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Pharmacotherapy of type 2 diabetes mellitus: navigating current and new therapies.

Diabetes is a complex disease that affects an estimated 29.1 million adults (9.3%) in the United States. The prevalence of diagnosed diabetes is higher among certain minorities, including American Indians and Alaska Natives (15.9%), non-Hispanic Black adults (13.2%), Hispanics (12.8%), and Asian Americans (9.0%), than in non-Hispanic White adults (7.6%) (Centers for Disease Control and Prevention [CDC], 2014a). Diabetes prevalence is highest (>10%) in Puerto Rico and southern and Appalachian states; age-adjusted prevalence of diagnosed diabetes is as high as 12.7% in Alabama and 13.7% in Puerto Rico (CDC, 2013). If current trends continue, the prevalence of diabetes may reach 21%-33% of the population in the United States by 2050 (Boyle, Thompson, Gregg, Barker, & Williamson, 2010).

Type 2 diabetes mellitus (T2DM) accounts for 90%-95% of newly diagnosed cases of diabetes (CDC, 2014a). Reduced sensitivity to insulin in liver, muscle, and adipose tissue, as well as a decline in pancreatic (3-cell function leading to impaired insulin secretion, are among the pathophysiologic processes that eventually result in hyperglycemia (Kahn, Cooper, & Del Prato, 2014). Over the past decade, new antidiabetic medications have been approved for the treatment of T2DM, including dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, an amylin analogue, and sodium-glucose cotransporter 2 (SGLT2) inhibitors (Drucker et al., 2010; Nauck, 2014).

The purpose of this review is to discuss treatment goals and guidelines for T2DM, as well as current treatment options, with particular emphasis on the newest approved antidiabetic agents (SGLT2 inhibitors). Relevant articles and clinical practice guidelines were retrieved from a PubMed search from January 2010 through September 2015, using the search terms type 2 diabetes, antidiabetic medication, glucose reabsorption, and SGLT2. Pivotal clinical trials upon which treatment guidelines are based also were included.

Treatment Goals

T2DM is a major risk factor for cardiovascular (CV) disease, blindness in adults, and kidney failure requiring dialysis or transplantation (American Diabetes Association [ADA], 2015; CDC, 2014b). Hyperglycemia is the key determinant of diabetes complications, and intensive glycemic control can reduce the risk of microvascular complications (retinopathy, nephropathy, and neuropathy) in patients with newly diagnosed T2DM (ADA, 2015). Moreover, early intensive glycemic control at the time of diagnosis of T2DM is associated with significantly decreased risk of myocardial infarction and death from any cause over the long term (Dailey, 2011; Holman, Paul, Bethel, Matthews, & Neil, 2008). In patients with T2DM and albuminuria, lifestyle changes and multiple risk factor control (e.g., hypertension, dyslipidemia, smoking) with antidiabetic therapy substantially reduces rates of death, CV events, and progression to end-stage renal disease and retinopathy (ADA, 2015; Gaede, LundAndersen, Parving, & Pedersen, 2008). However, intensive glycemic control has not been shown to reduce CV risk in patients with established T2DM and comorbidities or pre-existing CV disease (Dailey, 2011; Duckworth et al., 2009; Gerstein et al., 2008; Patel et al., 2008).

National and international guidelines recommend glucose control be monitored by measurement of glycated hemoglobin (HbAlc) at least twice a year in all patients with T2DM or more frequently based on degree of glycemic control. The American Diabetes Association/ European Association for the Study of Diabetes (ADA/EASD) and the American Association of Clinical Endocrinologists (AACE) guidelines stress the need for glycemic goals to be individualized and recommend general HbAlc targets of less than 7% and less than or equal to 6.5%, respectively, for most adult patients (ADA, 2015; Handelsman et al., 2015; Inzucchi et al., 2015).

Patient-directed approaches to glycemic control, including diabetes self-management education, blood glucose self-monitoring, and lifestyle changes (e.g., healthy diet, weight loss, increased physical activity) have broad benefits in controlling hyperglycemia and CV risk factors in patients with T2DM (Wing et al., 2011). However, in the Look AHEAD trial of overweight or obese individuals with T2DM, intensive lifestyle changes (including weight loss) did not reduce CV events compared with a program of diabetes education and support (Look Ahead Research Group, 2013). Because weight loss and physical activity are difficult to maintain over the long term, most patients will require pharmacotherapy to achieve and maintain glycemic control. Moreover, with impaired insulin sensitivity and continuing deterioration of (3-cell function, most patients will require higher doses and additional antidiabetic medications over time, and eventually insulin therapy to achieve glycemic control (ADA, 2015).

Pharmacotherapy

Pharmacotherapy should be customized for each patient, based on the potential of lowering HbAlc, side effects, tolerability, ease of use, long-term adherence, and expense (ADA, 2015).

Metformin

Metformin (e.g., Glucophage[R]), the most widely used oral drug for T2DM, decreases hepatic glucose output by enhancing the liver's sensitivity to insulin (Viollet et al., 2012). Metformin is recommended as first-line pharmacotherapy for T2DM as long as the patient has no contraindications or unacceptable tolerance issues (ADA, 2015; Handelsman et al., 2015). Many approved fixed-dose combinations of metformin are available with other oral antidiabetic medications, including sulfonylureas, meglitinides, thiazolidinediones (TZDs), DPP-4 inhibitors (Blonde & San Juan, 2012), and SGLT2 inhibitors. Metformin is weight neutral and associated with a low risk of hypoglycemia (ADA, 2015). Metformin generally is well tolerated, although gastrointestinal side effects (e.g., diarrhea in up to 50% of patients) are reported commonly during initiation of therapy (ADA, 2015; Bristol-Myers Squibb Company, 2009). Metformin is contraindicated in patients with renal impairment because it may increase the risk of lactic acidosis, a very rare but potentially fatal condition (Amin & Suksomboon, 2014; Inzucchi, Lipska, Mayo, Bailey, & McGuire, 2014).

Sulfonylureas

Sulfonylureas (e.g., glimepiride [Amaryl[R]], glipizide [Glucotrol[R]], glyburide [Micronase[R]]) bind to specific receptors on pancreatic (3-cells, resulting in stimulation of insulin secretion (ADA, 2015). The efficacy of sulfonylureas is generally similar to that of metformin (Hemmingsen et al., 2014). Side effects of particular concern include hypoglycemia and weight gain (ADA, 2015).

Meglitinides

Meglitinides (e.g., nateglinide [Starlix[R]], repaglinide [Prandin[R]]) increase insulin secretion by a similar mechanism as sulfonylureas, with similar efficacy in reducing HbA1c (Bennett et al., 2011). They have a more rapid onset but shorter duration of action than sulfonylureas. Because of this, meglitinides usually are administered before each meal (Skugor, 2014). Similar to sulfonylureas, meglitinides can cause hypoglycemia and weight gain (ADA, 2015).

Thiazolidinediones

TZDs (e.g., pioglitazone [Actos[R]], rosiglitazone [Avandia[R]]) increase the sensitivity of skeletal muscle and adipose tissue to insulin (Handelsman et al., 2015), leading to increased uptake and metabolism of glucose by these tissues. TZDs reduce HbAlc (ADA, 2015) but are associated with fluid retention, weight gain, and an increased risk of congestive heart failure in patients with preexisting CV comorbidities (Handelsman et al., 2015).

[alpha]-Glucosidase Inhibitors

[alpha]-Glucosidase inhibitors (e.g., miglitol [Glyset[R]], acarbose [Precose[R]]) delay the absorption of carbohydrates by inhibiting conversion of oligosaccharides to monosaccharides in the intestine and thus lower postprandial blood glucose and insulin concentration (ADA, 2015). They are less effective than metformin and sulfonylureas in reducing HbAlc but have a low risk of hypoglycemia and weight gain (ADA, 2015; Garber et al., 2015). The major adverse effect of [alpha]-glucosidase inhibitors is gastrointestinal discomfort, which can limit use (ADA, 2015).

Glucagon-like Peptide-1 Receptor Agonists

Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone secreted in response to nutrient absorption (Nauck, 2011). GLP-1 enhances insulin secretion, decreases glucagon secretion, delays gastric emptying, increases satiety, and decreases food intake (Nauck, 2011). GLP-1 receptor agonists are injectable, longer-acting analogs of the endogenous peptide that improve glycemic control and may promote weight loss (average loss 1-4 kg depending on background anti-diabetic thera py) (Drucker et al., 2010; Reid, 2012). Currently approved GLP-1 receptor agonists are given twice daily (exenatide [Byetta[R]]), once daily (liraglutide [Victoza[R]]), or once weekly (exenatide extended release [Bydureon[R]], albiglutide [Tanzeum[R]], dulaglutide [Trulicity[R]]) (ADA, 2015; Trujillo, Nuffer, & Ellis, 2015). GLP-1 receptor agonists have a low risk of causing hypoglycemia but are associated with gastrointestinal disturbances (Nauck, Baranov, Ritzel, & Meier, 2013). Pancreatitis has been reported with GLP-1 receptor agonist therapy but a causal relationship is uncertain (Butler, Elashoff, Elashoff, & Gale, 2013; Nauck, 2013).

Dipeptidyl Peptidase-4 Inhibitors

In addition to GLP-1, glucosedependent insulinotropic polypeptide (GIP) is the other key gastrointestinal hormone that stimulates postprandial insulin secretion (Brown & Evans, 2012). GLP-1 and GIP are metabolized rapidly to inactive metabolites by DPP-4 (Drucker et al., 2010). DPP-4 inhibitors (e.g., sitagliptin [Januvia[R]], saxagliptin [Onglyza[R]], linagliptin [Tradjenta[R]], and alogliptin [Nesina[R]]) delay degradation of endogenous GLP-1 and GIP. This increases availability of endogenous peptides, leading to reduction of hyperglycemia (ADA, 2015). DPP-4 inhibitors are administered once daily, and dose adjustments are required in patients with renal impairment who are prescribed sitagliptin, saxagliptin, or alogliptin (but not linagliptin) (AstraZeneca, 2015a; Boehringer Ingelheim, 2015; Merck & Co., 2015; Takeda Pharmaceuticals American, Inc., 2015). DPP-4 inhibitors have a low risk of hypoglycemia and generally are well tolerated, with little or no effect on body weight (ADA, 2015). Nasopharyngitis, urinary tract infection, and headache are the most common side effects associated with DPP-4 inhibitors (Dicker, 2011).

Recent CV outcome trials have reported that saxagliptin, alogliptin, and sitagliptin as add-ons to standard of care did not increase or decrease major adverse CV events in patients with T2DM and high CV risk compared with add-on of placebo (Green et al., 2015; Scirica et al., 2013; White et al., 2013). However, add-ons increased risk for hospitalization for heart failure was observed in patients treated with saxagliptin (Scirica et al., 2013). Rates of acute and chronic pancreatitis were similar among treatment groups in each CV outcome trial for saxagliptin, alogliptin, and sitagliptin (Green et al., 2015; Scirica et al., 2013; White et al., 2013).

Insulin

Insulin is the oldest and most effective antidiabetic agent (Walia, 2012), and insulin analogs with different pharmacokinetic profiles are available (ADA, 2015). No dose limits exist for insulin use (Barnard, Batch, & Lien, 2011), and therapy is associated with a nearly universal response (ADA, 2015). Insulin therapy usually requires additional patient education for injection technique and dose adjustment. Initial therapy in patients with T2DM usually aims to increase basal insulin supply using long-acting insulin (basal therapy). In general, basal analogs are preferred over Neutral Protamine Hagedorn insulin because of lower risk for hypoglycemia (Handelsman et al., 2015). However, patients may require additional mealtime therapy with short- or rapid-acting insulins (basal-bolus therapy). Hypoglycemia and weight gain are the most substantial side effects associated with insulin use (Handelsman et al., 2015).

SGLT2 Inhibitors

SGLT2 inhibitors are the newest class of antihyperglycemic agents approved for use in patients with T2DM. SGLT2 is a glucose transporter located in the kidneys and is responsible for reabsorption of the majority of glucose filtered by the kidneys (List & Whaley, 2011). Under normal conditions, the kidneys reabsorb virtually all filtered glucose. In individuals with T2DM, the kidneys' capacity to reabsorb glucose is increased (DeFronzo et al., 2013), further contributing to existing hyperglycemia. Inhibition of SGLT2 is therefore an attractive mechanism to reduce hyperglycemia by increasing renal glucose excretion. Because the mechanism of action of SGLT2 inhibitors is independent of insulin secretion or action, less risk exists for major hypoglycemic events (List & Whaley, 2011). Moreover, the loss of calories associated with increased renal excretion of glucose typically results in weight loss.

Dapagliflozin (Farxiga[R]), canagliflozin (Invokana[R]), and empagliflozin (Jardiance[R]) are SGLT2 inhibitors approved as adjuncts to diet and exercise to improve glycemic control in adults with T2DM (Nauck, 2014). SGLT2 inhibitors are effective in reducing HbAlc, fasting plasma glucose, postprandial serum glucose, and generally are well tolerated (Nauck, 2014). In a meta analysis of 58 clinical trials with 16,407 patients, SGLT2 inhibitors reduced HbA1c by an average of 0.6% to 0.8% as monotherapy or add-on therapy to other antihyperglycemic medications compared with placebo (Vasilakou et al., 2013). These agents also reduced body weight by approximately 1.7 kg and systolic blood pressure by up to 5 mm Hg. Reduction in body weight appeared to be largely the result of a reduction in fat mass (Bolinder et al., 2012; Cefalu et al., 2013). Dapagliflozin also is effective and well tolerated in patients with T2DM with comorbid CV disease and hypertension (Cefalu et al., 2015) or with a history of CV disease (Leiter et al., 2014). Findings from the empagliflozin CV outcomes study were reported recently. In this study of more than 7,000 adults with T2DM who were at high risk for CV events, empagliflozin as add-on to the standard of care was superior to add-on placebo in reducing CV risk over a median follow-up period of 3.1 years (Zinman et al., 2015). Prospective long-term CV outcome studies in patients at high risk for CV events are ongoing for canagliflozin and dapagliflozin (National Institutes of Health, 2015; Neal et al., 2013).

Incidence of hypoglycemia is low except when SGLT2 inhibitors are used with sulfonylureas or insulin (Vasilakou et al., 2013). Increased urinary tract and genital infections that occur more frequently in women than men appear to be a class effect (Nauck, 2014). Studies with data up to 4 years indicate SGLT2 inhibitors provide durable glycemic control and consistent tolerability in diverse patient populations (Bailey et al., 2015; Bode et al., 2014; Cefalu et al., 2015; Del Prato et al., 2015; Ferrannini et al., 2013; Leiter et al., 2014). Because the efficacy of SGLT2 inhibitors depends on the amount of glucose filtered by the kidneys, they are less effective in patients with moderate to severe renal impairment (Barnett et al., 2014; Kohan, Fioretto, Tang, & List, 2014; Yale et al., 2013). Kidney function should be assessed before initiating treatment with SGLT2 inhibitors; these agents should not be used in patients with estimated glomerular filtration rates of less than 45 mL/min/1.73[m.sup.2] (canagliflozin, empagliflozin) (Eli Lilly and Company, 2015; Janssen Pharmaceuticals, 2015) or less than 60 mL/min/1.73[m.sup.2] (dapagliflozin) (AstraZeneca, 2015b).

Other Agents

Other, less commonly used drugs for T2DM include pramlintide (Symlin[R], not licensed in Europe for T2DM), colesevelam (Welchol[R]), and bromocriptine (Parlodel[R]). Pramlintide is a synthetic analog of amylin that has many of the actions of the endogenous hormone, including slowed gastric emptying, increased satiety, and inhibition of glucagon secretion (ADA, 2015). In T2DM, amylin is not recommended for use as monotherapy but can improve glycemia and attenuate weight gain when used as adjunct therapy in patients receiving insulin (Handelsman et al., 2015). Common adverse effects include gastrointestinal discomfort, particularly nausea and vomiting (ADA, 2015).

Colesevelam is a bile acid sequestrant that lowers HbAlc, fasting plasma glucose, and low-density lipoprotein cholesterol (Fonseca, Handelsman, & Staels, 2010). The mechanism of action is poorly understood. Side effects are gastrointestinal. Bromocriptine is a centrally acting dopamine agonist that reduces HbAlc in patients with T2DM (DeFronzo, 2011). Its mechanism of action is unclear. Side effects include nausea, asthenia, constipation, and dizziness.

Treatment Recommendations

Treatment recommendations from the ADA/EASD (Inzucchi et al., 2015) and the AACE (Handelsman et al., 2015) stress the importance of individualization of HbAlc goals as well as individual tailoring of medications used to meet these goals. In addition, guidelines recommend treatment intensification with combination therapy if HbAlc goals are not attained. Diet and exercise together with metformin monotherapy usually are recommended as initial therapy for individuals with T2DM. If target HbAlc is not achieved or maintained, or if patients have an initial HbAlc equal to or greater than 7.5% (AACE) or 9% (ADA), dual therapy with metformin plus a sulfonylurea, TZD, GLP-1 receptor agonist, DPP-4 inhibitor, or SGLT2 inhibitor is recommended (ADA, 2015; Garber et al., 2015). If HbAlc exceeds 9% and the patient has no symptoms at presentation, triple therapy may be initiated; however, insulin with or without other agents may be appropriate if the patient has high HbAlc and symptoms of hyperglycemia (Garber et al., 2015; Handelsman et al., 2015).

Although many antidiabetic medications are available, analysis of patients with diagnosed diabetes from the National Health and Nutrition Examination Survey found that despite a decline in mean HbAlc over time (7.42% in 1999-2004 to 7.07% in 2005-2010), only 55.1% of patients taking antidiabetic medications in 2005-2010 achieved HbAlc less than 7% (Selvin, Parrinello, Sacks, & Coresh, 2014). Reasons for failure to achieve glycemic goals may include lack of treatment initiation and intensification, patient nonadherence, intolerability, and progressive decline in (1-cell function that renders therapies dependent on insulin secretion or action less effective over time (Garcia-Perez, Alvarez, Dilla, Gil-Guillen, & Orozco-Beltran, 2013; Khunti, Wolden, Thorsted, Andersen, & Davies, 2013; Saisho, 2014). Therefore, additional pharmacologic therapies with novel mechanisms of action independent of insulin and with acceptable safety profiles may improve patients' chances of achieving and maintaining glycemic control.

Conclusion

The significant burden imposed by T2DM on individuals and society underscores the need to achieve better control of the disease. The keys to optimal control are early diagnosis and intervention with lifestyle changes and use of pharmacotherapies that address various abnormalities in T2DM (see Figure 1) (ADA, 2015; Kahn et al., 2014). Novel medications can offer new therapeutic options by using different mechanisms of action than current drugs. Combined with additional benefits, such as lower rates of hypoglycemia and weight neutrality or reduction, this can be important for long-term glycemic control and for improving disease outcomes. Specifically, the new class of SGLT2 inhibitors has been shown to improve glycemic control and promote weight loss (Nauck, 2014). This and other new therapies may serve as needed additional tools to improve glycemic control in patients with T2DM. EH3

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Kelley Newlin Lew, DNSc, ARNP-C, CDE, is Assistant Professor, University of Connecticut, School of Nursing, Storrs, CT.

Allison Wick, FNP-C, MSN, ARNP, CDE, is Director of Education and Program Development, Diabetes Research Institute's Eleanor and Joseph Kosow Diabetes Treatment Center, University of Miami Miller School of Medicine, Miami, FL.

Acknowledgments: Editorial support was provided by Richard M. Edwards, PhD, and Janet E. Matsuura, PhD, from Complete Healthcare Communications, LLC, and was funded by BristolMyers Squibb and AstraZeneca.
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Title Annotation:CNE SERIES
Author:Lew, Kelley Newlin; Wick, Allison
Publication:MedSurg Nursing
Date:Nov 1, 2015
Words:5367
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