6 page paper on diabetes.

November-December 2015 • Vol. 24/No. 6 413

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 Bristol- Myers Squibb and AstraZeneca.

Pharmacotherapy of Type 2 Diabetes Mellitus: Navigating Current and New

Therapies

D iabetes 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-adjust- ed 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, & Wil - liamson, 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 pancre- atic b-cell function leading to impaired insulin secretion, are among the pathophysiologic proc - esses that eventually result in hyper glycemia (Kahn, Cooper, & Del Prato, 2014). Over the past decade, new antidiabetic medica- tions 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-glu-

cose cotransporter 2 (SGLT2) inhi - bitors (Drucker et al., 2010; Nauck, 2014).

The purpose of this review is to discuss treatment goals and guide- lines for T2DM, as well as current treatment options, with particular emphasis on the newest approved antidiabetic agents (SGLT2 inhib - itors). 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 car-

diovascular (CV) disease, blindness in adults, and kidney failure requiring dialysis or transplantation (American Diabetes Association [ADA], 2015;

CDC, 2014b). Hyper glycemia is the key determinant of diabetes compli- cations, and intensive glycemic con- trol can reduce the risk of microvas- cular complications (retinopathy, neph ro pathy, and neuropathy) in pa - tients with newly diagnosed T2DM (ADA, 2015). Moreover, early inten- sive 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 pa tients with T2DM and albuminuria, life - style changes and multiple risk factor control (e.g., hypertension, dyslipi- demia, smoking) with antidiabetic therapy substantially reduces rates of death, CV events, and progres sion to end-stage renal disease and retino - pathy (ADA, 2015; Gaede, Lund- Andersen, Parving, & Peder sen, 2008). However, intensive glycemic control has not been shown to reduce CV risk in patients with

Kelley Newlin Lew Allison Wick

The keys to optimal glycemic control in patients with type 2 dia- betes are early diagnosis and interventions that include lifestyle changes and pharmacotherapy. This review discusses therapeutic goals and current options for treatment of type 2 diabetes.

Instructions for Continuing Nursing Education Contact Hours appear on page 419.

November-December 2015 • Vol. 24/No. 6414

established T2DM and comorbidi- ties or pre-existing CV disease (Dailey, 2011; Duckworth et al., 2009; Gerstein et al., 2008; Patel et al., 2008).

National and international guide - lines recommend glucose control be monitored by measurement of gly- cated hemoglobin (HbA1c) at least twice a year in all patients with T2DM or more frequently based on degree of glycemic control. The American Diabetes Association/ European Asso ciation for the Study of Diabetes (ADA/EASD) and the American Association of Clinical Endocrin olo gists (AACE) guidelines stress the need for glycemic goals to be individualized and recommend general HbA1c 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 dia- betes self-management education, blood glucose self-monitoring, and lifestyle changes (e.g., healthy diet, weight loss, increased physical activity) have broad benefits in con- trolling 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 (includ- ing 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 pharmacother- apy to achieve and maintain gly - cemic control. Moreover, with im - paired insulin sensitivity and con- tinuing deterioration of b-cell func- tion, most patients will require higher doses and additional antidi- abetic medications over time, and eventually insulin therapy to achieve glycemic control (ADA, 2015).

Pharmacotherapy Pharmacotherapy should be cus-

tomized for each patient, based on

the potential of lowering HbA1c, side effects, tolerability, ease of use, long-term adherence, and expense (ADA, 2015).

Metformin Metformin (e.g., Glucophage®),

the most widely used oral drug for T2DM, decreases hepatic glucose output by enhancing the liver’s sen- sitivity 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; Hand - els man et al., 2015). Many approved fixed-dose combinations of met- formin are available with other oral antidiabetic medications, including sulfonylureas, meglitinides, thiazo- lidinediones (TZDs), DPP-4 inhib - itors (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 com- monly during initiation of therapy (ADA, 2015; Bristol-Myers Squibb Company, 2009). Metformin is con- traindicated 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®], glipizide [Glucotrol®], glyburide [Micronase®]) bind to spe- cific receptors on pancreatic b-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 particu- lar concern include hypoglycemia and weight gain (ADA, 2015).

Meglitinides Meglitinides (e.g., nateglinide

[Starlix®], repaglinide [Prandin®]) increase insulin secretion by a simi- lar 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 sulfony- lureas. 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®],

rosiglitazone [Avandia®]) 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 HbA1c (ADA, 2015) but are associat- ed with fluid retention, weight gain, and an increased risk of congestive heart failure in patients with pre- existing CV comorbidities (Handels - man et al., 2015 ).

a-Glucosidase Inhibitors a-Glucosidase inhibitors (e.g., mi -

glitol [Glyset®], acarbose [Precose®]) delay the absorption of carbohy- drates 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 met- formin and sulfonylureas in reduc- ing HbA1c but have a low risk of hypoglycemia and weight gain (ADA, 2015; Garber et al., 2015). The major adverse effect of a-glu- cosidase inhibitors is gastrointesti- nal discomfort, which can limit use (ADA, 2015).

Glucagon-like Peptide-1 Receptor Agonists

Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone secret- ed in response to nutrient absorp- tion (Nauck, 2011). GLP-1 enhances insulin secretion, decreases gluca - gon secretion, delays gastric empty- ing, increases satiety, and decreases food intake (Nauck, 2011). GLP-1 receptor agonists are injectable, longer-acting analogs of the endoge- nous peptide that improve glycemic control and may promote weight loss (average loss 1-4 kg depending on background anti-diabetic thera-

November-December 2015 • Vol. 24/No. 6 415

py) (Drucker et al., 2010; Reid, 2012). Currently approved GLP-1 receptor agonists are given twice daily (exe- natide [Byetta®]), once daily (liraglu- tide [Victoza®]), or once weekly (exe- natide extended release [Bydureon®], albiglutide [Tanzeum®], dulaglutide [Trulicity®]) (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, glucose- dependent insulino tropic polypep- tide (GIP) is the other key gastroin- testinal 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 inhi bitors (e.g., sitagliptin [Januvia®], saxagliptin [Onglyza®], linagliptin [Tradjenta®], and alogliptin [Nesina®]) 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 adminis- tered once daily, and dose adjust- ments 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 Pharma - ceuticals 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). Naso - pharyngitis, urinary tract infection, and headache are the most com- mon side effects associated with DPP-4 inhibitors (Dicker, 2011).

Recent CV outcome trials have

Pharmacotherapy of Type 2 Diabetes Mellitus: Navigating Current and New Therapies

FIGURE 1. Site and Mechanism of Action of Antidiabetic Medications

Pancreas

Sulfonylureas • Increase insulin release Glinides • Increase insulin release GLP-1 RAs • Increase insulin release • Decrease glucagon release DPP-4 inhibitors • Inhibit breakdown of GLP-1

and GIP Amylin analog • Decrease glucagon release

Brain

Amyline analog • Promotes satiety GLP-1 RAs • Promote satiety Dopamine agonist • Metabolic control?

Fat

Insulin • Antilipolytic TZDs • Insulin sensitizer

Kidney

SGLT2 inhibitors • Increase glucose

excretion

Liver

Insulin • Decrease hepatic glucose

production Metformin • Insulin sensitizer TZDs • Insulin sensitizer

Muscle

Insulin • Increase glucose uptake TZDs • Insulin sensitizer

GI Tract

a-Glucosidase inhibitors • Decrease carbohydrate

absorption Bile acid sequestrant • Decrease carbohydrate

absorption? GLP-1 RAs • Decrease gastric emptying Amylin analog • Decrease gastric emptying

Reduce Hyperglycemia

Notes: DPP-4 = dipeptidyl peptidase-4; GIP = glucose-dependent insulinotropic polypeptide; GLP-1 = glucagon-like peptide-1; GLP-1 RAs = glucagon-like peptide-1 receptor agonists; SGLT2 = sodium-glucose cotransporter 2; TZDs = thiazolidinediones.

November-December 2015 • Vol. 24/No. 6416

re ported that saxagliptin, alogliptin, and sitagliptin as add-ons to stan- dard of care did not increase or decrease major adverse CV events in patients with T2DM and high CV risk compared with add-on of place- bo (Green et al., 2015; Scirica et al., 2013; White et al., 2013). How ever, add-ons in creased risk for hospital- ization for heart failure was ob - served in patients treated with saxagliptin (Scirica et al., 2013). Rates of acute and chronic pancre- atitis were similar among treatment groups in each CV outcome trial for saxagliptin, alogliptin, and sitaglip - tin (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 dif- ferent pharmacokinetic profiles are available (ADA, 2015). No dose lim- its exist for insulin use (Barnard, Batch, & Lien, 2011), and therapy is associated with a nearly universal response (ADA, 2015). Insulin ther- apy 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 in - sulin because of lower risk for hypo- glycemia (Handelsman et al., 2015). However, patients may require additional mealtime therapy with short- or rapid-acting in sulins (basal-bolus therapy). Hypoglyce - mia 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 trans- porter 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 kid- neys 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 hypergly - cemia 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 & Whal - ey, 2011). Moreover, the loss of calories associated with increased renal excretion of glucose typically results in weight loss.

Dapagliflozin (Farxiga®), canagli - flozin (Invokana®), and empagli - flozin (Jardiance®) are SGLT2 inhi - bitors approved as adjuncts to diet and exercise to improve glycemic control in adults with T2DM (Nauck, 2014). SGLT2 inhi bitors are effective in reducing HbA1c, 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 mono therapy or add-on therapy to other antihyperglycemic medications com pared with placebo (Vasilakou et al., 2013). These agents also reduced body weight by ap - proximately 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). Dapa gliflozin 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, empa - gliflozin as add-on to the standard of care was superior to add-on place- bo in reducing CV risk over a medi- an 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 canaglif lozin 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 fre- quently 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 esti- mated glomerular filtration rates of less than 45 mL/min/1.73m2 (cana - gli flozin, empagliflozin) (Eli Lilly and Company, 2015; Janssen Pharma ceuticals, 2015) or less than 60 mL/min/1.73m2 (dapagliflozin) (AstraZeneca, 2015b).

Other Agents Other, less commonly used drugs

for T2DM include pramlintide (Symlin®, not licensed in Europe for T2DM), colesevelam (Welchol®), and bromocriptine (Parlodel®). Pramlin - tide 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 in sulin (Handels - man et al., 2015). Common adverse effects include gastrointestinal dis- comfort, particularly nausea and vomiting (ADA, 2015).

Colesevelam is a bile acid seques-

November-December 2015 • Vol. 24/No. 6 417

trant that lowers HbA1c, fasting plasma glucose, and low-density lipoprotein cholesterol (Fonseca, Handelsman, & Staels, 2010). The mechanism of action is poorly understood. Side effects are gas- trointestinal. Bromocriptine is a centrally acting dopamine agonist that reduces HbA1c in patients with T2DM (DeFronzo, 2011). Its mecha- nism 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 (Handels man et al., 2015) stress the importance of individualization of HbA1c goals as well as individual tailoring of med- ications used to meet these goals. In addition, guidelines recommend treatment intensification with com- bination therapy if HbA1c goals are not attained. Diet and exercise together with metformin mono - therapy usually are recommended as initial therapy for individuals with T2DM. If target HbA1c is not achieved or maintained, or if patients have an initial HbA1c 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 rec- ommended (ADA, 2015; Garber et al., 2015). If HbA1c exceeds 9% and the patient has no symptoms at presentation, triple therapy may be initiated; however, insulin with or without other agents may be appro- priate if the patient has high HbA1c and symptoms of hyperglycemia (Garber et al., 2015; Handelsman et al., 2015).

Although many antidiabetic medi - cations are available, analysis of pa - tients with diagnosed diabetes from the National Health and Nutrition Examination Survey found that despite a decline in mean HbA1c over time (7.42% in 1999-2004 to 7.07% in 2005-2010), only 55.1% of patients taking antidiabetic medica- tions in 2005-2010 achieved HbA1c less than 7% (Selvin, Parrinello,

Sacks, & Coresh, 2014). Reasons for failure to achieve glycemic goals may include lack of treatment initiation and intensification, patient nonad- herence, intolerability, and progres- sive decline in b-cell function that renders therapies dependent on insulin secretion or action less effec- tive over time (Garcia-Perez, Alvarez, Dilla, Gil-Guillen, & Orozco-Beltran, 2013; Khunti, Wolden, Thorsted, Ander sen, & Davies, 2013; Saisho, 2014). Therefore, additional pharma- cologic therapies with novel mecha- nisms of action independent of insulin and with acceptable safety profiles may improve patients’ chances of achieving and maintain- ing glycem ic control.

Conclusion The significant burden imposed

by T2DM on individuals and society underscores the need to achieve bet- ter control of the disease. The keys to optimal control are early diagnosis and intervention with lifestyle changes and use of pharmacothera- pies that address various abnormali- ties in T2DM (see Figure 1) (ADA, 2015; Kahn et al., 2014). Novel med- ications can offer new therapeutic options by using different mecha- nisms 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 addi- tional tools to improve glycemic control in patients with T2DM.

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Pharmacotherapy of Type 2 Diabetes Mellitus: Navigating Current and New Therapies

Instructions For Continuing Nursing Education Contact Hours

Pharmacotherapy of Type 2 Diabetes Mellitus: Navigating Current and New Therapies

Deadline for Submission: December 31, 2017 MSN J1517

To Obtain CNE Contact Hours 1. For those wishing to obtain CNE contact hours, you must read the

article and complete the evaluation through the AMSN Online Library. Complete your evaluation online and print your CNE certificate immediately, or later. Simply go to www.amsn.org/library

2. Evaluations must be completed online by December 31, 2017. Upon completion of the evaluation, a certificate for 1.3 contact hour(s) which includes 1.3 contact hours of pharmacology credit, may be printed.

Learning Outcome After completing this learning activity, the learner will be able to describe therapeutic goals and current treament options of type 2 diabetes.

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November-December 2015 • Vol. 24/No. 6438

Navigating Current and New Therapies continued from page 419

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Yale, J.F., Bakris, G., Cariou, B., Yue, D., David-Neto, E., Xi, L., ... Meininger, G. (2013). Efficacy and safety of canagliflozin in sub- jects with type 2 diabetes and chronic kidney disease. Diabetes, Obesity and Metabolism, 15(5), 463-473.

Zinman, B., Wanner, C., Lachin, J.M., Fitchett, D., Bluhmki, E., Hantel, S., ... the EMPA-REG OUTCOME Investigators. (2015). Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. New England Journal of Medicine. Epub ahead of print.

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