Registered clinical trials targeting type 2 diabetes remission with pharmacological interventions.

Introduction

T2D is an increasingly significant public health concern with a prevalence of 10.5% (537 million adults) in 2021, projected to rise by 46% to 783 million adults by 20451. It is traditionally managed as a chronic, progressive disease with irreversible pancreatic beta-cell failure, aiming for glycemic and metabolic control to prevent short and long-term complications. Treatment options for the disease and its sequelae include dietary change, physical activity, metabolic surgery, bariatric endoscopy, and pharmacological interventions. T2D and its complications come with a high economic cost, projected to increase to $2.2 trillion or 2.2% of global GDP by 20302. This and the quality of life burden have shifted the care pathway towards a goal of T2D remission i.e. the reversal of the disease, achieving non-diabetic glycated hemoglobin (HbA1c) and/or oral glucose tolerance test (OGTT) results without the use of blood glucose-lowering medications for at least 3 months3.

Systematic reviews with meta-analyses suggest that patients adhering to dietary interventions had a higher rate of T2D remission compared to those who did not4,5, leading to improved beta-cell function and hepatic insulin sensitivity, increased suppression of hepatic glucose output and increased first-phase insulin response6, especially for patients within the first 6 years of diagnosis7. There is also evidence that metabolic surgery can increase the likelihood of achieving T2D remission for up to 5 years8 and that it can be more effective than pharmacological and lifestyle interventions9,10. Studies have shown up to 34.9–37.5% of patients undergoing metabolic surgery achieve complete remission depending on criteria, either HbA1c ≤ 6.5% (48 mmol/mol)9 or HbA1c < 6% (42 mmol/mol)11, at 36–50 months follow-up.

Comparatively, less data exists on the impact of pharmacological interventions targeting T2D remission. Short-term intensive insulin therapy can improve beta-cell function, increase insulin sensitivity, and reduce hepatic insulin resistance12, increasing the chances of achieving T2D remission weeks or months after treatment is ceased13 compared to treatment with oral hypoglycemic agents alone14,15. Although studies have suggested improved rates of remission with a combination of insulin and oral hypoglycemic agents, they lacked statistical significance to support these conclusions16,17. Evaluation of pharmacological intervention studies in T2D remission is lacking and a summary of clinical trials in this space is required.

Here, we search clinical trial registries and conduct a systematic mapping of registered randomized clinical trials (RCTs) in T2D remission-focused pharmacological interventions: to identify their main features, summarize the registered trials to date, and guide future research in this space.

Methods

Protocol and registration

This is a systematic mapping of registered RCTs investigating pharmacological interventions for T2D remission from clinical trial registry inception to 19th March 2024. The protocol was registered with the International Prospective Register of systematic reviews (PROSPERO CRD42024511198).

Eligibility criteria

We included RCTs registrations: (1) registered in English, (2) reviewing an adult population with T2D, (3) who included at least one pharmacological intervention and (4) aimed to assess T2D remission via a non-diabetic HbA1c, normal oral glucose tolerance test (OGTT) result and/or measurement of normalized beta-cell function off pharmacological treatment. Trials were only included if they measured remission after ceasing pharmacological treatment.

Trials were excluded if they met the following criteria: (1) non-randomized design, (2) included participants with type 1 or autoimmune diabetes mellitus, prediabetes, impaired glucose tolerance, gestational diabetes, individuals under the age of 18, or pregnant women, and (3) studies that solely assessed dietary or surgical interventions.

Search strategy and selection process

We conducted searches of three clinical trial registries: Clinicaltrials.gov, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), and the European Union Clinical Trials Information System (EU-CTIS). Clinical trials in the European Union are currently in the process of a 3-year transition period from the EU Clinical Trials Register (EUCTR) to the EU-CTIS to abide by clinical trials regulations. For our study, we included current EU-CTIS trials and pre-2022 EUCTR trials. We focused on the two key concepts of ‘T2D mellitus’ and ‘remission’ and included synonyms in our searches18. We included trials from all dates, regardless of trial and publication status. For Clinicaltrials.gov we searched: (1) ‘type 2 diabetes remission’, (2) ‘type 2 diabetes mellitus’ AND ‘remission’, (3) ‘type 2 diabetes mellitus’ AND ‘remission’ as an outcome, (4) ‘type 2 diabetes mellitus’ AND ‘reversal’ as an outcome and (5) ‘type 2 diabetes mellitus’ AND ‘beta cell function’ as an outcome. For the WHO ICTRP, we searched (1) ‘type 2 diabetes remission’, (2) ‘type 2 diabetes reversal’ and (3) ‘type 2 diabetes beta cell function’. Finally, given the smaller sized EU-CTIS/EUCTR database, and lack of results when using the previous search terms, we used a broad search term of ‘diabetes’.

As per recommendations for searching clinical trial registers18 one reviewer (NS) independently reviewed each trial; first by removing duplicate records, then screening trial titles to exclude irrelevant records, and finally full record screening to select registered trials that met pre-specified eligibility criteria. Selected trials were independently reviewed by a second reviewer (NR) to ensure they were appropriately selected and any discrepancies were resolved by consensus with a third reviewer (SC).

Data collection and extraction

Once registered trials were deemed eligible and selected for inclusion, a data extraction form was used including trial ID, funding source, year of registration, location, center, trial status, completion date (if applicable), study design, sample size, interventions, comparators, outcomes and follow-up time. In all trials, pharmacological treatment was ceased before measuring for remission. Follow-up time was defined as the first follow-up off pharmacological treatment; it should be noted that some trials measured remission with multiple follow-ups. The funding source was distinguished by assigning an industry label for pharmaceutical or private companies and a non-industry label for hospital or government-funded trials. The eligibility criteria for individuals in each trial were also extracted and included parameters such as participant body mass index (BMI), HbA1c, time since T2D diagnosis, and age. Finally, we searched for trials that reached completion and published results by utilizing the clinical trial number and author name in searches of PubMed and Google Scholar.

Statistical analysis

All statistical analyses were conducted using Microsoft® Excel for Mac Version 16.65. Continuous variables such as sample size are expressed as median (interquartile range[IQR]) and categorical variables will be shown as frequencies with percentages.

Data visualization

We present the trial and population characteristics including the type of funding, geographical location, and interventions used.

Results

Systematic literature search

Our search of three clinical trial registries and the trial selection process is represented in Fig. 1: a total of 1108 results were yielded, of these 296 were duplicates, and 778 were excluded as they did not fit our predefined eligibility criteria. In total, 34 clinical trial registrations were included in our final analysis (Online Resource Table 1). For clinical trial registry search results, there were 86 duplicate results between Clinicaltrials.gov and WHO ICTRP, and one duplicate result between Clinicaltrials.gov and EU-CTIS. There were no duplicate results between the WHO ICTRP and EU-CTIS registry (Online Resource Fig. 1).Fig. 1Literature search and selection process flowchart.Table 1Trial characteristics.Trial characteristics (N = 34)No. (%)FundingNon-Industry24 (70.6%)Industry10 (29.4%)CenterSingle23 (67.6%)Multi9 (26.5%)Unknown2 (5.9%)Year of registration2000–20041 (2.9%)2005–20095 (14.7%)2010–201412 (35.3%)2015–201912 (35.3%)2020—Current4 (11.8%)LocationAsia22 (64.7%)North America8 (23.5%)Europe4 (11.8%)Africa-Oceania-South America-T2DM DiagnosisNewly diagnosed15 (44.1%)Within 1 year6 (17.6%)Within 1–6 years9 (26.5%)> 6 years2 (5.9%)Not reported1 (2.9%)Other1 (2.9%)BMI range included18.5–24.9 kg/m221 (61.8%)25–29.9 kg/m226 (76.5%)> 30 kg/m226 (76.5%)Not reported7 (20.6%)HbA1c minimum for inclusion < 6.5% (48 mmol/mol)1 (2.9%)6.5–7% (48–53 mmol/mol)5 (14.7%)7.1–8% (54–64 mmol/mol)4 (11.8%)More than 8%6 (17.6%)Only uses FPG criteria5 (14.7%)Different criteria dependent on treatment8 (23.5%)Not reported4 (11.8%)Other1 (2.9%)

Literature search and selection process flowchart.

Trial characteristics.

Trial characteristics

Of the 34 eligible trial registrations identified, the majority were non-industry funded (70.6%, n = 24), 67.6% (n = 23) were single-center trials and 70.6% (n = 24) were registered between 2010–2019 (Table 1). Online Resource Fig. 2 displays the number of trials registered by year and the proportion of industry and non-industry-funded trials. Geographically, 64.7% (n = 22) of the trials were registered in Asia (Fig. 2) and the median sample size of all trials was 146[87.3–207.5].Fig. 2Trials registered around the world.

Trials registered around the world.

Eligibility criteria and target populations

Table 1 displays the characteristics of the eligible clinical trials, including their target population and inclusion criteria. Newly diagnosed T2D was the highest targeted demographic making up 44.1% (n = 15) of trials. In total, 88.2% (n = 30) of trials registered to investigate a population within 6 years of diagnosis. The trials included a range of participant BMIs, though 20.6% (n = 7) did not report any BMI eligibility criteria (Online Resource Table 1). HbA1c criteria for inclusion in trials also varied, with 44.1% (n = 15) of trials including participants with a minimum HbA1c of ≥ 6.5% (48 mmol/mol). The remainder had differing criteria including fasting plasma glucose (FPG) levels or varying HbA1c thresholds based on treatment at the time of expected study inclusion. For trials that registered and defined inclusion age criteria, the median minimum age was 22.5 years [IQR 18-30] and the median maximum age was 70 years [IQR 65–75] (Online Resource Table 1).

Treatments/interventions

As their primary intervention, 55.9% (n = 19) of trials registered pharmacological combination therapy, with the remaining 44.1% (n = 15) of trials aimed at pharmacological monotherapy (Table 2). In the 19 trials that registered combination therapy, the three most commonly used drugs were metformin, insulin, and a glucagon-like peptide 1 (GLP-1) agonist (Online Resource Table 2). The frequency and combinations of registered interventions are represented as a network diagram in Fig. 3. Of the 15 monotherapy trials, the majority (66.7%, n = 10) targeted insulin use (Online Resource Table 2).Table 2Trial interventions, outcomes, current and publication status.Primary intervention usedPharmacological combination therapy19 (55.9%)Monotherapy15 (44.1%)Insulin usedTotal number of trials where insulin was used21 (61.8%)Subcutaneous injectable insulin12 (35.3%)Insulin pump/CSII9 (26.5%)ComparatorPharmacological combination therapy12 (35.3%)Subcutaneous injectable insulin monotherapy8 (23.5%)Standard care5 (14.7%)Placebo5 (14.7%)Metformin monotherapy2 (5.9%)CSII monotherapy1 (2.9%)Lifestyle interventions1 (2.9%)Primary outcomeHbA1c minimum cut-off6 (17.6%)< 6.0% (42 mmol/mol)–< 6.5% (48 mmol/mol)4 (11.8%)< 7% (53 mmol/mol)1 (2.9%)Combination of HbA1c and FPG criteria2 (5.9%)Beta-cell function6 (17.6%)Time to diabetes relapse4 (11.8%)Normal OGTT1 (2.9%)Specific criteria not reported12 (35.3%)Not investigated4 (11.8%)Secondary outcomeHbA1c minimum cut-off3 (8.8%)< 6.0% (42 mmol/mol)1 (2.9%)< 6.5% (48 mmol/mol)1 (2.9%)< 7% (53 mmol/mol)1 (2.9%)Combination of HbA1c and FPG criteria–Beta-cell function14 (41.2%)Time to diabetes relapse1 (2.9%)Normal OGTT1 (2.9%)Specific criteria not reported3 (8.8%)Not investigated12 (35.3%)Trial statusCompleted15 (44.1%)Active11 (32.4%)Unknown7 (20.6%)Suspended1 (2.9%)Study publicationPublished13 (38.2%)North America6 (17.6%)Asia4 (11.8%)Europe3 (8.8%)Not Published21 (61.8%)Fig. 3A network representation of the combination treatments used: nodes represent drugs and edges represent how drugs were combined as a primary intervention in the trials.

Trial interventions, outcomes, current and publication status.

A network representation of the combination treatments used: nodes represent drugs and edges represent how drugs were combined as a primary intervention in the trials.

Insulin was registered as a primary intervention in 61.8% (n = 21) of trials, with 29.4% (n = 10) of trials registering it as a monotherapy (Online Resource Table 2). Regarding mode of delivery, subcutaneous injectable insulin use was registered in 35.3% (n = 12) of trials and an insulin pump/continuous subcutaneous insulin infusion (CSII) in 26.5% (n = 9) of trials (Table 2).

The most common comparator was pharmacological combination therapy, in 35.3% (n = 12) of trials, followed by subcutaneous injectable insulin monotherapy in 23.5% (n = 8) of trials (Table 2).

Outcomes studied

Table 2 displays the varying ways trials looked to measure T2D remission as a primary and/or secondary outcome. Trials aimed to evaluate remission in different ways including different HbA1c cut-offs, fasting plasma glucose levels, a combination of both, a normal oral glucose tolerance test (OGTT) or assessment of beta-cell function. Some did not publish the specific criteria to be used to measure remission or evaluated time to diabetes relapse. Detailed description of planned remission assessment via beta-cell function varied between trials, with some only referring to measuring “beta-cell function” and others providing explanations including measurement via arginine-stimulated first phase insulin secretion, insulin sensitivity measured via hyperglycemic clamp or measurement of insulin response to a meal test. Online Resource Table 1 displays the various ways beta-cell function was measured and the different registered definitions used by each trial to determine remission in both primary and secondary outcomes.

Evaluating remission as a primary outcome occurred in 88.2% (n = 30) of trials, though the majority of trials (35.3%, n = 12) did not define specific criteria and methods of measurement used to determine remission in the registration. As a secondary outcome, 64.7% (n = 22) of the trials evaluated remission and the majority (41.2%, n = 14) of trials aimed to assess beta-cell function. The median registered time for the first follow-up of outcomes after ceasing pharmacological treatment was 20 weeks[12–52]. Seven trials did not report any specific follow-up time and two trials measured remission before the recommended 3 months off pharmacological treatment.

Study completion and publication

In total, 44.1% (n = 15) of trials have updated the registry as being complete (Table 2). The proportion of trials reaching completion was higher in industry-funded trials compared to non-industry-funded trials: with 80% (n = 8) of industry-funded trials reaching completion compared to 29.2% (n = 7) of non-industry-funded trials. (Online Resource Fig. 3). In total, 38.2% (n = 13) of trials have published their results. Three (15.8%) of the trials still displayed as incomplete on the registry have published their results in a journal. Two of the completed trials (13.3%) did not proceed with journal publication and another completed trial had a registered completion date that was later in time than the publication date. When reviewing studies that registered primary completion dates and proceeded to publish their findings (n = 9), the median time from registered completion to journal publication was 27 months[IQR 20–34] (Table 2).

Discussion

We searched three clinical trial registries and presented the first systematic mapping of registered RCTs of pharmacological interventions in T2D remission: displaying trends in previous research, the need for transparency and updating of the registries, and suggestions for areas of future research.

There is a shift in the care pathway of T2D towards a goal of remission. Research in metabolic surgery, its effect on obesity-related disease, and its role in glucose homeostasis, insulin resistance, and beta-cell function, continues to grow19. Published consensus recommendations have suggested that T2D remission is achievable through lifestyle interventions; a combination of medical nutrition therapy, physical activity, and psychological support20. The DiRECT trial, an evidence-based weight management program, achieved remission for 46% of patients at 12 months and 36% of patients at 24 months7. Unfortunately, an extension study found this remission rate reduced to 13% at 5 years21, highlighting a need for other sustainable management options.

Our study shows that the majority of registered trials reviewed patients with newly diagnosed T2D, targeting patients before they have progressive deterioration in their pancreatic β-cell function22,23 and where β-cell function and mass may be reversible24. The majority of trials aimed to investigate T2D remission in patients within 6 years of diagnosis; in keeping with the DiRECT trial’s findings that remission should be targeted for all patients within this timeframe and with a higher success rate for those with a lower baseline HbA1c7. The lack of trials including patients with well-established T2D suggests ongoing concern about the reversibility of the β-cell disease process, even with increasing evidence of reversibility in some populations25 from pharmacological means alone. The trials we have selected included participants with BMI in the normal (18.5–24.9 kg/m2), overweight (25–29.9 kg/m2), and obesity (30 kg/m2 and above) ranges; accurately reflecting the 80–90% of people with T2D who are living with overweight or obesity26 and allowing for improved external validity of results.

We searched for clinical trial registries from inception, with the earliest registered trial dating back to 2004. As such, available pharmacological interventions have changed through the years as research and clinical evidence have advanced. The majority of trials have targeted the use of a combination of pharmacological therapies as their primary intervention; most commonly metformin, insulin, and GLP-1 agonists. In keeping with previous findings suggesting insulin’s role in the recovery of beta-cell function and T2D remission12,13, the majority of trials included insulin in their primary intervention. Of note, four of the seven trials conducted since 2019 included insulin as a primary intervention and of these, three used a short-term intensive insulin regimen. Though insulin has been registered for use in 61.8% of trials, the trend of pharmacological interventions used indicates that there has been a shift away from using insulin monotherapy or for prolonged periods when researching diabetes remission. Since 2019 only one trial has used insulin monotherapy, compared to the nine trials prior. This is likely due to its role in inhibiting lipolysis and promoting lipogenesis, with subsequent weight gain and increased insulin resistance27. In comparison, there has been little use of DPP4 inhibitors, sulfonylureas, and SGLT2-inhibitors, and no registrations of trials reviewing the newer glucose-dependent insulinotropic polypeptide (GIP) analogs. This was something we had expected due to the recency of some of these medications. As previous research has shown that achieving weight loss earlier in the course of T2D increases the chances of achieving remission28 the use of GLP-1 receptor agonists and newer dual agonists that include GIP analogues may have a role29,30. Though they have seen increased clinical use in recent years for the treatment of T2D, only two trials since 2019 have used a GLP-1 receptor agonist to target remission: liraglutide in 2019 and oral semaglutide in 2022. This class of drugs should be assessed in future studies for their potential role in T2D remission. Further, individuals may achieve remission with ≥ 10% or ≥ 10 kg weight loss7 which is a feasible goal with the use of GLP-1 receptor agonists and GIP analogs in patients living with overweight or obesity30–32; though the issue of regaining lost weight after withdrawal of treatment33,34 continues to be a complex paradox of using pharmacological interventions to achieve diabetes remission. This paradox may be the limiting factor in the number of future trials that will measure diabetes remission on these agents. This needs to be investigated further to ascertain whether early or first-line use of these newer agents may have a role in achieving type 2 diabetes remission: for example, in newly diagnosed patients where weight loss and preservation of endogenous pancreatic function may play a role. If trials are able to establish that remission is truly not achievable in these patients then a discussion needs to be considered to shift the goal from remission, back to achieving normoglycaemia, beta-cell function, and optimization of metabolic health on treatment and potentially looking at reaching this goal on monotherapy.

Historically, there have been differences in the way clinicians and researchers defined remission and this lack of consistency and standard definition makes comparison of results difficult. In present times, a consensus has provided a standardized definition of remission: recommending an HbA1c < 6.5% (48 mmol/mol) after three months off antidiabetic drugs35. Twenty-five of the trials included in our study measured remission a minimum of three months off treatment. Two trials measured remission prior to this, with one measuring remission after four weeks and another measuring two months off pharmacological treatment; it should be noted that both these trials were registered and started prior to the published consensus report35. Seven trials did not report how long after ceasing treatment they measured remission, the majority of these from the Chinese Clinical Trial Register (ChiCTR) where follow-up time was not listed in the registry. Future studies adopting the current consensus definition of remission would allow for improved comparison of trial results and add strength to future systematic reviews in the field. In our study, only four trials explicitly stated that the current accepted criteria for remission were investigated as their primary outcome. Furthermore, follow-up time should be extended to investigate the sustainability of results: allowing for long-term comparison between dietary, pharmacological, and surgical interventions and assessing the economic and quality of life impact of these treatments at an individual and population level. There was a lack of uniformity in how trials aimed to measure remission as an outcome, either through varying HbA1c cut-offs and fasting plasma glucose levels, normal OGTT results, or lack of registering any specific criteria at all. Though not a direct measurement of remission, there was also a lack of consistency in how beta-cell function was measured, with some trials registering specific methods involving mixed meal tests or hyperglycemic clamps, and others providing no criteria whatsoever. If we consider the normalization of beta-cell function as a measurement of diabetes remission, we would also suggest standardizing the measurement of beta-cell function in both methods used and biochemical parameters assessed, as well as a clear description of these when registering trials. Future trials could consider using OGTT measuring glucose and insulin levels as a measure of beta-cell function as this is less difficult and requires less resources than glycemic clamps, allowing easier standardization across trials. Based on previous studies, improvement in first-phase insulin secretion has been correlated with a return to a pancreas volume and morphology similar to that of people without diabetes36. As such, we also aimed to include studies using an outcome of radiological change in pancreatic size or morphology; though were unable to find any that fit the eligibility criteria.

Geographically, Asia had the most registered clinical trials, making this the most active area of research. Though they had the highest number of registered RCTs, only 18.2% (n = 4) went on to journal publication. This is in contrast to North American and European trials, of which 75% (n = 6 and n = 4 respectively) were published. It is important that research continues across diverse populations and geographic areas as the prevalence of different sub-classifications of T2D37, and their response to treatment, may differ. Results of research across different populations would allow comparison of findings, identification of responses by sub-classification and potentiate further improvements in precision medicine. To investigate for potential publication and reporting bias, we assigned industry vs. non-industry labels to trials according to their lead sponsor. Gresham et al. have demonstrated that industry-funded trials have the highest completion rate and the shortest median completion times38. Our findings align with this trend, as the non-industry-funded trials had a lower completion rate compared to industry-funded trials. In the article, Gresham et al. also recommended the improvement of registration systems to include a specific data element for funding sources in Clinicaltrials.gov. As funding sources has been demonstrated to have an impact on trial completion, we would suggest the same improvements be extended to other registries. There are also other key data elements of registries could be improved; for example, trials listed on the WHO ICTRP from the ChiCTR did not report a follow-up period to measure their outcomes. As such, it was not possible to ascertain whether the trial follow-up timeframe was in line with current recommendations to measure diabetes remission after three months off treatment. It is unclear if this is due to a lack of compulsory requirements for entering these details when registering for a trial. We suggest enforcing mandatory input of this data across all trial registries for improved standardization, transparency, adherence to protocol and reduced reporting bias.

In regards to transparency, it is important that registered trials have timely updating and the full involvement of the research team throughout the trial to reduce biased results39. Our findings suggest there is poor updating of clinical trial registries: three trials have not updated their status as complete but have gone on to journal publication, and another trial with a registry completion date 35 months after publication. In addition, multiple trials with an unknown progress status, as well as an active trial, were registered as far back as 2011. There were two trials registered as completed in March and July 2023, which remain unpublished. Given the median time of 27 months between trial completion and publication, these may still be in the process of writing. Nonetheless, they are non-compliant with requirements to publish results within 12 months of completion; a common finding among registered clinical trials that remains an issue to this day40.

Our study focuses on RCTs only, a choice made based on their strength in the pyramid of evidence and the aim to support clinical decision-making with high levels of evidence. One of the limitations of our study is that we are restricted by the timeliness of updates and the availability of registry data provided by researchers. We can only extract the most recently registered data, some of which has not been updated for years. This could lead to discrepancies and may not accurately reflect research methods or deviations from initially registered protocols.

In conclusion, our systematic mapping summarizes the previous and existing registered clinical trials reviewing pharmacological interventions in T2D remission. We suggest future clinical trials use a standardized and consistent definition of T2D remission and beta-cell function measurement across trials. Examining T2D remission across various populations may also assess the effect on various subclassifications of T2D. In addition, we suggest future trials focus on the use of GLP-1 receptor agonists and GIP analogs, and their role in weight loss and T2D remission. Finally, detailed clinical trial registration along with timely updating of clinical trial registries and results publication should be improved to reduce research waste, reporting bias, and publication bias.

Supplementary Information

Supplementary Information.

Supplementary Information.