Continuing Education Activity

The most effective management of diabetes mellitus demands an interprofessional approach involving both lifestyle modifications with diet and exercise, and pharmacologic therapies as necessary to meet individualized glycemic goals. Lifestyle modifications must be combined 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. This activity outlines the indications, mechanisms of action, methods of administration, significant adverse effects, contraindications, monitoring, and toxicity of oral hypoglycemic medications, so providers can direct patient therapy to optimal outcomes where glycemic control and diabetes play a role in outcomes.

Objectives:

• Identify the various mechanisms of action of oral hypoglycemic drugs.
• Review the adverse events associated with each class of oral hypoglycemic medications.
• Summarize the contraindications to each class of oral hypoglycemic drugs.
• Explain the importance of improving care coordination among the interprofessional team to enhance the delivery of care for patients who can benefit from therapy with oral hypoglycemic medications.

Indications

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.[1][2][3][4][5]

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.

Mechanism of Action

• Sulfonylureas bind to adenosine triphosphate-sensitive potassium channels (K-ATP channels) in the beta cells of the pancreas; this leads to the inhibition of those channels and alters the resting membrane potential of the cell, causing an influx of calcium and the stimulation of insulin secretion.
• Meglitinides exerts its effects via different pancreatic beta-cell receptors, but they act similar to sulfonylureas by regulating adenosine triphosphate-sensitive potassium channels in pancreatic beta cells, thereby causing an increase in insulin secretion.
• Metformin increases hepatic adenosine monophosphate-activated protein kinase activity, thus reducing hepatic gluconeogenesis and lipogenesis, as well as increasing insulin-mediated uptake of glucose in muscles.
• Thiazolidinediones activate peroxisome proliferator-activated receptor gamma (PPAR-γ), a nuclear receptor, to increase insulin sensitivity and resultant peripheral uptake of glucose, and also increase the level of adiponectin, a fat tissue-secreted cytokine, that increases not only the number of insulin-sensitive adipocytes but also stimulate fatty acid oxidation.
•  Alpha-glucosidase inhibitors competitively inhibit alpha-glucosidase enzymes in the intestinal brush border cells that digest the dietary starch, thus inhibiting the polysaccharide reabsorption as well as the metabolism of sucrose to glucose and fructose.
• DPP-4 inhibitors inhibit the enzyme dipeptidyl peptidase 4 (DPP- 4). These deactivate glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), among others. Therefore, these influence glucose control through multiple effects, such as decreasing glucagon release and increasing glucose-dependent insulin release, decreasing gastric emptying, and increasing satiety.SGLT2 inhibitors inhibit sodium-glucose co-transporter 2 (SGLT-2) in proximal tubules of renal glomeruli, causing inhibition of 90% glucose reabsorption and resulting in glycosuria in people with diabetes which in turn lowers the plasma glucose levels.
• Cycloset, a sympatholytic dopamine D2 receptor agonist, that reset the hypothalamic circadian rhythm, which might have been altered by obesity. This action results in the reversal of insulin resistance and a decrease in glucose production.

Administration

• Glipizide is a 2.5 mg to 10 mg tablet, taken as a single dose or in two divided doses, 30 minutes before breakfast. Glimepiride is available as a 1 mg, 2 mg, or 4 mg tablets, taken once a day with breakfast or twice a day with meals. For patients at increased risk for hypoglycemia, such as older patients or those with chronic kidney disease, the initial dose could be as low as 0.5 mg daily. Glyburide is available as a 1.25 mg, 2.5 mg, or 5 mg tablets, taken as a single dose or in two divided doses.
• Repaglinide is available as a 0.5 mg, 1 mg, or 2 mg tablets, taken orally in two to three divided doses per day.
• Metformin is the initial drug-of-choice in patients with type 2 diabetes mellitus. It is given orally in 500 to 1000 mg tablets twice a day.
• Alpha-glucosidase inhibitors are available as 25 mg, 50 mg, or 100 mg tablets, given three times a day just before meals. 
• Pioglitazone is given as 15 mg, 30 mg, or 45 mg tablets daily. Rosiglitazone, while rarely used, is given as 2 mg, 4 mg, or 8 mg daily.
• Among the DPP- 4 inhibitors, linagliptin is available as 5 mg daily. Vildagliptin is given as 50 mg once or twice weekly, Sitagliptin as 25 mg, 50 mg, or 100 mg once daily, and Saxagliptin as 2.5 mg or 5 mg once daily.
• Among the SGLT2 inhibitors, canagliflozin is initially given as 100 mg daily, which is gradually increased to 300 mg daily, dapagliflozin as 5 mg or 10 mg daily, and empagliflozin as 10 mg or 25 mg daily.
• Cycloset has an initial dose of 0.8 mg once daily, which is gradually increased to the usual dose of 1.6 mg to 4.8 mg once daily.

Adverse Effects

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%).

DPP4 inhibitors:

• 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.

Contraindications

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

Monitoring

• Fasting blood sugar, pre-meal blood sugar, and hemoglobin A1c are measured semi-annually in patients with good blood sugar control and quarterly in those who did not meet treatment goals or have a change in therapy.[6][7][8][9]
• In patients taking metformin, initial and frequent monitoring of hemoglobin, RBC indices, and renal function tests prior to therapy initiation, and at least every year. The clinician should repeat these tests every 3 to 6 months if the glomerular filtration rate is 45 to less than 60 mL/min/1.73 m2, and every three months if glomerular filtration rate is from 30 to less than 45 mL/min/1.73 m2. Serum vitamin B12 and folate levels should be measured if the patient is on long-term metformin to rule out megaloblastic anemia.
• In patients who are taking pioglitazone, aspartate transaminase, alanine transaminase, alkaline phosphatase, and total bilirubin are measured before initiation and periodically. Signs and symptoms of heart failure, weight gain, features suggestive of bladder cancer (hematuria, dysuria, and urinary urgency), and periodic ophthalmologic exams require monitoring.
• Note any signs and symptoms of hypoglycemia (fatigue, excessive hunger, profuse sweating, numbness of extremities), abnormal liver function, and weight fluctuations (due to the potential to cause weight gain) in patients taking sulfonylureas.
• In patients taking acarbose, serum creatinine and serum transaminase levels should be monitored every three months during the first year of treatment and periodically thereafter.
• Renal function (baseline and periodically during treatment) and LDL require monitoring for patients with SGLT 2 inhibitors.

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.