CLINICAL STATEMENTS AND GUIDELINES leading to a reduction in hyperglycemia in adults with T2DM. In a substudy of the UKPDS (United Kingdom Prospective Diabetes Study), metformin, compared with conventional therapy (ie, lifestyle modifications alone), resulted in a 32% reduc- tion in microvascular and macrovascular diabetes- related outcomes, a 39% reduction in MI, and a 36% reduction in all-cause mortality rate.S4.2-5 A 2016 systematic review and meta-analysis of glu- cose-lowering therapies for T2DM supported the use of metformin as first-line therapy for T2DM because of its beneficial effects on HbA1c, weight, and improved ASCVD outcomes (compared with sulfonylureas), as well as its acceptable safety pro- file and low cost. However, a separate systematic review found no evidence of reduced CVD events or CVD deaths with metformin.S4.2-8 Metformin carries a small risk of lactic acidosis and must be used with caution in patients with CKD. For younger individuals or those with a mildly elevated HbA1c at the time of diagnosis of T2DM, clinicians can consider a trial of lifestyle therapies for 3 to 6 months before reconsideration of metformin. 4. Several classes of medications have been shown to effectively lower blood glucose but may or may not affect ASCVD risk.S4.2-23 S4.2-26 However, 2 classes of glucose-lowering medications have recently been demonstrated to reduce CVD events in adults with T2DM and high ASCVD risk. SGLT-2 inhibitors act in the proximal tubule to increase urinary excre- tion of glucose and sodium, leading to a reduction in HbA1c, body weight, and BP. 