New medications for the treatment of diabetes (2012)

A number of new medications are being developed for the treatment of diabetes. In this chapter, we review recent papers describing some of these. We begin with insulins – an overview paper, two papers about insulin degludec (one each for type 2 and type 1 diabetes), one paper about a pre-mixed insulin combining insulin degludec with insulin aspart, one paper about very early development of a possible method to prolong the action of insulin glargine, and two papers about ultra-rapid-acting insulins – one that uses an inhaled insulin formulation in which insulin is adsorbed onto fumaryl diketopiperazine powder, and one in which action is accelerated by mixture with hyaluronidase. Next we cover a new weekly formulation of the glucagon-like peptide 1 (GLP-1) receptor agonist exenatide; the development of two new classes of antidiabetic drugs, sodium glucose cotransporter 2 (SGLT-2) inhibitors and glucokinase activators; a potential new indication for the GLP-1 receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors – use in type 1 diabetes; and finally we look at new studies trying to prevent type 2 diabetes. Simon AC, DeVries JH Department of Internal Medicine, Academic Medical Centre, Amsterdam, The Netherlands Diabetes Technol Ther 2011; 13 (Suppl 1): S103–8 Background: Both patients and physicians are often reluctant to start or intensify insulin therapy because of perceived fear of painful injections, hypoglycaemia, weight gain, complexity of insulin regimens, and drug costs. Optimising basal insulin therapy and addressing these barriers can facilitate the achievement of optimal glycaemic control in patients with type 2 diabetes. The currently available long-acting basal insulin analogues (detemir and glargine) show advantages compared with the NPH insulin. The aim of this review is to present an overview of the candidates for improved basal insulin in the pharmaceutical pipeline. Results: The first new basal insulin to enter the market is most probably insulin degludec (IDeg), currently reporting in phase 3 of development, from Novo Nordisk (Bagsvaerd, Denmark), which has a longer duration of action than currently available analogues. Phase 2 studies show comparable efficacy and safety outcomes compared with insulin glargine once daily with less hypoglycaemia in type 1 diabetes. The final results of phase 3 studies seem to confirm this, also in type 2 diabetes. Biodel (Danbury, CT, USA) has two long-acting basal insulin formulations in the pipeline, both in the pre-clinical phase of development: BIOD-Adjustable Basal, a modified formulation of insulin glargine, is being developed in long-, medium- and short-acting forms and could be mixed, and BIOD-Smart Basal releases insulin proportional to the subcutaneous glucose concentration. Clinical trials with the new patch pump from CeQur (Montreux, Switzerland) have recently started in Europe. This pump delivers subcutaneously both basal and bolus doses and is intended for people with type 2 diabetes who need multiple daily injection insulin therapy. Comment: Simon and DeVries project the future of basal insulin supplementation in this paper. They highlight some new information on insulin degludec (not yet approved in any part of the world). Phase 2 studies on insulin degludec show significantly lower hypoglycaemia in subjects with type 1 diabetes. The authors also report on Biodel-adjustable basal, a modified formulation of insulin glargine that could possibly be mixed with ultra-fast-acting insulin for a single injection treatment. The ideal way to deliver basal insulin might be the use of patch pumps using rapid-acting or ultra-fast-acting insulin to replicate what happens in healthy individuals. Below are some of the studies with new basal insulins and their development. Zinman B 1 , Fulcher G 2 , Rao PV 3 , Thomas N 4, Endahl LA 5 , Johansen T 5 , Lindh R 5 , Lewin A 6 , Rosenstock J 7 , Pinget M 8 , Mathieu C 9 1 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada, 2 Royal North Shore Hospital and University of Sydney, Sydney, NSW, Australia, 3 Nizam’s Institute of Medical Sciences University, Hyderabad, India, 4 Christian Medical College, Vellore, India, 5 Novo Nordisk, Soeborg, Denmark, 6 National Research Institute, Los Angeles, CA, USA, 7 Dallas Diabetes and Endocrine Center at Medical City, Dallas, TX, USA, 8 University Hospital Strasbourg, Strasbourg, France, and 9 UZ Gasthuisberg Katholieke Universiteit Leuven, Leuven, Belgium Lancet 2011; 377 : 924–31 Background: Insulin degludec is an ultra-long-acting insulin in clinical development, and its action profile is mainly attributable to formation of soluble multihexamers at the injection site, from which monomers gradually separate and are absorbed into the circulation, resulting in a flat and stable pharmacokinetic profile at steady state. This clinical proof-of-concept trial aimed to assess efficacy and safety of insulin degludec once a day or three times a week compared with insulin glargine once a day, in combination with metformin, in insulin-naive patients with type 2 diabetes who were inadequately controlled on antidiabetic This a clinical in Canada, India, and the USA) phase 2 trial of in which with type 2 diabetes were and were in a to insulin degludec once a day or three times a week or insulin glargine once a day, in combination with were to The of treatment. Results: patients were for were to insulin degludec three times a week injection 9 to insulin degludec once a day 6 to insulin degludec once a day 9 and to insulin glargine 6 once a were the treatment treatment from insulin by with insulin glargine, were to for the three week to for A and to for hypoglycaemia and the number of the with from this trial show that insulin degludec can glycaemic control to insulin glargine new or of in insulin-naive people with type 2 diabetes. The efficacy and use of treatment for insulin degludec need to be Comment: Zinman report phase 2 results on insulin degludec in patients with type 2 diabetes. comparable glycaemic control and the of hypoglycaemia This also insulin degludec in could possibly be three times a the number of is to the development of a new basal be that insulin degludec to insulin glargine in of glycaemic 1 , 2 , 3 , 4 , Johansen T 5 , Endahl LA 5 , 5 , JH 6 , 7 , DeVries JH 8 , 9 1 University Hospital and of Medicine, 2 University, 3 in Internal and 4 Research Institute, USA, 5 Novo Nordisk Soeborg, Denmark, 6 University Hospital, 7 Royal Hospital, Australia, 8 University of Amsterdam, Amsterdam, The and 9 University of of Medicine, Diabetes 2011; : Background: the advantages by basal insulin hypoglycaemia a treatment Insulin degludec is a ultra-long-acting basal insulin that forms soluble multihexamers subcutaneous resulting in an profile and a and stable pharmacokinetic profile at steady state. are to improved glycaemic control and to lower the of The aim of this trial to the safety and of two formulations and with insulin glargine in combination with insulin in people with type 1 diabetes. A in which patients glucose subcutaneous of or insulin glargine once daily in the and insulin at Results: comparable for and glucose and of hypoglycaemia were lower for compared with and lower for compared with of hypoglycaemia were lower for and lower for daily insulin to The and of insulin This clinical trial that in combination with is a and treatment in patients with type 1 comparable glycaemic control to insulin glargine at comparable doses with lower of Comment: to the trial in type 1 diabetes for 4 an in hypoglycaemia, with glucose This two formulations of and that is and in patients with type 1 diabetes compared with The that to be is are and T 1 , 2 , R 3 , J 4 , 5 , A 6 , 7 , 8 , 8 , R 9 1 2 University, Medical Centre, The 3 Diabetes USA, 4 Department of Medicine, of University of Medical Dallas, TX, USA, 5 France, 6 Center for Diabetes and 7 University of 8 Novo Nordisk Denmark, and 9 Institute of Clinical Medicine, University of Diabetes 2011; : Background: Insulin degludec can be with insulin resulting in a soluble two insulin analogues basal insulin and both basal and rapid-acting insulin analogues in one could be an to the of insulin therapy with basal insulin on of antidiabetic In this clinical the safety and efficacy of compared with insulin glargine both once daily in combination with in insulin-naive subjects with type 2 diabetes inadequately controlled on antidiabetic therapy. the optimal of to an formulation of a of also In this subjects were to or in combination with Insulin the and to a glucose of Results: in to comparable A of subjects hypoglycaemia in the 4 of treatment glucose lower for and than for glucose were lower for and than for and for and compared with the of this proof-of-concept with a a treatment duration and an show to be a treatment for insulin therapy in subjects with type 2 diabetes inadequately controlled with antidiabetic and comparable glycaemic control to with lower doses and with the of glucose control that in an of Comment: This is a proof-of-concept using a new pre-mixed insulin – a combination of insulin degludec and insulin a for diabetes. This trial lower with with glucose control compared with be a in glucose has a rapid-acting insulin rapid-acting with A have a currently available pre-mixed insulin. with a combination of and basal in the future might patients with type 2 diabetes to both lower glucose and a in the in glucose their 1 , T 1 , 1 , 1 , 2 , N 3 , 3 , 2 , 1 1 of University, 2 of University, and 3 J 2011; : Background: Insulin glargine is the first long-acting basal insulin for subcutaneous once daily in patients with type 1 or type 2 diabetes The aim of the to the potential use of with the of of the on of insulin glargine, the the on and of insulin glargine and the of insulin glargine subcutaneous injection into insulin glargine and glucose of were The of the insulin glargine in in the and of subcutaneously into and at were Results: the and of insulin glargine in at probably to the of with of insulin In accelerated the of insulin glargine from its compared with that of insulin glargine subcutaneous of an insulin glargine with the of insulin glargine and the glucose possibly to the of on the at the injection both and a of the of insulin glargine subcutaneous injection to probably to the of on the at the injection site, resulting from with the insulin glargine that can be a for of insulin Comment: basal insulin treatment is in patients with type 2 start to on is an to the of insulin glargine or to a basal insulin. In this the authors on the of insulin results that can be a for of insulin the are also studies being with of insulin glargine or to these in basal insulin than insulin glargine in Rosenstock J 1 , 2 , 3 , 4 , 4 , 4 , 4 , 4 , 4 1 Dallas Diabetes and Endocrine Center at Medical City, Dallas, TX, USA, 2 Diabetes Diabetes and USA, 3 for Medicine, and 4 CA, Lancet : Background: Insulin therapy is often a in patients with type 2 diabetes because is with weight gain, hypoglycaemia and the need for subcutaneous The aim of this to the efficacy and safety of inhaled insulin insulin glargine daily insulin for treatment of type 2 diabetes in patients with with or This a of patients with type 2 diabetes and glycaemic control insulin with or antidiabetic were in a to treatment with inhaled insulin insulin glargine, or daily pre-mixed insulin insulin and insulin of The a of in from to week treatment the by for of the Results: were to inhaled insulin insulin glargine and to insulin patients on inhaled insulin insulin glargine and on insulin the A of patients on inhaled insulin insulin glargine and on insulin were in in with inhaled insulin insulin glargine to and to that with insulin to The to significantly lower weight and and on inhaled insulin insulin glargine than on insulin. The safety and profile for both from of and in in the inhaled insulin insulin insulin insulin glargine, or in combination with an antidiabetic drug is an to insulin therapy in type 2 diabetes. Comment: insulin has the of the of insulin with that which in healthy individuals. inhaled insulin is one formulation that that development uses a the of a two are in to the inhaled insulin which pharmacokinetic insulin and a and In the less weight and less hypoglycaemia with the inhaled insulin insulin glargine probably to the action and of that which the of hypoglycaemia and results in weight M 1 , 2 , 1 , 2 1 Institute for Clinical CA, USA, and 2 CA, Diabetes 2011; : Background: patients with diabetes to glucose that the pharmacokinetic and efficacy of available insulin be A that the of the insulin and insulin in healthy The aim of this to confirm these in patients with type 1 diabetes using doses of insulin and to the of these pharmacokinetic on glycaemic to a This a patients with type 1 diabetes who of doses of or with and a Results: early insulin by for and for compared with the insulin glucose for and for the for glucose by and of hypoglycaemia were comparable for with or of and The results of this that a of insulins with for patients with diabetes by the for Comment: to insulin results in and is for the action of insulin resulting in an ultra-rapid-acting of The that the is and that both insulin and insulin analogues can have their are way this insulin in clinical 1 , C 2 , 3 , J 3 , B 3 , 3 , 3 , J 4 , 3 1 Diabetes Center at USA, 2 USA, 3 CA, USA, and 4 Lancet : Background: patients with type 2 diabetes begin with need treatment. In this in and with a of the safety and of three for patients controlled on once weekly receptor and approved doses of and In this trial of patients with type 2 diabetes who with of glucose of weight of were were to 2 once weekly once or once daily once or once daily once The in and week by to for patients who at one of Results: A of patients were to to and to In patients at one of drug and were in the on on and on with to significantly than to or to were to for and to for with to significantly than with to or to of hypoglycaemia The most with and were and and were the most with This one of the most of with to The in and with with a number of that this drug be an to in patients who need in glucose control and and in the of hypoglycaemia to be to a C 1 , R 2 , J 3 , 3 , B 3 , J 4 , 3 1 USA, 2 Diabetes Center at USA, 3 CA, USA, and 4 and 2011; : Background: In the of the trial in patients with type 2 diabetes on metformin, the GLP-1 receptor agonist once weekly in and weight compared with approved daily doses of or This trial to the glycaemic and of in patients with once weekly for who from daily of to a therapy that results in to of the GLP-1 receptor agonist exenatide; and who from daily receptor with which insulin to a therapy that insulin and is with weight In a medications were and patients once the patients glucose weight who into the patients Results: who once weekly in glucose and weight who from to once weekly in glucose and weight who from to once weekly and glucose with weight once weekly and were or in the most in this hypoglycaemia once weekly has to compared with three that are insulin The that once weekly also be a treatment in patients with type 2 diabetes on a of who are currently glycaemic control with a or in is a Comment: once weekly is a long-acting formulation of a GLP-1 receptor the first diabetes drug that can be on a weekly The studies are a of trials that once weekly with diabetes In the is with the and the in patients with the first in the Lancet paper, both of and weight with once weekly than with or the in the paper, patients who on or were to once on in both and weight on and weight with the this that once weekly the potential to the of to once weekly both glycaemic control and weight 1 , 2 , A 3 , A 4 , 4 1 and University, 2 Endocrine 3 and 4 Clinical Lancet : Background: of and of are in the of type 2 diabetes. a sodium glucose (SGLT-2) glucose in an This the efficacy and safety of to in patients with type 2 diabetes who are controlled with In this phase with type 2 diabetes who were daily and glycaemic control were to one of three doses of 5 or or once to their The from in at patients who at one of and who both a and at one were in the Results: In patients were in the of the 5 week by to in the compared with to in the to in the 5 and to in the of hypoglycaemia in of patients in the and and of were in the patients 5 than in the patients in each of the and in the This trial that can glycaemic control in patients who have control with The drug of and is with of and of the drug were also of to a new for the treatment of type 2 diabetes. Comment: are inhibitors currently development. is the first of these to to a of a and in The inhibitors of glucose in the resulting in of glucose in the and of In this of glucose resulting in improved insulin and insulin are in this of might have potential in the of diabetes. the the the of and The be with The some into this G 1 , R 2 , M 2 , G 2 1 Hospital, and 2 Department of Internal Medicine, University of of assess the efficacy and safety of the new antidiabetic inhibitors in type 2 diabetes. papers on and 13 trials were papers and by outcomes were using or Results: significantly to glucose to to to and to and to inhibitors treatment the of and also the of hypoglycaemia with insulin. from controlled this that inhibitors are and for treatment in type 2 diabetes. Comment: The authors report a of clinical trials of on the in in patients to compared with antidiabetic treatment. this also a in and with a in with insulin. In this is probably early to the efficacy and safety of 1 , T 2 , C 3 , C 2 , A 4 , J 3 , J 3 , 3 , R 5 1 of and Department of Medicine, University of of Medicine, 2 Institute, 3 , USA, 4 Department of Clinical and and University of and 5 J : Background: a in glucose can lower glucose in both and type 2 diabetes. The present to the of the action of glucokinase in patients with type 2 diabetes in both and glucose This a phase trial of two and doses of using a glucose and of the insulin to assess glucose and A single of to the of the with drug treatment. The glucose concentration. The and glucose Results: a of glucose in both and In the a in a in glucose and a in glucose use In the the of were on The glucokinase has both in the and a glucose The these a to of with a of glucose in the and a in of the the glucose is potential of in glucose which at times a glucose be this that be a antidiabetic with a in Comment: is an in the a glucose a in because the of of glucose to is the in insulin In the glucokinase the of glucose and of of glucokinase be to in in glucose a number of glucokinase are development potential for diabetes. is one have using glucokinase in this is one of the first studies in We studies both with and glucokinase of Diabetes and University of at and J 2011; : Background: The use of a GLP-1 in and the in glucose in type 1 diabetes. The aim of the present trial to the of to insulin to patients with type 1 diabetes to an in glycaemic control and glycaemic In this patients with controlled type 1 diabetes on glucose and insulin therapy were with for 1 the therapy for Results: In the and weekly glucose significantly 1 week from to 8 and from to significantly improved at 1 The glucose from to 6 and the of from to 7 a in basal insulin from 6 to 6 and bolus insulin from 4 to 4 In patients who therapy with for weekly glucose glycaemic and basal and bolus insulin also significantly significantly at from to the by The of to insulin therapy in controlled type 1 diabetes patients in a and in glycaemic with a in insulin and a in and The glycaemic were the of treatment. significantly in the for , 1 , 1 , 1 , 1 , 1 Center for USA, 2 Department of Clinical University of USA, and 3 Department of Internal and University of 2011; : Background: with type 1 diabetes have significantly inhibitors by GLP-1 and peptide which in in both type 1 and type 2 diabetes. The of this to assess the clinical of in patients with type 1 diabetes. This subjects with type 1 diabetes or for 4 and glucose and the in glucose from glucose and insulin Results: significantly glucose and the and insulin on glucose improved of glycaemic glucose and in for treatment and insulin the also significantly patients were This that significantly both the and the in patients with type 1 diabetes. also significantly daily insulin and glucose from glucose and in the is in patients with type 1 diabetes in a to assess both clinical outcomes and of Comment: two are studies the potential of the GLP-1 receptor agonist and the in type 1 diabetes. Both studies that is a is that patients with type 1 diabetes from these that their of action in this is of of insulin and is to of has an in insulin in type 1 diabetes and the that some patients with type 1 diabetes and have the of type 1 diabetes type 2 diabetes. the potential of GLP-1 receptor agonists or inhibitors weight or weight also studies in glucose control in patients with type 1 diabetes with or studies with these are and we to Zinman B , 3 , J 1 , 4 , 1 , J , 1 , 1 Sinai for Department of Medicine, Mount Sinai Hospital, and University of Toronto, Toronto, ON, Canada, 2 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada, 3 for in Medicine, University of ON, Canada, 4 of and and the Research Institute, Department of Medicine, University, and ON, Canada, 5 of University Toronto, ON, Canada, and 6 of and Department of and University of Toronto, Toronto, ON, Lancet : Background: The of type 2 diabetes has to assess the safety and efficacy of diabetes and have of action insulin and glucose and have both to the development of diabetes in patients with glucose The trial combination therapy with the of and on a of a prevent type 2 diabetes in with glucose In a controlled trial in in patients with glucose were to combination and daily or for a of The to development of by an glucose or two glucose of or Results: In were to and metformin, and to were in and at of in the and and in the diabetes in significantly in the treatment than in the The and the In patients in the treatment to glucose compared with in the Insulin by in the to and with and treatment to The in by the insulin to and to often in the treatment compared with the 6 from the trial have that the combination of the with at the in of diabetes and in of glucose in with glucose with on the of these two results to the of the use of combination an to 1 , 1 , , M 5 , 6 , 7 , 8 , 9 , 7 , 9 , 7 , 9 , , 2 , 9 , N 1 , 3 1 Diabetes Institute and University of TX, USA, 2 TX, USA, 3 USA, 4 of and University, USA, 5 Center at USA, 6 Research University, USA, 7 University of of Medicine, Los Angeles, CA, USA, 8 of and University, USA, 9 and University of at CA, and University of of Diabetes and USA, and Research Institute, J 2011; : Background: glucose is with of and to type 2 diabetes that prevent or are of clinical The aim of the present to the of on diabetes and in with glucose A patients that were to or glucose and glucose were to diabetes on the of the results of The Results: for type 2 diabetes were in the and in the and the for to diabetes in the to glucose in of the patients in the and of in the with compared with with significantly of glucose of glucose of and of an of therapy also with a in a of and a in the of with than with and with in patients with glucose the of with weight and of improved and of and and of with and 1 , 2 , A 3 , 4 , 5 , M 6 , 7 , Rao PV 8 , Zinman B 9 , , , J 1 , 1 1 University and Sciences and Research Institute, ON, Canada, 2 Diabetes Centre, India, 3 Research Institute of 4 Diabetes Center at USA, 5 University of Canada, 6 7 8 Nizam’s Institute of Medical Sciences University, Hyderabad, India, 9 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada, and Research Institute, ON, 2011; : Background: The Diabetes with and trial a trial of in people and with glucose glucose the treatment the of the of diabetes or by diabetes by and the of to by A of in the trial the treatment phase of the The aim of this to an on diabetes than therapy has The at of the were to have a glucose therapy A of diabetes at that on a or glucose of or or a by a to a and glucose of and Results: a of the of the trial and a lower of the and to the to the a of both the and in people from both treatment and were new diabetes from have any that 3 of treatment have a on that is being the Comment: three studies the potential use of in the or of type 2 diabetes. in combination with at The a of a of subjects in the with of these in to type 2 diabetes and the of to with treatment compared with In of of to diabetes and of were in both treatment This is a in that that treatment be to the The of in that this be with doses of The development of weight and in at the doses A trial with which these seem The is is to the glycaemic for of diabetes to who have of yet diabetes by the for diabetes are with at with the of new treatment are we have new of medications to new uses of and to to the of the We that this of development we are to this has from Novo Nordisk, and is on the of a for and an for