Q: I have several patients with type 2 diabetes and they're all on different medications. What medications are used now to manage type 2 diabetes and how do they work?
There are currently 12 classes of glucose lowering agents available to treat type 2 diabetes. The American Diabetes Association (ADA) (2017) provides useful information in the ADA Standards of Medical Care in Diabetes-2017 that help clinicians understand the physiological actions, advantages, and disadvantages of each. It's important to remember that all medications should be used with lifestyle management considerations.
First-line therapy for newly diagnosed type 2 diabetes is often lifestyle modifications to improve health, along with metformin (a biguanide); however, this will be determined based on patient-specific factors such as current A1C results, symptoms, medication characteristics, and patient preference. Metformin works by decreasing hepatic glucose production, which means hypoglycemia is rare. Other benefits include a reduced risk of cardiovascular events, ability to use in patients with an estimated glomerular filtration rate as low as 30 mL/min/1.73 m2, and it is inexpensive. There are a few disadvantages to be aware of, for example, some patients experience gastrointestinal side effects, vitamin B12 deficiency, and rarely lactic acidosis (ADA, 2017).
For patients with an A1C between 9% and 10% or if target A1C is not achieved after 3 months on metformin alone, then combination therapy is often considered with one of the following available options: sulfonylurea, meglitinide, thiazolidinedione, dipeptidyl peptidase-4 (DPP-4) inhibitor, glucagon-like peptide 1 (GLP-1) receptor agonist, sodium-glucose co-transporter-2 (SGLT2) inhibitor, or basal insulin. Again, the drug of choice will be determined based on patient preference, disease, and drug characteristics. For example, sulfonylureas work by increasing insulin secretion; therefore, hypoglycemia is a risk. Also, any time you increase circulating insulin there is a risk for weight gain. The benefits of sulfonylureas include reduced microvascular risk and they are relatively inexpensive. For patients with sulfa allergies, meglitinides (which also increase insulin secretion) may be used. This class of medication also has a risk for hypoglycemia and weight gain, but reduces postprandial hyperglycemia and offers more dosing flexibility; however, it is more expensive (ADA, 2017).
Thiazolidinediones work primarily by increasing insulin sensitivity, rather than insulin secretion, so the risk for hypoglycemia is low. Another benefit is the lower cost, and for patients using pioglitazone, a reduction in triglycerides. The disadvantages of this medication include an increased risk for weight gain, heart failure, bone fractures, and for patients taking rosiglitazone, an increase in LDL-C levels (ADA, 2017).
DPP-4 inhibitors decrease glucagon secretion and increase insulin secretion, but both are dependent on the blood glucose level; therefore, hypoglycemia is rare. Disadvantages include angioedema/urticaria and other immune-mediated dermatological effects and a potential increase in heart failure. Plus, the cost for this medication is high (ADA, 2017).
GLP-1 receptor agonists also decrease glucagon secretion and increase insulin secretion, but like DPP-4 inhibitors, this response is glucose dependent so the risk for hypoglycemia is low. This medication also slows gastric emptying and increases satiety, which can help with weight loss. Other benefits include decreased postprandial hyperglycemia, a reduction in some cardiovascular risk factors, and for patients taking liraglutide, lower cardiovascular disease (CVD) event rates and mortality have been noted in patients with CVD. Disadvantages include gastrointestinal side effects, increased heart rate, and the potential for acute pancreatitis. Like insulin, this medication must be injected, so training requirements must be considered (ADA, 2017).
SGLT2 inhibitors block glucose reabsorption by the kidney, resulting in increased glucosuria. The benefits of this medication include weight loss, decreased blood pressure, and for patients taking empagliflozin, the potential for lower cardiovascular events and mortality in patients with CVD. Another plus is that hypoglycemia is rare. Disadvantages include polyuria, volume depletion, hypotension, dizziness, elevated LDL-C and creatinine levels, genitourinary infections that may lead to pyelonephritis or urosepsis, and the potential for diabetic ketoacidosis (ADA, 2017).
The remaining four classes of medications (a-glucosidase inhibitors, amylin mimetics, bile acid sequestrants, and dopamine-2 agonists) are used less frequently due to modest efficacy in type 2 diabetes, administration requirements, the potential for drug interactions, and/or side effects (ADA, 2017).
Finally, it is well known that due to the progressive nature of type 2 diabetes many patients eventually require exogenous insulin. Basal insulin may be initiated with metformin or in combination with other noninsulin medications. It is a convenient, less threatening way to initiate insulin therapy because of the once-daily dosing. Insulin works by increasing glucose disposal, decreasing hepatic glucose production, and by suppressing ketogenesis. The advantages of insulin include unlimited efficacy, a nearly universal response, and a reduction in microvascular risk. The disadvantages include a risk for hypoglycemia, weight gain, and depending on the brand/type of insulin the cost can be quite high (analogs are more expensive than human insulins). As most insulins are injected, training requirements must be considered. For example, it is best to help patients self-titrate insulin doses based on self-monitoring of blood glucose, perhaps using an algorithm based on blood glucose results. In addition to insulin injection training, patients will need education on blood glucose monitoring, nutrition, and prevention, recognition, and treatment of hypoglycemia (ADA, 2017).
If target A1C is not achieved after 3 months on dual therapy, a 3-drug combination is recommended with any of the above-mentioned medications. For more specific information about the sequencing of glucose-lowering medications in combination therapy, see the ADA Standards of Medical Care in Diabetes-2017, Figure 8.1.
For patients with an A1C 10% or greater, or if the blood glucose is 300 mg/dL, or if the patient has symptoms of hyperglycemia, then combination insulin injection therapy should be considered. For example, in addition to basal insulin some patients may need a bolus of insulin before meals to prevent hyperglycemia. In this case, a rapid-acting insulin analog is used because of the quick onset of action. However, other choices include use of a premixed insulin with a basal and prandial component, such as a neutral protamine hagedorn and regular insulin combination. There are multiple combinations on the market to consider based on the patient's needs. For patients requiring high doses of insulin, there are concentrated forms of insulin on the market. For example, U-500 regular insulin is five times as concentrated as U-100 regular insulin; however, it has a delayed onset and longer duration of action, so it covers both prandial and basal needs (ADA, 2017).
Clearly there are many choices available today to help patients control their blood glucose levels. As a clinician, it is important to stay up-to-date on potential treatment regimens. The ADA Standards of Medical Care in Diabetes-2017 is an evidence-based resource that can help.
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