UNLABELLED: Current state of affairs: The potential for hypoglycaemia is a 100-year-long challenge that can complicate blood glucose lowering therapy in people with type 2 diabetes. This omnipresent imminent risk continues to the present day, particularly with insulin or sulfonylurea treatment. Specific objective: This clinical perspective seeks to synthesize new insights and tools to help reduce the hypoglycaemic burden related to type 2 diabetes pharmacotherapy by suggesting a synergistic triad approach: Guidance using an innovative approach based on comprehensive network analyses evaluating differential risk of diabetes medications for severe hypoglycaemic events (SHEs) observed in randomized controlled trials. These show an estimated background risk of 60 SHEs per 1000 patients over five years in the trial control populations allocated to standard treatments. Adopting this approach, the data indicate that the highest risk (~ fivefold higher) relates to therapy with sulfonylureas or with basal-bolus insulin regimens, whereas novel therapies with sodium-glucose transport protein 2 inhibitors (SGLT2is) or glucagon-like peptide-1 receptor agonists (GLP1-RAs) have minimal risk of SHEs, with the non-steroidal mineralocorticoid receptor antagonist finerenone showing a potential risk reduction. Recognition of these insights and translating them into treatment guidance should underpin the approach to minimizing the risk of hypoglycaemia, as they likely reflect drug related hypoglycaemia risk more broadly across all degrees of hypoglycaemia. Following this approach would be particularly helpful in those either with specific risk factors for hypoglycaemia (Fig. 1) or with the recently established frail phenotype at dual risk of SHEs and cardiovascular (CV) events in the context of multiple co-morbidities including heart failure, frailty or cancer and a high Charlson Co-Morbidity Index. Also the acute CV risk related to arrhythmias and mortality must not be ignored. Continuous glucose monitoring (CGM) for people with type 2 diabetes is advisable given it has been shown convincingly to provide a powerful new tool in those at dual risk of hypoglycaemia and CV events by reducing related hospitalization emergencies by ~ 50%. Conclusion: Each of these new insights and tools comprise an important step forward in their own right. Used together in a synergistic manner they, for the first time in over one hundred years, appear to provide the capacity to mitigate the threats of hypoglycaemia related to type 2 diabetes pharmacotherapy. GRAPHICAL ABSTRACT: [Image: see text]