Insulin Glargine Solostar Drug Information
Generic name: INSULIN GLARGINE
Insulin Analog [EPC]
Uses of Insulin Glargine Solostar
Insulin glargine is indicated to improve glycemic control in adults and pediatric patients with type 1 diabetes mellitus and in adults with type 2 diabetes mellitus. Insulin glargine is a long-acting human insulin analog indicated to improve glycemic control in adults and pediatric patients with type 1 diabetes mellitus and in adults with type 2 diabetes mellitus. Limitations of Use Not recommended for treating diabetic ketoacidosis.
Limitations of Use Insulin glargine is not recommended for the treatment of diabetic ketoacidosis.
Dosage & Administration of Insulin Glargine Solostar
Important
Administration Instructions Administer Insulin glargine subcutaneously once daily at any time of day but at the same time every day. Prior to initiation of Insulin glargine, train patients on proper use and injection technique. Patient should follow the Instructions for Use to correctly administer Insulin glargine.
Administer Insulin glargine subcutaneously into the abdominal area, thigh, or deltoid, and rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis . During changes to a patient's insulin regimen, increase the frequency of blood glucose monitoring . Visually inspect Insulin glargine vials and SoloStar prefilled pens for particulate matter and discoloration prior to administration. Only use if the solution is clear and colorless with no visible particles.
The Insulin glargine SoloStar prefilled pen dials in 1-unit increments. Use Insulin glargine SoloStar prefilled pen with caution in patients with visual impairment who may rely on audible clicks to dial their dose. Refrigerate unused (unopened) Insulin glargine vials and SoloStar ® prefilled pens.
Do not administer intravenously or via an insulin pump. Do not dilute or mix Insulin glargine with any other insulin or solution. The SoloStar prefilled pen is for single patient use only .
General Dosing Instructions Individualize and adjust the dosage of Insulin glargine based
on the individual's metabolic needs, blood glucose monitoring results and glycemic control goal. Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), during acute illness, or changes in renal or hepatic function. Dosage adjustments should only be made under medical supervision with appropriate glucose monitoring .
Initiation of Insulin Glargine Therapy Type 1 Diabetes
In patients with type 1 diabetes, Insulin glargine must be used concomitantly with short-acting insulin. The recommended starting dose of Insulin glargine in patients with type 1 diabetes should be approximately one-third of the total daily insulin requirements. Short-acting, premeal insulin should be used to satisfy the remainder of the daily insulin requirements.
Type 2 Diabetes The recommended starting dose of Insulin glargine in patients with type 2 diabetes who are not currently treated with insulin is 0.2 units/kg or up to 10 units once daily. One may need to adjust the amount and timing of short- or rapid-acting insulins and dosages of any oral antidiabetic drugs.
Changing to Insulin Glargine from Other Insulin Therapies
If changing patients from once-daily TOUJEO (insulin glargine) 300 units/mL to once-daily Insulin glargine, the recommended initial Insulin glargine dose is 80% of the TOUJEO dose that is being discontinued. This dose reduction will lower the likelihood of hypoglycemia. If changing from a treatment regimen with an intermediate or long-acting insulin to a regimen with Insulin glargine, a change in the dose of the basal insulin may be required and the amount and timing of the shorter-acting insulins and doses of any oral antidiabetic drugs may need to be adjusted.
If changing patients from once-daily NPH insulin to once-daily Insulin glargine, the recommended initial Insulin glargine dose is the same as the dose of NPH that is being discontinued. If changing patients from twice-daily NPH insulin to once-daily Insulin glargine, the recommended initial Insulin glargine dosage is 80% of the total NPH dose that is being discontinued. This dosage reduction will lower the likelihood of hypoglycemia.
Side Effects of Insulin Glargine Solostar
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice. The data in Table 1 reflect the exposure of 2327 patients with type 1 diabetes to Insulin glargine or NPH. The type 1 diabetes population had the following characteristics: Mean age was 38.5 years. Fifty-four percent were male, 96.9% were Caucasian, 1.8% were Black or African American and 2.7% were Hispanic.
The mean BMI was 25.1 kg/m 2. The data in Table 2 reflect the exposure of 1563 patients with type 2 diabetes to Insulin glargine or NPH. The type 2 diabetes population had the following characteristics: Mean age was 59.3 years. Fifty-eight percent were male, 86.7% were Caucasian, 7.8% were Black or African American and 9% were Hispanic. The mean BMI was 29.2 kg/m 2. The frequencies of adverse events during Insulin glargine clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables below.
Table 1: Adverse Events in Pooled Clinical Trials up to 28 Weeks Duration in Adults with Type 1 Diabetes (adverse events with frequency ≥5%) Insulin glargine, % (n=1257) NPH, % (n=1070) Upper respiratory tract infection 22.4
Infection Body system not specified 9.4 10.3 Accidental injury 5.7 6.4 Headache
5.5
Table 2: Adverse Events in Pooled Clinical Trials up to 1 Year
Duration in Adults with Type 2 Diabetes (adverse events with frequency ≥5%) Insulin glargine, % (n=849) NPH, % (n=714) Upper respiratory tract infection 11.4
Infection Body system not specified 10.4 11.6 Retinal vascular disorder 5.8 7.4
Table 3: Adverse Events in a 5-Year Trial of Adults with Type 2 Diabetes (adverse events with frequency ≥10%) Insulin glargine, % (n=514) NPH, % (n=503) Upper respiratory tract infection 29.0
Cataract 18.1 15.9 Bronchitis 15.2 14.1 Arthralgia 14.2 16.1 Pain in extremity
13.0
Back pain 12.8 12.3 Cough 12.1 7.4 Urinary tract infection 10.7 10.1
Diarrhea 10.7
Depression 10.5 9.7 Headache 10.3 9.3 Table 4: Adverse Events in a
28-Week Clinical Trial of Children and Adolescents with Type 1 Diabetes (adverse events with frequency ≥5%) Insulin glargine, % (n=174) NPH, % (n=175) Infection Body system not specified 13.8
Upper respiratory tract infection 13.8 16.0 Pharyngitis 7.5 8.6 Rhinitis 5.2 5.1
Severe Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including Insulin glargine . Tables 5, 6, and 7 summarize the incidence of severe hypoglycemia in the Insulin glargine individual clinical trials. Severe symptomatic hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring the assistance of another person and associated with either a blood glucose below 50 mg/dL (≤56 mg/dL in the 5-year trial and ≤36 mg/dL in the ORIGIN trial) or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration. Percentages of Insulin glargine–treated adult patients experiencing severe symptomatic hypoglycemia in the Insulin glargine clinical trials were comparable to percentages of NPH-treated patients for all treatment regimens (see Tables 5 and 6 ). In the pediatric phase 3 clinical trial, children and adolescents with type 1 diabetes had a higher incidence of severe symptomatic hypoglycemia in the two treatment groups compared to the adult trials with type 1 diabetes.
Table 5: Severe Symptomatic Hypoglycemia in Patients with Type 1 Diabetes Study A Type 1 Diabetes Adults 28 weeks In combination with regular insulin Study B Type 1 Diabetes Adults 28 weeks In combination with regular insulin Study C Type 1 Diabetes Adults 16 weeks In combination with insulin lispro Study D Type 1 Diabetes Pediatrics 26 weeks In combination with regular insulin Insulin glargine N=292 NPH N=293 Insulin glargine N=264 NPH N=270 Insulin glargine N=310 NPH N=309 Insulin glargine N=174 NPH N=175 Percent of patients 10.6 15.0 8.7 10.4 6.5 5.2 23.0
Table 6: Severe Symptomatic Hypoglycemia in Patients with Type 2 Diabetes Study
E Type 2 Diabetes Adults 52 weeks In combination with oral agents Study F Type 2 Diabetes Adults 28 weeks In combination with regular insulin Study G Type 2 Diabetes Adults 5 years In combination with regular insulin Insulin glargine N=289 NPH N=281 Insulin glargine N=259 NPH N=259 Insulin glargine N=513 NPH N=504 Percent of patients 1.7 1.1 0.4 2.3 7.8
Table 7 displays the proportion of patients experiencing severe symptomatic hypoglycemia in
the Insulin glargine and Standard Care groups in the ORIGIN Trial . Table 7: Severe Symptomatic Hypoglycemia in the ORIGIN Trial ORIGIN Trial Median duration of follow-up: 6.2 years Insulin glargine N=6231 Standard Care N=6273 Percent of patients 5.6
Peripheral Edema Some patients taking Insulin glargine have experienced sodium retention and
edema, particularly if previously poor metabolic control is improved by intensified insulin therapy. Lipodystrophy Administration of insulin subcutaneously, including Insulin glargine, has resulted in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) in some patients . Insulin Initiation and Intensification of Glucose Control Intensification or rapid improvement in glucose control has been associated with a transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy.
Weight Gain Weight gain has occurred with some insulin therapies including Insulin glargine and has been attributed to the anabolic effects of insulin and the decrease in glucosuria. Allergic Reactions Local allergy As with any insulin therapy, patients taking Insulin glargine may experience injection site reactions, including redness, pain, itching, urticaria, edema, and inflammation. In clinical studies in adult patients, there was a higher incidence of treatment-emergent injection site pain in Insulin glargine–treated patients (2.7%) compared to NPH insulin-treated patients (0.7%). The reports of pain at the injection site did not result in discontinuation of therapy.
Systemic allergy Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including Insulin glargine and may be life threatening.
Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. All
insulin products can elicit the formation of insulin antibodies. The presence of such insulin antibodies may increase or decrease the efficacy of insulin and may require adjustment of the insulin dose. In phase 3 clinical trials of Insulin glargine, increases in titers of antibodies to insulin were observed in NPH insulin and Insulin glargine treatment groups with similar incidences.
Postmarketing Experience
The following adverse reactions have been identified during postapproval use of Insulin glargine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Medication errors have been reported in which other insulins, particularly rapid-acting insulins, have been accidentally administered instead of Insulin glargine . To avoid medication errors between Insulin glargine and other insulins, patients should be instructed to always verify the insulin label before each injection.
Localized cutaneous amyloidosis at the injection site has occurred. Hyperglycemia has been reported with repeated insulin injections into areas of localized cutaneous amyloidosis; hypoglycemia has been reported with a sudden change to an unaffected injection site.
Warnings & Cautions for Insulin Glargine Solostar
Never Share an Insulin Glargine SoloStar Prefilled Pen, Syringe, or Needle Between
Patients Insulin glargine SoloStar prefilled pens must never be shared between patients, even if the needle is changed. Patients using Insulin glargine vials must never re-use or share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens.
Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen Changes in an insulin
regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to unaffected area) has been reported to result in hypoglycemia . Make any changes to a patient's insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia.
For patients with type 2 diabetes, dosage adjustments of concomitant oral and antidiabetic products may be needed.
Hypoglycemia Hypoglycemia is the most common adverse reaction associated with insulin, including
Insulin glargine. Severe hypoglycemia can cause seizures, may be life-threatening or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place an individual and others at risk in situations where these abilities are important (e.g., driving or operating other machinery). Hypoglycemia can happen suddenly and symptoms may differ in each individual and change over time in the same individual.
Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic nerve disease, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers) , or in patients who experience recurrent hypoglycemia. Risk Factors for Hypoglycemia The risk of hypoglycemia after an injection is related to the duration of action of the insulin and, in general, is highest when the glucose lowering effect of the insulin is maximal. As with all insulin preparations, the glucose lowering effect time course of Insulin glargine may vary in different individuals or at different times in the same individual and depends on many conditions, including the area of injection as well as the injection site blood supply and temperature . Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical activity, or changes to coadministered medication . Patients with renal or hepatic impairment may be at higher risk of hypoglycemia . Risk Mitigation Strategies for Hypoglycemia Patients and caregivers must be educated to recognize and manage hypoglycemia.
Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended. The long-acting effect of Insulin glargine may delay recovery from hypoglycemia.
Medication Errors Accidental mix-ups among insulin products, particularly between long-acting insulins and
rapid-acting insulins, have been reported. To avoid medication errors between Insulin glargine and other insulins, instruct patients to always check the insulin label before each injection .
Hypersensitivity and Allergic Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, can occur
with insulin products, including Insulin glargine. If hypersensitivity reactions occur, discontinue Insulin glargine; treat per standard of care and monitor until symptoms and signs resolve . Insulin glargine is contraindicated in patients who have had hypersensitivity reactions to insulin glargine or one of the excipients .
Hypokalemia All insulin products, including Insulin glargine, cause a shift in potassium
from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients at risk for hypokalemia, if indicated (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations).
Fluid Retention and Heart Failure with
Concomitant Use of PPAR-gamma Agonists Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including Insulin glargine, and a PPAR-gamma agonist should be observed for signs and symptoms of heart failure.
If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be considered.
Drug Interactions with Insulin Glargine Solostar
Table 8 includes clinically significant drug interactions with Insulin glargine. Table 8: Clinically Significant Drug Interactions with Insulin Glargine Drugs that May Increase the Risk of Hypoglycemia Drugs : Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics. Intervention : Dose reductions and increased frequency of glucose monitoring may be required when Insulin glargine is coadministered with these drugs.
Drugs that May Decrease the Blood Glucose Lowering Effect of Insulin Glargine Drugs : Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones. Intervention : Dose increases and increased frequency of glucose monitoring may be required when Insulin glargine is coadministered with these drugs. Drugs that May Increase or Decrease the Blood Glucose Lowering Effect of Insulin Glargine Drugs : Alcohol, beta-blockers, clonidine, and lithium salts.
Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Intervention : Dose adjustment and increased frequency of glucose monitoring may be required when Insulin glargine is coadministered with these drugs. Drugs that May Blunt Signs and Symptoms of Hypoglycemia Drugs : Beta-blockers, clonidine, guanethidine, and reserpine.
Intervention : Increased frequency of glucose monitoring may be required when Insulin glargine is coadministered with these drugs. Drugs that affect glucose metabolism : Adjustment of insulin dosage may be needed; closely monitor blood glucose. Antiadrenergic Drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Signs and symptoms of hypoglycemia may be reduced or absent.
Pregnancy Safety for Insulin Glargine Solostar
Pregnancy Risk Summary Published studies with use of insulin glargine during pregnancy have not reported a clear association with insulin glargine and adverse developmental outcomes . There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy . Rats and rabbits were exposed to insulin glargine in animal reproduction studies during organogenesis, respectively 50 times and 10 times the human subcutaneous dose of 0.2 units/kg/day. Overall, the effects of insulin glargine did not generally differ from those observed with regular human insulin . The estimated background risk of major birth defects is 6% to 10% in women with pregestational diabetes with an HbA1c >7 and has been reported to be as high as 20% to 25% in women with a HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Clinical Considerations Disease-associated maternal and/or embryo-fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity. Data Human data Published data do not report a clear association with insulin glargine and major birth defects, miscarriage, or adverse maternal or fetal outcomes when insulin glargine is used during pregnancy.
However, these studies cannot definitely establish the absence of any risk because of methodological limitations including small sample size and some lacking comparator groups. Animal data Subcutaneous reproduction and teratology studies have been performed with insulin glargine and regular human insulin in rats and Himalayan rabbits. Insulin glargine was given to female rats before mating, during mating, and throughout pregnancy at doses up to 0.36 mg/kg/day, which is approximately 50 times the recommended human subcutaneous starting dose of 0.2 units/kg/day (0.007 mg/kg/day), on a mg/kg basis.
In rabbits, doses of 0.072 mg/kg/day, which is approximately 10 times the recommended human subcutaneous starting dose of 0.2 units/kg/day on a mg/kg basis, were administered during organogenesis. The effects of insulin glargine did not generally differ from those observed with regular human insulin in rats or rabbits. However, in rabbits, five fetuses from two litters of the high-dose group exhibited dilation of the cerebral ventricles.
Fertility and early embryonic development appeared normal.
Pediatric Use of Insulin Glargine Solostar
Pediatric Use The safety and effectiveness of Insulin glargine have been established in pediatric patients (age 6 to 15 years) with type 1 diabetes . The safety and effectiveness of Insulin glargine in pediatric patients younger than 6 years of age with type 1 diabetes and pediatric patients with type 2 diabetes have not been established. The dosage recommendation when changing to Insulin glargine in pediatric patients (age 6 to 15 years) with type 1 diabetes is the same as that described for adults . As in adults, the dosage of Insulin glargine must be individualized in pediatric patients (age 6 to 15 years) with type 1 diabetes based on metabolic needs and frequent monitoring of blood glucose. In the pediatric clinical trial, pediatric patients (age 6 to 15 years) with type 1 diabetes had a higher incidence of severe symptomatic hypoglycemia compared to the adults in trials with type 1 diabetes .
Contraindications for Insulin Glargine Solostar
Insulin glargine is contraindicated: during episodes of hypoglycemia in patients with hypersensitivity to Insulin glargine or one of its excipients During episodes of hypoglycemia Hypersensitivity to Insulin glargine or one of its excipients
Overdosage Information for Insulin Glargine Solostar
Excess insulin administration may cause hypoglycemia and hypokalemia . Mild episodes of hypoglycemia can usually be treated with oral carbohydrates. Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes of hypoglycemia with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose.
After apparent clinical recovery from hypoglycemia, continued observation and additional carbohydrate intake may be necessary to avoid recurrence of hypoglycemia. Hypokalemia must be corrected appropriately.
Clinical Studies of Insulin Glargine Solostar
Overview of Clinical Studies
The safety and effectiveness of Insulin glargine given once-daily at bedtime was compared to that of once-daily and twice-daily NPH insulin in open-label, randomized, active-controlled, parallel studies of 2,327 adult patients and 349 pediatric patients with type 1 diabetes mellitus and 1,563 adult patients with type 2 diabetes mellitus (see Tables 9–11). In general, the reduction in glycated hemoglobin (HbA1c) with Insulin glargine was similar to that with NPH insulin.
Clinical Studies in Adult and Pediatric Patients with Type 1 Diabetes
In two clinical studies (Studies A and B), patients with type 1 diabetes (Study A n=585, Study B n=534) were randomized to 28 weeks of basal-bolus treatment with Insulin glargine or NPH insulin. Regular human insulin was administered before each meal. Insulin glargine was administered at bedtime.
NPH insulin was administered either as once daily at bedtime or in the morning and at bedtime when used twice daily. In Study A, the average age was 39.2 years. The majority of patients were White (99%) and 55.7% were male.
The mean BMI was approximately 24.9 kg/m 2. The mean duration of diabetes was 15.5 years. In Study B, the average age was 38.5 years. The majority of patients were White (95.3%) and 50.6% were male.
The mean BMI was approximately 25.8 kg/m 2. The mean duration of diabetes was 17.4 years. In another clinical study (Study C), patients with type 1 diabetes (n=619) were randomized to 16 weeks of basal-bolus treatment with Insulin glargine or NPH insulin. Insulin lispro was used before each meal.
Insulin glargine was administered once daily at bedtime and NPH insulin was administered once or twice daily. The average age was 39.2 years. The majority of patients were White (96.9%) and 50.6% were male.
The mean BMI was approximately 25.6 kg/m 2. The mean duration of diabetes was 18.5 years. In these 3 studies, Insulin glargine and NPH insulin had similar effects on HbA1c (Table 9) with a similar overall rate of severe symptomatic hypoglycemia . Table 9: Type 1 Diabetes Mellitus – Adult Study A Study B Study C Treatment duration 28 weeks 28 weeks 16 weeks Treatment in combination with Regular insulin Regular insulin Insulin lispro Insulin glargine NPH Insulin glargine NPH Insulin glargine NPH Number of subjects treated 292 293 264 270 310 309 HbA1c Baseline HbA1c 8.0 8.0 7.7 7.7 7.6
Adjusted mean change at trial end +0.2 +0.1 -0.2 -0.2 -0.1 -0.1
Treatment Difference (95% CI) +0.1 (0.0; +0.2) +0.1 (-0.1; +0.2) 0.0 (-0.1; +0.1) Basal insulin dose Baseline mean 21 23 29 29 28 28 Mean change from baseline -2 0 -4 +2 -5 +1 Total insulin dose Baseline mean 48 52 50 51 50 50 Mean change from baseline -1 0 0 +4 -3 0 Fasting blood glucose (mg/dL) Baseline mean 167 166 166 175 175 173 Adj. mean change from baseline -21 -16 -20 -17 -29 -12 Body weight (kg) Baseline mean 73.2 74.8 75.5 75.0 74.8
Mean change from baseline 0.1 -0.0 0.7 1.0 0.1 0.5 Type 1
Diabetes – Pediatric (see Table 10 ) In a randomized, controlled clinical study (Study D), pediatric patients (age range 6 to 15 years) with type 1 diabetes (n=349) were treated for 28 weeks with a basal-bolus insulin regimen where regular human insulin was used before each meal. Insulin glargine was administered once daily at bedtime and NPH insulin was administered once or twice daily. The average age was 11.7 years.
The majority of patients were White (96.8%) and 51.9% were male. The mean BMI was approximately 18.9 kg/m 2. The mean duration of diabetes was 4.8 years. Similar effects on HbA1c (Table 10) were observed in both treatment groups . Table 10: Type 1 Diabetes Mellitus – Pediatric Study D Treatment duration 28 weeks Treatment in combination with Regular insulin Insulin glargine + Regular Insulin NPH + Regular Insulin Number of subjects treated 174 175 HbA1c Baseline mean 8.5
Change from baseline (adjusted mean) +0.3 +0.3 Difference from
NPH (adjusted mean) 0.0 (95% CI ) (-0.2; +0.3) Basal insulin dose Baseline mean 19 19 Mean change from baseline -1 +2 Total insulin dose Baseline mean 43 43 Mean change from baseline +2 +3 Fasting blood glucose (mg/dL) Baseline mean 194 191 Mean change from baseline -23 -12 Body weight (kg) Baseline mean 45.5
Mean change from baseline 2.2 2.5 14.3 Clinical Studies in Adults with
Type 2 Diabetes In a randomized, controlled clinical study (Study E) (n=570), Insulin glargine was evaluated for 52 weeks in combination with oral antidiabetic medications (a sulfonylurea, metformin, acarbose, or combinations of these drugs). The average age was 59.5 years. The majority of patients were White (92.8%) and 53.7% were male. The mean BMI was approximately 29.1 kg/m 2. The mean duration of diabetes was 10.3 years.
Insulin glargine administered once daily at bedtime was as effective as NPH insulin administered once daily at bedtime in reducing HbA1c and fasting glucose (Table 11). The rate of severe symptomatic hypoglycemia was similar in Insulin glargine and NPH insulin treated patients . In a randomized, controlled clinical study (Study F), in patients with type 2 diabetes not using oral antidiabetic medications (n=518), a basal-bolus regimen of Insulin glargine once daily at bedtime or NPH insulin administered once or twice daily was evaluated for 28 weeks. Regular human insulin was used before meals, as needed. The average age was 59.3 years.
The majority of patients were White (80.7%) and 60% were male. The mean BMI was approximately 30.5 kg/m 2. The mean duration of diabetes was 13.7 years. Insulin glargine had similar effectiveness as either once- or twice-daily NPH insulin in reducing HbA1c and fasting glucose (Table 11) with a similar incidence of hypoglycemia . In a randomized, controlled clinical study (Study G), patients with type 2 diabetes were randomized to 5 years of treatment with once-daily Insulin glargine or twice-daily NPH insulin.
For patients not previously treated with insulin, the starting dose of Insulin glargine or NPH insulin was 10 units daily. Patients who were already treated with NPH insulin either continued on the same total daily NPH insulin dose or started Insulin glargine at a dose that was 80% of the total previous NPH insulin dose. The primary endpoint for this study was a comparison of the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale.
HbA1c change from baseline was a secondary endpoint. Similar glycemic control in the 2 treatment groups was desired in order to not confound the interpretation of the retinal data. Patients or study personnel used an algorithm to adjust the Insulin glargine and NPH insulin doses to a target fasting plasma glucose ≤100 mg/dL. After the Insulin glargine or NPH insulin dose was adjusted, other antidiabetic agents, including premeal insulin were to be adjusted or added.
The average age was 55.1 years. The majority of patients were White (85.3%) and 53.9% were male. The mean BMI was approximately 34.3 kg/m 2. The mean duration of diabetes was 10.8 years.
The Insulin glargine group had a smaller mean reduction from baseline in HbA1c compared to the NPH insulin group, which may be explained by the lower daily basal insulin doses in the Insulin glargine group (Table 11). The incidences of severe symptomatic hypoglycemia were similar between groups . Table 11: Type 2 Diabetes Mellitus – Adult Study E Study F Study G Treatment duration 52 weeks 28 weeks 5 years Treatment in combination with Oral agents Regular insulin Regular insulin Insulin glargine NPH Insulin glargine NPH Insulin glargine NPH Number of subjects treated 289 281 259 259 513 504 HbA1c Baseline mean 9.0 8.9 8.6 8.5 8.4
Adjusted mean change from baseline -0.5 -0.4 -0.4 -0.6 -0.6 -0.8 Insulin
glargine – NPH -0.1 +0.2 +0.2 95% CI for Treatment difference (-0.3; +0.1) (0.0; +0.4) (+0.1; +0.4) Basal insulin dose In Study G, the baseline dose of basal or total insulin was the first available on-treatment dose prescribed during the study (on visit month 1.5). Baseline mean 14 15 44.1 45.5 39 44 Mean change from baseline +12 +9 -1 +7 +23 +30 Total insulin dose Baseline mean 14 15 64 67 48 53 Mean change from baseline +12 +9 +10 +13 +41 +40 Fasting blood glucose (mg/dL) Baseline mean 179 180 164 166 190 180 Adj. mean change from baseline -49 -46 -24 -22 -45 -44 Body weight (kg) Baseline mean 83.5 82.1 89.6 90.7 100 99 Adj. mean change from baseline 2.0 1.9 0.4 1.4 3.7
Insulin Glargine Timing of Daily Dosing (see Table 12 )
The safety and efficacy of Insulin glargine administered pre-breakfast, pre-dinner, or at bedtime were evaluated in a randomized, controlled clinical study in patients with type 1 diabetes (Study H, n=378). Patients were also treated with insulin lispro at mealtime. The average age was 40.9 years. All patients were White (100%) and 53.7% were male.
The mean BMI was approximately 25.3 kg/m 2. The mean duration of diabetes was 17.3 years. Insulin glargine administered at different times of the day resulted in similar reductions in HbA1c compared to that with bedtime administration (see Table 12 ). In these patients, data are available from 8-point home glucose monitoring. The maximum mean blood glucose was observed just prior to injection of Insulin glargine regardless of time of administration.
In this study, 5% of patients in the Insulin glargine–breakfast arm discontinued treatment because of lack of efficacy. No patients in the other two arms discontinued for this reason. The safety and efficacy of Insulin glargine administered pre-breakfast or at bedtime were also evaluated in a randomized, active-controlled clinical study (Study I, n=697) in patients with type 2 diabetes not adequately controlled on oral antidiabetic therapy.
All patients in this study also received glimepiride 3 mg daily. The average age was 60.8 years. The majority of patients were White (96.6%) and 53.7% were male.
The mean BMI was approximately 28.7 kg/m 2. The mean duration of diabetes was 10.1 years. Insulin glargine given before breakfast was at least as effective in lowering HbA1c as Insulin glargine given at bedtime or NPH insulin given at bedtime (see Table 12 ). Table 12: Insulin Glargine Timing of Daily Dosing in Type 1 (Study H) and Type 2 (Study I) Diabetes Mellitus Study H Study I Treatment duration 24 weeks 24 weeks Treatment in combination with Insulin lispro Glimepiride Insulin glargine Breakfast Insulin glargine Dinner Insulin glargine Bedtime Insulin glargine Breakfast Insulin glargine Bedtime NPH Bedtime Number of subjects treated Intent-to-treat 112 124 128 234 226 227 HbA1c Baseline mean 7.6 7.5 7.6 9.1 9.1
Mean change from baseline -0.2 -0.1 0.0 -1.3 -1.0 -0.8 Basal insulin
dose (U) Baseline mean 22 23 21 19 20 19 Mean change from baseline 5 2 2 11 18 18 Total insulin dose (U) NA Not applicable NA NA Baseline mean 52 52 49 – – – Mean change from baseline 2 3 2 – – – Body weight (kg) Baseline mean 77.1 77.8 74.5 80.7 82 81 Mean change from baseline 0.7 0.1 0.4 3.9 3.7
Five-Year Trial Evaluating the Progression of Retinopathy Retinopathy was evaluated in the
Insulin glargine clinical studies by analysis of reported retinal adverse events and fundus photography. The numbers of retinal adverse events reported for Insulin glargine and NPH insulin treatment groups were similar for patients with type 1 and type 2 diabetes. Insulin glargine was compared to NPH insulin in a 5-year randomized clinical trial that evaluated the progression of retinopathy as assessed with fundus photography using a grading protocol derived from the Early Treatment Diabetic Retinopathy Scale (ETDRS). Patients had type 2 diabetes (mean age 55 years) with no (86%) or mild (14%) retinopathy at baseline.
Mean baseline HbA1c was 8.4%. The primary outcome was progression by 3 or more steps on the ETDRS scale at study endpoint. Patients with prespecified postbaseline eye procedures (pan-retinal photocoagulation for proliferative or severe nonproliferative diabetic retinopathy, local photocoagulation for new vessels, and vitrectomy for diabetic retinopathy) were also considered as 3-step progressors regardless of actual change in ETDRS score from baseline. Retinopathy graders were blinded to treatment group assignment.
The results for the primary endpoint are shown in Table 13 for both the per-protocol and intent-to-treat populations, and indicate similarity of Insulin glargine to NPH in the progression of diabetic retinopathy as assessed by this outcome. Table 13: Number (%) of Patients with 3 or More Step Progression on ETDRS Scale at Endpoint Insulin glargine (%) NPH (%) Difference Difference = Insulin glargine – NPH, Using a generalized linear model (SAS GENMOD) with treatment and baseline HbA1c strata (cutoff 9.0%) as the classified independent variables, and with binomial distribution and identity link function (SE) 95% CI for difference Per-protocol 53/374 (14.2%) 57/363 (15.7%) -2.0% (2.6%) -7.0% to +3.1% Intent-to-Treat 63/502 (12.5%) 71/487 (14.6%) -2.1% (2.1%) -6.3% to +2.1% The Origin Study The Outcome Reduction with Initial Glargine Intervention trial (i.e., ORIGIN) was an open-label, randomized, 2-by-2, factorial design study. One intervention in ORIGIN compared the effect of Insulin glargine to standard care on major adverse cardiovascular outcomes in 12,537 participants ≥50 years of age with abnormal glucose levels (i.e., impaired fasting glucose and/or impaired glucose tolerance ) or early type 2 diabetes mellitus and established cardiovascular (i.e., CV) disease or CV risk factors at baseline.
The objective of the trial was to demonstrate that Insulin glargine use could significantly lower the risk of major cardiovascular outcomes compared to standard care. Two coprimary composite cardiovascular endpoints were used in ORIGIN. The first coprimary endpoint was the time to first occurrence of a major adverse cardiovascular event defined as the composite of CV death, nonfatal myocardial infarction, and nonfatal stroke. The second coprimary endpoint was the time to the first occurrence of CV death or nonfatal myocardial infarction or nonfatal stroke or revascularization procedure or hospitalization for heart failure.
Participants were randomized to either Insulin glargine (N=6264) titrated to a goal fasting plasma glucose of ≤95 mg/dL or to standard care (N=6273). Anthropometric and disease characteristics were balanced at baseline. The mean age was 64 years and 8% of participants were 75 years of age or older. The majority of participants were male (65%). Fifty nine percent were Caucasian, 25% were Latin, 10% were Asian and 3% were Black.
The median baseline BMI was 29 kg/m 2. Approximately 12% of participants had abnormal glucose levels (IGT and/or IFG) at baseline and 88% had type 2 diabetes. For patients with type 2 diabetes, 59% were treated with a single oral antidiabetic drug, 23% had known diabetes but were on no antidiabetic drug and 6% were newly diagnosed during the screening procedure. The mean HbA1c (SD) at baseline was 6.5%. Fifty-nine percent of participants had had a prior cardiovascular event and 39% had documented coronary artery disease or other cardiovascular risk factors.
Vital status was available for 99.9% and 99.8% of participants randomized to Insulin glargine and standard care respectively at end of trial. The median duration of follow-up was 6.2 years (range: 8 days to 7.9 years). The mean HbA1c (SD) at the end of the trial was 6.5% and 6.8% in the Insulin glargine and standard care group respectively. The median dose of Insulin glargine at end of trial was 0.45 U/kg.
Eighty-one percent of patients randomized to Insulin glargine were using Insulin glargine at end of the study. The mean change in body weight from baseline to the last treatment visit was 2.2 kg greater in the Insulin glargine group than in the standard care group. Overall, the incidence of major adverse cardiovascular outcomes was similar between groups (see Table 14 ). All-cause mortality was also similar between groups.
Table 14: Cardiovascular Outcomes in ORIGIN – Time to First Event Analyses Insulin glargine N=6264 Standard Care N=6273 Insulin glargine vs Standard Care n (Events per 100 PY) n (Events per 100 PY) Hazard Ratio (95% CI) Coprimary endpoints CV death, nonfatal myocardial infarction, or nonfatal stroke 1041 1013 1.02 CV death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure or revascularization procedure 1792 1727 1.04 Components of coprimary endpoints CV death 580 576 1.00 Myocardial Infarction (fatal or nonfatal) 336 326 1.03 Stroke (fatal or nonfatal) 331 319 1.03 Revascularizations 908 860 1.06 Hospitalization for heart failure 310 343 0.90 In the ORIGIN trial, the overall incidence of cancer (all types combined) or death from cancer (Table 15) was similar between treatment groups. Table 15: Cancer Outcomes in ORIGIN – Time to First Event Analyses Insulin glargine N=6264 Standard Care N=6273 Insulin glargine vs Standard Care n (Events per 100 PY) n (Events per 100 PY) Hazard Ratio (95% CI) Cancer endpoints Any cancer event (new or recurrent) 559 561 0.99 New cancer events 524 535 0.96 Death due to Cancer 189 201 0.94
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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