More than 29 million people in the United States have diabetes, the seventh leading cause of mortality and a major cause of stroke, heart disease, kidney failure, blindness, and other serious conditions.1 As the US population ages and the number of higher-risk minority groups grows, the incidence of diabetes is projected to nearly double from approximately 8 cases per 1000 individuals in 2008 to approximately 15 cases per 1000 in 2050.2
Diabetes is one of the most costly chronic medical conditions. The American Diabetes Association estimated that the total cost (direct and indirect) of diabetes in the United States reached $245 billion in 2012.1
Patients with diabetes manage their condition with lifestyle changes, including exercise and weight management, as well as medications. The specific goals related to glycated hemoglobin (HbA1c) levels are individualized based on the patient's age, comorbid conditions, disease duration, and the ability to adhere to therapy. Diabetes control is critical to reducing the risk for disease-related macrovascular changes and microvascular complications (eg, neuropathy, nephropathy, retinopathy).1,3
Type 1 diabetes is characterized by a lack of production or secretion of insulin.1 Medical treatments include insulin, administered as injections (basal and mealtime insulin) or as continuous subcutaneous infusions.3 Type 2 diabetes is characterized by insulin resistance.
Pharmacologic treatments for type 2 diabetes include metformin, sulfonylureas, meglitinides, thiazolidinediones (peroxisome proliferator-activated receptor [PPAR]-gamma agonists), dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors, and insulin.4
Basal or background insulins are designed to ensure consistent blood glucose levels during periods of fasting. Several basal insulin drugs are currently available in the United States, including insulin glargine 100 units/mL (Lantus), a more concentrated version known as insulin glargine 300 units/mL, and insulin detemir.5-7
FDA Approves Tresiba and Ryzodeg for Patients with Diabetes Mellitus
On September 25, 2015, the US Food and Drug Administration (FDA) approved 2 drugs to improve glycemic control in adults with diabetes mellitus—insulin degludec injection (Tresiba; Novo Nordisk) and a combination of insulin degludec plus insulin aspart (Ryzodeg 70/30; Novo Nordisk).8-10 Insulin degludec is a long-acting insulin analog, and insulin aspart is a rapid-acting insulin analog. The drug labels for insulin degludec and for insulin degludec plus insulin aspart note that these 2 drugs are not recommended for the treatment of patients with diabetic ketoacidosis.9,10
Commenting on the FDA approval, Jean-Marc Guettier, MD, Director of the FDA's Division of Metabolism and Endocrinology Products, said, "Long-acting insulins play an essential role in the treatment of patients with type 1 diabetes and in patients with type 2 diabetes with advanced disease. The FDA remains committed to support the development of innovative therapies for the treatment of diabetes."8
Mechanism of Action
Insulin and insulin analogs, such as insulin degludec and insulin aspart, regulate glucose metabolism.9,10 By stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting glucose production in the liver, insulin and its analogs reduce blood glucose levels. Insulin also inhibits lipolysis and proteolysis, and enhances protein synthesis.9,10
When injected into the subcutaneous tissue, insulin degludec forms multihexamers that result in a subcutaneous depot of insulin degludec.9,10 Overall, 2 phenomena contribute to its protracted time-action profile—(1) delayed absorption of insulin degludec from the subcutaneous tissue into the systemic circulation, and (2) binding of insulin degludec to circulating albumin.9,10 A study in patients with type 1 diabetes demonstrated that the glucose-lowering effect of insulin degludec lasted at least 42 hours after the last of 8 once-daily injections.9 Unlike insulin degludec, which has a delayed absorption into the circulation, insulin aspart monomers are released rapidly into the circulation.10
Dosing and Administration
Insulin degludec is available in 2 dosages—100 units/mL (U-100) in a 3-mL FlexTouch pen, and 200 units/mL (U-200) in a 3-mL FlexTouch pen; these 2 concentrations deliver a maximum of 80 units and 160 units per single injection, respectively.9 In patients with insulin-naïve type 1 diabetes, the recommended starting dose is approximately one-third to one-half of the total daily insulin dose.9 The remainder of the total daily insulin dose should be administered as a short-acting insulin divided between each daily meal.9 In patients with insulin-naïve type 2 diabetes, the recommended starting dose is 10 units once daily.9
Patients who already use insulin should start insulin degludec using the same unit dose as their total daily long- or intermediate-acting insulin unit dose.9
Insulin degludec should be injected subcutaneously once daily into the thigh, upper arm, or abdomen, rotating sites daily to avoid lipodystrophy; the drug can be administered at any time of day.9 The dose of insulin degludec should be individualized and titrated based on the patient's metabolic needs, blood glucose levels, and glycemic control goal. Dose increases should occur after 3 to 4 days.9
Insulin Degludec plus Insulin Aspart
Insulin degludec plus insulin aspart is available as a clear and colorless solution for injection at 100 units/mL (U-100) in a 3-mL FlexTouch disposable prefilled pen.10
The recommended starting dose in patients with insulin-naïve type 1 or type 2 diabetes is approximately one-third to one-half of the total daily insulin dose. The remainder of the dose should be administered as a short-acting insulin divided between each meal.10
The starting dose for patients taking once- or twice- daily premix or self-mix insulin alone or as part of multiple daily injections should be at the same unit dose and injection schedule as the premix or self-mix insulin.10 In patients also using short- or rapid-acting insulin at mealtimes, short- or rapid-acting insulin should be continued at the same dose for meals not covered by insulin degludec plus insulin aspart.10
Insulin degludec plus insulin aspart should be started at the same unit dose and injection schedule in patients with type 2 diabetes switching from a once- or twice-daily basal insulin regimen.10
In patients switching from multiple daily injections with a basal and short- or rapid-acting insulin at mealtimes, insulin degludec plus insulin aspart should be started once daily with the main meal at the same unit dose as the basal insulin, and the short- or rapid-acting insulin should be continued at the same dose for meals not covered by insulin degludec plus insulin aspart.10
The approval of insulin degludec was based on data from the BEGIN clinical trial program.11-13 This program included 9 studies that assessed the efficacy and safety of insulin degludec in patients with inadequate blood glucose control. In Study A, B, and C, more than 1100 patients with type 1 diabetes received insulin degludec combined with mealtime insulin or an active control.8 The other 6 studies evaluated the combination of insulin degludec and mealtime insulin or as an adjunct to common background oral antidiabetic drugs for type 2 diabetes.8
In studies conducted in patients with type 1 diabetes, the primary end point was a reduction in HbA1c levels from baseline. The active comparators were insulin glargine or insulin detemir. Data from these studies showed that insulin degludec enhanced glycemic control, achieving similar reductions in HbA1c levels compared with FDA-approved comparators (Table 1).9
In Study C, insulin degludec was administered at the same time each day or at any time in combination with a rapid-acting insulin analog at mealtimes.9 This 26-week randomized, open-label, multicenter clinical trial conducted in 493 patients with type 1 diabetes was designed to simulate a "worst-case scenario" injection schedule of alternating short and long, once-daily, dosing intervals (ie, 8-40 hours between doses).9 At week 26, the difference in HbA1c reduction from baseline between insulin degludec (N = 164) administered at alternating times and insulin glargine U-100 (N = 164) was 0.17% (95% confidence interval [CI], 0.04%-0.30%), which met the prespecified noninferiority margin of 0.4%.9
Overall, 6 studies assessed the efficacy and safety of insulin degludec combined with mealtime insulin or common background oral antidiabetic drugs in more than 2700 patients with type 2 diabetes who had inadequate blood glucose control.8,9 Insulin degludec therapy reduced HbA1c levels in a fashion comparable to previously approved long-acting insulins.9
In Study A, patients were randomized to receive insulin degludec once daily at any time of day or sitagliptin once daily according to its approved label.9 All patients also received 1 or 2 oral antidiabetic drugs. At the end of 26 weeks, insulin degludec demonstrated superior reduction in HbA1c levels compared with sitagliptin (P <.001).9
Insulin Degludec plus Insulin Aspart
The approval of insulin degludec plus insulin aspart was based on 5 clinical trials of patients with type 1 or type 2 diabetes.10,14 A 26-week, randomized, open-label, treat-to-target, active-controlled trial involved 548 patients with type 1 diabetes. Patients were randomized to receive insulin degludec plus insulin aspart once daily during the main meal of the day or insulin detemir once daily during the evening meal or at bedtime; insulin aspart was administered for the remaining insulin-requiring meals.10
At week 26, the difference in HbA1c level reduction from baseline between insulin degludec plus insulin aspart and insulin detemir was -0.05% (95% CI, -0.18 to 0.08), which met the prespecified noninferiority margin of 0.4% (Table 2).10
Overall, 4 randomized, open-label, treat-to-target, active-controlled clinical trials involving 1860 patients with type 2 diabetes assessed the efficacy of insulin degludec plus insulin aspart when administered once or twice daily with the main meals and used with common oral antidiabetic drugs, including insulin glargine and biphasic insulin aspart 70/30.10
Patients who received insulin degludec plus insulin aspart achieved levels of glycemic control similar to those who received insulin glargine and biphasic insulin aspart 70/30.10
The safety of insulin degludec was evaluated in 9 clinical trials lasting 6 to 12 months in 1102 patients with type 1 diabetes and in 2713 patients with type 2 diabetes.9 Mean treatment durations in these cohorts were 34 weeks and 36 weeks, respectively.9 The mean HbA1c levels at baseline were 7.8% and 8.3%, respectively.9
A baseline history of neuropathy, ophthalmopathy, nephropathy, and cardiovascular disease was reported in 11%, 16%, 7%, and 0.5%, respectively, in patients with type 1 diabetes.9 A baseline history of the same conditions was reported in 14%, 10%, 6%, and 0.6%, respectively, of patients with type 2 diabetes.9
Common adverse reactions (excluding hypoglycemia) reported with insulin degludec included nasopharyngitis, upper respiratory tract infection, headache, sinusitis, diarrhea, and gastroenteritis. Hypersensitivity, lipodystrophy, injection-site reactions, weight gain, and peripheral edema were also reported.9
Hypoglycemia is the most common side effect associated with insulin degludec. Among patients with type 1 diabetes, the rate of severe hypoglycemia with insulin aspart was 12.3% in Study A (52 weeks), 10.6% in Study B (26 weeks), and 12.7% in Study C (26 weeks) when insulin aspart was taken at the same time daily.9
Insulin Degludec plus Insulin Aspart
The safety of insulin degludec plus insulin aspart in patients with type 1 or type 2 diabetes was evaluated in 5 treat-to-target clinical trials lasting 6 to 12 months.10 Adverse reactions occurring in ≥5% of patients with type 1 diabetes included nasopharyngitis (24.6%), headache (9.7%), upper respiratory tract infection (9.1%), and influenza (6.9%).10 Adverse reactions occurring in ≥5% of patients with type 2 diabetes included nasopharyngitis (11.1%), upper respiratory tract infection (5.7%), and headache (5.6%).10
Insulin degludec and the combination of insulin degludec plus insulin aspart should not be used concomitantly with drugs that may increase the risk for hypoglycemia, drugs that may increase or decrease the blood glucose—lowering effect of these 2 drugs, and drugs that may blunt the signs of hypoglycemia.9,10
Insulin degludec and the combination of insulin degludec plus insulin aspart are contraindicated during episodes of hypoglycemia and in patients with hypersensitivity to these 2 drugs or to any of their excipients.
Warnings and Precautions
Never share insulin pens. Because of the risk for transmitting blood-borne pathogens, patients should not share insulin pens, even if the needle is changed.9,10
Hypoglycemia. Severe hypoglycemia can cause seizures and death. Insulin degludec and the combination of insulin degludec plus insulin aspart should not be used in patients with hypoglycemia.9,10
Hyperglycemia with regimen changes. Glycemic control can be affected when insulin, manufacturer, type, or method of administration is altered.9,10 Changes in insulin regimens should be made with caution, and blood glucose monitoring frequency should be increased. Patients with type 2 diabetes may need to adjust their oral antidiabetic drug dose.9,10
Hypoglycemia from medication errors. Accidental mix-ups between basal insulin and other insulins have been reported. To avoid medication errors, patients should check the insulin label before each injection.9,10
Hypersensitivity and allergic reactions. Life-threatening generalized allergy and anaphylaxis have been reported with insulin drugs; insulin degludec and the combination of insulin degludec plus insulin aspart should be discontinued if hypersensitivity reactions occur.9,10
Hypokalemia. All insulin drugs cause a shift in potassium from the extracellular space to the intracellular space, which can lead to hypokalemia.9,10 If not treated, hypokalemia can cause respiratory paralysis, ventricular arrhythmia, and death. At-risk patients should be monitored.9,10
Fluid retention and congestive heart failure with PPAR-gamma agonists. When used in combination with insulin degludec or insulin degludec plus insulin aspart, PPAR-gamma agonists can cause dose-related fluid retention, which can lead to or worsen congestive heart failure.9,10 If the latter occurs, the PPAR-gamma agonist should be discontinued or the dose reduced.9,10
Use in Specific Populations
Pregnancy. No adequate and well-controlled studies of insulin degludec and insulin degludec plus insulin aspart were conducted in pregnant women.9,10
Nursing mothers. It is not known whether insulin degludec or insulin aspart are present in human breast milk.9,10
Pediatric use. The safety and efficacy of insulin degludec and insulin degludec plus insulin aspart have not been established in patients aged ≤18 years.9,10
Geriatric use. Subgroup analyses comparing patients aged >65 years and younger patients using insulin degludec or insulin degludec plus insulin aspart did not suggest differences in the safety or efficacy of these 2 drugs.9,10
Renal impairment. In a study comparing the pharmacokinetics of insulin degludec in healthy patients versus those with a renal impairment, including end-stage renal disease, no clinical differences were identified.9 As with all insulin drugs, glucose monitoring should be intensified and the dosage adjusted in patients with renal impairment.9,10
Hepatic impairment. No clinically relevant differences were identified in healthy patients compared with those with mild, moderate, and severe liver impairment.9
Glycemic control is key to preventing the complications associated with diabetes, and insulin therapy has been shown to achieve glycemic control in patients with diabetes. The 2 recently FDA-approved insulins—insulin degludec, a novel formulation of long-acting insulin, and the combination of insulin degludec plus insulin aspart, a rapid-acting insulin—have demonstrated efficacy and acceptable safety comparable to that of currently available basal insulin drugs for the treatment of patients with type 1 or type 2 diabetes.
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 October 22, 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. Executive summary: standards of medical care in diabetes—2014. Diabetes Care. 2014;37(suppl 1):S5-S13.
4. Inzucchi SE, Bergenstal RM, Buse JB, et al; for the American Diabetes Association (ADA); European Association for the Study of Diabetes (EASD). Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35:1364-1379. Erratum in: Diabetes Care. 2013;36:490.
5. Toujeo (insulin glargine injection) U-300 [prescribing information]. Bridgewater, NJ: sanofi-aventis US; September 2015.
6. Lantus (insulin glargine injection) solution [prescribing information]. Bridgewater, NJ: sanofi-aventis US; August 2015.
7. Levemir (insulin detemir [rDNA origin] injection) solution [prescribing information]. Plainsboro, NJ: Novo Nordisk; February 2015.
8. US Food and Drug Administration. FDA approves two new drug treatments for diabetes mellitus. Press release. September 25, 2015. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm464321.htm. Accessed October 22, 2015.
9. Tresiba (insulin degludec injection) [prescribing information]. Plainsboro, NJ: Novo Nordisk; September 2015.
10. Ryzodeg 70/30 (insulin degludec and insulin aspart injection) [prescribing information]. Plainsboro, NJ: Novo Nordisk; September 2015.
11. Davies MJ, Gross JL, Ono Y, et al; for the BEGIN BB T1 Study Group. Efficacy and safety of insulin degludec given as part of basal-bolus treatment with mealtime insulin aspart in type 1 diabetes: a 26-week randomized, open-label, treat-to-target non-inferiority trial. Diabetes Obes Metab. 2014;16:922-930.
12. Zinman B, DeVries JH, Bode B, et al; for the NN1250-3724 (BEGIN:EASY AM) and NN1250-3718 (BEGIN:EASY PM) Trial Investigators. Efficacy and safety of insulin degludec three times a week versus insulin glargine once a day in insulin-naive patients with type 2 diabetes: results of two phase 3, 26 week, randomised, open-label, treat-to-target, non-inferiority trials. Lancet Diabetes Endocrinol. 2013;1:123-131.
13. Garber AJ, King AB, Del Prato S, et al; for the NN1250-3582 (BEGIN BB T2D) Trial Investigators. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet. 2012;379:1498-1507.
14. Fulcher GR, Christiansen JS, Bantwal G, et al; for the BOOST: Intensify Premix I Investigators. 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.