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September 2015, Vol 3, No 9 - Inside Drug Update
Loretta Fala

Diabetes is a chronic disease that affects a staggering 29.1 million individuals in the United States—approximately 9.3% of the population.1 In addition, approximately 37% of all US adults aged ≥20 years (51% of individuals aged ≥65 years) have prediabetes, a condition that substantially increases the risk for diabetes.1 Today, diabetes affects 1 in 10 adults.2 The prevalence of diabetes is projected to increase to 1 in 3 adults by 2050, based on current trends and the aging of the US population during the next few decades.2 The appropriate management of diabetes can help to reduce its rising prevalence.2

Type 1 diabetes mellitus develops when the beta-cells in the pancreas are destroyed by the body’s immune system, thereby eliminating the production and secretion of insulin that is necessary to lower blood glucose levels.1 Type 2 diabetes mellitus is characterized by insulin resistance and a gradual decline in the ability of the pancreas to produce sufficient quantities of insulin. Type 1 diabetes accounts for 5% to 10% of all cases of diabetes, whereas type 2 diabetes accounts for 90% to 95% of all cases of diabetes in the United States.1

Diabetes is the seventh leading cause of mortality and a major cause of stroke, heart disease, kidney failure, blindness, and other serious conditions in the United States.1 Furthermore, diabetes is associated with microvascular, macrovascular, and neuropathic complications that can profoundly impact an individual’s health and quality of life.1

The annual US healthcare costs attributed to diabetes totaled $245 billion in 2012, including $176 billion in direct medical costs and $69 billion in indirect costs (eg, absenteeism, reduced or lost productivity, and disability).3 Overall, the medical costs of patients with diabetes are more than twice as high as the medical costs for individuals without diabetes, with more than 1 in 5 US healthcare dollars being spent on diabetes care.3

Diabetes management includes approaches that incorporate lifestyle changes and self-management, provide appropriate education, minimize the risk for weight gain and for hypoglycemia, and target the patient’s glycated hemoglobin (HbA1c) goal on an individual basis, based on factors such as age, comorbid conditions, disease duration, and adherence to therapy.4

Patients with diabetes require ongoing monitoring to evaluate the effectiveness of their therapies toward achieving stable glycemic control.4

Improvements in glycemic control are associated with improved outcomes for patients with type 1 or type 2 diabetes. Effective glycemic control reduces the risk for diabetes-related microvascular complications (eg, diabetic neuropathy, nephropathy, and retinopathy) and macrovascular disease.1,5

Pharmacologic treatments for type 1 diabetes include multiple daily insulin injections (basal and prandial insulin) or continuous subcutaneous insulin infusions.5 The American Diabetes Association (ADA) recommends that the majority of patients with type 1 diabetes are treated with insulin analogs to reduce the risk for hypoglycemia.5 Pharmacologic treatments for type 2 diabetes include metformin, sulfonylureas, meglitinides, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors, and insulin therapy.6

Insulin Glargine U-300: A New Option for Patients with Type 1 or Type 2 Diabetes

On February 25, 2015, insulin glargine U-300 (300 units/mL [Toujeo; sanofi-aventis]), a once-daily, long-acting basal insulin, was approved by the US Food and Drug Administration (FDA) to improve glycemic control in adults with type 1 or type 2 diabetes mellitus.7,8 Insulin glargine U-300 is not recommended for use in patients with diabetic ketoacidosis.8 Insulin glargine U-100 (100 units/mL [Lantus; sanofi-aventis]), another long-acting basal insulin, was initially approved by the FDA in 2000 to improve glycemic control in adults and pediatric patients with type 1 diabetes and in adults with type 2 diabetes.9

The FDA approval of insulin glargine U-300 was based on the results from the EDITION clinical trial program, a series of international phase 3 studies that included more than 3500 adults with type 1 or type 2 diabetes.7

According to John Anderson, MD, an internal medicine and diabetes specialist, Frist Clinic of Nashville, TN, and Past President of the ADA, “Nearly 50 percent of people living with diabetes remain uncontrolled.” Dr Anderson added, “Despite the proven efficacy of insulin, ensuring effective titration and maintenance can be a challenge for both patients and healthcare professionals due to hypoglycemia concerns. Toujeo provides a new option that may help patients manage their diabetes.”7

Mechanism of Action

Insulin glargine U-300, a long-acting analog of insulin, regulates glucose metabolism. Insulin and its analogs lower blood glucose levels by stimulating peripheral glucose uptake, especially via skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis and proteolysis and enhances protein synthesis.8

Dosing and Administration

Insulin glargine U-300 is a long-acting human insulin analog containing 300 units/mL of insulin glargine and supplied as a sterile solution in a 1.5 SoloSTAR disposable prefilled pen for subcutaneous injection.8

The dosing of insulin glargine U-300 is individualized based on the patient’s diabetes type, metabolic needs, blood glucose monitoring results, and HbA1c goal. Insulin glargine U-300 is administered subcutaneously once daily at any time during the day, at the same time every day.8 The injection sites should be rotated to reduce the risk for lipodystrophy. Insulin glargine U-300 should not be diluted or mixed with any other insulin or solution. Patients’ glucose levels should be closely monitored when they change to insulin glargine from another medication and during the initial weeks thereafter.8

Clinical Studies

The safety and efficacy of insulin glargine U-300 were compared with that of once-daily insulin glargine U-100 in the EDITION clinical trial program, a series of open-label, randomized, active-control, parallel studies for up to 26 weeks in patients with type 1 and type 2 diabetes.8 At the end of these clinical trials, the reduction in HbA1c levels and fasting plasma glucose levels with insulin glargine U-300 was similar to that of glargine U-100. In addition, depending on the patient population and the concomitant therapy, patients received a higher dose of insulin glargine U-300 than of insulin glargine U-100.8

Type 1 Diabetes: EDITION 4 Study

In the EDITION 4 Study, 546 adults with type 1 diabetes were randomized to receive basal-bolus insulin glargine U-300 or insulin glargine U-100 for 26 weeks.8,10 Insulin glargine U-300 and insulin glargine U-100 were administered before each meal. The patients’ mean age was 47.3 years, the mean body mass index (BMI) was 27.6 kg/m2, and the mean duration of diabetes was 21 years.8,10

At week 26, treatment with insulin glargine U-300 provided a mean reduction in HbA1c levels that met the prespecified noninferiority margin of 0.4% (Table 1).8 In addition, patients who received insulin glargine U-300 used 17.5% more basal insulin than patients who received insulin glargine U-100.8

Table 1

No clinically important differences were seen in glycemic control when insulin glargine U-300 was administered once daily in the morning or in the evening. During the first 8 weeks of treatment, insulin glargine U-300 was associated with less frequent nocturnal hypoglycemia compared with that of insulin glargine U-100.10 There were no clinically important differences in body weight between the treatment groups.8

Type 2 Diabetes: EDITION 1, 2, and 3 Studies

In the EDITION 1 clinical trial, a 26-week, open-label, controlled study, 804 adults with type 2 diabetes were randomized to receive once-daily insulin glargine U-300 or insulin glargine U-100.8,11 Short-acting mealtime insulin analogs, with or without metformin, were also administered. The patients’ average age was 60 years, and the mean BMI was approximately 36.6 kg/m2. At week 26, treatment with insulin glargine U-300 provided a mean reduction in HbA1c levels that met the prespecified noninferiority margin of 0.4% compared with insulin glargine U-100 (Table 2).8,11 In addition, patients who received insulin glargine U-300 used 11% more basal insulin than patients who received insulin glargine U-100.8 There were no clinically important differences in body weight between the treatment groups.8

Table 2

In the EDITION 2 and EDITION 3 open-label controlled studies, 1670 adults with type 2 diabetes were randomized to receive once-daily insulin glargine U-300 or insulin glargine U-100 for 26 weeks as part of a combination therapy regimen with noninsulin antidiabetic drugs (Table 2).8,12,13

In the EDITION 2 study (patients’ average age, 58.2 years; mean BMI, 34.8 kg/m2) at week 26, treatment with insulin glargine U-300 provided a mean reduction in HbA1c levels that met the prespecified noninferiority margin of 0.4% compared with insulin glargine U-100.8,12 There were no clinically impor­tant differences in body weight between the treatment groups.8

In the EDITION 3 study (patients’ average age, 57.7 years; mean BMI, 33 kg/m2) at week 26, patients who received insulin glargine U-300 showed a mean reduction in HbA1c levels that met the prespecified noninferiority margin compared with insulin glargine U-100.8,13 There were no clinically important differences in body weight between the treatment groups.8

A meta-analysis of the EDITION 1, 2, and 3 studies revealed that insulin glargine U-300 was comparable to insulin glargine U-100 in improving glycemic control. In addition, insulin glargine U-300 was associated with less hypoglycemia at any time of day and less frequent nocturnal hypoglycemia than that of glargine U-100.14

Safety

The most common adverse reactions associated with the use of insulin glargine U-300 (≥5%) include hypoglycemia, allergic reactions, injection-site reaction, lipodystrophy, pruritus, rash, edema, and weight gain.8

Drug Interactions

Drugs that affect glucose metabolism
The insulin dosage may need to be adjusted and the patient’s blood glucose levels should be closely monitored when insulin glargine U-300 is used with drugs that affect glucose metabolism.8

Antiadrenergic drugs
The signs and symptoms of hypoglycemia may be reduced or absent when insulin glargine U-300 is used with antiadrenergic drugs (eg, beta-blockers, clonidine, guanethidine, and reserpine).8

Contraindications

The use of insulin glargine U-300 is contraindicated during episodes of hypoglycemia and in patients who are hypersensitive to insulin glargine or to any of its excipients.8

Warnings and Precautions

Never share the disposable pen
The insulin glargine disposable prefilled pens must never be shared between patients, even if the needle is changed. Pen sharing poses a risk for transmission of blood-borne pathogens.8

Hyperglycemia/hypoglycemia with changes in insulin regimen
Changes in insulin strength, manufacturer, type, or method of administration may affect glycemic control and predispose patients to hypoglycemia or hyperglycemia.8 These changes should be made cautiously and only under close medical supervision, and the frequency of blood glucose monitoring should be increased. Dosage adjustments of concomitant oral antidiabetic drugs may be needed for patients with type 2 diabetes.8

Hypoglycemia
Severe hypoglycemia can cause seizures and may be life-threatening. The frequency of glucose monitoring should be increased with changes to insulin dosage, coadministered glucose-lowering medications, meal pattern, physical activity, and in patients with renal impairment, hepatic impairment, or hypoglycemia unawareness.8

Medication errors
Accidental mix-ups between insulin drugs can occur. Patients should be instructed to check insulin labels before injection.8

Hypersensitivity and allergic reactions
Severe, life-threatening generalized allergy, including anaphylaxis, can occur with insulin drugs, including insulin glargine U-300. If hypersensitivity reactions occur, insulin glargine U-300 should be discontinued, and patients should be treated according to the standard of care. In addition, patients should be monitored until the signs and symptoms of hypersensitivity reactions resolve.8

Hypokalemia
All insulin drugs, including insulin glargine, cause a shift in potassium from the extracellular to the intracellular space, possibly leading to hypokalemia, which may be life-threatening. Potassium levels should be monitored in patients at risk for hypokalemia.8

Fluid retention and heart failure
Fluid retention and heart failure can occur when insulin is used concomitantly with thiazolidinediones. Patients should be observed for signs and symptoms of heart failure, and dosage reduction or the discontinuation of insulin glargine U-300 should be considered if heart failure occurs.8

Use in Specific Populations

Pregnancy
It is recommended that insulin glargine U-300 be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.8 Female patients should be advised to inform their physicians if they intend to become, or if they become, pregnant while taking insulin glargine U-300.8

Nursing mothers
It is not known whether insulin glargine U-300 is excreted in human milk.8 Caution should be exercised when insulin glargine U-300 is administered to a nursing woman. The use of insulin glargine U-300 is compatible with breastfeeding, but women with diabetes who are lactating may require adjustments of their insulin doses.8

Pediatric use
The safety and efficacy of insulin glargine U-300 have not been established in pediatric patients.8

Geriatric use
No overall differences in the efficacy and safety of insulin glargine U-300 were observed between patients aged ≥65 years and younger patients.8 Nevertheless, caution should be exercised when insulin glargine U-300 is administered to geriatric patients. In elderly patients with diabetes, the initial dosing, dose increments, and the maintenance dosage should be conservative to avoid hypoglycemia.8

Hepatic impairment
The effects of hepatic impairment on the pharmacokinetics of insulin glargine U-300 have not been studied.8 Frequent glucose monitoring and dose adjustment of insulin glargine U-300 may be necessary in patients with hepatic impairment.8

Renal impairment
The effects of renal impairment on the pharmacokinetics of insulin glargine U-300 have not been studied.8 Frequent glucose monitoring and dose adjustment of insulin glargine U-300 may be necessary in patients with renal impairment.8

Obesity
No overall differences in the efficacy and safety of insulin glargine U-300 were observed in the subgroup analyses based on the BMI.8

Conclusion

With the recent FDA approval of insulin glargine U-300, a new once-daily basal insulin option became available to improve glycemic control in adults with type 1 or type 2 diabetes. The safety and efficacy of insulin glargine U-300 were evaluated in more than 3500 patients in phase 3 clinical trials. In all 4 of the EDITION studies, insulin glargine U-300 met the primary end points, demonstrating similar glycemic control compared with that of insulin glargine U-100.

Insulin glargine U-300, available in a disposable prefilled pen containing 450 units of the drug, requires one-third the injection volume of insulin glargine U-100 to deliver the same measure of insulin units. Dispensing a maximum single injection dose of 80 international units, insulin glargine U-300 may accommodate many patients who require 80 international units of basal insulin daily.

Copyright © American Health & Drug Benefits. Used with permission. All Rights Reserved.




References

  1. Centers for Disease Control and Prevention. National diabetes statistics report: estimates of diabetes and its burden in the United States, 2014. 2014. www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf. Accessed June 1, 2015.
  2. Boyle JP, Thompson TJ, Gregg EW, et al. Projection of the year 2050 burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence. Popul Health Metr. 2010;8:29.
  3. American Diabetes Association. Economic costs of diabetes in the U.S. in 2012. Diabetes Care. 2013;36:1033-1046. Erratum in: Diabetes Care. 2013;36:1797.
  4. Garber AJ, Abrahamson MJ, Barzilay JI, et al; for the American Association of Clinical Endocrinologists. AACE comprehensive diabetes management algorithm: 2013. Endocr Pract. 2013;19:327-336.
  5. American Diabetes Association. Executive summary: standards of medical care in diabetes—2014. Diabetes Care. 2014;37(suppl 1):S5-S13.
  6. Mayo Clinic staff. Diseases and conditions: type 2 diabetes: treatments and drugs. July 24, 2014. www.mayoclinic.org/diseases-conditions/type-2-diabetes/basics/treatment/con-20031902. Accessed June 3, 2015.
  7. sanofi-aventis US. Sanofi receives FDA approval of once-daily basal insulin Toujeo. Press release. February 25, 2015. www.news.sanofi.us/2015-02-25-Sanofi-Receives-FDA-Approval-of-Once-Daily-Basal-Insulin-Toujeo. Accessed May 21, 2015.
  8. Toujeo (insulin glargine injection) U-300 [prescribing information]. Bridgewater, NJ: sanofi-aventis US LLC; May 2015.
  9. Lantus (insulin glargine [rDNA origin] injection) U-100 [prescribing information]. Bridgewater, NJ: sanofi-aventis US LLC; February 2015.
  10. Home PD, Bergenstal RM, Riddle MC, et al. Glycaemic control and hypoglycaemia with new insulin glargine 300 U/mL in people with type 1 diabetes (EDITION 4). Presented at the 50th European Association for the Study of Diabetes Annual Meeting; September 15-19, 2014; Vienna, Austria.
  11. Riddle MC, Bolli GB, Ziemen M, et al; for the EDITION 1 Study Investigators. New insulin glargine 300 units/mL versus glargine 100 units/mL in people with type 2 diabetes using basal and mealtime insulin: glucose control and hypoglycemia in a 6-month randomized controlled trial (EDITION 1). Diabetes Care. 2014;37:2755-2762.
  12. Yki-Järvinen H, Bergenstal R, Ziemen M, et al; for the EDITION 2 Study Investigators. New insulin glargine 300 units/mL versus glargine 100 units/mL in people with type 2 diabetes using oral agents and basal insulin: glucose control and hypoglycemia in a 6-month randomized controlled trial (EDITION 2). Diabetes Care. 2014;37:3235-3243.
  13. Bolli GB, Riddle MC, Bergenstal RM, et al; for the EDITION 3 Study Investigators. New insulin glargine 300 U/ml compared with glargine 100 U/ml in insulin-naïve people with type 2 diabetes on oral glucose-lowering drugs: a randomized controlled trial (EDITION 3). Diabetes Obes Metab. 2015;17:386-394.
  14. Ritzel RA, Roussel R, Bolli GB, et al. New insulin glargine 300 U/ml: glycaemic control and hypoglycaemia in a meta-analysis of phase 3a EDITION clinical trials in people with type 2 diabetes mellitus. Presented at the 50th European Association for the Study of Diabetes Annual Meeting; September 15-19, 2014; Vienna, Austria.
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