Type 2 diabetes is a chronic condition where the body does not make enough insulin or has insulin resistance resulting in elevated glucose levels. Current medications work by increasing the amount of insulin in the body, by improving insulin sensitivity, or a combination of both. Managing blood glucose requires a multimodal approach, including healthy eating and physical activity alongside medications. Consider personalizing non-insulin antihyperglycemic agents based on a patient’s comorbidities, adverse effects, and treatment goals.
Related CE course for pharmacists: Noninsulin Antihyperglycemic Agents for the Treatment of Type 2 Diabetes
First line non-insulin antihyperglycemic agents
First line non-insulin antihyperglycemic agents for treatment of type 2 diabetes include:
- Biguanides
- Sodium glucose cotransporter 2 inhibitors (SGLT2)
- Glucagon-like peptide-1 receptor agonists (GLP RA)
- Glucagon like peptide-1/gastric inhibitory polypeptide receptor agonists (GLP-1/GIP RA)
Biguanides (metformin)
Metformin decreases hepatic glucose production, reduces intestinal glucose absorption, and enhances insulin sensitivity. It works by increasing peripheral glucose uptake and utilization. Metformin has a high glucose-lowering effect and a minimal risk of hypoglycemia.
- CV effects: Beneficial effects on MACE outcomes
- Weight impact: Neutral (may see slight weight loss)
- Clinical pearls:
- Metformin does not cause renal damage but should be avoided in those with an eGFR of < 30 mL/min/1.73m2 due to the potential of lactic acidosis.
- GI side effects are common and may be mitigated with slow titration, administering with food or using an extended-release product.
- Potential to cause a vitamin B12 deficiency.
SGLT2 inhibitors
SGLT2 is a transporter responsible for the reabsorption of glucose in the proximal tubule. Inhibition of the SGLT2 leads to an increase in urinary glucose excretion. It works by lowering the renal threshold of glucose and reducing the reabsorption of filtered glucose. SGLT2 inhibitors have a moderate glucose-lowering effect with a minimal risk of hypoglycemia.
- CV effects: Reduction of CV death or hospitalization in those with heart failure (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin) and beneficial effects on MACE outcomes (empagliflozin, canagliflozin).
- Kidney effects: Beneficial in reducing progression of CKD (canagliflozin, dapagliflozin, empagliflozin).
- Weight impact: Moderate weight loss
- Clinical pearls:
- Minimal glucose-lowering effect in those with eGFR of <45 ml/min/1.73m2, however, CKD and CV benefits continue in that population.
- Potential for euglycemic DKA in those with insulin deficiency
- May require discontinuation for sick days, surgery or prolonged fasting.
- Genital mycotic infections are possible. Avoid this in patients at high risk for infection.
Related CE course for pharmacists: Diabetes Medications: Pharmacology and Healthcare Considerations
GLP-1 RA
Glucagon-like peptide is a hormone responsible for glucose regulation. GLP-1 RA medications stimulate insulin secretion from pancreatic beta cells in a glucose-dependent manner. This decreases glucagon release and slows gastric emptying. GLP-1 RAs have a high glucose-lowering effect and a minimal hypoglycemic risk.
- CV effects: Beneficial effects on MACE outcomes (dulaglutide, semaglutide (SQ), liraglutide).
- Kidney effects: Beneficial in reducing risk of CKD progression (semaglutide).
- Weight impact: High weight loss
- Clinical pearls:
- No dose adjustment necessary in renal impairment. Dehydration due to GI side effects may lead to acute kidney injuries.
- Potential benefit in those with MASH.
- Use a slow dose titration to reduce risk of GI side effects.
- Oral drug absorption may be altered during dose titration. Patients may need to be monitored for impaired absorption, including those on oral contraception.
GIP/GLP-1 RA
GIP/GLP-1 RAs are similar to GLP-1 RAs. They stimulate insulin secretion from pancreatic beta cells in a glucose-dependent manner. This reduces postprandial and fasting glucagon concentrations, increasing insulin sensitivity and slowing gastric emptying. GIP/GLP-1 RAs have a high glucose-lowering effect and a minimal hypoglycemic risk.
- CV effects: Currently under investigation
- Weight impact: High weight loss
- Clinical pearls
- No renal adjustments necessary. Dehydration due to GI side effects may lead to acute kidney injuries.
- Potential benefit in those with MASH
- Use a slow dose titration to reduce risk of GI side effects
- Oral drug absorption may be altered during dose titration. Patients may need to be monitored for impaired absorption, including those on oral contraception.
Non-first line agents: DPP-4 inhibitors
DPP-4 is responsible for the degradation of the incretin hormones GLP-1 and GIP. Inhibition of DPP-4 results in higher concentrations of endogenous incretin hormones, which increases insulin secretion and decrease glucagon secretion. DPP-4 inhibitors have a low glucose-lowering effect and minimal hypoglycemic risk.
- CV effects: No benefit
- Weight impact: Weight neutral
- Clinical pearls:
- Renal adjustments are needed for certain agents (sitagliptin, saxagliptin, alogliptin).
- Joint pain has been described in post-marketing reports.
- DPP-4 inhibitors should not be used in combination with GLP-1 agents.
Thiazolidinedione (pioglitazone)
Pioglitazone improves insulin resistance. It also increases insulin-dependent glucose disposal, along with a decrease in hepatic glucose output. Pioglitazone has a high glucose-lowering effect and minimal hypoglycemic risk.
- CV effects: No benefit. Avoid pioglitazone in cases of heart failure due to potential exacerbation of heart failure.
- Weight impact: Expect weight gain
- Clinical pearls:
- Risk of bone fractures. Use with caution in those at risk of fractures.
- Avoid in those with active bladder cancer. Use with caution in those with a history of bladder cancer.
Sulfonylureas
Sulfonylureas stimulate the release of insulin from pancreatic beta cells. These have a high glucose-lowering effect and a high risk of hypoglycemia.
- CV effects: No benefit
- Weight impact: Expect weight gain
- Clinical pearls:
- Limit use in those on insulin therapy due to increased risk of hypoglycemia.
- Use with caution in renal impairment or the elderly. Glipizide may be less likely to cause hypoglycemia in renal impairment due to it having no active metabolites.
Using non-insulin antihyperglycemic agents to treat diabetes
Clinicians should evaluate these key factors when deciding on therapeutic choices:
- Patient characteristics: Age, BMI, renal function, comorbidities, and lifestyle.
- Adherence potential: Consider pill burden, side effect profiles, and cost.
- Polypharmacy challenges: Review drug interactions and simplify regimens when possible.
- Patient education: Focus on medication administration, expected benefits, and managing adverse effects.
Written by Patrick Welch, PharmD, BCACP
