Diabetes Mellitus Agents

Chapter 53


Diabetes Mellitus Agents


Jane Kapustin




DRUG OVERVIEW





































































































































































































Class Subclass Generic Name Trade Name
Insulin Rapid acting insulin lispro Humalog image
    insulin aspart NovoLog image
    insulin glulisine Apidra
  Short acting Regular insulin Humulin R
Novolin R
  Intermediate acting NPH insulin Humulin N
Novolin N
  Long acting insulin glargine Lantus image
    insulin detemir Levemir image
  Mixtures 70/30 (70% NPH, 30% regular)
70/30 (70% aspart protamine/30% aspart)		 Novolin 70/30
Humulin 70/30
NovoLog Mix 70/30
    50/50 (50% NPH, 50% regular)
50/50 (50% lispro protamine/50% lispro)		 Humalog Mix 50/50
    75/25 Humalog (75% lispro protamine, 25% lispro) Humalog Mix 75/25
ORAL MEDICATIONS
 Second-generation sulfonylureas
   glyburide Micronase, DiaBeta; Glynase (micronized)
    glipizide image Glucotrol, Glucotrol XL
    glimepiride Amaryl
 Biguanides   metformin
metformin ER		 Glucophage, Glucophage XR, Fortamet
 Thiazolidinediones   rosiglitazone∗ image Avandia
    pioglitazone Actos image
 Nonsulfonylureas secretagogues (meglitinides)   nateglinide Starlix
    repaglinide Prandin
 α-Glucosidase inhibitors   acarbose image Precose
    miglitol Glyset
 Incretin agents Amylin analogs pramlintide Symlin
  Glucagon-like peptides (GLP-1) liraglutide Victoza image
  Incretin mimetics exenatide
exenatide XR		 Byetta
Bydureon
  Dipeptidyl peptidase-4 (DPP-4 inhibitors) linagliptin Tradjenta
    saxagliptin Onglyza
    sitagliptin phosphate Januvia image
Bile acid sequestrants   colesevelam Welchol
Bromocriptines   bromocriptine Cycloset
Combination therapies   metformin/rosiglitazone Avandamet
    metformin/glyburide Glucovance
    metformin/glipizide Metaglip
    metformin/pioglitazone Actoplus Met
    rosiglitazone/glimepiride Avandaryl
    repaglinide/metformin PrandiMet
    sitagliptin/metformin Janumet image
    saxagliptin/metformin Kombiglyze
    pioglitazone/glimepiride Duetact


image


image Top 100 drug; image key drug.


∗Removed from market 2011 but available by special FDA permission.




INDICATIONS




Pharmacologic agents are used in conjunction with diet and exercise to control blood glucose in those with diabetes. These agents include various insulins and seven classes of oral agents. Type 1 diabetes requires the use of insulin. Type 2 diabetes is present in approximately 90% of the 25.8 million Americans who have diabetes. These patients are usually started on oral medication, with the first choice as metformin. Insulin is added when oral medications provide inadequate control or there are contraindications to oral agents. The American Diabetes Association (ADA) and the American College of Endocrinology (ACE) diagnostic and treatment criteria are used in these guidelines.



Therapeutic Overview


Anatomy and Physiology


The pancreas is a gland with both endocrine and exocrine functions. The islets of Langerhans, which constitute only 1% to 2% of the gland, contain more than 1 million cells. Eighty percent of these cells are β-cells that produce and secrete insulin. α-Cells, also a component of the islets, produce glucagon, a potent hormone that promotes glycogenolysis and gluconeogenesis in the liver. The pancreas and the liver are the primary organs of glucose regulation attained via a negative feedback mechanism. When blood glucose rises, β-cells are stimulated by elevated glucose to release insulin. Insulin allows the muscle and the liver to use glucose and to store it as glycogen in the liver. Insulin also facilitates fat storage in adipose tissue, as well as uptake and conversion of amino acids to protein. As blood glucose levels fall, the cells are stimulated to release glucagon, resulting in glycogenolysis and gluconeogenesis in the liver. Glycogenolysis (conversion of glycogen into glucose) and gluconeogenesis (production of glucose from lactate and amino acids) result in increased serum glucose levels.


Insulin lowers blood glucose by enhancing glucose transport via facilitated diffusion into target tissues. Insulin binds to and stimulates receptors on each cell; this in turn fosters transport of glucose through the cell wall. Tissue insensitivity to insulin can occur when defects in receptors or defects in receptor response to insulin are present. Insulin also inhibits lipoprotein lipase, thereby preventing the release of fatty acids into the blood. Insulin promotes the transport and storage of glucose as triglycerides in fat cells.



Pathophysiology


The onset of diabetes involves a relative or absolute lack of insulin and/or insulin resistance and impaired or insufficient target cell receptors. These effects cause a lack of available glucose for cellular metabolism, resulting in glycogenolysis, lipolysis, and gluconeogenesis. Glucose uptake by the liver is impaired with a resultant increase in circulating glucagon. Protein storage is decreased. Overproduction of free fatty acids by fat cells has been noted. Elevated plasma free fatty acid levels increase hepatic glucose production by stimulating gluconeogenesis.


Type 2 diabetes is characterized by two phenomena: insulin resistance and β-cell dysfunction. The cause of type 2 diabetes is unknown, but certain factors increase the risk of development of the disease. With type 2 diabetes, secretion is impaired, hepatic glucose production is increased, and insensitivity to insulin in the tissues (i.e., insulin resistance) occurs.


Initially in type 2 diabetes, tissues become insensitive or resistant to insulin. As a compensatory mechanism, insulin release is increased so that normal glucose levels can be maintained. In fact, often, those in whom type 2 diabetes is newly diagnosed exhibit elevated insulin levels in an attempt to overcome resistance. Type 2 diabetes is a progressive disease that displays further deterioration of β-cell function over time, even when management is optimized. At diagnosis, approximately 50% of β-cell function has been lost.


Insulin secretion occurs in a biphasic manner. The first phase occurs rapidly, peaks in 3 to 5 minutes, and lasts about 10 minutes. This phase is triggered by a meal or a glucose challenge. If the blood glucose concentration remains elevated, then the second phase of insulin is triggered. This involves a slow release of insulin. Persons with type 2 diabetes lose first-phase insulin release, and postprandial hyperglycemia is the first sign. As the body endures continued exposure to hyperglycemia, the β-cells become more dysfunctional; this is referred to as glucotoxicity. This process often begins years prior to diagnosis of type 2 diabetes. With now a relative lack of insulin, gluconeogenesis and glycogenolysis are increased in the liver because these processes are dependent not on levels of glucose but on insulin levels. This further contributes to hyperglycemia and is often responsible for elevated fasting glucose levels.


Autoimmune destruction of β-cells is implicated in the diagnosis of type 1 diabetes. Environmental and genetic predisposition also may play a role. Onset of type 1 diabetes may occur suddenly as with the onset of diabetic ketoacidosis, or slowly with less risk of ketoacidosis as in the case of latent autoimmune diabetes of adults (LADA).



Disease Process


Testing for type 2 diabetes should be considered in all adults who are overweight (BMI ≥25 kg/m2) who have one or more risk factors. In the absence of risk factors, screening should begin at 45 years and older. Testing should be repeated every 3 years. According to the ADA, risk factors for the development of diabetes that should alert the provider to screen for diabetes include the following:




History of Vascular Disease


The Expert Committee on the Diagnosis and Classification of Diabetes under the sponsorship of the ADA modified criteria for diagnosis in 2012. These criteria were adopted by the ADA and represent current guidelines for diagnosis (Box 53-1).



BOX 53-1   Criteria for the Diagnosis of Diabetes Mellitus


A1c >6.5%. The test should be performed in a laboratory using a method that is NGSP certified and standardized to the DCCT assay.∗


Or


Fasting plasma glucose >126 mg/dl (7 mmol/L). Fasting is defined as no caloric intake for at least 8 hours.


Or


Two-hour plasma glucose >200 mg/dl (11.1 mmol/L) during an oral glucose tolerance test. The test should be performed as described by the WHO using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.∗


Or


In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose >200 mg/dl (11.1 mmol/L)


∗Taken from the American Diabetes Association (Position Statement, 2012).


Complications of diabetes include microvascular disease (e.g., nephropathy, retinopathy), macrovascular disease (e.g., coronary artery disease, peripheral vascular disease, cerebrovascular disease, neuropathy), and neuropathic disease (e.g., autonomic and peripheral). Vascular and neuropathic disease contributes to the increased risk of amputation. Multiple studies, such as the Diabetes Mellitus Control and Complications Trial research group (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS), continue to show that intensive glucose control at or below glycosylated hemoglobin (A1c) of 7% may prevent and/or delay the onset of complications.



Assessment


Conducting a thorough history and physical examination enables the provider to obtain a baseline evaluation, identify early effects and complications of diabetes, and, together with the patient, determine individual glycemic goals. ADA clinical practice recommendations list the following:



• History should include questions about skin changes, visual problems (e.g., history of retinopathy, date of last ophthalmologic examination), thyroid function (e.g., history of hypothyroid or hyperthyroid disease), cardiac arrhythmias, hypertension, lipid abnormalities, history of CAD and/or CHF, and hematologic, pulmonary, GI (e.g., chronic diarrhea, constipation, early satiety, liver disease), GU (e.g., urinary tract infection, difficulty voiding, incontinence, erectile dysfunction), obstetric and gynecologic (e.g., history of gestational diabetes, anticipation of pregnancy, contraceptive use), neurologic (e.g., weakness, muscle wasting, paresthesias, hyperesthesia, hypoglycemic unawareness), and vascular problems (e.g., leg pain, transient ischemic attacks).


• Physical examination should include assessment of height, weight, BMI, BP, vital signs, eye, mouth, thyroid, heart, lungs, abdomen (e.g., hepatic enlargement), bruits, pulses, hands, feet, skin (e.g., acanthosis nigricans, inflammation, infection), and nervous system (e.g., reflexes, sensory examination of feet).


• Laboratory evaluation includes CBC, CMP (including creatinine, BUN, TSH, Hbg, and HbA1c), fasting lipid profile, urinalysis, test for microalbuminuria, and ECG in adults. The HbA1c reflects the state of glycemia for the past 8 to 12 weeks.



Mechanism of Action


See Tables 53-1 and 53-2.





Insulin


Insulins are proteins that bind to cell wall receptors to allow cellular utilization of glucose. Insulin lowers blood glucose levels by stimulating peripheral glucose uptake, particularly in skeletal muscle and fat, and by inhibiting hepatic glucose production. An adequate supply of insulin is needed for transport of glucose across the cell membrane to sustain life.


Most insulin used today is produced by deoxyribonucleic acid (DNA) recombinant technology and is synthesized in a nonpathogenic strain of Escherichia coli bacteria or Saccharomyces cerevisiae fungus. Advantages of using synthetic human insulin include a decrease in the production of insulin antibodies and a diminished risk for the development of lipodystrophy at the injection site.


Insulin analogs are insulin preparations that are produced by modifying the structure of human insulin. Changing human insulin properties with amino acid substitutions improves the pharmacokinetic profile for optimal physiologic insulin replacement.





Thiazolidinediones


Rosiglitazone and pioglitazone increase sensitivity in the muscle and liver by improving control of glycemic utilization. This in turn reduces circulating insulin levels. Functioning β-cells are required for these medications to work. Specifically, these drugs are agonists for peroxisome proliferator–activated receptors-γ (PPAR-γ), which are found in adipose tissue, skeletal muscle, and liver. Activation of PPAR-γ receptors regulates the insulin-responsive genes involved in the control of glucose production, transport, and utilization and facilitates the regulation of fatty acid metabolism.


Rosiglitazone and all products containing rosiglitazone have been required to undergo a risk evaluation and mitigation strategy (REMS) so that products are only available by restricted access and distribution system due to the increased risk for heart attacks. Pioglitazone and all pioglitazone containing products now bear warnings about a possible risk of bladder cancer associated with use for more than 1 year.





Incretin Agents


Amylin Replacement


Pramlintide is an analog of amylin; it is an endogenous peptide that is secreted in conjunction with insulin by the pancreatic β-cells. Pramlintide produces the same physiologic effects as are caused by amylin, but it is stable enough to be used as a medication. Amylin is known to do the following:



Pramlintide is indicated in patients with type 1 diabetes and in those with insulin-requiring type 2 diabetes. It is given by subcutaneous injection three times a day before meals. This agent must be administered as a separate subcutaneous injection but in conjunction with insulin. It is helpful for patients with wide glycemic swings. It is weight neutral or may cause weight loss. The risk of hypoglycemia is significant, and close monitoring of blood glucose followed by frequent adjustments in the dosages of other diabetes medications is required. Its ability to induce weight loss makes it an attractive option for overweight patients. Other adverse reactions include nausea, anorexia, early satiety, and vomiting.




Exenatide (Byetta and Bydureon)


This agent is derived from a component of the saliva of the Gila monster lizard and has been approved as adjunctive therapy for type 2 diabetes. Exenatide binds to GLP-1 receptors and stimulates insulin secretion when blood sugar is high. It is the first drug that has been shown to restore first-phase insulin secretion, which does not occur in persons with type 2 diabetes. This metabolic defect is responsible for postprandial hyperglycemia. Exenatide also acts to stimulate β-cell replication and neogenesis, increase β-cell mass, and improve glucose tolerance. It is given as an injection before the morning and evening meals. Adverse effects of exenatide include nausea, vomiting, diarrhea, and upper respiratory symptoms. It may cause a reduction in food intake that will necessitate adjustment of the patient’s other diabetes drugs to prevent hypoglycemia. The risk of hypoglycemia is not increased when used with metformin, but this risk is increased when used with sulfonylureas. Exenatide is clearly associated with weight loss.



DPP-4 Inhibitors


Endogenous GLP-1 is rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4). Therefore, drugs that inhibit DPP-4 will prolong the activity of GLP-1. The first DPP-4 inhibitor, sitagliptin, was approved by the FDA in October 2006 as a once-daily oral medication. It can be used as monotherapy or can be combined with metformin or a thiazolidinedione. It reduces fasting and postprandial hyperglycemia in patients with type 2 diabetes and does not cause weight gain or hypoglycemia. Hypersensitivity to this product is the only listed contraindication for sitagliptin. Saxagliptin and linagliptin are also available for use. Linagliptin’s advantage is that it does not need to be decreased for renal or hepatic dysfunction, and it appears to have less cardiovascular risk than the other DPP-4 inhibitors; however, this requires further study.





Treatment Principles


Standardized Guidelines


Generally accepted guidelines for managing diabetes have been established by the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (ACE). Although subtle differences are evident, most guidelines are similar. See http://care.diabetesjournals.org/content/35/Supplement_1/S11.full.pdf+html and http://care.diabetesjournals.org/content/35/3/660.1.full.




Cardinal Points of Treatment




• To prevent or delay onset of diabetes, patients with impaired glucose tolerance (IGT) or IFG should be advised to lose 5% to 10% of body weight and to increase physical activity to at least 150 minutes per week of moderate activity such as walking. Follow-up counseling seems to improve the likelihood of success.


• Metformin therapy should be considered in patients who are at very high risk for diabetes, based on combined IFG and IGT, plus other risk factors, and who are obese and younger than 60 years of age.


• Studies show that intensive glucose control (A1c 6.5% to 7%) improves mortality and morbidity and reduces costs.


• Because lowering A1c levels to an average of about 7% has been shown to reduce microvascular and neuropathic complications of diabetes, the target A1c goal for nonpregnant women is generally less than 7% (less than 6.5% per AACE guidelines). However, A1c and other treatment goals should be individualized.


• For selected individual patients, the A1c goal is as close to normal (<6%) as possible without significant hypoglycemia, in light of epidemiologic studies showing a small but incremental benefit to lowering A1c from 7% into the normal range.


• Because of the progressive nature of diabetes, practitioners should expect to titrate medications and augment therapy over time.


• For children, patients with a history of severe hypoglycemia, those with limited life expectancies, individuals with comorbid conditions, and those with long duration of diabetes and minimal or stable microvascular complications, less stringent A1c goals may be appropriate.


• As glucotoxicity and further β-cell dysfunction occur, the patient most likely will require higher doses of medications or the addition of new agents to maintain HbA1c at goal.


• Monitoring carbohydrate intake is essential to achieving glycemic control, whether by carbohydrate counting, exchanges, or experience-based estimation. For patients with diabetes, glycemic index and glycemic load use may modestly improve glycemic control vs. that observed when considering only total carbohydrate.


• People with diabetes should perform at least 150 minutes per week of moderate-intensity aerobic physical activity (50% to 70% of maximum heart rate), and unless there are contraindications, those with type 2 diabetes should perform resistance training three times per week.


• Goals of care must be established with the patient and should reflect the individualized plan of care specifically designed for that patient. The plan of care should account for costs, side effects, preferences, and A1c goals.


• Evidence shows that maintaining individualized glycemic goals should be followed in treatment for the elderly. Importance is placed on maintaining optimal control to lessen the vascular and neurologic complications of the disease.



Nonpharmacologic Treatment


Establish Goals


The first step is to establish glycemic goals for the individual patient. The patient’s age, ability to provide self-care, other medical problems, social support, and financial issues all play a role in decisions regarding individual glycemic goals. (See Table 53-1 for ADA-recommended glycemic goals.)


For patients who have type 2 diabetes, an initial physician referral or collaboration may be needed, especially if the patient’s condition has been compromised. Patients with type 1 diabetes may require a referral to an endocrinologist or a diabetes specialist APRN.


The second step focuses on nonpharmacologic therapeutic techniques such as diet and exercise. Individuals may benefit from nutritional counseling and physical therapy. Bariatric surgery is used in select patients who have severe hypertension and who are morbidly obese.


Many patients with diabetes resist taking medications and may rely on herbal products to control symptoms. Some of these herbal products have potential interactions with other medications that the patient may be taking. (See Table 53-9 for a list of potential drug interactions.)

< div class='tao-gold-member'>

Only gold members can continue reading. Log In or Register to continue

Related posts:

  1. Complementary and Alternative Therapies
  2. Design and Implementation of Patient Education
  3. Antiparkinson Agents
  4. Upper Respiratory Agents

Stay updated, free articles. Join our Telegram channel
Tags:
Jul 22, 2016 | Posted by in PHARMACY | Comments Off on Diabetes Mellitus Agents

Full access? Get Clinical Tree
Get Clinical Tree app for offline access