The FullSTEP® Stepwise Approach

with Helena W. Rodbard, MD, FACP, MACE

Medical Director, Endocrine and Metabolic Consultants, Rockville, MD



As a health care professional who treats patients with diabetes, you know how challenging it can be to get patients to initiate a basal-bolus insulin regimen. Patients may find some treatment algorithms complex or they may simply be reluctant to add more injections to their daily treatment regimen. But you can help your patients take a more active role in the management of their diabetes with the FullSTEP® stepwise approach.




Here are some common questions I hear about the FullSTEP® stepwise approach.

What is the FullSTEP® stepwise approach?

The FullSTEP® study compared glycemic control between 2 groups of patients: 1 group added mealtime insulin 3 times a day or full basal-bolus from the beginning. The other group added mealtime insulin 1 dose at a time in a stepwise approach. Both groups frequently measured their blood glucose to adjust both the basal and bolus insulin. Measurements in the basal-bolus group were performed more frequently than in the stepwise group, to coincide with number of injections. Basal insulin was titrated during the run in period by the patient and then after randomization by the investigator as per his/her decision. Patients in both groups were actively involved in their therapy.1 In the stepwise arm of the study, around 50% of patients used only 1 or 2 doses of bolus insulin by the end of the study.


How does the safety and efficacy of the stepwise arm compare with the full basal-bolus arm?

In the FullSTEP® study, the stepwise approach was found to be non-inferior to the full basal-bolus approach in terms of A1C reduction.1 Similar A1C and FPG results were demonstrated by the end of study, whether NovoLog® was initiated with 1 dose at a time or 3 doses from the beginning (A1C: P=0.088; FPG: P=0.64).1 In addition, patients in the stepwise arm of the study experienced significantly fewer hypoglycemic events than patients in the full basal-bolus arm.1,a

aBecause clinical trials are conducted under widely varying designs, the adverse reaction rates reported in 1 clinical trial may not be easily compared with those rates reported in another clinical trial and may not reflect the rates actually observed in clinical practice.

Patients in the stepwise arm of the study experienced significantly fewer hypoglycemic events than patients in the full basal-bolus arm.4

 

See a detailed breakdown of the FullSTEP® study safety and efficacy results

See a detailed breakdown of the FullSTEP® study safety and efficacy results

The FullSTEP® Study Results: Self Titration with Rapid-Acting Insulin

  1. Data on file. Novo Nordisk Inc; Plainsboro, NJ.
  2. Inzucchi SE, Bergenstal RM, Buse JB, et al. 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(6):1364-1379.
  3. NovoLog [package insert]. Plainsboro, NJ: Novo Nordisk Inc.; 2013.
  4. Levemir® [package insert]. Plainsboro, NJ: Novo Nordisk Inc.; 2013.
  5. Rodbard HW, Visco VE, Andersen H, Hiort LC, Shu DHW. Treatment intensification with stepwise addition of prandial insulin aspart boluses compared with full basal-bolus therapy (FullSTEP Study): a randomised, treat-to-target clinical trial. Lancet Diabetes Endocrinol. 2014;2:30-37.

In the "Distribution of Mealtime Injections in the Stepwise Arm at End of Trial" chart, the values do not equal 100% as patients who did not complete the trial are not depicted in this chart (N = 201).1



Patients in stepwise arm of the study experienced fewer hypoglycemic events than patients in the full basal-bolus arm

Patients in the stepwise arm of the study experienced significantly fewer hypoglycemic events than patients in the full basal-bolus arm.1


Study results

Study results

At the end of the FullSTEP® study at 32 weeks, more than half of the patients completing the stepwise arm of the trial received only 1 or 2 injections of NovoLog® daily. Additionally, 86% of patients in the stepwise arm continued on therapy until the end of study (32 weeks) compared with 74% in the full basal-bolus arm.b

bSignificantly more patients in the full basal-bolus arm (n=52) withdrew vs the stepwise arm (n=28; P=0.002). The number of patients who completed the study was higher in the stepwise arm (n=173) than in the full basal-bolus arm (n=148). There were no serious adverse events that led to withdrawal. Withdrawal criteria included pregnancy or intention of becoming pregnant, hypoglycemia that posed a safety problem, major protocol deviation having influence on efficacy or safety data, and initiation or change in any systemic treatment.


In the stepwise arm

In the stepwise arm 86% of patients continued on therapy to study end vs 74% in the full basal bolus arm (p=0.002)

of patients continued on therapy to study end vs 74% in the full basal bolus arm (P=0.002)a


What is the potential benefit of a patient-led titration approach?

Research has shown that patient engagement and education make a difference.1 Patients want to be involved in their own care2—and informed and engaged patients can make more appropriate choices, which may lead to better outcomes.3 The American Diabetes Association recommends adding 1 to 3 injections of rapid-acting insulin analog when A1C remains above target with basal insulin titrated to an acceptable FPG level3—and the FullSTEP® stepwise approach is one way to empower your patients with diabetes who are appropriate candidates with the knowledge to take a more active role in their treatment. 



In the DAWN2 study

In the DAWN2 study 49% of people with diabetes reported participation in diabetes education

of people with diabetes reported participation in diabetes education.2


How was mealtime insulin initiated in the FullSTEP® study?

In the stepwise arm of the study, NovoLog® was added to patients’ treatment plans using a 3-step approach1:

Add—Patients added 4 units of NovoLog® to perceived largest meal of the day.

Adjust—Patients took a self-monitored plasma glucose (SMPG) reading daily before their next meal or at bedtime and used this reading to self-titrate the next day’s dose.    

Assess—A second and/or third dose of NovoLog® was added if A1C was ≥7% at weeks 11 and 22, respectively.

  1. Add—Patients added 4 units of NovoLog® to perceived largest meal of the day.
  2. Adjust—Patients took an SMPG reading daily before their next meal or at bedtime and used this reading to self-titrate the next day’s dose.
  3. Assess—A second and/or third dose of NovoLog® was added if A1C was ≥7% at weeks 11 and 22, respectively.


What algorithm did the patients use to self-titrate their mealtime dose?

Patients in the stepwise arm of the FullSTEP® study were instructed to take an SMPG reading daily, either before their next meal or at bedtime, depending on which meal required pre-meal bolus insulin. The patient then used that SMPG reading to titrate the bolus insulin for the next day. Self-titration followed a 1-0-1 algorithm. For instance, if a glucose reading was less than 70 mg/dL, the patient’s dose would be reduced accordingly (by reducing 1 unit) before the corresponding meal on the following day.

Algorithm patients used to self-titrate their mealtime insulin

 

During run-in period; patients titrated their basal insulin doses weekly by averaging prebreakfast SMPG readings for the 3 consecutive days prior to each visit and self-titrated based on a 3-0-3 algorithm.

NovoLog® should be administered within 5 to 10 minutes prior to the start of a meal.

Utilize this dosing algorithm if appropriate for your patients. NovoLog® dosing must be individualized.


Do you have a patient who may be an appropriate candidate?

Once patients understand mealtime insulin and the role of postprandial glucose (PPG), they might be appropriate candidates for the FullSTEP® stepwise approach. A patient may be appropriate if they meet the following criteria:

  • Is the patient able to follow instructions independently or under your guidance?3
  • Do you feel confident that the patient can make the necessary adjustments?5
  • Has the patient been familiarized with the FullSTEP® Dosing Tool and reviewed it with you or your staff? 

Is the patient able to follow instructions independently or under your guidance?3

Do you feel confident that the patient can make the necessary adjustments?4

Has the patient been familiarized with the FullSTEP® Dosing Tool and reviewed it with you or your staff? 


 

How can I help my patients initiating bolus insulin using the FullSTEP® stepwise approach?

To help your appropriate patients initiate NovoLog® using the FullSTEP® approach, Novo Nordisk has created a downloadable dosing tool to share with your patients. The FullSTEP® Dosing Tool is designed to help you explain the step-by-step approach, and help your patients understand how to monitor and record their glucose readings and insulin dosages and use that information to follow the 1-0-1 algorithm to titrate their bolus insulin or their prandial insulin.

Get the FullSTEP® Dosing Tool




Get more details about the FullSTEP® study





Study design

Rodbard et al (FullSTEP®), a randomized, open-label, multinational, non-inferiority, 32-week treat-to-target trial. Patients with type 2 diabetes inadequately controlled on basal insulin with or without oral antidiabetic drugs were randomized to either a stepwise arm or full basal-bolus arm. In the stepwise arm (n=201), NovoLog® was initially added to basal insulin at the patient-perceived largest meal. Additional doses were added to the next largest patient-perceived meal at weeks 11 and 22 if A1C ≥7%. In the full basal-bolus arm (n=200), NovoLog® was added at all 3 main meals from the start. Patients in both arms self-titrated NovoLog® daily based on the previous day’s premeal or bedtime SMPG levels.

Selected Important Safety Information

Contraindications

  • NovoLog® is contraindicated during episodes of hypoglycemia and in patients hypersensitive to NovoLog® or one of its excipients. 

Warnings and Precautions

  • Never Share a NovoLog® FlexPen, NovoLog® FlexTouch®, PenFill® Cartridge, or PenFill® Cartridge Device Between Patients, even if the needle is changed. Patients using NovoLog® vials must never share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens. 
  • Changes in insulin strength, manufacturer, type, or method of administration may affect glycemic control and predispose to hypoglycemia or hyperglycemia. These changes should be made cautiously under close medical supervision and the frequency of blood glucose monitoring should be increased.

NovoLog® (insulin aspart injection) 100 U/mL Indications and Usage

NovoLog® (insulin aspart injection) 100 U/mL is an insulin analog indicated to improve glycemic control in adults and children with diabetes mellitus. 

Important Safety Information

Contraindications

  • NovoLog® is contraindicated during episodes of hypoglycemia and in patients hypersensitive to NovoLog® or one of its excipients. 

Warnings and Precautions

  • Never Share a NovoLog® FlexPen, NovoLog® FlexTouch®, PenFill® Cartridge, or PenFill® Cartridge Device Between Patients, even if the needle is changed. Patients using NovoLog® vials must never share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens. 
  • Changes in insulin strength, manufacturer, type, or method of administration may affect glycemic control and predispose to hypoglycemia or hyperglycemia. These changes should be made cautiously under close medical supervision and the frequency of blood glucose monitoring should be increased. 
  • Hypoglycemia is the most common adverse effect of insulin therapy. The timing of hypoglycemia may reflect the time-action profile of the insulin formulation. Glucose monitoring is recommended for all patients with diabetes and is particularly important for patients using external pump infusion therapy. 
  • To avoid medication errors and accidental mix-ups between NovoLog® and other insulin products, instruct patients to always check the insulin label before injection. 
  • Severe, life-threatening, generalized allergy, including anaphylaxis, may occur with insulin products, including NovoLog®
  • As with all insulins, NovoLog® use can lead to life-threatening hypokalemia, which then may cause respiratory paralysis, ventricular arrhythmia, and death.  Monitor potassium levels in patients at risk for hypokalemia and treat if indicated.
  • Fluid retention and heart failure can occur with concomitant use of thiazolidinediones (TZDs), which are PPAR-gamma agonists, and insulin, including NovoLog®. Patients should be observed for signs and symptoms of heart failure. If heart failure occurs, dosage reduction or discontinuation of the TZD must be considered. 
  • Malfunction of the insulin pump or insulin infusion set or insulin degradation can rapidly lead to hyperglycemia and ketoacidosis. Patients using insulin infusion pump therapy must be trained to administer insulin by injection and have alternate insulin therapy available in case of pump failure. 

NovoLog® continuous subcutaneous infusion route (insulin pump): Do not mix NovoLog® with any other insulin or diluent. 

Adverse Reactions

  • Adverse reactions observed with NovoLog® include hypoglycemia, allergic reactions, local injection site reactions, lipodystrophy, rash, and pruritus. 

Use in Specific Populations

  • NovoLog® has not been studied in children with type 2 diabetes or in children with type 1 diabetes who are younger than 2 years of age. 
  • Like all insulins, NovoLog® requirements may be reduced in patients with renal impairment or hepatic impairment. These patients may require more frequent blood glucose monitoring and dose adjustments. 

Please click here for Prescribing Information.

 

References:

  1. Rodbard HW, Visco VE, Andersen H, Hiort LC, Shu DHW. Treatment intensification with stepwise addition of prandial insulin aspart boluses compared with full basal-bolus therapy (FullSTEP Study): a randomised, treat-to-target clinical trial. Lancet Diabetes Endocrinol. 2014;2:30-37.
  2. Nicolucci A, Kovacs Burns K, Holt RIG, et al. Diabetes Attitudes, Wishes and Needs second study (DAWN2™): cross-national benchmarking of diabetes-related psychosocial outcomes for people with diabetes. Diabet Med. 2013;30:767-777.
  3. American Diabetes Association. Standards of medical care in diabetes—2016. Diabetes Care. 2016;39(suppl 1):S1-S112.
  4. Rubin RR. Adherence to pharmacologic therapy in patients with type 2 diabetes mellitus. Am J Med. 2005;118(5A):27S-34S.