New medications for the treatment of diabetes

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 oral antidiabetic medications. Methods: This was a multicentre (28 clinical sites in Canada, India, South Africa and the USA) randomised open-label, parallel-group phase 2 trial of 16 weeks in which participants with type 2 diabetes (age 18–75 years, HbA1c 7%–11%) were enrolled and treated. Participants were randomly allocated in a 1:1:1:1 ratio to receive insulin degludec either once a day or three times a week or insulin glargine once a day, all in combination with metformin. Investigators were masked to data until database release. The primary outcome was HbA1c after 16 weeks of treatment. Results: Of 367 patients screened, 245 were eligible for inclusion. Of these, 62 participants were randomly allocated to receive insulin degludec three times a week [starting dose 20 U per injection (1 U = 9 nmol)], 60 to receive insulin degludec once a day [starting dose 10 U (1 U = 6 nmol); group A], 61 to receive insulin degludec once a day [starting dose 10 U (1 U = 9 nmol); group B] and 62 to receive insulin glargine [starting dose 10 U (1 U = 6 nmol)] once a day. At study end, mean HbA1c levels were the same across treatment groups. Estimated mean HbA1c treatment differences from insulin degludec, by comparison with insulin glargine, were 0.08% [95% confidence interval (CI) –0.23 to 0.40] for the three dose per week schedule, 0.17% (–0.15 to 0.48) for group A and 0.28% (–0.04 to 0.59) for group B. Few participants had hypoglycaemia and the number of adverse events was the same across groups, with no apparent treatment-specific pattern. Conclusions: Findings from this trial show that insulin degludec can provide equivalent glycaemic control to insulin glargine without new or increased rates of adverse events in insulin-naive people with type 2 diabetes. The safety, efficacy and optimum use of treatment regimens for insulin degludec need to be established. Comment: Zinman et al. report phase 2 results on insulin degludec in patients with type 2 diabetes. There was comparable glycaemic control and the rates of hypoglycaemia did not differ between groups. This study also explored whether insulin degludec given in higher dose could possibly be given three times a week, thus limiting the number of injections per week. Although it is interesting to see the development of a new basal insulin, it should be noted that insulin degludec was similar to insulin glargine in terms of glycaemic control. Birkeland KI 1 , Home PD 2 , Wendisch U 3 , Ratner RE 4 , Johansen T 5 , Endahl LA 5 , Lyby K 5 , Jendle JH 6 , Roberts AP 7 , DeVries JH 8 , Meneghini LF 9 1 Oslo University Hospital and Faculty of Medicine, Oslo, Norway, 2 Newcastle University, Newcastle upon Tyne, UK, 3 Group Practice in Internal Medicine and Diabetology, Hamburg, Germany, 4 MedStar Research Institute, Washington, DC, USA, 5 Novo Nordisk A/S, Soeborg, Denmark, 6 Örebro University Hospital, Örebro, Sweden, 7 Royal Adelaide Hospital, Adelaide, SA, Australia, 8 University of Amsterdam, Amsterdam, The Netherlands, and 9 University of Miami Miller School of Medicine, Miami, FL, USA Diabetes Care 2011; 34 : 661–5 Background: Despite the advantages offered by current basal insulin analogues, hypoglycaemia remains a treatment limitation. Insulin degludec (IDeg) is a new-generation ultra-long-acting basal insulin that forms soluble multihexamers after subcutaneous injection, resulting in an ultra-long-action profile and a smooth and stable pharmacokinetic profile at steady state. These attributes are expected to provide improved glycaemic control and to lower the risk of hypoglycaemia. The aim of this trial was to compare the efficacy, safety and tolerability of two different IDeg formulations (IDeg(A) and IDeg(B)) with insulin glargine (IGlar), all in combination with insulin aspart (IAsp) as mealtime insulin, in people with type 1 diabetes. Methods: A 16-week, randomised, open-label trial, in which patients (mean age 45.8 years, A1c 8.4%, fasting plasma glucose 9.9 mmol/l, body mass index 26.9 kg/m2) received subcutaneous injections of IDeg(A) (600 μmol/l; n = 59), IDeg(B) (900 μmol/l; n = 60) or insulin glargine (IGlar; n = 59), all given once daily in the evening, and insulin aspart was administered at mealtimes. Results: At 16 weeks, mean A1c was comparable for IDeg(A) (7.8 ± 0.8%), IDeg(B) (8.0 ± 1.0%) and IGlar (7.6 ± 0.8%), as was fasting plasma glucose (8.3 ± 4.0, 8.3 ± 2.8 and 8.9 ± 3.5 mmol/l, respectively). Estimated mean rates of confirmed hypoglycaemia were 28% lower for IDeg(A) compared with IGlar [rate ratio (RR) 0.72 (95% CI 0.52–1.00)] and 10% lower for IDeg(B) compared with IGlar [RR 0.90 (0.65–1.24)]; rates of nocturnal hypoglycaemia were 58% lower for IDeg(A) [RR 0.42 (0.25–0.69)] and 29% lower for IDeg(B) [RR 0.71 (0.44–1.16)]. Mean total daily insulin dose was similar to baseline. The frequency and pattern of adverse events was similar between insulin treatments. Conclusions: This clinical trial showed that IDeg, used in combination with mealtime IAsp, is a well tolerated and efficacious treatment when used in patients with type 1 diabetes, providing comparable glycaemic control to insulin glargine at comparable doses but with lower rates of hypoglycaemia. Comment: Similar to the trial reported above, IDeg used in type 1 diabetes for 4 months had an apparent, but not statistically significant, reduction in hypoglycaemia, with similar glucose control. This study investigated two different formulations of IDeg and concluded that it is safe and well tolerated in patients with type 1 diabetes compared with IGlar. The real question that still needs to be answered is whether there are meaningful differences between IDeg and IGlar. Heise T 1 , Tack CJ 2 , Cuddihy R 3 , Davidson J 4 , Gouet D 5 , Liebl A 6 , Romero E 7 , Mersebach H 8 , Dykiel P 8 , Jorde R 9 1 Profil Institut für Stoffwechselforschung, Neuss, Germany, 2 Radboud University, Nijmegen Medical Centre, Nijmegen, The Netherlands, 3 International Diabetes Center, Park Nicollet, Minneapolis, MN, USA, 4 Department of Medicine, Division of Endocrinology, University of Texas, Southwestern Medical School, Dallas, TX, USA, 5 Hôpital Saint Louis, Centre Hospitalier de La Rochelle, La Rochelle, France, 6 Center for Diabetes and Metabolism, Fachklinik, Bad Heilbrunn, Germany, 7 University of Valladolid, Instituto de Endocrinología y Nutrición, Valladolid, Spain, 8 Novo Nordisk A/S, Søborg, Denmark, and 9 Institute of Clinical Medicine, University of Tromsø, Tromsø, Norway Diabetes Care 2011; 34 : 669–74 Background: Insulin degludec (IDeg) can be co-formulated with insulin aspart (IAsp) resulting in a soluble preparation comprising two different insulin analogues (IDegAsp: 70% v/v IDeg as basal insulin and 30% v/v IAsp as prandial insulin). By providing both basal and rapid-acting insulin analogues in one injection, IDegAsp could be an attractive alternative to the common strategy of initiating insulin therapy with basal insulin only on top of oral antidiabetic drugs. In this clinical proof-of concept trial, the safety and efficacy of IDegAsp was compared with insulin glargine (IGlar), both given once daily in combination with metformin in insulin-naive subjects with type 2 diabetes inadequately controlled on oral antidiabetic therapy. To establish the optimal ratio of IDeg to IAsp, an alternative formulation of IDegAsp (AF) containing a higher percentage of IAsp (45%) was also evaluated. Methods: In this 16-week, open-label trial, subjects (mean age 59.1 years, A1c 8.5%, body mass index 30.3 kg/m2) were randomised to once-daily IDegAsp (n = 59), AF (n = 59) or IGlar (n = 60), all in combination with metformin. Insulin was administered before the evening meal and dose-titrated to a fasting plasma glucose target of 4.0–6.0 mmol/l. Results: After 16 weeks, mean A1c decreased in all groups to comparable levels (IDegAsp 7.0%; AF 7.2%; IGlar 7.1%). A similar proportion of subjects achieved A1c < 7.0% without confirmed hypoglycaemia in the last 4 weeks of treatment (IDegAsp 51%; AF 47%; IGlar 50%). Mean 2-h post-dinner plasma glucose increase was lower for IDegAsp (0.13 mmol/l) and AF (0.24 mmol/l) than for IGlar (1.63 mmol/l), whereas mean fasting plasma glucose was similar (IDegAsp 6.8 mmol/l; AF 7.4 mmol/l; IGlar 7.0 mmol/l). Hypoglycaemia rates were lower for IDegAsp and IGlar than for AF (1.2, 0.7 and 2.4 events per patient-year). Nocturnal hypoglycaemic events occurred rarely for IDegAsp and IGlar compared with AF (27 events). Conclusions: Despite the limitations of this proof-of-concept study with a small sample size, a relatively short treatment duration and an open study design, it did show IDegAsp to be a promising treatment option for initiating insulin therapy in subjects with type 2 diabetes inadequately controlled with oral antidiabetic drugs. IDegAsp was safe and well tolerated, providing comparable overall glycaemic control to IGlar with lower doses and with the additional benefit of post-dinner plasma glucose control that did not result in an increased risk of nocturnal hypoglycaemia. Comment: This is a proof-of-concept study using a new pre-mixed insulin – a combination of insulin degludec and insulin aspart (IDegAsp) as a 'basal plus' concept for managing diabetes. This 4-month trial documented lower hypoglycaemic events with IDegAsp with similar glucose control (A1c) compared with IGlar. As should be expected, there was a significant decrease in post-dinner glucose levels since IDegAsp has a rapid-acting insulin component. However, there was no rapid-acting component with IGlar. A better comparator would have been a currently available pre-mixed insulin. Such preparations, with a combination of rapid and basal insulin, in the future might allow uncontrolled patients with type 2 diabetes to achieve both lower fasting glucose and a reduction in the rise in blood glucose after eating their major meal. Uehata K 1 , Anno T 1 , Hayashida K 1 , Motoyama K 1 , Hirayama F 2 , Ono N 3 , Pipkin JD 3 , Uekama K 2 , Arima H 1 1 Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan, 2 Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan, and 3 CyDex Pharmaceuticals Inc., Lenexa, KS, USA Int J Pharm 2011; 419 : 71–6 Background: Insulin glargine is the first long-acting basal insulin analogue used for subcutaneous administration once daily in patients with type 1 or type 2 diabetes mellitus. The aim of the study was to evaluate the potential use of sulfobutyl ether-β-cyclodextrin (SBE4-β-CyD), with the degree of substitution of the sulfobutyl ether group 3.9, on bioavailability of insulin glargine, the sustained-glucose lowering effect, the effects on physicochemical properties and pharmacokinetics/pharmacodynamics of insulin glargine and the release of insulin glargine after subcutaneous injection into rats. Methods: Serum insulin glargine and glucose levels of rats were measured. The solution of the insulin glargine in phosphate buffer in the absence and presence of SBE4-β-CyD was subcutaneously injected into male rats, and at appropriate intervals blood samples were taken. Results: SBE4-β-CyD increased the solubility and suppressed aggregation of insulin glargine in phosphate buffer at pH 9.5, probably due to the interaction of SBE4-β-CyD with aromatic amino acid residues such as tyrosine of insulin glargine. In addition, SBE4-β-CyD accelerated the dissolution rate of insulin glargine from its precipitates, compared with that of insulin glargine alone. Furthermore, subcutaneous administration of an insulin glargine solution with SBE4-β-CyD enhanced the bioavailability of insulin glargine and sustained the glucose lowering effect, possibly due to the inhibitory effects of SBE4-β-CyD on the enzymatic degradation at the injection site. Conclusions: SBE4-β-CyD enhanced both bioavailability and a persistence of the blood-glucose lowering effect of insulin glargine after subcutaneous injection to rats, probably due to the inhibitory effects of SBE4-β-CyD on the enzymatic degradation at the injection site, resulting from interaction with the insulin glargine molecule. These findings indicate that SBE4-β-CyD can be a useful excipient for sustained release of insulin glargine. Comment: Since basal insulin treatment is becoming more popular in patients with type 2 diabetes, especially when they start to fail on oral hypoglycaemic agents and/or incretin therapies, there is an ongoing effort to improve the qualities of insulin glargine or to develop a better basal insulin. In this study, the authors investigated SBE4-β-CyD on the properties of insulin glargine. Their results conclude that SBE4-β-CyD can be a useful excipient for sustained release of insulin glargine. To achieve the same effect, there are also studies being pursued with higher concentrations of insulin glargine (U-200 or U-500) to see if these result in better basal insulin effect than insulin glargine in U-100 formulations. Rosenstock J 1 , Lorber DL 2 , Gnudi L 3 , Howard CP 4 , Bilheimer DW 4 , Chang PC 4 , Petrucci RE 4 , Boss AH 4 , Richardson PC 4 1 Dallas Diabetes and Endocrine Center at Medical City, Dallas, TX, USA, 2 Diabetes Control Foundation, Diabetes Care and Information Center, Flushing, NY, USA, 3 Unit for Metabolic Medicine, Cardiovascular Division, King's College London, London, UK, and 4 MannKind Corporation, Valencia, CA, USA Lancet 2010; 375 : 2244–53 Background: Insulin therapy is often a delayed strategy in patients with type 2 diabetes mellitus because it is associated with weight gain, hypoglycaemia and the need for subcutaneous injections. The aim of this study was to compare the efficacy and safety of prandial Technosphere inhaled insulin plus bedtime insulin glargine vs. twice daily biaspart insulin for treatment of type 2 diabetes in patients previously treated with insulin, with or without oral agents. Methods: This was a multicentre multinational randomised, open-label, parallel-group study of adult patients with type 2 diabetes and poor glycaemic control despite insulin therapy, with or without oral antidiabetic drugs. Patients were randomly allocated in a 1:1 ratio to receive 52 weeks' treatment with prandial Technosphere inhaled insulin powder plus bedtime insulin glargine, or twice daily pre-mixed biaspart insulin (70% insulin aspart protamine suspension and 30% insulin aspart of rDNA origin). The primary endpoint was a comparison of change in HbA1c from baseline to week 52 between treatment groups; the non-inferiority margin was 0.4%. Analysis was by per protocol for non-inferiority testing of the primary endpoint. Results: Patients were allocated to inhaled insulin plus insulin glargine (n = 334) and to biaspart insulin (n = 343); 107 patients on inhaled insulin plus insulin glargine and 85 on biaspart insulin discontinued the trial. A total of 211 patients on inhaled insulin plus insulin glargine and 237 on biaspart insulin were included in per-protocol analyses. Change in HbA1c with inhaled insulin plus insulin glargine (–0.68%, SE 0.077, 95% CI –0.83 to was similar and to that with biaspart insulin to The was 95% CI to Patients had significantly lower weight and and hypoglycaemic events on inhaled insulin plus insulin glargine than on biaspart insulin. The safety and tolerability profile was similar for both from increased of and change in in the group inhaled insulin plus insulin glargine. Conclusions: insulin plus insulin glargine, or in combination with an oral antidiabetic drug is an alternative to insulin therapy in uncontrolled type 2 diabetes. Comment: insulin has the of the of insulin with that which would in healthy individuals. Technosphere inhaled insulin powder is one formulation that that current development uses a small the of a These two are in to the previously inhaled insulin which offered no pharmacokinetic vs. injected prandial insulin and had a and In the current study, there was less weight and less hypoglycaemia with the inhaled insulin plus insulin glargine probably to the rapid action and rapid of effect, that there was no which the risk of hypoglycaemia and results in weight M 1 , 2 , L 1 , 2 1 Profil Institute for Clinical CA, USA, and 2 CA, USA Diabetes Care 2011; 34 : Background: patients with diabetes fail to target blood glucose that the pharmacokinetic and efficacy of available prandial insulin should be A study that the of the insulin analogue and insulin in healthy The aim of this study was to confirm these findings in patients with type 1 diabetes using doses of insulin and to the of these pharmacokinetic effects on glycaemic to a meal. Methods: This was a study patients with type 1 diabetes (n = who received injections of doses of or with and without before a meal. Results: early insulin increased by = for and < for compared with the insulin alone. blood glucose decreased for = and for = the for blood glucose by = and = of hypoglycaemia were comparable for with or without whereas of and hypoglycaemia. Conclusions: The results of this study that a of prandial insulins with provide for patients with diabetes by without the risk for hypoglycaemic Comment: to insulin results in more rapid and is strategy for the action of insulin resulting in an ultra-rapid-acting of The current study that the concept is and that both insulin and current rapid insulin analogues can have their are way testing this insulin in clinical 1 , C 2 , L 3 , J 3 , B 3 , P 3 , K 3 , J 4 , 3 Group 1 International Diabetes Center at Park Nicollet, Minneapolis, MN, USA, 2 USA, 3 CA, USA, and 4 USA Lancet 2010; : Background: patients with type 2 diabetes begin with metformin but need additional treatment. In this study in and with a comparison of the efficacy, safety and tolerability of three for patients not controlled on metformin was once weekly receptor and approved doses of and Methods: In this multicentre randomised, trial of weeks, patients with type 2 diabetes who had been treated with metformin mean HbA1c of 8.5%, fasting plasma glucose of mmol/l, weight of were Patients were randomly to receive 2 injected once weekly plus oral once or oral once daily plus injected once or oral once daily plus injected once The primary endpoint was change in HbA1c between baseline and week Analysis was by to for all patients who received at one dose of study Results: A total of patients were to receive to receive and to receive In patients received at one dose of study drug and were included in the on on and on with HbA1c mean 95% CI to significantly more than did to or to differences were (95% CI to < for vs. and to = for vs. with 95% CI to was significantly than with 95% CI to = or to < of hypoglycaemia The most adverse events with and were and and were the most events with Conclusions: This study one of the most of outcome with to metformin. The in HbA1c and with with a number of hypoglycaemic that this drug should be as an to metformin in patients who need in glucose control and and in the risk of hypoglycaemia needs to be to a C 1 , R 2 , J 3 , P 3 , B 3 , J 4 , K 3 1 USA, 2 International Diabetes Center at Park Nicollet, Minneapolis, MN, USA, 3 Pharmaceuticals Inc., CA, USA, and 4 and USA Medicine 2011; : Background: In the of the trial in patients with type 2 diabetes on metformin, the GLP-1 receptor agonist once weekly in HbA1c and weight reduction compared with approved daily doses of or This trial was to evaluate the glycaemic and blood fasting of in patients treated with once weekly for 52 who from daily of to a therapy that results in to concentrations of the GLP-1 receptor agonist exenatide; and who from daily receptor with which insulin to a therapy that insulin and is associated with weight Methods: In a open-label, uncontrolled oral medications were discontinued and all patients received once Of the patients HbA1c ± fasting plasma glucose ± mmol/l, weight ± 20 who into the open-label patients 52 Results: Patients who received only once weekly significant in HbA1c ± fasting plasma glucose ± mmol/l) and weight ± Patients who from to once weekly significant in HbA1c ± fasting plasma glucose ± mmol/l) and weight ± Patients who from to once weekly

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