New Medications for the Treatment of Diabetes.

Abstract

Diabetes Technology & TherapeuticsVol. 19, No. S1 Original ArticlesFree AccessNew Medications for the Treatment of DiabetesSatish K. Garg, Dominique Giordano, Tyler Gallo, and Viral N. ShahSatish K. GargSearch for more papers by this author, Dominique GiordanoSearch for more papers by this author, Tyler GalloSearch for more papers by this author, and Viral N. ShahSearch for more papers by this authorPublished Online:1 Feb 2017https://doi.org/10.1089/dia.2017.2512AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail IntroductionWith the rising prevalence of diabetes worldwide, there has been an increasing interest in finding new ways to manage diabetes. In this chapter, we are going to review abstracts related to newer medications that are being used or that are under investigation for the management of diabetes. We reviewed hundreds of manuscripts/abstracts indexed in PubMed from July 2015 to June 2016 and chose the following to highlight new therapeutic choices for diabetes management. As in the past, we are not going to include much on new insulin treatment options or the artificial pancreas as these have been covered in other chapters in this article.Key Articles Reviewed for the ArticleOptions for empagliflozin in combination therapy in type 2 diabetes mellitusHershon KSInt J Gen Med 2016;9: 155–172.Current status of computer-aided drug design for type 2 diabetesBibi S, Sakata KCurr Comput Aided Drug Des 2016. [Epub ahead of print]Insulin-degrading enzyme: new therapeutic target for diabetes and Alzheimer's disease?Pivovarova O, Höhn A, Grune T, Pfeiffer AF, Rudovich NAnn Med 2016;48: 614–624.Glucagon-like peptide-1 and gastric inhibitory polypeptide: new advancesGallwitz BCurr Opin Endocrinol Diabetes Obes 201623: 23–27Investigational insulin secretagogues for type 2 diabetesScheen AJExpert Opin Investig Drugs 2016;25: 405–422.Future glucose-lowering drugs for type 2 diabetesBailey CJ, Tahrani AA, Barnett AHLancet Diabetes Endocrinol. 2016;4: 3509.A mathematical model of the pathogenesis, prevention, and reversal of type 2 diabetesHa J, Satin LS, Sherman ASEndocrinology 2016;157: 624–635.Identifying barriers to appropriate use of metabolic/bariatric surgery for type 2 diabetes treatment: Policy Lab resultsRubin JK, Hinrichs-Krapels S, Hesketh R, Martin A, Herman WH, Rubino FDiabetes Care 2016;39: 954–963.Efficacy and safety of otelixizumab use in new-onset type 1 diabetes mellitusGuglielmi C, Williams SR, Del Toro R, Pozzilli PExpert Opin Biol Ther 2016;16: 841–846.Addressing unmet medical needs in type 1 diabetes: a review of drugs under developmentMittermayer F, Caveney E, De Oliveira C, Alexander Fleming G, Gourgiotis L, Puri M, Tai LJ, Rick Turer JCurr Diabetes Rev 2016. [Epub ahead of print]Strategies for clinical trials in type 1 diabetesEhlers MRJ Autoimmun 2016; 71: 88–96.Effect of metformin added to insulin on glycemic control among overweight/obese adolescents with type 1 diabetes: a randomized clinical trialLibman IM, Miller KM, DiMeglio LA, Bethin KE, Katz ML, Shah A, Simmons JH, Haller MJ, Raman S, Tamborlane WV, Coffey JK, Saenz AM, Beck RW, Nadeau KJ; for the T1D Exchange Clinic Network Metformin RCT Study GroupJAMA 2015;314: 2241–2250A new role for an old drug: metformin targets microRNAs in treating diabetes and cancerZhou JY, Xu B, Li LDrug Dev Res 2015;76: 263–269.Continuous glucose monitoring: a consensus conference of the American Association of Clinical Endocrinologists and American College of EndocrinologyFonseca VA, Grunberger G, Anhalt H, Bailey TS, Blevins T, Garg SK, Handelsman Y, Hirsch IB, Orzeck EA, Roberts VL, Tamborlane W; on behalf of the Consensus Conference Writing CommitteeEndocr Pract 2016;22: 1008–1021.Ipragliflozin improves hepatic steatosis in obese mice and liver dysfunction in type 2 diabetic patients irrespective of body weight reductionKomiya C, Tsuchiya K, Shiba K, Miyachi Y, Furuke S, Shimazu N, Yamaguchi S, Kanno K, Ogawa YPLoS One 2016;11: e0151511.Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in ratsHarriman G, Greenwood J, Bhat S, Huang X, Wang R, Paul D, Tong L, Saha AK, Westlin WF, Kapeller R, Harwood HJ JrProc Natl Acad Sci USA 2016;113: E1796–1805.New therapeutic approaches in diabetic retinopathyVaziri K, Schwartz SG, Relhan N, Kishor KS, Flynn HW JrRev Diabet Stud. 2015;12: 196–210.Diabetic macular edema: options for adjunct therapyCalvo P, Abadia B, Ferreras A, Ruiz-Moreno O, Verdes G, Pablo LEDrugs 2015;75: 1461–1469.Place of sulfonylureas in the management of type 2 diabetes mellitus in South Asia: a consensus statementKalra S, Aamir AH, Raza A, Das AK, Azad Khan AK, Shrestha D, Qureshi F, Fariduddin, Pathan F, Jawad F, Bhattarai J, Tandon N, Somasundaram N, Katulanda P, Sahay R, Dhungel S, Bajaj S, Chowdhury S, Ghosh S, Madhu SV, Ahmed T, Bulughapitiya UIndian J Endocrinol Metab 2015;19: 577–596Gastrointestinal microbiome modulator improves glucose tolerance in overweight and obese subjects: a randomized controlled pilot trialRebello CJ, Burton J, Heiman M, Greenway FLJ Diabetes Complications 2015;29: 1272–1276.Gut microorganisms as promising targets for the management of type 2 diabetesDelzenne NM, Cani PD, Everard A, Neyrinck AM, Bindels LBDiabetologia 2015;58: 2206–2217.Current Status of Sodium Glucose Co-Transporter (sglt) Inhibitors in Diabetes ManagementOptions for empagliflozin in combination therapy in type 2 diabetes mellitusHershon KS1,21North Shore Diabetes and Endocrine Associates, New Hyde Park, NY2Department of Medicine, Hofstra Northwell School of Medicine, Hempstead, NYInt J Gen Med 2016;9: 155–172ObjectivePresent clinicians with an updated overview of empagliflozin for the treatment of type 2 diabetes mellitus (T2DM), with focus on its use in combination regimens.MethodsUsing the Medline database, keyword searches were undertaken to identify literature reporting the use of empagliflozin treatment in clinical trials with a minimum duration of 12 weeks relating to patients with T2DM.ResultsWhen given as monotherapy or in combination therapy (as single-pill therapy or an add-on) with sulfonylurea, metformin, linagliptin, pioglitazone, and insulin, empagliflozin was able to produce reductions that were clinically meaningful in glycated hemoglobin levels, bodyweight, plasma glucose concentrations, and blood pressure, which changes were sustained during long-term treatment. In a dedicated cardiovascular event trial, on top of standard care, empagliflozin demonstrated a significant reduction in the risk of all-cause mortality as well as cardiovascular mortality. Across the clinical trials, combination therapies with empagliflozin were well tolerated, and used alone, empagliflozin was not associated with an increased risk of hypoglycemia versus placebo. In fact, the combination of metformin and empagliflozin had a significantly reduced rate of hypoglycemia compared with the combination of metformin with a sulfonylurea. However, empagliflozin treatment did have increased risk of genital infections compared with a placebo. To date, in clinical trials diabetic ketoacidosis was not seen more frequently with empagliflozin than with placebo, although physicians should remain alert to the possible occurrence of this rare event.ConclusionsFor patients with T2DM, empagliflozin has the potential to make an important contribution to their treatment. For some patients, empagliflozin may be used as monotherapy, but its most likely use is in combination with other therapies. Given that when empagliflozin was employed in addition to standard care in patients having high cardiovascular risk there was a reduced risk of mortality, in combination with the lack of alternative options for patients with a lower cardiovascular risk, it is possible that empagliflozin will be added to ongoing regimens for a significant proportion of patients.CommentThe cardiovascular outcome trials (CVOTs) have recently added interesting choices for possible medical interventions while managing type 2 diabetes, although the drugs are from the same family. Specifically, an empagliflozin study was shown to have reduced overall mortality, especially from cardiovascular disease. Even though the CVOTs were criticized by many endocrinologists and the Food and Drug Administration (FDA) was blamed for making this a burden for new diabetes drug approvals, it appears that the outcome of many of these trials are guiding the providers to individualize therapy for patients with diabetes. It also appears that different medications from the families of glucagon like peptide-1 (GLP-1) analogs or SGLT2 inhibitors may be significantly different with cardiovascular outcomes or overall mortality by using these drugs in patients with type 2 diabetes. One caveat is that the population evaluated in many of the CVOTs are not identical and sometimes it is hard to extrapolate data between trials. The ideal trial/study would be a head to head comparison between different molecules from the same family of drugs in similar high risk individuals with cardiovascular disease, and evaluate the long-term outcomes in mortality and cardiovascular death. Unfortunately, such studies are unlikely to be done unless the National Institute of Health (NIH) or other non-profit organizations are willing to fund such a long-term study.Newer Investigational AgentsCurrent status of computer-aided drug design for type 2 diabetesBibi S, Sakata KDepartment of Environment and Life Engineering, Graduate School of Engineering, Maebashi Institute of Technology, Maebashi, Gunma, JapanCurr Comput Aided Drug Des 2016. [Epub ahead of print]BackgroundDiabetes is a metabolic disorder requiring multiple therapeutic approaches. The ability of the pancreas to produce insulin hormone properly is lost in patients with diabetes mellitus. During 2012, more than one million people across the globe died of diabetes. This was the eighth leading cause of death.ObjectiveMost of the currently available drugs that are approved by the U.S. Food and Drug Administration cannot attain an adequate level of glycemic control in diabetic patients, and they have many side effects; therefore, new classes of compounds are needed. Efforts based on computer-aided drug design (CADD) are able to mine a large number of databases to produce new and potent possibilities and to minimize the requirement in terms of time and dollars for new discoveries to be made.MethodsThe pharmaceutical sciences have made advances in drug design concepts. Virtual screening of large databases is compatible with a number of computational methods including molecular docking, quantitative structure-activity relationship, pharmacophore, and molecular dynamic simulation. The contribution of these methods in the selection of antidiabetic compounds was discussed.ResultsThe CADD approach has contributed to the successful discovery of novel antidiabetic agents. This mini-review focuses on the CADD approach in terms of currently approved drugs and new therapeutic agents in development that might achieve desirable glucose levels and decrease the risk of hypoglycemia, which latter is a major obstacle to glucose control and a particular concern for therapies where insulin levels are increased.ConclusionDrug design and development for type 2 diabetes were actively studied. However, a large number of drugs for diabetes are still in the early stages of development. The conventional target- and structure-based approaches can be viewed as a part of the efforts toward therapeutic mechanism-based drug design for the treatment of type 2 diabetes. It is expected that further improvement in the CADD approach will improve new discoveries.CommentMost drugs that are approved by the FDA or the European Medical Agency (EMA) have to go through a rigorous clinical trial program and, in many cases, it may include CVOT trials. These pathways are expensive and add to the cost of medications while delaying the introduction of possible therapies for patients with diabetes. Many efforts are being made in computer-aided drug design (CADD) programs that can minimize the duration of time and significantly reduce the cost for new therapeutic choices. This will require new thinking on the part of regulatory agencies where computer aided drug design programs can be used for drug approvals.Insulin-degrading enzyme: new therapeutic target for diabetes and Alzheimer's disease?Pivovarova O1,2,3, Höhn A3,4, Grune T3,4,5, Pfeiffer AF1,2,3, Rudovich N1,2,31Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany2Department of Endocrinology, Diabetes and Nutrition, Campus Benjamin Franklin, Charite University Medicine, Berlin, Germany3German Center for Diabetes Research, München, Germany4Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany5German Center for Cardiovascular Research, Berlin, GermanyAnn Med 2016;48: 614–624.Insulin-degrading is caused mainly by Insulin-degrading enzyme (IDE). It also degrades many other targets including atrial natriuretic peptide, glucagon, and beta-amyloid peptide and also regulates proteasomal degradation as well as other cell functions. IDE represents a pathophysiological link between late onset Alzheimer's disease (AD) and type 2 diabetes (T2DM). Potent and selective modulators of the activity of IDE are potential drugs for therapies of both of these diseases. Acute treatment with one such novel IDE inhibitor was recently tested on mice as therapy for T2DM. In contrast, effective IDE activators can be used as treatment for AD. However, because of the pleiotropic action of IDE, sustained treatment with systemic IDE modulators should be tested carefully in animal studies. Substrate-selective IDE modulators have the potential to overcome possible adverse effects of IDE modulators that are associated with multiplicity of IDE targets. In summary, IDE represents a pathophysiological link between T2DM and AD. Some modulators of IDE activity are candidate drugs for treating both T2DM and AD. Development of substrate-selective IDE modulators could overcome possible adverse effects of IDE modulators associated with multiplicity of IDE targets.CommentInsulin-degrading enzyme (IDE) is mostly responsible for degrading insulin subcutaneously. In addition, IDE degrades many other target hormones like glucagon and atrial natriuretic peptide etc. Selective IDE inhibitors have been shown to positively affect Alzheimer's disease (AD). It appears that type 2 diabetes (T2D) and AD have a potential pathophysiological link. Thus, selective modulators of IDE activity are potential drugs for both AD and T2D. This is a fascinating area of research and may facilitate newer therapeutic substrate specific choices with fewer side effects.Glucagon-like peptide-1 and gastric inhibitory polypeptide: new advancesGallwitz BDepartment of Medicine IV, Eberhard-Karls-University Tübingen, Tübingen, GermanyCurr Opin Endocrinol Diabetes Obes 2016;23: 23–27ObjectiveGlucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) are gastrointestinal peptides that both play an important role as incretin hormones in the regulation of insulin secretion and plasma glucose. Therefore GLP-1-based therapies have been used as treatment for type 2 diabetes (T2D). The aim of this review is to summarize the new treatment options relating to T2D that employ GLP-1-based therapies. In addition, we also summarize relevant extrapancreatic effects that have been recently characterized for both peptides.FindingsThe review highlights novel findings that regard changes in GLP-1 secretion after bariatric surgery in which GLP-1 plays a role in promoting body weight loss and diabetes remission. For T2D therapy, novel options with long-acting GLP-1 analogs that show a desirable safety and efficacy profile are summarized, also in combination with insulin and for obesity treatment. As GIP is not suitable for T2D therapy, recent characterization of the extrapancreatic effects of GIP, mainly on bone metabolism, are described. These illustrate that the activated GIP receptor is important to allow optimal bone structure and mass.SummaryThis review summarizes new findings on the physiology and pathophysiology of GLP-1 and GIP and novel therapeutic aspects.Investigational insulin secretagogues for type 2 diabetesScheen AJ1,21Division of Clinical Pharmacology, Center for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium2Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU, Liège, BelgiumExpert Opin Investig Drugs 2016;25: 405–422.IntroductionKey features in the pathophysiology of type 2 diabetes (T2D) are insulin secretory defects. Classical insulin-secreting agents, for example sulfonlyureas, stimulate insulin secretion independently of glucose and cause hypoglycemia. In spite of the advantages offered by incretin-based therapies, there remains a requirement for the development of new insulin secretagogues for the treatment of T2D.Area CoveredThis article discusses the following areas: new advances in the field of incretin-based therapies, glucokinase (GK) activators, imeglimin, free fatty acid receptor (FFAR) or G protein-coupled receptor (GPR) agonists (GPR40, GPR119, GPR120), and some other insulin secretagogues with different and wide ranging mechanisms of action that are still in preclinical development.Expert OpinionNew insulin secretagogues should be able to offer major advantages compared to sulfonylureas and gliptins. The challenges are the avoidance of uncontrolled insulin secretion and minimization of the risk of hypoglycemia, protection of cells from a progressive loss of mass, as well as function, for a better durability of glucose control, and a good safety profile. A number of approaches are in development although it is too early to tell if one novel pharmacological class will emerge as a clinically useful insulin secretagogue in the near feature.Future glucose-lowering drugs for type 2 diabetesBailey CJ1, Tahrani AA2, Barnett AH2,31School of Life and Health Sciences, Aston University, Birmingham, UK2Department of Diabetes and Endocrinology, Heart of England NHS Foundation Trust, Birmingham, UK3Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Birmingham, UKLancet Diabetes Endocrinol. 2016;4: 3509.The progressive and multivariable natural history of type 2 diabetes limits how effective available glucose-lowering drugs can be. Constraints that are imposed by comorbidities (particularly cardiovascular disease and renal impairment) together with the need to avoid weight gain, hypoglycemia, and drug interactions further complicate the treatment process. Alongside research into new pharmacological entities, these challenges have prompted development of new formulations and delivery methods for existing drugs. Advances in incretin-based therapies include a miniature osmotic pump that can be implanted 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 properties of selected incretins and other peptides are in the early stages of development, and proof of concept has been demonstrated for small nonpeptide molecules to activate glucagon-like peptide-1 receptors. Additional sodium-glucose cotransporter inhibitors are advancing through development as well as potential small-molecule inhibitors of glucagon action and novel insulin-releasing biological agents. Adiponectin receptor agonists, selective peroxisome proliferator-activated receptor modulators, cellular glucocorticoid inhibitors, and analogues of fibroblast growth factor 21 are being considered as possible new approaches to the lowering of glucose. Future opportunities for treatment have been suggested by compounds that can enhance insulin receptor and postreceptor signaling cascades or directly promote selected pathways of glucose metabolism. However, pharmacological interventions that are able to restore normal β-cell function and β-cell mass, normalize insulin action, and fully correct glucose homoeostasis are a distant vision.A mathematical model of the pathogenesis, prevention, and reversal of type 2 diabetesHa J1, Satin LS2, Sherman AS11Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD2Department of Pharmacology and Brehm Diabetes Research Center, University of Michigan, Ann Arbor, MIEndocrinology 2016;157: 624–635.Type 2 diabetes (T2D) is generally believed to result from the combination of 2 metabolic defects, resistance to insulin, which results in an increase in the level of insulin required to maintain glucose within the normal range, and the failure of insulin-secreting pancreatic β-cells to compensate for the increased demand. We develop a mathematical model based on that pioneered by Topp and colleagues to determine how compensation succeeds or fails. Their model had an additional layer of slow negative feedback compared to the classic insulin-glucose loop in the form of a slow, glucose-dependent birth and death law that governed β-cell mass. We have added regulation of 2 aspects of β-cell function on intermediate time scales to that model. The model quantifies the relative contributions of insulin secretion defects and insulin action to T2D and elucidates why prevention is easier than cure. The latter is a result of a threshold that separates the normoglycemic and diabetic states (bistability), which is also responsible for the success of bariatric surgery and acute caloric restriction in rapidly reversing T2D. The threshold concept allows for new insight into “Starling's Law of the Pancreas,” whereby insulin secretion is higher for both prediabetics and early diabetics than for normal individuals.CommentThe above four abstracts highlight different approaches to managing type 2 diabetes. Combining GLP-1 and GIP hormones might offer an advantage of managing type 2 diabetes specifically due to extra pancreatic effects of GIP, mainly on the bone metabolism.There are many investigational insulin secretagogues for better management of type 2 diabetes that can possibly reduce the risk of hypoglycemia and may help in protecting cells in progressive loss of beta cell mass. Different secretagogues include GK activators, FFAR, GPR, GPR-40 and Imeglimin. It may be too premature to conclude if any of these are going to make for human use from what has been seen in the animal studies.The last article highlights a mathematical model pioneered by the authors to elucidate how compensation succeeds or fails. Their threshold concept gives new insight to “Starling's Law of Pancreas” where insulin secretion is higher for subjects with prediabetes and early diabetes than for normal individuals.Surgical Approach for Management of Type 2 DiabetesIdentifying barriers to appropriate use of metabolic/bariatric surgery for type 2 diabetes treatment: Policy Lab resultsRubin JK1, Hinrichs-Krapels S1, Hesketh R1, Martin A2, Herman WH3, Rubino F41The Policy Institute at King's, King's College London, London, UK2RAND Europe, Cambridge, UK3University of Michigan, Ann Arbor, MI4Metabolic and Bariatric Surgery, Division of Diabetes and Nutritional Sciences, King's College London and King's College Hospital, London, UKDiabetes Care 2016;39: 954–963.Despite the fact of increasing recognition of the safety, efficacy, and cost-effectiveness of bariatric/metabolic surgery in the treatment of type 2 diabetes, few potential candidates among patients who might benefit from this type of surgery avail themselves of this treatment option. To identify the practical and conceptual barriers relating to the appropriate use of surgical procedures, a Policy Lab was hosted at the third World Congress on Interventional Therapies for Type 2 Diabetes on 29 September 2015. Twenty-six stakeholders participated in the Policy Lab, including clinicians, policy-makers, academics industry leaders, and patient representatives. Each participant was provided with a summary of the available evidence regarding the cost-effectiveness of bariatric/metabolic surgery together with the costs related to increasing the use of bariatric/metabolic surgery using scenarios in the United States and the United Kingdom as examples of distinct systems of health-care. Among this stakeholder group there was widespread agreement that bariatric/metabolic surgery is a cost-effective and legitimate approach to treating type 2 diabetes in obese patients.Four building blocks were identified as facilitating policy changes, these were: (1) communicating the scale of the harms and the costs that are associated with the rising prevalence of type 2 diabetes; (2) articulating well the role of bariatric/metabolic surgery with particular population groups; (3) identifying new funding sources for bariatric/metabolic surgery; and (4) incorporating bariatric/metabolic surgery into the most appropriate clinical pathways. While more research is needed to identify appropriate clinical scenarios where bariatric/metabolic surgery might be prioritized, the case appears now to be strong enough that relevant policy-makers and practitioners should be engaged in a concerted discussion regarding how to make better use of metabolic surgical resources together with other interventions in good diabetes practice.CommentMetabolic/bariatric surgery for treatment of type 2 diabetes is being practiced at more centers across the globe. Therefore, it is necessary to assess the efficacy, safety, and cost effectiveness of such treatment. It is also imperative that appropriate guidelines and candidates who might benefit from such treatments be properly established. The consensus so far has been that bariatric surgery in morbidly obese people with type 2 diabetes is cost effective and is a legitimate course for management of the disease. One does not know if bariatric surgery done before the onset of type 2 diabetes may in fact completely prevent the onset of type 2 diabetes. The anecdotal data suggests that to be the case. Unfortunately, even in subjects with type 1 diabetes, significant obesity (BMI >35) is quite common and many such individuals may be subjected to this extreme metabolic surgery. However, such treatment in type 1 diabetes has been done only in limited number of cases across the globe. It is important to consider patient safety before implementing such invasive steps as individuals with type 1 diabetes will be on insulin for the rest of their life and are at high risk of severe hypoglycemia. In patients with T1D, special protocols may need to be devised for good outcomes after the bariatric surgery.Newer Agents for Management of Type 1 DiabetesEfficacy and safety of otelixizumab use in new-onset type 1 diabetes mellitusGuglielmi C1, Williams SR2, Del Toro R1, Pozzilli P1,21Unit of Endocrinology and Diabetes, Department of Medicine, University Campus Bio-Medico di Roma, Rome, Italy2Centre of Immunology, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, London, UKExpert Opin Biol Ther 2016;16: 841–846.IntroductionType 1 diabetes (T1DM), an immune-mediated disease that is induced by antigen-specific T-cells infiltrating pancreatic beta cells, leads to a progressive loss of endogenous secretion of insulin.Areas CoveredSpecific components of the autoimmune response have been identified to favor implementation of a number of immunomodulatory therapies that include the antiCD3 monoclonal antibody (mAb) known as otelixizumab. Otelixizumab, a chimeric monoclonal antibody, targets the ɛ-chain of the CD3T-lymphocyte surface receptor that was developed to enable short therapeutic courses that are capable of inducing a state of remission of T1DM. Clinical trials have been undertaken with otelixizumab to evaluate its efficacy and safety, however, although the results of the Phase I and II studies have been positive, the results of the Phase III studies are contradictory.Expert OpinionHigh doses of otelixizumab have been shown to have beneficial effects on the beta cell function whereas a dose that is lower, tested to avoid adverse effects associated with the higher doses, was not effective for beta cells preservation. We believe that otelixizumab is a drug of possible interest in the treatment of new onsetT1DM patients and it should be considered for use in combination with other immunomodulatory agents as a solution that circumvents adverse effects while maintaining efficacy.Addressing unmet medical needs in type 1 diabetes: a review of drugs under developmentMittermayer F, Caveney E, De Oliveira C, Alexander Fleming G, Gourgiotis L, Puri M, Tai LJ, Rick Turner JQuintiles GmbH, Vienna, AustriaCurr Diabetes Rev 2016. [Epub ahead of print]The occurrence of type 1 diabetes (T1D) is increasing across the globe and there is an extremely important requirement for effective therapies. Apart from pramlintide and insulin, essentially there are no pharmacologic therapies that are currently approved for the treatment of T1D. Drugs that are already used for type 2 diabetes together with a number of new drugs, are under clinical development for T1D that include compounds that have both new and established mechanisms of action. The majority of the new compounds that are in clinical development are currently in Phases 1 and 2. In this review, the drug classes discussed include new insulins, GLP-1 agonists, SGLT inhibitors, immunomodulatory drugs including anticytokines and autoantigens, and agents that regenerate β-cells. Considerations are also provided with regard