Diabetes is the leading cause of kidney failure, nontraumatic lower-limb amputations, and new cases of blindness among adults in the United States. It is a major cause of heart disease and stroke and is the seventh leading cause of death among US adults.2 The total estimated cost for diabetes in the United States in 2007 was $174 billion,2 and between 2007 and 2009, the estimated cost attributable to pharmacologic intervention in the treatment of diabetes increased from $12.5 billion to $16.9 billion.3-5 Global sales for diabetes medications totaled $35 billion in 2010 and could rise to $48 billion by 2015, according to the drug research company IMS Health.6,7 In 2009, $1.1 billion was spent on diabetes research by the National Institutes of Health.8 Despite these staggering costs, currently there are still no proved strategies to prevent this disease or its serious complications.
According to the 1999-2000 National Health and Nutrition Examination Survey, only 36% of patients with type 2 diabetes achieve glycemic control—defined as hemoglobin (Hb) A1c <7%—with currently available therapies.9 Lifestyle modification remains the most important and effective way to treat diabetes; however, the majority of patients with type 2 diabetes are unable to maintain such a rigid lifestyle regimen. For most patients with type 2 diabetes, pharmacologic intervention will therefore be needed to maintain glycemic control.2
Tables 1 and 2 list the 13 classes of medication currently approved by the US Food and Drug Administra tion (FDA) for the treatment of type 2 diabetes. Despite this abundance of pharmacotherapies, new medications with different mechanisms of action or new approaches to therapy are needed to improve patient outcomes and reduce the clinical and cost burden of this serious condition. Indeed, the number of diabetes medications for type 2 diabetes is expected to grow in the next few years, considering the many promising investigational therapeutic options currently in development that may gain FDA approval in the future. This article reviews some of the therapies that are currently being tested and may soon become new options for the treatment of type 2 diabetes (Table 3).
Sodium-Glucose Cotransporter-2 Inhibitors
The sodium-glucose cotransporter (SGLT)-2 inhibitors are a new investigational drug class for the treatment of type 2 diabetes. These agents work at the kidney through insulin-independent mechanisms and should, therefore, theoretically reduce the risk for weight gain that often plagues some of the current antidiabetes drugs. The kidney contributes to glucose balance by:
- Producing glucose through gluconeogenesis10
- Utilizing glucose in the renal medulla10
- Reabsorbing up to 100% of the filtered glucose to maintain the normal circulating glucose pool.11
Two sodium-dependent glucose transporters—SGLT1 and SGLT2—have been identified as the major transporters of glucose in humans.12,13 SGLT2 is expressed almost exclusively in the S1 segment of the proximal tubule and accounts for >90% of renal glucose reabsorption. SGLT1 is expressed in the heart, gastrointestinal tract, skeletal muscle, liver, and lung, and in the S3 segment of the proximal tubule, where it accounts for only <10% of filtered glucose reabsorption.14 SGLT2 is therefore the major transporter responsible for renal glucose reabsorption and is a useful therapeutic target for the treatment of diabetes.
Selective inhibition of this transporter will decrease the reabsorption of filtered glucose, lower plasma glucose concentration, and improve glycemic control. Few studies have indicated that the expression of SGLT2 is up-regulated in diabetes,15,16 a finding that emphasizes the importance of blocking this pathway to control or decrease plasma glucose. Several SGLT2 inhibitors have been developed and are in various phases of clinical trials.17
The most advanced agent in this class is dapagliflozin, which has been tested in phase 3 clinical trials in patients with type 2 diabetes as monotherapy,18 with metformin19 or with glimepiride,20 or in combination with insulin, and with insulin plus oral antidiabetic agents.21 Overall, the HbA1c-lowering effect of dapagliflozin ranged from 0.35% to 0.90% (change from baseline and placebo subtracted).18-23
In addition, dapagliflozin also had beneficial effects on fasting blood glucose, with reductions from baseline of 10 mg/dL to 25 mg/dL,19,20 as well as postprandial area under the curve, systolic blood pressure (3-6 mm Hg),22 and body weight (0.46-4.5 kg).18-23 Small increases in blood urea nitrogen and hematocrit, as well as a higher risk for reversible genitourinary infections, were seen with dapagliflozin.18-23
The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) recently (July 19, 2011) reviewed the global clinical development program database for dapagliflozin and voted 9 to 6 against recommending its approval, citing “fears that the product may cause about a 5-fold increase in breast and bladder cancer.” 24 Some EMDAC members did not accept the sponsor’s explanation that the increased risk seen in patients taking this drug was preexisting and was likely linked to the study’s uneven subject selection process. Although some analysts suggest that an outside panel of experts will still recommend the approval of dapagliflozin, such an approval may come with strong warnings about the drug’s potential for risk of malignancy.25
Despite the recent setback from the FDA’s advisory board, the future for this drug class (ie, SGLT2 inhibitors) is promising. Some 4 clinical trials involving SGLT2 inhibitors are currently recruiting patients. Of all the diabetes drugs in the pipeline, SGLT2 inhibitors will most likely be the next class of drugs to be added to the clinician’s armamentarium for the management of patients with type 2 diabetes.
11Beta-Hydroxysteroid Dehydrogenase Type 1 Inhibitors
The 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitor is an enzyme that converts the inert hormone cortisone to its active form, cortisol, in target tissues.26 Excess cortisol can cause insulin resistance by inhibiting pancreatic beta-cell insulin secretion and peripheral glucose uptake, and by promoting gluconeogenesis. 27 11beta-HSD1 is up-regulated in adipose tissues of patients with the metabolic syndrome.28
In animal studies, transgenic mice overexpressing 11beta-HSD1 eventually develop glucose intolerance, insulin resistance, dyslipidemia, and hypertension.29,30 Because of its specific role in glucocorticoid interconversion, inhibition of this enzyme can decrease glucocorticoid activity and improve the components involved in the metabolic syndrome. Using 11beta-HSD1–knockout animals, researchers have shown that such inhibition can improve insulin sensitivity, reduce body weight, and lower triglyceride levels.31
In humans, 11beta-HSD1 inhibitors have been shown to improve lipid profiles, fasting glucose levels,32 and hepatic insulin sensitivity.33 The most advanced drug in this class in development is INCB13739.34 In a double- blind placebo-controlled phase 2b clinical trial, 302 patients with type 2 diabetes (mean HbA1c, 8.3%) who had been receiving metformin monotherapy (mean dose, 1.5 g daily) were randomized to receive 1 of 5 doses of INCB13739, or placebo, once daily for 12 weeks.34
After 12 weeks, compared with placebo, patients who received 200 mg of INCB13739 demonstrated significantly lower HbA1c (–0.6%), fasting plasma glucose (–24 mg/dL), and homeostasis model assessment–insulin resistance (–24%). A reversible dose-dependent elevation in adrenocorticotrophic hormone, generally within the normal reference range, was also noted.
Therapy with INCB13739 did not change basal cortisol homeo stasis, testosterone levels in men, and the free androgen index in women. Adverse events were similar across all treatment groups.34
The 11beta-HSD1 is an interesting drug class that is still in very early stages of development. Available data so far strongly suggest that 11beta-HSD1 inhibitors are potential options for the treatment of type 2 diabetes, although additional clinical testing is needed.35 No drug in this class has entered phase 3 clinical trials.
Glycogen Phosphorylase Inhibitors
The liver is central to glucose handling and homeostasis. It accounts for approximately 90% of the body’s endogenous glucose production. In patients with type 2 diabetes, excessive hepatic glucose production, along with insulin resistance, can contribute to hyperglycemia. Hepatic glucose production has 2 major pathways— glycogenolysis and gluconeogenesis. Inhibition of hepatic glucose production has become the focus of newer antidiabetic agents for the treatment of type 2 diabetes.36
One specific target is glycogen phosphorylase, which catalyzes the phosphorolytic cleavage of glycogen to produce glucose-1-phosphate, which is then isomerized by phosphoglucomutase to glucose-6-phosphate and then enters the glycolytic pathway to produce glucose.36 Creating an inhibitor that specifically targets glycogen phosphorylase would then essentially decrease the amount of glucose produced by the liver.
There are 5 binding sites on the glycogen phosphorylase enzyme that have been found to be potential targets— the catalytic site, inhibitor site, adenosine monophosphate (AMP) allosteric site, glycogen storage site, and a new allosteric binding site.37 Findings from a study by Martin and colleagues show that CP- 91149 is a glycogen phosphorylase inhibitor that binds to the inhibitor site and reduces plasma glucose levels in mice.38
Martin and colleagues found that oral CP-91149 indirectly inhibits gluconeogenesis via the disruption of glucose/ glycogen cycling and inhibits the human liver glycogen phosphorylase a enzyme, thereby improving glucose levels. In addition, CP-91149, which has been characterized in vitro and in vivo, suppressed glycogenolysis in both rat and human liver cells.38 When studying obese mice, the investigators found that a single 50-mg/kg oral dose of CP-91149 reduced plasma glucose concentrations to near-normal levels 3 hours after administration (plasma glucose, 235 ± 21 mg/dL with vehicle vs 134 ± 7 mg/dL with CP-91149).38
Using kinetic experiments, Oikonomakos and colleagues found that the T-state of glycogen phosphorylase b enzyme is the best confirmation to target when looking for glycogen phosphorylase inhibitors.39 They found CP- 320626 to be an inhibitor of the human liver glycogen phosphorylase by binding at the allosteric site compared with the inhibitor site that CP-91149 binds to, which conforms glycogen phosphorylase to its T-state.39
The development of glycogen phosphorylase inhibitors is promising; continued research to identify other potential targets of hepatic glucose production is needed.
Glucokinase is a monomer that resides in the liver and the pancreas. It determines the rate of glucose metabolism by regulating the amount of insulin produced and released from pancreatic beta-cells in response to the amount of glucose in the blood; elevated levels of glucose will increase glucokinase levels in the pancreas, thereby increasing the release of insulin. In addition, glucokinase influences hepatic lipid metabolism and gluconeogenesis in the liver.40
Glucokinase has been found to function in patients with type 2 diabetes but to a lesser degree than in individuals without diabetes. The development of a compound that would directly affect glucokinase may help to increase the amount of insulin released in those who have insulin deficiency.
According to Grimsby and colleagues, glucokinase in the pancreas is a glucose sensor, causing insulin to be released once blood glucose levels reach a certain threshold, approximately 5 mM.41 Glucokinase in the liver is regulated by a glucokinase regulatory protein, which prevents glucokinase from becoming activated and available until glucose must be metabolized, such as after meals, when insulin must be released to normalize blood glucose. In patients with type 2 diabetes, glucokinase in the liver has been found to be reduced by approximately 50%.42
Using the kinetic activity of glucokinase, recent studies have shown many glucokinase activators (GKAs), including GKAs 1 through 14, that increase the enzymatic activity of glucokinase. GKAs bind to the allosteric site of glucokinase, which increases the maximum velocity and/or glucose affinity of glucokinase via glucose metabolism.43
As mentioned earlier, one possible side effect of GKAs is that they can induce moderate hypoglycemia, because they increase the amount of insulin released. This side effect can be reduced by creating a GKA that has less of an impact on the glucose concentration at half the maximum velocity.43 As a result of the active role that glucokinase plays in glucose homeostasis and, as a glucose sensor, in the release of insulin to decrease blood glucose levels, the development of a drug that can increase the impact or activity of glucokinase looks promising for treating type 2 diabetes.
G Protein–Coupled Receptor 119 Agonists
G protein–coupled receptor 119 (GPR119) is a longchain fatty acid receptor that is chiefly expressed by pancreatic beta-cells.44 The physiologic role of GPR119 remains unknown. Even so, its function has been elucidated through GPR119 agonists that have been shown to couple to Gas.44 Upon activation by an agonist ligand, GPR119 increases cyclic AMP (cAMP) and induces insulin release. Indirectly, activating GPR119 also stimulates the release of incretins glucagon-like peptide (GLP)-1 and gastric inhibitory peptide. Taken together, GPR119 agonists may act as a potential target for glycemic control in patients with type 2 diabetes through direct insulinotropic effects and indirectly through incretin release.44
Using in situ hybridization analysis, Chu and colleagues demonstrated that GPR119 was highly expressed by beta-cell islet population.44 To determine the significance of GPR119 in glucose homeostasis, the investigators used the highly selective GPR119 agonist AR231453. They found that AR231453 significantly increased cAMP levels in HEK 293 cells, suggesting that GPR119 couples to Gas.44 Moreover, to demonstrate that AR231453 effectively stimulated GPR119 endogenously, the hamster beta-cell line HIT-T15 expressing GPR119 was used, which in the presence of AR231453 increased cAMP levels.
In addition, the cAMP levels increased in the presence of only a modest amount of glucose, indicating that GPR119 agonists are glucose-dependent for activation.44 Using a model involving GPR119 beta-cell–expressing mice with type 2 diabetes, the investigators demonstrated a significant improvement in glucose tolerance by enhancement of glucose-dependent insulin release. However, in mice with GPR119 gene deletion from the X-chromosome, AR231453 had no effect on glucose levels. 44 Surprisingly, Chu and colleagues showed that oral treatment with a GPR119 agonist AR231453 provided better glycemic control than intravenous treatment, which suggests possible incretin involvement.44
Adding to these results, Yoshida and colleagues confirmed that the GPR119 agonist AS1907417 is effective in preserving beta-cells and controlling glucose levels in HEK293 cells expressing human GPR119.45 Further more, Flock and colleagues demonstrated that AR231453 not only directly increases insulin, incretin, and GLP-1 levels but also, independently of incretins, slows gastric emptying.46 Overall, GPR119 agonists, by activating several complementary pathways, may provide a mechanism for glucose control in patients with type 2 diabetes.
Protein Tyrosine Phosphatase 1B Inhibitors
Protein tyrosine phosphatase (PTP) 1B inhibitors may be a possible oral therapeutic target for glycemic control and weight management through sustained insulin and leptin release in patients with type 2 diabetes. PTP1B is part of the protein tyrosine phosphatase family that is found ubiquitously in cells whose function is the removal of a phosphate group from the tyrosine phosphate receptor. In the insulin cascade, a cytosolic protein tyrosine phosphatase negatively controls insulin release by the dephosphorylation of several of the insulin receptor kinase substrates.47
In addition, PTP1B inhibitors play a role in downregulation of leptin signaling by dephosphorylating Janus kinase 2 found downstream of the leptin receptor.48 As a result of its involvement in increasing insulin and leptin sensitivity and improving glucose homeostasis, PTP1B may be an oral therapeutic alternative for patients who have type 2 diabetes with functioning beta-cells.
PTP1B has been shown to be an important part in the insulin and leptin signaling pathway. A study with PTP1B-knockout mice demonstrated resistance to obesity and increased insulin sensitivity.49 In a recent study in monkeys, inhibition of PTP1B with antisense oligo nucleotides led to improved insulin sensitivity.50 Along with peripheral tissues, neuronal PTP1B has also been implicated in controlling adiposity and leptin sensitivity.51
Many PTP1B inhibitors are being manufactured and studied. However, the drawbacks of PTP1B inhibitors include their low affinity to and selectivity for the enzyme and their difficulty with membrane permeability. 48 The catalytic domain contains 2 negative charges, therefore making charged ligands preferred for affinity and selectivity. Charged molecules have decreased membrane permeability. One strategy enlisted to increase membrane permeability has been the addition of a hydrophobic region.52 More research is needed to determine the best strategy for delivery of the inhibitor to the cytosol and to determine the selectivity of that inhibitor for PTP1B to achieve the most benefit from oral PTP1B inhibitor therapy.
Glucagon is a peptide hormone secreted by alphacells in the pancreas. It raises blood glucose by enhancing glycogenolysis and gluconeogenesis through the activation of cAMP-dependent protein kinase cascade in the liver, and it is the primary counterregulatory hormone to insulin.53 When excess glucagon is secreted, a process frequently seen in type 2 diabetes, fasting and postprandial hyperglycemia ensues.54,55
Accordingly, new therapeutic agents that can block glucagon action could lower fasting and postprandial blood glucose and potentially emerge as a new drug class in the treatment of type 2 diabetes.
Although many glucagon-receptor antagonists have been developed and tested over the past 20 years, only one human study had been published. Bay 27-9955, a nonpeptide compound that competitively blocks the interaction of glucagon with the human glucagon receptor, was tested in 8 normal volunteers in a double-blind, placebo-controlled, crossover study. A single dose of 200 mg was able to block the effect of exogenous glucagon, thereby stabilizing plasma glucose concentrations and the rate of glucose production in the study participants.56
The future for this drug class is uncertain, because of the limited published human data currently available. Much more information is needed to elucidate the efficacy and safety of this potential treatment.
Diabetes is a complex and costly disease. Although a cure is not imminent, many treatment options are currently available to aid in the control and management of this disease that is continuing to increase in the United States. However, despite this abundance of therapeutic options, the majority of American patients with type 2 diabetes are not achieving appropriate glycemic control. Novel therapies are in various stages of development, and some are showing promising results in clinical trials. Adding new options with new mechanisms of action to the treatment armamentarium may eventually help improve outcomes and reduce the cost burden of this condition. It is prudent to remain optimistic as the research in this field continues to evolve.
Author Disclosure Statement
Dr Quang Nguyen, Ms Thomas, Ms Lyons, Dr Loida Nguyen, and Dr Plodkowski have nothing to disclose.
Dr Quang Nguyen, Endocrinology Department, Carson Tahoe Physician Clinics–Carson City, Assistant Clinical Professor of Endocrinology and Internal Medicine, University of Nevada School of Medicine, Reno, and Adjunct Associate Professor of Endocrinology and Internal Medicine, Touro University Nevada, Henderson, College of Osteopathic Medicine; Ms Thomas is Clinical Registered Dietitian, Carson Tahoe Physician Clinics and University of Nevada, Reno, Depart ment of Endocrinology, Nutrition and Metabolism; Ms Lyons is a medical student, University of Nevada School of Medicine, Reno; Dr Loida Nguyen is Clinical Pharmacist, Sierra Nevada Healthcare System, Veterans Affairs Medical Center, Reno; and
Dr Plodkowski is Chief of Endocrinology, University of Nevada, and Veterans Affairs Medical Center, Reno.
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