Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes

Hyperglycemia plays an important role in the pathogenesis of type 2 diabetes mellitus, i.e., glucotoxicity, and it also is the major risk factor for microvascular complications. Thus, effective glycemic control will not only reduce the incidence of microvascular complications but also correct some of the metabolic abnormalities that contribute to the progression of the disease. Achieving durable tight glycemic control is challenging because of progressive β-cell failure and is hampered by increased frequency of side effects, e.g., hypoglycemia and weight gain. Most recently, inhibitors of the renal sodium-glucose cotransporter have been developed to produce glucosuria and reduce the plasma glucose concentration. These oral antidiabetic agents have the potential to improve glycemic control while avoiding hypoglycemia, to correct the glucotoxicity, and to promote weight loss. In this review, we will summarize the available data concerning the mechanism of action, efficacy, and safety of this novel antidiabetic therapeutic approach.     

SGLT2抑制剂降低糖尿病患者心血管风险的研究进展

Na+-葡萄糖协同转运蛋白(SGLT)2抑制剂是一类新型降糖药物,通过抑制肾脏近端小管SGLT2对葡萄糖的重吸收而降低血糖.EMPA-REG OUTCOME试验表明,恩格列净可降低合并高危心血管风险的糖尿病患者的主要不良心血管事件.SGLT2抑制剂可能通过降低血压、降低血容量、促进钠盐排出、对肾脏血流动力学的改善、减轻体重、增加胰岛素敏感性、抑制心肌重构、降低尿酸等发挥其心血管保护作用,但其确切机制目前仍未明确.     

Sodium-glucose cotransporter type 2 inhibitors (SGLT2): from familial renal glucosuria to the treatment of type 2 diabetes mellitus

For centuries, the kidney has been considered primarily an organ of elimination and a regulator of salt and ion balance. Although once thought that the kidney was the structural cause of diabetes, which in recent years has been ignored as a regulator of glucose homeostasis, is now recognized as a major player in the field of metabolic regulation carbohydrate. During fasting, 55% of the glucose comes from gluconeogenesis. Only 2 organs have this capability: the liver and kidney. The latter is responsible for 20% of total glucose production and 40% of that produced by gluconeogenesis. Today we have a better understanding of the physiology of renal glucose transport via specific transporters, such as type 2 sodium-glucose cotransporter  (SGLT2). A natural compound, phlorizin, was isolated in early 1800 and for decades played an important role in diabetes and renal physiology research. Finally, at the nexus of these findings mentioned above, recognized the effect of phlorizin-like compounds in the renal glucose transporter, which has offered a new mechanism to treat hyperglycemia. This has led to the development of several potentially effective treatment modalities for the treatment of diabetes.     

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 .     

Effects of sodium glucose cotransporter type 2 inhibitors on heart failure

Heart failure (HF) is emerging as one of the most common cardiovascular (CV) events in patients with type 2 diabetes (T2D), and the one associated with the worst prognosis. T2D and insulin resistance are strong predictors of incident HF, especially HF with preserved ejection fraction (HFpEF). Recent data suggest that even when all traditional risk factors for ASCVD are well controlled, patients with T2D continue to have a substantially greater risk of developing HF—indicating that traditional risk factor control is insufficient from a HF prevention standpoint, and highlighting the need for novel, more effective strategies for both prevention and treatment of heart failure in patients with T2D. Until recently, medications developed for glucose-lowering had, at best, neutral effect on heart failure outcomes in patients with T2D, while several classes of T2D medications had little data in regards to HF risk, and others actually increased the risk of HF hospitalization. Sodium glucose cotransporter type 2 inhibitors (SGLT-2i) have a novel and unique mechanism of action. By inhibiting sodium and glucose reabsorption in the proximal tubule, SGLT-2i result in a number of downstream effects, including glucosuria, weight loss, osmotic diuresis and natriuresis, which should theoretically be beneficial in HF. Three CVOTs of various SGLT-2i (EMPA-REG OUTCOME, CANVAS and DECLARE-TIMI 58) enrolled markedly different patient populations in terms of ASCVD risk, but have demonstrated robust and consistent benefits in reduction of hospitalization for HF. In a meta-analysis of the three outcomes trials, SGLT-2i significantly reduced the risk of cardiovascular death or hospitalization for HF by 23% and hospitalization for HF by 31%. Although the declines in HF hospitalization with SGLT-2is are impressive, only a small proportion of patients with established HF were enrolled in these trials, and these benefits, therefore, represent primarily a HF prevention signal. Whether this prevention of HF benefit will translate to better outcomes for those patients with established HF (with or without diabetes), and whether it will extend across the spectrum of HF phenotypes (HFrEF and HFpEF) is yet to be determined, and is being actively investigated in several large ongoing trials.     

The potential of cinnamon to reduce blood glucose levels in patients with type 2 diabetes and insulin resistance

Aim: Cinnamon has a long history as an antidiabetic spice, but trials involving cinnamon supplementation have produced contrasting results. The aim of this review was to examine the results of randomized controlled clinical trials of cinnamon and evaluate the therapeutic potential amongst patients with diabetes and insulin-resistant patients, particularly the ability to reduce blood glucose levels and inhibit protein glycation.
Methods: A systematic electronic literature search using the medical subject headings 'cinnamon' and 'blood glucose' was carried out to include randomized, placebo-controlled in vivo clinical trials using Cinnamomum verum or Cinnamomum cassia conducted between January 2003 and July 2008.
Results: Five type 2 diabetic and three non-diabetic studies (total N = 311) were eligible. Two of the diabetic studies illustrated significant fasting blood glucose (FBG) reductions of 18–29% and 10.3% (p < 0.05), supported by one non-diabetic trial reporting an 8.4% FBG reduction (p < 0.01) vs. placebo, and another illustrating significant reductions in glucose response using oral glucose tolerance tests (p < 0.05). Three diabetic studies reported no significant results.
Conclusions: Whilst definitive conclusions cannot be drawn regarding the use of cinnamon as an antidiabetic therapy, it does possess antihyperglycaemic properties and potential to reduce postprandial blood glucose levels. Further research is required to confirm a possible correlation between baseline FBG and blood glucose reduction and to assess the potential to reduce pathogenic diabetic complications with cinnamon supplementation.     

Efficacy,renal safety and tolerability of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in elderly patients with type 2 diabetes: A real-world experience

AimsTo evaluate efficacy, renal safety and tolerability of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in a cohort of patients with type 2 diabetes (T2DM) aged ≥65 years.MethodsWe retrospectively evaluated 364 elderly individuals with T2DM starting SGLT2i from June 2015 to June 2018. Patients were divided into 2 subgroups based on median age (70 years). Linear mixed effect models were used to estimate changes in glycated hemoglobin (HbA1c), body mass index (BMI), and glomerular filtration rate (eGFR). SGLT2i discontinuation rate and causes of treatment interruption were also recorded.ResultsA significantly higher percentage of patients achieved HbA1c <7.5% (46.7% vs. 31.6%, p < 0.01) and <8.0% (68.9% vs. 47.2%, p < 0.01) compared to baseline. Each year of therapy was associated with an average HbA1c decrease of 0.34% (p < 0.01) and BMI loss of 0.71 kg/m² (p < 0.01), without significant interaction across age classes. In the younger group eGFR increased by 1.02 ml/min/year, while in the older group it declined by 0.42 ml/min/year (p = 0.08). Overall discontinuation rate during the follow-up period was similar across age groups (34.2% vs. 36.1%, long-rank p = 0.26). Genitourinary infections were the most frequent cause of treatment interruption (15.8% vs. 17.2%, p = 0.69) in both study groups, while persistent eGFR decline (4.4%) and orthostatic hypotension (1.7%) were only present in older age class.ConclusionsEfficacy, renal safety and tolerability of SGLT2i were similar in people >70 compared to 65–70 years of age, suggesting that a wider use should not be worried even in the elderly. However, some caution must be paid to the occurrence of persistent eGFR decline and orthostatic hypotension, especially in patients >70 years old.     

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.     

钠-葡萄糖协同转运蛋白2抑制剂改善2型糖尿病患者心血管结局的机制探讨

钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂是近年来在临床逐渐得到广泛应用的一类降糖药物。此外,目前的研究表明,除了安全有效的降糖效应以外,SGLT2抑制剂在改善心血管结局方面具有明确的益处,然而机制研究还尚不明确,目前的研究表明,SGLT2抑制剂可能从保护心脏结构和功能、延缓动脉粥样硬化进程、改善心血管高危因素等多个...     

The effect of sodium‐glucose cotransporter 2 inhibitors and glucagon‐like peptide 1 agonists on cardiovascular disease in patients with type 2 diabetes

Patients with type 2 diabetes have a significantly increased risk of cardiovascular disease (CVD) compared to the general population—with CVD accounting for two out of every three deaths in patients with diabetes. In 2008, the FDA suggested that CVD risk should be evaluated for any new antidiabetic therapy, leading to a multitude of large CVD outcome trials to assess CVD risk from these medications. Interestingly, several of these outcome trials with new novel antidiabetic therapies have demonstrated a clear and definite CVD advantage at mid‐term follow up in high‐risk patients with T2DM. In this review, we discuss two relatively new classes of diabetic drugs, sodium‐glucose cotransporter 2 inhibitors and glucagon‐like peptide 1 agonists, and their efficacy in improving cardiovascular outcomes.     

SGLT2 inhibitors in the treatment of type 2 diabetes

The kidney plays an important role in glucose homeostasis via its production, utilization, and, most importantly, reabsorption of glucose from glomerular filtrate which is largely mediated via the sodium glucose co-transporter 2 (SGLT2). Pharmacological inhibition of SGLT2 increases urinary glucose excretion and decreases plasma glucose levels in an insulin-independent manner. Agents that inhibit SGLT2 represent a novel class of drugs, which has recently become available for treatment of type 2 diabetes. This article summarizes the rationale for use of these agents and reviews available clinical data on their efficacy, safety, and risks/benefits.     

Use of flash glucose monitoring system in assessing safety of the SGLT2 inhibitors during Ramadan fasting in high risk insulin treated patients with type 2 diabetes

BackgroundThe risks of hypoglycemia, dehydration and kidney injury may theoretically be aggravated by people with type 2 diabetes treated with Insulin and SGLT2 inhibitors during Ramadan. Data on safety and efficacy of SGLT2-I in people with type 2 diabetes treated with insulin is scanty. We aimed to assess the impact of SGLT2 inhibitors during Ramadan in high-risk patients with type 2 diabetes treated with insulin, on hypoglycemia, glycemic control and kidney function.MethodsThis is a prospective interventional study on high-risk diabetes patients who insisted on fasting. All patients were treated with insulin ± SGLT2I. All patients received a FGMS and Ramadan focused education. All patients attended clinic before and post Ramadan where they were advised on treatment modification as well as biometric and biochemical measurements.Results95 patients enrolled in the study and 49 of them were on SGLT2i. There was a no significant change in creatinine in both groups. FGMS showed an improvement in the sensor-calculated HbA1c from 7.3 ± 1.5 to 6.8 ± 1.1 and from 8 ± 1.6 to 7.7 ± 1.5 in the SGLT2 group and the non-SGT2i groups, respectively. The hypoglycemia was predominantly reported during Ramadan between 12:00 to 18:00 h, while in pre-Ramadan readings was during 2400–0600 and 1200–1800 slots.ConclusionsThis is the first study that assesses the use of SGLT2i along with insulin during Ramadan, using FGMS in high-risk patients with type 2 diabetes under optimal care. There was minimal interruption of fasting, significant improvement in glycemic control, and no significant change in the kidney function after Ramadan.