The most effective management of diabetes mellitus demands an interprofessional approach involving both lifestyle modifications with diet and exercise, and pharmacologic therapies as needed to meet individualized glycemic goals. Healthcare practitioners must encourage patients to combine lifestyle modifications with oral pharmacologic agents for optimal glycemic control, particularly as type 2 diabetes mellitus progresses with continued loss of pancreatic beta-cell function and insulin production.
Oral Hypoglycemic Medications
- Sulfonylureas (glipizide, glyburide, gliclazide, glimepiride)
- Meglitinides (repaglinide and nateglinide)
- Biguanides (metformin)
- Thiazolidinediones (rosiglitazone, pioglitazone)
- α-Glucosidase inhibitors (acarbose, miglitol, voglibose)
- DPP-4 inhibitors (sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin)
- SGLT2 inhibitors (dapagliflozin and canagliflozin)
- Cycloset (bromocriptine)
FDA approved indications for the use of oral hypoglycemic drugs include type 2 diabetes mellitus.
Non-FDA approved indications of oral hypoglycemic drugs, such as metformin, are for the prevention of type 2 diabetes mellitus, treatment of gestational diabetes mellitus, treatment of polycystic ovary syndrome (PCOS) with menstrual irregularities, and prevention of ovarian hyperstimulation syndrome in PCOS patients undergoing intracytoplasmic sperm injection (ICSI) or in vitro fertilization (IVF), and management of antipsychotic-induced weight gain.
The following are adverse effects of various hypoglycemic drugs:
Sulfonylureas: Syncope (less than 3%), dizziness (2% to 7%), nervousness (4%), anxiety (less than 3%), depression (<3%), hypoesthesia (less than 3%), insomnia (<3%), pain (<3%), paresthesia (less than 3%), drowsiness (2%), headache (2%), diaphoresis (less than 3%), pruritus (1% to less than 3%), hypoglycemia (less than 3%), increased lactate dehydrogenase, diarrhea (1% to 5%), flatulence (3%), dyspepsia (less than 3%), and vomiting (less than 3%).
Repaglinide: Hypoglycemia (16% to 31%), weight gain, headache (9% to 11%), upper respiratory tract infection (10% to 16%), and cardiovascular ischemia (4%).
Metformin: Gastrointestinal upset such as diarrhea (12% to 53%), nausea and vomiting (7% to 26%), flatulence (4% to 12%), chest discomfort, flushing, palpitation, headache (5% to 6%), chills, dizziness, taste disorder, diaphoresis, nail disease, skin rash, vitamin B12 deficiency. Also, in less than 1% of patients, it causes lactic acidosis, which can be life-threatening, and is precipitated by conditions predisposing to hypoperfusion and hypoxemia, such as severe renal failure (eGFR less than 30 ml/min/1.73 m2).
Thiazolidinediones: Edema (less than or equal to 27%), hypoglycemia (less than or equal to 27%), cardiac failure (less than or equal to 8%), headache, bone fracture (less than or equal to 5%), myalgia (5%), sinusitis (6%), and pharyngitis.
Alpha-glucosidase inhibitors: Adverse effects include flatulence (74%) that tends to decrease with time, diarrhea (31%), abdominal pain (19%), and increased serum transaminases (less than or equal to 4%).
- Sitagliptin: Hypoglycemia (1%), nasopharyngitis (5%), increased serum creatinine, acute pancreatitis (including hemorrhagic or necrotizing forms), and acute renal failure.
- Saxagliptin: Peripheral edema (4%), headache (7%), hypoglycemia (6%), urinary tract infection (7%), lymphocytopenia (2%), and acute pancreatitis.
- Linagliptin: Hypoglycemia (7%), increased uric acid (3%), increased serum lipase (8%; more than three times upper limit of normal), nasopharyngitis (7%), and acute pancreatitis.
SGLT-2 inhibitors: Dyslipidemia (3%), hyperphosphatemia (2%), hypovolemia (1%), nausea, fungal vaginosis (7% to 8%), urinary tract infection (6%), increased urine output (3% to 4%), dysuria (2%), influenza (2% to 3%), bone fracture (8%), and renal impairment.
Cycloset: Dizziness, fatigue, headache, constipation, rhinitis, nausea, and weakness.
The following are contraindications for different classes of oral hypoglycemic drugs.
- Metformin: Hypersensitivity to the drug, severe renal dysfunction (eGFR less than 30 mL/minute/1.73 m2), and metabolic acidosis, including diabetic ketoacidosis.
- Sulfonylureas: Hypersensitivity to the drug or sulfonamide derivatives, type 1 diabetes mellitus, and diabetic ketoacidosis.
- Pioglitazone: Hypersensitivity to the drug, New York Heart Association Class III or IV heart failure, serious hepatic impairment, bladder cancer, history of macroscopic hematuria, and pregnancy.
- Alpha-glucosidase inhibitors: Hypersensitivity to acarbose, diabetic ketoacidosis, cirrhosis, inflammatory bowel disease, ulcers of the intestine, partial intestinal obstruction, digestive and absorptive issues
- SGLT 2 inhibitors: History of serious hypersensitivity to the drug, end-stage renal disease (ESRD), and patients on dialysis.
- DPP-4 inhibitors: Dose adjustment of saxagliptin in needed for eGFR less than 45 mL/min/1.73 m^2 with the dose of 2.5 mg once daily. For Sitagliptin, a low dose of 25 mg daily is given in patients with a creatinine clearance of less than 30 ml/min/1.73 m^2 and is contraindicated in patients with hemodialysis or peritoneal dialysis. Linagliptin does not need any dose adjustment.
- Cycloset: Allergy to the drug, breastfeeding, and syncopal migraine
Enhancing Healthcare Team Outcomes
Oral hypoglycemic agents are often prescribed by the primary care provider, nurse practitioner, endocrinologist, and internist. However, it is essential to educate the patient on changes in lifestyle, which include dietary modifications and exercise therapy. A dietary consult is often necessary to educate the patient on a healthy diet. The patient should be urged to join an exercise program, stop smoking, and lower body weight. No matter what oral hypoglycemic agent the clinician prescribes, the healthcare worker must know the adverse effects and potential for interaction with other medications.