Adverse Effects of Insulin Therapy

Hypoglycemia 

Hypoglycemia is a condition caused by a very low level of blood sugar (glucose), your body’s main energy source.  

It is the most serious adverse effect of insulin therapy and the major hurdle to achieving good sugar control in patients with type 1 diabetes and insulin-requiring type 2 diabetes.  

Severe hypoglycemia can cause confusion, motor vehicle accidents, seizures and coma.  

Hypoglycemia also increases heart rate, blood pressure, myocardial contractility and cardiac output, which may adversely affect those who have underlying coronary artery disease (heart disease). 

Risk factors for hypoglycemia among insulin-treated patients include older age, longer duration of diabetes, renal insufficiency, hypoglycemia unawareness, prior hypoglycemia, and lower HbA1c.  

Avoidance of hypoglycemia therefore takes on particular importance in older patients, given the greater prevalence of cardiovascular disease, cognitive dysfunction, and higher risk of falls and fractures.  

To help reduce the incidence of hypoglycemia, the American Diabetes Association (ADA) advises targeting a higher HbA1c of less than 8% in patients with risk factors for insulin-induced hypoglycemia and underlying cardiovascular disease. 

All patients receiving insulin should learn to recognize the symptoms of hypoglycemia and how best to treat low glucose levels. 

Hypokalemia 

Hypokalemia (low blood potassium) may occur because insulin stimulates the movement of potassium from blood into cells. Combining insulin with potassium-lowering drugs may increase the risk of hypokalemia.  

Hypoglycemia) induces pro-arrhythmic effects sympathetic overdrive that is , and in conjunction with hypokalemia increases the risk of cardiac mortality especially in older patients with underlying cardiac disease. 

Weight Gain 

Weight gain is a common side effect of insulin therapy.  

The Diabetes Control and Complications Trial (DCCT) on type 1 patients and The UK Prospective Diabetes Study (UKPDS)(type 2 patients) found an insulin therapy-associated weight gain of 4.6 kg and 4.0 kg respectively. 

In part, the weight gain can be a result of frequent hypoglycemic episodes in which patients consume extra calories to treat the low glucose level and often overeat in response to hunger. However, insulin has anabolic effect which promote the uptake of fatty acids into adipose tissue.  

Generally basal insulin (determirglargine) causes less weight gain than rapid acting insulins (Insulin aspart, Lispro) 

Local Reactions 

True allergic reactions and cutaneous reactions are rare with human insulin and insulin analogs.  

Hypersensitivity reactions can rarely develop in response to the insulin or one of its additives (protamine for example) and can result in local erythema, pruritus, a wheal or more systemic reactions including anaphylaxis.  Lispro insulin appears to be less allergenic. 

Lipoatrophy (localized loss of fat tissue at injection site) was common with the use of less pure and animal insulins, but with use of recombinant DNA to synthesize insulin, it is no longer encountered.  

To avoid the lipohypertrophic effects (lump under the skin caused by accumulation of extra fat at the site of many subcutaneous injections) of insulin, patients should be instructed to rotate their insulin injection sites, preferably rotating within one area and not reusing for one week. 

Mitogenic Properties 

Several retrospective, observational studies and meta-analysis have shown correlations between insulin dose and cancer risk for most insulin types. These studies, however,have significant, inherent limitations, such as the potential for different pre-treatment characteristics of the groups, selection bias, the small numbers of cancer cases found, and short duration of follow-up that may affect the validity of the results.  

Other studies including a randomized 7-year, randomized ORIGIN trial assessing the cardiovascular effects of insulin glargine in more than 12,500 diabetic individuals found no increased risk of cancer. 

Cardiovascular Disease 

There are inconsistent reports on the cardiovascular effect of insulin preparations.  

Non-significant reductions in cardiovascular events were seen with intensive diabetes control when compared with standard control in ADVD (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation), and ACCORD (Action to Control Cardiovascular Risk in Diabetes) and VADT (Veterans Affairs Diabetes Trial), respectively 

However, increased mortality rate was observed after 3.5 years of among ACCORD patients receiving intensive therapy targeted at an HbA1c of less than 6.0%. 

The results of ACCORD support less aggressive diabetes management among patients at high risk for a cardiovascular event.  

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