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 The leading web portal for pharmacy resources, news, education and careers June 24, 2017
Pharmacy Choice - Diabetes Disease State Management - June 24, 2017

Diabetes Disease State Management

Diabetes and the Use of Noninsulin Medications
by Tara Muzyk, PharmD

Diabetes is a multifaceted disease involving more of the body than just the pancreas. In the body of a diabetic many aspects come into play such as a relative insulin deficiency, insulin resistance, increased hepatic glucose production, decreased gastric emptying rate and neuroendocrine dysfunction. Luckily these are also the targets of the noninsulin medications used to treat diabetes. Combining antidiabetic medications with different targets may help the patient obtain more effective control over their diabetes.

For most patients an A1C goal of <7% is reasonable but for older patients or patients who have comorbid conditions or a limited life expectancy a more relaxed goal of <8% or even <9% is reasonable. The other goals of therapy include a reduction or elimination of short-term complications such as hyper- and hypoglycemia and long-term complications such as microvascular and macrovascular complications. The cornerstone of therapy is therapeutic life style changes (TLC) including dietary counseling, regular exercise (30 minutes of moderate exercise 5 times per week), weight loss, stopping smoking, and limiting alcohol. Patients may not know where to start with TLC and may find appointments with a dietitian and a life coach helpful. For many patients instituting therapeutic lifestyle changes may be enough to obtain control over their diabetes, if a patient fails to meet their goal A1C with TLC alone initiating pharmacological therapy is usually necessary. Early detection of diabetes and initiation of medications was associated with better clinical outcomes over time.

Metformin is still considered to be the first line therapy for the prevention and treatment of diabetes due to glycemic efficacy, weight neutrality, tolerability and cost. One concern with the use of metformin was the clearance of metformin in patients with reduced kidney function. Recently the FDA revised the warning regarding the use of metformin in patients with reduced kidney function. If the eGFR is >45 mL/minute/1.73 m2 it is appropriate to start metformin but if the eGFR falls below 30 mL/minute/1.73 m2 metformin should be discontinued. The grey area lies between an eGFR of 30-45 mL/minute/1.73 m2, if the eGFR falls into this zone the risks and benefits of continuing metformin should be weighed. The most common side effects related to metformin are gastrointestinal and may be eliminated by starting with a slow titration or switching to the sustained release version.

If a patient has a contraindication or is unable to tolerate metformin several alternative therapies are available. Sulfonylureas are one of those options and work by increasing endogenous insulin release. They have been a mainstay in diabetes therapy due to efficacy and cost. Sulfonylureas can be used in combination with most other diabetes medications but once patients begin short or rapid acting insulin sulfonylureas are discontinued. It is prudent to start with the lowest dose and titrate to effect balancing glycemic control with avoidance of hypoglycemia. Patients should be warned regarding hypoglycemia and advised on methods of treatment. Weight gain is a concern with the use of sulfonylureas (especially when used in combination with insulin or higher carbohydrate diets) and hypersensitivity reactions especially when a past reaction to a sulfonamide has been severe.

Thiazolidinediones are another option which work uniquely by increasing insulin-dependent disposal of glucose in skeletal muscle and adipocytes and also decreasing hepatic glucose production. They work to reduce both fasting and postprandial blood glucose levels and are effective at lowering the A1C up to about 1.5%. The potential risk of heart failure, bone fracture and edema have to be weighed against the benefits of a moderate A1C reduction and no hypoglycemia when used as monotherapy. It is important for patients to understand that there is a delay in the onset of effectiveness with thiazolidinediones and therefore they may not see the benefit immediately.

Alpha glucosidase inhibitors inhibit an enzyme found in the brush boarder of the small intestine which is responsible for the breakdown of complex carbohydrates. Since there is a delay in the breakdown of the carbohydrates there is a corresponding delay in the postprandial blood glucose levels. The key to success with alpha glucosidase inhibitors is to take the product with the first bite of the meal. Patients should anticipate gastrointestinal side effects with these products and if these ADRs are not reported the patient may not be taking these products correctly. The A1C reduction is up to 1% when used as monotherapy.

Meglitinides are another option which work by stimulating insulin secretion from the pancreas but these products are dependent on functioning beta cells. The A1C reduction is up to 1% and the major ADRs are weight gain, hypoglycemia and flu like symptoms. Meglitinides should be avoided in patients with hypoglycemic unawareness or in patients who are unwilling/unable to check their blood glucose despite the fact that these products are associated with less hypoglycemia then sulfonylureas.

Dipeptidyl peptidase-4 inhibitors result in prolonged active incretin levels which results in regulation of glucose homeostasis by increasing insulin synthesis and release from beta cells. They also decrease glucagon secretion from pancreatic alpha cells. With a mild A1C reduction up to approximately 0.8%, DDP4s reduce post prandial glucose levels. These products are contraindicated in patients with a history of pancreatitis and there have been post marketing reports of acute pancreatitis and severe and disabling arthralgias. Regular monitoring of renal function and an adjustment of the dose is recommended if there is a decline in renal function. Linagliptin does not need to be renally adjusted.

The ergot dopamine agonist, bromocriptine is thought to reset the aberrant central neurometabolic control of peripheral metabolism which results in a reduction in insulin resistance. A mild reduction in A1C can be expected as well as ADRs such as nausea, vomiting, dizziness, and hallucinations at higher doses. Patients should also be aware of ADRs such as fibrotic valve thickening and melanoma. Bromocriptine is contraindicated in patients with uncontrolled hypertension, syncopal migraines, and in women who are lactating. Patients should be reminded that a slow taper to off is needed if product discontinuation is warranted.

Sodium glucose co-transporter-2 inhibitors (SGLT2) work by blocking the reabsorption of glucose by the kidney and filtering it out of the body through the urine which may result in an A1C reduction of up to 0.7%. All of the SGLT-2 products are renally dosed and genital mycotic or urinary tract infections are common. If the patient is taking a sulfonylurea or insulin the dose may need to be reduced when an SGLT-2 is initiated to avoid hypoglycemia. There are additional benefits with the use of SGLT-2s including weight loss and blood pressure reduction.

Amylin Analogs result in a glucose-dependent inhibition of glucagon secretion and therefore a reduced rate of gastric emptying and increased satiety. If the patient is on insulin when an amylin analog is initiated the dose of insulin should be reduced to avoid hypoglycemia. This agent should also be avoided in patients who are unable or unwilling to monitor their blood glucose and other medications which require rapid absorption should be taken at a different time from amylin analogs.

Glucagon-like peptide-1 receptor agonists (GLP-1, incretin mimetics) bind and activate the GLP-1 receptor and increase glucose-dependent insulin secretion. Once injected these medications are "turned on" by elevated blood glucose levels and "turned off" when the blood glucose levels fall. These products have an approximate A1C reduction up to 1.5% but carry ADRs related to pancreatitis, pancreatic inflammation and cancer and should be avoided in patients with a history (family or personal) of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2. Weight loss and a decreased appetite are positive side effects associated with GLP-1s. These products were not all studied with insulin and it is prudent to consider an insulin dose reduction when initiating a GLP-1.

The key to successful treatment of diabetes is initiating therapeutic life style changes and medications early in the course of the disease. With a myriad of options available to the clinician today, combinations of different therapies can be used to obtain tight control over diabetes. This tight control will help to delay or prevent the onset of complications related to diabetes allowing the patient to remain symptom free for a longer period of time.
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