Rapid-acting Insulin Analogues Research Articles

Are New Ultra-Rapid-Acting Insulins Associated with Improved Glycemic Control and Reduced Hypoglycemia in Comparison to Conventional Rapid-Acting Insulins for Individuals with Type 1 and Type 2 Diabetes? A Systematic Review and Meta-Analysis.

Introduction: This study aimed to compare efficacy and safety of ultra-rapid-acting insulin analogs (URAIs; faster aspart [FAsp], ultra-rapid lispro [URLi], and technosphere insulin [TI]) with rapid-acting insulin analogs (RAI) in individuals with type 1 (T1D) or type 2 diabetes (T2D). Methods: Searching for randomized control trial comparing the effects of URAI versus RAI that lasted at least 12 weeks, we initially selected 15 studies for analysis. Three studies involving TI were excluded due to a high degree of heterogeneity. The final meta-analysis included only 12 studies with either FAsp or URLi. Results: Mealtime URAI significantly reduced overall early 1 h postprandial glycemia in individuals with T1D (-20.230 mg/dL [95% confidence interval, 95% CI -24.040 to -16.421]; P < 0.001; I2 = 33.42%) and those with T2D (-9.138 mg/dL [95% CI -12.612 to -5.663]; P < 0.001; I2 = 0%). However, the significant reduction in 2 h postprandial glucose remained only in individuals with T1D (-17.620 mg/dL [95% CI -26.047 to -9.193]; P < 0.001; I2 = 65.88%). These benefits were lost when URAI was administered postmeal. At 24-26 weeks, there was no significant difference in HbA1c between groups, but at 52 weeks, a slight reduction in HbA1c with mealtime URAI was observed (-0.080% [95% CI -0.147 to -0.013]; P = 0.019; I2 = 0%). No difference in weight or the rate of severe or confirmed hypoglycemia was observed. Only individuals with T1D showed a small, but significant increase in early 1-h hypoglycemia with URAI (1.468 [95% CI 1.235 to 1.747]; P < 0.001; I2 = 0%). Conclusion: Mealtime URAI improves 1 and 2 h postprandial glycemic control compared to RAI without increasing hypoglycemia or weight gain.

Safety and Efficacy of Switching SAR341402 Insulin Aspart and Originator Insulin Aspart vs Continuous Use of Originator Insulin Aspart in Adults With Type 1 Diabetes: The GEMELLI X Trial.

SAR341402 insulin aspart (SAR-Asp) is a rapid-acting insulin analog developed as an interchangeable biosimilar to the marketed insulin aspart reference product (NovoLog; NN-Asp). GEMELLI X was a randomized controlled trial to assess outcomes with a biosimilar in line with the US Food and Drug Administration requirements for designation as an interchangeable biosimilar. This report assessed whether multiple switches between SAR-Asp and NN-Asp lead to equivalent safety and efficacy compared with continuous use of NN-Asp in adults with type 1 diabetes (T1D) treated with multiple daily injections, using once-daily insulin glargine U100 (Lantus) as the basal insulin. This open-label randomized (1:1), parallel-group, phase 3 trial compared four × four weeks of alternating use of individually titrated SAR-Asp and NN-Asp (NN-Asp for first four weeks, SAR-Asp in last four weeks; switching group) vs 16 weeks of continuous use of NN-Asp (nonswitching group). End points included pharmacokinetics, immunogenicity, adverse events, hypoglycemia, insulin dose, and change in efficacy parameters. Of the 210 patients randomized, 200 (95.5%) completed the trial. Patients assigned to switching group (n = 104) and nonswitching group (n = 106) showed similar safety and tolerability, including anti-insulin aspart antibody responses, adverse events, and hypoglycemia. At week 16, there was no relevant difference between switching vs nonswitching groups in the change from baseline in glycated hemoglobin (least square [LS] mean difference = 0.05% [95% confidence interval [CI] = -0.13, 0.22]; 0.50 mmol/mol [-1.40, 2.39]), fasting plasma glucose (LS mean difference = 0.23 mmol/L [95% CI = -1.08, 1.53]; 4.12 mg/dL [-19.38, 27.62]), and changes in insulin dosages. Alternating doses of SAR-Asp and NN-Asp compared with continuous use of NN-Asp showed similar safety, immunogenicity, and clinical efficacy in adults with T1D. This study supports interchangeability between SAR-Asp and NN-Asp in T1D management.

Comparative physicochemical and structural characterisation studies establish high biosimilarity between BGL-ASP and reference insulin aspart

Biosimilar insulin analogues are increasing market access for diabetic patients globally. Scientific establishment of biosimilarity is cornerstone of this key change in the medical landscape. BGL-ASP is a biosimilar insulin aspart developed by BioGenomics Limited, India. BioGenomics has considered a stepwise approach in generating the totality of evidence required to establish similarity with reference product. Insulin aspart is a recombinant rapid-acting human insulin analogue utilised in the treatment of type-1 and type-2 diabetes mellitus. The single amino acid substitution at position B28 where proline is replaced with aspartic acid results in a decreased propensity to form hexamers, thus increasing the absorption rate on subcutaneous administration compared to native insulin. In order to establish the safety and efficacy of BGL-ASP, the critical quality attributes (CQAs) of BGL-ASP are identified based on the impact created on biological activity, pharmacokinetic/pharmacodynamic (PK/PD), immunogenicity and safety. The CQAs of insulin aspart are related to product structure, purity and functionality and are characterised using a series of state-of-the-art orthogonal analytical tools. The primary protein sequence, the secondary, tertiary and quaternary structure are found to be highly similar for BGL-ASP and reference product. The product related impurities of insulin aspart and the assay content are determined using high performance liquid chromatography (HPLC) based analysis and is similar for BGL-ASP and reference insulin aspart sourced from United States of America (US), Europe Union (EU) and India. The safety, efficacy and immunogenicity of BGL-ASP is also found to be comparable with reference product and is confirmed through the clinical trials conducted as recommended by International Council for Harmonisation of Technical Requirements of Pharmaceuticals for Human Use (ICH) and European Medicines Agency (EMA) guidelines. The data encompassed in this study demonstrates that reference insulin aspart and BGL-ASP are highly similar in terms of structural, physicochemical, and biological properties, thus confirming its safety and efficacy for usage as potential alternative economical medicinal treatment for diabetes mellitus.

The Role of Ultra-Rapid-Acting Insulin Analogs in Diabetes: An Expert Consensus.

Ultra-rapid-acting insulin analogs (URAA) are a further development and refinement of rapid-acting insulin analogs. Because of their adapted formulation, URAA provide an even faster pharmacokinetics and thus an accelerated onset of insulin action than conventional rapid-acting insulin analogs, allowing for a more physiologic delivery of exogenously applied insulin. Clinical trials have confirmed the superiority of URAA in controlling postprandial glucose excursions, with a safety profile that is comparable to the rapid-acting insulins. Consequently, many individuals with diabetes mellitus may benefit from URAA in terms of prandial glycemic control. Unfortunately, there are only few available recommendations from authoritative sources for use of URAA in clinical practice. Therefore, this expert consensus report aims to define populations of people with diabetes mellitus for whom URAA may be beneficial and to provide health care professionals with concrete, practical recommendations on how best to use URAA in this context.

THU326 Subcutaneous Insulin Aspart Every 4 Hours In the Treatment Of COVID-19 Patients With Diabetic Ketoacidosis: A Retrospective Study

Abstract Disclosure: D. Chiewchalermsri: None. C. Wanittansirichok: None. C. Sriphrapradang: None. SUBCUTANEOUS INSULIN ASPART EVERY 4 HOURS IN THE TREATMENT OF COVID-19 PATIENTS WITH DIABETIC KETOACIDOSIS: A RETROSPECTIVE STUDY Introduction: COVID-19 infection increases the risk of diabetic ketoacidosis (DKA). To limit the healthcare workers’ exposure when taking care of the COVID-19 patients, treatment of DKA with subcutaneous (SC) rapid-acting insulin analogs every 4 hours was suggested in many professional recommendations. However, the evidence to support this strategy is lacking. We aimed to report the efficacy and safety of SC insulin aspart every 4 hours in the management of DKA in COVID-19 patients. Methods: We retrospectively reviewed all confirmed COVID-19 patients aged &amp;gt;15 years who developed mild-moderate DKA between July 2020 and October 2021 in our institution. Insulin aspart was delivered 0.4 units/kg SC every 4 hours. When blood glucose (BG) decreased to &amp;lt;250 mg/dL, the dose of insulin aspart was reduced to 0.2 units/kg every 4 hours until resolution of DKA. SC Basal insulin 0.15-0.2 units/kg was also initiated at the time of DKA diagnosis. Result: A total of 7 patients had mean age of 67.43±13.19 years with body mass index of 25.49±3.42 kg/m2. Most was 71.4% of female and all had pre-existing type 2 diabetes mellitus. All patients received high-dose steroid for COVID-19 treatment. Initial biochemical parameters were BG of 449±157.3 mg/dL, hemoglobin A1c of 10.58±2.81%, pH of 7.34±0.07, beta-hydroxybutyrate of 4.0±1.51 mmol/L, and HCO3 of 15.5±2.17 mmol/L. Time to resolution of DKA were 12.7±5.82 hours. Conclusion: From our cohort, SC rapid-acting insulin administered every 4 hours could be applied in the selected COVID-19 patients with mild-moderate DKA. Presentation: Thursday, June 15, 2023

Comparison of Insulin Analogs and Human Insulins: A Narrative Review

Abstract Introduction Since insulin analogs have pharmacological properties that are similar to the normal physiological action of insulin, it has been suggested that they provide better glucose control and less rates of hypoglycemia compared to human insulins. Methods We performed a narrative, nonsystematic review of the literature including clinical trials, systematic reviews, meta-analyses, and professional guidelines related to the comparison of human insulins and insulin analogs in terms of glucose control, safety profile, and cost. Results Long-acting basal insulins result in mild improvement in glucose control and less rates of nocturnal hypoglycemic compared to neutral protamine Hagedorn insulin, mainly among patients with type 1 diabetes. Rapid-acting insulin analogs provide better glucose control and lower rates of hypoglycemia compared to regular insulin among patients with type 1 diabetes, whereas no advantage has been shown for insulin analogs among patients with type 2 diabetes for glucose control or hypoglycemia. Premixed insulin analogs provided no advantage in glucose control and inconsistent benefit in lowering the rates of hypoglycemia compared to human premixed insulins among patients with type 2 diabetes. The cost of insulin analogs is significantly higher than human insulins, and favorable cost-effectiveness has only been demonstrated for rapid-acting insulin analogs in type 1 diabetes. Conclusion Currently available evidence supports the use of rapid-acting insulin analogs and possibly long-acting basal insulin over human insulins for patients with type 1 diabetes. For patients with type 2 diabetes, the use of long-acting insulin analogs may be recommended for selected patients who are at an increased risk of significant hypoglycemia, while no clear benefits of meal insulin analogs over human insulins have been observed.

1014-P: Evaluation of Diabetic Ketoacidosis Management with a Subcutaneous Insulin Lispro PowerPlan

Diabetic ketoacidosis (DKA) has traditionally been treated with a continuous intravenous insulin infusion, often requiring management in an intensive care unit (ICU) or step-down unit. There has been growing evidence supporting the use of subcutaneous rapid-acting insulin analogs to treat mild-to-moderate DKA (alert patient able to tolerate oral fluid intake, pH &amp;gt;7.0, bicarbonate ≥10), helping to decrease costs and ICU-bed utilization. We sought to establish the efficacy and safety of a subcutaneous insulin lispro protocol developed at UPMC for the treatment of mild-to-moderate DKA. A retrospective chart review was performed on patients across 15 institutions in the UPMC network from February-October 2022 who had the adult DKA PowerPlan subcutaneous insulin lispro subphase ordered. Of 111 cases analyzed, 47 cases were included that properly used the PowerPlan to treat mild-to-moderate DKA. DKA resolution using the PowerPlan was reached in 45/47 (95.7%) cases. The two unsuccessful cases involved delayed recognition of DKA in the emergency department and premature transition to a prandial insulin regimen before DKA resolution. Hypoglycemia (defined as glucose &amp;lt;70) occurred in 9/47 (19.1%) encounters. Only 1/47 (2.1%) encounters involved hypoglycemia directly attributable to the subcutaneous insulin lispro PowerPlan. The remaining cases of hypoglycemia were attributed to not reducing insulin doses when glucoses were &amp;lt;250, giving insulin doses sooner than 2 hours before the prior dose, not starting dextrose-containing fluids when glucoses were &amp;lt;250, and higher co-administered basal insulin doses (&amp;gt;0.3 units/kg). Overall, these results suggest that a subcutaneous insulin analog can be safely and effectively used to treat mild-to-moderate DKA in non-ICU settings. Disclosure J.Quaytman: None. E.Karslioglu-french: Research Support; Abbott. A.Donihi: None.

Optimisation of induction conditions for a bacterial strain producing proinsulin aspart

Diabetes poses a serious threat to the health of people around the world. Therefore, in 2021, the World Health Organisation launched the Global Diabetes Compact, an initiative aimed at improving the management and prevention of diabetes. The rapid growth in the number of diabetic patients has increased the need for insulin. Rapid-acting human insulin analogues, including insulin aspart, improve the efficacy of insulin therapy. Methods for insulin aspart production include its biosynthesis in the proinsulin form in Escherichia coli. However, the yield of the recombinant protein largely depends on the optimisation of the production process.The aim of the study was to optimise the induction conditions for an E. coli strain expressing recombinant proinsulin aspart through applying the Design of Experiment (DoE) approach to enhance bacterial cell productivity.Materials and methods. The study focused on a strain of E. coli producing proinsulin aspart. The authors planned the experiment using MODDE software and the reduced face-centred central composite design (CCF) enabling the assessment of factor interactions and the creation of design spaces. The authors carried out fermentations of the producing strain in a 5 L Biostat® B bioreactor and measured proinsulin aspart concentrations by capillary gel electrophoresis. The results were analysed using GraphPad Prism 6.Results. Using the DoE approach, the authors optimised the conditions for the growth of the producer strain and the biosynthesis of proinsulin aspart. Based on data from response surface plots for wet biomass concentration, specific productivity, and volumetric productivity, as well as plotted models, the authors established design spaces for the induction of proinsulin aspart expression in E. coli. The plotted models demonstrated high predictive power and high reproducibility of the results. The authors successfully validated the induction process for the synthesis of proinsulin aspart in a bioreactor under optimised conditions. The volumetric productivity of the strain producing proinsulin aspart increased from 3.06±0.16 g/L (conventional conditions) to 4.93±0.80 g/L (optimised conditions).Conclusions. The authors achieved a 60% increase in the volumetric yield of proinsulin aspart. The study results may be used to intensify the industrial production of insulin aspart.

Modern Insulin, Device, and Technology: Tips For Clinicians

Insulin has been a lifesaving treatment for people with diabetes since its discovery in 1921. However, the way insulin is delivered evolved over time. Modern insulin, devices, and technology have transformed the management of diabetes and improved the quality of life for millions of people worldwide.Modern insulins are designed to match the needs of people with diabetes better. Traditional insulins, such as regular and NPH insulin, have a delayed onset and peak, making it difficult to manage blood sugar levels. Newer insulins, such as rapid-acting insulin analogs like aspart, glulisine, and lispro, have a faster onset and shorter duration of action, allowing for greater dosing and timing flexibility. Long-acting insulin analogs, like glargine and detemir, provide more consistent blood sugar control and less hypoglycemia risk.Insulin delivery devices have also advanced significantly. The most common device is the insulin pen, which looks like a large pen and uses disposable insulin cartridges. The pen has replaced traditional syringes and vials for many people with diabetes, offering greater convenience and ease of use. Insulin pumps are also becoming more popular, especially among people with type 1 diabetes. A pump delivers insulin through a catheter inserted under the skin, which can be programmed to provide a continuous infusion of insulin or a bolus dose before meals.Technological advancements have also revolutionized diabetes management. Continuous glucose monitoring (CGM) systems use a small sensor inserted under the skin to measure glucose levels every few minutes, providing real-time data to help people make more informed decisions about insulin dosing and food choices. Some CGM systems also offer alerts for high and low blood sugar levels, making it easier to avoid dangerous fluctuations. Automated insulin delivery systems, also known as closed-loop systems or artificial pancreas systems, use CGM data to automatically adjust insulin delivery, reducing the burden of constant monitoring and decision-making for people with diabetes.In summary, modern insulin, devices, and technology have greatly improved the management of diabetes, allowing for better blood sugar control and a better quality of life for people with diabetes. As technology continues to advance, the future of diabetes management looks promising. Bangladesh J Medicine 2023; Vol. 34, No. 2(1) Supplement: 191

Increased Time in Range with Ultra Rapid Lispro Treatment in Participants with Type 2 Diabetes: PRONTO-Time in Range.

To evaluate time in range metrics and HbA1c in people with type 2 diabetes (T2D) treated with ultra rapid lispro (URLi) using continuous glucose monitoring (CGM) for the first time in this population. This was a Phase 3b, 12-week, single-treatment study in adults with T2D on basal-bolus multiple daily injection (MDI) therapy using basal insulin glargine U-100 along with a rapid-acting insulin analog. Following a 4-week baseline period, 176 participants were newly treated with prandial URLi. Participants used unblinded CGM (Freestyle Libre). Primary endpoint was time in range (TIR) (70-180mg/dl) during the daytime period at Week 12 compared to baseline with gated secondary endpoints of HbA1c change from baseline and 24-h TIR (70-180mg/dl). Improved glycemic control was observed at Week 12 versus baseline including mean daytime TIR (change from baseline [Δ] 3.8%; P = 0.007), HbA1c (Δ - 0.44%; P < 0.001), and 24-h TIR (Δ 3.3%; P = 0.016) with no significant difference in time below range (TBR). After 12weeks, there was a statistically significant decrease in postprandial glucose incremental area under curve, overall, across all meals, within 1h (P = 0.005) or 2h (P < 0.001) after the start of a meal. Basal, bolus, and total insulin dose were intensified with increased bolus/total dose ratio at Week 12 (50.7%) versus baseline (44.5%; P < 0.001). There were no severe hypoglycemia events during the treatment period. In people with T2D, URLi in an MDI regimen was efficacious with improved glycemic control including TIR, HbA1c, and postprandial glucose without increased hypoglycemia/TBR. CLINICALTRIAL REGISTRATION NUMBER: NCT04605991.

Insulin Management for Type 2 Diabetes During Ramadan: A Narrative Review for Clinicians.

Muslims with insulin-dependent type 2 diabetes are at high risk for adverse events while fasting during the month of Ramadan. However, advances in pharmacologic therapy coupled with creative strategies of insulin administration can mitigate complications. This narrative literature review investigates which insulin subtypes are likely to prevent hypoglycemic events and reduce hyperglycemia during the Ramadan fasting season for this high-risk population. Narrative literature review Eligibility Criteria: The following MeSH terms were used: "Diabetes Mellitus, Type 2" and "Insulin," and the "Text Words": "Ramadan", "iftar", "Muslim fast", and "religious fast." The primary focus was on adult, non-pregnant, insulin-dependent type 2 diabetes during Ramadan. Anything beyond this focus was excluded. A total of nine pertinent studies were included for narrative review and analysis. PubMed, EMBASE and Medline. The studies identified suggest long-acting insulins reduce the risk of hypoglycemia, and rapid-acting insulin analogues may improve post-iftar hyperglycemia. Moreover, utilizing flexible glycemic targets during Ramadan is a novel strategy that has demonstrated improved outcomes after the fasting season. Certain insulin subtypes and dosing strategies may be advantageous to use during Ramadan. However, a systematic, comprehensive, and updated review, including a critical appraisal of each original study, is needed to improve clinical care of insulin-dependent type 2 diabetes during Ramadan.

[Treatment of acute diabetic metabolic crises in adults (Update2023) : Hyperglycemic hyperosmolar state and ketoacidotic metabolic disorder].

Diabetic ketoacidosis (DKA) and the hyperglycemic hyperosmolar state (HHS) represent potentially life-threatening situations in adults. Therefore, rapid comprehensive diagnostic and therapeutic measures with close monitoring of vital and laboratory parameters are required. The treatment of DKA and HHS is essentially the same and replacement of the mostly substantial fluid deficit with several liters of aphysiological crystalloid solution is the first and most important step. Serum potassium concentrations need to be carefully monitored to guide its substitution. Regular insulin or rapid acting insulin analogues can be initially administered as an i.v. bolus followed by continuous infusion. Insulin should be switched to subcutaneous injections only after correction of the acidosis and stable glucose concentrations within an acceptable range.

Role of New Insulin Analogs in the Management of Diabetes. A Clinical Review

This paper has reviewed different insulin analogs currently available in the market and pharma industry, their safety, efficacy and their roles in the diabetes management, comparing with human regular and NPH insulin. Traditional insulins (human regular and NPH insulins) do not have constant or smoother pharmacokinetic and pharmacodynamic profiles and are usually associated with erratic blood glucose profiles with hypoglycemia or hyperglycemia when compared with analog insulins. Similarly they do not match physiologic insulin profiles with basal bolus format. According to the medical literature, current insulin analogs are more efficacious and also it has been documented in research trials that recent insulin analogs are better and safer as compared to human regular and NPH insulin in terms of hypoglycemia and HbA1c reductions. Hence this paper has reviewed these insulins analogs (longer acting basal and rapid acting insulin analogs) for their safety and efficacy in terms of hypoglycemia and HbA1c control, for the management of both type-1 and type-2 diabetics in hospitals and clinics.

Current Insights on the Use of Insulin and the Potential Use of Insulin Mimetics in Targeting Insulin Signalling in Alzheimer’s Disease

Alzheimer's disease (AD) and type 2 diabetes (T2D) are chronic diseases that share several pathological mechanisms, including insulin resistance and impaired insulin signalling. Their shared features have prompted the evaluation of the drugs used to manage diabetes for the treatment of AD. Insulin delivery itself has been utilized, with promising effects, in improving cognition and reducing AD related neuropathology. The most recent clinical trial involving intranasal insulin reported no slowing of cognitive decline; however, several factors may have impacted the trial outcomes. Long-acting and rapid-acting insulin analogues have also been evaluated within the context of AD with a lack of consistent outcomes. This narrative review provided insight into how targeting insulin signalling in the brain has potential as a therapeutic target for AD and provided a detailed update on the efficacy of insulin, its analogues and the outcomes of human clinical trials. We also discussed the current evidence that warrants the further investigation of the use of the mimetics of insulin for AD. These small molecules may provide a modifiable alternative to insulin, aiding in developing drugs that selectively target insulin signalling in the brain with the aim to attenuate cognitive dysfunction and AD pathologies.

Optimal Prandial Timing of Insulin Bolus in Youths with Type 1 Diabetes: A Systematic Review.

The aim of this systematic review was to report the evidence on optimal prandial timing of insulin bolus in youths with type 1 diabetes. A systematic search was performed including studies published in the last 20 years (2002-2022). A PICOS framework was used in the selection process and evidence was assessed using the GRADE system. Up to one third of children and adolescents with type 1 diabetes injected rapid-acting insulin analogues after a meal. Moderate-high level quality studies showed that a pre-meal bolus compared with a bolus given at the start or after the meal was associated with a lower peak blood glucose after one to two hours, particularly after breakfast, as well as with reduced HbA1c, without any difference in the frequency of hypoglycemia. There were no differences related to the timing of bolus in total daily insulin and BMI, although these results were based on a single study. Data on individuals' treatment satisfaction were limited but did not show any effect of timing of bolus on quality of life. In addition, post-prandial administration of fast-acting analogues was superior to rapid-acting analogues on post-prandial glycemia. There was no evidence for any difference in outcomes related to the timing of insulin bolus across age groups in the two studies. In conclusion, prandial insulin injected before a meal, particularly at breakfast, provides better post-prandial glycemia and HbA1c without increasing the risk of hypoglycemia, and without affecting total daily insulin dose and BMI. For young children who often have variable eating behaviors, fast-acting analogues administered at mealtime or post-meal could provide an additional advantage.

Management of Individuals With Diabetes at High Risk for Hypoglycemia: An Endocrine Society Clinical Practice Guideline.

Hypoglycemia in people with diabetes is common, especially in those taking medications such as insulin and sulfonylureas (SU) that place them at higher risk. Hypoglycemia is associated with distress in those with diabetes and their families, medication nonadherence, and disruption of life and work, and it leads to costly emergency department visits and hospitalizations, morbidity, and mortality. To review and update the diabetes-specific parts of the 2009 Evaluation and Management of Adult Hypoglycemic Disorders: Endocrine Society Clinical Practice Guideline and to address developing issues surrounding hypoglycemia in both adults and children living with diabetes. The overriding objectives are to reduce and prevent hypoglycemia. A multidisciplinary panel of clinician experts, together with a patient representative, and methodologists with expertise in evidence synthesis and guideline development, identified and prioritized 10 clinical questions related to hypoglycemia in people living with diabetes. Systematic reviews were conducted to address all the questions. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make recommendations. The panel agreed on 10 questions specific to hypoglycemia risk and prevention in people with diabetes for which 10 recommendations were made. The guideline includes conditional recommendations for use of real-time continuous glucose monitoring (CGM) and algorithm-driven insulin pumps in people with type 1 diabetes (T1D), use of CGM for outpatients with type 2 diabetes at high risk for hypoglycemia, use of long-acting and rapid-acting insulin analogs, and initiation of and continuation of CGM for select inpatient populations at high risk for hypoglycemia. Strong recommendations were made for structured diabetes education programs for those at high risk for hypoglycemia, use of glucagon preparations that do not require reconstitution vs those that do for managing severe outpatient hypoglycemia for adults and children, use of real-time CGM for individuals with T1D receiving multiple daily injections, and the use of inpatient glycemic management programs leveraging electronic health record data to reduce the risk of hypoglycemia. The recommendations are based on the consideration of critical outcomes as well as implementation factors such as feasibility and values and preferences of people with diabetes. These recommendations can be used to inform clinical practice and health care system improvement for this important complication for people living with diabetes.

ISPAD Clinical Practice Consensus Guidelines 2022: Ramadan and other religious fasting by young people with diabetes.

Fasting is advised, with variable rules, in healthy adults and adolescents in different religions. A common purpose of fasting in these religions is to gain self-restraint, arouse spiritual consciousness, and better understand the plight of the poor and hungry. In this section, general rules and religious guidance on observing and breaking fasting in different religions are given, with emphasis on potential effects on health and glycemic outcomes in children and adolescents with T1D who choose to fast. Ramadan fasting is one of the five pillars of Islam and is obligatory for all healthy adult and adolescent Muslims from the time of completing puberty.1 As per the Islamic rules and guidance from Sunnah (the way of prophet Mohamed), an individual becomes subject to Shari'a rulings that apply when specific features of puberty are attained. Approximately 1.9 billion Muslims celebrate the ninth month of the Hijri (lunar) calendar notable for Ramadan fasting all over the world.2 The Epidemiology of Diabetes and Ramadan (EPIDIAR), a population-based study conducted in 13 countries and involving almost 13,000 adults with diabetes, showed that 78.7% of individuals with type 2 diabetes (T2D) and 42.8% of those with T1D fast for at least for 15 days during Ramadan. Saudi Arabia had the maximum number of individuals with T1D who chose to fast.3 The duration of fasting during Ramadan varies based on geographical location and season but is mandated to be between dawn and dusk. During this period, people who fast abstain from eating, drinking, use of oral medications, and smoking. There are no restrictions on food or fluid intake between dusk and dawn.1, 4 Fasting during Ramadan is not intended to bring excessive difficulty or cause any adverse effect to the individual. Islam has allowed many categories of people to be exempted from fasting; for example, menstruating, pregnant or breastfeeding women, prepubertal children, the elderly, individuals with any acute or chronic illness in whom fasting would be detrimental to health, individuals with an intellectual disability, or individuals who are traveling.1 These principles formed the basis of all the consensus statements by several groups.5-7 The provisions of al-Fitr (i.e., Not to observe the fast) in Ramadan apply if there is any sickness, according to the Almighty saying: “Whoever of you is sick or on a journey, and some of the other days, and on those who support him, ransom poor food.”1 Therefore, if a person fasts and experiences harm or serious hardship while fasting, he/she may be committing a sin.4 Various beliefs exist regarding diabetes management practices during Ramadan. In a study of fasting during Ramadan that included 800 individuals with diabetes, 67% indicated that pricking the skin to measure BGLs breaks the fast.8 Such a belief might endanger individuals with diabetes and predispose them to acute complications. Medical counseling and liaison with Islamic scholars can help correct wrong interpretation as well as understanding and ensure safer fasting. Although some experts would consider fasting, particularly during Ramadan, a practice at high risk for metabolic deterioration, recent studies have demonstrated that individuals with T1D can fast safely during Ramadan, provided they comply with the fasting-focused management plan and are under close professional supervision.6, 9 The Eastern Christian Orthodox Church is the second-largest Christian church, with ~300 million members.10 Orthodox Fasting (OF) is a basic and traditional component of the religion, practiced by a large proportion of the Orthodox population.11 OF includes three main fasting periods: 40 days prior to Christmas, 48 days prior to Easter, 14 days prior to Assumption, along with the fasting period prior to the feast of the Holy Apostles (lasting from 0 to 30 days depending on Easter feast), three other daily feasts (January 5, August 29, September 14), as well as every Wednesday and Friday. Individuals 18–59 years old are expected to fast during these periods. OF is a kind of periodical diet which recommends abstaining from meat, dairy products and eggs for about 180 days annually, and also abstaining from fish for 155 days. The diet during periods of fasting is characterized by increased consumption of cereals, legumes, fruits, vegetables, nuts and seafood. For this reason, it may be considered as a vegetarian dietary pattern, where fasting and non-fasting periods alternate, sharing common features with the classical Mediterranean Diet.11, 12 Studies on OF followers conducted in three different countries (Greece, United States, and Egypt), reported low total energy intake, low fat (total, saturated and trans), low animal and high vegetable protein intake, high complex carbohydrate and fiber intake, high vitamin C, folate and magnesium intake, low calcium and vitamin D intake during different fasting periods.13, 14 The OF meal plan tends to be high in carbohydrate content. Thus, it is advisable for people with T1D to choose carbohydrates with a low glycemic index, and consume them in combination with fiber, proteins (legumes, seafood) or fats (olive oil). Rye, barley, oats, brown rice, quinoa or amaranth are also suitable.15 Although data on the effect of OF diet on metabolic health are heterogenous, a potential benefit on lipid profile has been suggested, whereas there are no data on the effects on cardiovascular and musculoskeletal outcomes. Negative aspects of OF, primarily attributed to dietary limitations of specific vitamins (D and B12) and minerals (calcium and iron), should not be ignored, and relevant guidance might be provided to people following OF by health care professionals.13 Yom Kippur fasting is a major fast and the holiest day in the Jewish religion and calendar.16 It is obligatory for all healthy adult and adolescent Jews from the age of 13 years in males and 12 years in females. All observant and most non-observant Jews practice this 25 h long fasting. It starts at dusk (end of the ninth of Tishrei—first month of the Jewish lunar year) and ends on the following day (10th of Tishrei) at sunset.16 The activity during this fast involves mostly prayer and soul searching within synagogues. Jewish law includes five other days of fasting between dawn and dusk, and these are mostly practiced only by observant Jews. During fasting, Jews abstain from eating, drinking, and smoking. Fasting is not intended to cause any adverse effect to the individual.17 Jewish law allows many categories of people to be exempted from fasting; for example, prepubertal children, women in and around delivery days, individuals with illnesses in whom fasting may be detrimental to health, and individuals with an intellectual disability.17 Jewish law defines an intermediate state where people who need to break their fast due to health reasons can intermittently eat small portions of 30 g in line with a scheduled time plan.16 Various approaches for diabetes management during fasting have been used. Initially, prior to the era of glucometers and CGM, people with diabetes were exempt from fasting. In the last two decades, several studies showed that insulin dose adjustments and close monitoring may enable safe fasting for individuals with T1D.18-21 Jewish law indicates that specific medical counseling and liaison with Jewish legal scholars should facilitate and help to ensure safer fasting for the individual.19-21 Fasting is also common in other religions in the world. It is well known that followers of Hinduism, Buddhism and Jainism believe that the act of fasting would result in the spiritual transformation of the individual or community. In Hinduism, different forms of fasting are frequently practised throughout the year. Fasting is not considered an obligation, but a spiritual and moral act, the aim being to purify the body and mind to acquire self-restraint and divine grace. There are different forms of fasting which vary according to personal, family and community beliefs, which may be strict and difficult to follow, or relatively easy and readily amenable to modifications. The fasting period can be for a single day, weekly (on specific day/s throughout the year), bi-monthly (Pradosha—13th day of every fortnight of the Hindu calendar), monthly (Ekadashi—11th day of the Hindu lunar month, and Purnima—the full moon day). Longer fasting periods may last 9 days and are followed once or twice a year (Navratras), or of 1-month duration (Kartik month). Variability exists according to timing, duration and type of food intake, including no food and water intake, only water allowed; fruit and milk allowed, and broken rice or millets allowed.22 In Buddhism, while fasting is generally practiced by monks, lay people may fast voluntarily as part of a personal spiritual observance. Buddhist Lent is the fast and feast observed for three lunar months every year during the rainy season, when Buddhists fast for a 12-h period, from noon to midnight, followed by feasting for 12 h from midnight to noon.23 Some devout lay Buddhists also follow the rule during special days of religious observance when one must not eat after the noon meal. The duration of fasting can vary from three (sanzhai) to 6 days (liuzhai).24 In the first half of the first, fifth, and ninth months, a continuous long fast (changzhai) is also observed. Fasting is similarly prevalent in Jainism, observed during festivals, holy days, birthdays and anniversaries. There are several types of fasts, varying from 24–36 h to several days and months. Paryushan is the main festival during the monsoons, which usually lasts eight or 10 days, respectively, in the Swetambara and Digambara Jain tradition (the two main sects of Jainism).25 Digambar Jains usually will not consume food and/or water (boiled) more than once in a day; while Shwetambar Jains drink only boiled water during their fast days. Many Jains observe a type of fasting by abstaining from food and water after sunset. Varshitap (year-long fast) is a type of fasting in Jainism where devotees fast for 13 months and 13 days, in which they fast completely on alternate days and eat a limited diet between sunrise and sunset on the other days. The Bahais fast for 19 days in the month of Ala (March), when no food or water is consumed from sunrise to sunset by persons 15–70 years old. In Taoism, fasting is observed in the form of “Bigu,” where grains are avoided. Many reviews, consensus statements, and expert opinions detailing the principles of diabetes care during fasting (especially during Ramadan) have been published.5-7, 26-28 A comprehensive guide has been developed by the International Islamic Fiqh Academy, along with the Islamic organization of health sciences, after a thorough literature review of possible risks to people with diabetes associated with Ramadan fasting. Among defined risk stratification groups, T1D is considered to be a very high-risk group.29, 30 However, this document is not specific to young people with diabetes, and overall studies on religious fasting in this population are limited.31 A survey by Elbarbary et al. highlighted variations among physicians, from 16 predominantly Muslim countries, in the management of children and adolescents with T1D. There are substantial variations in the perceptions, beliefs, general management, and the practice of insulin therapy in this age group during fasting.32 The survey also highlighted limitations related to relying on data on the safety and metabolic impact of fasting based on studies conducted in adults with T2D.32 Furthermore, there is minimal literature on fasting-related issues in religions other than Islam. In many diabetes centers managing Muslim populations, healthcare professionals agree that adolescents can fast if they have reasonable glycemic control, good hypoglycemia awareness, and the willingness to frequently monitor their BGLs during fasting.33 A recent survey indicated that almost 80% of physicians looking after children and adolescents with diabetes would allow them to fast if they wished.32 Pre-fasting assessment and education are vital to ensure the suitability and safety of fasting in young people with diabetes. Many diabetes units run special education sessions prior to the month of Ramadan to ensure safe fasting. The lack of pre-fasting assessment and proper diabetes education are major obstacles for safe fasting in people with T1D.32, 34 Eid et al. showed that an educational program consisting of weekly sessions before and during Ramadan, enabled people with diabetes to fast safely, with a reduced number of hypoglycemic events per month.35 A systematic review showed that Ramadan-focused diabetes education in T2D resulted in a substantial reduction of hypoglycemia and improvement in HbA1c.36 Structured education has also been associated with a 61% decrease in DKA risk in adults with T1D.37 The dose adjustment for normal eating (DAFNE) education program highlights the importance of flexible dosing, carbohydrate counting and matching insulin to carbohydrate intake.38 This, together with rtCGM or isCGM, can help people with uncomplicated T1D to safely fast during Ramadan.39, 40 In a study from Kuwait, people with T1D using CGM and provided with DAFNE training had a reduced incidence of hypoglycemia during Ramadan compared with the pre-Ramadan period. No episodes of severe hypoglycemia, DKA, acute kidney injury, or hospitalization occurred during Ramadan, including no evidence of increased glucose variability.39, 40 Other studies demonstrated that individuals with T1D who received Ramadan-focused education showed more willingness to fast, since they were more capable of managing their diabetes, and they had better glycemic outcomes and fewer complications.41, 42 Qualitative studies suggest that structured Ramadan-focused education needs to be developed and implemented in clinic practice.38, 41, 43 The DAR practical guidelines 2021 also suggested that individuals with diabetes wishing to fast and receiving pre-Ramadan assessment and education, should fast for a few days during the 2 months preceding Ramadan.9 In summary, wider implementation of fasting-focused education for both individuals with T1D and T2D, especially those on insulin therapy, is of paramount importance. Based on the growing number of technologies that support diabetes care, telemedicine has been proposed as an important solution to meet the need of expanding care for the benefit of people with diabetes, while improving efficiency and containing costs.44 During the COVID-19 pandemic, telemedicine and telemonitoring have shifted from an aspirational goal to a de facto standard of care for diabetes management.45 Limited studies have investigated the role of telemedicine in the management of diabetes during Ramadan or other religious fasting, especially in adolescents with T1D. In 2020 and 2021, the Holy Month of Ramadan coincided with the COVID-19 pandemic and lockdown. Limited access to healthcare and the continuous need for diabetes assessment and consultation before and during Ramadan highlighted the urgent need for digital health solutions in diabetes care. The DAR Global Survey on 1483 Muslim participants with T1D showed that 26.8% of those aged <18 years and 73.2% of those aged ≥18 years fasted during Ramadan during the 2020 COVID pandemic.46 When comparing the short-term benefits of a telemonitoring-supplemented focused diabetes education with education alone in individuals with T2D who fasted during Ramadan, frequency of hypoglycemia was lower in the telemonitored group.47 Similarly, the “Making Ramadan Fasting A Safer Experience (MRFAST)” study showed reduced episodes of hypoglycemia and greater reduction in HbA1c in participants with T2D assigned to the telemonitoring group compared to the control group.48 Participants viewed telemedicine as a more convenient alternative, although technological barriers remain a concern. A prospective study assessed the role of a 24-h Helpline Service for people with diabetes during Ramadan and supported its key role in promoting safe fasting and reducing unnecessary hospital visits and admissions.49 More than half of the 927 calls were queries related to glucose monitoring data and insulin dose adjustment in T1D. Overall, telemonitoring offers an attractive option for managing diabetes during Ramadan and other religious fasting, but further data in adolescents with diabetes are needed.50 In healthy individuals, during fasting circulating BGLs tend to fall leading to decreased insulin secretion. In addition, levels of glucagon and catecholamines rise, stimulating glycogenolysis and gluconeogenesis.51 In the early hours of fasting, glycogenolysis meets the glucose requirements of the body. This is followed by gluconeogenesis, and later ketogenesis, if the duration of fasting is prolonged. Similar responses, albeit to a lesser extent, occur during the intermittent fasting that occurs during Ramadan. In people with T1D, hypoglycemia that occurs during fasting may not elicit an adequate glucagon response.52, 53 In addition, individuals with autonomic neuropathy can have defective epinephrine secretion to counteract hypoglycemia.54 In individuals with T1D fasting during Ramadan or other religious observances, abnormalities in the counter-regulatory hormones (glucagon, cortisol and catecholamines) may also be present due to disruption of the normal circadian rhythms and the sleep-wake cycle. In addition, there is risk of hypoglycemia associated with exogenous insulin treatment during fasting with changes in meal timing.53 Several studies have focused on the changes in glucose homeostasis during Ramadan fasting. In a study in young adults without diabetes55 using CGM 1- to 2 weeks before, in the middle and 4 to 6 weeks after Ramadan, an increase in the hyperglycemic area above 140 mg/dl was noted after Ramadan, compared with both before and during Ramadan, along with increased glucose variability.55 However, limited data are available on the safety and metabolic effects of fasting in children and adolescents with T1D.3 In a study assessing the impact of Ramadan fasting on resting metabolic rate (RMR), activity, and total energy expenditure (TEE), fasting was associated with reduced physical activity and reduced RMR, without an overall reduction in TEE. Ramadan differs from both prolonged and short-term starvation, as the former decreases RMR, whereas short-term starvation may increase RMR, and this has been attributed to a rise in norepinephrine concentrations.56 Many adolescents with T1D prefer to fast to feel equal to their peers without diabetes.57 Fasting may boost their self-esteem and make them happier as they feel “mature and capable” in fulfilling their religious obligations. However, considering the risk of acute metabolic complications in individuals with T1D, they are often advised not to fast.5-7, 26, 28, 58 Despite the fact that having diabetes grants an exemption from fasting, a large number of youth with diabetes are passionate about Ramadan, and undergo fasting based on social and cultural reasons and a religious sense of fulfillment.3, 57 Young people with diabetes may often fast without the knowledge or approval of their physicians.59 Predictably, there is a general fear among persons with T1D and their health-care providers about the use of insulin therapy during the fast, due to the increased risk of hypoglycemia.60 Hypoglycemia during the daytime is the most disliked complication as its treatment entails the intake of carbohydrate and therefore leads to breaking the fast prematurely. The interruption of fasting may induce a sense of guilt and failure.61 Data indicate that the majority of Muslim adolescents and older children with T1D are able to fast during Ramadan, with a high proportion of them encouraged by their parents to do so.61 Their expectations of developing complications are realistic, but they underestimate the deterioration in glycemic control during the month. It is reassuring that the majority agree to break their fast should complications arise, which makes fasting safer for them. The DEAR program (Diabetes Education and medication Adjustment in Ramadan) aimed to optimize glycemic control prior to Ramadan, and provide risk assessment, preparation, monitoring and intervention pre-, during and post-Ramadan.62 The program was also initiated to focus on covering the relevant religious and medical aspects through engaging a religious leader and Muslim healthcare professional team. The study highlighted that deficiencies in knowledge among healthcare professionals regarding Ramadan fasting can lead to people with diabetes choosing not to inform their healthcare team that they will fast, particularly in Muslim minority countries.62 Depending on where the adolescents live, they often attend school for the whole day, and partake in after-school activities, including sports, during Ramadan, even though they experience sleep disturbances and changes to routines, with late-breaking of the fast and waking early to have the pre-dawn Suhoor. For adolescents with T1D, fasting adds more challenges, especially for those living in Muslim minority societies, where there may not be adjustments made to school and sports schedules, particularly when the hours of fasting are longer (summers). The psychological effects of fasting during Ramadan can vary. Both healthy individuals and people with diabetes can experience opposing psychological outcomes for different reasons, including the changes that accompany the practice of fasting.63 Further research is needed to assess the psychological effects of fasting during Ramadan in adults as well as adolescents with T1D or T2D. Potential risks associated with fasting are hyperglycemia, hypoglycemia, DKA, thrombotic episodes, and dehydration.5-7 Although most of the available data are based on adult studies, an individualized approach, close monitoring of BGLs and weekly follow-up with the medical team is the best approach to prevent acute complications in both adults and young people with diabetes.64 Data on the impact of Ramadan fasting on glycemic outcomes are based on few small studies with inconsistent results. Some studies in children with diabetes demonstrated a significant improvement in fructosamine levels, whereas others showed no changes, or even an increase in HbA1c levels.57, 61, 65-68 Some studies3, 68 have shown that Ramadan fasting in individuals with T1D might predispose to acute complications, although this has not been confirmed by others. Overall, fasting can be considered a safe practice if people with diabetes monitor BGLs frequently and break the fast when hypoglycemia or marked hyperglycemia occur18, 58, 64, 69, 70 Besides, Ramadan fasting has been found safe when pre-fasting medical assessment, focused education, appropriately adjusted insulin regimens, diet control, and management of daily activities have been implemented in individuals with stable diabetes control and no comorbidities57, 68, 70 Studies have shown that adolescents are able to fast for several days during the Ramadan month,71, 72 but unplanned fasting may predispose to hypoglycemia and hyperglycemia with or without ketosis.28, 59 Hypoglycemia is a major complication of fasting. The EPIDIAR study of 1070 adults with T1D reported that fasting during Ramadan increased the risk of severe hypoglycemia by 7.5-fold. During Ramadan, 2% of people with diabetes experienced at least one episode of severe hypoglycemia requiring hospitalization.3 In a pediatric study symptomatic hypoglycemia resulted in breaking the fast on 15% of the days.72 In addition, CGM data have shown wide BGL fluctuations during fasting and eating hours and episodes of unreported hypoglycemia.72 The frequency and duration of hypoglycemia, hyperglycemia, and severe hyperglycemia were significantly higher in adolescents with T1D who had pre-Ramadan suboptimal than those with good glycemic control.73 In a retrospective study of 50 children and adolescents with T1D (age 12.7 ± 2.1 years), those with HbA1c >8.5% had more frequent episodes of hypoglycemia than those with HbA1c ≤8.5%.74 Hypoglycemia has been typically encountered during the hours preceding Iftar.75 Young adults with suboptimal management of T1D experienced wide fluctuations in glucose levels between the fasting and eating hours, with a greater tendency toward hyperglycemia.76 Monitoring BGLs during fasting is essential to predict, prevent, and treat hypoglycemia. It is of paramount importance that BGL is checked if any symptoms suggestive of hypoglycemia are experienced, so that the fast is interrupted promptly. However, some young people may not be willing to break their fast, particularly if hypoglycemia occurs close to sunset (time to end the fast for the day), and this may predispose them to a severe hypoglycemia. A study of 33 children with T1D in Bangladesh showed that only 3 out of 13 children broke their fasting following onset of symptoms of hypoglycemia.77 However, in another study61 most children and adolescents were willing to terminate their fasting when hypoglycemia occurred, regardless of the time of the day. Education might persuade young people with diabetes to break the fast when hypoglycemia occurs. Fasting increases glucagon levels and accelerates lipolysis and ketosis. These pathophysiological changes, in conjunction with fasting itself, may lead to metabolic decompensation in people with diabetes. Episodes of DKA have been reported during Ramadan fasting.78, 79 Detection of euglycemic ketosis during fasting requires evaluation of acid–base state, blood glucose and ketone values (ideally blood ketone measurements, if available) to differentiate DKA from ketosis due to prolonged fasting.80 See ISPAD 2022 Consensus Guidelines Chapter 12 on Sick Day Management in Diabetes for further details on ketosis monitoring. Knowledge of insulin action, interpreting glucose values and adjusting insulin doses for Iftar and Suhoor meals, is a prerequisite for safe Ramadan fasting. Based on clinical experience, different recommendations on how to adjust the type, dose, and timing of insulin in adults have been suggested.69, 81, 82 However, clear evidence-based guidelines on insulin adjustment for adolescents with T1D are lacking. Current recommendations for people on multiple daily injections (MDI) include a reduction of the total daily dose (TDD) of insulin to 70%–85% of the pre-fasting TDD27, 82 or 60%–70% of the pre-fasting dose of basal insulin.7 For people on continuous subcutaneous insulin (CSII), a reduction of the basal rate of insulin infusion by 20%–40% in the last 3–4 h of fasting is recommended.7 The South Asian Guidelines for Management of Endocrine Disorders in Ramadan recommend reducing basal insulin by 10%–20% during the fast days.79, 80 However, these recommendations are not based on data from large cohort studies or randomized controlled studies. Some studies have not shown a reduction in frequency of hypoglycemia with reduction of basal insulin in MDI and CSII regimens, although this has not been confirmed by all studies.83, 84 A suggested guide for adjustment of insulin dosages is given in Figure 1. Management of diabetes during fasting should be discussed on an individual basis, depending on access to different insulins and technology. Once fasting has started, insulin dosing should be regularly adjusted based on the results of glucose monitoring. Frequent BGL measurement is essential. MDI and CSII are the preferred regimens in young people with T1D during Ramadan.85 In some regions, treatment with two or three daily injections with NPH and short-acting insulin may be used. Use of premixed insulin regimens require fixed intake of carbohydrates at set times and is not advised. Insulin analogs have been safe for the management of well-controlled young people with diabetes during a fasting period of 17–19 h. A significant decline in glucose levels, with periods of hypoglycemia, is seen mostly near the end of the fasting period, although no episodes of severe hypoglycemia have been reported.7, 57, 65, 69, 72, 86, 87 It is recommended that during Ramadan, the pre-Ramadan basal insulin dose should be reduced by 20%, when given in the evening.5, 27, 57, 68-71, 87 When taken at Iftar, a further reduction may be needed—up to 40% of the pre-Ramadan basal dose.7, 88 Further individualized adjustment of the dose needs to be considered. Based on the pharmacodynamic profile of NPH, there is a considerable risk of mid-day hypoglycemia and end-of-the-day hyperglycemia. Reduction of the dose is needed to prevent hypoglycemia, at the possible expense of higher BGLs at the end of the day. In most studies, the pre-Iftar and pre-Suhoor rapid-acting insulin doses are equal to the pre-Ramadan lunch and dinner doses, respectively. In some reports, the pre-dawn dose is reduced by 25%–50%,7 depending on the carbohydrate content of the meal and the pre-meal BGL. In an adult study, the use of rapid-acting insulin analogs was associated with fewer hypoglycemic events and an improvement in postprandial glycemia compared with regular insulin.89 Higher BGLs may require an additional dose of insulin administered as a correction dose, which is usually based on the pre-Ramadan correction factor. Two daily injections of NPH and regular insulin allow less flexibility in lifestyle and nutrition with more risk of hyperglycemia and hypoglycemia; therefore, their use is strongly discouraged. Owing to the NPH peak effect, dose adjustment for a 12–16 h period of fasting is more challenging.84 Children on a twice-daily insulin regimen are much more prone to experience hyperglycemia with/without ketones than those on a basal-bolus regimen.84 Using twice-daily insulin regimens during Ramadan requires more dose adjustments, taking the usual morning dose before the sunset meal and only sho

Efficacy and safety of ultra-rapid insulin analogues in insulin pumps in patients with Type 1 Diabetes Mellitus: A systematic review and meta-analysis

AimsTo assess the efficacy and safety of ultra-rapid insulin analogues used with continuous subcutaneous insulin infusion systems (CSII) in adults with type 1 diabetes (T1DM). MethodsWe searched MEDLINE and Cochrane Library up to May 2022 for randomized controlled trials comparing ultra-rapid with rapid-acting insulin analogues (RAIAs) used with CSII. We performed random effects meta-analyses for % of 24-h time in range of 70–180 mg/dl (TIR), time in hypoglycaemia (<70 mg/dl) and hyperglycaemia (>180 mg/dl), 1- and 2-hour post-prandial glucose [PPG] increment after a meal test, HbA1c and average insulin dose at endpoint, unplanned infusion set changes and severe hypoglycaemia. ResultsNine studies (1,156 participants) were included. Ultra-rapid insulins were superior to RAIAs on TIR (mean difference [MD] 1.1 %, 95 % CI 0.11–2.11), time spent in hypoglycaemia (MD −0.47 %, 95 % CI −0.63 to −30), and 1- and 2-hour PPG (MD −12.20 mg/dl, 95 % CI −19.85 to −4.54 and MD −17.61 mg/dl, 95 % CI −28.55 to −6.66, respectively). Ultra-rapid insulins increased odds of unplanned infusion set changes (odds ratio 1.60, 95 % CI 1.26–2.03). ConclusionUltra-rapid acting insulins provided better PPG control compared to RAIAs but their use might result in more infusion set changes.

The Effect of Two Different Insulin Formulations on Postprandial Hyperglycemia after High and Low Glycemic-Index Meal in Type 1 Diabetes.

Despite multiple pharmacological options, including rapid-acting insulin analogs, postprandial hyperglycemia is still highly prevalent in patients with type 1 and type 2 diabetes. We hypothesize that the new rapid-acting insulin formulation, the so-called faster-acting Aspart, may have a different effect in controlling postprandial hyperglycemic burden according to the quality of the meal compared to the traditional Aspart. Twenty-five patients with type 1 diabetes were consecutively recruited at the diabetes care center of the University Hospital affiliate of the Magna Græcia University of Catanzaro. Each patient performed four meal tests one week apart, two with a predefined high glycemic index (HGI) food and two with a low glycemic index (LGI) food using insulin Aspart once and Faster Aspart the other time. The 0–30 min, 0–60 min, and 0–120 min glucose Area Under the Curve (AUC) of postprandial glycemic excursion, calculated from continuous glucose monitoring data, were significantly lower with Faster Aspart administered before the HGI test meal as compared to Aspart. A significant difference in favor of Faster Aspart was also found when comparing the 0–60 min and 0–120 min AUC after the LGI meal. Faster Aspart may provide better postprandial glucose control than Aspart regardless of the glycemic index of the meal.

A comparison of the rapid-acting insulin analogue glulisine with lispro and aspart for the pump treatment of patients with type 1 diabetes.

(1) To describe the population of patients with type 1 diabetes (T1DM) using the rapid-acting insulin analogue glulisine versus lispro and aspart during continuous subcutaneous insulin infusion (CSII); (2) to describe insulin relative effectiveness based on hemoglobin A1c (HbA1c), fasting blood glucose (FBG) and dose; (3) to determine rates of hyperglycemia, hypoglycemia, and diabetic ketoacidosis (DKA). The analysis used March 2021 data from the Diabetes-Patienten-Verlaufsdokumentation registry, which contains data of 618,903 patients with diabetes. Patients were propensity-matched by age, sex, and diabetes duration. Overall, 42,736 patients of any age were eligible for analysis based on insulin pump usage with either glulisine (N = 707) or lispro/aspart (N = 42,029) between 2004 and 2020. Patients receiving glulisine were older (median 20.0 vs. 16.2years), equally often male (47.2% vs. 47.8%) and had a longer diabetes duration (median 9.4 vs. 7.4years). After propensity score matching, 707 pairs remained (total N = 1414). Patient characteristics between groups were similar. Achieved HbA1c values were also comparable: 8.04%, 64mmol/mol versus 7.96%, 63mmol/mol for glulisine and lispro/aspart [LS mean difference 0.08 (95%CI -0.08, 0.25)]. FBG was 9.37mmol/L (168.9mg/dL) and 9.58mmol/L (172.6mg/dL) in the glulisine and lispro/aspart groups [LS mean diff. -0.21; (95%CI -1.13, 0.72)]. Total daily insulin doses and prandial to total insulin ratios were also similar. Glulisine group patients had higher rates of lipodystrophy (0.85% vs. 0.71%) (LS mean diff. 0.18 [95% CI -1.01, 1.38]) and non-severe DKA (3.11% vs. 0.57%; p = 0.002). Fewer patients in the glulisine group had severe hypoglycemic events (7.66 vs. 9.09; p = 0.333) and severe ketoacidosis events (0.57% vs. 1.56%; p = 0.082) but more had hypoglycemic coma events (p = 0.773), although the differences were not statistically significant. Insulin glulisine had comparable glucose control to lispro/aspart. The use of glulisine was less frequent in the present analysis compared to the previous trials.