Initiating and Intensifying Insulin in Type 2 Diabetes

Educational Objectives

The goal of this program is to improve the treatment of diabetes. After hearing and assimilating this program, the clinician will better be able to:

1. Identify patients with type 2 diabetes who should be started on insulin.

2. Choose the best initial insulin regimen for particular patient.

3. Follow a patient and intensify the insulin regimen if it fails to achieve adequate glycemic control.

4. Educate patients about insulin in ways that alleviate their fears.

Summary

Background: At the time of diagnosis of type 2 diabetes ≈50% of beta cell function has typically been lost. Progressive loss of beta cell function results in minimal function after 10 to 15 years. Target hemoglobin A1c is generally <7%, but it may differ for individual patients. Guidelines from the American Diabetes Association (ADA) state that A1C should be as close to normal as possible without causing hypoglycemia. The target A1C for individual patients considers life expectancy and presence of complications. Insulin is effective for treating hyperglycemia and produces minimal side effects, but inappropriate use of insulin can be life threatening.

When to start insulin: If patients with type 2 diabetes fail to achieve their target A1C with metformin, insulin is an option. More commonly, insulin is started after a combination of oral agents fails. Insulin should be considered for any patient with a very high A1C (>9%) or symptoms of severe hyperglycemia (eg, polyuria, polydipsia), even as first-line treatment.

Insulin preparations: Insulin is divided into human insulin and insulin analogues. Different preparations vary by onset and duration of action (ultra-rapid acting, rapid acting, short acting, intermediate acting, and long acting). There are premixed combinations.

Insulin structures: Human insulin consists of an alpha chain (with 21 amino acids) and a beta chain (with 30 amino acids). The structure of regular insulin is identical to human insulin. In the analogue insulin lispro, lysine and proline are switched on the alpha chain. In insulin aspart, the beta chain contains aspart instead of proline. Long-acting insulin glargine contains additional arginine on the beta chain, and glycine replaces alanine. Insulin detemir has one less amino acid on the beta chain than human insulin, and it has a chain of fatty acids attached to the last amino acid on the beta chain that binds with albumin.

The structure of insulin affects the onset and duration of action. When regular insulin is injected into subcutaneous fat it forms a hexamer, which cannot pass through the capillary membrane. To enter the circulation, insulin must undergo dissociation to convert a hexamer to a monomer; dissociation occurs more quickly with rapid-acting than regular insulin. Insulin glargine is acidic, and therefore it precipitates and forms crystals. The large cluster turns into a hexamer, then dimer, then monomer. Insulin glargine is longer acting because this process of absorption takes longer than with other types of insulin.

Initiating insulin: In the Treating to Target in Type 2 Diabetes (4-T) study, patients on oral agents who were not meeting target A1C were randomized to receive premixed (biphasic) insulin, prandial insulin, or basal insulin. A1C decreased >1% with premixed and prandial insulin and 0.8% with basal insulin (statistically significant difference). Weight gain was ≈5 kg in the premixed insulin group, ≈6 kg in the prandial insulin group, and 2 kg in the basal insulin group. The rate of hypoglycemia was lowest with basal insulin.

The APOLLO trial asked the same question about basal vs rapid-acting insulin but used different preparations. The study randomized patients who failed to achieve glycemic control with oral agents to basal insulin (glargine) or rapid-acting insulin (lispro) before each meal. There was no significant difference in the lowering of A1C between the two groups. The rate of hypoglycemia was significantly higher in the prandial (insulin lispro) group.

Basal insulin: The guidelines recommend starting patients on basal insulin. It is simpler for patients and causes less weight gain and hypoglycemia. Start with 10 units per day or 0.1 to 0.2 units/kg per day and titrate the dose; follow-up and titration are crucial. The particular method for adjusting the dose does not matter as long as hypoglycemia is avoided. Basal insulin suppresses hepatic glucose production. The main effect is on fasting blood glucose. Titration should be based on fasting glucose levels.

“Wherever you start, you need to titrate. Usually your first guess is not the right answer.”

Adding bolus insulin: Add bolus insulin for patients who continue to have high A1C, even if fasting blood glucose levels are acceptable. The options are adding one bolus injection of short-acting insulin before the largest meal of the day (“basal plus”) or adding bolus injections before every meal. The choice depends on the willingness of the patient to inject insulin four times a day. Premixed insulin is another option. Bolus insulin should also be considered for patients who have hypoglycemia overnight or during the day when meals are skipped and A1C is not at target.

Basal-bolus: Basal insulin suppresses glucose production from the liver and bolus insulin takes care of hyperglycemia excursions after meals. Usually, 50% of the total insulin dose is given as basal and 50% as prandial (10% to 20% of the total daily dose is given before each meal).

Transition to basal-bolus insulin: May start prandial insulin at 4 units before each meal or 10% of total daily insulin dose and titrate. Before starting, check bedtime and morning blood glucose levels. If patients have normal blood glucose overnight, they will have hypoglycemia when prandial insulin is started. Decrease the basal insulin dose before adding prandial insulin.

Bolus insulin: Bolus insulin includes prandial and correction. The prandial dose is based on the meal. Some patients can count carbohydrates and calculate the dose. Give patients who cannot do this a fixed dose, but instruct them to be consistent in the amount of carbohydrates they eat. If premeal blood glucose is high, a correction dose is needed.

Inhaled insulin: The onset of action of the recently approved inhalable insulin Afrezza is faster than rapid-acting insulin and similar to normal physiology. The small, easy-to-use device contains dry powder insulin in a small matrix (ie, “technosphere” inhaled insulin [TI]). When inhaled, the matrix and insulin are separated and absorbed through the lung. It is not yet known whether any particles remain in the lung.

A study of people with type 2 diabetes found that TI added to oral agents lowered A1C ≈0.8%, which was greater than technosphere placebo. A study that compared TI with premixed insulin showed similar efficacy in the two arms. Cough is the most common side effect, occurring in ≈25% of patients. Inhaled insulin is contraindicated in people with chronic lung diseases (eg, asthma, chronic obstructive pulmonary disease). A pulmonary function test must be done before starting inhaled insulin. Pulmonary function worsens over time, but is completely reversible within 3 months of stopping the drug.

Concentrated insulin: U-500 is a concentrated form of regular insulin for patients who require >200 units per day. It may cause hypoglycemia. A new form of concentrated insulin, U-300 insulin glargine (Toujeo), was recently approved. It is 3 times more concentrated and has a longer duration of action (≤40 hours). In clinical trials, the rate of nocturnal hypoglycemia was lower with U-300 insulin glargine than with insulin glargine (U-100) and they had similar efficacy. U-300 insulin glargine is available in a prefilled SoloSTAR pen that contains 450 units. The maximum single injection dose is 80 units.

Case: A patient on 55 units of insulin glargine and 12 units before each meal is not at A1C goal. The first step is to review blood glucose levels, focusing on hypoglycemia and trying to find a pattern. In this case, fasting blood glucose levels were acceptable, but there was a significant decrease in glucose level overnight. There also was a significant increase in glucose level between dinner and bedtime. This patient needs to be educated about avoiding hypoglycemia. The patient is on fixed dose insulin, so consistent carbohydrate intake is important. The dose of basal insulin was decreased and the dose of prandial insulin before dinner increased.

Newer insulins: Longer-, faster-, and shorter-acting insulins are under development.

Insulin degludec, which is approved in Europe but not yet in the United States, is longer acting than insulin detemir. It is associated with a lower rate of hypoglycemia than other basal insulins.

One insulin being studied is bound to the molecule phenylboronic acid, which makes the insulin inactive. When the glucose level rises above a certain level, the insulin becomes active. Studies in animals have shown that this insulin has glucose-lowering effects equivalent to other insulins but only in the presence of high glucose levels.

Readings

Bretzel RG et al: Once-daily basal insulin glargine versus thrice-daily prandial insulin lispro in people with type 2 diabetes on oral hypoglycaemic agents (APOLLO): an open randomised controlled trial. Lancet 2008;371:1073-84; Chou DH et al: Glucose-responsive insulin activity by covalent modification with aliphatic phenylboronic acid conjugates. Proc Natl Acad Sci U S A 2015;112:2401-6; Holman RR et al: Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes. N Engl J Med 2007;357:1716-30; Kugler AJ et al: Inhaled technosphere insulin: a novel delivery system and formulation for the treatment of types 1 and 2 diabetes mellitus. Pharmacotherapy 2015;35:298-314; Rendell M: Technosphere inhaled insulin (Afrezza). Drugs Today (Barc) 2014;50:813-27; Rosenstock J et al: Efficacy and safety of Technosphere inhaled insulin compared with Technosphere powder placebo in insulin-naive type 2 diabetes suboptimally controlled with oral agents. Diabetes Care 2008;31:2177-82.

Disclosures

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. Dr. Anderson reported relationships with Amylin Pharmaceuticals (B), Daichi Sankyo Company (B), Eli Lilly and Company (B), Novo Nordisk (B), and sanofi-aventis UC (A). Dr. Rasouli disclosed relationships with AstraZeneca (G), Novo Nordisk (G), Pfizer (G), and sanofi-aventis (G). Members of the planning committee reported nothing to disclose.

A=Advisory panel B=Speakers bureau
C=Consultant G=Grant or other research support

Acknowledgements

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

DI061201

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.