Precautions of ANTIdiabetic medications

Metformin (Glucophage) is the first choice for the treatment of type 2 diabetes. Well tolerated and does not cause hypoglycemia....

INTRODUCTION ㅡ Glycemic goals and the therapies used to achieve them must be individualized for each patient based on several factors, one of the more important being coexisting conditions such as renal disease, liver disease, and cardiovascular disease. The AACE published a consensus statement that the focus is placed on the avoidance of weight gain and hypoglycemia caused by antidiabetic medications and by using lifestyle modifications, diabetes education, dietary consultation, selfmonitoring of blood glucose levels, and concomitant drug therapy.

METFORMIN

Metformin (Glucophage) is the first choice for the treatment of type 2 diabetes. Well tolerated and does not cause hypoglycemia. Metformin may result in modest weight loss. The most commonly reported adverse effect is gastrointestinal distress, including nausea, abdominal pain, and diarrhea. These effects can be attenuated by titrating the dosage slowly and taking it with meals.

Contraindications and cautions ㅡ Metformin is contraindicated in patients with acute illness and those undergoing radiocontrast studies or surgery. Metformin is not recommended in patients with hepatic dysfunction, chronic heart failure (CHF), metabolic acidosis, dehydration, or alcoholism due to the risk of lactic acidosis, which is a rare but potentially fatal complication. Lactic acidosis has occurred primarily in patients with type 2 diabetes who have significant renal impairment, including renal hypoperfusion and renal disease. Because blood lactate levels can become elevated in patients with cardiogenic shock or other illnesses that decrease tissue perfusion, metformin is also not recommended for use in that population. Due to the increased risk of lactic acidosis with increasing age, metformin is generally not used. In patients aged 80 years or older due to decreasing renal function over time. Metformin is contraindicated in patients with elevated serum creatinine concentrations (≥ 1.5 mg/dL in men, and ≥ 1.4 mg/dL in women).

SULFONULUREA

Sulfonylureas lower blood glucose levels by enhancing insulin secretion. Not expensive and commonly prescribed to patients. Use of sulfonylureas is associated with weight gain and hypoglycemia. Sulfonylureas may cause hypoglycemia, and common with the use of first-generation sulfonylureas, such as glyburide, than with second-generation sulfonylureas. Second-generation sulfonylureas are preferable. These agents must be used carefully, and patients should be closely monitored.

THIAZOLIDINEDIONES

Thiazolidinediones are insulin-sensitizing agents in muscle and fat, and are used as monotherapy or as add-on therapy with metformin. Hypoglycemia with thiazolidinediones is fairly rare.

Common adverse reactions ㅡ Fluid retention and edema and should be used cautiously in patients with liver insufficiency. It increase the risk of nonosteoporotic fractures in women, particularly in the upper arm, hand, and foot.

Contraindications ㅡ Thiazolidinediones are also contraindicated in patients with New York Heart Association class III or IV heart failure and should be used with caution in patients at risk for CHF. Pioglitazone (Actos) for more than 1 year may be associated with an increased risk of bladder cancer. Pioglitazone (Actos) should not be used in patients with active bladder cancer and should be used with caution in patients with a previous history of bladder cancer.

DIPEPTIDYL PEPTIDASE-4 INHIBITORS

Dipeptidyl peptidase-4 (DPP-4) inhibitors reduce the breakdown of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide, the main incretins, resulting in an increase in glucose-mediated insulin secretion and suppression of glucagon secretion. DPP-4 inhibitors rarely cause hypoglycemia as monotherapy. For renal patients, dosage adjustment is recommended for saxagliptin (Onglyza) and sitagliptin (Januvia) in patients with moderate-to-severe renal insufficiency (creatinine clearance ≤ 50 ml/minute). Linagliptin (Trajenta) does not require renal dosage adjustment.

Drug interactions ㅡ Saxagliptin is metabolized by cytochrome P450 (CYP) 3A4/5, a dosage of 2.5 mg/day should be used when coadministered with strong CYP3A4/5 inhibitors such as ketoconazole, clarithromycin, itraconazole, ritonavir, and telithromycin. The efficacy of linagliptin may be reduced when used with strong CYP3A4 inducers; therefore, the use of alternative treatments is recommended.

Common adverse reactions ㅡ Pancreatitis including necrotizing pancreatitis. Clinicians should inform patients of the signs and symptoms of pancreatitis.

GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONIST

The GLP-1 receptor agonists exenatide (Byetta) and liraglutide (Victoza) are indicated to supplement dietary modifications and exercise in the treatment of adults with type 2 diabetes. The antihyperglycemic properties of these drugs are due to glucose-dependent insulin secretion by β cells, suppression of glucagon secretion, and delay in gastric emptying.

Exenatide and liraglutide result in significant weight and rarely cause hypoglycemia.
Exenatide may lead to pancreatitis and contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min).
Exenatide not recommended in patients with severe gastrointestinal conditions, such as gastroparesis.
No dosage adjustments for liraglutide are necessary in patients with renal or hepatic impairment, but caution is recommended.

SPECIAL SITUATIONS

RENAL DISEASE ㅡ Diabetic nephropathy is the primary cause of end-stage renal disease and occurs in 20–40% of patients with type 2 diabetes. Optimizing glucose control and blood pressure can reduce the risk of nephropathy or slow its progression.

Microalbuminuria (persistent albuminuria of 30–299 mg/24 hrs) is a marker for nephropathy. Angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) can delay the progression to macroalbuminuria in patients with type 2 diabetes, hypertension, macroalbuminuria, and renal insufficiency (serum creatinine concentration > 1.5 mg/dL). For further information, see topic on ACEI or an ARB for hypertension or diabetic kidney disease. These medications should be used in nonpregnant patients with micro- or macroalbuminuria.

Exenatide, metformin, sitagliptin, and saxagliptin, are either contraindicated or must be carefully monitored and their dosages adjusted in patients with moderate, severe, or end-stage renal disease. Dose of sulfonylureas should be adjusted, for example, Glimepiride (Amaryl) 1 mg/day may be used cautiously to avoid hypoglycemia in patients with renal disease, as they are more sensitive to the glucose lowering effects of this agent. Liraglutide and insulin have been found to be safe in patients with renal disease.

LIVER DISEASE ㅡ Medical therapy for patients with type 2 diabetes and liver disease may be the same for patients without liver disease. Metformin is an appropriate first-line therapy for most patients except those with advanced liver disease who have an increased risk of lactic acidosis. Thiazolidinediones may be useful in patients with nonalcoholic fatty liver disease, monitor alanine aminotransferase levels and other liver function test results. Stop thiazolidinediones therapy if ALT > 2.5 times the upper limit of normal. Sulfonylureas are considered safe in patients with hepatic disease, and drugs with short half-lives, such as glipizide, are often appropriate choices.

Acarbose (Glucobay), an glucosidase inhibitor, works directly in the gastrointestinal tract to decrease carbohydrate metabolism and glucose absorption. It appears to be safe and effective in patients with hepatic encephalopathy and type 2 diabetes. Insulin can be used successfully in patients with liver disease, but higher doses may be required due to increased insulin resistance.

CARDIOVASCULAR DISEASE ㅡ Cardiovascular disease is a major cause of morbidity and mortality in patients with diabetes, with hypertension and dyslipidemia being two of the most common comorbidities in these patients. Blood pressure goal of less than 130/80 mmHg. For a patient with atherosclerotic cardiovascular disease, preference is to use a drug proven to reduce major cardiovascular events and/or cardiovascular mortality. Strongest evidence for cardiovascular benefit has been demonstrated with liraglutide, semaglutide, empagliflozin, and canagliflozin. SGLT2 inhibitors are recommended for patients with clinical heart failure. Thiazolidinedione class is contraindicated in class III and class IV heart failure. Some studies (not all) have reported an association between dipeptidyl-peptidase IV inhibitors and worsening heart failure; use with caution, if at all.

HOSPITALIZED PATIENTS ㅡ Hyperglycemia is common in all hospitalized patients, regardless of whether they have diabetes, due to increased concentrations of stress hormones. The sliding-scale insulin regimen is commonly used for the self-administration of regular human insulin; however, this regimen is not useful for hospitalized patients who do not have diabetes. In addition, the sliding-scale insulin regimen is no longer endorsed by the ADA because it is reactive and episodic, and does not consider a patient’s previous response to other regimens. Its use may result in hyperglycemic or hypoglycemic episodes due to rapid changes in insulin requirements, insulin sensitivity, and blood glucose levels. For further information, see topics on..

REFERENCES

Marquess, J.G. (2011). Managing Special Populations among Patients with Type 2 Diabetes Mellitus. Pharmacotherapy, 31(12S), pp.65S-72S. Available at: https://accpjournals.onlinelibrary.wiley.com/doi/pdfdirect/10.1592/phco.31.12.65S
Davies, M.J., D’Alessio, D.A., Fradkin, J., Kernan, W.N., Mathieu, C., Mingrone, G., Rossing, P., Tsapas, A., Wexler, D.J. and Buse, J.B. (2018). Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care, [online] 41(12), pp.2669–2701. Available at: http://care.diabetesjournals.org/content/41/12/2669