Causes of diabetic ketoacidosis among adults with type 1 diabetes mellitus: insulin pump users and non-users

Flores, Monica Velasquez; Amir, Maryam; Ahmed, Ramsha; Alashi, Suleiman; Li, Manshi; Lansang, M. Cecilia; Al-Jaghbeer, Mohammed

doi:10.1136/bmjdrc-2020-001329

Cited by 22 publications

(7 citation statements)

References 23 publications

(10 reference statements)

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“…The same may be true for some people with T1D who have difficulty with medication compliance and who experience recurrent diabetic ketoacidosis (DKA) because of inconsistent insulin administration. In these patients, once-weekly insulins may provide benefit because of their stable and predictable profile considering that a common precipitating factor for DKA is insulin nonadherence, especially in teenagers ( 162 ). Furthermore, the long duration of action of these insulins could, in theory, restrain ketogenic hormone production.…”

Section: Potential Benefits and Concerns With Once-weekly Basal Insulinmentioning

confidence: 99%

The Basis for Weekly Insulin Therapy: Evolving Evidence With Insulin Icodec and Insulin Efsitora Alfa

Rosenstock,

Juneja,

Beals

et al. 2024

Endocrine Reviews

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Basal insulin continues to be a vital part of therapy for many people with diabetes. First attempts to prolong the duration of insulin formulations were through the development of suspensions that required homogenization prior to injection. These insulins, which required once- or twice-daily injections, introduced wide variations in insulin exposure contributing to unpredictable effects on glycemia. Advances over the last 2 decades have resulted in long-acting, soluble basal insulin analogues with prolonged and less variable pharmacokinetic exposure, improving their efficacy and safety, notably by reducing nocturnal hypoglycemia. However, adherence and persistence with once-daily basal insulin treatment remains low for many reasons including hypoglycemia concerns and treatment burden. A soluble basal insulin with a longer and flatter exposure profile could reduce pharmacodynamic variability, potentially reducing hypoglycemia, have similar efficacy to once-daily basal insulins, simplify dosing regimens, and improve treatment adherence. Insulin icodec (Novo Nordisk) and insulin efsitora alfa (basal insulin Fc [BIF], Eli Lilly and Company) are 2 such insulins designed for once-weekly administration, which have the potential to provide a further advance in basal insulin replacement. Icodec and efsitora phase 2 clinical trials, as well as data from the phase 3 icodec program indicate that once-weekly insulins provide comparable glycemic control to once-daily analogues, with a similar risk of hypoglycemia. This manuscript details the technology used in the development of once-weekly basal insulins. It highlights the clinical rationale and potential benefits of these weekly insulins while also discussing the limitations and challenges these molecules could pose in clinical practice.

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Section: Potential Benefits and Concerns With Once-weekly Basal Insulinmentioning

confidence: 99%

The Basis for Weekly Insulin Therapy: Evolving Evidence With Insulin Icodec and Insulin Efsitora Alfa

Rosenstock,

Juneja,

Beals

et al. 2024

Endocrine Reviews

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“…1 Approximately one third of people with T1D and approximately three quarters of their physicians reported regular omission of or nonadherence to daily basal insulin, 2 which was shown to result in reduced glycaemic control 3 and could cause diabetic ketoacidosis. 4 Decreasing the frequency of basal insulin injections to once weekly could therefore relieve the treatment burden and have the potential to increase adherence and improve glycaemic outcomes and to decrease the incidence of diabetic ketoacidosis. 5 Insulin icodec (icodec) is a novel once-weekly basal insulin in latestage clinical development.…”

Section: Introductionmentioning

confidence: 99%

“…The need for multiple frequent insulin injections is considered a significant burden for individuals with type 1 diabetes (T1D) who receive insulin in a basal‐bolus regimen 1 . Approximately one third of people with T1D and approximately three quarters of their physicians reported regular omission of or nonadherence to daily basal insulin, 2 which was shown to result in reduced glycaemic control 3 and could cause diabetic ketoacidosis 4 . Decreasing the frequency of basal insulin injections to once weekly could therefore relieve the treatment burden and have the potential to increase adherence and improve glycaemic outcomes and to decrease the incidence of diabetic ketoacidosis 5 …”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic and pharmacodynamic properties of once‐weekly insulin icodec in individuals with type 1 diabetes

Hövelmann,

Engberg,

Heise

et al. 2024

Diabetes Obesity Metabolism

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AimsTo investigate the pharmacokinetic/pharmacodynamic properties of once‐weekly insulin icodec in individuals with type 1 diabetes (T1D).Materials and MethodsIn this randomized, open‐label, two‐period crossover trial, 66 individuals with T1D (age 18–64 years; glycated haemoglobin ≤75 mmol/mol [≤ 9%]) were to receive once‐weekly icodec (8 weeks) and once‐daily insulin glargine U100 (2 weeks) at individualized fixed equimolar total weekly doses established during up to 10 weeks' run‐in with glargine U100 titrated to pre‐breakfast plasma glucose (PG) of 4.4–7.2 mmol/L (80–130 mg/dL). Insulin aspart was used as bolus insulin. Blood sampling for icodec pharmacokinetics was performed from the first icodec dose until 35 days after the last dose. The glucose infusion rate at steady state was assessed in glucose clamps (target 6.7 mmol/L [120 mg/dL]) at 16–52 h and 138–168 h after the last icodec dose and 0–24 h after the last glargine U100 dose. Icodec pharmacodynamics during 1 week were predicted by pharmacokinetic‐pharmacodynamic modelling. Hypoglycaemia was recorded during the treatment periods based on self‐measured PG.ResultsIcodec reached pharmacokinetic steady state on average within 2–3 weeks. At steady state, model‐predicted daily proportions of glucose infusion rate during the 1‐week dosing interval were 14.3%, 19.6%, 18.3%, 15.7%, 13.1%, 10.6% and 8.4%, respectively. Rates and duration of Level 2 hypoglycaemic episodes (PG <3.0 mmol/L [54 mg/dL]) were 32.8 versus 23.9 episodes per participant‐year of exposure and 33 ± 25 versus 30 ± 18 min (mean ± SD) for icodec versus glargine U100.ConclusionsThe pharmacokinetic/pharmacodynamic properties of icodec suggest its potential to provide basal coverage in a basal‐bolus insulin regimen in people with T1D.

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“…Research indicates a 22% probability of missing at least one basal insulin dose in a 14-day period, linked to poorer glycemic control [10] and increased rates of diabetic ketoacidosis [11]. Over the past two decades, extensive research has aimed to develop longacting basal insulin analogs with more predictable, reliable, and stable pharmacokinetic and pharmacodynamic profiles, substantially reducing the risk of hypoglycemia compared to previous formulations [7].…”

Section: Introductionmentioning

confidence: 99%

Which Diabetes Patients Will Benefit the Most from Once-Weekly Basal Insulin Analogs? A Review with a Special Focus on Type 1 Diabetes Patients

Kosmeri,

Baltogianni,

Giapros

et al. 2024

Endocrines

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Basal insulin analogs, typically administered once or twice daily, have been one of the two pillars of the multiple daily injection (MDI) insulin therapy of patients with type 1 diabetes (T1D) for the last twenty years. Recently, once-weekly basal insulin analogs have been developed and are in late-phase clinical trials. One of these analogs is insulin icodec (icodec), appropriately developed to bind reversibly to albumin and to be gradually released into the patient’s circulation. Icodec has been tried mostly in clinical trials of adult patients with type 2 diabetes. A recent phase 3a clinical trial comprising adult patients with T1D was designed to evaluate icodec’s efficacy and safety compared with a daily basal insulin analog (degludec) after a 26-week main phase plus a safety extension of another 26 weeks. Icodec showed non-inferiority to once-daily degludec in glycated hemoglobin (HbA1c) reduction at week 26, and no significant differences in time in range (TIR) (70–180 mg/dL) and in time above range (TAR) (>180 mg/dL). On the other hand, it was associated with increased rates of clinically significant hypoglycemia (blood glucose < 54 mg/dL) and severe hypoglycemia (external assistance need for recovery), remaining either below or close to the internationally recommended targets for hypoglycemia. Another once-weekly insulin analog, basal insulin Fc (BIF), has been investigated in a phase 2 clinical trial comprising adult patients with T1D, with equally promising results. These preliminary data suggest that once-weekly insulin analogs could be of use for some patients with T1D, for example, patients not taking insulin regularly or those who are on MDI and wish for fewer injections. In addition, due to its prolonged mode of action, it could decrease the risk of diabetic ketoacidosis and the need for hospitalization. Additionally, patients with T1D that struggle with wearing diabetes mellitus devices/closed-loop insulin pumps either due to the cost or due to skin issues may also benefit from long-acting insulin. There is increasing evidence of the benefits of adjunctive therapies to insulin in T1D patients, but these therapies are not FDA-approved due to a possible higher risk of diabetic ketoacidosis. These long-acting insulin analogues could be used with adjunctive therapies in selected patients. This review aims to present available data on the mode of action, clinical trial results, and possible benefits of once-weekly insulin analogs for patients with T1D. In addition, it intends to suggest a future research framework for important clinical questions, such as once-weekly insulin analog use and exercise, sick days, or surgery, that will enhance our knowledge regarding this indisputable innovation in insulin management.

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Causes of diabetic ketoacidosis among adults with type 1 diabetes mellitus: insulin pump users and non-users

Cited by 22 publications

References 23 publications

The Basis for Weekly Insulin Therapy: Evolving Evidence With Insulin Icodec and Insulin Efsitora Alfa

The Basis for Weekly Insulin Therapy: Evolving Evidence With Insulin Icodec and Insulin Efsitora Alfa

Pharmacokinetic and pharmacodynamic properties of once‐weekly insulin icodec in individuals with type 1 diabetes

Which Diabetes Patients Will Benefit the Most from Once-Weekly Basal Insulin Analogs? A Review with a Special Focus on Type 1 Diabetes Patients

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