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    Comparative efficacy and safety of blood pressure-lowering agents in adults with diabetes and kidney disease: a network meta-analysis. Palmer Suetonia C,Mavridis Dimitris,Navarese Eliano,Craig Jonathan C,Tonelli Marcello,Salanti Georgia,Wiebe Natasha,Ruospo Marinella,Wheeler David C,Strippoli Giovanni F M Lancet (London, England) BACKGROUND:The comparative efficacy and safety of pharmacological agents to lower blood pressure in adults with diabetes and kidney disease remains controversial. We aimed to investigate the benefits and harms of blood pressure-lowering drugs in this population of patients. METHODS:We did a network meta-analysis of randomised trials from around the world comparing blood pressure-lowering agents in adults with diabetic kidney disease. Electronic databases (the Cochrane Collaboration, Medline, and Embase) were searched systematically up to January, 2014, for trials in adults with diabetes and kidney disease comparing orally administered blood pressure-lowering drugs. Primary outcomes were all-cause mortality and end-stage kidney disease. We also assessed secondary safety and cardiovascular outcomes. We did random-effects network meta-analysis to obtain estimates for primary and secondary outcomes and we presented these estimates as odds ratios or standardised mean differences with 95% CIs. We ranked the comparative effects of all drugs against placebo with surface under the cumulative ranking (SUCRA) probabilities. FINDINGS:157 studies comprising 43,256 participants, mostly with type 2 diabetes and chronic kidney disease, were included in the network meta-analysis. No drug regimen was more effective than placebo for reducing all-cause mortality. However, compared with placebo, end-stage renal disease was significantly less likely after dual treatment with an angiotensin-receptor blocker (ARB) and an angiotensin-converting-enzyme (ACE) inhibitor (odds ratio 0·62, 95% CI 0·43-0·90) and after ARB monotherapy (0·77, 0·65-0·92). No regimen significantly increased hyperkalaemia or acute kidney injury, although combined ACE inhibitor and ARB treatment had the lowest rank among all interventions because of borderline increases in estimated risks of these harms (odds ratio 2·69, 95% CI 0·97-7·47 for hyperkalaemia; 2·69, 0·98-7·38 for acute kidney injury). INTERPRETATION:No blood pressure-lowering strategy prolonged survival in adults with diabetes and kidney disease. ACE inhibitors and ARBs, alone or in combination, were the most effective strategies against end-stage kidney disease. Any benefits of combined ACE inhibitor and ARB treatment need to be balanced against potential harms of hyperkalaemia and acute kidney injury. FUNDING:Canterbury Medical Research Foundation, Italian Medicines Agency. 10.1016/S0140-6736(14)62459-4
    Future glucose-lowering drugs for type 2 diabetes. Bailey Clifford J,Tahrani Abd A,Barnett Anthony H The lancet. Diabetes & endocrinology The multivariable and progressive natural history of type 2 diabetes limits the effectiveness of available glucose-lowering drugs. Constraints imposed by comorbidities (notably cardiovascular disease and renal impairment) and the need to avoid hypoglycaemia, weight gain, and drug interactions further complicate the treatment process. These challenges have prompted the development of new formulations and delivery methods for existing drugs alongside research into novel pharmacological entities. Advances in incretin-based therapies include a miniature implantable osmotic pump to give continuous delivery of a glucagon-like peptide-1 receptor agonist for 6-12 months and once-weekly tablets of dipeptidyl peptidase-4 inhibitors. Hybrid molecules that combine the properties of selected incretins and other peptides are at early stages of development, and proof of concept has been shown for small non-peptide molecules to activate glucagon-like peptide-1 receptors. Additional sodium-glucose co-transporter inhibitors are progressing in development as well as possible new insulin-releasing biological agents and small-molecule inhibitors of glucagon action. Adiponectin receptor agonists, selective peroxisome proliferator-activated receptor modulators, cellular glucocorticoid inhibitors, and analogues of fibroblast growth factor 21 are being considered as potential new approaches to glucose lowering. Compounds that can enhance insulin receptor and post-receptor signalling cascades or directly promote selected pathways of glucose metabolism have suggested opportunities for future treatments. However, pharmacological interventions that are able to restore normal β-cell function and β-cell mass, normalise insulin action, and fully correct glucose homoeostasis are a distant vision. 10.1016/S2213-8587(15)00462-3
    Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis. Wu Jason H Y,Foote Celine,Blomster Juuso,Toyama Tadashi,Perkovic Vlado,Sundström Johan,Neal Bruce The lancet. Diabetes & endocrinology BACKGROUND:In patients with type 2 diabetes, sodium-glucose cotransporter-2 (SGLT2) inhibitors are known to reduce glucose concentrations, blood pressure, and weight, but to increase LDL cholesterol and the incidence of urogenital infections. Protection against cardiovascular events has also been reported, as have possible increased risks of adverse outcomes such as ketoacidosis and bone fracture. We aimed to establish the effects of SGLT2 inhibitors on cardiovascular events, death, and safety outcomes in adults with type 2 diabetes, both overall and separately for individual drugs. METHODS:In this systematic review and meta-analysis, we searched MEDLINE, Embase, the Cochrane Library, and websites of US, European, and Japanese regulatory authorities from Jan 1, 1950, to Sept 30, 2015, for data from prospective randomised controlled trials assessing the effects of SGLT2 treatment compared with controls. We excluded duplicate reports, trials of compound drugs, trials that lasted 7 days or fewer, trials that did not report on outcomes of interest, and articles that presented pooled trial data for which the individual trials could not be identified. We extracted data in duplicate using a standardised approach. The primary outcome was major adverse cardiovascular events. Secondary outcomes were cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, admission to hospital for unstable angina, heart failure, and all-cause mortality. We estimated summary relative risks with fixed-effects meta-analysis, with the I(2) statistic used to estimate heterogeneity of results beyond chance. FINDINGS:The analyses included data from six regulatory submissions (37 525 participants) and 57 published trials (33 385 participants), which provided data for seven different SGLT2 inhibitors. SGLT2 inhibitors protected against the risk of major adverse cardiovascular events (relative risk 0·84 [95% CI 0·75-0·95]; p=0·006), cardiovascular death (0·63 [0·51-0·77]; p<0·0001), heart failure (0·65 [0·50-0·85]; p=0·002), and death from any cause (0·71 [0·61-0·83]; p<0·0001). No clear effect was apparent for non-fatal myocardial infarction (0·88 [0·72-1·07]; p=0·18) or angina (0·95 [0·73-1·23]; p=0·70), but we noted an adverse effect for non-fatal stroke (1·30 [1·00-1·68]; p=0·049). We noted no clear evidence that the individual drugs had different effects on cardiovascular outcomes or death (all I(2)<43%). Safety analyses showed consistent increased risks of genital infections (regulatory submissions 4·75 [4·00-5·63]; scientific reports 2·88 [2·48-3·34]), but findings for some safety outcomes varied depending on whether anlayses were based on data extracted from regulatory submissions or trials reported in the scientific literature. INTERPRETATION:These data suggest net protection of SGLT2 inhibitors against cardiovascular outcomes and death. The efficacy results were driven by findings for empagliflozin (the only SGLT2 inhibitor for which data from a dedicated long-term cardiovascular safety trial have been reported), although results for the other drugs in the class were not clearly different. Adverse events were more difficult to quantify than was efficacy, with the effects of individual drugs in the class seeming to differ for some safety outcomes. Results from ongoing studies will be crucial to substantiate these findings across the drug class, but the available data provide a strong rationale to expect benefit from use of SGLT2 inhibitors in patients with type 2 diabetes at high risk of cardiovascular events. FUNDING:National Health and Medical Research Council of Australia. 10.1016/S2213-8587(16)00052-8
    Novel Diabetes Drugs and the Cardiovascular Specialist. Sattar Naveed,Petrie Mark C,Zinman Bernard,Januzzi James L Journal of the American College of Cardiology Recently, treatment with 2 newer classes of type 2 diabetes drugs were found to reduce events in patients with diabetes and cardiovascular (CV) disease, a group common in cardiology clinics. The sodium-glucose cotransporter 2 inhibitor, empagliflozin, markedly and rapidly reduced CV death and heart failure hospitalization, likely with hemodynamic/metabolic-driven mechanisms of action. More recently, the glucagon-like peptide-1 receptor agonists liraglutide and semaglutide also reduced CV death and/or major adverse CV events, but did so more slowly and did not influence heart failure risks, suggesting alternative mechanisms of benefit. We will discuss drug therapy for diabetes relative to CV risk, briefly summarize key findings of CV benefit from recent trials, discuss potential mechanisms for benefits of sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 agonists, and suggest how such drugs might be embraced by CV specialists to reduce CV events and mortality in their patients. 10.1016/j.jacc.2017.04.014
    Impact of glucose-lowering drugs on cardiovascular disease in type 2 diabetes. Ferrannini Ele,DeFronzo Ralph A European heart journal Type 2 diabetes mellitus (T2DM) is characterized by multiple pathophysiologic abnormalities. With time, multiple glucose-lowering medications are commonly required to reduce and maintain plasma glucose concentrations within the normal range. Type 2 diabetes mellitus individuals also are at a very high risk for microvascular complications and the incidence of heart attack and stroke is increased two- to three-fold compared with non-diabetic individuals. Therefore, when selecting medications to normalize glucose levels in T2DM patients, it is important that the agent not aggravate, and ideally even improve, cardiovascular risk factors (CVRFs) and reduce cardiovascular morbidity and mortality. In this review, we examine the effect of oral (metformin, sulfonylureas, meglitinides, thiazolidinediones, DPP4 inhibitors, SGLT2 inhibitors, and α-glucosidase inhibitors) and injectable (glucagon-like peptide-1 receptor agonists and insulin) glucose-lowering drugs on established CVRFs and long-term studies of cardiovascular outcomes. Firm evidence that in T2DM cardiovascular disease can be reversed or prevented by improving glycaemic control is still incomplete and must await large, long-term clinical trials in patients at low risk using modern treatment strategies, i.e., drug combinations designed to maximize HbA1c reduction while minimizing hypoglycaemia and excessive weight gain. 10.1093/eurheartj/ehv239
    Therapeutic medications against diabetes: What we have and what we expect. Hu Cheng,Jia Weiping Advanced drug delivery reviews Diabetes has become one of the largest global health and economic burdens, with its increased prevalence and high complication ratio. Stable and satisfactory blood glucose control are vital to reduce diabetes-related complications. Therefore, continuous attempts have been made in antidiabetic drugs, treatment routes, and traditional Chinese medicine to achieve better disease control. New antidiabetic drugs and appropriate combinations of these drugs have increased diabetes control significantly. Besides, novel treatment routes including oral antidiabetic peptide delivery, nanocarrier delivery system, implantable drug delivery system are also pivotal for diabetes control, with its greater efficiency, increased bioavailability, decreased toxicity and reduced dosing frequency. Among these new routes, nanotechnology, artificial pancreas and islet cell implantation have shown great potential in diabetes therapy. Traditional Chinese medicine also offer new options for diabetes treatment. Our paper aim to overview these therapeutic methods for diabetes therapy. Proper combinations of these existing anti-diabetic medications and searching for novel routes are both necessary for better diabetes control. 10.1016/j.addr.2018.11.008
    Combination immunotherapies for type 1 diabetes mellitus. Pozzilli Paolo,Maddaloni Ernesto,Buzzetti Raffaella Nature reviews. Endocrinology Immunotherapies for type 1 diabetes mellitus (T1DM) have been the focus of intense basic and clinical research over the past few decades. Restoring β-cell function is the ultimate goal of intervention trials that target the immune system in T1DM. In an attempt to achieve this aim, different combination therapies have been proposed over the past few years that are based on treatments tackling the various mechanisms involved in the destruction of β cells. The results of clinical trials have not matched expectations based on the positive results from preclinical studies. The heterogeneity of T1DM might explain the negative results obtained, but previous trials have not addressed this issue. However, novel promising combination therapies are being developed, including those that couple immunomodulators with drugs that stimulate β-cell regeneration in order to restore normoglycaemia. This strategy is an encouraging one to pursue the goal of finding a cure for T1DM. This Review summarizes the available data about combination immunotherapies in T1DM, particularly addressing their clinical importance. The available data supporting the use of registered drugs, such as proton pump inhibitors and incretin-based agents, that have been shown to induce β-cell regeneration will also be discussed. 10.1038/nrendo.2015.8
    Glucagon-like peptide-1 receptor agonists for diabetes mellitus: a role in cardiovascular disease. Smilowitz Nathaniel R,Donnino Robert,Schwartzbard Arthur Circulation 10.1161/CIRCULATIONAHA.113.006985
    Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus. Tahrani Abd A,Barnett Anthony H,Bailey Clifford J Nature reviews. Endocrinology Type 2 diabetes mellitus (T2DM) is a global epidemic that poses a major challenge to health-care systems. Improving metabolic control to approach normal glycaemia (where practical) greatly benefits long-term prognoses and justifies early, effective, sustained and safety-conscious intervention. Improvements in the understanding of the complex pathogenesis of T2DM have underpinned the development of glucose-lowering therapies with complementary mechanisms of action, which have expanded treatment options and facilitated individualized management strategies. Over the past decade, several new classes of glucose-lowering agents have been licensed, including glucagon-like peptide 1 receptor (GLP-1R) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium/glucose cotransporter 2 (SGLT2) inhibitors. These agents can be used individually or in combination with well-established treatments such as biguanides, sulfonylureas and thiazolidinediones. Although novel agents have potential advantages including low risk of hypoglycaemia and help with weight control, long-term safety has yet to be established. In this Review, we assess the pharmacokinetics, pharmacodynamics and safety profiles, including cardiovascular safety, of currently available therapies for management of hyperglycaemia in patients with T2DM within the context of disease pathogenesis and natural history. In addition, we briefly describe treatment algorithms for patients with T2DM and lessons from present therapies to inform the development of future therapies. 10.1038/nrendo.2016.86
    Non-insulin drugs to treat hyperglycaemia in type 1 diabetes mellitus. Frandsen Christian Seerup,Dejgaard Thomas Fremming,Madsbad Sten The lancet. Diabetes & endocrinology Insulin treatment of individuals with type 1 diabetes has shortcomings and many patients do not achieve glycaemic and metabolic targets. Consequently, the focus is on novel non-insulin therapeutic approaches that reduce hyperglycaemia and improve metabolic variables without increasing the risk of hypoglycaemia or other adverse events. Several therapies given in conjunction with insulin have been investigated in clinical trials, including pramlintide, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter inhibitors, metformin, sulfonylureas, and thiazolidinediones. These drugs have pleiotropic effects on glucose metabolism and different actions complementary to those of insulin-this Review reports the effects of these drugs on glycaemic control, glucose variability, hypoglycaemia, insulin requirements, and bodyweight. Existing studies are of short duration with few participants; evidence for the efficacy of concomitant treatments is scarce and largely clinically insignificant. A subgroup of patients with type 1 diabetes for whom non-insulin antidiabetic drugs could significantly benefit glycaemic control cannot yet be defined, but we suggest that obese patients prone to hypoglycaemia and patients with residual β-cell function are populations of interest for future trials. 10.1016/S2213-8587(16)00039-5
    Heart Failure End Points in Cardiovascular Outcome Trials of Sodium Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Critical Evaluation of Clinical and Regulatory Issues. Butler Javed,Packer Milton,Greene Stephen J,Fiuzat Mona,Anker Stefan D,Anstrom Kevin J,Carson Peter E,Cooper Lauren B,Fonarow Gregg C,Hernandez Adrian F,Januzzi James L,Jessup Mariell,Kalyani Rita R,Kaul Sanjay,Kosiborod Mikhail,Lindenfeld JoAnn,McGuire Darren K,Sabatine Marc S,Solomon Scott D,Teerlink John R,Vaduganathan Muthiah,Yancy Clyde W,Stockbridge Norman,O'Connor Christopher M Circulation Following regulatory guidance set forth in 2008 by the US Food and Drug Administration for new drugs for type 2 diabetes mellitus, many large randomized, controlled trials have been conducted with the primary goal of assessing the safety of antihyperglycemic medications on the primary end point of major adverse cardiovascular events, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Heart failure (HF) was not specifically mentioned in the US Food and Drug Administration guidance and therefore it was not a focus of these studies when planned. Several trials subsequently showed the impact of antihyperglycemic drugs on HF outcomes, which were not originally specified as the primary end point of the trials. The most impressive finding has been the substantial and consistent risk reduction in HF hospitalization seen across 4 trials of sodium glucose cotransporter 2 inhibitors. However, to date, these results have not led to regulatory approval of any of these drugs for a HF indication or a recommendation for use by US HF guidelines. It is therefore important to explore to what extent persuasive treatment effects on nonprimary end points can be used to support regulatory claims and guideline recommendations. This topic was discussed by researchers, clinicians, industry sponsors, regulators, and representatives from professional societies, who convened on the US Food and Drug Administration campus on March 6, 2019. This report summarizes these discussions and the key takeaway messages from this meeting. 10.1161/CIRCULATIONAHA.119.042155
    Pharmacogenomics in diabetes mellitus: insights into drug action and drug discovery. Zhou Kaixin,Pedersen Helle Krogh,Dawed Adem Y,Pearson Ewan R Nature reviews. Endocrinology Genomic studies have greatly advanced our understanding of the multifactorial aetiology of type 2 diabetes mellitus (T2DM) as well as the multiple subtypes of monogenic diabetes mellitus. In this Review, we discuss the existing pharmacogenetic evidence in both monogenic diabetes mellitus and T2DM. We highlight mechanistic insights from the study of adverse effects and the efficacy of antidiabetic drugs. The identification of extreme sulfonylurea sensitivity in patients with diabetes mellitus owing to heterozygous mutations in HNF1A represents a clear example of how pharmacogenetics can direct patient care. However, pharmacogenomic studies of response to antidiabetic drugs in T2DM has yet to be translated into clinical practice, although some moderate genetic effects have now been described that merit follow-up in trials in which patients are selected according to genotype. We also discuss how future pharmacogenomic findings could provide insights into treatment response in diabetes mellitus that, in addition to other areas of human genetics, facilitates drug discovery and drug development for T2DM. 10.1038/nrendo.2016.51
    Clinical Update: Cardiovascular Disease in Diabetes Mellitus: Atherosclerotic Cardiovascular Disease and Heart Failure in Type 2 Diabetes Mellitus - Mechanisms, Management, and Clinical Considerations. Low Wang Cecilia C,Hess Connie N,Hiatt William R,Goldfine Allison B Circulation Cardiovascular disease remains the principal cause of death and disability among patients with diabetes mellitus. Diabetes mellitus exacerbates mechanisms underlying atherosclerosis and heart failure. Unfortunately, these mechanisms are not adequately modulated by therapeutic strategies focusing solely on optimal glycemic control with currently available drugs or approaches. In the setting of multifactorial risk reduction with statins and other lipid-lowering agents, antihypertensive therapies, and antihyperglycemic treatment strategies, cardiovascular complication rates are falling, yet remain higher for patients with diabetes mellitus than for those without. This review considers the mechanisms, history, controversies, new pharmacological agents, and recent evidence for current guidelines for cardiovascular management in the patient with diabetes mellitus to support evidence-based care in the patient with diabetes mellitus and heart disease outside of the acute care setting. 10.1161/CIRCULATIONAHA.116.022194
    Cardiovascular benefits and safety of non-insulin medications used in the treatment of type 2 diabetes mellitus. Yandrapalli Srikanth,Jolly George,Horblitt Adam,Sanaani Abdallah,Aronow Wilbert S Postgraduate medicine Diabetes mellitus is a growing in exponential proportions. If the current growth trend continues, it may result in every third adult in the United States having diabetes mellitus by 2050, and every 10 adult worldwide. Type 2 diabetes mellitus (T2DM) confers a 2- to 3-fold increased risk of cardiovascular (CV) events compared with non-diabetic patients, and CV mortality is responsible for around 80% mortality in this population. Patients with T2DM can have other features of insulin resistance-metabolic syndrome like hypertension, lipid abnormalities, and obesity which are all associated with increased CV disease and stroke risk even in the absence of T2DM. The management of a T2DM calls for employing a holistic risk factor control approach. Metformin is the first line therapy for T2DM and has been shown to have cardiovascular beneficial effects. Intense debate regarding the risk of myocardial infarction with rosiglitazone led to regulatory agencies necessitating cardiovascular outcome trials with upcoming anti-diabetic medications. Glucagon like peptide-1 agonists and sodium glucose co-transporter-2 inhibitors have shown promising CV safety and additional CV benefit in recent clinical trials. These drugs have favorable effects on traditional CV risk factors. The findings from these studies further support that fact that CV risk factor control plays an important role in reducing morbidity and mortality in T2DM patients. This review article will discuss briefly the cardiovascular safety and benefits of the oral medications which are currently being used for T2DM and will then discuss in detail about the newer medications being investigated for the treatment of T2DM. 10.1080/00325481.2017.1358064
    Effects of oral antidiabetic drugs and glucagon-like peptide-1 receptor agonists on left ventricular diastolic function in patients with type 2 diabetes mellitus: a systematic review and network meta-analysis. Ida Satoshi,Kaneko Ryutaro,Imataka Kanako,Okubo Kaoru,Shirakura Yoshitaka,Azuma Kentaro,Fujiwara Ryoko,Takahashi Hiroka,Murata Kazuya Heart failure reviews The present study aimed to compare the effects of oral antidiabetic drugs (OADs) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) on left ventricular diastolic function in patients with type 2 diabetes mellitus using a network meta-analysis of randomized controlled trials (RCTs). Literature searches were conducted on Medline, the Cochrane Controlled Trials Registry, and ClinicalTrials.gov. RCTs that assessed the effects on left ventricular diastolic function of OADs and GLP-1RAs in patients with type 2 diabetes were included. The outcome was the value (E/e') obtained by dividing peak early diastolic transmitral flow velocity (E) by the mitral annular early diastolic velocity (e'). Standardized mean differences (SMD) and 95% confidence intervals (CIs) were calculated from a random-effects network meta-analysis. Eight RCTs (592 patients) identified in a literature search met the eligibility criteria for this study and were included in the network meta-analysis. Compared with placebo, liraglutide was the only drug that caused a significant improvement in left ventricular diastolic function (SMD, - 0.65; 95% CI, - 1.23 to - 0.08). In addition, when the effects on left ventricular diastolic function were evaluated across drugs, liraglutide alone caused a significant improvement in left ventricular diastolic function compared with OADs (sitagliptin, linagliptin, pioglitazone, rosiglitazone, voglibose, and glimepiride). From the perspective of preventing the onset of heart failure, the administration of liraglutide for type 2 diabetes is promising. 10.1007/s10741-020-09936-w
    Systematic Review of the Cost Effectiveness of Insulin Analogues in Type 1 and Type 2 Diabetes Mellitus. Shafie Asrul Akmal,Ng Chin Hui,Tan Yui Ping,Chaiyakunapruk Nathorn PharmacoEconomics BACKGROUND:Insulin analogues have a pharmacokinetic advantage over human insulin and are increasingly used to treat diabetes mellitus. A summary of their cost effectiveness versus other available treatments was required. OBJECTIVE:Our objective was to systematically review the published cost-effectiveness studies of insulin analogues for the treatment of patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). METHODS:We searched major databases and health technology assessment agency reports for economic evaluation studies published up until 30 September 2015. Two reviewers performed data extraction and assessed the quality of the data using the CHEERS (Consolidated Health Economic Evaluation Reporting Standards) guidelines. RESULTS:Seven of the included studies assessed short-acting insulin analogues, 12 assessed biphasic insulin analogues, 30 assessed long-acting insulin analogues and one assessed a combination of short- and long-acting insulin analogues. Only 17 studies involved patients with T1DM, all were modelling studies and 12 were conducted in Canada. The incremental cost-effectiveness ratios (ICERs) for short-acting insulin analogues ranged from dominant to $US435,913 per quality-adjusted life-year (QALY) gained, the ICERs for biphasic insulin analogues ranged from dominant to $US57,636 per QALY gained and the ICERs for long-acting insulin analogues ranged from dominant to $US599,863 per QALY gained. A total of 15 studies met all the CHEERS guidelines reporting quality criteria. Only 26 % of the studies assessed heterogeneity in their analyses. CONCLUSION:Current evidence indicates that insulin analogues are cost effective for T1DM; however, evidence for their use in T2DM is not convincing. Additional evidence regarding compliance and efficacy is required to support the broader use of long-acting and biphasic insulin analogues in T2DM. The value of insulin analogues depends strongly on reductions in hypoglycaemia event rates and its efficacy in lowering glycated haemoglobin (HbA). 10.1007/s40273-016-0456-2
    Linagliptin versus sitagliptin in patients with type 2 diabetes mellitus: a network meta-analysis of randomized clinical trials. Keshavarz Khosro,Lotfi Farhad,Sanati Ehsan,Salesi Mahmood,Hashemi-Meshkini Amir,Jafari Mojtaba,Mojahedian Mohammad M,Najafi Behzad,Nikfar Shekoufeh Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences BACKGROUND:Diabetes is one of the most common chronic and costly diseases worldwide and type 2 diabetes is the most common type which accounts for about 90% of cases with diabetes. New medication-therapy regimens such as those containing linagliptin alone or in combination with other medications (within the category of DDP-4 inhibitors) must be evaluated in terms of efficacy and compared with other currently used drugs and then enter the medication list of the country. Hence, this study aimed to compare the clinical efficacy of the two drugs, i.e. linagliptin and sitagliptin, in patients with type 2 diabetes. METHODS:A systematic review was conducted to identify all clinical trials published by 2015 which compared the two drugs in patients with type 2 diabetes. Using keywords such as "linagliptin", "type 2 diabetes mellitus", "sitagliptin" and related combinations, we searched databases including Scopus, PubMed, and Web of Science. The quality of the selected studies was evaluated using the Jadad score. Considering primary and secondary outcomes extracted from the reviewed studies, a network meta-analysis was used to conduct a systematic comparison between the two studied drugs. RESULTS:This network meta-analysis included 32 studies (Linagliptin vs PLB: n = 8, Sitagliptin vs PLB: n = 13, Linagliptin + MET vs PLB + MET: n = 4, and Sitagliptin + MET vs PLB + MET: n = 7) and a total of 13,747 patients. The results showed no significant difference between linagliptin and sitagliptin in terms of key efficacy and safety outcomes such as HbA1c changes from baseline, body weight change from baseline, percentage of patients achieving HbA1c <7, and percentage of patients experiencing hypoglycemic events (p > 0.05). The results showed that the efficacy of the two drug regimens was the same. CONCLUSIONS:Based on the results, there was no significant difference between the two drugs, i.e. linagliptin and sitagliptin, in terms of efficacy; in other words, the efficacy of the two drugs was the same. Therefore, the use of these two drugs depends on their availability and cost. Graphical abstract of the network meta-analysis performed to evaluate the alternatives under the study. 10.1186/s40199-017-0189-6
    Drugs for the treatment of pediatric type 2 diabetes mellitus and related co-morbidities. Tabatabaei-Malazy Ozra,Nikfar Shekoufeh,Larijani Bagher,Abdollahi Mohammad Expert opinion on pharmacotherapy INTRODUCTION:The continuing global epidemic of obesity in adolescents has raised the prevalence of type 2 diabetes mellitus (T2DM). Despite the wealth of information concerning T2DM in adults, rare data are available targeting treatment of T2DM in pediatric. Areas covered: This article has reviewed clinical practice guidelines, particularly the American Diabetes Association and the Pediatric Endocrine Society consensus, jointly with clinical trial data available in databases with respect to the use of available pharmacological options to treat T2DM and its complications in youth. Expert opinion: The use of other pharmacological treatments of T2DM in addition to metformin and insulin entails several problems. Since rare studies have been conducted on the medications available to manage T2DM in children, treating them may be more difficult than that of adults. It needs longer and larger size clinical trials along with better pharmacological agents to affect various pathophysiological mechanisms of diabetes. Meanwhile, the efficacy and safety of combinations therapies should be completed in preclinical and clinical phases. 10.1080/14656566.2016.1258057
    Potential Effects of Nonsteroidal Anti-Inflammatory Drugs in the Prevention and Treatment of Type 2 Diabetes Mellitus. Bellucci Pamela Natalia,González Bagnes María Florencia,Di Girolamo Guillermo,González Claudio Daniel Journal of pharmacy practice Nonsteroidal anti-inflammatory drugs (NSAIDs) are a group of heterogeneous drugs largely known for their anti-inflammatory, antipyretic, and analgesic effects, which are met by means of the inhibition of the cyclooxygenase (COX) enzymes. Even when their use in patients with diabetes mellitus is limited due to relevant adverse events, some pharmacological and metabolic effects of NSAIDs have been further studied to be potentially beneficial in the prevention and/or treatment of diabetic subjects. Effects on endogenous glucose production, peripheral insulin resistance, pancreatic islet, and systemic inflammation and the insulin clearance have been reported. In this article, we overview the scientific literature of the last 5 years regarding the potential effects of NSAID treatment on diabetes prevention/treatment. The selected papers showed information in both humans and animal models. Furthermore, we included papers that suggest new areas for further investigation, and we discussed our own suggestions on this matter. 10.1177/0897190016649551
    The Potential Role of SGLT2 Inhibitors in the Treatment of Type 1 Diabetes Mellitus. Fattah Hadi,Vallon Volker Drugs Type 1 diabetes mellitus is a difficult disease to treat due to the relative paucity of therapeutic options other than injectable insulin. The latter, however, can induce hypoglycemia, which has been linked to enhanced cardiovascular risk. Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of oral anti-hyperglycemic medications that do not increase the hypoglycemia risk and are US Food and Drug Administration (FDA) approved in type 2 diabetes mellitus. SGLT2 inhibitors may also be of benefit in type 1 diabetic patients, in addition to insulin, although they have not yet been approved for this indication. By blocking SGLT2 in the early proximal tubules of the kidney, these drugs decrease renal glucose retention, which is enhanced in hyperglycemia, thereby improving blood glucose control, in type 1 and type 2 diabetic patents. Their low hypoglycemia risk is due to the compensating reabsorption capacity of another glucose transporter, SGLT1, in the downstream late proximal tubule and the body's metabolic counter-regulation, which remains intact during SGLT2 inhibition. When insulin dosage is lowered too much, SGLT2 inhibitors can enhance ketogenesis to the extent that the risk of diabetic ketoacidosis increases, particularly in type 1 diabetic patients. SGLT2 inhibitors improve the renal and cardiovascular outcome in type 2 diabetic patients. The mechanisms likely include a reduction in glomerular hyperfiltration, blood pressure, volume overload, and body weight, as well as lowering blood glucose without increasing the hypoglycemia risk. The same mechanistic effects are induced in type 1 diabetic patients. More studies are needed with SGLT2 inhibitors in type 1 diabetic patients, including renal and cardiovascular clinical outcome trials, to fully evaluate their therapeutic potential in this specific population. 10.1007/s40265-018-0901-y
    Targeting AMPK signaling pathway by natural products for treatment of diabetes mellitus and its complications. Joshi Tanuj,Singh Amit Kumar,Haratipour Pouya,Sah Archana Negi,Pandey Abhay K,Naseri Rozita,Juyal Vijay,Farzaei Mohammad H Journal of cellular physiology Diabetes affects a large population of the world. Lifestyle, obesity, dietary habits, and genetic factors contribute to this metabolic disease. A target pathway to control diabetes is the 5'-adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. AMPK is a heterotrimeric protein with α, β, and γ subunits. In several studies, AMPK activation enhanced glucose uptake into cells and inhibited intracellular glucose production. Impairment of AMPK activity is present in diabetes, according to some studies. Drugs used in the treatment of diabetes, such as metformin, are also known to act through regulation of AMPK. Thus, drugs that activate and regulate AMPK are potential candidates for the treatment of diabetes. In addition, many patients encounter important adverse effects, like hypoglycemia, while using allopathic drugs. As a result, the investigation of plant-derived natural drugs that lack adverse side effects and treat diabetes is necessary. Natural products like berberine, quercetin, resveratrol, and so forth have shown significant potential in regulating and activating the AMPK pathway which can lead to manage diabetes mellitus and its complications. 10.1002/jcp.28528
    Activation and Inhibition of Sodium-Hydrogen Exchanger Is a Mechanism That Links the Pathophysiology and Treatment of Diabetes Mellitus With That of Heart Failure. Packer Milton Circulation The mechanisms underlying the progression of diabetes mellitus and heart failure are closely intertwined, such that worsening of one condition is frequently accompanied by worsening of the other; the degree of clinical acceleration is marked when the 2 coexist. Activation of the sodium-hydrogen exchanger in the heart and vasculature (NHE1 isoform) and the kidneys (NHE3 isoform) may serve as a common mechanism that links both disorders and may underlie their interplay. Insulin insensitivity and adipokine abnormalities (the hallmarks of type 2 diabetes mellitus) are characteristic features of heart failure; conversely, neurohormonal systems activated in heart failure (norepinephrine, angiotensin II, aldosterone, and neprilysin) impair insulin sensitivity and contribute to microvascular disease in diabetes mellitus. Each of these neurohormonal derangements may act through increased activity of both NHE1 and NHE3. Drugs used to treat diabetes mellitus may favorably affect the pathophysiological mechanisms of heart failure by inhibiting either or both NHE isoforms, and drugs used to treat heart failure may have beneficial effects on glucose tolerance and the complications of diabetes mellitus by interfering with the actions of NHE1 and NHE3. The efficacy of NHE inhibitors on the risk of cardiovascular events may be enhanced when heart failure and glucose intolerance coexist and may be attenuated when drugs with NHE inhibitory actions are given concomitantly. Therefore, the sodium-hydrogen exchanger may play a central role in the interplay of diabetes mellitus and heart failure, contribute to the physiological and clinical progression of both diseases, and explain certain drug-drug and drug-disease interactions that have been reported in large-scale randomized clinical trials. 10.1161/CIRCULATIONAHA.117.030418
    Assessment of cardiovascular risk of new drugs for the treatment of diabetes mellitus: risk assessment vs. risk aversion. Zannad Faiez,Stough Wendy Gattis,Lipicky Raymond J,Tamargo Juan,Bakris George L,Borer Jeffrey S,Alonso García Maria de Los Angeles,Hadjadj Samy,Koenig Wolfgang,Kupfer Stuart,McCullough Peter A,Mosenzon Ofri,Pocock Stuart,Scheen André J,Sourij Harald,Van der Schueren Bart,Stahre Christina,White William B,Calvo Gonzalo European heart journal. Cardiovascular pharmacotherapy The Food and Drug Administration issued guidance for evaluating the cardiovascular risk of new diabetes mellitus drugs in 2008. Accumulating evidence from several completed trials conducted within this framework raises questions as to whether requiring safety outcome studies for all new diabetes mellitus therapies remains justified. Given the burden of cardiovascular disease in patients with diabetes, the focus should shift towards cardiovascular outcome studies designed to evaluate efficacy (i.e. to determine the efficacy of a drug over placebo or standard care) rather than demonstrating that risk is not increased by a pre-specified safety margin. All stakeholders are responsible for ensuring that new drug approvals occur under conditions of appropriate safety and effectiveness. It is also a shared responsibility to avoid unnecessary hurdles that may compromise access to useful drugs and threaten the sustainability of health systems. It is critical to renew this debate so that stakeholders can collectively determine the optimal approach for developing new drugs to treat type 2 diabetes mellitus. 10.1093/ehjcvp/pvw007
    The effect of diabetes mellitus on pharmacokinetics, pharmacodynamics and adverse drug reactions of anticancer drugs. Mashayekhi-Sardoo Habibeh,Mohammadpour Amir Hooshang,Nomani Homa,Sahebkar Amirhossein Journal of cellular physiology Diabetes mellitus (DM) and cancer are global problems carrying huge human, social, and economic impact. Type 2 diabetes (T2DM) is associated with an increased risk for a number of cancers, including breast, pancreatic, and liver cancer. Moreover, adverse drug reactions are higher in paitents with cancer with T2DM compared to cancer patients without T2DM. Cellular mechanisms of hyperglycemia and chemotherapy efficacy may be different depending upon the particular cancer type and the condition of the patient. This review evaluates the effect of DM on the pharmacokinetic, pharmacodynamic, and adverse drug reactions of commonly used anticancer drugs such as cisplatin, methotrexate, paclitaxel, doxorubicin, and adriamycin in both clinical and animal models. A literature search was conducted in scientific databases including Web of Science, PubMed, Scopus, and Google Scholar including the relevant keywords. The results of the effectiveness of anticancer therapies in patients with DM are, however, inconsistent because DM can negatively impact multiple diverse entities including nerves and vascular structures, insulin-like growth factor 1, the function of the innate immune system, drug pharmacokinetics, the expression levels of hepatic CYP , Mdr and enzymes that then lead to drug toxicity. However, in a few circumstances, DM led to attenuation of the toxicity of anticancer drugs secondary to attenuation of the energy-dependent renal uptake process. Overall, the impact of DM on patients with cancer is variable because of the diverse types of cancers and the spectrum of anticancer drugs. With respect to the evidence for cancer involvement in DM pathophysiology and the response to anticancer treatment in patients with DM, many questions still remain and further clinical trials are needed. 10.1002/jcp.28644
    A novel therapeutic effect of statins on nephrogenic diabetes insipidus. Bonfrate Leonilde,Procino Giuseppe,Wang David Q-H,Svelto Maria,Portincasa Piero Journal of cellular and molecular medicine Statins competitively inhibit hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase, resulting in reduced plasma total and low-density lipoprotein cholesterol levels. Recently, it has been shown that statins exert additional 'pleiotropic' effects by increasing expression levels of the membrane water channels aquaporin 2 (AQP2). AQP2 is localized mainly in the kidney and plays a critical role in determining cellular water content. This additional effect is independent of cholesterol homoeostasis, and depends on depletion of mevalonate-derived intermediates of sterol synthetic pathways, i.e. farnesylpyrophosphate and geranylgeranylpyrophosphate. By up-regulating the expression levels of AQP2, statins increase water reabsorption by the kidney, thus opening up a new avenue in treating patients with nephrogenic diabetes insipidus (NDI), a hereditary disease that yet lacks high-powered and limited side effects therapy. Aspects related to water balance determined by AQP2 in the kidney, as well as standard and novel therapeutic strategies of NDI are discussed. 10.1111/jcmm.12422
    Drug Delivery System in the Treatment of Diabetes Mellitus. Zhao Ruichen,Lu Zhiguo,Yang Jun,Zhang Liqun,Li Yan,Zhang Xin Frontiers in bioengineering and biotechnology Diabetes mellitus has been described as a chronic endocrine and metabolic disease, which is characterized by hyperglycemia and the coexistence of multiple complications. At present, the drugs widely applied in clinical treatment of diabetes mellitus mainly include insulin, insulin analogs, non-insulin oral hypoglycemic drugs and genetic drugs. Nevertheless, there is still no complete therapy strategy for diabetes mellitus management by far due to the intrinsic deficiencies of drugs and limits in administration routes such as the adverse reactions caused by long-term subcutaneous injection and various challenges in oral administration, such as enzymatic degradation, chemical instability and poor gastrointestinal absorption. Therefore, it is remarkably necessary to develop appropriate delivery systems and explore complete therapy strategies according to the characters of drugs and diabetes mellitus. Delivery systems have been found to be potentially beneficial in many aspects for effective diabetes treatment, such as improving the stability of drugs, overcoming different biological barriers to increase bioavailability, and acting as an intelligent automatized system to mimic endogenous insulin delivery and reduce the risk of hypoglycemia. This review aims to provide an overview related with the research advances, development trend of drug therapy and the application of delivery systems in the treatment diabetes mellitus, which could offer reference for the application of various drugs in the field of diabetes mellitus treatment. 10.3389/fbioe.2020.00880
    Effects of antidiabetic drugs on the incidence of macrovascular complications and mortality in type 2 diabetes mellitus: a new perspective on sodium-glucose co-transporter 2 inhibitors. Rahelić Dario,Javor Eugen,Lucijanić Tomo,Skelin Marko Annals of medicine Elevated hemoglobin A (HbA) values correlate with microvascular and macrovascular complications. Thus, patients with type 2 diabetes mellitus (T2DM) are at an increased risk of developing macrovascular events. Treatment of T2DM should be based on a multifactorial approach because of its evidence regarding reduction of macrovascular complications and mortality in T2DM. It is well known that intensive glucose control reduces the risk of microvascular complications in T2DM, but the effects of antidiabetic drugs on macrovascular complications and mortality in T2DM are less clear. The results of recent trials have demonstrated clear evidence that empagliflozin and liraglutide reduce cardiovascular (CV) and all-cause mortality in T2DM, an effect that is absent in other members of antidiabetic drugs. Empagliflozin is a member of a novel class of antidiabetic drugs, the sodium-glucose co-transporter 2 (SGLT2) inhibitors. Two ongoing randomized clinical trials involving other SGLT2 inhibitors, canagliflozin and dapagliflozin, will provide additional evidence of the beneficial effects of SGLT2 inhibitors in T2DM population. The aim of this paper is to systematically present the latest evidence regarding the usage of antidiabetic drugs, and the reduction of macrovascular complications and mortality. A special emphasis is put on the novel class of antidiabetic drugs, of SGLT2 inhibitors. Key messages Macrovascular complications and mortality are best clinical trial endpoints for evaluating the efficacy of antidiabetic drugs. The first antidiabetic drug that demonstrated a reduction in mortality in the treatment of type 2 diabetes mellitus (T2DM) was empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor. SGLT2 inhibitors are novel class of antidiabetic drugs that play a promising role in the treatment of T2DM. 10.1080/07853890.2016.1226514
    Effects of oral antidiabetic drugs on left ventricular mass in patients with type 2 diabetes mellitus: a network meta-analysis. Ida Satoshi,Kaneko Ryutaro,Murata Kazuya Cardiovascular diabetology BACKGROUND:We used a network meta-analysis of randomized controlled trials (RCTs) to comparatively examine the effects of oral antidiabetic drugs (OADs) on left ventricular mass (LVM) in patients with type 2 diabetes. METHODS:Document searches were implemented using Medline, Cochrane Controlled Trials Registry, and ClinicalTrials.gov. We decided to include RCTs that evaluated the impact of LVM using the administration of OADs to patients with type 2 diabetes. The outcome evaluations used standardized mean difference (SMD) and 95% confidence intervals (CIs). We then performed a comparative examination of LVM related to the administration of OADs using random effects network meta-analysis. RESULTS:The document search found 11 RCTs (1410 people) that satisfied the eligibility criteria for this study, and these RCTs were incorporated into the network meta-analysis. The only medication that significantly reduced LVM compared to a placebo was gliclazide (SMD, -1.09; 95% CI, -1.62 to  - 0.57). Further, when comparing the impact on LVM between OADs, only gliclazide significantly reduced LVM compared to other OADs (glyburide, voglibose, metformin, pioglitazone, rosiglitazone, and sitagliptin). CONCLUSIONS:In the present study, gliclazide was the only medication that significantly reduced LVM in patients with type 2 diabetes. When considered from the perspective of causing heart failure and preventing recurrence, it is possible that the use of gliclazide in patients with type 2 diabetes will provide multiple benefits. 10.1186/s12933-018-0773-1
    Recent development of single preparations and fixed-dose combination tablets for the treatment of non-insulin-dependent diabetes mellitus : A comprehensive summary for antidiabetic drugs. Li Jianwen,Lian He Archives of pharmacal research As a complex endocrine and metabolic disorder, type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus, NIDDM) has become a major threat to human health. Because of the heterogeneous and progressive disorders induced by insulin resistance and pancreatic b-cell dysfunction, the treatment of NIDDM is still challenging. Although antidiabetic drugs with different pharmacological mechanisms of action have been used clinically, different degrees of undesirable glucose control and the incidences of a variety of side effects, including hypoglycemia, cardiovascular complications and weight gain require the better treatment options. This article has overviewed the current literature about commercially available antidiabetic drugs with different pharmacological mechanisms of action in the treatment of NIDDM, and summarized the published data regarding the efficacy, tolerability, and safety of currently available single preparations and fixed-dose combinations, aiming to provide important information for the development and application of antidiabetic drugs in the future. The literature search from 1989 to 2015 was conducted by PubMed, ScienceDirect, Springer, American Diabetes Association, and U.S. FDA Drugs databases. 10.1007/s12272-016-0762-4
    A Mechanistic Review on Medicinal Plants Used for Diabetes Mellitus in Traditional Persian Medicine. Farzaei Fatemeh,Morovati Mohammad Reza,Farjadmand Fatemeh,Farzaei Mohammad Hosein Journal of evidence-based complementary & alternative medicine Diabetes mellitus is the most common endocrine disorder and a major cause of morbidity and mortality. Traditional medicines worldwide suggest a wide range of natural remedies for the prevention and treatment of chronic disorders, including diabetes mellitus. This mechanistic review aims to highlight the significance of medicinal plants traditionally used as dietary supplements in Persian medicine in adjunct with restricted conventional drugs for the prevention and treatment of diabetes mellitus. Mounting evidence suggests that these natural agents perform their protective and therapeutic effect on diabetes mellitus via several cellular mechanisms, including regeneration of pancreatic β cell, limitation of glycogen degradation and gluconeogenesis, anti-inflammatory, immunoregulatory, antiapoptosis, antioxidative stress, as well as modulation of intracellular signaling transduction pathways. In conclusion, traditional medicinal plants used in Persian medicine can be considered as dietary supplements with therapeutic potential for diabetes mellitus and maybe potential sources of new orally active agent(s). 10.1177/2156587216686461
    Gadofullerene Nanoparticles Reverse Dysfunctions of Pancreas and Improve Hepatic Insulin Resistance for Type 2 Diabetes Mellitus Treatment. Li Xue,Zhen Mingming,Zhou Chen,Deng Ruijun,Yu Tong,Wu Yingjie,Shu Chunying,Wang Chunru,Bai Chunli ACS nano Type 2 diabetes mellitus (T2DM) has been one of the most prevalent metabolic disorders. Nonetheless, the commonly used anti-T2DM drugs failed to substant to treat T2DM when anti-T2DM was withdrawn. Here we put forward a superior and sustainable anti-diabetic strategy using intraperitoneal administration of amino-acid-functionalized gadofullerene nanoparticles (GFNPs) in db/db diabetic mice. Highly accumulated in the pancreas and liver, GFNPs could prominently decrease hyperglycemia, along with permanently maintaining normal blood sugar levels in T2DM mice and even stopping administration. Importantly, GFNPs reversed the pancreas islets dysfunctions by reducing oxidative stress and inflammation responses and fundamentally normalized the insulin secretory function of the pancreas islets. Mechanistically, GFNPs improved hepatic insulin resistance by regulating glucose and lipid metabolism through the activation of IRS2/PI3K/AKT signal pathways, resulting in inhibiting gluconeogenesis and increasing glycogenesis in the liver. Additionally, GFNPs relieved hepatic steatosis in the liver, ultimately maintaining systemic glucose and lipid metabolic homeostasis without obvious toxicity. Together, GFNPs reverse the dysfunctions of the pancreas and improve hepatic insulin resistance, providing a promising approach for T2DM treatment. 10.1021/acsnano.9b02050
    Boswellic extracts and 11-keto-ß-boswellic acids prevent type 1 and type 2 diabetes mellitus by suppressing the expression of proinflammatory cytokines. Ammon H P T Phytomedicine : international journal of phytotherapy and phytopharmacology BACKGROUND:Type 1 diabetes is an autoimmune disease directed to the pancreatic islets where inflammation leads to the death of insulin-producing ß cells and insulin deficiency. Type 2 diabetes, which is closely related to overweight, is characterized by insulin resistance. In both cases, proinflammatory cytokines play an important role by causing insulitis and insulin resistance. The gum resin of Boswellia species and its pharmacologically active compounds, including 11-keto-ß-boswellic acids have been shown to suppress the expression of proinflammatory cytokines in various immune-competent cells. PURPOSE:To review the present evidence of the therapeutic effects of boswellic extracts (BE) and/or 11-keto-ß-boswellic acids in the prevention/treatment of diabetes mellitus and to provide comprehensive insights into the underlying molecular mechanisms. METHODS:This review considers all available informations from preclinical and clinical studies concerning BEs, 11-keto-ß-boswellic acids, proinflammatory cytokines and diabetes mellitus collected via electronic search (PubMed) and related publications of the author. RESULTS:Type 1 diabetes: Studies in mice with autoimmune diabetes revealed that in the model of multiple injections of low doses of streptozotocin (MLD-STZ), an extract of the gum resin of Boswellia serrata and 11-keto-ß-boswellic acid (KBA) suppressed the increase in proinflammatory cytokines in the blood, infiltration of lymphocytes into pancreatic islets and increase in blood glucose. In a second model, i.e. the nonobese diabetic (NOD) mouse, KBA prevented the infiltration of lymphocytes into pancreatic islets. Regarding the clinical effects, a case report provided evidence that BE suppressed the blood levels of tyrosine phosphatase antibody (IA-A), a marker for insulitis, in a patient with late-onset autoimmune diabetes of the adult (LADA). Type 2 diabetes: In a preclinical study in rats where obesity was alimentary induced, the administration of BE significantly reduced food intake, overweight, proinflammatory cytokines such as interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) and ameliorated the parameters of glucose and lipid metabolism. Similar results were obtained in a second animal study, where type 2 diabetes was induced by a combination of a high-fat/high-fructose diet and a single dose of streptozotocin. Two clinical trials with patients with type 2 diabetes receiving the resin of Boswellia serrata demonstrated improvement in the blood glucose, HbA and lipid parameters. CONCLUSION:Preclinical and clinical data suggest that BE and/or 11-keto-ß-boswellic acids by inhibiting the expression of proinflammatory cytokines from immune-competent cells, may prevent insulitis and insulin resistance in type 1 and type 2 diabetes, respectively, and therefore may be an option in the treatment/prevention of type 1 and type 2 diabetes. It is hypothesized that molecularly, BE and 11-keto-ß-boswellic acids act via interference with the IκB kinase/Nuclear Transcription Factor-κB (IKK/NF-κB) signaling pathway through inhibition of the phosphorylation activity of IKK. However, further investigations and well-designed clinical studies are required. 10.1016/j.phymed.2019.153002
    Type 2 Diabetes Mellitus: A Review of Multi-Target Drugs. Artasensi Angelica,Pedretti Alessandro,Vistoli Giulio,Fumagalli Laura Molecules (Basel, Switzerland) Diabetes Mellitus (DM) is a multi-factorial chronic health condition that affects a large part of population and according to the World Health Organization (WHO) the number of adults living with diabetes is expected to increase. Since type 2 diabetes mellitus (T2DM) is suffered by the majority of diabetic patients (around 90-95%) and often the mono-target therapy fails in managing blood glucose levels and the other comorbidities, this review focuses on the potential drugs acting on multi-targets involved in the treatment of this type of diabetes. In particular, the review considers the main systems directly involved in T2DM or involved in diabetes comorbidities. Agonists acting on incretin, glucagon systems, as well as on peroxisome proliferation activated receptors are considered. Inhibitors which target either aldose reductase and tyrosine phosphatase 1B or sodium glucose transporters 1 and 2 are taken into account. Moreover, with a view at the multi-target approaches for T2DM some phytocomplexes are also discussed. 10.3390/molecules25081987
    Hypolipidemic Drugs and Diabetes Mellitus-Mechanisms and Data From Genetic Trials. Filippatos Theodosios D,Panagiotopoulou Thalia,Tzavella Eleftheria,Elisaf Moses S Journal of cardiovascular pharmacology and therapeutics Clinical trials and meta-analyses have shown that statins can dose dependently increase the incidence of new-onset diabetes mellitus (DM) especially in patients with underlying abnormalities of carbohydrate homeostasis. Mendelian randomization studies support these findings since genetic variants in the gene encoding the target of statins, the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase, are associated with increased incidence of new-onset DM, suggesting that the so-called diabetogenic effect of statins is an "on-target effect" possibly related to their main mechanism of action, that is the increased low-density lipoprotein (LDL) receptor expression. Additionally, Mendelian randomization studies have shown that genetic variants as proxies of other drugs that increase LDL receptor expression (ezetimibe and proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors) also increase the risk of new-onset DM. This concept is supported by the fact of decreased DM prevalence in patients with familial hypercholesterolemia who have decreased LDL receptor expression. In contrast, hypolipidemic drugs, such as the cholesteryl ester transfer protein inhibitors, that decrease LDL cholesterol without directly interfering with the LDL receptor expression do not seem to detrimentally affect carbohydrate homeostasis. However, the clinical trials of ezetimibe and PCSK9 inhibitors have not shown an increased DM risk, possibly suggesting that other potential non-well-defined "off-target effects" of hypolipidemic drugs may affect carbohydrate homeostasis. Thus, the long-term effect of hypolipidemic drugs on DM risk depends not only on their final mechanism of hypolipidemic action but also on other "on-target" and "off-target" effects of these drugs. 10.1177/1074248418757011
    Prevention of atherothrombotic events in patients with diabetes mellitus: from antithrombotic therapies to new-generation glucose-lowering drugs. Patti Giuseppe,Cavallari Ilaria,Andreotti Felicita,Calabrò Paolo,Cirillo Plinio,Denas Gentian,Galli Mattia,Golia Enrica,Maddaloni Ernesto,Marcucci Rossella,Parato Vito Maurizio,Pengo Vittorio,Prisco Domenico,Ricottini Elisabetta,Renda Giulia,Santilli Francesca,Simeone Paola,De Caterina Raffaele, Nature reviews. Cardiology Diabetes mellitus is an important risk factor for a first cardiovascular event and for worse outcomes after a cardiovascular event has occurred. This situation might be caused, at least in part, by the prothrombotic status observed in patients with diabetes. Therefore, contemporary antithrombotic strategies, including more potent agents or drug combinations, might provide greater clinical benefit in patients with diabetes than in those without diabetes. In this Consensus Statement, our Working Group explores the mechanisms of platelet and coagulation activity, the current debate on antiplatelet therapy in primary cardiovascular disease prevention, and the benefit of various antithrombotic approaches in secondary prevention of cardiovascular disease in patients with diabetes. While acknowledging that current data are often derived from underpowered, observational studies or subgroup analyses of larger trials, we propose antithrombotic strategies for patients with diabetes in various cardiovascular settings (primary prevention, stable coronary artery disease, acute coronary syndromes, ischaemic stroke and transient ischaemic attack, peripheral artery disease, atrial fibrillation, and venous thromboembolism). Finally, we summarize the improvements in cardiovascular outcomes observed with the latest glucose-lowering drugs, and on the basis of the available evidence, we expand and integrate current guideline recommendations on antithrombotic strategies in patients with diabetes for both primary and secondary prevention of cardiovascular disease. 10.1038/s41569-018-0080-2
    Comparative risk of new-onset diabetes mellitus for antihypertensive drugs: A network meta-analysis. Li Zimeng,Li Yi,Liu Yulong,Xu Wenbo,Wang Qing Journal of clinical hypertension (Greenwich, Conn.) New-onset diabetes mellitus (NOD) refers to forms of diabetes mellitus that develop during the therapeutic processes of other diseases such as hypertension. This study has been conducted in a network meta-analysis to compare antihypertensive drugs by identifying both the advantages and disadvantages on NOD by focusing on their respective effect rates. Odd ratios and corresponding 95% confidence intervals or credible intervals were calculated within pairwise and network meta-analysis. A total of 38 articles with 224 140 patients were included to evaluate the preventive effect of hypertension drugs on NOD. From the network meta-analysis it was evident that both angiotensin-converting enzyme inhibitor as well as angiotensin receptor blocker treatments are associated with a lower risk of developing NOD compared with placebo, with ranking probabilities of 79.81% and 72.77%, respectively, while β-blockers and calcium channel blockers may significantly increase the probability of developing NOD (β-blockers: odds ratio, 2.18 [95% credible intervals: 1.36-3.50]; calcium channel blockers: odds ratio, 1.16 [95% credible intervals, 1.05-1.29]). In conclusion, angiotensin receptor blockers have an advantage over the other treatments regarding the NOD. 10.1111/jch.13108
    Efficacy of different antidiabetic drugs based on metformin in the treatment of type 2 diabetes mellitus: A network meta-analysis involving eight eligible randomized-controlled trials. Peng Yan,Chen Shu-Hong,Liu Xiao-Nan,Sun Qing-Yun Journal of cellular physiology Diabetes mellitus is one of the most prevalent metabolic diseases globally and it is increasing in prevalence. It is one of the most expensive diseases with respect to total health care costs per patient as a result of its chronic nature and its severe complications. To provide a more effective treatment of type 2 diabetes mellitus (T2DM), this study aims to compare different efficacies of six kinds of hypoglycemic drugs based on metformin, including glimepiride, pioglitazone, exenatide, glibenclamide, rosiglitazone, and vildagliptin, in T2DM by a network meta-analysis that were verified by randomized-controlled trials (RCTs). Eight eligible RCT in consistency with the aforementioned six hypoglycemic drugs for T2DM were included. The results of network meta-analysis demonstrated that the exenatide + metformin and vildagliptin + metformin regimens presented with better efficacy. Patients with T2DM with unsatisfactory blood glucose control based on diet control, proper exercise, and metformin treatment were included. The original regimen and dose of medication were unchanged, followed by the addition of glimepiride, pioglitazone, exenatide, glibenclamide, rosiglitazone, and vildagliptin. The results of RCTs showed that all these six kinds of drugs reduced the HbA1c level. Compared with other regimens, exenatide + metformin reduced fasting plasma glucose (FPG), fasting plasma insulin (FPI), total cholesterol (TC), and homeostasis model assessment insulin resistance index (HOMA-IR) levels, but increased the high-density lipoprotein (HDL) level; vildagliptin + metformin decreased FPI and low-density lipoprotein (LDL) levels; glibenclamide + metformin decreased the FPG level, but promoted HDL; and glimepiride + metformin decreased the TC level and rosiglitazone + metformin reduced the LDL level. Our findings indicated that exenatide + metformin and vildagliptin + metformin have better efficacy in T2DM since they can improve insulin sensitivity. 10.1002/jcp.27097
    Assessment of Drug-Drug Interactions between Taspoglutide, a Glucagon-Like Peptide-1 Agonist, and Drugs Commonly Used in Type 2 Diabetes Mellitus: Results of Five Phase I Trials. Bogman Katrijn,Brumm Jochen,Hofmann Carsten,Giraudon Mylène,Niggli Markus,Sturm-Pellanda Carolina,Sauter Annette,Sturm Stefan,Mangold Bernhard,Schmitt Christophe Clinical pharmacokinetics BACKGROUND AND OBJECTIVE:Taspoglutide, a glucagon-like peptide-1 agonist, like native glucagon-like peptide-1, delays gastric emptying time and prolongs intestinal transit time, which may alter the pharmacokinetics of concomitantly administered oral drugs. The effect of taspoglutide on the pharmacokinetics of five oral drugs commonly used in patients with type 2 diabetes mellitus was assessed in healthy subjects. METHODS:Five clinical pharmacology studies evaluated the potential drug-drug interaction between multiple subcutaneous taspoglutide doses and a single dose of lisinopril, warfarin, and simvastatin and multiple doses of digoxin and an oral contraceptive containing ethinylestradiol and levonorgestrel. The extent of interaction was quantified using geometric mean ratios and 90% confidence intervals for the maximum plasma concentration and area under the plasma concentration-time curve. In addition to pharmacokinetics, pharmacodynamic effects were assessed for warfarin and the oral contraceptive. RESULTS:Among the tested drugs, the effect of taspoglutide on the pharmacokinetics of simvastatin was most pronounced, on the day of taspoglutide administration, the average exposure to simvastatin was decreased by - 26% and - 58% for the area under the plasma concentration-time curve and maximum plasma concentration, respectively, accompanied by an increase in average exposure to its active metabolite, simvastatin β-hydroxy acid (+ 74% and + 23% for area under the plasma concentration-time curve and maximum plasma concentration, respectively). Although statistically significant changes in exposure were observed for other test drugs, the 90% confidence intervals for the geometric mean ratio for maximum plasma concentration and area under the plasma concentration-time curve were within the 0.7-1.3 interval. No clinically relevant changes on coagulation (for warfarin) and ovulation-suppressing activity (for the oral contraceptive) were apparent. CONCLUSION:Overall, multiple doses of taspoglutide did not result in changes in the pharmacokinetics of digoxin, an oral contraceptive containing ethinylestradiol and levonorgestrel, lisinopril, warfarin, and simvastatin that would be considered of clinical relevance. Therefore, no dose adjustments are warranted upon co-administration. 10.1007/s40262-019-00757-1