Daily Endocrinology Research Analysis

OBJECTIVE: To provide up-to-date evidence on key benefits, harms, and uncertainties regarding medications for adults with type 2 diabetes. DESIGN: Living systematic review and network meta-analysis (NMA), using frequentist random effects and GRADE (grading of recommendations, assessment, development and evaluation) approaches. Updates are planned at least two times a year. DATA SOURCES: Medline and Embase, searched up to 31 July 2024 for the current iteration. STUDY SELECTION: Randomised controlled trials of at least 24 weeks comparing one or more medications with standard treatment, placebo, or each other. RESULTS: The systematic review and NMA includes 493 168 participants from 869 trials (adding 53 trials since October 2022) reporting data for 13 drug classes (63 drugs) and 26 outcomes of interest. Regarding benefits, moderate to high certainty evidence confirms the well established cardiovascular and kidney benefits of sodium-glucose cotransporter-2 (SGLT-2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and finerenone (the last for patients with established chronic kidney disease). The most effective drugs in reducing body weight were tirzepatide (mean difference (MD) -8.63 kg (95% confidence interval -9.34 to -7.93); moderate certainty) and orforglipron (MD -7.87 kg (-10.24 to -5.50); low certainty), followed by eight other GLP-1RAs (high to moderate certainty). Absolute benefits of medications vary substantially depending on the baseline risk of cardiovascular and kidney outcomes; risk-stratified absolute effects of medications are summarised using an interactive multiple comparisons tool (https://matchit.magicevidence.org/250709dist-diabetes/#!/). Regarding medication-specific harms, SGLT-2 inhibitors increase genital infections (odds ratio (OR) 3.29 (95% CI 2.88 to 3.77); high certainty) and ketoacidosis due to diabetes (OR 2.08 (1.45 to 2.99); high certainty), and probably increase amputations (OR 1.27 (1.01 to 1.61); moderate certainty); tirzepatide and GLP-1RAs probably increase severe gastrointestinal events (most increased risk with tirzepatide (OR 4.21 (1.87 to 9.49); moderate certainty)); finerenone increases severe hyperkalaemia (OR 5.92 (3.02 to 11.62); high certainty); and thiazolidinediones increase major osteoporotic fractures and probably increase hospitalisation for heart failure. Sulfonylureas, insulin, and dipeptidyl peptidase-4 inhibitors probably increase the risk of severe hypoglycaemia. There is low to very low certainty evidence for effects on other diabetes-related complications, including neuropathy and visual impairment. Despite interest in the issue, there is uncertainty about whether GLP-1RAs may reduce dementia (OR 0.92 (0.83 to 1.02); low certainty). CONCLUSIONS: This living systematic review provides a comprehensive summary of the cardiovascular, kidney, and weight loss benefits, as well as medication-specific harms of medications for adults with type 2 diabetes, including effects of SGLT-2 inhibitors, GLP-1RAs, finerenone and tirzepatide. SYSTEMATIC REVIEW REGISTRATION: PROSPERO number: CRD42022325948. A more detailed protocol is available at https://data.aliveevidence.org/records/q02rv-km486. READERS' NOTES: This article is the first version of a living systematic review. It is linked to a living

CLINICAL QUESTION: What are the benefits and harms of medications for adults with type 2 diabetes at varied risks of cardiovascular and kidney related complications? CONTEXT: Emerging clinical trials of novel medications have demonstrated benefits on cardiovascular, kidney, and weight related outcomes in people with type 2 diabetes. Dynamically updated practice guidelines adhering to standards of trustworthiness are necessary in response to a rapidly evolving evidence base and the availability of multiple medication alternatives. This living practice guideline incorporates the latest available medications and evidence and provides recommendations stratified by risks of cardiovascular and kidney complications to inform diabetes management. RECOMMENDATIONS: The panel issued risk-stratified recommendations regarding four prioritised medications for adults with type 2 diabetes (SGLT-2 inhibitors, GLP-1 receptor agonists, finerenone and tirzepatide):• Lower risk (three or fewer cardiovascular risk factors without established cardiovascular disease (CVD) or chronic kidney disease (CKD)): weak recommendation against SGLT-2 inhibitors or GLP-1 receptor agonists.• Moderate risk (more than three cardiovascular risk factors without established CVD or CKD; or established CVD and/or CKD at lower risk of complications): weak recommendation in favour of SGLT-2 inhibitors or GLP-1 receptor agonists; and a weak recommendation against finerenone in adults with CKD.• Higher risk (established CVD and/or CKD at higher risk of complications, or established heart failure): strong recommendation in favour of SGLT-2 inhibitors or GLP-1 receptor agonists; and a weak recommendation in favour of finerenone in adults with CKD.• Across risk strata: weak recommendation in favour of tirzepatide in adults with obesity. ABOUT THIS GUIDELINE AND HOW IT WAS CREATED: An international panel including two patient partners, clinicians, and methodologists produced these recommendations. The panel followed standards for trustworthy guidelines and used the GRADE approach, explicitly considering the balance of benefits, harms and burdens of treatment from an individual patient perspective. Recommendations were informed by a linked living systematic review and network meta-analysis evaluating relative benefits and harms updated to 31 July 2024; and by linked systematic reviews addressing risk prediction models and values and preferences of adults with type 2 diabetes. Candidate therapeutics are prioritised based on availability of sufficient randomised trial data, relevance to a global audience and likelihood of changing practice.This is the first version of the living guideline. The guideline is part of the

BACKGROUND: The mechanistic basis underlying the remission of prediabetes (ie, the return to normoglycaemia) has been suggested to be amelioration of insulin resistance without improvement of β-cell function. We aimed to characterise the relative contributions of changes in insulin sensitivity and β-cell function to the remission of prediabetes. METHODS: In this prospective cohort study, conducted at Mount Sinai Hospital (Toronto, ON, Canada), we screened pregnant women for gestational diabetes, aiming to recruit participants with varying degrees of dysglycaemia and conduct serial postpartum metabolic evaluations. The study population comprised participants who were diagnosed with prediabetes following pregnancy (designated visit 1) and had a subsequent visit at which they could be assessed for remission of prediabetes (visit 2); study visits occurred at 3 months, 1 year, 3 years, or 5 years postpartum. Both visits included oral glucose tolerance tests, enabling assessment of glucose tolerance, insulin sensitivity and resistance (with the Matsuda index and Homeostasis Model Assessment for Insulin Resistance [HOMA-IR]), and β-cell function (with the Insulin Secretion-Sensitivity Index-2 [ISSI-2] and insulinogenic index divided by fasting plasma insulin [IGI/FPI]). Using logistic regression analyses, we evaluated changes in the log-transformed Matsuda index, HOMA-IR, ISSI-2, and IGI/FPI occurring between visits as predictors of remission of prediabetes, after adjustment for clinical risk factors for diabetes (age, ethnicity, family history of diabetes, BMI at visit 1, and duration of breastfeeding at visit 2). The contribution of each of the four indicated changes to the adjusted model was assessed and ranked. FINDINGS: Between Sept 22, 2003, and Nov 30, 2018, 787 pregnant women were screened for gestational diabetes. We identified 182 participants with prediabetes at visit 1 (median 3·5 months [IQR 3·0-12·3] postpartum) and stratified them into those with (n=100) and without (n=82) remission on reassessment at visit 2 (median 13·0 months [11·8-27·9] postpartum). At baseline (visit 1), participants who subsequently attained remission had higher ISSI-2 than those who did not attain remission (median 576 [IQR 493-674] vs 496 [391-600]; p<0·0004). At follow-up (visit 2), participants in remission had higher Matsuda index values (5·8 [3·9-7·9] vs 3·9 [2·6-6·7], p=0·0004) and better β-cell function (ISSI-2 650 [563-820] vs 478 [389-590], p<0·0001; IGI/FPI 1·9 [1·2-2·5] vs 1·3 [0·8-2·0], p=0·0002) than those who were not in remission. On logistic regression analyses, the between-visit changes in log ISSI-2 (adjusted odds ratio 3·80, 95% CI 1·53-9·41) and log Matsuda index (2·28, 1·21-4·31) were associated with remission of prediabetes. The top-ranked predictor was change in log ISSI-2 (change in model deviance 8·49), with change in log Matsuda index ranked second (change in model deviance 6·56). INTERPRETATION: Recovery of β-cell function is the dominant determinant of the remission of prediabetes, akin to its role in remission of diabetes but at an earlier point in the natural history of dysglycaemia. FUNDING: Canadian Institutes of Health Research.