Oral antidiabetic drug classes and their adverse effects

What it is

The agents for type 2 diabetes fall into classes that differ in their effect on weight, their risk of hypoglycemia, their safety in renal insufficiency, and how far each lowers A1c: metformin, the biguanide, 1.0%-2.0%; the sulfonylureas 1.0%-2.0%; pioglitazone, a TZD, 1.0%-1.5%; the DPP-IV inhibitors, for example sitagliptin, 0.5%-0.8%; and the GLP-1 receptor agonist, for example exenatide, 0.5%-1.0%. Metformin is a biguanide and is the initial therapeutic agent for most type 2 diabetics; the other classes are the sulfonylureas, for example gliclazide and glipizide, the DPP-4 inhibitors, for example sitagliptin and alogliptin, the thiazolidinediones, that is pioglitazone, the SGLT2 inhibitors, for example empagliflozin, and the GLP-1 receptor agonists, for example exenatide and liraglutide.

How it is treated

Metformin should be the first medication prescribed for diabetes mellitus when an oral agent is required, together with lifestyle measures. It increases insulin sensitivity and reduces hepatic glucose production, can efficiently lower glycemic levels, is linked to weight loss and fewer occurrences of hypoglycemia, and is less expensive than most other options. If more than one agent is required, continuing metformin is recommended along with the addition of one or more of a sulfonylurea such as glipizide, a thiazolidinedione such as pioglitazone, an SGLT2 inhibitor such as empagliflozin, or a DPP-4 inhibitor such as alogliptin. One stepwise scheme has a gate before each step. Monotherapy is metformin with lifestyle, and it is the step if HbA1C is less than 7.5. Dual therapy is the step if HbA1C is 7.5 or more, or for monotherapy that has failed after 3 months: metformin plus a sulfonylurea first line, metformin plus a DPP-4 inhibitor second line, a DPP-4 inhibitor plus a sulfonylurea third line, and a GLP-1 receptor agonist plus metformin fourth line. Triple therapy is considered if the dual therapy has failed after 3 months, and it is metformin, a sulfonylurea and a DPP-4 inhibitor, or metformin, a sulfonylurea and a GLP-1 receptor agonist by tertiary care. Insulin is started for patients who failed the triple therapy and for those with a high HbA1c, 8.0% or more, while on dual therapy, beginning with basal insulin and adding a prandial short acting insulin.

The second-line choice can be made by comorbidity. For atherosclerotic cardiovascular disease the best option is a GLP-1 receptor agonist such as liraglutide or an SGLT2 inhibitor such as empagliflozin, for proven cardiovascular benefit. For heart failure it is an SGLT2 inhibitor, which reduces hospitalizations and cardiovascular mortality. For chronic kidney disease it is an SGLT2 inhibitor, which slows progression of CKD. Where hypoglycemia must be avoided, a DPP-4 inhibitor, a GLP-1 receptor agonist or an SGLT2 inhibitor is safe; where weight loss is desired, a GLP-1 receptor agonist or an SGLT2 inhibitor; where cost is a concern, a sulfonylurea such as gliclazide, or metformin. Sulfonylureas are generally added in patients with metformin failure, and a GLP-1 receptor agonist such as exenatide is a possible second agent for metformin failure, especially if weight loss is desired. Pioglitazone is used if the patient is unable to tolerate metformin or sulfonylureas, and both pioglitazone and the DPP-4 inhibitors can be used in renal insufficiency. Empagliflozin is the second-line choice for patients intolerant of metformin, who are unlikely to be successful with a third trial of that agent.

The first step, and when to move past it, is set out. In addition to lifestyle modification, metformin is the preferred initial therapy unless it is contraindicated or not tolerated, and once initiated it is continued even if insulin is later added. If the glycemic target is not achieved within 3 months of therapy, additional therapy is required: a second agent joins the metformin, and the metformin is not stopped in its place. Dual therapy is considered at diagnosis itself when the A1C is 2% above the glycemic target. What is added after metformin is then individualized, because people with type 2 diabetes form heterogeneous groups.