Pharmacotherapy of type 2 diabetes mellitus: navigating current and new therapies.
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.
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 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 (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 (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 (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).
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 (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 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 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, 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 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.
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
American Diabetes Association (ADA). (2015). Standards of medical care in diabetes-2015. Diabetes Care, 38(Suppl. 1), S1-S93.
Amin, M., & Suksomboon, N. (2014). Pharmacotherapy of type 2 diabetes mellitus: An update on drug-drug interactions. Drug Safety, 37(11), 903-919. doi; 10.1007/S40264-014-0223-2
AstraZeneca. (2015a). Onglyza[R] (saxagliptin). Full prescribing information. Wilmington, DE: Author. Retrieved from http://www. azpicentral.com/onglyza/pi_onglyza.pdf #page=1
AstraZeneca. (2015b). Farx/ga[R] (dapagliflozin). Full prescribing information. Wilmington, DE: Author. Retrieved from http://www1.astrazeneca-us.com/pi/ pi_farxiga.pdf
Bailey, C.J., Morales Villegas, E.C., Woo, V., Tang, W., Ptaszynska, A., & List, J.F. (2015). Efficacy and safety of dapagliflozin monotherapy in people with type 2 diabetes: A randomized doubleblind placebo-controlled 102-week trial. Diabetic Medicine, 32(4), 531-541.
Barnard, K., Batch, B., & Lien, L.F. (2011). Subcutaneous insulin: A guide for dosing regimens in the hospital. In L. Lien (Ed.), Glycemic control in the hospitalized patient (pp. 7-16): New York, NY: Springer-Verlag.
Barnett, A.H., Mithal, A., Manassie, J., Jones, R., Rattunde, H., Woerle, H.J.,... EMPAREG RENAL Trial Investigators. (2014). Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: A randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinology, 2(5), 369-384.
Bennett, W.L., Maruthur, N.M., Singh, S., Segal, J. B., Wilson, L. M., Chatterjee, R., ... Bolen, S. (2011). Comparative effectiveness and safety of medications for type 2 diabetes: An update including new drugs and 2-drug combinations. Annals of Internal Medicine, 154, 602-613.
Blonde, L., & San Juan, Z.T. (2012). Fixeddose combinations for treatment of type 2 diabetes mellitus. Advances in Therapy, 29(1), 1-13.
Bode, B., Stenlof, K., Harris, S., Sullivan, D., Fung, A., Usiskin, K., & Meininger, G. (2015). Long-term efficacy and safety of canagliflozin over 104 weeks in patients aged 55-80 years with type 2 diabetes. Diabetes, Obesity and Metabolism, 17(3), 294-303.
Boehringer Ingelheim. (2015). Tradjenta[R] (linagliptin). Full prescribing information. Ridgefield, CT: Author. Retrieved from http://docs.boehringer-ingelheim.com/ Prescribing%20Information/Pls/Tradjenta /Tradjenta.pdf
Bolinder, J., Ljunggren, O., Kullberg, J., Johansson, L., Wilding, J., Langkilde, A.M.... Parikh, S. (2012). Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. Journal of Clinical Endocrinology and Metabolism, 97(3), 1020-1031.
Boyle, J.P., Thompson, T.J., Gregg, E.W., Barker, L.E., & Williamson, D.F. (2010). Projection of the year 2050 burden of diabetes in the US adult population: Dynamic modeling of incidence, mortality, and prediabetes prevalence. Population Health Metrics, 3(1), 29. doi:10. 1186/1478-7954-8-29
Bristol-Myers Squibb Company. (2009). Glucophage (metformin hydrochloride) and Glucophage XR (metformin hydrochloride extended-release). Full prescribing information. Princeton, NJ: Author. Retrieved from http://package inserts.bms.com/pi/pi_glucophage.pdf
Brown, D.X., & Evans, M. (2012). Choosing between GLP-1 receptor agonists and DPP-4 inhibitors: A pharmacological perspective. Journal of Nutrition and Metabolism, 1-10. [Epub 20012, Oct. 18]. doi:10.1155/2012/381713.
Butler, PC., Elashoff, M., Elashoff, R., & Gale, E.A. (2013). A critical analysis of the clinical use of incretin-based therapies: Are the GLP-1 therapies safe? Diabetes Care, 36(7), 2118-2125.
Cefalu, W.T., Leiter, L.A., de Bruin, T.W., Gause-Nilsson, I., Sugg, J., & Parikh, S.J. (2015). Dapagliflozin's effects on glycemia and cardiovascular risk factors in high-risk patients with type 2 diabetes: A 24-week, multicenter, randomized, double-blind, placebo-controlled study with a 28-week extension. Diabetes Care, 38(7), 1218-1227.
Cefalu, W.T., Leiter, L.A., Yoon, K.H., Arias, R, Niskanen, L., Xie, J..... Meininger, G. (2013). Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATASU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet, 382(9896), 941-950.
Centers for Disease Control and Prevention (CDC). (2013). Trends in diabetes and risk factors. Diagnosed diabetes among adults. Retrieved from http://www.cdc. gov/diabetes/atlas/obesityrisk/atlas.html
Centers for Disease Control and Prevention (CDC). (2014a). National diabetes statistics report: Estimates of diabetes and its burden in the United States, 2014. Retrieved from http://www.cdc.gov/ diabetes/pubs/statsreport14/nationaldiabetes-report-web.pdf
Centers for Disease Control and Prevention (CDC). (2014b). National chronic kidney disease fact sheet 2014. Retrieved from http://www.cdc.gov/diabetes/pubs/pdf/ kidney_Factsheet.pdf
Dailey, G. (2011). Early and intensive therapy for management of hyperglycemia and cardiovascular risk factors in patients with type 2 diabetes. Clinical Therapeutics, 33(6), 665-678. doi:10.1016/ j.clinthera.2011.04.025
DeFronzo, R.A. (2011). Bromocriptine: A sympatholytic, d2-dopamine agonist for the treatment of type 2 diabetes. Diabetes Care, 34(4), 789-794.
DeFronzo, R.A., Flompesch, M., Kasichayanula, S., Liu, X., Flong, Y.,
Pfister, M..... Griffen, S.C. (2013).
Characterization of renal glucose reabsorption in response to dapagliflozin in healthy subjects and subjects with type 2 diabetes. Diabetes Care, 36(10), 3169SI 76.
Del Prato, S., Nauck, M., Duran-Garcia, S., Maffei, L., Rohwedder, K., Theuerkauf, A., & Parikh, S. (2015). Long-term glycaemic response and tolerability of dapagliflozin versus a sulphonylurea as add-on therapy to metformin in type 2 diabetes patients: 4-year data. Diabetes, Obesity and Metabolism, 17(6), 581-590. doi:10.1111/dom.12459
Dicker, D. (2011). DPP-4 inhibitors: Impact on glycemic control and cardiovascular risk factors. Diabetes Care, 34(Suppl. 2), S276-278.
Drucker, D.J., Sherman, S.I., Gorelick, F.S., Bergenstal, R.M., Sherwin, R.S., & Buse, J.B. (2010). Incretin-based therapies for the treatment of type 2 diabetes: Evaluation of the risks and benefits. Diabetes Care, 33(2), 428-433.
Duckworth, W., Abraira, C., Moritz, T., Reda, D., Emanuele, N., Reaven, P.D., ... Huang, G.D. (2009). Glucose control and vascular complications in veterans with type 2 diabetes. New England Journal of Medicine, 360(2), 129-139. doi: 10.1056/ NEJMoa0808431
Eli Lilly and Company. (2015). JardianceP (empagliflozin). Full prescribing information. Indianapolis, IN: Author. Retrieved from http://docs.boehringer-ingelheim. com/Prescribing%20Information/Pls/ Jardiance4ardiance.pdf
Ferrannini, E., Berk, A., Hantel, S., Pinnetti, S., Hach, T., Woerle, H.J., & Broedl, U.C. (2013). Long-term safety and efficacy of empagliflozin, sitagliptin, and metformin: An active-controlled, parallel-group, randomized, 78-week open-label extension study in patients with type 2 diabetes. Diabetes Care, 36(12), 4015-4021.
Fonseca, V.A., Handelsman, Y., & Staels, B. (2010). Colesevelam lowers glucose and lipid levels in type 2 diabetes: The clinical evidence. Diabetes, Obesity and Metabolism, 12(5), 384-392.
Gaede, P., Lund-Andersen, H., Parving, H.H., & Pedersen, O. (2008). Effect of a multifactorial intervention on mortality in type 2 diabetes: Results and projections from the Steno-2 study. New England Journal of Medicine, 358(6), 580-591. doi: 10. 1056/NEJMoa0706245
Garber, A.J., Abrahamson, M.J., Barzilay, J.I., Blonde, L., Bloomgarden, Z.T., Bush, M.A. ... Davidson, M.H. (2015). American Association of Clinical Endocrinologists/American College of Endocrinology comprehensive diabetes management algorithm. Endocrine Practice, 21(4), e1-e10.
Garcia-Perez, L.E., Alvarez, M., Dilla, T., GilGuillen, V., & Orozco-Beltran, D. (2013). Adherence to therapies in patients with type 2 diabetes. Diabetes Therapy, 4(2), 175-194.
Gerstein, H.C., Miller, M.E., Byington, R.P., Goff, D.C., Jr., Bigger, J.T., Buse, J.B..... Friedewald, W.T. (2008). Effects of intensive glucose lowering in type 2 diabetes. New England Journal of Medicine, 358(24), 2545-2559. doi: 10.1056/NEJM oa0802743
Green, J.B., Bethel, M.A., Armstrong, P.W., Buse, J.B., Engel, S.S., Garg, J..... TECOS Study Group. (2015). Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. New England Journal of Medicine, 373(3), 232-242. doi: 10.1056/ NEJMoa1501352
Handelsman, Y., Bloomgarden, Z.T., Grunberger, G., Umpierrez, G.E., Zimmerman, R. S., Bailey, T., ... Zangeneh, F. (2015). American Association of Clinical Endocrinologists and American College of Endocrinology clinical practice guidelines for developing a diabetes mellitus comprehensive care plan-2015. Endocrine Practice, 2f(Suppl. 1), 1-87.
Hemmingsen, B., Schroll, J.B., Wetterslev, J., Gluud, C., Vaag, A., Sonne, D.P., ... Almdal, T. (2014). Sulfonylurea versus metformin monotherapy in patients with type 2 diabetes: A Cochrane systematic review and meta-analysis of randomized clinical trials and trial sequential analysis. CMAJ Open, 2(3), E162-175. doi: 10.9778/cmajo.20130073
Holman, R.R., Paul, S.K., Bethel, M.A., Matthews, D.R., & Neil, H.A. (2008). 10year follow-up of intensive glucose control in type 2 diabetes. New England Journal of Medicine, 359(15), 15771589.
Inzucchi, S.E., Bergenstal, R.M., Buse, J.B., Diamant, M., Ferrannini, E., Nauck, M.,... Matthews, D.R. (2015). Management of hyperglycemia in type 2 diabetes, 2015: A patient-centered approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care, 38(1), 140-149.
Inzucchi, S.E., Lipska, K.J., Mayo, H., Bailey, C.J., & McGuire, D.K. (2014). Metformin in patients with type 2 diabetes and kidney disease: A systematic review. Journal of the American Medical Association, 312(24), 2668-2675. doi: 10.1001 /jama.2014.15298
Janssen Pharmaceuticals. (2015). InvokanaP (canagliflozin). Full prescribing information. Titusville, NJ: Author. Retrieved from https://www.janssenmd.com/pdf/ invokana/PI-INVOKANA.pdf
Kahn, S.E., Cooper, M.E., & Del Prato, S. (2014). Pathophysiology and treatment of type 2 diabetes: Perspectives on the past, present, and future. Lancet, 383(9922), 1068-1083.
Khunti, K., Wolden, M.L., Thorsted, B.L., Andersen, M., & Davies, M.J. (2013). Clinical inertia in people with type 2 diabetes: A retrospective cohort study of more than 80,000 people. Diabetes Care, 36(11), 3411-3417.
Kohan, D.E., Fioretto, P., Tang, W., & List, J.F. (2014). Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney International, 85(4), 962-971.
Leiter, L.A., Cefalu, W.T., de Bruin, T.W., Gause-Nilsson, I., Sugg, J., & Parikh, S. J. (2014). Dapagliflozin added to usual care in individuals with type 2 diabetes mellitus with preexisting cardiovascular disease: A 24-week, multicenter, ran domized, double-blind, placebo-controlled study with a 28-week extension. Journal of the American Geriatrics Society, 62(7), 1252-1262.
List, J.F., & Whaley, J.M. (2011). Glucose dynamics and mechanistic implications of SGLT2 inhibitors in animals and humans. Kidney International, 79(Suppl. 120), S20-S27.
Look Ahead Research Group. (2013). Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. New England Journal of Medicine, 369(2), 145-154.
Merck & Co. (2015). JanuviaP (sitagliptin). Full prescribing information. Whitehouse Station, NJ: Author. Retrieved from http://www.merck.com/product/usa/pi_ circulars/j/januvia/januvia_pi.pdf
National Institutes of Health. (2015). Multicenter trial to evaluate the effect of dapagiifiozin on the incidence of cardiovascular events (DECLARE-TIMI58). Retrieved from http://clinicaltrials.gov/ ct2/show/NCT01730534?term=declare& rank=2
Nauck, M.A. (2011). Incretin-based therapies for type 2 diabetes mellitus: Properties, functions, and clinical implications. American Journal of Medicine, 124(Suppl. 1), S3-S18.
Nauck, M.A. (2013). A critical analysis of the clinical use of incretin-based therapies: The benefits by far outweigh the potential risks. Diabetes Care, 36(7), 21262132.
Nauck, M.A. (2014). Update on developments with SGLT2 inhibitors in the management of type 2 diabetes. Drug Design, Development and Therapy, 8,1335-1380.
Nauck, M.A., Baranov, O., Ritzel, R.A., & Meier, J.J. (2013). Do current incretin mimetics exploit the full therapeutic potential inherent in GLP-1 receptor stimulation? Diabetoiogia, 56(9), 18781883.
Neal, B., Perkovic, V., de Zeeuw, D., Mahaffey, K.W., Fulcher, G., Stein, P,... Matthews, D. (2013). Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)--a randomized placebocontrolled trial. American Heart Journal, 166(2), 217-223 e211.
Patel, A., MacMahon, S., Chalmers, J., Neal, B., Billot, L., Woodward, M.....Travert, F. (2008). Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. New England Journal of Medicine, 358(24), 2560-2572. doi:10. 1056/NEJMoa0802987
Reid, T.S. (2012). Choosing GLP-1 receptor agonists or DPP-4 inhibitors: Weighing the clinical trial evidence. Clinical Diabetes, 30(1), 3-12.
Saisho, Y. (2014). Importance of beta cell function for the treatment of type 2 diabetes. Journal of Clinical Medicine, 3(3), 923-943. doi:10.3390/jcm3030923
Scirica, B.M., Bhatt, D.L., Braunwald, E., Steg, P.G., Davidson, J., Hirshberg, B.....the Savor-Timi Steering Committee Investigators. (2013). Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. New England Journal of Medicine, 369(14), 1317-1326.
Selvin, E., Parrinello, C.M., Sacks, D.B., & Coresh, J. (2014). Trends in prevalence and control of diabetes in the United States, 1988-1994 and 1999-2010. Annals of Internal Medicine, 160(8), 517525. doi:10.7326/M13-2411
Skugor, M. (2014). Diabetes mellitus treatment. Retrieved from http://www.deve landclinicmeded.com/medicalpubs/ diseasemanagement/endocrinology/ diabetes-mellitus-treatment/Default.htm
Takeda Pharmaceuticals America, Inc. (2015). Nesine[R] (alogliptin). Full prescribing information. Deerfield, IL: Author. Retrieved from http://www.accessdata. fda.gov/drugsatfda_docs/label/2013/ 022271s000lbl.pdf
Trujillo, J.M., Nuffer, W., & Ellis, S.L. (2015). GLP-1 receptor agonists: A review of head-to-head clinical studies. Therapeutic Advances in Endocrinology and Metabolism, 6(1), 19-28. doi:10.1177/ 2042018814559725
Vasilakou, D., Karagiannis, T., Athanasiadou, E., Mainou, M., Liakos, A., Bekiari, E..... Tsapas, A. (2013). Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: A systematic review and metaanalysis. Annals of Internal Medicine, 159(4), 262-274.
Viollet, B., Guigas, B., Sanz Garcia, N., Leclerc, J., Foretz, M., & Andreelli, F. (2012). Cellular and molecular mechanisms of metformin: An overview. Clinical Science (Lond), 122(6), 253-270.
Walia, R. (2012). Insulin therapy. In Y. Munjal (Ed.), API textbook of medicine (9th ed.). Mumbai, India: Association of Physicians of India.
White, W.B., Cannon, C.P., Heller, S.R., Nissen, S.E., Bergenstal, R.M., Bakris, G.L., ... the Examine Investigators. (2013). Alogliptin after acute coronary syndrome in patients with type 2 diabetes. New England Journal of Medicine, 369(14), 1327-1335.
Wing, R.R., Lang, W., Wadden, T.A., Safford, M., Knowler, W.C., Bertoni, A.G.... Look Ahead Research Group. (2011). Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. Diabetes Care, 34(1), 1481-1486.
Yale, J.F., Bakris, G., Cariou, B., Yue, D., David-Neto, E., Xi, L.... Meininger, G. (2013). Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes, Obesity and Metabolism, 75(5), 463-473.
Zinman, B., Wanner, C., Lachin, J.M., Fitchett, D., Bluhmki, E., Flantel, 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.
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|
|Date:||Nov 1, 2015|
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