Individualizing Treatment of Hyperglycemia in Type 2 Diabetes

Eliminate Options with Unacceptable Adverse Effects

When the pharmacologic options with acceptable A1C-lowering potential have been identified, the ones with contraindications and potential serious adverse effects for the individual patient can immediately be eliminated (Table 4). For example, if a patient has an eGFR < 30 mL/min/1.73 m ², metformin, sulfonylureas, GLP-1 receptor agonists, most DPP-4 inhibitors, and SGLT-2 inhibitors are either contraindicated or should be used with caution. In patients with severe osteoporosis, SGLT-2 inhibitors may not be the best option. In patients with a history of diabetic ketoacidosis (DKA), caution should be used with metformin and SGLT-2 inhibitors. There have been concerns of possible acute pancreatitis and neoplasia with the incretin-based agents, the DPP-4 inhibitors and GLP-1 receptor agonists [40,41], although other clinical trials and observational data have not found increased risk [42–45]. Nevertheless, these agents potentially should be avoided in patients with a history of pancreatitis or neoplasm. SGLT-2 inhibitors may be associated with genitourinary infections and volume depletion [46–48] and probably should be avoided in patients at high risk for these conditions.

If the adverse effects are not serious, changing the way the medication is administered may allow the patient to tolerate agents with high potential benefits. For example, metformin is commonly associated with gastrointestinal (GI) adverse effects, which can be reduced or avoided with slow titration of the dose [6] or by switching to an extended-release formulation [49]. GLP-1 receptor agonists are associated with GI adverse effects [6] and in most cases slow titration is recommended.

Evaluate Potential Risks/Benefits of Remaining Options

Hypoglycemia. The barrier of hypoglycemia generally precludes maintenance of euglycemia and full realization of the long-term benefits of good glucose control over a lifetime. Once considered a trivial issue, concerns about hypoglycemia in T2DM are increasingly being raised [19,50–55]. Clearly, hypoglycemia occurs more often as glycemic targets are lowered to near-normal values, especially in those with advanced age and multiple comorbidities [55]. Various comorbidities frequently encountered particularly as patients age also are associated with increasing propensity for experiencing hypoglycemia and untoward outcomes from it. These include coronary artery disease, heart failure, renal and liver disease, and dementia. Hypoglycemia, when it occurs, may lead to dysrhythmias, dizziness, accidents and falls, work disability, and decreased quality of life. In addition to relaxing blood glucose targets in high-risk patients, drug selection should favor agents that do not precipitate such events (Table 4).

Fortunately, the commonly used non-insulin agents are not associated with hypoglycemia unless they are used in combination with sulfonylureas or insulin. Sulfonylureas should be used with caution and other options considered in patients with high risk for hypoglycemia. When insulin is required, regimens which minimize risk of hypoglycemia should be used. For example, adding a GLP-1 receptor agonist to basal insulin as an alternative to mealtime insulin has been shown to be equally effective with a lower risk of hypoglycemia [4,6]. Also, premixed insulin preparations should be avoided or used cautiously in individuals who miss meals frequently. Additionally, newer basal insulins that exhibit longer duration of action are now available in the United States. Preliminary studies have shown that the newly FDA-approved longer-acting basal insulins, insulin degludec and glargine U-300, may be associated with a reduced risk for hypoglycemia [56,57]. However, it remains unclear how and when these newer agents will best be incorporated into a treatment regimen.