Prediabetes (PD) is a bridge between normoglycemia and hyperglycemia or diabetes mellitus (DM) characterized by higher than normal blood glucose but not fulfilling the criteria for type 2 DM (T2DM). PD is defined by impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and/or hemoglobin A1c (HbA1c) above 5.7% but <6.4%. Individuals with PD are at increased risk of progressing to T2DM at a pace of 5-10% every year and other micro- and macrovascular complications, including cardiovascular diseases. Prevalence of IGT and IFG in 2021 was 9.1% (about 464 million), which is projected to increase to 10.0% (638 million) in 2045; that of IFG was 5.8% (about 298 million), projected to increase to 6.5% (414 million) in 2045 globally. That is why we must seriously take aggressive steps to prevent progression to T2DM and to reduce the morbidity and mortality associated with DM, its complications, and healthcare burden. Why PD is important? Why PD to be treated? Individuals with PD have a 5-10% annual risk of progressing to T2DM and are associated with increased risk of micro- and macrovascular complications like nephropathy, retinopathy, neuropathy, and cardiovascular risks, myocardial infarction, and stroke. To prevent progression or conversion of PD to DM, we must be very aggressive. These are sufficient reasons for treatment of PD by lifestyle intervention or pharmacotherapy, as intensive lifestyle modifications, dietary modification, and enhanced physical activity have been shown to reduce the progression of PD to T2DM by 40-70%. These measures also lead to weight loss and better cardiovascular health. PD develops due to insulin resistance, impaired insulin secretion, and increased hepatic glucose production. Therefore, pharmacotherapy with metformin, pioglitazone, α-glucosidase inhibitors (AGIs), dipeptidyl peptidase IV (DPP IV) inhibitors, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and glucagon-like peptide-1 receptor agonists (GLP1 RA) targeting these defects are efficacious in preventing T2DM in PD. Diabetes Prevention Program (DPP) has shown 31% reduction in DM incidence with metformin. There is increasing evidence for prevention of DM in adults with PD by pharmacotherapy, but options other than metformin have adverse effects, and there is no unanimity for their use in PD. The role of pharmacotherapy is still debatable, and no consensus is made. We recommend that patients who are at high risk, having a strong family history of DM, signs of severe insulin resistance like acanthosis nigricans, severe obesity, or associated comorbidities, must be considered for disease-modifying pharmacotherapy like SGLT2 inhibitors, DPP IV inhibitors, and GLP1 RA. Those who do not have the above risk factors should be followed up at regular intervals, at least every year. Why PD not to be treated? When we treat DM, our "treat to target" is HbA1c of 7% or less, and organizations like the European Association for the Study of Diabetes (EASD) recommend a stricter target of 6.5%, which is above the diagnostic criteria for PD. Then the million-dollar question arises: are we justified in treating PD, as diagnostic criteria for PD are lower than the DM treatment target of 7% or less? There is another issue of overdiagnosis and overmedication; labeling individuals as PD and treating them with pharmacotherapy may lead to increased medication and healthcare costs, as well as stigma associated with a chronic disease and its treatment. Long-term studies are required to evaluate the risk-benefit of pharmacotherapy. We suggest that persons identified to have PD must be under vigilance and investigated at regular intervals. If they are found to have incremental blood glucose and HbA1c and a high risk of progression or conversion to DM, it is logical to treat. Those who are stable in the prediabetic range without associated comorbidities should be observed regularly and advised lifestyle modification (diet and exercise) and weight reduction.
