Noninsulin antihyperglycemic drugs in type 2 diabetes mellitus
Noninsulin antihyperglycemic drugs are the oral and injectable agents used to lower glucose in type 2 diabetes mellitus once lifestyle modification alone is insufficient, chosen in a patient-centered stepwise sequence built around metformin. Metformin, titrated to 850-1000 mg PO twice daily (max 2550 mg/day), is first-line for essentially every patient; an SGLT2 inhibitor or GLP-1 receptor agonist is added next for established or high-risk atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease, with further agents layered by hypoglycemia risk, weight effect, and cost.
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What this article covers
- Overview
Definition: noninsulin antihyperglycemic drugs are the oral and non-insulin injectable medications used to lower blood glucose in type 2 diabetes mellitus, used as monotherapy or in combination once…
- Epidemiology
Type 2 diabetes accounts for the large majority of diabetes mellitus in adults, and essentially all patients who do not reach targets on lifestyle modification alone require a noninsulin antihyperglycemic drug.
- Risk factors
Failure to reach individualized glycemic targets on lifestyle modification alone is the primary trigger for starting pharmacotherapy.
- Pathophysiology
Metformin (biguanide) decreases hepatic glucose production and increases insulin-mediated muscle glucose uptake without stimulating insulin secretion, which is why it does not cause hypoglycemia alone.
- Clinical features
Type 2 diabetes itself is typically identified by screening or incidental hyperglycemia rather than by symptoms; polyuria and polydipsia occur only with more marked hyperglycemia.
- Differential diagnosis
Type 1 diabetes mellitus: insulin deficiency with tendency toward ketoacidosis rather than gradual beta-cell decline; unlike type 2 diabetes, insulin is required from diagnosis, not noninsulin agents.
- Diagnosis
Type 2 diabetes mellitus is diagnosed using American Diabetes Association criteria, any one of which is sufficient; an abnormal result in an asymptomatic person requires confirmation with a repeat…
- Management
First, start comprehensive lifestyle modification (weight management, physical activity) in every patient, and add pharmacotherapy if individualized glycemic targets are not met.
- Complications
Hypoglycemia is the most clinically significant complication of sulfonylureas, meglitinides, and insulin, more likely with long half-life sulfonylureas or in older patients; not expected with…
- Prognosis
Metformin reduces cardiovascular events in overweight patients with type 2 diabetes (UKPDS), supporting its role as first-line therapy.
- Prevention
Screen overweight/obese adults (BMI 25 or greater, or 23 or greater in Asian American patients) with a risk factor, or all adults 45 years or older; rescreen every 3 years if normal.
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Related articles
- Type 2 diabetes mellitus
Type 2 diabetes is hyperglycemia from insulin resistance with progressive relative insulin deficiency, diagnosed by a hemoglobin A1c of 6.5% or higher, a fasting glucose of 126 mg/dL or higher, or a 2-hour oral glucose tolerance test value of 200 mg/dL or higher. First-line treatment is lifestyle modification plus metformin, with an SGLT2 inhibitor or GLP-1 receptor agonist added early for patients with atherosclerotic disease, kidney disease, or heart failure.
- Sodium-glucose cotransporter-2 (SGLT2) inhibitors
Sodium-glucose cotransporter-2 (SGLT2) inhibitors block renal glucose reabsorption to lower blood glucose, and independently reduce cardiovascular death, heart failure hospitalization, and kidney disease progression in high-risk patients with type 2 diabetes. Empagliflozin, canagliflozin, or dapagliflozin 10 mg (canagliflozin 100 mg) PO once daily is added early, regardless of hemoglobin A1c, in patients with established or high-risk atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease, with dose held during acute illness, prolonged fasting, or perioperatively to avoid euglycemic diabetic ketoacidosis.
- Insulin therapy in diabetes mellitus
Insulin therapy replaces or supplements endogenous insulin to control hyperglycemia, and is lifelong and mandatory in type 1 diabetes because of absolute beta-cell failure, while in type 2 diabetes it is added when oral and noninjectable agents fail to reach glycemic goals. First-line therapy is a basal-bolus regimen started at 0.4-1.0 units/kg/day in type 1 diabetes, or basal insulin glargine 10 units/day (or 0.1-0.2 units/kg/day) in type 2 diabetes, titrated to a fasting glucose target.
- Hypoglycemia in adults
Hypoglycemia is a plasma glucose below 70 mg/dL, most often a complication of insulin or sulfonylurea therapy for diabetes, and in a person without diabetes it requires a Whipple triad-based evaluation for insulinoma or another endogenous cause. An alert patient is treated with 15 to 20 g of fast-acting oral carbohydrate, while a patient unable to swallow safely receives intramuscular glucagon 1 mg or intravenous dextrose 50% 25 g.