Background Evidence supporting the addition of specific insulin regimens to oral therapy in patients with type 2 diabetes mellitus is limited. Methods In this 3-year open-label, multicenter trial, we evaluated 708 patients who had suboptimal glycated hemoglobin levels while taking metformin and sulfonylurea therapy. Patients were randomly assigned to receive biphasic insulin aspart twice daily, prandial insulin aspart three times daily, or basal insulin detemir once daily (twice if required). Sulfonylurea therapy was replaced by a second type of insulin if hyperglycemia became unacceptable during the first year of the study or subsequently if glycated hemoglobin levels were more than 6.5%. Outcome measures were glycated hemoglobin levels, the proportion of patients with a glycated hemoglobin level of 6.5% or less, the rate of hypoglycemia, and weight gain. Results Median glycated hemoglobin levels were similar for patients receiving biphasic (7.1%), prandial (6.8%), and basal (6.9%) insulin-based regimens...

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Three-Year Efficacy of Complex Insulin Regimens in Type 2 Diabetes

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(14)60976-4.pdf

Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial

The discovery of glucagon-like peptide-1 (GLP-1), an incretin hormone with important effects on glycemic control and body weight regulation, led to efforts to extend its half-life and make it therapeutically effective in people with type 2 diabetes (T2D). The development of short- and then long-acting GLP-1 receptor agonists (GLP-1RAs) followed. Our article charts the discovery and development of the long-acting GLP-1 analogs liraglutide and, subsequently, semaglutide. We examine the chemistry employed in designing liraglutide and semaglutide, the human and non-human studies used to investigate their cellular targets and pharmacological effects, and ongoing investigations into new applications and formulations of these drugs. Reversible binding to albumin was used for the systemic protraction of liraglutide and semaglutide, with optimal fatty acid and linker combinations identified to maximize albumin binding while maintaining GLP-1 receptor (GLP-1R) potency. GLP-1RAs mediate their effects via this receptor, which is expressed in the pancreas, gastrointestinal tract, heart, lungs, kidneys, and brain. GLP-1Rs in the pancreas and brain have been shown to account for the respective improvements in glycemic control and body weight that are evident with liraglutide and semaglutide. Both liraglutide and semaglutide also positively affect cardiovascular (CV) outcomes in individuals with T2D, although the precise mechanism is still being explored. Significant weight loss, through an effect to reduce energy intake, led to the approval of liraglutide (3.0 mg) for the treatment of obesity, an indication currently under investigation with semaglutide. Other ongoing investigations with semaglutide include the treatment of non-alcoholic fatty liver disease (NASH) and its use in an oral formulation for the treatment of T2D. In summary, rational design has led to the development of two long-acting GLP-1 analogs, liraglutide and semaglutide, that have made a vast contribution to the management of T2D in terms of improvements in glycemic control, body weight, blood pressure, lipids, beta-cell function, and CV outcomes. Furthermore, the development of an oral formulation for semaglutide may provide individuals with additional benefits in relation to treatment adherence. In addition to T2D, liraglutide is used in the treatment of obesity, while semaglutide is currently under investigation for use in obesity and NASH.

/pdf/the-discovery-and-development-of-liraglutide-and-semaglutide-4ez3cjffh5.pdf

The Discovery and Development of Liraglutide and Semaglutide

Over the last few years, incretin-based therapies have emerged as important agents in the treatment of type 2 diabetes (T2D). These agents exert their effect via the incretin system, specifically targeting the receptor for the incretin hormone glucagon-like peptide 1 (GLP-1), which is partly responsible for augmenting glucose-dependent insulin secretion in response to nutrient intake (the 'incretin effect'). In patients with T2D, pharmacological doses/concentrations of GLP-1 can compensate for the inability of diabetic β cells to respond to the main incretin hormone glucose-dependent insulinotropic polypeptide, and this is therefore a suitable parent compound for incretin-based glucose-lowering medications. Two classes of incretin-based therapies are available: GLP-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors. GLP-1RAs promote GLP-1 receptor (GLP-1R) signalling by providing GLP-1R stimulation through 'incretin mimetics' circulating at pharmacological concentrations, whereas DPP-4 inhibitors prevent the degradation of endogenously released GLP-1. Both agents produce reductions in plasma glucose and, as a result of their glucose-dependent mode of action, this is associated with low rates of hypoglycaemia; however, there are distinct modes of action resulting in differing efficacy and tolerability profiles. Furthermore, as their actions are not restricted to stimulating insulin secretion, these agents have also been associated with additional non-glycaemic benefits such as weight loss, improvements in β-cell function and cardiovascular risk markers. These attributes have made incretin therapies attractive treatments for the management of T2D and have presented physicians with an opportunity to tailor treatment plans. This review endeavours to outline the commonalities and differences among incretin-based therapies and to provide guidance regarding agents most suitable for treating T2D in individual patients.

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Incretin therapies: highlighting common features and differences in the modes of action of glucagon‐like peptide‐1 receptor agonists and dipeptidyl peptidase‐4 inhibitors

Biotherapeutic proteins represent a mainstay of treatment for a multitude of conditions, for example, autoimmune disorders, hematologic disorders, hormonal dysregulation, cancers, infectious diseases and genetic disorders. The technologies behind their production have changed substantially since biotherapeutic proteins were first approved in the 1980s. Although most biotherapeutic proteins developed to date have been produced using the mammalian Chinese hamster ovary and murine myeloma (NS0, Sp2/0) cell lines, there has been a recent shift toward the use of human cell lines. One of the most important advantages of using human cell lines for protein production is the greater likelihood that the resulting recombinant protein will bear post-translational modifications (PTMs) that are consistent with those seen on endogenous human proteins. Although other mammalian cell lines can produce PTMs similar to human cells, they also produce non-human PTMs, such as galactose-α1,3-galactose and N-glycolylneuraminic acid, which are potentially immunogenic. In addition, human cell lines are grown easily in a serum-free suspension culture, reproduce rapidly and have efficient protein production. A possible disadvantage of using human cell lines is the potential for human-specific viral contamination, although this risk can be mitigated with multiple viral inactivation or clearance steps. In addition, while human cell lines are currently widely used for biopharmaceutical research, vaccine production and production of some licensed protein therapeutics, there is a relative paucity of clinical experience with human cell lines because they have only recently begun to be used for the manufacture of proteins (compared with other types of cell lines). With additional research investment, human cell lines may be further optimized for routine commercial production of a broader range of biotherapeutic proteins.

https://www.tandfonline.com/doi/pdf/10.3109/07388551.2015.1084266

Human cell lines for biopharmaceutical manufacturing: history, status, and future perspectives

OBJECTIVE To compare the efficacy and safety of dulaglutide, a once-weekly GLP-1 receptor agonist, with placebo and exenatide in type 2 diabetic patients. The primary objective was to determine superiority of dulaglutide 1.5 mg versus placebo in HbA 1c change at 26 weeks. RESEARCH DESIGN AND METHODS This 52-week, multicenter, parallel-arm study (primary end point: 26 weeks) randomized patients (2:2:2:1) to dulaglutide 1.5 mg, dulaglutide 0.75 mg, exenatide 10 μg, or placebo (placebo-controlled period: 26 weeks). Patients were treated with metformin (1,500–3,000 mg) and pioglitazone (30–45 mg). Mean baseline HbA 1c was 8.1% (65 mmol/mol). RESULTS Least squares mean ± SE HbA 1c change from baseline to the primary end point was −1.51 ± 0.06% (−16.5 ± 0.7 mmol/mol) for dulaglutide 1.5 mg, −1.30 ± 0.06% (−14.2 ± 0.7 mmol/mol) for dulaglutide 0.75 mg, −0.99 ± 0.06% (−10.8 ± 0.7 mmol/mol) for exenatide, and −0.46 ± 0.08% (−5.0 ± 0.9 mmol/mol) for placebo. Both dulaglutide doses were superior to placebo at 26 weeks (both adjusted one-sided P P 1c targets with dulaglutide 1.5 mg and 0.75 mg than with placebo and exenatide (all P CONCLUSIONS Both once-weekly dulaglutide doses demonstrated superior glycemic control versus placebo and exenatide with an acceptable tolerability and safety profile.

https://care.diabetesjournals.org/content/diacare/archive/37/8/2159/1.full.pdf

Efficacy and Safety of Dulaglutide Added Onto Pioglitazone and Metformin Versus Exenatide in Type 2 Diabetes in a Randomized Controlled Trial (AWARD-1)

OBJECTIVE: Compare two analog insulin therapies (prandial premixed therapy [PPT] vs. basal bolus therapy [BBT]) in type 2 diabetes patients previously treated with insulin glargine (≥30 units/d) + oral agents, with the aim of demonstrating non-inferiority of PPT to BBT. RESEARCH DESIGN AND METHODS: Patients were randomized to PPT (lispro mix 50/50; 50% insulin lispro protamine suspension [ILPS], 50% lispro; n=187) tid with meals or BBT (glargine at bedtime + mealtime lispro; n=187) in a 24-wk, multicenter, open-label, non-inferiority trial. Investigators could replace lispro mix 50/50 with lispro mix 75/25 at the evening meal if fasting PG target was unachievable. RESULTS: Baseline A1C was similar (PPT 8.8%, BBT 8.9%, P=0.598). At wk 24, A1C was lower with BBT (6.78 vs. 6.95%, P=0.021). A1C was reduced significantly from baseline for both therapies (P CONCLUSIONS: While non-inferiority of PPT to BBT was not demonstrated, findings on A1C reduction, % achieving A1C targets, hypoglycemia, and number of required injections should be considered in the individual decision-making process of advancing insulin replacement to PPT vs. BBT in type 2 diabetes.

https://care.diabetesjournals.org/content/diacare/31/1/20.full.pdf

Advancing Insulin Therapy in Type 2 Diabetes Previously Treated With Glargine Plus Oral Agents Prandial premixed (insulin lispro protamine suspension/lispro) versus basal/bolus (glargine/lispro) therapy

In the print version of the article cited above, a footnote was omitted with respect to antidrug antibodies (ADAs) in Table 2. Exenatide values reported in the last row in Table 2 are not treatment-emergent ADAs; they are total reported ADAs. The last three rows of Table 2 should have appeared as …

https://care.diabetesjournals.org/content/diacare/38/7/1393.3.full.pdf

Erratum. Efficacy and Safety of Dulaglutide Added Onto Pioglitazone and Metformin Versus Exenatide in Type 2 Diabetes in a Randomized Controlled Trial (AWARD-1). Diabetes Care 2014;37:2159-2167.

Efficacy and Safety of Dulaglutide Versus Placebo and Exenatide in Type 2 Diabetes (AWARD-1)

This Phase 3, randomized, parallel-arm study compared efficacy and safety of 2 doses of dulaglutide (DU), a longacting GLP-1-receptoragonist, with exenatide (EX) or placebo (PL) in patients (pts) with type 2 diabetes treated with metformin (1500-3000 mg) and pioglitazone (30-45 mg). Pts [n = 976; mean baseline (BL) characteristics: age, 55.6 years; A1C, 8.1%; weight, 96.0 kg] were randomized (2:2:2:1 ratio) openly to twice-daily EX 10 μg or in a double- blind fashion to once-weekly DU 1.5 mg, DU 0.75 mg, or PL.

Gildred Colon

Papers

Efficacy and Safety of Dulaglutide Added Onto Pioglitazone and Metformin Versus Exenatide in Type 2 Diabetes in a Randomized Controlled Trial (AWARD-1)

Advancing Insulin Therapy in Type 2 Diabetes Previously Treated With Glargine Plus Oral Agents Prandial premixed (insulin lispro protamine suspension/lispro) versus basal/bolus (glargine/lispro) therapy

Erratum. Efficacy and Safety of Dulaglutide Added Onto Pioglitazone and Metformin Versus Exenatide in Type 2 Diabetes in a Randomized Controlled Trial (AWARD-1). Diabetes Care 2014;37:2159-2167.

Efficacy and Safety of Dulaglutide Versus Placebo and Exenatide in Type 2 Diabetes (AWARD-1)

1.2 Efficacy and Safety of Dulaglutide versus Placebo and Exenatide in Type 2 Diabetes (AWARD-1) (66-OR)