New Developments in the Treatment of Type 2 Diabetes Mellitus

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

LY2605541 is a long-acting basal insulin analogue that is currently being evaluated in phase III studies in T2DM patients.¹⁶ Insulin lispro is modified with a 20 kDa polyethylene glycol moiety that results in a molecule with large hydronamic size. The proposed effects of this larger molecule are a delay in insulin absorption and reduced clearance, thus leading to a longer duration of action.¹⁷ Additionally, transport may be greater into the liver relative to muscle and fat tissues, which may result in more hepatic action.¹⁷ The results of an RCT phase II study that compared LY2605541 with insulin glargine, an FDA-approved basal insulin, demonstrated that after 12 weeks of treatment, fasting blood glucose levels were similar. Investigators also noticed reduced weight loss and less nocturnal hypoglycemia with LY2605541. Three phase III trials are ongoing and are currently investigating T2DM patients using LY2605541. IMAGINE 2 compares the use of LY2605541 with insulin glargine over 52 weeks. This study, which is longer than previously published studies, will evaluate the changes in A1C from baseline to 52 weeks. Additionally, other secondary outcomes, which include nocturnal hypoglycemia events, weight, and liver transaminases, will be evaluated.¹⁸ Another phase III study, IMAGINE 4, will compare the effects of LY2605541 with insulin glargine on A1C after 26 weeks in patients also receiving patient-specific preprandial and supplemental doses of the rapid-acting insulin analogue, insulin lispro.¹⁹ The third actively recruiting study is IMAGINE 5, which may last up to 52 weeks. The primary objective of this study is to examine the changes in A1C over 26 weeks. LY2605541 compared with insulin glargine alone or in combination with up to 3 pre-study oral antihyperglycemia medications will be evaluated.²⁰

11-β-hydroxysteroid dehydrogenase type 1 (11-β-HSD1)

The glucocorticoid, cortisol, serves several biological purposes which include the stimulation of gluconeogenesis in the liver and hindering insulin-mediated glucose uptake into adipose and muscle tissues.²¹ Studies have demonstrated that 11-β-HSD1 is a catalyst capable of reactivating inert cortisone into cortisol within non-adrenal tissue, including adipose and liver tissues. Preclinical evidence indicates that 11-β-HSD1 has a function in both obesity and metabolic disease in rodents, which suggests that inhibiting this catalyst in liver and adipose tissues may lead to enhanced hepatic and peripheral insulin sensitivity, thus improving overall glucose levels and possibly decreasing overall macrovascular risk.²¹ A 12-week, randomized, double-blind, placebo-controlled study evaluated the 11-β-HSD1 inhibitor, INCB13739, in patients with T2DM receiving a mean dose of 1.5 g per day of metformin. Investigators demonstrated a dose-dependent reduction in A1C, the primary objective, in patients receiving INCB13739 plus metformin versus metformin alone. A1C reduction was greatest among patients receiving 200 mg daily (the maximum dose in the study) and in those with a body mass index over 30 kg/m2. INCB13739 was well tolerated with no drug-related serious adverse effects or hypoglycemic episodes occurring during the treatment phase.²²

Glucokinase Activators

Glucokinase plays a role in glucose metabolism and adenosine triphosphate (ATP) production via glucose phosphorylation. The production of ATP has an effect on insulin secretion by closing potassium-ATP channels, thus triggering calcium ion channels to open, thereby activating calciumdependent enzymes hat control the release of insulin. The development of glucokinase activators has provided another pharmacologic mechanism to increase insulin secretion and decrease glucose secretion by enhancing the effects of glucokinase in beta cells. It is also thought that these agents have a secondary mechanism which decreases hepatic glucose metabolism, further decreasing glucose concentration. Unfortunately, these agents do have adverse effects. Incidences of increased triglyceride levels and hypoglycemia have been associated with the glucokinase activators.³

LY2599506, a glucokinase activator 1, was nvestigated in a phase II study; however, the study was terminated after enrolling 38 patients, due to non-clinical safety effects. The non-clinical safety effects were not identified.²³

Glucagon Receptor Antagonist

Incretins are intestinal factors that are released in response to nutrients, contributing to blood glucose lowering. Incretin mimetics, such as exenatide and liraglutide, along with DPP-4 inhibitors, are currently available to treat patients with T2DM by addressing decreased concentrations of GLP-1. Aless-well-known incretin is glucosedependent insulinotropic peptide, or GIP. Currently in development, glucagon receptor antagonists (GRAs) belong to a new class of oral drugs that block the actions of GIP. In animal models, this blockade results in increasing energyless-well-known incretin is glucosedependent insulinotropic peptide, or GIP. Currently in development, glucagon receptor antagonists (GRAs) belong to a new class of oral drugs that block the actions of GIP. In animal models, this blockade results in increasing energy expenditure, as well as reduced fat deposition and lipotoxicity.³ Investigators have identified MK-0893, a potent, selective, small-molecule GRA (which is a reversible and competitive agonist) with high binding affinity.²⁴ MK-0893 demonstrated 24-hour weighted mean glucose lowering effects similar to those seen with the combination of sitagliptin and metformin.^24-26 In this phase II study that evaluated MK-0893 with 2000 mg metformin daily, MK-0893 with sitagliptin 100 mg daily, or 100 mg sitagliptin plus 2000 mg metformin daily, MK-0893 plus sitagliptin was statistically less effective than the sitagliptin/metformin combination.²⁵ LY2409021, a potent and selective GRA, has been evaluated in phase I and II studies.²⁷ The results of a phase I, first-in-man study resulted in clinically significant glucose lowering without incidences of hypoglycemia or changes in laboratory tests, vital signs, or electrocardiograms.²⁸ Although both GRAs have been well tolerated, concerns about increased liver transaminases have arisen. A study evaluating the effects of LY2409021 on the liver is currently recruiting.²⁹

Other Agents

Several other agents are being investigated for the management of T2DM. Glycogen phosphorylase is a catalyst for glycogenolysis, which increases glucose output from the liver. In a preclinical study, a glycogen phosphorylase inhibitor, CP-316819, prevented hyperglycemia after a glucagon challenge.³ Protein tyrosine phosphatase 1B inhibitors enhance the effects of insulinby decreasing dephosphorylation of the β-subunit of insulin receptors, thus extending phosphorylation after insulin binding. In hyperglycemic animal models, protein tyrosine phosphatase 1B inhibitors reduce blood glucose levels, and may also improve weight loss and endothelial function.³ In patients with T2DM, one consideration in postprandial hyperglycemia is the reduction of glucose- stimulated insulin secretion (GSIS). Activation of G protein—coupled receptor (GPR) 119, which is primarily expressed in pancreatic β-cells and intestinal L-cells, leads to insulin and GLP-1 release. A preclinical study demonstrated that AS1535907, a GPR119 agonist, stimulated the first phase of GSIS, resulting in an insulin release which was greater than that seen with the comparator sulfunoylurea.³⁰ Another study demonstrated that, in vitro, AS1535907 howed selective agonist activity for human GPR119 and could activate human insulin promoter. The study also demonstrated A1C-lowering effects in diabetic animal models.³¹ GPR119 agonists currently in development include MBX-2982 and GSK-1292263.³²

Conclusion

EBDM

Diabetes has profound effects on the economic burden of both patients and healthcare system. While new pipeline agents are currently in development, the cost-benefit analysis must be scrutinized in the presence of often less-expensive standards of care. Several novel agents have shown promise in the treatment of T2DM; however, it is too soon to determine their clinical and financial impacts. It is unclear if these agents will be used in combination with current therapies or primarily as first-line agents, but the ability of some of these drugs to mitigate weight gain suggests that they may have a role in both. Further, if ongoing studies validate the additive benefits seen with reducing macrovascular complications and blood pressure, there is a greater opportunity to influence current prescribing patterns. However, in the absence of long-term studies, caution should be exercised when considering a change from current therapies. Adverse effects of the new medication classes may limit their utility. That being said, when the costs of the drugs are known, these newer agents should be watched closely by benefit managers to evaluate the impact on total costs of care, as the benefit may outweigh the increased medication costs. Overall, the emphasis in the treatment of T2DM should still remain heavily on lifestyle modifications in conjunction with the use of evidencebased practice guidelines.

Author Affiliation: From the University of Louisiana at Monroe College of Pharmacy—Baton Rouge Campus, Baton Rouge, LA.

Funding Source: None.

Author Disclosure: The author reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; and critical revision of the manuscript for important intellectual content.

Address correspondence to: Brice Labruzzo Mohundro, PharmD, BCACP, University of Louisiana at Monroe College of Pharmacy—Baton Rouge Campus, 3849N Boulevard, Baton Rouge, LA 70806. E-mail: labruzzo@ulm.edu.References

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