Weight loss differences seen between glucagon-like peptide–1 receptor agonists and sodium–glucose cotransporter–2 inhibitors for treatment of type 2 diabetes

BackgroundWeight loss is an advantageous quality for diabetic medications because it can improve insulin sensitivity and glucose control and reduce cardiovascular risk factors and comorbidities. Glucagon-like peptide–1 (GLP-1) receptor agonists and sodium–glucose cotransporter–2 (SGLT-2) inhibitors are both preferred agents for use after metformin therapy, and both cause modest weight loss.ObjectiveThe aim of this study was to evaluate the difference in weight loss between GLP-1 receptor agonists and SGLT-2 inhibitors in patients with type 2 diabetes (T2D).MethodsThis was a retrospective study that was conducted at a level 3 patient-centered medical home in Buffalo, NY. The participants were adults with T2D treated with either a GLP-1 receptor agonist or an SGLT-2 inhibitor, in addition to background diabetes medications, between January 1, 2012, and September 20, 2017. The outcome measures included the median weight loss after 6 months of consecutive therapy compared between the 2 antidiabetic classes and the median differences in blood pressure, glycosylated hemoglobin (A1C) levels, and renal function markers compared between the 2 classes.ResultsA total of 73 patients were included in the final analysis, with 31 receiving SGLT-2 inhibitors and 42 receiving therapy with GLP-1 receptor agonists. The SGLT-2 inhibitor cohort presented a median weight loss of –2.80 kg (interquartile range [IQR] –5.40 to –1.50), and the GLP-1 receptor agonist cohort presented a median weight loss of –1.15 kg (IQR –3.38 to 0.975) (P = 0.014). There were no statistically significant differences in A1C levels, blood pressure, or renal function markers.ConclusionSGLT-2 inhibitors, when used in combination with background diabetes regimens, can lead to more statistically significant weight loss than GLP-1 receptor agonists without compromising renal function.     

Combination therapy of sodium–glucose co-transporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors in type 2 diabetes: rationale and evidences

No single antidiabetic agent can correct all the pathophysiologic defects manifested in type 2 diabetes mellitus (T2DM) and, therefore, multiple agents are often required to achieve optimal glycemic control. Combination therapies, having different mechanisms of action, not only have the potential to complement their action, but may possess the properties to counter the undesired compensatory response. Recent finding suggests that sodium–glucose co-transporter-2 inhibitors (SGLT2i) increase endogenous glucose production (EGP) from liver, due to the increase in glucagon which may offset its glucose-lowering potential. In contrast, dipeptidyl peptidase-4 inhibitors (DPP4i) decrease glucagon and EGP. Especially in the light of this finding, combination therapies with SGLT2i and DPP4i are particularly appealing, and are expected to produce an additive effect. Indeed, studies find no drug–drug interaction between SGLT2i and DPP4i. Moreover, significant reduction in glycated hemoglobin has also been observed. This article aims to review the efficacy and safety of combination therapy of SGLT2i and DPP4i in T2DM.     

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.     

Metabolite profiling and enzyme reaction phenotyping of luseogliflozin,a sodium–glucose cotransporter 2 inhibitor,in humans

1.?To understand the clearance mechanism of luseogliflozin, a sodium–glucose cotransporter 2 (SGLT2) inhibitor, we investigated its human metabolite profile and metabolic enzymes responsible for the primary metabolic pathways in human using reaction phenotyping.

2.?Sixteen metabolites of luseogliflozin were found in human plasma and/or urine and their structural information indicated that the drug was metabolized via multiple metabolic pathways. The primary metabolic pathways involve (1) O-deethylation to form M2 and subsequent glucuronidation to form M12, (2) ω-hydroxylation at ethoxy group to form M3 followed by oxidation to form the corresponding carboxylic acid metabolite (M17) and (3) direct glucuronidation to form M8.

3.?The reaction phenotyping studies indicated that the formation of M2 was mainly mediated by cytochrome P450 (CYP) 3A4/5, and subsequently M12 formation was catalyzed by UGT1A1, UGT1A8 and UGT1A9. The formation of M3 was mediated by CYP4A11, CYP4F2 and CYP4F3B, and the further oxidation of M3 to M17 was mediated by alcohol dehydrogenase and aldehyde dehydrogenase. The formation of M8 was catalyzed by UGT1A1.

4.?These results demonstrate that luseogliflozin is metabolized through multiple pathways, including CYP-mediated oxidation and glucuronidation, in human.     

Practical considerations for the use of sodium–glucose co-transporter type 2 inhibitors in treating hyperglycemia in type 2 diabetes

Sodium–glucose co-transporter type 2 (SGLT2) inhibitors are a new class of oral anti-diabetic agents with a unique, insulin-independent mode of action. In patients with diabetes who have adequate renal function, SGLT2 inhibitors reduce hyperglycemia by blocking renal glucose reabsorption and increasing urinary glucose excretion. These agents are indicated for the treatment of hyperglycemia in type 2 diabetes mellitus (T2DM), as an adjunct to diet and exercise. In terms of efficacy, they are comparable to most other oral agents, and carry a low risk of hypoglycemia unless combined with sulfonylureas or insulin. They may be used in combination regimens with metformin, sulfonylureas, or insulin. Beyond glucose lowering, SGLT2 inhibitors are associated with modest weight loss and mild anti-hypertensive effects. Emerging cardiovascular and renal outcomes data suggest other potentially beneficial non-glycemic effects, although these findings await confirmation from further studies. The main adverse effects are increased risk of volume depletion and of genitourinary infections, although these can be managed with standard interventions. Rare cases of euglycemic ketoacidosis have been reported in a subset of patients treated with these agents, an issue currently under investigation. SGLT2 inhibitors represent a promising alternative treatment option for T2DM patients in whom the effectiveness of oral anti-hyperglycemic therapy is limited by the risk of hypoglycemia, weight gain, or other adverse effects. Safety and efficacy (up to 4 years) have been demonstrated in a range of T2DM patient populations, although more studies will be needed to determine whether treatment with SGLT2 inhibitors improves patient-important outcomes in the longer term.     

Cardiovascular hazard of selective COX-2 inhibitors: myth or reality?

Since 1998, two selective inhibitors of COX-2 have been approved in many countries for the treatment of rheumatoid arthritis, osteoarthritis and acute pain. These new drugs have a significantly reduced gastrointestinal toxicity when compared with non-selective COX inhibitors. However, the results of two large clinical trials conducted in patients with osteoarthritis and rheumatoid arthritis have recently raised some concerns regarding the cardiovascular safety of these new drugs. The purpose of this paper is to review the potential mechanisms whereby selective COX-2 inhibitors could increase the cardiovascular risk of patients and to analyse the data indicating that this clinical risk indeed exists. The authors' analysis shows that even though there are pathophysiological mechanisms which could explain why selective COX-2 inhibition might increase the cardiovascular risk in patients, the actual level of evidence demonstrating that the risk is indeed increased is weak. Because of the importance of the issue, additional studies must be conducted with this class of agents. Meanwhile, it is crucial to emphasise that neither selective COX-2 inhibitors nor conventional NSAIDs replace aspirin in patients with a high cardiovascular risk.     

Discovery of novel N-β-D-xylosylindole derivatives as sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the management of hyperglycemia in diabetes

A novel series of N-linked β-D-xylosides were synthesized and evaluated for inhibitory activity against sodium-dependent glucose cotransporter 2 (SGLT2) in a cell-based assay. Of these, the 4-chloro-3-(4-cyclopropylbenzyl)-1-(β-D-xylopyranosyl)-1H-indole 19m was found to be the most potent inhibitor, with an EC(50) value similar to that of the natural SGLT2 inhibitor phlorizin. Further studies in Sprague-Dawley (SD) rats indicated that 19m significantly increased urine glucose excretion in a dose-dependent manner with oral administration. The antihyperglycemic effect of 19m was also observed in streptozotocin (STZ) induced diabetic SD rats. These results described here are a good starting point for further investigations into N-glycoside SGLT2 inhibitors.     

Luseogliflozin and other sodium-glucose cotransporter 2 inhibitors: no enemy but time?

Glycosuria is being increasingly recognised as not only a symptom but also as a novel therapeutic approach in the management of type 2 diabetes mellitus (T2DM). This is accomplished through sodium glucose co-transporter 2 (SGLT2) inhibitors. Consequently, the safety and efficacy of these new agents have been thoroughly studied, both in randomised controlled trials and in systematic reviews and meta-analyses. More recently, a review on the mechanism of action, clinical efficacy and safety of luseogliflozin, a new highly selective SGLT2 inhibitor approved and launched in Japan for T2DM, has documented that this drug lowers plasma glucose concentration and body weight, and that it exhibits benefits in other metabolic parameters with a good safety profile. Despite the promising characteristics of this drug, important issues await consideration. These include the question as to when and to whom early use of SGLT2 inhibitors would be most suitable, as well as instructions on reduction of sulfonylurea dosage during add-on treatment. Further important questions are long-term safety concerns and cost-effectiveness of this new therapeutic class. Finally, we need to know more about the potential differences between the various SGLT2 inhibitors, as such differences might prove clinically useful in selection of hypoglycaemic agents.     

Exposure?response modelling for empagliflozin,a sodium glucose cotransporter 2 (SGLT2) inhibitor,in patients with type 2 diabetes

Aims

To provide model-based clinical development decision support including dose selection guidance for empagliflozin, an orally administered sodium glucose cotransporter 2 inhibitor, through developed exposure−response (E−R) models for efficacy and tolerability in patients with type 2 diabetes mellitus (T2DM).

Methods

Five randomized, placebo-controlled, multiple oral dose studies of empagliflozin in patients with T2DM (n = 974; 1–100 mg once daily, duration ≤12 weeks) were used to develop E−R models for efficacy (glycosylated haemoglobin [HbA_1c], fasting plasma glucose [FPG] and urinary glucose excretion). Two studies (n = 748, 12 weeks) were used to evaluate tolerability E−R.

Results

The efficacy model predicted maximal decreases in FPG and HbA_1c of 16% and 0.6%, respectively, assuming a baseline FPG concentration of 8 mm (144 mg dl⁻¹) and 10–25 mg every day empagliflozin targeted 80–90% of these maximums. Increases in exposure had no effect on incidence rates of hypoglycaemia (n = 4), urinary tract infection (n = 17) or genital/vulvovaginal-related (n = 16) events, although low prevalence rates may have precluded more accurate evaluation.

Conclusions

E−R analyses indicated that 10 and 25 mg once daily empagliflozin doses achieved near maximal glucose lowering efficacy.     

Growth hormone secretagogue actions on the pituitary gland: multiple receptors for multiple ligands?

1. Growth hormone (GH) secretion is thought to occur under the reciprocal regulation of two hypothalamic hormones, namely GH-releasing hormone (GHRH) and somatostatin (SRIF), through their engagement with specific cell-surface receptors on the anterior pituitary somatotropes. 2. In addition to GHRH and SRIF, synthetic GH-releasing peptides (GHRP) or GH secretagogue(s) (GHS) regulate GH release through the activation of a novel receptor, the GHS receptor (GHS-R). 3. The cloning of the GHS-R from human, swine and rat identifies a novel G-protein-coupled receptor involved in the control of GH secretion and supports the existence of an undiscovered hormone that may activate this receptor. 4. Varieties of intracellular signalling systems are suggested to mediate the action of GHS, which include changes in intracellular free Ca2+ ([Ca2+]i), cAMP, protein kinases A and C, phospholipase C etc. 5. With regard to the use of signalling systems by GHS, especially a new form of GHRP or GHRP-2, a clear species difference has been demonstrated, supporting the possibility of more than one type of GHS-R.     

Long-term effects of BRAF inhibitors in melanoma treatment: friend or foe?

The clinical development of selective BRAF inhibitors for metastatic BRAF V600 mutant melanoma patients has been a major breakthrough in targeted therapeutics. Objective response rates of approximately 50% have been observed in the Phase III studies of the BRAF inhibitors vemurafenib and dabrafenib. The side effects can be relatively common, including proliferative skin toxicities. The latter range from hyperkeratosis and keratoacanthomas (KAs) to squamous cell carcinomas (SCCs) and new primary melanomas. In addition, case reports on the emergence of gastric/colonic polyps and RAS mutant malignancies have been described during BRAF inhibitor therapy. These events have been attributed to paradoxical activation of the MAPK pathway in BRAF wild-type cells exposed to selective BRAF inhibitors in addition to increased RAS activity. Combined BRAF and MEK inhibition appears to improve clinical outcomes and reduce cutaneous proliferation events as fewer KAs and SCCs have been observed with combination therapy. Next-generation pan-RAF inhibitors (‘paradox breakers’) and ERK inhibitors may further enhance clinical activity in metastatic BRAF-mutant melanoma patients and mitigate this paradoxical oncogenesis. Further investigation into the potential long-term effects of selective BRAF inhibitors is warranted as expanded use of these agents is expected in patients with BRAF-mutant melanoma and other malignancies.     

Inhibitory effects of vinpocetine on sodium current in rat cardiomyocytes

目的：研究长春西汀对心肌细胞钠电流的作用．方法：用全细胞膜片箝技术记录大鼠心肌细胞钠电流．结果：长春西汀可逆性抑制心肌细胞钠电流的作用为剂量依赖性和电压依赖性，但未发现频率或使用依赖性．长春西汀１０－８０μｍｏｌ·Ｌ－１，对钠电流的抑制作用为１３％±２％至７５％±６％．半数抑制浓度ＩＣ５０值（９５％可信限）为３６４（２８１－４７１）μｍｏｌ·Ｌ－１．在膜电位以１０ｍＶ的间隔从－９０ｍＶ阶梯状去极化至＋４０ｍＶ时，抑制作用呈逐渐增加的趋势，约在０ｍＶ左右达到最大抑制．长春西汀对钠通道的稳态激活和失活过程的影响，可使钠窗电流（缓慢失活的钠电流）减少．结论：长春西汀抑制大鼠心肌细胞的钠电流     

Guidelines for prevention and treatment of adverse effects of antipsychotic drugs on glucose–insulin homeostasis and lipid metabolism

Rationale With the antipsychotic drugs available today, especially with some of the newer, atypical antipsychotics, metabolic side effects, such as weight gain, diabetes mellitus and lipid abnormalities, have become a complication to the drug therapy that have to be recognized and treated.Objective The aim of this article is to suggest guidelines for prevention and treatment of adverse effects of antipsychotics on glucose–insulin homeostasis and lipid metabolism, whereas strategies for management of antipsychotic-induced weight gain are summarized elsewhere.Method The guidelines are based on results of experimental and clinical studies presented in the article, as well as on a recently published review of 180 articles in the field.Results Both conventional and atypical antipsychotics can indirectly, by causing obesity, promote development of insulin resistance and type-2 diabetes. In addition, some atypical agents probably directly induce hyperinsulinemia, followed by weight gain, insulin resistance and drug-induced, sometimes insulin-dependent, diabetes.Conclusion In this article, guidelines for the management of adverse metabolic effects of antipsychotics are described.     

Cardiovascular side effects of new antidepressants and antipsychotics: new drugs, old concerns?

The cardiovascular toxicity of older generation of tricyclic antidepressants (e.g. imipramine, desipramine, amitriptyline, clomipramine) and neuroleptics (e.g. haloperidol, droperidol, thioridazine, pimozide) is well established. These drugs inhibit cardiovascular Na(+), Ca(2+) and K(+) channels often leading to life-threatening arrhythmia. To overcome the toxicity of old generation of antidepressants and antipsychotics, selective serotonin reuptake inhibitor antidepressants (SSRIs: fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, venlafaxin) and several new antipsychotics (e.g. clozapine, olanzapine, risperidone, sertindole, aripiprazole, ziprasidone, quetiapine) were introduced during the past decade. Although these new compounds are not more effective in treating psychiatric disorders than older medications, they gained incredible popularity since they have been reported to have fewer and more benign side effect profile (including cardiovascular) than predecessors. Surprisingly, an increasing number of case reports have demonstrated that the use of SSRIs and new antipsychotics (e.g. clozapine, olanzapine, risperidone, sertindole, aripiprazole, ziprasidone, quetiapine) is associated with cases of arrhythmias, prolonged QTc interval on electrocardiogram (ECG) and orthostatic hypotension in patients lacking cardiovascular disorders, raising new concerns about the putative cardiovascular safety of these compounds. In agreement with these clinical reports these new compounds indeed show marked cardiovascular depressant effects in different mammalian and human cardiovascular preparations by inhibiting cardiac and vascular Na(+), Ca(2+) and K(+) channels. Taken together, these results suggest that the new generation of antidepressants and antipsychotics also have clinically important cardiac as well as vascular effects. Clinicians should be more vigilant about these potential adverse reactions and ECG control may be suggested during therapy, especially in patients with cardiovascular disorders. The primary goal of this review is to shed light on the recently observed clinically important cardiovascular effects of new antidepressants and antipsychotics and discuss the mechanism beyond this phenomenon.     

Nitrite–glucose–glucose oxidase system directly induces rat heart homogenate oxidation and tyrosine nitration: Effects of some flavonoids

Protein tyrosine nitration is a common post-translational modification occurring under conditions of nitrative/oxidative stress in a number of diseases. It has been found that in the presence of nitrite and hydrogen peroxide, hemoprotein catalyzes protein tyrosine nitration. In this paper, it was found that in heart homogenate, protein nitration and oxidation could be induced by a nitrite–glucose–glucose oxidase system without addition of exogenous heme or hemoprotein. Several structural diversity flavonoids (quercetin, rutin, baicalein, baicalin, apigenin, puerarin, and (+)-catechin) could, more or less, protect rat heart homogenate from oxidative and nitrative injury induced by nitrite–glucose–glucose oxidase in vitro. The inhibitory effects of flavonoids on protein nitration and lipid peroxidation were consistent with their antioxidant activities, whereas the inhibitory effects on protein oxidation were almost contrary to their antioxidant activities. These results mean that nitrite–glucose–glucose oxidase system can cause heart homogenate protein nitration and protein oxidation in different pathways, and those flavonoids with strong antioxidant activities may contribute their protective effect partly through inhibiting protein nitration.     

Relative potency of proton-pump inhibitors—comparison of effects on intragastric pH

Aim  Comparative potency of proton-pump inhibitors (PPIs) is an important clinical issue. Most available trials have compared the different PPIs at one or a few selected specific dosages, making it difficult to derive quantitative equivalence dosages. Here we derived PPI dose equivalents based on a comprehensive assessment of dose-dependent effects on intragastric pH. Methods  All available clinical studies reporting the effects of PPIs on mean 24-h intragastric pH were sought from electronic databases including Medline. Studies included were restricted to those targeting the Caucasian population, and healthy volunteers or gastroesophageal reflux disease (GERD) patients. The dose-effect relationships for mean 24-h intragastric pH and for percentage of time with pH > 4 in 24 h were analyzed for each PPI using pharmacodynamic modeling with NONMEM and a model integrating all available data. Results  Fifty-seven studies fulfilled the inclusion criteria. Based on the mean 24-h gastric pH, the relative potencies of the five PPIs compared to omeprazole were 0.23, 0.90, 1.00, 1.60, and 1.82 for pantoprazole, lansoprazole, omeprazole, esomeprazole, and rabeprazole, respectively. Compared with healthy volunteers, patients with GERD needed a 1.9-fold higher dose and Helicobacter pylori-positive individuals needed only about 20% of the dose to achieve a given increase in mean 24-h intragastric pH. Conclusion  The present meta-analysis provides quantitative estimates on clinical potency of individual PPIs that may be helpful when switching between PPIs and for assessing the cost-effectiveness of specific PPIs. However, our estimates must be viewed with caution because only a limited dose range has been tested and not exactly the same study conditions were applied for the different substances.