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Evidence-Based Diabetes Management March/April
The Controversial Question of Metabolic Syndrome
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New Developments in the Treatment of Type 2 Diabetes Mellitus
Brice Labruzzo Mohundro, PharmD, BCACP
Examining Models of Care and Reimbursement, Including Patient Management Fees, ACOs, and PCMHs: A Panel Discussion
Is There a Business Case for Diabetes Disease Management?
Stanton R. Mehr
Real-World Examples of Patient-Centered Healthcare
Targeting Insulin Resistance: The Ongoing Paradigm Shift in Diabetes Prevention
Tara Dall, MD; Dawn Thiselton, PhD; and Stephen Varvel, PhD
Can Financial Incentives Improve Self-Management Behaviors?
Kim Farina, PhD
Reexamining the Roles of Diabetes Educators
Kim Farina, PhD
Diabetes and the Patient-Centered Medical Home
Teresa L. Pearson, MS, RN, CDE
Measuring the Value of Better Diabetes Management
Darius N. Lakdawalla, PhD; Michael R. Eber, BSE; Felicia M. Forma, BSc; Jeffrey Sullivan, MS; Pierre-Carl Michaud, PhD; Lily A. Bradley, MBA; and Dana P. Goldman, PhD

New Developments in the Treatment of Type 2 Diabetes Mellitus

Brice Labruzzo Mohundro, PharmD, BCACP
Benefits May Outweigh Increase to Costs of Care
Diabetes, a progressive disease of the endocrine system with a significant economic burden, is estimated to affect more than 371 million people worldwide   and over 24 million Americans in 2012. In 2011, 4.6 million deaths could be attributed to diabetes, and diabetes healthcare expenditures, including costs to the healthcare system and the patient, were at least 465 billion US dollars, of which 11% of total healthcare expenditures were from adults aged 20 to 79 years, and 75% of that cost was spent on those aged 50 to 79 years.1

Current American Diabetes Association (ADA) Standards of Care recommend metformin for pharmacologic management of type 2 diabetes mellitus (T2DM),  if no contraindications are present, at the time of diagnosis. If therapeutic goals are not met with monotherapy at maximal doses, a second oral agent, such  as a glucagon-like peptide-1 (GLP-1) agonist or insulin, are recommended for addition. For patients who are newly diagnosed, markedly symptomatic upon diagnosis, and/or have markedly elevated blood glucose or glycated hemoglobin (A1C) levels, initial pharmacologic therapy with insulin should be considered, with or without the addition of other agents.2

The current classes of medications that are available to treat T2DM include biguanides, sulfonylureas, meglitinides, thiazolidinediones (TZDs), alpha glucosidase inhibitors, dipeptidyl peptidase-IV (DPP-4) inhibitors, GLP-1 agonists, bile acid sequestrants, dopamine-2 agonists, and insulin. Although these agents are effective initially, glucose-lowering effects are not typically sustained long term as beta cell dysfunction progresses. Therefore, newer agents that are able to lower glucose long term without causing hypoglycemia, delay decline in beta cell dysfunction, assist with weight loss, and have beneficial effects on  cardiovascular disease need to be developed. It is important to acknowledge that, in addition to the aforementioned therapeutic effects, adverse effects must be  minimized. 3 Several new classes of medications are currently in development, as well as a new long-acting insulin.

Sodium-Glucose Cotransporter-2 Inhibitors (SGLT-2)

SGLT-2, a low-affinity but high-capacity transporter found in the brush border of the proximal tubule, is a mediator of glucose reabsorption in the kidneys.  The kidneys contribute to glucose homeostasis via renal gluconeogenesis, glucose utilization, and reabsorption from glomerular filtration.3,4 Data suggest  that renal gluconeogenesis, renal glucose uptake, and renal glucose reabsorption are all increased in patients with T2DM due to the upregulation of  SGLT-2.5 In essence, SGLT-2 inhibitors exert their effects by causing the kidneys to excrete glucose into the urine. The effects are also independent of  insulin secretion. These proposed mechanisms make SGLT-2 a viable target to help combat hyperglycemia in patients with T2DM. A review of the literature,  conducted through a PubMed search of SGLT-2 inhibitors through April 2012, found that these agents decreased A1C anywhere from 0.5 to 1.5%, promoted  weight loss, and demonstrated low incidences of hypoglycemia. Incidence of adverse effects with these agents has been low with no severe episodes of hypoglycemia documented. The most common adverse effects reported with these agents were urinary tract infections (UTIs) and/or genital tract infections.6

Dapagliflozin, a first-in-class SGLT-2 inhibitor, has been studied the most extensively. In a small study that evaluated 5 doses of dapagliflozin (2.5, 5, 10, 20,  or 50 mg), extended-release metformin (titrated to 1500 mg), and placebo in drug-naïve patients with T2DM, dapagliflozin demonstrated statistically significant reductions in A1C of 0.55% to 0.9% over 12 weeks when compared with a decrease of 0.18% with placebo. A reduction of 0.73% was noted with patients taking metformin. Additionally, weight loss of 1.3 kg to 2 kg was observed in study participants.7 Patients with T2DM who were inadequately  controlled on metformin were evaluated in a phase 3, double-blind, placebo-controlled randomized controlled trial (RCT). Patients received metformin plus  once-daily dapagliflozin 2.5, 5, or 10 mg, or matching placebo. Statistically significant decreases in mean A1C from baseline at 24 weeks were observed  when dapagliflozin was compared with placebo (2.5 mg: −0.67%, 5 mg: −0.7%, 10 mg: −0.84%, placebo: –0.3%). Weight loss was also seen in the  dapagliflozin groups. Dapagliflozin was well tolerated; however, more genital infections were seen in patients receiving dapagliflozin.8 A more recently  published study shared results of the effects of dapagliflozin in patients not controlled with the TZD pioglitazone. Patients were randomized to receive open-label pioglitazone plus either 5 mg or 10 mg of dapagliflozin for 48 weeks after a 10-week dose optimization phase with pioglitazone. Statistically significant reductions in A1C were seen after 24 weeks with both 5- and 10-mg strengths (5 mg: –0.82%, 10 mg: –0.97%, pioglitazone monotherapy: 0.48%), and these reductions were maintained through week 48. The decrease in A1C at 48 weeks was greater with each group: 0.95%, 1.21%, and 0.54%, respectively. Dapagliflozin also decreased the effect of pioglitazone-associated weight gain and edema. Overall, dapagliflozin was well tolerated; however,  the incidence of genital infections was increased compared with placebo.9 A total of 800 patients with T2DM who were inadequately controlled on 30 units  or more of insulin were evaluated in a double-blind, placebo-controlled RCT that investigated the effects of 24 weeks of dapagliflozin or placebo on A1C.  Patients may have been also taking up to 2 oral antidiabetic agents. Patients were randomized to receive 2.5, 5, or 10 mg of dapagliflozin or placebo in addition to their usual insulin dose and oral agents. At 24 weeks, patients receiving dapagliflozin experienced statistically significant decreases in A1C (2.5 mg: –0.79%, 5 mg: –0.89%, 10 mg: –0.96%) compared with placebo (–0.39%). A secondary outcome was to evaluate the change in A1C at week 48.  Statistically significant decreases in A1C were maintained (2.5 mg: –0.79%, 5 mg: –0.96%, 10 mg: –1.01%). Over 48 weeks, increases in mean insulin doses increased with time in patients of the placebo group (10.54 units) but not with dapagliflozin therapy. Decreases in body weight were observed in patients  taking dapagliflozin, but increased with the placebo. Rates of hypoglycemic episodes, genital infection, and UTIs were higher in patients taking dapagliflozin.10 Despite the positive effects on A1C, dapagliflozin has not been approved by the US Food and Drug Administration (FDA) due to concerns of a potential link to breast and bladder cancers.11 SGLT-2 is not thought to be expressed in either bladder or breast tissue, and therefore the mechanism of  SGLT-2 inhibitors should not have a link to breast and bladder cancer risk; however, long-term surveillance is needed to exclude the association.10 Proposed explanations for the increased incidence include the use of more urinalyses due to the increased incidence of UTIs, which may have led to earlier findings of  hematuria or other abnormalities that are suggestive of bladder cancer. As far as the breast cancer incidences, breast masses may have been more easily   identified after weight loss occurred in patients taking dapafliglozin.6 The co-developers of dapagliflozin remain devoted to the development of the SGLT-2  inhibitor and will provide additional information as requested by the FDA.11

Canagliflozin is another SGLT-2 inhibitor currently in phase III development. A dose-ranging, double-blind RCT of canagliflozin added to metformin therapy demonstrated A1C reduction over a 12-week period. Canagliflozin therapy (50, 100, 200, or 300 mg once daily or 300 mg twice daily) was compared with the DPP-4 inhibitor, sitagliptin, which was used as an active reference treatment   group, or placebo. A1C reduction with canagliflozin was noted with all doses investigated; however, the largest reductions were seen with 300 mg daily  (–0.92%) and 300 mg twice daily (–0.95%) versus with placebo (–0.22%). A weight loss of 2 kg to 2.9 kg was noted with canagliflozin compared with 0.8 kg with placebo and 0.4 kg with sitagliptin. Canagliflozin was well tolerated; however, females experienced an increased frequency of genital infections, including vulvovaginal mycotic infections and candidiasis, which responded to standard antifungal treatment and did not lead to patients discontinuing the study. It is thought that this increase in mycotic genital infections is due to the increased urinary excretion of glucose that occurs with SGLT-2 inhibitors, thus leading to increased colonization with Candida.12

A third SGLT-2 inhibitor in phase III development is empagliflozin. Empagliflozin demonstrated A1C lowering and improvements in glucose tolerance in  animal studies, and had the highest selectivity of the SGLT-2 receptors compared with dapagliflozin, canagliflozin, and other SGLT-2 inhibitors.13,14 Data from pooled phase IIb studies demonstrating that empagliflozin lowers A1C, weight, and systolic blood pressure were presented at the 48th European  Association for the Study of Diabetes annual meeting.15 A phase III clinical program is currently ongoing, which includes 10 phase III studies with a goal of  enrolling over 14,500 patients. In addition to studies that are evaluating effects on glucose and weight, a large cardiovascular outcome trial will be  included.15

Novel Long-Acting Basal Insulin

 
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