Glucose-lowering Efficacy Research Articles

Bioactivity-guided separation of potential \u03b1-glycosidase inhibitor from clerodendranthus spicatus based on HSCCC coupled with molecular docking

Clerodendranthus Spicatus is a traditional Dais medi-edible plant and it has been proven to have good blood glucose-lowering efficacy. However, the material basis of Clerodendranthus Spicatus has not been clarified yet and therefore needs to be determined. In this paper, the effective ingredients of this medicine were purified by high-speed counter-current chromatography. Alongside, their potential hypoglycemic activity was determined by α-glucosidase inhibitory activities in vitro and molecular docking. Finally, five compounds were purified and identified as 2-caffeoyl-L-tartaric acid (1), N-(E)-caffeoyldopamine (2), rosmarinc acid (3), methyl rosmarinate (4), 6,7,8,3′,4′-Pentamethoxyflavone (5). Examination of α-glucosidase inhibitory activity in vitro showed that 2-caffeoyl-L-tartaric acid and rosmarinic acid had a higher inhibitory activity than acarbose. Molecular docking indicated that the affinity energy of the identified compounds ranged from − 7.6 to − 8.6 kcal/mol, a more desirable result than acarbose (− 6.6 kcal/mol). Particularly, rosmarinc acid with the lowest affinity energy of − 8.6 kcal/mol was wrapped with 6 hydrogen bonds. Overall, α-glucosidase inhibitory activities and molecular docking suggested that rosmarinc acid was likely to be a promising hypoglycemic drug.

S3-2, a novel long-lasting oxyntomodulin derivative, exerts improvement on diabesity and renal injury through activating GLP-1 and glucagon receptors

AimsTo prolong the short lifespan of oxyntomodulin (OXM) for treating obesity and diabetes, we designed a novel fused OXM analog, containing an albumin-binding sequence, a protease cleavable tetrapeptide, and a mutated OXM. Main methodsWe screened two albumin-binding sequences (S3 and S6) to construct OXM derivatives, termed S3-2 (with two cysteines) and S6-0 (without cysteine). After peptides were synthesized, isothermal titration calorimetry (ITC) was applied to assess binding-affinity for HSA. Further in vivo acute efficacies evaluation and candidate selection were performed in diabetic db/db mice via oral glucose tolerance test (OGTT) and glucose-lowering duration test. Chronic efficacy test of selected candidate was also performed in diabetic mice. ResultsFirstly, S3-2 and S6-0 with purity over 99% were prepared. ITC measurements demonstrated that S3-2 and S6-0 associate with HSA with high-affinity (Kd = 12.81 ± 1.11 nM and 26.98 ± 2.39 nM, respectively). Then hypoglycemic efficacies showed deoxidation S3-2 (S3-2re) showed longer hypoglycemic duration than the oxidation one (S3-2ox), and better blood glucose level (BGL) control effect than S6-0. OGTTs in diabetic mice revealed the glucose-lowering efficacies of S3-2re were similar to Liraglutide. The protracted antidiabetic effects of S3-2re were further confirmed by multiple OGTTs in db/db mice. Furthermore, twice weekly injection of S3-2re to db/db mice achieved beneficial effects on body weight gain, glucose tolerance, postprandial BGL and obesity. Moreover, S3-2 produces significantly protective effects on the impaired renal functions of the diabetic mice. ConclusionS3-2re exhibits outstanding therapeutical potential as a candidate drug for treating the obesity and diabetes.

High baseline FGF21 levels are associated with poor glucose-lowering efficacy of exenatide in patients with type 2 diabetes

To investigate the association between fibroblast growth factor 21 (FGF21) levels and glycemic response to exenatide in patients with type 2 diabetes. The exploratory analysis of a multi-center trial included 190 patients with type 2 diabetes inadequately controlled by monotherapy or combination therapy of metformin and insulin secretagogues. All participants received exenatide twice daily as an add-on therapy for 16weeks. Serum FGF21 and other information at the baseline and end of follow-ups were obtained. Linear regression analysis was used to determine the correlations between baseline FGF21 levels and HbA1c reduction from baseline after the treatment. After 16weeks of treatment with exenatide, a decline in the HbA1c levels from baseline was associated with higher baseline FGF21 levels among all participants (r = 0.193, P = 0.008) and in subgroup of the participants receiving background metformin monotherapy (r = 0.231, P = 0.034). Compared with patients in the lowest FGF21 quartile, patients in the highest FGF21 quartile showed a significantly weakened decline in HbA1c levels from baseline among all participants (β = - 0.16 [95% Cl - 0.31 to - 0.01], P < 0.05) and in subgroup of the participants receiving background metformin monotherapy (β = - 0.23 [95% Cl - 0.43 to - 0.03], P < 0.05), after adjusting for the confounding factors, including age, sex, and baseline HbA1c levels. The high baseline FGF21 levels are associated with poor glycemic responses to exenatide in patients with type 2 diabetes. Therefore, FGF21 could be used as a biomarker for predicting the efficacy of exenatide treatment. ChiCTR-IPR-15006558, date registered May 27, 2015.

Rational design and evaluation of GLP-1 derivative for treating hyperglycemia combined with overexercise-induced myocardial injury

AimsTo design and evaluate the anti-hyperglycemia and overexercise-induced myocardial injury efficacies of a novel long-acting glucagon-like peptide-1 (GLP-1)-based therapeutic peptide in rodent animals. Main methodsHere, we designed and prepared a new pro-drug, termed RYHSB-1, which was connected by a mutated GLP-1(A8G) and an albumin binding peptide via a protease-cleavable linker. Moreover, isothermal titration calorimetry (ITC) was applied to detect its binding affinity for HSA. GLP-1 release assay was conducted in mouse serum in vitro and quantified using LC-MS/MS method. Modified intraperitoneal glucose tolerance test (IPGTT), chronic efficacies study in rodent animals with overexercise-induced myocardial injury were subjected to evaluate the druggability of RYHSB-1. ResultsRYHSB-1 with purity over 99% was prepared and ITC measurement demonstrated high binding affinity for HSA with KD of 0.06 μM. Protease cleavage assay demonstrated slowly controlled-release of transient GLP-1 from RYHSB-1 under the hydrolysis catalyzed by thrombin in vitro. Moreover, IPGTT showed clearly dose-dependent glucose-lowering efficacies of RYHSB-1 within 0.1–0.9 mg/kg. The prolonged anti-diabetic efficacy of RYHSB-1 was further assessed via multiple IPGTTs and hypoglycemic duration test. Furthermore, long-term administration of RYHSB-1 in diabetic mice achieved promising efficacies on hyperglycemia and overexercise-induced myocardial injury. SignificanceRYHSB-1 holds outstanding pharmaceutical potential as an anti- overexercise-induced myocardial injury drug. The strategy of albumin-conjugation also could be applied to other active peptides develop long effecting therapeutic drugs.

Glucose-lowering efficacy of Xultophy with low doses by FreeStyle Libre as continuous glucose monitoring (CGM)

Glucose-lowering efficacy of Xultophy with low doses by FreeStyle Libre as continuous glucose monitoring (CGM)

Pharmacological Management of Diabetes for Reducing Glucose Levels and Cardiovascular Disease Risk: What Evidence in South Asians?

South Asians experience more type 2 diabetes, which is earlier in onset and with more rapid glycaemic deterioration, although average body mass indices are lower than in whites. Cardiovascular outcomes from diabetes drug trials are now reported as standard, with data from newer therapies influencing patient management. However, less is known of the effect of such therapies in South Asians. The aim of this narrative review was to extract, wherever possible, the glucose-lowering efficacy and cardiovascular and renal outcome data for these therapies in South Asians. Despite the higher prevalence and global burden of type 2 diabetes and adverse outcomes in South Asians, they remain underrepresented in global trials. Even when recruited, the current method of classifying ethnicity does not commonly allow South Asian data to be extracted and reported separately from all Asians. Interrogation of available trial data suggests broadly comparable effects on glycaemia and weight in Asians to other ethnicities with use of glucagon-like peptide 1 receptor agonists (GLP-1 RAs), but a potentially early, albeit marginally, greater glycaemia benefit with Dipeptidyl peptidase-4 inhibitors (DPP4is) which may not be sustained. Furthermore, there appears a potentially greater glycaemia benefit with use of sodium-glucose transport protein 2 inhibitors (SGLT2is) in Asians compared to whites. Whether such findings are true in all Asians subgroups requires further direct study. For cardiovascular outcomes, available data suggest at least comparable and potentially greater outcome benefits in Asians; point estimates were more favourable for Asians in the vast majority of GLP-1 RAs and SGLT2is outcome trials. It was, however, impossible to determine whether the effects were similar across all Asian subgroups. We conclude that trialists should be encouraged to record ethnicity with better granularity to allow differing ethnic groups data to be better interrogated. In the meantime, doctors should, where possible, confidently follow newer guidelines for the use of newer glucose lowering agents for treating glycaemia and for the prevention of cardiovascular and cardiorenal complications in South Asian people with type 2 diabetes.

Type 2 diabetes in the US managed care setting: the burden of disease and rationale for an oral glucagon-like peptide-1 receptor agonist.

Diabetes affects an estimated 34 million US adults, with type 2 diabetes (T2D) accounting for 90% to 95% of cases. The downstream consequences of uncontrolled T2D are substantial, including an increased risk of microvascular complications (eg, renal impairment, retinopathy, and peripheral neuropathy), cardiovascular disease, impaired quality of life, and death. Overall, diabetes places a significant strain on the US health care system, with 7.8 million hospitalizations annually among patients with diabetes, and $237 billion in direct medical costs. Injectable glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been available for T2D for over a decade, and are recommended, in particular, for patients with a compelling need to minimize hypoglycemia risk, curtail weight gain, or promote weight loss, and for patients with established cardiovascular disease. Despite being associated with high glucose-lowering efficacy, weight loss, and a low risk of hypoglycemia, injectable GLP-1RAs are relatively underutilized, and are associated with suboptimal adherence and persistence. These challenges may relate in part to the injectable route of administration, given that injection-related concerns have been linked with a failure to intensify T2D therapy in a timely manner (ie, therapeutic inertia), and are cited by patients as a barrier to initiating and persisting with injectable treatments. The approval of the first tablet formulation of a GLP-1RA for T2D, oral semaglutide, has the potential to address these challenges. In this context, we review the burden of T2D in the United States, the role of GLP-1RAs, the challenges of therapeutic inertia and poor adherence, and the rationale for an oral GLP-1RA, focusing on considerations for managed care.

Once-Weekly Insulin for Type 2 Diabetes without Previous Insulin Treatment

BackgroundIt is thought that a reduction in the frequency of basal insulin injections might facilitate treatment acceptance and adherence among patients with type 2 diabetes. Insulin icodec is a basal insulin analogue designed for once-weekly administration that is in development for the treatment of diabetes.MethodsWe conducted a 26-week, randomized, double-blind, double-dummy, phase 2 trial to investigate the efficacy and safety of once-weekly insulin icodec as compared with once-daily insulin glargine U100 in patients who had not previously received long-term insulin treatment and whose type 2 diabetes was inadequately controlled (glycated hemoglobin level, 7.0 to 9.5%) while taking metformin with or without a dipeptidyl peptidase 4 inhibitor. The primary end point was the change in glycated hemoglobin level from baseline to week 26. Safety end points, including episodes of hypoglycemia and insulin-related adverse events, were also evaluated.ResultsA total of 247 participants were randomly assigned (1:1) to receive icodec or glargine. Baseline characteristics were similar in the two groups; the mean baseline glycated hemoglobin level was 8.09% in the icodec group and 7.96% in the glargine group. The estimated mean change from baseline in the glycated hemoglobin level was −1.33 percentage points in the icodec group and −1.15 percentage points in the glargine group, to estimated means of 6.69% and 6.87%, respectively, at week 26; the estimated between-group difference in the change from baseline was −0.18 percentage points (95% CI, –0.38 to 0.02, P=0.08). The observed rates of hypoglycemia with severity of level 2 (blood glucose level, <54 mg per deciliter) or level 3 (severe cognitive impairment) were low (icodec group, 0.53 events per patient-year; glargine group, 0.46 events per patient-year; estimated rate ratio, 1.09; 95% CI, 0.45 to 2.65). There was no between-group difference in insulin-related key adverse events, and rates of hypersensitivity and injection-site reactions were low. Most adverse events were mild, and no serious events were deemed to be related to the trial medications.ConclusionsOnce-weekly treatment with insulin icodec had glucose-lowering efficacy and a safety profile similar to those of once-daily insulin glargine U100 in patients with type 2 diabetes. (Funded by Novo Nordisk; NN1436-4383 ClinicalTrials.gov number, NCT03751657.)

Magnoflorine prevent the skeletal muscle atrophy via Akt/mTOR/FoxO signal pathway and increase slow-MyHC production in streptozotocin-induced diabetic rats

Ethnopharmacological relevanceTinospora cordifolia (TC) is being used as a blood purifier in Ayurveda since ancient time. It is a very popular immunomodulator and holds anti-inflammatory and anti-oxidative potential, hence anti-aging properties. Therefore, it is also known as ‘Amrita’ in Ayurveda and is widely used to treat diabetes mellitus type II (T2DM) and its secondary complications; however, its underlying mechanism was not expedited to date. Aim-To explore the in vivo therapeutic efficiency and mechanism of action of TC and its secondary constitute magnoflorine on the skeletal muscle atrophy in the rat model of T2DM. MethodAnimal model of T2DM was developed using streptozotocin (STZ) injection followed by intervention with TC, metformin, and magnoflorine for three weeks. Confirmation of T2DM and abrogation of atrophic markers and possible mechanisms on supplementation of TC and magnoflorine were explored using histology, bio-assays, Western blotting, and q-PCR. ResultTC and Magnoflorine supplementations significantly (p ≤ 0.05) decreased the fasting blood glucose (FBG) levels in T2DM rats. Both treatments prevented the lean body, individual skeletal muscle mass, and myotubes diameter loss (p ≤ 0.05). Magnoflorine significantly reduced the degradation of the protein indicated by biochemical markers of atrophy i.e. decreased serum creatine kinase (CK) levels and increased myosin heavy chain-β (MyHC-β) levels in muscles. Q-PCR and western blotting supported the findings that magnoflorine significantly increased the mRNA and protein abundances (~3 fold) of MyHC-β.TC and magnoflorine efficiently decreased the expression of ubiquitin-proteasomal E3-ligases (Fn-14/TWEAK, MuRF1, and Atrogin 1), autophagy (Bcl-2/LC3B), and caspase related genes along with calpains activities in T2DM rats. Both TC and magnoflorine also increased the activity of superoxide dismutase, GSH-Px, decreased the activities of β-glucuronidase, LPO, and prevented any alteration in the catalase activity. In contrast, magnoflorine increased expression of TNF-α and IL-6 whereas TC and metformin efficiently decreased the levels of these pro-inflammatory cytokines (p ≤ 0.05). However, magnoflorine was found to increase phosphorylation of Akt more efficiently than TC and metformin. ConclusionTC, and magnoflorine are found to be effective to control fasting blood glucose levels significantly in T2DM rats. It also promoted the Akt phosphorylation, suppressed autophagy and proteolysis that might be related to blood glucose-lowering efficacy of magnoflorine and TC. However, increased muscle weight, specifically of the soleus muscle, expression of IL-6, and slow MyHC indicated the increased myogenesis in response to magnoflorine and independent from its hypoglycemic activity.

Harms and benefits fo sodium-glucose co-transporter 2 inhibitors

SUMMARY Sodium-glucose co-transporter 2 inhibitors are oral glucose-lowering drugs that increase the urinary excretion of glucose. In patients with type 2 diabetes and cardiovascular disease they reduce all-cause mortality, cardiac mortality, rates of hospitalisation for heart failure and the progression of renal diseaseThere are adverse effects related to the mechanism of action. These include polyuria and intravascular volume depletion from osmotic diuresis, and genitourinary infections from glycosuria. Ketoacidosis is a rare adverse effectThe glucose-lowering efficacy of sodium-glucose co-transporter 2 inhibitors decreases with increasing renal impairment

Hypoglycemic efficacy and safety of Momordica charantia (bitter melon) in patients with type 2 diabetes mellitus

IntroductionMomordica charantia (bitter melon) is widely used for its glucose-lowering effects. This study was conducted to assess the efficacy and safety of M. charantia as an adjuvant treatment in patients with type 2 diabetes. MethodsWe performed a randomized, placebo-controlled study. Blood glucose levels, lipid profile, and adverse events were investigated after 12 weeks of treatment. Ninety subjects were included in the final analysis for glucose lowering efficacy of bitter melon. ResultsThere were no differences in age, sex, or glycated hemoglobin (HbA1c) levels between the bitter melon extract and placebo groups. After treatment with bitter melon extract for 12 weeks, the HbA1c levels of the bitter melon and placebo groups remained unchanged; however, the average fasting glucose level of the bitter melon group decreased (p = 0.014). No serious adverse events were reported during the treatment period. ConclusionsOur data showed that bitter melon has effects of glucose lowering in patients with type 2 diabetes.

Development of disulfide-derived fructose-1,6-bisphosphatase (FBPase) covalent inhibitors for the treatment of type 2 diabetes

Fructose-1,6-bisphosphatase (FBPase), as a key rate-limiting enzyme in the gluconeogenesis (GNG) pathway, represents a practical therapeutic strategy for type 2 diabetes (T2D). Our previous work first identified cysteine residue 128 (C128) was an important allosteric site in the structure of FBPase, while pharmacologically targeting C128 attenuated the catalytic ability of FBPase. Herein, ten approved cysteine covalent drugs were selected for exploring FBPase inhibitory activities, and the alcohol deterrent disulfiram displayed superior inhibitory efficacy among those drugs. Based on the structure of lead compound disulfiram, 58 disulfide-derived compounds were designed and synthesized for investigating FBPase inhibitory activities. Optimal compound 3a exhibited significant FBPase inhibition and glucose-lowering efficacy in vitro and in vivo. Furthermore, 3a covalently modified the C128 site, and then regulated the N125–S124–S123 allosteric pathway of FBPase in mechanism. In summary, 3a has the potential to be a novel FBPase inhibitor for T2D therapy.

Efficacy of Modern Diabetes Treatments DPP-4i, SGLT-2i, and GLP-1RA in White and Asian Patients With Diabetes: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUNDThe pathophysiology of type 2 diabetes differs markedly by ethnicity.PURPOSEA systematic review and meta-analysis was conducted to assess the impact of ethnicity on the glucose-lowering efficacy of the newer oral agents, sodium–glucose cotransporter 2 inhibitors (SGLT-2i), glucagon-like peptide 1 receptor agonists (GLP-1RA), and dipeptidyl peptidase 4 inhibitors (DPP-4i), using evidence from randomized clinical trials (RCTs).DATA SOURCESA literature search was conducted in PubMed of all randomized, placebo-controlled trials of DPP-4i, SGLT-2i, and GLP-1RA. The search strategy was developed based on Medical Subject Headings (MeSH) terms and keywords.STUDY SELECTIONA total of 64 studies that qualified for meta-analysis after full-text review based on predefined inclusion and exclusion criteria—RCTs with at least 50 patients in each arm, >70% of population from Asian or white group, duration ≥24 weeks, and publication up to March 2019—were selected for systematic review and meta-analysis.DATA EXTRACTIONData extraction was done for aggregated study-level data by two independent researchers. Absolute changes in HbA1c (%) from baseline to 24 weeks between the drug and placebo were considered as the primary end point of the study.DATA SYNTHESISChange in HbA1c was evaluated by computing mean differences and 95% CIs between treatment and placebo arms.LIMITATIONSThe study is based on summarized data and could not be separated based on East Asians and South Asians.CONCLUSIONSThe glucose-lowering efficacy of SGLT-2i, and to a lesser extent DPP-4i, was greater in studies of predominantly Asian ethnicity compared with studies of predominantly white ethnicity. There was no difference seen by ethnicity for GLP-1RA.

In Situ Forming Injectable Thermoresponsive Hydrogels for Controlled Delivery of Biomacromolecules.

Due to their relatively large molecular sizes and delicate nature, biologic drugs such as peptides, proteins, and antibodies often require high and repeated dosing, which can cause undesired side effects and physical discomfort in patients and render many therapies inordinately expensive. To enhance the efficacy of biologic drugs, they could be encapsulated into polymeric hydrogel formulations to preserve their stability and help tune their release in the body to their most favorable profile of action for a given therapy. In this study, a series of injectable, thermoresponsive hydrogel formulations were evaluated as controlled delivery systems for various peptides and proteins, including insulin, Merck proprietary peptides (glucagon-like peptide analogue and modified insulin analogue), bovine serum albumin, and immunoglobulin G. These hydrogels were prepared using concentrated solutions of poly(lactide-co-glycolide)–block-poly(ethylene glycol)–block-poly(lactide-co-glycolide) (PLGA–PEG–PLGA), which can undergo temperature-induced sol–gel transitions and spontaneously solidify into hydrogels near the body temperature, serving as an in situ depot for sustained drug release. The thermoresponsiveness and gelation properties of these triblock copolymers were characterized by dynamic light scattering (DLS) and oscillatory rheology, respectively. The impact of different hydrogel-forming polymers on release kinetics was systematically investigated based on their hydrophobicity (LA/GA ratios), polymer concentrations (20, 25, and 30%), and phase stability. These hydrogels were able to release active peptides and proteins in a controlled manner from 4 to 35 days, depending on the polymer concentration, solubility nature, and molecular sizes of the cargoes. Biophysical studies via size exclusion chromatography (SEC) and circular dichroism (CD) indicated that the encapsulation and release did not adversely affect the protein conformation and stability. Finally, a selected PLGA–PEG–PLGA hydrogel system was further investigated by the encapsulation of a therapeutic glucagon-like peptide analogue and a modified insulin peptide analogue in diabetic mouse and minipig models for studies of glucose-lowering efficacy and pharmacokinetics, where superior sustained peptide release profiles and long-lasting glucose-lowering effects were observed in vivo without any significant tolerability issues compared to peptide solution controls. These results suggest the promise of developing injectable thermoresponsive hydrogel formulations for the tunable release of protein therapeutics to improve patient’s comfort, convenience, and compliance.

Oral antidiabetes agents for the management of inpatient hyperglycaemia: so far, yet so close.

Hyperglycaemia is an ongoing challenge in hospital settings and is associated with poor outcomes. Current recommendations for the management of inpatient hyperglycaemia suggest insulin as the main glucose-lowering treatment choice and limit the administration of oral antidiabetes agents to a small proportion of cases because of safety concerns. To present and critically appraise the available evidence on the use of oral antidiabetes agents in the hospital setting and the risk-benefit balance of such an approach in the era of cardiovascular outcomes trials. PubMed, Embase and Google Scholar databases were searched to identify relevant published work. Available evidence on the efficacy and the safety profile of oral agents in the context of their use in hospitalized individuals are summarized and discussed in this narrative review. There is no robust evidence to suggest the use of metformin,thiazolidinediones, sulfonylureas and sodium-glucose co-transporter-2 inhibitors in the hospital setting, although some of their effects on acute outcomes deserve further evaluation in future studies. However, the use of dipeptidyl peptidase-4 inhibitors in inpatients with type 2 diabetes is supported by a few, well-designed, randomized controlled trials.These trials have demonstrated good safety and tolerability profiles, comparable to insulin glucose-lowering efficacy, and a reduction in insulin dose when dipeptidyl peptidase-4 inhibitors are co-administered with insulin, in individualswith mild to moderate hyperglycaemia and a stable clinical condition. The administration of dipeptidyl peptidase-4 inhibitors to specific groups of inpatients might be a safe and effective alternative to insulin.

GIP as a Therapeutic Target in Diabetes and Obesity: Insight From Incretin Co-agonists.

The 2 hormones responsible for the amplification of insulin secretion after oral as opposed to intravenous nutrient administration are the gut peptides, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). However, whereas GLP-1 also inhibits appetite and food intake and improves glucose regulation in patients with type 2 diabetes (T2DM), GIP seems to be devoid of these activities, although the 2 hormones as well as their receptors are highly related. In fact, numerous studies have suggested that GIP may promote obesity. However, chimeric peptides, combining elements of both peptides and capable of activating both receptors, have recently been demonstrated to have remarkable weight-losing and glucose-lowering efficacy in obese individuals with T2DM. At the same time, antagonists of the GIP receptor have been reported to reduce weight gain/cause weight loss in experimental animals including nonhuman primates. This suggests that both agonists and antagonist of the GIP receptor should be useful, at least for weight-losing therapy. How is this possible? We here review recent experimental evidence that agonist-induced internalization of the two receptors differs markedly and that modifications of the ligand structures, as in co-agonists, profoundly influence these cellular processes and may explain that an antagonist may activate while an agonist may block receptor signaling.

Cardiovascular protection with sodium-glucose co-transporter-2 inhibitors in type 2 diabetes: Does it apply to all patients?

Patients with type 2 diabetes (T2D) are at an increased risk of cardiovascular disease (CVD). Cardiovascular risk in these patients should be considered as a continuum, and comprehensive treatment strategies should aim to target multiple disease risk factors. Large‐scale clinical trials of sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors have shown an impact on cardiovascular outcomes, including heart failure hospitalization and cardiovascular death, which appears to be independent of their glucose‐lowering efficacy. Reductions in major cardiovascular events appear to be greatest in patients with established CVD, particularly those with prior myocardial infarction, but are independent of heart failure or renal risk. Most large‐scale trials of SGLT2 inhibitors predominantly include patients with T2D with pre‐existing CVD and high cardiovascular risk at baseline, limiting their applicability to patients typically observed in clinical practice. Real‐world evidence from observational studies suggests that there might also be beneficial effects of SGLT2 inhibitors on heart failure hospitalization and all‐cause mortality in various cohorts of lower risk patients. The most common adverse events reported in clinical and observational studies are genital infections; however, the overall risk of these events appears to be low and easily managed. Similar safety profiles have been reported for elderly and younger patients. There is still some debate regarding the safety of canagliflozin in patients at high risk of fracture and amputation. Outstanding questions include specific patterns of cardiovascular protection according to baseline risk.

Use of incretin-based medications: what do current international recommendations suggest with respect to GLP-1 receptor agonists and DPP-4 inhibitors?

In recent years guidelines for the treatment of type 2 diabetes (T2DM) have evolved substantially. Initially limited to a few glucose lowering agents, early guidelines predicated strict glycemic control as a main goal in the attempt to reduce the risk of long-term diabetic complications. Nowadays, guidelines are not limited to such a goal but include cardiovascular (and renal) protection. This rapid evolution was made possible by the introduction of new glucose lowering agents, which have been extensively tested in randomized clinical studies including large cardiovascular outcome trials (CVOTs). In this review we will specifically consider the use of incretin-based medications in T2DM as recommended in the recent ADA/EASD consensus, and other international guidelines, with special consideration of their glucose-lowering efficacy, their cardiovascular (and renal) benefit, their effect on body weight and risk of hypoglycemia, as well as the economic implications for their use.

Rationale and methodology for a European pooled analysis of postmarketing interventional and observational studies of insulin glargine 300 U/mL in diabetes: protocol of REALI project

IntroductionType 2 diabetes mellitus (T2DM) is a common and heterogeneous disease. Using advanced analytic approaches to explore real-world data may identify different disease characteristics, responses to treatment and progression patterns....

SGLT 2 inhibitors: Antidiabetic agents with promising effects beyond glucose control

Type 2 diabetes mellitus is a growing public health problem worldwide. It has a close relation with metabolic problems like obesity, hypertension, dyslipidemia and atherosclerotic cardiovascular diseases. There are different antidiabetic agents being used in the treatment of diabetes mellitus with different mechanisms of action and a patient centered approach is required when choosing the appropriate treatment option. Sodium-glucose cotransporter (SGLT) 2 inhibitors also called glucoretics or gliflozins are members of a relatively new group of antidiabetic agents with promising cardioprotective and renoprotective effects beyond their glucose lowering efficacies.