2.1 Important Preparation and Administration Instructions

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Always check insulin labels before administration [see Warnings and Precautions (5.4)].

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Inspect NOVOLOG MIX 70/30 visually before use. It should appear uniformly white and cloudy. Do not use it if it looks clear or if it contains solid particles.

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NOVOLOG MIX 70/30 must be resuspended immediately before use. Resuspension is easier when the insulin has reached room temperature.

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When using the:

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Vial, roll the vial gently in hands in a horizontal position 10 times until the suspension appears uniformly white and cloudy. Inject immediately.

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NOVOLOG MIX 70/30 FlexPen, roll NOVOLOG MIX 70/30 FlexPen gently between hands in a horizontal position 10 times. Then, turn NOVOLOG MIX 70/30 FlexPen upside down so that the glass ball moves from one end of the reservoir to the other 10 times until the suspension appears uniformly white and cloudy. Inject immediately.

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The NOVOLOG MIX 70/30 FlexPen dials in 1-unit increments.

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Use NOVOLOG MIX 70/30 FlexPen with caution in patients with visual impairment who may rely on audible clicks to dial their dose.

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Inject NOVOLOG MIX 70/30 subcutaneously in the abdominal region, buttocks, thigh, or upper arm.

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Administer the dose within 15 minutes before meal initiation. For patients with type 2 diabetes, the dose may also be given after meal initiation.

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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 [see Warnings and Precautions (5.2) and Adverse Reactions (6.1, 6.3)].

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Do not administer NOVOLOG MIX 70/30 intravenously or use in insulin infusion pumps.

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Do not mix NOVOLOG MIX 70/30 with any other insulins.

2.2 Dosage Recommendations

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NOVOLOG MIX 70/30 is typically dosed twice-daily (with each dose intended to cover 2 meals or a meal and a snack).

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Individualize the dosage of NOVOLOG MIX 70/30 based on the patient's metabolic needs, blood glucose monitoring results and glycemic control goal.

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Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic function or during acute illness [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6, 8.7)].

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When switching from another insulin to NOVOLOG MIX 70/30, a different dosage of NOVOLOG MIX 70/30 may be needed [see Warnings and Precautions (5.2)].

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During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2)].

2.3 Dosage Modifications for Drug Interactions

Dosage modification may be needed when NOVOLOG MIX 70/30 is used concomitantly with certain drugs [see Drug Interactions (7)].

5.1 Never Share NOVOLOG MIX 70/30 FlexPen Between Patients

NOVOLOG MIX 70/30 FlexPen should never be shared between patients, even if the needle is changed. Patients using NOVOLOG MIX 70/30 vials must never share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens.

5.2 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 [see Warnings and Precautions (5.3)] 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 an unaffected area) has been reported to result in hypoglycemia [see Adverse Reactions (6.1, 6.3)]. 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 anti-diabetic products may be needed.

5.3 Hypoglycemia

Hypoglycemia is the most common adverse reaction of all insulins, including NOVOLOG MIX 70/30. Severe hypoglycemia can cause seizures, may lead to unconsciousness, 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) [see Drug Interactions (7)], 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 insulins, the glucose lowering effect time course of NOVOLOG MIX 70/30 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 [see Clinical Pharmacology (12.2)]. 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 concomitantly administered medication [see Drug Interactions (7)]. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations (8.6, 8.7)].

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; increased frequency of blood glucose monitoring is recommended. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.

5.4 Hypoglycemia Due to Medication Errors

Accidental mix-ups between insulin products have been reported. To avoid medication errors between NOVOLOG MIX 70/30 and other insulins, instruct patients to always check the insulin label before each injection.

5.5 Hypersensitivity Reactions

Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including NOVOLOG MIX 70/30. If hypersensitivity reactions occur, discontinue NOVOLOG MIX 70/30; treat per standard of care and monitor until symptoms and signs resolve [see Adverse Reactions (6)]. NOVOLOG MIX 70/30 is contraindicated in patients who have had hypersensitivity reactions to insulin aspart or one of the excipients [see Contraindications (4)].

5.6 Hypokalemia

All insulins, including NOVOLOG MIX 70/30, can 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 concentration).

5.7 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 NOVOLOG MIX 70/30, 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.

6.1 Clinical Trial Experience

Clinical trials are conducted under widely varying designs, therefore, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice. The data in:

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Table 1 reflects the exposure of 55 patients with type 1 diabetes to NOVOLOG MIX 70/30 with a mean exposure duration of three months. The mean age was 43 years old. Sixty-four percent were male and 100% were White. The mean body mass index (BMI) was 26.1 kg/m2. The mean duration of diabetes was 15 years.

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Table 2 reflects the exposure of 85 patients with type 2 diabetes to NOVOLOG MIX 70/30 with a mean exposure duration of three months. The mean age was 63 years old. Fifty-four percent were male and 100% were White. The mean body mass index (BMI) was 28.1 kg/m2. The mean duration of diabetes was 15 years.

Common adverse reactions were defined as events that occurred in ≥5%, excluding hypoglycemia, of the population studied. Common adverse reactions that occurred for NOVOLOG MIX 70/30-treated patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in Table 1 and Table 2, respectively. The trial was a three-month, open-label trial in patients with type 1 or type 2 diabetes who were treated twice daily (before breakfast and before supper) with NOVOLOG MIX 70/30.

Table 1: Adverse Reactions that Occurred in ≥ 5% of Type 1 Diabetes Mellitus Adult Patients Treated with NOVOLOG MIX 70/30

Table 2: Adverse Reactions that Occurred in ≥ 5% of Type 2 Diabetes Mellitus Adult Patients Treated with NOVOLOG MIX 70/30

Severe Hypoglycemia

Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including NOVOLOG MIX 70/30. The rates of reported hypoglycemia depend on the definition of hypoglycemia used, diabetes type, insulin dose, intensity of glucose control, background therapies, and other intrinsic and extrinsic patient factors. For these reasons, comparing rates of hypoglycemia in clinical trials for NOVOLOG MIX 70/30 with the incidence of hypoglycemia for other products may be misleading and also, may not be representative of hypoglycemia rates that will occur in clinical practice.

Severe hypoglycemia requiring the assistance of another person and/or parenteral glucose infusion or glucagon administration has been observed in clinical trials with insulin, including trials with NOVOLOG MIX 70/30.

The incidence of severe hypoglycemia in adult patients receiving subcutaneous NOVOLOG MIX 70/30 was 16% and 4% for type 1 and type 2 diabetes patients respectively at 12 weeks [see Clinical Studies (14)].

Allergic Reactions

Patients have experienced reactions such as erythema, edema or pruritus at the site of NOVOLOG MIX 70/30 injection. These reactions usually resolve in a few days to a few weeks, but in some occasions, have required discontinuation of NOVOLOG MIX 70/30. Severe cases of generalized allergy (anaphylaxis) have been reported.

Adverse Reactions Associated with Insulin Initiation and Glucose Control Intensification

Intensification or rapid improvement in glucose control has been associated with 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.

Lipodystrophy

Long-term use of insulin, including NOVOLOG MIX 70/30, can cause lipodystrophy at the site of repeated insulin injections. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin absorption [see Dosage and Administration (2.1)].

Weight Gain

Weight gain can occur with insulins, including NOVOLOG MIX 70/30, and has been attributed to the anabolic effects of insulin and the decrease in glycosuria.

Peripheral Edema

Insulins, including NOVOLOG MIX 70/30, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to NOVOLOG MIX 70/30 in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

In a 3-month study with an extension in adult patients with type 2 diabetes, 100% of patients who received NOVOLOG MIX 70/30 were positive for anti-insulin antibodies (AIA) at least once during the first 12 months of the study including 91.4% that were positive at baseline. A total of 91.4% of patients who received NOVOLOG MIX 70/30 were positive for anti-drug antibodies (ADA) at least once during the first 12 months of the study, including 62.1% that were positive at baseline.

In a type 2 diabetes clinical trial of NOVOLOG MIX 70/30, initial increase in titers of antibodies to insulin followed by a decrease approaching to baseline values was observed in NOVOLOG MIX 70/30 and Novolin 70/30 treatment groups with similar incidences. These antibodies did not cause deterioration in glycemic control or necessitate increases in insulin dose.

6.3 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of NOVOLOG MIX 70/30. Because these adverse reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Medication errors in which other insulins have been accidentally substituted for NOVOLOG MIX 70/30 have been reported.

Localized cutaneous amyloidosis at the injection site has occurred with insulin aspart. 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.

8.1 Pregnancy

Risk Summary

There are no available data with NOVOLOG MIX 70/30 in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Available information from published randomized controlled trials with insulin aspart use during the second trimester of pregnancy have not reported an association with insulin aspart and major birth defects or adverse maternal or fetal outcomes [see Data]. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations].

In animal reproduction studies, administration of subcutaneous insulin aspart to pregnant rats and rabbits during the period of organogenesis did not cause adverse developmental effects at exposures 8-times and equal to the human subcutaneous dose of 1 unit/kg/day, respectively. Pre- and post-implantation losses and visceral/skeletal abnormalities were seen at higher exposures, which are considered secondary to maternal hypoglycemia. These effects were similar to those observed in rats administered regular human insulin [see Data].

The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c >7% and has been reported to be as high as 20-25% 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 2-4% and 15-20%, 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, still birth, and macrosomia related morbidity.

Data

Human Data

Published data from 5 randomized controlled trials of 441 pregnant women with diabetes mellitus treated with insulin aspart during the late 2nd trimester of pregnancy did not identify an association of insulin aspart with major birth defects or adverse maternal or fetal outcomes. However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including a variable duration of treatment and small size of the majority of the trials.

Animal Data

Fertility, embryo-fetal and pre- and postnatal development studies have been performed with insulin aspart and regular human insulin in rats and rabbits. In a combined fertility and embryo-fetal development study in rats, insulin aspart was administered before mating, during mating, and throughout pregnancy. Further, in a pre- and postnatal development study insulin aspart was given throughout pregnancy and during lactation to rats. In an embryo-fetal development study insulin aspart was given to female rabbits during organogenesis. The effects of insulin aspart did not differ from those observed with subcutaneous regular human insulin. Insulin aspart, like human insulin, caused pre- and post-implantation losses and visceral/skeletal abnormalities in rats at a dose of 200 units/kg/day (approximately 32 times the human subcutaneous dose of 1 unit/kg/day, based on human exposure equivalents) and in rabbits at a dose of 10 units/kg/day (approximately three times the human subcutaneous dose of 1 unit/kg/day, based on human exposure equivalents). No significant effects were observed in rats at a dose of 50 units/kg/day and in rabbits at a dose of 3 units/kg/day. These doses are approximately 8 times the human subcutaneous dose of 1 unit/kg/day for rats and equal to the human subcutaneous dose of 1 unit/kg/day for rabbits, based on human exposure equivalents. The effects are considered secondary to maternal hypoglycemia.

8.2 Lactation

Risk Summary

There are no data on the presence of NOVOLOG MIX 70/30 in human milk, the effects on the breastfed infant, or the effect on milk production. One small published study reported that exogenous insulin, including insulin aspart, was present in human milk. However, there is insufficient information to determine the effects of insulin aspart on the breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NOVOLOG MIX 70/30, and any potential adverse effects on the breastfed infant from NOVOLOG MIX 70/30, or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness of NOVOLOG MIX 70/30 have not been established in pediatric patients with diabetes mellitus.

8.5 Geriatric Use

Clinical studies of NOVOLOG MIX 70/30 did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger adult patients. In geriatric patients with diabetes, the initial dosing, dose increments should be conservative to avoid hypoglycemic reactions. Hypoglycemia may be difficult to recognize in geriatric patients.

8.6 Renal Impairment

The effect of renal impairment on the pharmacokinetics of NOVOLOG MIX 70/30 has not been studied. Some studies with human insulin have shown increased circulating levels of insulin in patients with renal failure. Patients with renal impairment may be at increased risk of hypoglycemia and may require more frequent NOVOLOG MIX 70/30 dose adjustment and more frequent blood glucose monitoring [see Warnings and Precautions (5.3)].

8.7 Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of NOVOLOG MIX 70/30 has not been studied. Patients with hepatic impairment may be at increased risk of hypoglycemia and may require more frequent NOVOLOG MIX 70/30 dose adjustment and more frequent blood glucose monitoring [see Warnings and Precautions (5.3)].

12.1 Mechanism of Action

The primary activity of insulin, including NOVOLOG MIX 70/30 is the regulation of glucose metabolism. Insulin and its analog lower blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis and proteolysis, and enhances protein synthesis.

12.2 Pharmacodynamics

A euglycemic clamp study described below assessed glucose utilization after subcutaneous dosing of NOVOLOG MIX 70/30 in healthy subjects (n = 24). Following a 0.3 units/kg single subcutaneous dose of NOVOLOG MIX 70/30, the onset of action is between 10-20 minutes and the mean ± SD time to peak activity is 2.7 hr ± 0.9 hr. The duration of action may be as long as 24 hours (see Figure 2).

Figure 2. Pharmacodynamic Activity Profile of NOVOLOG MIX 70/30 in healthy subjects after a single 0.3 units/kg subcutaneous dose

12.3 Pharmacokinetics

The single substitution of the amino acid proline with aspartic acid at position B28 in insulin aspart (NOVOLOG) reduces the molecule’s tendency to form hexamers as observed with regular human insulin. The rapid absorption characteristics of NOVOLOG are maintained by NOVOLOG MIX 70/30.

Absorption and Bioavailability

The 30% insulin aspart in the soluble component of NOVOLOG MIX 70/30 is absorbed rapidly from the subcutaneous layer. The remaining 70% is in crystalline form as insulin aspart protamine which has a prolonged absorption profile after subcutaneous injection.

The relative bioavailability of NOVOLOG MIX 70/30 compared to NOVOLOG indicates that the insulins are absorbed to similar extent. In a euglycemic clamp study in healthy subjects (n=24) after dosing with NOVOLOG MIX 70/30 (0.3 units/kg), a mean maximum serum concentration (Cmax) of 61.3 ± 20.1 milliunits/L was reached after 85 minutes. Serum insulin levels returned to baseline 16 to 20 hours after a subcutaneous dose of NOVOLOG MIX 70/30 (see Fig. 3 for pharmacokinetic profile).

Figure 3. Pharmacokinetic Profile of NOVOLOG MIX 70/30 after a single 0.3 units/kg subcutaneous dose

Distribution and Elimination

Insulin aspart has a low binding affinity to plasma proteins (<10%), similar to that seen with regular human insulin.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Standard 2-year carcinogenicity studies in animals have not been performed to evaluate the carcinogenic potential of NOVOLOG MIX 70/30. In 52-week studies, Sprague-Dawley rats were dosed subcutaneously with NOVOLOG, the rapid-acting component of NOVOLOG MIX 70/30, at 10, 50, and 200 units/kg/day (approximately 2, 8, and 32 times the human subcutaneous dose of 1.0 unit/kg/day, based on units/body surface area, respectively). At a dose of 200 units/kg/day, NOVOLOG increased the incidence of mammary gland tumors in females when compared to untreated controls. The relevance of these findings to humans is not known.

NOVOLOG was not genotoxic in the following tests: Ames test, mouse lymphoma cell forward gene mutation test, human peripheral blood lymphocyte chromosome aberration test, in vivo micronucleus test in mice, and in ex vivo UDS test in rat liver hepatocytes.

In fertility studies in male and female rats, NOVOLOG at subcutaneous doses up to 200 units/kg/day (approximately 32 times the human subcutaneous dose, based on units/body surface area) had no direct adverse effects on male and female fertility, or on general reproductive performance of animals.

14.1 Clinical Studies in Adult Patients with Type 1 and Type 2 Diabetes

In a three-month, open-label trial, adult patients with type 1 (n=104) or type 2 (n=187) diabetes mellitus were treated twice daily (before breakfast and before supper) with NOVOLOG MIX 70/30 or Novolin 70/30. Patients had received insulin for at least 24 months before the study. Oral hypoglycemic agents were not allowed within 1 month prior to the study or during the study. The small changes in HbA1c were comparable across the treatment groups (see Table 4).

For patients with type 1 diabetes mellitus (T1DM) the mean age was 43 years old, 64% were male, 100% were White, the mean body mass index (BMI) was 26.1 kg/m2, and mean duration of diabetes mellitus was 15 years. For patients with type 2 diabetes mellitus (T2DM), the mean age was 63 years old, 54% were male, 100% were White, the BMI 28.1 kg/m2, and the mean duration of diabetes mellitus was 15 years.

Table 4: Glycemic Parameters at the End of Treatment [Mean ± SD (n subjects)]

The significance, with respect to the long-term clinical sequelae of diabetes, of the differences in postprandial hyperglycemia between treatment groups has not been established.

14.2 Clinical Studies in Adult Patients with Type 2 Diabetes with Insulin and Oral Antidiabetic Agents

Trial 1:

In a 34-week, open-label trial (Trial 1), insulin-naïve patients with type 2 diabetes mellitus currently treated with 2 oral antidiabetic agents were switched to treatment with metformin and pioglitazone. The mean age of the trial population was 53 years and mean duration of diabetes was 9.2 years. Forty-six percent were male. Eighty-five percent were White, 12% were Black and 3% were Asian. The mean BMI was approximately 32.4 kg/m2. During an 8-week optimization period metformin and pioglitazone were increased to 2,500 mg per day and 30 or 45 mg per day, respectively. After the optimization period, patients were randomized to receive either NOVOLOG MIX 70/30 twice daily added on to the metformin and pioglitazone regimen or continue the current optimized metformin and pioglitazone therapy. NOVOLOG MIX 70/30 was started at a dose of 6 international units twice daily (before breakfast and before supper). Insulin doses were titrated to a pre-meal glucose goal of 80-110 mg/dL. The total daily insulin dose at the end of the study was 56.9 ± 30.5 international units.

Table 5: Combination Therapy with Metformin and Pioglitazone in Patients with Type 2 Diabetes Mellitus [Mean (SD)] (Trial 1)

 

 *Adjusted mean per group, treatment difference, and 95% CI were obtained based on an ANCOVA model with treatment, FPG stratum, and secretagogue stratum as fixed factors and baseline HbA1c as the covariate.

 

 Trial 2:

 

In a 28-week, open-label trial (Trial 2), insulin-naïve patients with type 2 diabetes with fasting plasma glucose above 140 mg/dL currently treated with metformin ± thiazolidinedione therapy were randomized to receive either NOVOLOG MIX 70/30 twice daily [before breakfast and before supper] or insulin glargine once daily (see Table 6). NOVOLOG MIX 70/30 was started at an average dose of 5-6 international units (0.07 ± 0.03 international units/kg) twice daily (before breakfast and before supper), and bedtime insulin glargine was started at 10-12 international units (0.13 ± 0.03 international units/kg). Insulin doses were titrated weekly by decrements or increments of -2 to +6 units per injection to a pre-meal glucose goal of 80-110 mg/dL. The metformin dose was adjusted to 2,550 mg/day. Approximately one-third of the patients in each group were also treated with pioglitazone (30 mg/day). Insulin secretagogues were discontinued in order to reduce the risk of hypoglycemia. Most patients were White (53%), and the mean initial weight was 90 kg.

 

The mean age of the trial population was 53 years old and mean duration of diabetes was 9.5 years. Fifty three percent were male. Fifty-five percent were White, 15% Black, 27% were Hispanic, 2% were Asian and 2% were Other. The mean BMI was approximately 31.5 kg/m2.

Table 6:Combination Therapy with Metformin ± Pioglitazone and Two Types of Insulin in Patients with Type 2 Diabetes Mellitus [Mean (SD)] (Trial 2)