Precision medicine in type 2 diabetes: A systematic review of treatment effect heterogeneity for GLP1-receptor agonists and SGLT2-inhibitors

Young, Kue; McInnes, Eram Haider; Massey, Robert J.; Kahkoska, Anna R.; Pilla, Scott J.; Raghavan, Sridharan; Stanislawski, Maggi A; Tobias, Deirdre K; McGovern, Andrew; Dawed, Adem Y; Jones, Angus G.; Pearson, Ewan R.; Dennis, John

doi:10.1101/2023.04.21.23288868

Cited by 3 publications

(1 citation statement)

References 185 publications

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“…Further exploration of heterogeneity is required, both in terms of treatment effect and participant characteristics 71 . However, pharmacotherapy may present less heterogeneity compared to other treatment modalities.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological interventions for the management of children and adolescents living with obesity—An update of a Cochrane systematic review with meta‐analyses

Torbahn,

Jones,

Griffiths

et al. 2024

Pediatric Obesity

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SummaryImportanceThe effectiveness of anti‐obesity medications for children and adolescents is unclear.ObjectiveTo update the evidence on the benefits and harms of anti‐obesity medication.Data SourcesCochrane CENTRAL, MEDLINE, ClinicalTrials.gov and WHO ICTRP (1/1/16–17/3/23).Study SelectionRandomized controlled trials ≥6 months in people <19 years living with obesity.Data Extraction and SynthesisScreening, data extraction and quality assessment conducted in duplicate, independently.Main Outcomes and MeasuresBody mass index (BMI): 95th percentile BMI, adverse events and quality of life.ResultsThirty‐five trials (N = 4331), follow‐up: 6–24 months; age: 8.8–16.3 years; BMI: 26.2–41.7 kg/m2. Moderate certainty evidence demonstrated a −1.71 (95% confidence interval [CI]: −2.27 to −1.14)‐unit BMI reduction, ranging from −0.8 to −5.9 units between individual drugs with semaglutide producing the largest reduction of −5.88 kg/m2 (95% CI: −6.99 to −4.77, N = 201). Drug type explained ~44% of heterogeneity. Low certainty evidence demonstrated reduction in 95th percentile BMI: −11.88 percentage points (95% CI: −18.43 to −5.30, N = 668). Serious adverse events and study discontinuation due to adverse events did not differ between medications and comparators, but medication dose adjustments were higher compared to comparator (10.6% vs 1.7%; RR = 3.74 [95% CI: 1.51 to 9.26], I2 = 15%), regardless of approval status. There was a trend towards improved quality of life. Evidence gaps exist for children, psychosocial outcomes, comorbidities and weight loss maintenance.Conclusions and RelevanceAnti‐obesity medications in addition to behaviour change improve BMI but may require dose adjustment, with 1 in 100 adolescents experiencing a serious adverse event.

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Section: Discussionmentioning

confidence: 99%

Pharmacological interventions for the management of children and adolescents living with obesity—An update of a Cochrane systematic review with meta‐analyses

Torbahn,

Jones,

Griffiths

et al. 2024

Pediatric Obesity

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Phenotype-based targeted treatment of SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes

Cardoso

Young

Nair

et al. 2023

Preprint

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A precision medicine approach in type 2 diabetes (T2D) could enhance targeting specific glucose-lowering therapies to individual patients most likely to benefit. We utilised Bayesian non-parametric modelling to develop and validate an individualised treatment selection algorithm for two major T2D drug classes, SGLT2-inhibitors (SGLT2i) and GLP1-receptor agonists (GLP1-RA). The algorithm is designed to predict differences in 12-month glycaemic outcome (HbA1c) between the 2 therapies, based on routine clinical features of 46,394 people with T2D in England (27,319 for model development, 19,075 for hold-out validation), with additional external validation in 2,252 people with T2D from Scotland. Routine clinical features, including sex (with females markedly more responsive to GLP1-RA), were associated with differences in glycaemic outcomes. Our algorithm identifies clearly delineable subgroups with reproducible ≥5mmol/mol HbA1cbenefits associated with each drug class. Moreover, we demonstrate that targeting the therapies based on predicted glycaemic response is associated with improvements in short-term tolerability and long-term risk of new-onset microvascular complications. These results show that precision medicine approaches to T2D can facilitate effective individualised treatment selection, and that use of routinely collected clinical features could support low-cost deployment in many countries.

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Antidiabetic Advancements In Silico: Pioneering Novel Heterocyclic Derivatives through Computational Design

Mehra,

Mehra

2024

CST

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Background:: Deficiency of insulin signaling in type 2 diabetes results from insulin resistance or defective insulin secretion and induced hyperglycemia. By reducing glycated hemoglobin, SGLT2 inhibitors improve hyperuricemia, blood lipids, and weight loss without increasing the risk of hypoglycemia. By targeting this pathway, SGLT2 inhibitors can become a prominent target in the management of type 2 diabetes. Objective:: This study aimed to carry out the molecular docking and ADMET prediction of novel imidazo(2,1-b)-1,3,4 thiadiazole derivatives as SGLT2 inhibitors. Methods:: The chemical structures of 108 molecules were drawn by using ChemDraw Professional 15.0. Further, their energy minimization was also carried out by using Chem Bio Draw three-dimensional (3D) Ultra 12.0. Molecular docking was also carried out using a Molegro Virtual Docker to identify the best-fitting molecules and to identify the potential leads on the basis of dock score. The predicted parameters of drug-likeness according to Lipinski’s rule of five, such as molecular weight, log P, hydrogen bond acceptor, hydrogen bond donors, and number of rotatable bonds of the selected compounds, were predicted using pKCSM software. Results:: About 108 molecules were designed by employing different substitutions on imidazothiadiazole nucleus as SGLT2 inhibitors. Out of these, 10 compounds were found to have better interactions with the active site of SGLT2 protein and the highest dock scores compared to canagliflozin. Compounds 39a and 39b demonstrated good interactions and the highest docking scores of -155.428 and -142.786, respectively. The in silico physicochemical properties of the best compounds were also determined. Additionally, these compounds suggested a good pharmacokinetic profile as per Lipinski's rule of five (orally active drugs). Conclusion:: Novel imidazo (2,1-b)-1,3,4 thiadiazole derivatives were strategically designed, and their binding affinity was meticulously evaluated against the SGLT2 protein. This endeavor yielded pioneering lead compounds characterized by ultimate binding affinity, coupled with optimal ADMET properties in adherence to Lipinski's rule of five and favourable noncarcinogenic profile.

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Precision medicine in type 2 diabetes: A systematic review of treatment effect heterogeneity for GLP1-receptor agonists and SGLT2-inhibitors

Cited by 3 publications

References 185 publications

Pharmacological interventions for the management of children and adolescents living with obesity—An update of a Cochrane systematic review with meta‐analyses

Pharmacological interventions for the management of children and adolescents living with obesity—An update of a Cochrane systematic review with meta‐analyses

Phenotype-based targeted treatment of SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes

Antidiabetic Advancements In Silico: Pioneering Novel Heterocyclic Derivatives through Computational Design

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