Oral Hypoglycemic Drugs For Type 2 Diabetes

Last updated on September 28th, 2022

Oral hypoglycemic drugs are anti-diabetes medications intended to help type 2 diabetic patients manage their condition. This article explains what are these medications, their classification, their doses, side effects, interactions, or precautionary measures.

What are Hypoglycemic Agents?

Oral hypoglycemic drugs are used to lower the quantity of glucose present in the bloodstream. These medications are not insulin; however, they promote the pancreas to form insulin. These drugs are generally helpful for treating Type 2 or non-insulin-dependent diabetes (adult-onset diabetes mellitus).

Take care that these oral hypoglycemic agents won’t cure your diabetes, but helps in controlling the condition.

The oral hypoglycemic agents in combination with diabetic diet and exercise plans must help a diabetic maintain normal blood sugar levels. A stable sugar level aids in decreasing the risk of diabetic complications like eye, heart, kidney, or blood vessel disorders. So, this was about the oral hypoglycemic agent definition. Now, coming to the types of oral hypoglycemic agents.

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Oral Hypoglycemic Drugs Classification

• Sulfonylureas (gliclazide, glimepiride, glipizide, glyburide)
• Meglitinides (nateglinide, repaglinide)
• Biguanides (metformin)
• Thiazolidinediones (pioglitazone, rosiglitazone)
• Alpha Glucosidase inhibitors (miglitol, voglibose, acarbose)
• DPP-4 inhibitors (vildagliptin, linagliptin, sitagliptin, saxagliptin)
• SGLT2 inhibitors (canagliflozin, dapagliflozin)
• Cycloset (bromocriptine)

Indications of OHA Drugs

• Indications approved by FDA: chiefly concentrate on type 2 diabetes.
• Non-FDA-approved uses of OHAs like metformin: preventing type 2 diabetes, treating pregnancy-related diabetes i.e., gestational diabetes, treating polycystic ovary syndrome (PCOS) with menstrual abnormalities, and preventing ovarian hyperstimulation syndrome in PCOS females taking IVF treatment.

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Mechanism of Action of the Oral Hypoglycemic Drugs List

Sulfonylureas

These agents attach to the ATP channels present in the pancreatic beta cells. This causes blockage of those channels and changes the resting membrane potential of the pancreatic cell. Hence, leads to calcium entry and in turn stimulation of insulin secretion.

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Meglitinides 

These medications work with the help of varied pancreatic beta-cell receptors. However, their mode of action is quite similar to sulfonylureas. That is, they control the ATP-sensitive potassium channels present in the pancreatic beta cells, hence resulting in augmented insulin secretion.

Metformin 

The drug augmented the activity of the enzyme, adenosine monophosphate-activated protein kinase in liver (hepatic) cells. As a result, it lowers hepatic gluconeogenesis and lipogenesis. Hence, augments the insulin-mediated uptake of sugar in muscles.

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Thiazolidinediones 

These medicines promote the activity of peroxisome proliferator-activated receptor-gamma (PPAR-γ), a nuclear receptor. Thereby, augmenting insulin sensitivity and increasing the peripheral uptake of sugar. Also, the medications augment the level of adiponectin, a fat tissue-secreted cytokine. This augments both the number of insulin-sensitive adipocytes and promotes the oxidation of fatty acids.

Alpha-glucosidase Inhibitors 

These are the competitive inhibitors of enzymes, alpha-glucosidase. These enzymes are present in the intestinal brush border cells helpful for digesting the dietary starch. As a result, they block the reabsorption of the polysaccharides and metabolize sucrose to glucose and fructose.

DPP-4 Inhibitors 

These medicines block the enzyme DPP-4 or dipeptidyl peptidase 4. The enzyme deactivates glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP). As a result, these affect sugar control via multiple effects. These effects can be:

• Increase in glucose-dependent insulin release
• Reduction of glucagon release
• Reduction of gastric emptying and,
• Increase of feelings of satiety.

SGLT2 inhibitors block sodium-glucose co-transporter 2 (SGLT-2) present in the proximal tubules of renal glomeruli. They result in the inhibition of 90% glucose reabsorption and cause glycosuria in diabetic patients. And, hence reduces the levels of glucose in the plasma.

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Cycloset

This drug is a sympatholytic dopamine D2 receptor agonist. It works by resetting the hypothalamic circadian rhythm, which may be modified by obesity. This activity causes the reversal of insulin resistance and reduced glucose formation.

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Dosage and Administration

Glipizide

Glipizide comes in the form of a tablet with a dose strength of 2.5 mg to 10 mg. People usually take it as a single dose or in two divided doses half an hour before breakfast. Glimepiride comes in 1 mg, 2 mg, or 4 mg tablets. People consume it once a day with breakfast or two times a day with food. For people at high risk for hypoglycemia, like older patients or people having chronic renal disorder, the starting dose might be as low as 0.5 mg daily. Glyburide comes in 1.25 mg, 2.5 mg, or 5 mg tablets. People take it as a single dose or in two divided doses.

Metformin

Metformin is the primary drug of choice in type 2 diabetic patients. People take it via oral route in 500 to 1000 mg tablets two times a day.

Repaglinide

Repaglinide comes as 0.5 mg, 1 mg, or 2 mg tablets. People consume it via oral route in 2-3 divided doses each day.

Alpha-glucosidase Inhibitors

Alpha-glucosidase inhibitors come in dose strengths of 25 mg, 50 mg, or 100 mg. people take this medication thrice a day just prior to meals.

Pioglitazone

Pioglitazone comes as 15 mg, 30 mg, or 45 mg tablets to be taken daily. Rosiglitazone, rarely used, is taken as 2 mg, 4 mg, or 8 mg on a daily basis.

Linagliptin

Linagliptin comes as 5 mg to be taken on a daily basis. Sitagliptin is available in doses of 25 mg, 50 mg, or 100 mg once daily. Vildagliptin comes in the dose of 50 mg one time or two times weekly. Moreover, Saxagliptin is available as 2.5 mg or 5 mg once daily.

Canagliflozin

Canagliflozin is at first taken as 100 mg daily, which is slowly augmented to 300 mg daily. And, dapagliflozin is given as 5 mg or 10 mg daily, and empagliflozin as 10 mg or 25 mg on a daily basis.

Cycloset

The initial dose of Cycloset is 0.8 mg one time daily. The dose is slowly increased to the usual dose of 1.6 mg to 4.8 mg one time daily.

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Side Effects of Oral Hypoglycemic Drugs

The most commonly reported side effect of hypoglycemic drugs is hypoglycemia or low blood glucose level. Every individual’s response to low blood glucose differs. The following are the low blood glucose symptoms:

• Hunger
• Trembling
• Fast Heartbeat
• Irritation
• Cold Sweat

If a person notices any of the above symptoms, he or she must:

• Check the levels of blood glucose if monitoring at home.
• Consume or have something comprising sugar: 4 oz of orange juice or regular soda.

Category-wise, the following are the side effects of several hypoglycemic agents :

Sulfonylureas

• Headache
• Flatulence
• Diarrhea
• Acidity
• Vomiting
• Skin reactions like pruritis
• Low blood sugar
• Increase in the enzyme lactate dehydrogenase
• Drowsiness
• Anxiety
• Depression

Repaglinide

• Headache
• Weight Gain
• Low blood glucose
• Upper respiratory tract infection
• Cardiovascular ischemia (shortage of oxygen and blood flow to the heart muscle).

Metformin

Gastrointestinal upset like nausea, vomiting, diarrhea, flatulence

• Chest uneasiness
• Flushing
• Headache
• Palpitation
• Drowsiness
• Chills
• Skin rashes
• Taste disorder
• Vitamin B12 deficiency.

In addition, in 1% of patients, it results in lactic acidosis, which may be risky to lives.

Thiazolidinediones

• Edema (fluid retention)
• Headache
• Low blood sugar
• Heart failure
• Muscle pain
• Bone fracture
• Inflammation in pharynx

Alpha-glucosidase Inhibitors

• Flatulence tends to reduce gradually
• Abdominal pain
• Diarrhea
• Increase in the levels of serum transaminases (below or equal to 4%).

DPP4 Inhibitors

• Saxagliptin: headache, peripheral edema, low blood sugar, urinary tract infection, and acute pancreatitis.
• Sitagliptin: low blood sugar, nasopharyngitis, short-term kidney failure, increased serum creatinine.
• Linagliptin: low blood glucose, high uric acid, high levels of serum lipase (8%; above thrice the upper limit of normal), acute pancreatitis, and nasopharyngitis.

SGLT-2 Inhibitors

• Increase in lipid levels
• Low body volume
• Nausea
• Urinary tract infection
• Dysuria
• Influenza
• Increased urine output
• Bone fracture
• Kidney impairment.

Cycloset

• Drowsiness
• Weakness
• Constipation
• Headache
• Nausea
• Rhinitis

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Special Contraindications

These are as follows different categories 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 is needed for eGFR less than 45 mL/min/1.73 m^2 with a 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 on hemodialysis or peritoneal dialysis. Linagliptin does not need any dose adjustment.
• Cycloset: Allergy to the drug, breastfeeding, and syncopal migraine.

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Monitoring

• Fasting blood glucose, before-meal blood glucose, and HbA1c measurements are done semi-annually in people with good blood glucose control and quarterly in people who fail to meet their treatment goals.
• Observe any symptoms of low blood sugar (weakness, too much hunger, intense sweating, numbness of extremities), weight changes, and irregular liver function in patients consuming sulfonylureas.
• In people consuming metformin, preliminary and recurrent monitoring of Hb, RBC indices, and kidney function tests prior to therapy commencement and annually is important. The doctor repeats these tests every 3-6 months if the GFR is 45 to below 60 mL/min/1.73 m2, and every 3 months if the GRF is between 30 to below 45 mL/min/1.73 m^2. Also, measurements of serum vitamin B12 and folate must be done if a person is taking Metformin for a long time. This helps in ruling out megaloblastic anemia.
• In people consuming pioglitazone, alanine transaminase, alkaline phosphatase, aspartate transaminase, and total bilirubin evaluations must be done periodically. Signs of cardiac failure, bladder cancer signs, and weight gain demand monitoring.
• In people consuming acarbose, serum transaminase and serum creatinine levels must be monitored every 3 months during the initial treatment year and periodically afterward.
• In people taking SGLT 2 inhibitors, monitoring of renal function and LDL cholesterol checking must be done.

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FAQs:

References

1. https://www.ncbi.nlm.nih.gov/books/NBK482386/
2. https://www.diabetes.co.uk/diabetes-medication/diabetes-and-oral-hypoglycemics.html
3. https://www.revespcardiol.org/en-new-oral-hypoglycemic-agents-cardiovascular-articulo-S1885585716302249

Last Updated on September 28, 2022 by Dr. Damanjit Duggal