Virginia Valentine, APRN-CNS, BC-ADM, CDE, FAADE1
1Clinical Nurse Specialist, Clinica La Esperanza, Albuquerque, NM.
Getting where you want to go by setting appropriate goals is the first and most important step in managing diabetes. This process is a complex negotiation among competing priorities and primarily must be focused on patient desires, needs, and capabilities. Patient-centered care is defined as an approach to “providing care that is respectful of and responsive to individual patient preferences, needs, and values and ensuring that patient values guide all clinical decisions.”1
To assist clinicians in the management of type 2 diabetes (T2D), the American Diabetes Association (the Association) provides guidance in their Standards of Medical Care, Glycemic Targets.2 In this guideline, one can gauge the level of seven different patient factors that affect how stringent one should be in establishing goals for control (Figure 7.1). For most people, lowering the A1C to 7% has been shown to reduce microvascular complications of diabetes. For most people, a goal of ~7% is reasonable but could be lower or higher based on diabetes duration, life expectancy, and other patient factors.
Figure 7.1—Approach to the management of hyperglycemia.
Source: Reprinted with permission from American Diabetes Association.2
Once goals are set and agreed on, choosing appropriate therapies becomes the next task at hand. The Association’s Standards of Medical Care provides guidance on therapies based on relative efficacy, cost, and risks.2
Of course, lifestyle change is the first step in managing diabetes. Once it is apparent that medications will be needed, it helps to understand the defects that can lead to T2D. If glucose is to be used or stored efficiently in the body, the pancreas must secrete sufficient insulin, and it must be used properly by the body. In T2D, this altered process represents two main defects. People with T2D have insufficient insulin production; however, the deficiency is relative when compared to the production of insulin that would occur in response to the same degree of hyperglycemia in the absence of diabetes.3 In addition to insulin deficiency, the predominant problem is increased insulin resistance in the muscle, adipose cells, and liver.3 In individuals with T2D, overproduction of glucose by the liver appears to coexist with a relative or absolute decrease of insulin secretion and increased insulin resistance.3
Research in the past several years has revealed other factors in the pathophysiology of T2D. Glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP), which are secreted in the gut (incretin hormones), and amylin (a neuroendocrine hormone), which is secreted in the β-cells of the pancreas, all appear to have an impact on glucose homeostasis. Research into these hormones has led to the development of medications to address these hormonal defects. GLP-1 receptor agonists and dipeptidyl peptidase (DPP-4) inhibitors (indirectly) stimulate insulin secretion while inhibiting glucagon, thus lowering blood glucose.3 Amylin regulates glucose metabolism in the stomach and liver by delaying glucose transport in the postprandial state.4 The GLP-1 receptor agonists and amylin have an added benefit of producing satiety and possibly weight loss in some patients.
An additional defect is the excess reabsorption of glucose in the kidney in people with diabetes, which results in maintaining elevated blood glucose levels. The inhibition of sodium-glucose co-transporter 2 (SGLT-2) in the proximal tubule of the kidney produces increased glycosuria and lowers glucose and has the potential to lower weight.
CLASSES OF T2D MEDICATIONS
A good strategy to use when treating patients with T2D is to select medications that address these defects. Each major class of medications will be addressed with a summary of action and key facts.
Biguanides
Biguanides, of which metformin is the only one, work to control diabetes by decreasing glucose production in the liver (particularly during the night), thus lowering fasting blood glucose levels. Metformin counters insulin resistance; it does not stimulate insulin secretion, and when used as monotherapy, it does not cause hypoglycemia.5 Metformin generally is recognized as the best choice for initial medication. Lactic acidosis, although rare, is a potential risk of this category of medication. The FDA revised the guidance for the use of metformin in diabetic kidney disease in 2016, recommending the use of the eGFR instead of the serum creatinine as the basis for determining safe use and when to discontinue use. The revised guidelines state that metformin should not be initiated if the eGFR is <45 mL/min/1.73 m2. If the individual is on metformin and the eGFR is <60 mL/min/1.73 m2, a reduction in dose should be considered. If the eGFR is <30 mL/min/1.73 m2, the drug should be discontinued. Pooled data from 347 comparative trials and cohort studies revealed no cases of fatal or nonfatal lactic acidosis in 70,490 patient-years of metformin use or in 55,451 patient-years in the non-metformin group.6 To reduce the risk of lactic acidosis, metformin should not be prescribed for those with New York Heart Association (NYHA) class III or IV heart failure or those who use alcohol excessively. Caution should be taken in the elderly, and kidney function should be evaluated and closely monitored. The common side effect seen with biguanides is gastrointestinal complaints, especially if the dosage is advanced too quickly when initiated or initiated at too high a dose. This side effect is lessened when the medication is taken with food and gradually titrated or when an extended-release formulation is used. Many patients report a decrease in appetite and subsequent modest weight loss when taking biguanides.7 Metformin should be stopped the day of any procedure using iodinated contrast media or major surgical procedures and should be restarted 48 h later after adequate renal function has been confirmed. Metformin has also been associated with B12 deficiency and the Assocation recommends periodic measurement for B12 levels.
Nursing Considerations
As many as 40% of people starting metformin will have some GI side effects but most will be able to tolerate after a few weeks. Patients should be advised to take metformin with food and doses should be started low and titrated up as tolerated. Some people will have fewer GI side effects with the extended-release version. Caution should be taken in the elderly and people with deteriorating kidney function. Lactic acidosis is rare but the symptoms of lactic acidosis to be monitored include abdominal or stomach discomfort; decreased appetite; diarrhea; fast, shallow breathing; a general feeling of discomfort; muscle pain or cramping; and somnolence, tiredness, or weakness.
SELECTING THE NEXT-STEP THERAPY
The following classes of medication are all options for second-line therapy after an initial 3 months of metformin if A1C target is not reached (Figure 7.2).
Figure 7.2—Antihyperglycemic therapy in type 2 diabetes.
Source: From American Diabetes Association.2
Sulfonylureas
A class of long-acting insulin secretagogues known as sulfonylureas has been in existence since the 1950s. Sulfonylureas, which stimulate the β-cells in the pancreas to produce more insulin, appear to work quickly in reducing blood glucose levels.
When sulfonylureas were first introduced, health-care providers often were disappointed with the unpredictable way in which they stimulated the β-cells to secrete insulin. The first-generation sulfonylureas often encouraged insulin secretion when insulin was not needed, resulting in hypoglycemia. Fortunately, most of the second-generation sulfonylureas cause less hypoglycemia (except glyburide) than their predecessors.7 Weight gain and hypoglycemia continue to be potential side effects of this class of medications.7
The U.K. Prospective Diabetes Study (UKPDS) documented a progressive decline in β-cell function in individuals with T2D, commencing years before the actual diagnosis of diabetes and continuing throughout the person’s life, regardless of mode of treatment.8 For sulfonylureas to be effective, they require functioning β-cells; therefore, they are most useful in the earlier stages of T2D. Over time, sulfonylureas become less effective, and other medication will be needed to achieve glycemic targets.
Nursing Considerations
People on these medications should be cautioned that hypoglycemia is a potential adverse reaction. People taking sulfonylureas should not skip meals and should carry hypoglycemic treatment with them, especially when experiencing increased activity.
Meglitinides
Meglitinides are short-acting insulin secretagogues that are taken just before a meal. Meglitinides are more sensitive than sulfonylureas to being activated in the presence of hyperglycemia or a meal. For this reason, meglitinides appear to produce less hypoglycemia. Meglitinides should be taken immediately before a meal and omitted if the meal is skipped. This group of medications works well in individuals who have unpredictable eating patterns because the dose can be varied according to the size of the meal, or the dose can be skipped if the meal is missed. At the same time, because meglitinides are taken before every meal, they may not be the best choice for patients who have trouble remembering to take their medications.7
Thiazolidinediones
Thiazolidinediones decrease insulin resistance primarily in muscle and adipose cells. Their glucose-lowering effect is not based on stimulating insulin production; therefore, these agents do not produce hypoglycemia when used as monotherapy. The main side effects associated with thiazolidinediones are weight gain and edema. Thiazolidinediones can cause dose-related fluid retention when used alone or in combination with other antidiabetic medications and is most common when used in combination with insulin. Fluid retention may lead to or exacerbate congestive heart failure. Thiazolidinediones are not recommended for use in patients with NYHA class III or IV heart failure.9 Boxed warnings caution that thiazolidinediones can cause or worsen heart failure and should not be used if the patient is symptomatic for heart failure. Although older studies have suggested that an increased risk of coronary heart disease and heart attacks may be associated with rosiglitazone, pioglitazone treatment, in contrast, has shown significant protection from both micro- and macrovascular cardiovascular events. These studies led to a period of U.S. Food and Drug Administration (FDA) advisories from 2007 to 2013 that, aided by extensive media coverage, led to a substantial decrease in rosiglitazone use. In November 2013, the FDA announced it would remove the usage restrictions for rosiglitazone in patients with coronary artery disease.10 An increase of bone fractures has also been associated with thiazolidinediones therapy.
Nursing Considerations
People on thiazolidinediones should be advised of the dose-related risk of edema and weight gain and should be observed for excess edema and for signs and symptoms of heart failure. Additionally, people should be advised of dose-related weight gain and assisted to make modifications in diet to avoid weight gain and possibly promote weight loss.
Incretin-Based Therapies
Two naturally occurring incretin hormones play a role in the maintenance of glycemic control: GIP and GLP-1, both of which have a short half-life because of their rapid inactivation by DPP-4. GLP-1 receptor agonists (RAs) can be made resistant to DPP-4 degradation and thus provide pharmacological levels of GLP-1. These GLP-1 receptor agonists lower postprandial blood glucose by increasing insulin secretion from β-cells, lowering postprandial glucagon levels (without disturbing the glucagon response to hypoglycemia), suppressing appetite, and slowing gastric emptying. One of the benefits of this class is weight reduction.11 Recent evidence suggests that liraglutide may have cardioprotective benefit.12 Medications in this class are injected and vary from agents given twice daily, once daily, to once weekly. Figure 7.2 lists the currently available GLP-1 RAs. In addition, GLP-1 RAs in combination with long-acting insulin have recently been approved by the FDA.
The most common side effect of GLP-1 RAs is mild to moderate nausea, which frequently subsides with use.13 All of the long-acting GLP-1 RAs carry a warning regarding risk of thyroid C-cell tumors. These agents have caused dose-related and treatment duration–dependent increases in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure in male and female rats. It is unknown whether the agents cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance could not be determined from clinical or nonclinical studies. These agents are contraindicated in patients with a personal or family history of MTC and in patients with multiple endocrine neoplasia syndrome type 2. Routine serum calcitonin or thyroid ultrasound monitoring is of uncertain value in patients treated with GLP-1s. Patients should be counseled regarding the risk factors and symptoms of thyroid tumors.14
These medications have been implicated in reported cases of pancreatitis, but recent reviews of data on pancreatitis and pancreatic cancer have not produced firm conclusions. Ongoing studies will continue to evaluate the safety of the incretin-based medications.14
Nursing Considerations
People taking GLP-1 RAs should be advised that nausea and vomiting are potential side effects. Slow titration may make these medications more tolerable, and cessation of eating as soon as fullness is detected may help reduce these side effects.
DPP-4 Inhibitors
DPP-4 inhibitors work by blocking the DPP-4 enzyme. The DPP-4 enzyme is responsible for the rapid degradation of GLP-1, so by blocking this enzyme, the availability of GLP-1 and GIP is prolonged and the GLP-1 effect is enhanced: insulin secretion is increased and glucagon is suppressed. DPP-4s can be used as monotherapy or taken in conjunction with other oral diabetes medications. They should not be combined with GLP-1s. Unlike injectable incretins, these medications are not associated with weight loss. Kidney function should be assessed and dosage reductions should be made if needed for renal insufficiency. These drugs are not recommended for use in type 1 diabetes (T1D) or in ketoacidosis. Possible side effects include upper respiratory infection, nasopharyngitis, nausea, and headache.15
All of these medications have a warning for increased risk of pancreatitis. A 2014 meta-analysis found no evidence for increased pancreatic cancer risk in people treated with DPP-4 inhibitors; however, because of the modest amount of data available, the study was not able to completely exclude possible risk.16 The following agents currently are available on the U.S. market: sitagliptin (Januvia), saxagliptin (Onglyza), alogliptin (Nesina). Dose adjustments for these formulations are recommended if the eGFR is <50 mL/min/1.73m2. Linagliptin (Tradjenta) does not require dosage adjustment due to changes in renal status. These medications are available in fixed-dose combinations with various metformin doses. A number of DPP-4 inhibitor agents are in development.
Nursing Considerations
This class of medications has low risk for serious adverse events, but people taking these agents should be monitored for renal insufficiency and potential need for dose adjustment.
SGLT-2 Inhibitors
SGLT-2 inhibitors inhibit a sodium-glucose transport protein that is responsible for at least 90% of the glucose reabsorption in the kidney (SGLT-1 being responsible for the remaining 10%). Blocking this transport protein causes ~50–120 g of glucose per day (depending on the agent used) to be eliminated through the urine. These medications demonstrate A1C lowering of ~0.8–1.0% and additional benefits include a lowering of systolic blood pressure and modest weight reduction. Risks include volume contraction, genital mycotic infection, and small increases in low-density lipoprotein. Ketosis may be an issue if the patient is restricting carbohydrates, on insulin, and seriously ill and taking this class of medication. SGLT-2s should be stopped for patients who are hospitalized. Monitoring urine or blood ketones may be appropriate. Empagliflozin was found to significantly reduce deaths among individuals with type 2 diabetes and established cardiovascular disease (CVD) when compared with placebo.17 At this time we do not know if this is a class effect. Available medications in this class include: canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance). Dosing varies between agents based on eGFR. Canagliflozin and empagliflozin may be used at eGFR of >45 mL/min/1.73 m2, whereas dapagliflozin is approved for use with eGFR >60 mL/min/1.73 m. These medications also are available in fixed-dose combinations with metformin.18
Nursing Considerations
People taking these medications could be at risk for volume contraction–related adverse reactions, such as hypotension, and patients should be encouraged to drink extra fluids. Women and uncircumcised men should be advised of increased risk for genital mycotic infections.
Because of the significant glucose excretion in urine, glucose monitoring with urine glucose strips will be inaccurate. Use of the 1,5-anhydroglucitol (GlycoMark) assay may be unreliable as well.
Insulin Therapy
According to the Association’s guidelines, basal insulin is an option for second-line dual therapy with metformin.2 Because T2D is chronic and progressive, β-cell function is decreased by at least 50% at diagnosis and by 75% 6 years later.19 Additionally, β-cell function may be impaired temporarily in the case of severe hyperglycemia (also known as glucose toxicity).3
The Association’s Standards of Medical Care recommend initiation of insulin therapy in patients with T2D who have an initial A1C level >9%, or in those whose diabetes is uncontrolled despite optimal oral glycemic therapy.2 Insulin has the advantage of being effective where other medications may not be as effective in the presence of glucose toxicity. Insulin should be considered as part of any combination regimen when hyperglycemia is severe, especially if symptoms are present or any catabolic features (weight loss, ketosis) are present. The Standards of Care recommends initiating combination insulin injectable therapy when blood glucose is ≥300 mg/dL or A1C is ≥9%, or if the patient has symptoms of hyperglycemia (i.e., polyuria or polydipsia). As the patient’s glucose toxicity resolves, the regimen may, potentially, be simplified and insulin may able to be discontinued. This recommendation is based on expert opinion and not on the results of randomized controlled trials comparing different approaches in patients with an initial A1C level >9%.
The decision to initiate insulin therapy should be made based on glycemic control, not patient and provider readiness. When insulin is first mentioned to patients, it is not uncommon for them to plead for more time to eat better, exercise more, and improve their glycemic control. It should be stressed that the initiation of insulin is not intended to punish patients for not taking care of themselves; rather, it is simply necessary to achieve glycemic control. Insulin is a natural hormone that, when deficient, requires replacement. Many patients express a fear of weight gain and hypoglycemia while on insulin. Taking the time to explain the rationale for insulin and the benefit, promotes the patient-centered model of care. Providers are often reluctant to initiate insulin for many reasons including time constraints, belief that insulin may be a burden to the patient, and fear of hypoglycemia.
Weight gain as a result of initiating insulin therapy is a valid concern for patients with T2D and their health-care provider. As glycemic control improves, glycosuria decreases and calories once wasted by the body are now stored as fat. Intermittent overinsulinization may result in hypoglycemia that leads to hunger and an increase in caloric consumption.20 Weight gain can be minimized with attention given to carbohydrate counting and increased physical activity as insulin therapy is advanced. Concurrent use of metformin along with insulin therapy also has been shown to minimize weight gain.20 In two separate studies, bedtime administration of NPH instead of daytime NPH and use of insulin glargine instead of NPH yielded less weight gain.21 Levemir also has been associated with little or no weight gain.22
Many patients express the fear of actually injecting the insulin and of the increased risk of hypoglycemia with insulin therapy. In reality, the rates of severe hypoglycemia in T2D are low. The Kumamoto study,23 for example, showed an average A1C of 7.1% for the tightly controlled group and the same rate of mild hypoglycemia as that of the conventional therapy group, which had a mean A1C of 9.4%. Nurses can be influential in helping patients understand the benefits of insulin therapy, the ease of use, and the increased accuracy of new delivery devices, such as insulin pens.24 Patient education regarding the signs, symptoms, and especially prevention of hypoglycemia can allay fears. In addition, showing patients an insulin syringe or pen and short pen needle and asking them to try an injection usually is met with surprise at how tiny the needle actually is and how little pain is experienced.
The rationale for starting insulin for a patient with T2D is initially different from that in the case of T1D. This is because the pancreas in T2D patients still may be able to help by producing some insulin. The current philosophy is to use a simple and easy-to-follow regimen, maintain oral agents or GLP-1 RAs, and add a single injection of long-acting insulin once daily at a convenient time, such as in the morning or at bedtime.19 Current options include a long-acting basal insulin, such as glargine, degludec, or detemir; an intermediate-acting insulin, such as NPH; or a premixed biphasic insulin. Glargine, degludec, or detemir can be given either in the morning or at bedtime, depending on patient preference. A single injection of NPH often is given at bedtime. The premixed insulins are best given before meals, such as before breakfast and before supper. Because of insulin resistance, insulin dose requirements in T2D are often much higher than in T1D.20 Several choices of concentrated insulin now are available to achieve larger doses of insulin with smaller volumes. The important thing to remember is that there is no one treatment regimen for all patients but rather individual regimens should be designed or tailored to a patient’s particular needs and abilities.
In general, GLP-1 receptor agonists should not be discontinued with the initiation of basal insulin. Sulfonylureas, DPP-4 inhibitors, and GLP-1 RA are typically stopped once more complex insulin regimens beyond basal are used. 2
Nursing Considerations
Instructions for people starting insulin should include injection technique with either a syringe or pen device and patient practice with either insulin or saline. If instructing on a pen device and a small injection of insulin would not be appropriate, patients can practice injection techniques with no dose set and pretend to press the button after injection. Additionally, patients should be instructed on timing of dose, prevention and management of hypoglycemia, and proper storage. Patients should be given written and/or pictorial instructions.
Triple Therapy
The Association provides guidance for adding a third agent to the dual-therapy regimens.2 A DPP-4 inhibitor and GLP-1 RA should not be combined. If three oral agents or two oral agents plus GLP-1 RA are not bringing glucose into the goal range, basal insulin should be considered. Additionally, patients may require basal-bolus insulin regimens, or the addition of an amylin mimetic, such as pramlintide (Symlin), may be considered.
Practical Point
Insulin therapy should never be used as a threat. The natural progression of the disease tells us that most people with T2D eventually will need insulin, regardless of previous therapies. It does not indicate that the patient has failed in their efforts to control diabetes.
Pramlintide, a synthetic form of amylin, is an injectable medication that can be useful in optimizing glycemic control in patients taking insulin. Pramlintide works together with insulin to reduce postprandial hyperglycemia by suppressing glucagon secretion, slowing gastric emptying, and increasing satiety, thereby decreasing food intake. Pramlintide is particularly useful in patients who are on basal-bolus insulin therapy and still are unable to achieve optimal postprandial blood glucose levels. Pramlintide can be used in both T1D and insulin-treated T2D.25
Practical Point
As medications are being added or changed, remember to reinforce treatment goals with patients, stressing their relationship to avoiding diabetes-related complications. Make sure patients understand which medications may be stopped or continued when changing the treatment regimen. Most patients will find written instructions to be helpful.
ANTIHYPERGLYCEMIC THERAPY FOR T2D: GENERAL RECOMMENDATIONS 2017
Effective communication between the patient and health-care provider is crucial if patients are to execute complex treatment recommendations. At least 14% of the nation’s population speaks a language other than English at home.26Adhering to complex medication regimens may be especially difficult when a nurse attempts to assist a patient whose primary language is not English. Nurses must be proactive in developing strategies to deal with the needs of culturally diverse populations. The use of bicultural and bilingual staff, use of internal language banks, and language skills training may help nurses facilitate communication between themselves and diverse patients.27
Practical Point
To facilitate adherence to treatment recommendations, ensure that patients have written instructions on how they should be taking their medications and what they should do if they have questions about their medications before they leave your facility. An instruction form can be adapted to teach the mechanism of action and goals for control as well as to document doses to be taken. The teach back method of asking the patient to explain the instructions back to the provider is also helpful.
SUMMARY
T2D is a complex, progressive disease associated with numerous comorbidities, including hyperlipidemia, hypertension, obesity, and depression. Because of the progressive nature of the disease, and not the failure of the patient or health-care provider, most patients will need insulin in their lifetime. The nurse will play an important role in assisting patients in understanding the nature of their disease, including the necessity of medications to treat insulin resistance, insulin deficiency, and other defects of T2D as well as the importance of healthy lifestyle behaviors.
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