Oral Agents

Introduction

Current therapy for the treatment of hyperglycemia of T2D includes the following oral antidiabetic agents (Table 8-1):

• First- and second-generation sulfonylureas (SFUs)
• The biguanide metformin (MET)
• The alpha-glucosidase inhibitors (AGIs) acarbose and miglitol
• The meglitinide repaglinide
• The thiazolidinediones (TZDs) rosiglitazone and pioglitazone
• The d-phenylalanine derivative nateglinide
• Dipeptidyl peptidase-4 (DPP-4) inhibitors sitagliptin, saxagliptin, linagliptin and alogliptin
• The bile acid sequestrant (BAS) colesevelam
• The dopamine receptor agonist bromocriptine mesylate
• The sodium-glucose transporter 2 (SGLT2) inhibitors canagliflozin, dapagliflozin, empagliflozin and ertugliflozin
• The oral formulation of the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide.

According to the 2024 American Diabetes Association (ADA) Standards of Medical Care in Diabetes, oral antidiabetic drug (OAD) therapy (typically with MET) can be initiated concurrent with lifestyle intervention at diagnosis, depending on comorbidities, patient-centered treatment factors and management needs. The typical initial pharmacologic therapy is metformin (MET) (in the absence of specific contraindications) because of its effect on glycemia, absence of weight gain and hypoglycemia, generally low level of side effects, high level of acceptance and relatively low cost. MET treatment should be titrated to its maximally effective dose over 1 to 2 months, as tolerated. In patients with or at high risk of atherosclerotic cardiovascular disease (ASCVD), heart failure (HF) and/or chronic kidney disease (CKD), an sodium glucose cotransporter type 2 (SGLT2) inhibitor or GLP-1 receptor agonist with a demonstrated benefit in ASCVD, HF, or CKD risk reduction is the appropriate and ADA-recommended first-line OAD therapy (with or without MET, depending on glycemic control needs).

OADs have different pharmacokinetics, potency, metabolism and mechanisms of action that influence the choice of medication to use for initial and combination therapy. Careful examination of the patient’s metabolic profile, including weight, cholesterol levels, presence of glucose toxicity, duration of diabetes and concomitant use of other oral and injectable agents, will dictate the best OAD to use initially and in combination to achieve glycemic control. In general, OADs are contraindicated in patients who:

• Are pregnant or lactating
• Are seriously ill
• Have significant kidney or liver disease
• Have demonstrated allergic reactions.

In addition, patients with significant and prolonged hyperglycemia with marked symptoms, such as polyuria, polydipsia, or weight loss, should be considered for temporary insulin therapy before considering the institution of OADs. The rationale for insulin therapy is to acutely treat hyperglycemia to reduce glucotoxicity and enable the oral agents to be more effective.

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