Oral Hypoglycemic Medications

Article Author:
Kavitha Ganesan
Article Editor:
Senan Sultan
10/10/2019 3:17:43 PM
PubMed Link:
Oral Hypoglycemic Medications


The most effective management of diabetes mellitus demands a 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. [1][2][3][4][5]

Oral Hypopglycemic 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 are type 2 diabetes mellitus.

Non-FDA approved indications of some oral hypoglycemic drugs, such as metformin, are for the prevention of type 2 diabetes mellitus, polycystic ovary syndrome with menstrual irregularities, weight loss, gestational diabetes mellitus, and prevention of ovarian hyperstimulation syndrome.

Mechanism of Action

  • Sulfonylureas bind to adenosine triphosphate-sensitive potassium channel (K-ATP channel) 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 similarly 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 bind to peroxisome proliferator-activated receptor gamma to increase peripheral uptake of glucose and decrease hepatic glucose production.
  •  Alpha-glucosidase inhibitors competitively inhibit alpha-glucosidase enzymes in the intestine 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) and prolong the action of glucagon-like peptide. This inhibits glucagon release, increases insulin secretion, and decreases gastric emptying thus decreasing blood glucose levels.
  • SGLT2 inhibitors inhibit sodium-glucose cotransporter 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, will reset the hypothalamic circadian rhythm which might have been altered by obesity. This results in the reversal of insulin resistance and the decrease in glucose production.


  • Glipizide is taken as a 2.5 mg to 10 mg tablet, single dose or in two divided doses, 30 minutes before breakfast. Glimepiride is available as a 1, 2, and 4 mg tablet, 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 a chronic kidney disease, the initial dose could be as low as 0.5 mg daily. Glyburide is available as a 1.25, 2.5, and 5mg tablet, taken as a single dose or two divided doses.
  • Repaglinide is available as a  0.5, 1, or 2 mg tablet, taken orally as two to three divided doses in a  day.
  • Metformin is the first 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 a 25 mg, 50 mg, 100 mg tablet, given three times a day just before meals. 
  • Pioglitazone is given as 15, 30, or 45 mg tablet daily. Rosiglitazone, when rarely used, is given as 2, 4 and 8 mg daily.
  • Among the DPP- 4 inhibitors, Linagliptin is available as 5 mg daily, Vidagliptin is given as 50 mg once or twice weekly, Sitagliptin as 25, 50, and 100 mg once daily, and Saxagliptin as 2.5 and 5 mg once daily.
  • Among the SGLT2 inhibitors, Canagliflozin is given as 100 mg and 300 mg daily, dapagliflozin as 5 and 10 mg daily, and empagliflozin as 10 and 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 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, decreased vitamin B12 serum concentrate. Also in less than 1 % of patients it metformin causes cholestasis and lactic acidosis.

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:  Flatulence (74%) that tends to abate 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.
  • Saxaglitin: 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. 
  • Sulfonyl Ureas: 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. Dose adjustment of saxagliptin in needed for eGFR less than 45 mL/minute/1.73 m2) with the dose of 2.5 mg once daily. For Sitagliptin, a low dose of 25 mg daily is given in patients with creatinine clearance of less than 30 and is contraindicated in patients with hemodialysis or peritoneal dialysis.
  • Linagliptin: No dose adjustment needed.
  • Cycloset: Allergy to the drug, breastfeeding and syncopal migraine.


  • 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 who were taking metformin, initial and frequent monitoring of hemoglobin RBC indices and renal function tests prior to therapy initiation, and at least every year. These test should be every 3 to 6 months if patients glomerular filtration rate is 45 to less than 60 mL/ min/1.73 m2 and every 3 months if glomerular filtration rate is 30 to less than 45 mL/ min/1.73 m2. Vitamin B12 serum and folate concentrations 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 required 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 are watched.
  • Note any signs and symptoms of hypoglycemia (fatigue, excessive hunger, profuse sweating, numbness of extremities), liver function, weight (due to potential to cause weight gain) in patients taking sulfonylureas.
  • In patients who are 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 should be monitored 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 important to educate the patient on changes in lifestyle. A dietary consult should be sought to educate the patient on a healthy diet. The patient should be urged to join an exercise program, stop smoking and lower the body weight. No matter what oral hypoglycemic agent is prescribed, the healthcare worker must know adverse effects and potential for interaction with other medications.


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