Diabetes: New and Emerging Therapies

Approximately 29.1 million individuals in the United States have diabetes, and an estimated 8.1 million cases are undiagnosed.¹ In 2012, 1.7 million new diabetes cases were diagnosed in individuals 20 years and older, the majority of whom were 45 to 64 years of age. If this trend continues, it is estimated that 1 of every 3 Americans will suffer from diabetes by the year 2050.

Individuals with diabetes make up 9.3% of the US population, resulting in a significant economic burden. In 2012, the total estimated cost, direct and indirect, of diabetes in the United States was more than $240 billion. Well-known comorbid conditions and complications of diabetes, including hypertension, cardiovascular disease, stroke, chronic kidney disease, retinopathy, and depression, account for many of these expenditures.¹

The increasing prevalence of diabetes has led to new and emerging therapies. More than 14% of patients with a diabetes diagnosis receive treatment with both oral agents and insulin. The pill burden and complexity of regimens, in addition to costs and adverse effects (AEs), are all factors that contribute to nonadherence in these patients. Many of the new agents exhibit novel mechanisms to improve glycemic control, while others are focused on breaking down barriers of nonadherence. For example, many injectable medications have been formulated in pen devices and/or with less frequent dosing to help improve adherence.

Recently Approved Medications

Since January 2014, 10 new products marketed for the treatment of diabetes have been approved by the FDA.² Some are combination products of previously approved drugs, whereas others are new drug entities (Online Table 1^3-12).

Table 1: FDA-Approved Drugs for the Treatment of Diabetes from 2014 to 2015^3-12

Generic Name

(Brand)

FDA Approval Date

Dosage Form/Route

Drug Class

AWP

(30-day supply)

Insulin degludec^3,a

(Tresiba)

September 2015

U-100 or U-200 FlexTouch; SubQ

Insulin

N/A

Empagliflozin + Metformin⁴

(Synjardy)

August 2015

Tablet; Oral

SGLT-2 + Biguanide

$411.38

Insulin glargine⁵

(Toujeo)

February 2015

U-300 Solostar Pen; SubQ

Insulin

(300 U/mL)

$134.19^b

Empagliflozin + Linagliptin⁶

(Glyxambi)

January 2015

Tablet; Oral

SGLT-2 + DPP-4

$609.98

Dapagliflozin + Metformin⁷

(Xigduo XR)

October 2014

Tablet; Oral

SGLT-2 + Biguanide

$411.53

Dulaglutide ⁸

(Trulicity)

September 2014

Pen Injector; SubQ

GLP-1 agonist

$146.50^c

Empagliflozin⁹

(Jardiance)

August 2014

Tablet; Oral

SGLT-2

$411.38

Insulin rapid¹⁰

(Afrezza)

June 2014

Powder; Inhalation

Insulin

$271-27-$380.11^d

Albiglutide¹¹

(Tanzeum)

April 2014

Pen-injector; SubQ

GLP-1 agonist

$426.36

Dapagliflozin¹²

(Farxiga)

January 2014

Tablet; Oral

SGLT-2

$411.53

AWP = average wholesale price; SubQ = subcutaneous injection; SGLT-2 = sodium glucose cotransporter 2 inhibitor; GLP-1 = glucagon-like peptide 1 agonist.

^aCurrently not on the market; anticipated availability: first quarter of 2016.^bInsulin glargine (Toujeo) price based on 1 of the 1.5-mL pens.^cDulaglutide price based on 0.5-mL Pen-injector.^dPrice varies based on dosage strength.

The most recently FDA-approved agent is insulin degludec (Tresiba), a long-acting insulin indicated for the treatment of type 1 diabetes (T1D) and type 2 diabetes (T2D).³ Upon injection of insulin degludec, a subcutaneous depot is formed via a multihexamer, which results in delayed absorption that is responsible for the slow release and duration of the insulin. It is administered once daily at any time of day. The dose can be titrated every 3 or 4 days once steady state is achieved and based on glycemic control.³

The efficacy of insulin degludec was studied in patients with either T1D or T2D in clinical trials with coadministration of mealtime insulin or in combination with common oral antihyperglycemic agents. When compared with insulin glargine and insulin detemir, both with insulin aspart in patients with T1D, insulin degludec was found to achieve similar glycemic-lowering capabilities in regard to reduction in glycosylated hemoglobin (A1C) (95% CI, —0.14 to –0.11 and –0.23 to –0.05, respectively). In patients with T2D, insulin degludec was found to be noninferior to insulin glargine when added to oral glucoselowering agents. One study comparing insulin degludec with sitagliptin plus oral glucose-lowering agents found insulin degludec to be superior in regard to glycemic lowering (P <.001).³

The most common AEs (>5% of patients) reported during clinical trials include hypoglycemia, nasopharyngitis, headache, and upper respiratory tract infection. Hypoglycemia risk may be increased with changes in meal patterns, physical activity, or coadministered medications.³

Tresiba FlexTouch pens display the number of insulin units in the dosing window. Therefore, no adjustments or conversions are required when switching from the U-100 to the U-200 device or vice versa. Each pen is viable for up to 56 days after being opened, if stored at room temperature.³

Emerging Therapies

Sodium Glucose Cotransporter Dual Inhibitor

Three sodium-glucose cotransporter 2 (SGLT-2) inhibitors are available on the US market: canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance). A novel compound, LX4211, has a dual mechanism of inhibiting both SGLT-1 and SGLT-2 receptors.¹³ SGLT-1 receptors are responsible for reabsorption of the remaining 10% of glucose in the proximal tubule that is not reabsorbed by SGLT-2 receptors.¹⁴ A phase 2 randomized, placebo-controlled trial conducted from June 2011 to May 2012 evaluated the efficacy of LX4211 in combination with metformin in patients with T2D.¹³ The primary outcome of this 12-week, dose-ranging study was the change in A1C from baseline to week 12. The 299 patients were randomly assigned to 75 mg daily, 200 mg daily, 200 mg twice daily, and 400 mg once daily. The patients had an average age of 59.9 years and a baseline A1C of 8.1%. Results showed a dose-dependent decrease in A1C (—0.42 to –0.92%; P <.001. The 400-mg once-daily group demonstrated a greater A1C reduction than those who were randomized to 200 mg once daily, without increases in higher urinary glucose excretion. This is thought to be due to inhibition of the SGLT-1 receptor.¹³

Antianginal Agents

Three phase 3 clinical trials have been conducted to determine the safety and efficacy of ranolazine in patients with T2D (Online Table 2^{15- 17}). The proposed mechanism of ranolazine in diabetes is via inhibition of voltage-gated sodium channels on pancreatic alpha cells.¹⁸ Activation of the pancreatic alpha cells stimulates the release of glucagon, resulting in hepatic glucose production. Both the CARISA¹⁹ and MERLIN-TIMI-36 studies showed beneficial effects of ranolazine on glycemic control in patients with diabetes and chronic angina.^20,21 Two of the 3 phase 3 studies shown in Online Table 2^15-17 demonstrated statistically significant decreases in A1C without any significant differences in AEs between treatment groups.

Table 2: Summary of Phase 3 Clinical Trials Evaluating Efficacy and Safety of Ranolazine in Type 2 Diabetes^18-20

Phase

Study Design

Intervention

Baseline Characteristics

Change in HgbA1c from baseline

NCT01494987¹⁵

3

12-week, randomized, double-blind, placebo-controlled, parallel group

Ranolazine 1000 mg twice daily, plus glimepiride 4 mg

vs

placebo + glimepiride 4 mg

N = 431;

mean age: 59 years;

baseline A1C: 8.1;

mean duration of diabetes: 7.0 years

—0.45 vs 0.03

(P <.001)

Eckel et al.¹⁶

3

24-week, randomized, double-blind, placebo-controlled, parallel group

Ranolazine 500 mg twice daily

vs

placebo

N = 465;

mean age: 56 years;

baseline A1C: 8.04

mean duration of diabetes: 3 years

—0.8 vs –0.27

(P <.0001)

NCT01555164¹⁷

3

24-week, randomized, double-blind, parallel study

Ranolazine 1000 mg

plus metformin 1000 mg

vs

placebo + metformin 1000 mg

N = 442;

mean age, 56 years;

baseline A1C: 8.1;

mean duration of diabetes: 6.5 years

—0.2 vs –0.37

(P = .036)

A1C = glycosylated hemoglobin.

Basal Insulin

Polyethylene glycol (PEG)—ylated insulin Lispro (LY2605541; LY) is a basal insulin analogue that has been studied in both T1D and T2D.²² Addition of the PEG polymer to insulin lispro at the Lys^B28 amino acid allows delayed absorption from the subcutaneous tissue. It also protects the protein from proteolysis and reduces clearance from the circulation via endocytosis. Pharmacokinetic studies have demonstrated a duration of action of approximately 36 hours with very limited peak effect. Compared with insulin glargine in a 12-week trial of patients with T2D, LY demonstrated similar efficacy in reducing fasting blood glucose and A1C.²³ Similar results were seen in a phase 2 study comparing LY with insulin glargine in patients with T1D; however, patients in the LY study group had reduced weight at the end of the study compared with patients in the insulin glargine group.²⁴

Combination Basal Plus Bolus Insulin

Insulin degludec/insulin aspart (IDegAsp) is a combination of basalbolus insulin. Fulcher et al²⁵ compared IDegAsp with biphasic insulin aspart in a 26-week, randomized, open-label study. Patients were enrolled if they were previously uncontrolled on onceor twice-daily insulin with or without oral antihyperglycemic agents. The mean patient age was 58.7 years, and baseline A1C was 8.4%. Patients injected either IDegAsp (n = 224) or biphasic insulin aspart (n = 222) with breakfast and their main evening meal. Doses were titrated to a premeal target of 72 to 90 mg/dL. The primary end point (change from baseline A1C at week 26) was noninferior for IDegAsp compared with biphasic insulin aspart (95% CI, —0.18 to –0.13). A similar number of patients in the IDegAsp and the biphasic insulin aspart groups were able to achieve A1C goals of less than 7.0% (50.4% vs 48.6%, respectively), with a lower incidence of hypoglycemia in patients randomized to IDegAsp (P = .0049).²⁵

Conclusion

As more new diabetes agents come to the market, it is important to always reemphasize the importance of therapeutic lifestyle changes and adherence to prescribed regimens. Additionally, selection of therapeutic agents should be individualized for each patient. Aspects to consider when selecting an agent include glycemic effectiveness, cost, route of administration, frequency, AEs, and patient-perceived barriers.

Rachel Lee, PharmD, CPP, is a PGY2 ambulatory care resident at the University of North Carolina Hospitals and Clinics in Chapel Hill, North Carolina.

References

• Centers for Disease Control and Prevention. National diabetes statistics report: estimates of diabetes and its burden in the United States, 2014. Atlanta, GA: US Department of Health and Human Services; 2014.
• FDA website. www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed October 2, 2015.
• Tresiba [package insert]. Plainsboro, NJ: Novo Nordisk Inc; 2015.
• Synjardy [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2015.
• Toujeo [package insert]. Bridgewater, NJ: Sanofi-Aventis US LLC; 2015.
• Glyxambi [package insert]. Indianapolis, IN: Boehringer Ingelheim Pharmaceuticals, Inc; 2015.
• Xigduo XR [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2014.
• Trulicity [package insert]. Indianapolis, IN: Eli Lilly and Company; 2015.
• Jardiance [package insert]. Indianapolis, IN: Boehringer Ingelheim Pharmaceuticals, Inc; 2015.
• Afrezza [package insert]. Bridgewater, NJ: Sanofi-Aventis US LLC; 2015.
• Tanzeum [package insert]. Wilmington, DE: Glaxo SmithKline LLC; 2015.
• Farxiga [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2015.
• Rosenstock J, Cefalu W, Lapuerta P, et al. Greater dose-ranging effects on A1c levels than on glucosuria with LX4211, a dual inhibitor of SGLT1 and SGLT2, in patients with type 2 diabetes on metformin monotherapy. Diabetes Care. 2015;38:431-438.
• Thynne T, Doogue M. Sodium-glucose co-transporter inhibitors: mechanisms of action. Aust Prescr. 2014;37:14-16.
• Gilead Sciences. Ranolazine when added to glimepiride in subjects with type 2 diabetes mellitus. Bethesda, MD: National Library of Medicine; 2000. . https://clinicaltrials.gov/ct2/show/NCT01494987?term=NCT01494987&rank=1 NLM Identifier: NCT01494987. Accessed October 15, 2015.
• Eckel R, Henry R, Yue P, et al. Effect of ranolazine monotherapy on glycemic control in subjects with type 2 diabetes. Diabetes Care. 2015;38:1189-1196.
• Gilead Sciences. A phase 3 study of ranolazine in subjects with type 2 diabetes who are inadequately controlled on metformin alone. Bethesda, MD: National Library of Medicine: 2000. https://clinicaltrials.gov/ct2/show/NCT01555164?term=NCT01555164&rank=1 NLM Identifier: NCT01555164. Accessed October 15, 2015.
• Dhalla A, Yang M, Ning Y. Blockade of Na+ channels in pancreatic α-cells has antidiabetic effects. Diabetes. 2014;63:3545-3556.
• Timmis A, Chaitman B, Crager M. Effects of ranolazine on exercise tolerance and HbA1c in patients with chronic angina and diabetes. Eur Heart J. 2006;27:42-48.
• Morrow D, Scirica B, Chaitman B, et al; MERLIN-TIMI 36 investigators. Evaluation of the glycometabolic effects of ranolazine in patients with and without diabetes mellitus in the MERLIN-TIMI 36 randomized controlled trial. Circulation. 2009;119:2032-2039.
• Chisholm J, Goldfine A, Dhalla A, et al. Effect of ranolazine on A1C and glucose levels in hyperglycemic patients with non-ST elevation acute coronary syndrome. Diabetes Care. 2010;33:1163-1168.
• Caparrotta T, Evans, M. PEGylated insulin Lispro, (LY2605541): a new basal insulin analogue. Diabetes, Obesity and Metabolism. 2014;16:388-395.
• Bergenstal R, Rosenstock J, Arakaki R, et al. A randomized, controlled study of once-daily LY2605541, a novel long-acting basal insulin, vs. insulin glargine in basal insulin-treated patients with type 2 diabetes. Diabetes Care. 2012;35:2140-2147.
• Rosenstock J, Bergenstal R, Blevins T, et al. Better glycemic control and weight loss with the novel long-acting basal insulin LY2605541 compared with insulin glargine in type 1 diabetes a randomized, crossover study. Diabetes Care. 2012;36:522-528.
• Fulcher G, Christiansen J, Bantwal G, et al. Comparison of insulin degludec/insulin aspart and biphasic insulin aspart 30 in uncontrolled, insulin-treated type 2 diabetes: a phase 3a, randomized, treat-to-target trial. Diabetes Care. 2014;37:2084-2090.