Metabolic interventions as adjunctive therapies to insulin in type 1 diabetes: Current clinical landscape and perspectives

Abstract

Type 1 diabetes (T1D) is classically characterized as an autoimmune disease wherein the immune system erroneously attacks insulin‐producing pancreatic β‐cells, causing insulin insufficiency and severe metabolic dysregulation. However, intensive investigation and numerous clinical trials with immunotherapies have been largely unable to significantly alter the course of disease. Currently, there is no effective way to prevent or cure T1D, and insulin remains the cornerstone of T1D treatment. In recent years, a growing body of research suggests that β‐cells actively contribute to the immune response and to disease development. Factors including glucotoxicity, lipotoxicity, inflammation, endoplasmic reticulum (ER) and oxidative stress can induce β‐cell apoptosis and senescence, further promoting insulitis. Recent studies highlight the importance of targeting metabolic control for T1D management and treatment. Metabolic interventions, through their direct and indirect impacts on β‐cells, have shown promise in preserving β‐cell function. These interventions can reduce glucose toxicity, alleviate oxidative stress and inflammation, enhance insulin sensitivity, and indirectly mitigate the autoimmune responses. By preserving β‐cell function, individuals with T1D attain better glycaemic control, reduced complication risks and exhibit improved overall metabolic health. Here, we provide an overview of insights from clinical studies, systematic reviews and meta‐analyses that collectively demonstrate that adjunctive metabolic interventions can enhance glycaemic control, reduce insulin requirements and mitigate adverse effects associated with insulin monotherapy. They also show potential for halting disease progression, preserving residual β‐cell function and improving long‐term outcomes for newly diagnosed individuals. Future research should focus on optimizing these treatment strategies and establishing their long‐term efficacy and safety.

1. INTRODUCTION

T1D presents a significant global health challenge, impacting over 8 million people worldwide. ¹ Traditionally viewed as an autoimmune disorder where the immune system erroneously targets and destroys insulin‐producing pancreatic β‐cells, emerging evidence suggests a more complex relationship. ² A growing body of research indicates that β‐cells actively contribute to the immune response and disease development. For instance, glucotoxicity, lipotoxicity, inflammation, ER and oxidative stress can induce β‐cell apoptosis and senescence. ³ Stress‐induced senescence prompts β‐cells to adopt a senescence‐associated secretory phenotype, which releases signals attracting cytotoxic T‐cells, driving islet inflammation. ⁴ Additionally, β‐cell stress‐responsive pathways contribute to and exacerbate autoimmune dysfunction and cell death. ⁵ β‐cells exhibit a low expression of protective enzymes and anti‐apoptotic factors, making them ill‐equipped to survive an inflammatory environment. ⁴ Furthermore, despite extensive research and clinical trials, conventional immunosuppressive therapies alone have shown limited efficacy in halting T1D progression. Currently, only one medication, the anti‐CD3 monoclonal antibody Teplizumab, is approved for delaying the onset of Stage 3 T1D in those 8 years of age and older with stage 2 T1D, though its extreme cost prevents its widespread adoption. ⁶ It is increasingly evident that relying solely on immunotherapy is insufficient for achieving lasting and effective T1D treatment.

Insufficient insulin secretion impedes cellular glucose uptake, resulting in persistent hyperglycaemia. Additionally, the absence of insulin disrupts the liver's regulation of glucose production (HGP), leading to excessive gluconeogenesis, ⁷ exacerbating hyperglycaemia and contributing to long‐term micro‐ and macrovascular complications. ⁸ Moreover, decreased insulin levels fail to restrain lipolysis, increasing circulating fatty acids, which can lead to lipotoxic stress, insulin resistance and contribute to cardiovascular risk. ⁹ Insulin deficiency also decreases rates of protein synthesis while increasing protein breakdown, contributing to muscle wasting and loss of lean body mass, impaired physical function, slower wound healing and increased susceptibility to infections. ¹⁰ Overall, the metabolic disturbances in T1D have far‐reaching effects on various physiological processes, highlighting the importance of comprehensive management strategies aimed at controlling systemic metabolism and preventing complications.

Though the exact aetiology of T1D remains unknown, genetic predisposition, particularly involving the human leukocyte antigen (HLA) alleles, plays a significant role. Detection of circulating islet autoantibodies (IAAs) indicates susceptibility to T1D, with higher titres correlating to elevated risk. ¹¹ Environmental stressors can then trigger autoimmune β‐cell destruction, resulting in insulin deficiency, disrupted glucose regulation, clinical symptoms and an eventual T1D diagnosis. ² Concurrently, alpha cell dysfunction leads to hyperglucagonemia, further aggravating hyperglycaemia. ¹² Manifest hyperglycaemia can adversely affect major organs through microvascular (retinopathy, neuropathy, nephropathy) and macrovascular complications (coronary heart disease, myocardial infarction, stroke, peripheral vascular diseases). ¹³ Normalizing blood glucose levels can mitigate or prevent many of these complications. ¹³ Consequently, individuals with T1D require lifelong exogenous insulin therapy to manage these complications and restore metabolic function. ¹⁴

Exogenous insulin monotherapy has been the mainstay of T1D treatment for the last century. While effective, it remains an imperfect therapeutic strategy, requiring complex injectable regimens. ¹⁵ Current treatment guidelines involve frequent blood glucose monitoring and either multiple daily injections of prandial rapid‐acting and basal long‐acting insulin or continuous subcutaneous insulin infusions delivered via insulin pump (CSII). ¹⁵ Various insulin formulations and delivery methods have been developed to improve administration and convenience. Despite advancements, T1D patients still experience significant intra‐ and inter‐day glucose variability, with hypoglycaemia remaining a major concern. ¹⁶

On average, individuals with T1D experience about two symptomatic hypoglycaemic episodes per week. ¹⁴ These episodes are a key factor hindering the intensification of insulin therapy to achieve glycaemic goals. Glycated haemoglobin (HbA1c) tests provide a gauge of one's average blood sugar levels over the past 2–3 months. HbA1c levels <7% are recommended for individuals with T1D and associated with more favourable outcomes. ¹⁷ However, fewer than 20% of T1D patients currently achieve this target with insulin monotherapy. ¹⁸ Additionally, intensive insulin treatment often leads to weight gain, with nearly half of T1D patients being clinically obese. ¹⁹ Increased BMI is associated with a greater cardiometabolic risk and enhanced development of chronic complications. ²⁰ Furthermore, obese patients with T1D often experience insulin resistance, introducing further β‐cell stress. Weight gain increases insulin requirements and hinders weight management, complicating insulin dosing ²¹ and can compromise patient adherence to insulin therapy. ²² Moreover, insulin monotherapy fails to effectively target or prevent disease progression.

There is a persistent and unmet need for adjunctive treatments for T1D that complement insulin therapy, address its challenges, enhance glycaemic control and reduce the frequency of complications. Additionally, there is clear demand for safe and effective disease‐modifying therapies that can either prevent T1D development or halt progression.

Recent research has highlighted the significance of targeting metabolic control for effective disease management and treatment. ² Metabolic interventions, with their direct and indirect effects on β‐cells, offer promising avenues to preserve their function and mitigate destruction. By improving blood sugar control, these interventions can help combat the detrimental effects of glucotoxicity on β‐cells. ²² Moreover, metabolic interventions that reduce oxidative stress contribute to protecting β‐cells from damage, enhancing survival ²³ and strategies to minimize inflammation can indirectly mitigate the autoimmune attack ²⁴ and improve insulin sensitivity. By enhancing the body's ability to utilize insulin effectively, these interventions can help alleviate the β‐cell workload by reducing both biosynthetic and secretion demands. ²⁵ Ultimately, adopting a holistic approach to metabolic interventions in T1D holds promise in preserving β‐cell function and improving long‐term outcomes for individuals with the condition.

Recent clinical trials, systematic reviews and meta‐analyses have explored insulin adjunctive therapies aimed at improving metabolic control in T1D patients. These studies assess treatment success based on primary outcomes such as glycaemic control (HbA1c, fasting glucose, insulin dose, insulin sensitivity and C‐peptide levels), secondary outcomes including non‐glycaemic effects (body mass index [BMI], blood pressure and renal function) and safety measures (hypoglycaemic events, diabetic ketoacidosis [DKA] and major adverse effects). Here, we provide a consolidated and comprehensive overview of the findings and recommendations arising from these analyses, examining a range of metabolic interventions for T1D, including glucagon‐like peptide 1 receptor agonists (GLP1RAs), sodium‐glucose co‐transporter 2 inhibitors (SGLT2i), vitamins and calcium channel blockers (overview in Figure 1). The synthesized conclusions delineate potential future directions in the evolving realm of metabolic treatments and prevention strategies for T1D.

FIGURE 1.

Overview of metabolic interventions as adjuncts to insulin therapy in the treatment of T1D, focusing on their mechanisms of action, benefits, and limitations. GLP‐1 receptor agonists (GLP1RA, e.g. liraglutide, semaglutide) stimulate glucose‐dependent insulin secretion by activating GLP‐1 receptors on β‐cells and enhancing satiety and weight loss through central nervous system (CNS) pathways, thereby improving glycaemic control. Sodium‐glucose co‐transporter 2 inhibitors (SGLT2i, e.g. dapagliflozin) reduce blood glucose by inhibiting glucose reabsorption in the renal proximal tubules, promoting glucose excretion in urine, and lowering insulin requirements. Vitamin D (e.g. cholecalciferol) enhances glucose homeostasis by modulating immune responses and reducing pro‐inflammatory cytokines to improve β‐cell protection through vitamin D receptor (VDR) activation. Vitamin E strengthens antioxidant defences by mitigating oxidative stress and reactive oxygen species (ROS) in β‐cells and contributing to improved insulin sensitivity. Calcium channel blockers (e.g. verapamil) improve glucose regulation by inhibiting L‐type voltage‐dependent calcium channels (VDCC), reducing calcium influx, and downregulating thioredoxin‐interacting protein (TXNIP), a mediator of β‐cell stress and apoptosis.

2. METHODS

A comprehensive literature search was conducted using PubMed to identify relevant studies that focused on insulin‐adjunctive metabolic interventions in individuals with T1D. To ensure relevance to recent developments in T1D management, the search was confined to studies published from January 2000 to September 2024. The search terms included combinations of the following: ‘Type 1 diabetes’, ‘GLP‐1 receptor agonists’, ‘SGLT2 inhibitors’, ‘Vitamin E’, ‘Vitamin D’, ‘Verapamil’, ‘insulin’, ‘adjunctive therapy’, ‘glycemic control’ and ‘β‐cell preservation’. Following the search, titles and abstracts were screened to ensure relevance to the review's focus on insulin‐adjunctive therapies in T1D. Full‐text articles of the selected studies were reviewed to evaluate the quality of evidence. Meta‐analyses, systemic reviews and clinical studies providing insights into clinical outcomes such as glycaemic control or residual β‐cell function (measured through C‐peptide) were prioritized for discussion.

3. METABOLIC INTERVENTIONS

3.1. Glucagon‐like peptide 1 receptor agonists (GLP1RAs)

Incretin hormones are gut‐derived peptides that work to increase insulin secretion in a glucose‐dependent manner. ²⁶ GIP (glucose‐dependent insulinotropic polypeptide) and GLP‐1 are two such incretins released from the intestinal K and L cells, respectively. ²⁶ Together they facilitate the incretin effect: a robust twofold to threefold increase in insulin secretion following oral glucose intake compared with intravenous administration, enabling greater insulin release in response to the same glucose load. ²⁷ In individuals with T1D, this incretin effect is largely diminished. ²⁸ However, in T1D patients with residual β‐cell function, the insulinotropic effects of GLP‐1 can be potentiated pharmacologically by GLP1RAs to aid in reducing plasma glucose levels and enhance glycaemic control. ²⁹

There is a good rationale behind combining insulin with GLP1RA therapy for the treatment of T1D even in those with minimal β‐cell reserve. Firstly, GLP1RAs offer glucose‐lowering effects beyond their insulinotropic actions, suppressing glucagon release and delaying gastric emptying. ³⁰ By stimulating brain receptors, GLP1RAs induce feelings of satiety, which can lead to weight loss. ³¹ This may counteract the weight gain associated with insulin monotherapy and enhance insulin sensitivity, alleviating the workload on β‐cells to preserve functionality. Moreover, given the widespread distribution of GLP1Rs, GLP1RAs exhibit additional benefits, including cardioprotective and renal‐protective effects. ³² For instance, they promote endothelial nitric oxide (NO) production, reduce oxidative stress and exhibit anti‐atherogenic and anti‐inflammatory properties. ³³ These improvements are highly relevant in mitigating the risk of complications and improving overall health outcomes for individuals with T1D, highlighting the potential of GLP1RA‐insulin combination therapy to address various aspects of T1D management comprehensively.

Multiple clinical trials have investigated the effectiveness of GLP1RAs as adjuncts to insulin therapy in patients with T1D. As the results of individual clinical trials can have limited broad applicability and because GLP1RAs vary in structure, dosage, size and pharmacokinetics (including Liraglutide, Exenatide daily, Exenatide ER, Albiglutide and Semaglutide), meta‐analyses serve as valuable tools to consolidate findings. Accordingly, Tan et al. conducted an extensive meta‐analysis on 11 placebo‐controlled randomized trials lasting 26 and 52 weeks, involving 2856 participants with T1D, to explore the efficacy and safety of GLP1RAs as adjuncts to insulin therapy. ³⁴ The analysis revealed several enhancements in the patients' metabolic profiles. Compared with placebo, adjunctive GLP1RA therapy led to reductions in HbA1c (−0.21%; 95% confidence interval [CI], −0.33 to −0.10), weight (−4.04 kg; 95% CI −4.8 to −3.27) and systolic and diastolic blood pressure (−2.57 mmHg and −1.02 mmHg; 95% CI −4.11 to −1.03; −1.99 to −0.06). Additionally, there was a decrease in prandial (−4.23 IU; 95% CI −5.26 to −3.20), basal (−2.40 IU; 95% CI −3.93 to −0.87) and total insulin doses (−5.73 IU; 95% CI −10.61 to −0.86). Furthermore, adjunctive GLP1RA treatment did not increase the incidence of severe hypoglycaemia, DKA, or severe adverse events. However, it did raise the risk of hypoglycaemia and adverse gastrointestinal side effects such as nausea and vomiting. ³⁵ As weight gain from long‐term insulin monotherapy is a primary reason for the failure of intensive insulin therapy to improve the microvascular and macrovascular complications of diabetes, the use of GLP1RAs as an adjunct to insulin therapy may be preferred among patients with T1D. ³⁵ , ³⁶

Regarding the risks of hypoglycaemia associated with GLP1RAs as an insulin adjunct, a recent meta‐analysis by Karakasis et al. evaluated their effects on glycaemic control and continuous glucose monitoring (CGM) metrics in adults with T1D. The meta‐analysis included six RCTs involving 378 individuals with T1D. The addition of GLP1RA was associated with a modest but significant reduction in HbA1c (mean difference −0.21%, 95% CI −0.36 to −0.06; p = 0.007) and a similar time in range (TIR) compared with placebo (mean difference −0.22%, 95% CI −2.39 to 1.95; p = 0.84). ³⁷ While the glycaemic improvements were notable, including a significant reduction in the time above range (mean difference −1.83%, 95% CI −2.51 to −1.15; p < 0.001), GLP1RA therapy was associated with an increased time spent in hypoglycaemia/time below range (mean difference 1.13%, 95% CI 0.50 to 1.76; p < 0.001). The increased time spent in hypoglycaemia raises concerns, as prolonged hypoglycaemia can lead to adverse effects such as anxiety, palpitations, cognitive impairments, psychomotor abnormalities, and in severe cases, seizures and coma. ³⁸ Given these potential risks, careful monitoring is essential for patients using GLP1RAs as an adjunct to insulin. Advancements in CGM technology, including integrated systems with hypoglycaemia alarms and automated insulin delivery adjustments, ³⁹ could tip the risk–benefit profile in favour of GLP1RA therapy by allowing more precise glucose management and timely interventions during hypoglycaemic episodes. Future studies should incorporate these advanced CGM technologies to evaluate whether hypoglycaemia can be effectively controlled in T1D patients receiving GLP1RA adjunctive therapy, potentially enhancing the safety of this approach.

Two major limitations of GLP1RA studies in the T1D population are the lack of studies of GLP1RAs other than liraglutide and of those exceeding 1 year in duration. ³⁵ Tan et al.'s meta‐analysis assessed eight studies on Liraglutide, but only one on Exenatide, Exenatide ER and Albiglutide. Thus, while Liraglutide was the only GLP1RA to significantly improve glycaemic control, the greater number of participants could account for the differences. Efficacy and safety profiles of other GLP1RAs, notably Semaglutide, are essential. The ADJUNCT 1 and 2 trials assessed the efficacy and safety of Liraglutide as an adjunctive insulin therapy in individuals with T1D in multicentered, randomized, double‐blind, placebo‐controlled and 26‐week‐long studies. ADJUNCT 1 broadly enrolled those with T1D already receiving insulin, while ADJUNCT 2 specifically targeted those with T1D with inadequate glycaemic control despite optimized insulin therapy. ⁴⁰ Notably, in both trials, higher doses of Liraglutide led to greater reductions in HbA1c, blood pressure and insulin doses. ⁴¹ However, the glucose‐lowering efficacy tended to diminish over the 52 weeks of treatment, although remaining significant compared with placebo. Thus, data regarding whether the reduction in HbA1c would be sustained after a year of therapy is urgently needed.

Park et al. also conducted a meta‐analysis of 24 randomized controlled trials involving 3377 patients to assess the efficacy and adverse outcomes of GLP1RAs as adjunctive therapy to insulin in T1D. Similarly to Tan et al.'s findings, among the GLP1RAs studied, Liraglutide demonstrated the most substantial evidence, showing significant effects on HbA1c reduction (−0.09%), weight (−2.2 kg) and total daily insulin (−4.32 IU). Notably, Liraglutide dose was identified as the strongest predictor of greater weight loss and insulin dose reduction, although it was associated with a higher likelihood of nausea (OR 6.5; 95% CI 5.0–8.4). ⁴² In contrast to Tan et al., the analysis by Park et al. did identify a significantly greater risk of ketosis with Liraglutide (OR 1.34; 95% CI 1.04–1.79), though this was not considered a severe adverse event based on the author's criteria. ⁴² This remains a debated topic within the field and should be addressed in future trials with additional GLP1RAs such as semaglutide with CGM.

Liraglutide's dose‐dependent reduction in daily insulin requirements and insulin per body weight suggests that the observed improvements in glycaemic control may be linked to mechanisms like appetite suppression and a corresponding reduction in insulin resistance due to weight loss. These mechanisms have been previously observed in patients with Type 2 Diabetes (T2D), ⁴³ indicating a potential shared pathway in insulin sensitivity improvements. Moreover, Park et al. performed a subgroup analysis focusing on newly diagnosed T1D patients and those who were C‐peptide positive. The C‐peptide positive group experienced a greater reduction in HbA1c (−0.51% vs. −0.28% in the general population), with similar improvements in weight loss and insulin requirements. ⁴² This suggests that early initiation of GLP1RA therapy, particularly with Liraglutide, may offer protective benefits in preserving glycaemic control in newly diagnosed individuals, potentially enhancing residual β‐cell function and offering a more favourable metabolic profile in these patients.

Importantly, a recent clinical trial suggested that GLP1RAs may indeed preserve residual β‐cell function in newly diagnosed T1D patients. In a randomized, double‐blind phase 2 trial involving 308 participants with recently diagnosed T1D and residual β‐cell function, von Herrath et al. evaluated the impact of 54 weeks of Liraglutide alone or in combination with anti‐interleukin‐21 (anti‐IL‐21) antibody on T1D progression. ⁴⁴ IL‐21 is a cytokine involved in the regulation of the immune system and inflammation. It has gained attention due to its significant role in the pathogenesis of T1D, as it promotes the activation and expansion of autoreactive T‐cells and facilitates their infiltration into the islets. ⁴⁵ Study participants were matched into four groups: Liraglutide, anti‐IL‐21, Liraglutide+anti‐IL‐21 (combination), or placebo, all while maintaining insulin therapy. Combination treatment resulted in a significantly smaller decline in C‐peptide during the mixed‐meal tolerance test (MMTT) from baseline to week 54 (−10% compared with −39% with placebo). However, this effect was not observed with anti‐IL‐21 or Liraglutide alone. ⁴⁴ As C‐peptide is secreted in equimolar amounts with insulin, ⁴⁶ these results suggest greater preservation of β‐cell function in patients receiving combination therapy. Thus, early initiation of GLP1RAs in combination with immunotherapies could preserve β‐cell function and improve outcomes for newly diagnosed T1D patients, though efficacy and safety need further evaluation in larger phase 3 trials. Additionally, these findings justify exploring the ability of GLP1RAs to delay or prevent T1D onset in high‐risk individuals.

Although most studies of GLP1RAs in T1D have focused on Liraglutide, increasing attention is being directed toward Semaglutide as an adjunctive therapy to insulin for several reasons. In T2D, Semaglutide has demonstrated superior efficacy compared to other GLP1RAs like Liraglutide, notably in reducing HbA1c levels, promoting weight loss and enhancing insulin sensitivity. ⁴⁷ These benefits suggest that Semaglutide could offer similar or even greater improvements in glycaemic control for patients with T1D. One of Semaglutide's key advantages is its longer half‐life, which enables once weekly injections compared with daily injections with liraglutide. ⁴⁸ This extended dosing interval has the potential to enhance patient adherence and satisfaction, ⁴⁸ which is critical for long‐term glycaemic control in T1D, a condition that already requires multiple daily insulin injections or continuous infusion. Moreover, Semaglutide has demonstrated cardioprotective and renoprotective effects in T2D, which are particularly relevant to T1D, where cardiovascular and renal complications are prevalent. ⁴⁹ The potential for Semaglutide to confer these benefits in T1D adds further rationale for its investigation in this population.

Early studies examining Semaglutide in T1D, particularly in overweight and obese patients, show promising results. For instance, a retrospective chart review by Garg et al. followed 50 overweight or obese patients with T1D who were treated with once‐weekly Semaglutide for 1 year, comparing them to a control group of T1D patients. The Semaglutide group experienced significantly greater reductions in BMI (−7.9% ± 2.6%, p < 0.0001) and weight (−15.9 lbs ± 5.4 lbs, p < 0.0001). ⁵⁰ Additionally, Semaglutide treatment was associated with notable improvements in glycaemic parameters, further supporting its potential as an effective adjunctive therapy in T1D ⁴⁵ . Larger, randomized clinical trials are needed to confirm these early findings and fully assess the benefits of Semaglutide in T1D. An ongoing randomized controlled trial (NCT05537233) is currently investigating the effects of Semaglutide in inadequately controlled, obese adults with T1D. These studies will be instrumental in determining whether the clinical benefits of GLP1RAs outweigh their side effects, such as nausea and hypoglycaemic events, and whether the weight loss induced by GLP1RAs can be maintained over extended periods. In addition to assessing the effects of established GLP1RAs like Liraglutide, newer analogues such as Semaglutide warrant further investigation to evaluate their efficacy in the T1D population (NCT0530579). Another critical area for future research is the impact of GLP1RAs on microvascular and macrovascular outcomes, given the high cardiovascular and renal disease burden in T1D (NCT05478707, ACTRN12623001277639). Understanding how GLP1RA therapy influences these long‐term complications will be pivotal in determining their broader role in T1D management.

3.2. Sodium glucose co‐transporter 2 inhibitors (SGLT2i)

Under normal physiological conditions, plasma glucose undergoes filtration in the kidneys and is subsequently reabsorbed into the bloodstream, primarily through sodium‐glucose co‐transporter (SGLT) proteins, including SGLT2, in the proximal tubule of the nephron. ⁵¹ SGLT2i, including Dapagliflozin, Empagliflozin, Canagliflozin and Ertugliflozin, represent a class of oral medications designed to reduce glucose reabsorption at the proximal tubule, leading to increased glucose excretion. ⁵¹ By lowering blood glucose independently of insulin, they alleviate pressure on the β‐cells to maintain glycaemic control and reduce glucose toxicity. Consequently, there is speculation about their potential to assist in achieving glycaemic targets in individuals with T1D. ⁵²

Several large randomized controlled trials have reported benefits of SGLT2i as adjuncts to insulin therapy, yet questions persist regarding their long‐term efficacy and safety. A recent meta‐analysis by Rao et al. systematically reviewed the efficacy and safety of SGLT2i in randomized, double‐blind clinical trials involving patients with T1D. ⁵³ The analysis included 15 trials ranging from 1 to 52 weeks, involving 7109 T1D adults with inadequate glycaemic control on insulin therapy alone (CSII/MDI). The combination of SGLT2i and insulin significantly improved HbA1c (−0.39%; 95% CI −0.43 to −0.35), fasting plasma glucose (−1.15 mmol/L; 95% CI −1.37 to −0.93), total daily insulin dose (−5.83 IU/day; 95% CI −6.62 to −5.04), systolic and diastolic blood pressure (−3.15 mmHg, 95% CI −4.19 to −2.11; −1.59 mmHg, 95% CI −1.98 to −1.2) and body weight (−2.37 kg; 95% CI −2.82 to −1.92) compared with placebo. Additionally, SGLT2i treatment was found to improve glycaemic control by increasing the time in range and by reducing glycaemic variability. ⁵³ The beneficial effects on body weight and blood pressure were proposed as the results of osmotic diuresis and natriuresis. ⁵⁴ The reduction in blood pressure can be particularly beneficial for patients with T1D to reduce their risk of developing cardiovascular and kidney diseases and microvascular complications. ³⁶ A phase 3 clinical trial will specifically test the effects of Sotagliflozin, a dual SGLT1 and 2 inhibitor, for improving outcomes in those with T1D and diabetic kidney disease (NCT06217302).

Although SGLT2i treatment did not show differences in hypoglycaemia or severe hypoglycaemic events, it did lead to a significantly higher rate of ketosis and DKA at 52 weeks. In the absence of sufficient insulin, the body resorts to breaking down lipids for energy, resulting in ketone production. While ketones serve as an alternative fuel source, excessive production acidifies the blood, leading to DKA. ⁵⁵ Untreated, DKA leads to severe complications including cerebral edema, cardiac arrhythmias, hypovolemic shock and even death. ⁵⁵ As DKA is life‐threatening, the risk of developing DKA while taking SGLT2i limits their wide‐spread use as insulin adjuncts in T1D. ⁵⁶

When SGLT2i are used with insulin, insulin doses are often decreased to avoid hypoglycaemia. Therefore, the suggested mechanism underlying SGLT2i‐associated ketosis in T1D involves reduced insulin doses that result in inadequate suppression of lipolysis and ketogenesis, alongside increased glucagon secretion by pancreatic alpha cells as an adaptive or compensatory response to renal glucose loss. ⁵⁷ Evidence also suggests that SGLT2i may directly stimulate glucagon release. ⁵⁸

An extensive meta‐analysis evaluated the risk of DKA associated with SGLT2i treatment in adults with T1D through an analysis of 18 placebo‐controlled randomized clinical trials. ⁵⁶ Using a multivariate meta‐regression model, the study found that the greatest risk of SGLT2i‐associated DKA was explained by a BMI > 27 kg/m², insulin resistance, a higher ratio of insulin dose reduction to baseline insulin sensitivity, and dehydration. Notably, the factors associated with therapeutic effectiveness differed significantly from the risk factors for DKA. This information may enable the targeted use of SGLT2i for individuals with T1D who stand to benefit the most from SGLT2i treatment while minimizing the risk of DKA, thereby optimizing the benefit–risk profile of SGLT2i use in T1D. ⁵⁶

Moreover, if hyperglucagonemia is the driving force behind ketosis with SGLT2i, co‐administration of GLP1RAs or glucagon receptor antagonists (GRAs) could serve as a mitigation strategy. A randomized controlled trial involving 30 patients investigated this triple therapy. Over 12 weeks, Dapagliflozin or placebo was added to those with T1D already receiving Liraglutide and insulin. Addition of Dapagliflozin led to a significant reduction in HbA1c and body weight; however, it also significantly increased urinary and plasma ketone levels. ⁵⁹ A recent randomized, double‐blind, placebo‐controlled crossover trial evaluated the effects of three treatment regiments in 12 adults with T1D: baseline insulin‐only treatment, insulin with Dapagliflozin and insulin with both Dapagliflozin and the GRA Volagidemab. ⁶⁰ After 4 weeks, the percent time with glucose in the target range (70–180 mg/dL) improved with the combination therapy compared with baseline and the SGLT2i alone (86% vs. 70% and 78%, respectively, p < 0.001, p = 0.03). Additionally, peak β‐hydroxybutyrate levels, a marker of ketoacidosis, were lower with the combination therapy than the SGLT2i alone (2.0 vs. 2.4 mmol/L; p = 0.048). ⁶⁰ These findings suggest that glucagon antagonism enhances the therapeutic effects of SGLT2i in T1D while reducing the risk of DKA. Currently, a 52‐week two‐center trial investigating Semaglutide and Dapagliflozin (NCT03899402) is underway to further explore this triple therapy treatment option for T1D.

Furthermore, by reducing glucose toxicity and lowering insulin requirements, SGLT2i create a more favourable metabolic environment that could indirectly support the preservation of residual β‐cell function in T1D. ⁶¹ However, the potential long‐term benefits of SGLT2i in preserving β‐cell function, particularly in newly diagnosed individuals with T1D, remain largely unexplored. Most clinical trials involving SGLT2i as adjunctive therapy in T1D have not focused on newly diagnosed patients, a critical window where interventions might have the greatest impact on β‐cell preservation. Additionally, these studies often do not include measurements of C‐peptide, a key marker of endogenous insulin production and β‐cell activity. Incorporating C‐peptide measurements in future trials would provide crucial insights into whether SGLT2i therapy can extend the period of residual β‐cell function, which is known to correlate with improved glycaemic control and reduced risk of complications. ⁶² Targeting this specific patient population and evaluating β‐cell function markers would significantly advance our understanding of SGLT2i's role in T1D management. Such research could reveal whether SGLT2i, beyond their established metabolic benefits, offer the added advantage of β‐cell preservation, potentially altering the long‐term disease trajectory. This would be an important step toward optimizing T1D treatment, especially for those in the early stages of the disease.

Thus, evidence suggests that adjunctive insulin treatment with SGLT2i improves glycaemic control, body weight and blood pressure and reduces insulin doses without increasing the risks of hypoglycaemia. However, the notable risks of ketosis and DKA remain significant barriers to the widespread clinical adoption of SGLT2i for T1D treatment. Further studies of extended duration and larger sample sizes are necessary to ascertain the long‐term efficacy and safety of this therapy, define the specific patient population that stand to benefit the most from these medications, and investigate the hypothesis that GLP1RAs could potentially mitigate the risks of ketosis associated with SGLT2i treatment.

4. VITAMIN SUPPLEMENTATION

4.1. Vitamin D

Vitamin D is a fat‐soluble vitamin that plays a crucial role in various physiological processes, including bone health, immune function, cell growth and regulation of inflammation. Vitamin D exists in two major forms, including vitamin D₂ (Ergocalciferol) primarily obtained from dietary plant sources and supplements, and vitamin D₃ (Cholecalciferol) synthesized in the skin upon exposure to ultraviolet B radiation from sunlight or obtained from some animal‐based foods. ⁶³ In the body, these inactive forms are metabolized to become biologically active. The active form of vitamin D, calcitriol, binds to widely expressed vitamin D receptors (VDRs). ⁶³ Through VDR binding, calcitriol regulates immune responses, inflammation, growth and other physiological processes.

Vitamin D has been studied for its anti‐inflammatory and immunomodulatory properties that may impact the autoimmune mechanisms underlying T1D. ⁶⁴ In vitro and animal studies have demonstrated that vitamin D can prevent insulitis by reducing β‐cell production of pro‐inflammatory chemokines, acting through immunomodulatory pathways by directly influencing β‐cell VDRs. ⁶⁵ Researchers have also hypothesized that vitamin D's immunomodulatory effects favour Th2 immune responses, which could protect residual β‐cells from insulitis. ⁶⁶ Preclinical research also indicates that vitamin D plays a regulatory role in insulin secretion and β‐cell survival. ⁵³ Additionally, evidence suggests a link between vitamin D deficiency and islet autoimmunity, implying that vitamin D deficiency may contribute to the development of the disease, whereas early vitamin D supplementation could prevent its onset. ⁶⁷ A meta‐analysis of 10 cohort studies revealed that children with T1D had significantly lower serum vitamin D levels than in healthy controls (mean difference −0.60), suggesting that vitamin D supplementation may not only delay disease onset, but deficiency could play a causal role in T1D development. ⁶⁸

Despite extensive evidence from experimental and observational studies supporting the potential beneficial effects of vitamin D in preventing and treating T1D, findings from clinical studies have been inconsistent. Numerous meta‐analyses and systematic reviews exploring the impact of vitamin D supplementation on the risk and treatment of T1D have been conducted. Zipitis and Akobeng, Dong et al. and Hou et al. each performed a meta‐analysis examining the effect of early‐life vitamin D supplementation on the risk of developing T1D, analysing the results of 5, 8 and 15 observational studies, respectively. ⁶⁹ , ⁷⁰ , ⁷¹ They all demonstrated a significant reduction in the risk of T1D among children who received vitamin D supplementation compared with those who did not. However, since the meta‐analyses primarily relied on case–control studies, the absence of control for confounding factors increases the risk of confounding bias.

A recent systemic review aimed to assess the impact of vitamin D supplementation in individuals newly diagnosed with T1D. ⁷² The review included seven randomized controlled trials comprised of 287 individuals recently diagnosed with T1D. Results indicated that vitamin D supplementation (Alphacalcidole and Cholecalciferol) led to a significant decrease in daily insulin dosage and a significant increase in plasma C‐peptide levels. ⁷² Nwosu et al. also explored the impact of vitamin D supplementation on residual β‐cell function in newly diagnosed T1D patients. Their study, a randomized, double‐blind, placebo‐controlled trial, involved 36 recently diagnosed T1D patients who received either vitamin D (Ergocalciferol) or placebo. ⁷³ After 12 months, the group receiving vitamin D showed a significantly lower serum concentration of the proinflammatory cytokine tumour necrosis factor α (TNFα), compared with placebo (1.32 ± 0.03 pg/mL vs. 1.12 ± 0.01 pg/mL, p = 0.03). This supports the notion that vitamin D supplementation could produce anti‐inflammatory effects, potentially protecting residual β‐cells. Although there was not a statistically significant difference in HbA1c between the groups after 12 months (p = 0.09), the placebo group exhibited a faster rate of increase in HbA1c, with a mean rate of change of 0.46% every 3 months, compared with 0.14% in the vitamin D group (p = 0.04). Additionally, the vitamin D group experienced blunted increases in insulin dose adjusted HbA1c over time, with an increase of 0.77 every 3 months with placebo, compared with 0.30 every 3 months in the vitamin D group (p = 0.02). ⁷³ Although C‐peptide concentration was not different, the notably faster rate of increase in HbA1c and insulin dose adjusted HbA1c values in the placebo group suggests a quicker depletion of residual β‐cell function, indicating potential protection of β‐cell function by vitamin D during the honeymoon phase of T1D. ⁷³ Furthermore, these findings might also indicate that vitamin D supplementation mitigates the rise in insulin requirements by enhancing insulin sensitivity. ⁷³ Larger‐scale studies are required to precisely quantify the effect of vitamin D on insulin sensitivity and protection of β‐cell function during the honeymoon phase of T1D.

This ‘honeymoon phase’, or partial clinical remission (CR), occurs shortly after the onset of T1D and the initiation of insulin therapy in approximately two‐thirds of newly diagnosed individuals. ⁷⁴ This transient period, characterized by a significant reduction in exogenous insulin needs and near‐normal glucose control, represents a partial spontaneous remission in T1D. ⁷⁵ The duration of the honeymoon phase varies widely among patients, ⁷⁶ but a prolonged remission period is associated with reduced risks of chronic microvascular complications, ⁷⁷ making this an essential period for targeted research.

A recent study evaluated the effects of combination therapy with vitamin D3 and the dipeptidyl peptidase‐4 inhibitor (DPP‐4i) Sitagliptin on prolonging CR in T1D. DPP‐4is work by blocking the DPP‐4 enzyme which breaks down incretin hormones such as GLP‐1. By inhibiting DPP‐4, Sitagliptin increases endogenous GLP‐1 activity, potentially supporting β‐cell function and glucose regulation. ⁷⁸ Pinheiro et al.'s study used a case–control design with 10 years of data from medical records, analysing 46 newly diagnosed T1D patients, divided into a cases (27 patients with CR at 12 or 24 months) and controls (19 patients without CR at these intervals). Patients who received vitamin D3 and Sitagliptin demonstrated both a higher frequency and longer duration of CR. The odds ratio of achieving CR after 24 months in the Sitagliptin–vitamin D3 group was 9.0 (95% CI 2.21–20.18, p = 0.0036). Notably, insulin‐free CR was achieved by 33.6% and 14.8% of patients in this group at 12 months (mean HbA1c 5.68 ± 0.59%, 95% CI 5.23%–6.14%) and 24 months (mean HbA1c 5.7 ± 0.46%, 95% CI 4.95%–6.44%), respectively, outcomes not observed in those treated with insulin alone. ⁷⁹

These findings suggest that a dual therapy with Sitagliptin and vitamin D3 may extend the honeymoon phase, potentially offering a therapeutic strategy to maintain β‐cell function and improve long‐term glycaemic outcomes in T1D. Combination with pharmacological GLP1RAs Liraglutide or Semaglutide may provide even further metabolic benefit. Future randomized controlled trials are needed to validate these promising results and further explore the mechanisms and clinical benefits of this combination therapy in newly diagnosed patients.

4.2. Vitamin E

Elevated levels of reactive oxygen species (ROS) damage cellular proteins, membrane lipids and nucleic acids and can result in cellular death. Normally, there is a delicate balance between the production of ROS and the protective antioxidant defence mechanisms within cells. However, when this balance is disrupted, oxidative stress occurs, leading to tissue damage. ⁸⁰ A growing body of research suggests that oxidative stress plays a central role in the pathophysiology of T1D. Auto‐reactive T‐cell infiltration into islets and hyperglycaemic episodes can cause the β‐cells to produce more ROS, contributing to β‐cell destruction. ⁸⁰ , ⁸¹ Furthermore, because of their low expression and activity of endogenous antioxidants, β‐cells are especially vulnerable to the cytotoxic damage caused by ROS. ⁸²

Antioxidants work by either scavenging free radicals, donating electrons to stabilize free radicals, or preventing the formation of free radicals. ⁸³ Vitamin E is a clinically relevant antioxidant supplement, well‐tolerated even at high quantities. ⁸⁴ It is exclusively obtained from the diet and is the main lipid‐soluble component of a cell's antioxidant defence system, essential for preventing oxidative damage to cell membranes and lipids. ⁸⁵ Given its safety and antioxidant properties, researchers have explored the potential of vitamin E supplementation for treatment of T1D. ⁸⁵ , ⁸⁶ , ⁸⁷ In a clinical study conducted by Gupta et al., 40 children (20 with T1D and 20 control) received daily doses of 600 mg vitamin E for 3 months. Throughout the study, plasma levels of malondialdehyde (MDA) and glutathione (GSH) were monitored. MDA, a by‐product of fatty acid peroxidation, is increased by elevated free radicals. As such, MDA concentrations serve as indicators of oxidative stress. ⁸⁸ Conversely, GSH is a crucial antioxidant involved in many cellular functions that serves as an indicator of antioxidant capacity. ⁸⁹ At the beginning of the study, the T1D patients had reduced GSH levels and elevated MDA levels compared with the healthy controls. However, after 3 months of vitamin E supplementation, the T1D children experienced a significant decrease in MDA levels and significant increase in GSH levels. This study suggests that vitamin E supplementation strengthens the antioxidant defence system in individuals with T1D. ⁸¹

Clinical trials have also assessed the effectiveness of vitamin E supplementation for T1D management. Recently, Asbaghi et al. conducted a meta‐analysis of randomized controlled trials examining the impact of vitamin E supplementation on glycaemic control in patients with T1D. ⁹⁰ Their subgroup analysis, comprised of seven randomized controlled trials involving T1D patients, revealed that compared with placebo, vitamin E supplementation was well tolerated and significantly reduced HbA1c levels among individuals with T1D (weighted mean difference = −0.76, 95% CI −1.37 to −0.15). The meta‐analysis found vitamin E dosages between 400 and 700 mg/day as most effective for controlling HbA1c. ⁹⁰

In summary, supplementation with vitamins D and/or E could represent promising insulin adjuvant therapies for T1D. Vitamin supplementation could mitigate oxidative stress, inflammation and insulitis, and/or enhance insulin sensitivity, potentially preserving residual β‐cell function and prolonging the honeymoon phase in those newly diagnosed with T1D. However, the lack of large‐scale randomized, placebo‐controlled trials hampers our understanding of the efficacy and safety of these vitamins in preventing or treating T1D effectively. Comprehensive and long‐term randomized controlled trials of high quality are necessary to fully elucidate the role of vitamins D and E in β‐cell function and T1D treatment, both in newly diagnosed individuals and those at risk. With their low cost, accessibility and safety, vitamin D and E supplements continue to represent a promising T1D treatment avenue that could be easily incorporated into clinical practise.

5. VERAPAMIL

Thioredoxin‐interacting protein (TXNIP) is a cellular redox regulator involved in various cellular processes, including oxidative stress, inflammation and apoptosis. Several studies have suggested that β‐cell TXNIP may play a role in the development and progression of T1D. Preclinical studies have shown that high glucose upregulates β‐cell TXNIP, which activates the mitochondrial death pathway, induces inflammation and leads to β‐cell apoptosis. ⁹¹ , ⁹² Its deletion promotes β‐cell survival and confers protection against diabetes. ⁹³ TXNIP inhibition has also been found to promote insulin secretion and GLP‐1 signalling via regulation of microRNAs. ⁹² Verapamil, a calcium channel blocker clinically approved for the prevention of cardiac arrythmias and hypertension, has been found to effectively reduce TXNIP. ⁹⁴ Pre‐clinical T1D studies indicate that Verapamil decreases TXNIP expression, treats inflammation, improves insulin sensitivity and decreases β‐cell apoptosis, suggesting its use for preserving β‐cell function. ⁹³ , ⁹⁵

Studies have demonstrated that even small amounts of retained endogenous insulin production have significant benefits in managing glycaemic control, reducing insulin requirements, preventing complications and improving outcomes in T1D. ³⁷ As such, randomized placebo‐controlled trials have investigated the effects of Verapamil as an adjunct to insulin therapy in both children and adults with newly diagnosed T1D. ⁹⁶ , ⁹⁷ Forlenza et al. conducted a randomized clinical trial on 88 children and adolescents aged 7–17 with newly diagnosed T1D. ⁹⁶ Participants were randomly assigned to receive once‐daily oral Verapamil (n = 47) or placebo (n = 41) for 52 weeks. The primary outcome measured was the area under the curve (AUC) for C‐peptide levels assessed using a MMTT. The Verapamil group experienced no significant decline in mean C‐peptide AUC over the 52‐week treatment period (0.66 pmol/mL baseline and 0.65 pmol/mL at 52 weeks), compared with 0.60 pmol/mL at baseline and 0.44 pmol/mL at 52 weeks in the placebo group, representing a 30% higher C‐peptide AUC with Verapamil treatment. ⁹⁶ One limitation is that the baseline C‐peptide AUCs were already higher in the Verapamil group. Ovalle et al. similarly conducted a 52‐week randomized double‐blind placebo‐controlled clinical trial exploring the effects of Verapamil treatment in 24 adults with recent‐onset T1D. Consistently, C‐peptide AUC levels measured during an MMTT at 52 weeks were 35% higher with Verapamil treatment compared with placebo. Additionally, Verapamil was associated with reduced exogenous insulin dose requirements and fewer hypoglycaemic events compared with placebo. ⁹⁷ A recent meta‐analysis conducted by Dutta et al. evaluated the efficacy and safety of Verapamil in preserving β‐cell function by analysing the results of both clinical trials. ⁹⁸ The meta‐analysis revealed that 1‐year Verapamil treatment, compared with placebo, led to significant enhancements in C‐peptide secretion in children and adults newly diagnosed with T1D (mean difference +0.27 nmol/L; 95% CI 0.19–0.35). However, no significant changes in HbA1c levels were observed. Verapamil was also well tolerated, with no notable increases in serious adverse events, including severe hypoglycaemia or blood pressure changes. ⁹⁸

To gain further insights, Xu et al. conducted a follow‐up investigation on the cohort from Ovalle et al.'s clinical trial. ⁹⁷ , ⁹⁹ In this study, participants who received Verapamil during the first year after diagnosis either continued the treatment for an additional year or discontinued after the initial 1‐year period. These individuals were compared with control participants who never received Verapamil. Over the 2‐year period, C‐peptide AUC remained stable in the subjects who received Verapamil, whereas it continued to decline in the control group. Additionally, discontinuation of Verapamil led to a sharp drop in C‐peptide AUC during the second‐year post‐diagnosis. ⁹⁹ Daily insulin dose remained consistently low throughout the 2‐year period with Verapamil treatment but continuously rose in the control group. Cessation of Verapamil also resulted in a significant increase in insulin requirements during the second year. These findings underscore the long‐term benefit of continuous Verapamil treatment in preserving residual β‐cell function, sustaining endogenous insulin production and mitigating exogenous insulin needs, slowing progression of the disease.

Overall, with its metabolic benefits, good safety profile, tolerability and low cost of therapy, once‐daily oral Verapamil presents a promising option for maintaining β‐cell function and preserving endogenous insulin production in individuals newly diagnosed with T1D. ⁹⁸ When incorporated into standard insulin therapy, Verapamil treatment may offer a safe and effective means of halting disease progression. However, as both clinical trials included small sample sizes, larger and longer‐term studies are imperative to verify Verapamil's clinical efficacy and safety. Furthermore, considering the evidence from animal models demonstrating Verapamil's capacity to enhance functional β‐cell mass and prevent overt diabetes, ¹⁰⁰ clinical investigations should explore its potential for preventing or delaying T1D onset in at‐risk individuals.

6. CONCLUSIONS

Despite being the cornerstone of T1D management, insulin therapy presents several challenges such as hypoglycaemic episodes, weight gain and the inability to halt disease progression. Here, we highlight the significance of adjunctive metabolic‐based treatments to address the challenges associated with insulin monotherapy and improve glycaemic control. By reducing glucose toxicity, mitigating oxidative stress and inflammation, improving insulin sensitivity and reducing the autoimmune response, metabolic interventions, such as GLP1RAs, SGLT2i, vitamins D and E and Verapamil hold additional potential to improve the health and function of β‐cells. By protecting residual β‐cell function and improving glycaemic control, those with T1D can reduce risks of complications and improve overall metabolic health, reducing disease burden and improving quality of life.

Combining GLP1RAs with insulin offers notable benefits, including enhanced TIR, reduced insulin dosage and weight loss, all without increasing the risk of severe adverse effects. Further exploration of optimal dosing regimens, effects of different formulations (e.g. Semaglutide) and effectiveness beyond 1 year is necessary. Additionally, some concerns have been raised regarding increased time in hypoglycaemia and increased risk of ketosis, particularly with Liraglutide treatment. With the increasing clinical use of Semaglutide, it is imperative that future studies address these concerns, ideally including CGM as part of their study design. Similarly, SGLT2i have emerged as potential adjuncts to insulin showing improvements in glycaemic control and insulin requirements, while providing additional cardiovascular, renal and microvascular benefits from blood pressure reduction. However, concerns regarding the risk of DKA highlight the importance of careful patient selection and monitoring. Given that the risk of DKA is associated with higher BMI, combined therapies with GLP1RAs may have additional protective effects through contributing to substantial weight loss.

Integrating vitamin therapies into the management of T1D may hold promise for improving outcomes. Vitamin D, recognized for its anti‐inflammatory and immunomodulatory properties, may enhance β‐cell survival and prolong the honeymoon phase. Although some studies have demonstrated notable benefits of vitamin D supplementation, such as increased C‐peptide levels and reduced insulin requirements in individuals newly diagnosed with T1D, larger randomized controlled trials are required to confirm these findings and establish the efficacy of vitamin D supplementation in clinical practise for recent‐onset T1D. Similarly, vitamin E, with its antioxidant properties, has gained interest for its ability to alleviate oxidative stress, a key player in T1D pathogenesis. While clinical trials have indicated the vitamin E supplementation can improve glycaemic control, further research through larger and longer‐term studies is necessary to clarify the role and effectiveness of vitamin E supplementation in managing T1D. Additionally, the full therapeutic potential of these interventions may be realized through combination therapies with GLP1RAs and/or SGTLT2i. Given promising findings with vitamin D and DPP‐4i combination therapy, pharmacological activation of the GLP1R may have a more profound impact.

Over the past few decades, a variety of approaches have aimed to preserve C‐peptide secretion. Recent clinical trials have demonstrated that metabolic adjunctive therapies, such as Verapamil, can significantly improve residual β‐cell function, evidenced by increased C‐peptide levels and reduced insulin dependency. Importantly, the sustained benefits of Verapamil treatment in slowing disease progression highlight its potential as a safe and effective approach for managing T1D. This area of study, including alternative approaches to decreasing β‐cell TXNIP expression, is in its infancy and supported by a limited number of studies. Therefore, future research is needed to optimize these treatments, explore effects in larger and more diverse cohorts, and establish their long‐term efficacy and safety in T1D management.

Understanding how individuals living with T1D experience these metabolic interventions is crucial, as it could reveal whether these therapies improve overall treatment satisfaction or help reduce the challenges associated with managing diabetes. Unfortunately, the studies included in our review did not capture these patient‐reported outcomes (PROs), leaving an important knowledge gap about patient preferences. For instance, long‐term tolerability of common side effects, such as nausea or transient hypoglycaemic episodes associated with GLP1RAs, remains unclear. Incorporating PROs into future research will be essential for creating a more holistic view of these interventions, informing patients about the likely impacts on their quality of life, facilitating shared decision‐making and helping clinicians monitor outcomes to refine care. ¹⁰¹ Therefore, we advocate for the inclusion of PROs in upcoming RCTs to ensure a more comprehensive assessment of intervention impact. Additionally, our review was limited in its ability to address potential differences in intervention efficacy based on sex or ethnicity. Most of these RCTs have been performed in North American or Western European populations and are limited to populations with access to clinical trial centers. Both sex and ethnicity are crucial for ensuring that treatments are effective and equitable across diverse populations, and these variables require greater focus in future studies. Addressing these gaps will be pivotal for advancing metabolic adjunctive therapies in T1D management and optimizing treatment strategies that cater to the unique needs of all individuals with T1D.

In conclusion, the adoption of metabolic‐based interventions alongside insulin therapy holds strong promise for advancing T1D treatment by addressing the significant limitations of traditional insulin monotherapy. These adjunctive therapies offer novel pathways to improve glycaemic control and reduce insulin requirements, while also holding potential to delay or even halt disease progression by preserving residual β‐cell function. This capacity to modify disease trajectory is particularly impactful for individuals at risk or those recently diagnosed with T1D.

AUTHOR CONTRIBUTIONS

JP wrote and revised the manuscript. KJP conceived the idea, illustrated the figures and revised the manuscript.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

PEER REVIEW

The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer‐review/10.1111/dom.16154.

Podobnik J, Prentice KJ. Metabolic interventions as adjunctive therapies to insulin in type 1 diabetes: Current clinical landscape and perspectives. Diabetes Obes Metab. 2025;27(3):1032‐1044. doi: 10.1111/dom.16154

DATA AVAILABILITY STATEMENT

There is no primary data associated with this narrative review.