recently approved in Europe for the treatment of T2DM, improves glycaemic control in patients with T2DM when used as monotherapy or when added to other diabetes medications, such as metformin, sulfonylureas, pioglitazone, and insulin. As a class, SGLT2 inhibitors are well tolerated and have a low propensity to cause hypoglycaemia. An increase in signs, symptoms, and other events suggestive of genital and, in some studies, urinary tract infections has been reported with SGLT2 inhibitors. Results from ongoing and future clinical trials will help define the role for this new class of investigational compounds, with its unique mechanism of action, as a treatment option for reducing hyperglycaemia in patients with T2DM. Copyright © 2013 John Wiley & Sons, Ltd.     

Use of sodium–glucose cotransporter 2 inhibitors in older patients with type 2 diabetes mellitus

Aim

Sodium–glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic agents that act on the proximal renal tubules to lower blood glucose levels by inhibiting glucose reabsorption and promoting urinary glucose excretion. The present study assessed the long‐term use of SGLT2 inhibitors in older patients with diabetes.

Methods

A total of 117 older patients with type 2 diabetes who were given SGLT2 inhibitors were enrolled from April 2014 to March 2016.

Results

The mean age of the patients was 73.7 ± 10.0 years. During the follow‐up period (mean 289.3 days), there was no event associated with oral administration of SGLT2 inhibitors. These drugs significantly lowered fasting blood glucose and glycosylated hemoglobin levels at 6 months, and did not affect the creatinine level, blood urea nitrogen/creatinine ratio or estimated glomerular filtration rate during treatment. Although the treatment significantly increased hemoglobin and hematocrit levels, it did not affect the ultrasonographically determined diameter of the inferior vena cava, and no signs of intravascular collapse were observed. Changes in brain natriuretic peptide levels during the follow‐up period were assessed in 78 patients with a brain natriuretic peptide level exceeding the normal upper limit before treatment with SGLT2 inhibitors. The brain natriuretic peptide levels significantly decreased after 6 months of treatment.

Conclusions

In older Japanese patients with diabetes, treatment with SGLT2 inhibitors for 6 months exerted a favorable hypoglycemic effect, while no sign of dehydration was observed. Geriatr Gerontol Int 2018; 18: 108–114 .     

Pharmacokinetics and pharmacodynamics of dapagliflozin, a novel selective inhibitor of sodium-glucose co-transporter type 2, in Japanese subjects without and with type 2 diabetes mellitus

Aims: Dapagliflozin, a selective, orally active inhibitor of the renal sodium–glucose co‐transporter type 2 (SGLT2) is in development for the treatment of type 2 diabetes mellitus (T2DM). Here, the pharmacokinetics (PK) and pharmacodynamics (PD) of dapagliflozin were evaluated in healthy Japanese subjects and in Japanese subjects with T2DM. Methods: Two studies were conducted: a single‐ascending dose (SAD) study (2.5–50 mg) in 32 healthy subjects and a multiple‐ascending dose (MAD) study (2.5–20 mg QD for 14 days) in 36 subjects with T2DM. Safety and tolerability were assessed in both studies. Single and multiple dose PK of dapagliflozin and its inactive major metabolite, dapagliflozin 3‐O‐glucuronide, and PD (urinary glucose parameters) were characterized. Plasma glucose parameters were assessed over 14 days in the MAD study. Results: No serious adverse events or discontinuations due to adverse events occurred in either study. In healthy and T2DM subjects, dapagliflozin was rapidly absorbed with a time to maximum plasma concentration of 0.5–1.3 h. Systemic exposure of dapagliflozin and dapagliflozin 3‐O‐glucuronide, measured by maximum plasma concentration and area under the plasma concentration–time curve, increased proportional to dose. On a molar basis, systemic exposure to dapagliflozin 3‐O‐glucuronide was similar to parent dapagliflozin. There was a dose‐related increase in the amount of glucose excreted in the urine (SAD and MAD), which was associated with dose‐related decreases in plasma glucose parameters in subjects with T2DM (MAD). Conclusions: Dapagliflozin was well tolerated and showed predictable dose‐proportional PK and PD parameters in both healthy and T2DM Japanese subjects.     

Efficacy and safety of canagliflozin alone or as add‐on to other oral antihyperglycemic drugs in Japanese patients with type 2 diabetes: A 52‐week open‐label study

Aims/Introduction

Canagliflozin is a sodium–glucose cotransporter 2 inhibitor under development for the treatment of type 2 diabetes. Our aim was to examine its efficacy and safety as monotherapy or in combination with commonly used oral antihyperglycemic drugs in Japanese patients with type 2 diabetes.

Materials and Methods

Patients on diet/exercise alone or diet/exercise plus an oral antihyperglycemic drug (sulfonylurea, glinide, α-glucosidase inhibitor, biguanide, thiazolidinedione or dipeptidyl peptidase-4 inhibitor) were randomized to either 100 or 200 mg canagliflozin while continuing prior therapy. Patients were treated for 52 weeks in an open-label manner.

Results

Canagliflozin significantly reduced hemoglobin A1c, fasting plasma glucose and bodyweight in all the study groups. Improvements were apparent by 4 weeks of treatment, and were maintained for 52 weeks. The reduction in hemoglobin A1c ranged from −0.80 to −1.06%, and from −0.93 to −1.26% in the 100 and 200 mg canagliflozin groups, respectively. Drug-related adverse events occurred in approximately one-third of patients, and included hypoglycemia/asymptomatic hypoglycemia and pollakiuria. Hypoglycemia/asymptomatic hypoglycemia was most common in patients treated with a sulfonylurea. Most adverse events were classified as mild or moderate in severity.

Conclusions

The results of the present study confirmed that treatment with canagliflozin resulted in significant reductions in glycemic control and bodyweight that were maintained for 52 weeks of treatment irrespective of whether it was administered as monotherapy or in combination with another oral antihyperglycemic drug. Canagliflozin was well tolerated, with a low incidence of drug-related adverse events. This trial was registered with ClinicalTrials.gov (no. {"type":"clinical-trial","attrs":{"text":"NCT01387737","term_id":"NCT01387737"}}NCT01387737).     

The safety of dipeptidyl peptidase‐4 (DPP‐4) inhibitors or sodium‐glucose cotransporter 2 (SGLT‐2) inhibitors added to metformin background therapy in patients with type 2 diabetes mellitus: a systematic review and meta‐analysis

The aim of the present meta‐analysis was to assess the safety profile of dipeptidyl peptidase‐4 (DPP‐4) inhibitors and sodium‐glucose cotransporter 2 (SGLT‐2) inhibitors in comparison with placebo as add‐on to metformin therapy in patients with type 2 diabetes. Randomized controlled trials and controlled clinical trials were identified by searching Pubmed, Embase and the Cochrane Central Register of Controlled Trials database until 15 July 2013. All included studies were critically appraised and analysed with the use of Review Manager 5.1.0 software according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses statement protocol. Twenty randomized and double‐blinded studies published in 22 articles fulfilled the inclusion criteria for meta‐analysis. The overall results demonstrated that the use of oral antidiabetic agents (analysed separately and together) was not associated with any significantly increased risk of any serious adverse events including hypoglycaemia and gastrointestinal disorders. Moreover, the use of DPP‐4 or SGLT‐2 inhibitors significantly decreased risk of diarrhoea compared with placebo, when given concomitantly with metformin. However, we found that the SGLT‐2 inhibitors were more likely to cause a genital infection. Despite some limitations, the findings of this meta‐analysis indicate that DPP‐4 or SGLT‐2 inhibitors have favourable safety profile, and such therapy, when combined with metformin is well tolerated. Copyright © 2013 John Wiley & Sons, Ltd.     

Impact of empagliflozin in patients with diabetes and heart failure

Heart failure (HF) is a common disease with increased risk for mortality and morbidity among patients with type 2 diabetes mellitus (T2DM). Optimal glycemic control in this patient population is challenging as many available therapies can potentially exacerbate symptoms of HF. Empagliflozin is one in a novel class of agents, the sodium glucose co-transporter 2 (SGLT2) inhibitors, that lowers blood glucose by increasing urinary glucose excretion and improves glycemic control and lowers body weight and blood pressure. In the recent EMPA-REG OUTCOME trial, empagliflozin was shown to improve cardiovascular outcomes in patients with T2DM and established cardiovascular risk where it reduced HF hospitalizations and cardiovascular death, with a consistent benefit among patients both with and without baseline HF. Here, we review the empagliflozin data on HF outcomes and discuss potential mechanisms for its benefits in HF with a focus on the potentially significant impact that empagliflozin may have on the care of patients with T2DM and HF in the future.