Ace the Case: A 70-Year-Old Woman With a 25-Year History of Type 2 Diabetes Mellitus and an Elevated A1C

Clinical Review

In the natural history of type 2 diabetes mellitus (T2DM), most patients exhibit progressive beta cell dysfunction and loss of insulin secretion over time. As beta cell function decreases, most oral medications typically used in T2DM become insufficient to control glucose levels, leading to the need for insulin treatment. This patient has had T2DM for more than 25 years and, despite triple therapy with both oral and non-insulin injectable medications, her hemoglobin A1C has increased over the past 3 months to 8.8%. The patient has not changed her eating habits and is exercising regularly. In addition, she is taking her medications as prescribed. It is likely that she has progressive beta cell failure and requires insulin therapy to reduce her A1C. The goal of insulin therapy is to establish metabolic control, achieve glycemic targets, and prevent long-term complications. These goals must be balanced against the risk of hypoglycemia.

A major advancement in the past 20 years has been the development of human insulin analogs. Insulin analogs have been modified with amino acid changes and/or the addition of fatty acid moieties to alter absorption characteristics or half-life in the circulation and better mimic normal insulin secretion.2 Basal insulin refers to longer acting insulins that are meant to cover the body’s basal metabolic insulin requirement, in contrast to bolus or prandial insulin, which is meant to reduce glycemic excursions after meals (American Diabetes Association [ADA] consensus guidelines).2 Long-acting basal insulin analog formulations include once- or twice-daily administration of insulin detemir and once-daily administration of insulin glargine (U100 or U300) or insulin degludec (U100 or U200). Concentrated formulations of insulin degludec (U200) and insulin glargine (U300) are now available and allow for the injection of a reduced volume of insulin for patients on higher doses.2 When comparing human and analog insulins, differences in hypoglycemia risk are modest and differences in glycemic efficacy are minimal, but there can be large differences in cost.2 No insulin formulation has been shown to reduce the risk for cardiovascular disease, but data suggest that glargine (U100) and degludec do not increase the risk for major adverse cardiovascular events.3-5

Formulations, Efficacy, and Safety
Insulin glargine (U100) is identical to human insulin except for the substitution of glycine for asparagine in position A21 and the addition of 2 arginine molecules in the beta chain of the insulin molecule.6 These modifications yield a change in the pH such that, after subcutaneous administration, glargine precipitates in the tissue, forming hexamers, which delays absorption and prolongs duration of action. Insulin glargine’s duration of action is 24 hours with no appreciable peak.6 It cannot be mixed with rapid-acting insulins because the kinetics of both the glargine and rapid-acting insulin will be altered.6 Biosimilar formulations are now available for glargine with similar efficacy profile and lower cost.7

Insulin glargine (U300) is a concentrated form of insulin glargine that can be used to control hyperglycemia in patients with severe insulin resistance.8 The prefilled pen contains 450 units and allows for delivery of the same number of insulin units as insulin glargine (U100) but in a smaller volume. However, on a unit-to-unit basis, the glucose lowering effect of insulin glargine (U300) is less than insulin glargine (U100).8-10 In clinical trials comparing insulin glargine (U300) with insulin glargine (U100) in patients with T2DM who were inadequately controlled with oral agents and/or insulin, A1C levels decreased similarly in both glargine groups, with no difference in severe hypoglycemia and little difference in nocturnal hypoglycemia.8,10,11

Insulin detemir contains a fatty acid side chain that allows the molecule to bind to albumin and provides a prolonged duration of action.12 Compared with glargine, detemir does have a noticeable peak and rarely lasts 24 hours.12 Clinical trials in patients with T1DM have suggested that twice-daily injections may be necessary to achieve acceptable basal rate coverage and optimal glycemic control.12 In T2DM, where endogenous insulin secretion may mask any deficiencies in basal insulin, the data are less clear.13 In clinical experience, detemir often requires twice-daily administration in patients with T2DM.13 Detemir cannot be mixed with rapid-acting insulins because the kinetics of both detemir and the rapid-acting insulin will be altered.13

Insulin degludec is almost identical to human insulin, except for the deletion of the last amino acid from the beta chain and the addition of a glutamyl link from LysB29 to a hexadecanedioic fatty acid.14 This feature allows degludec to form soluble multihexamers at the injection site, from which monomers slowly separate and are absorbed. This property confers a long duration of action (greater than 40 hours) and reduces variability and plasma concentration with once-daily dosing.14

In contrast to glargine and detemir insulins, degludec may be mixed with rapid-acting insulins without altering the kinetics of the degludec or the rapid-acting insulin.14 Degludec is associated with a lower risk of severe hypoglycemia compared with insulin glargine (U100) when targeting intensive glycemic control in patients with long-standing T2DM at a high risk of cardiovascular disease.4 Among patients with T1DM and T2DM and at least one risk factor for hypoglycemia, 32 weeks of treatment with insulin degludec versus insulin glargine (U100) resulted in a reduced rate of overall symptomatic hypoglycemic episodes.15,16

Initiation of Basal Insulin
Because no single oral medication or combination of medications has durable effects in patients with T2DM, insulin therapy may become necessary several years after the diagnosis is established.17 A wide range of patients with T2DM may benefit from insulin therapy.17

The most common indications for the initiation of insulin therapy in T2DM are:17

  • Progressive beta cell dysfunction with insufficient insulin secretion relative to the degree of insulin resistance despite maximal treatment with oral or non-insulin therapies
  • Severe hyperglycemia with associated glucose toxicity
  • Hospitalization for an acute illness or surgery
  • Side effects with or contraindications to use of oral non-insulin therapies
  • Pregnancy
  • Patient preference

Using basal insulin in combination with oral medications is effective and causes less hypoglycemia and weight gain than combinations using premixed insulin formulations or prandial insulin.8 A standard approach for optimizing basal insulin regimens is to titrate the dose based on a target fasting glucose concentration. A patient's fasting glucose target should be customized based on the patient's individual characteristics, comorbidities, and risk of hypoglycemia. Long-acting insulin analogs (including degludec [U100 or U200], glargine [U100 and U300], and detemir) have been shown to be effective for controlling fasting glucose and reducing the risk of hypoglycemia, particularly overnight, when titrated to the same fasting glucose target as NPH insulin.18-22

The most recent consensus guidelines published by the ADA and the European Association for the Study of Diabetes (EASD) recommend initiation of basal insulin in patients whose A1C is above target despite dual/triple therapy.2 Starting doses can be weight-based (0.1 to 0.2 units/kg/day) or empirical (10 units/day).2 In our patient, one would consider starting a long-acting basal insulin analog at a dose between 10 and 20 units per day. It is important to review the signs and symptoms of hypoglycemia when patients are started on insulin therapy. Currently, our patient is not experiencing any hypoglycemia as a result of her combination therapy. The addition of basal insulin will increase the patient's risk of hypoglycemia, and it will be important that she is instructed on the proper identification and treatment of it. Patient self-titration is more effective according to the new consensus guidelines, and providers are encouraged to choose an evidence-based titration algorithm. The current consensus guidelines suggest increasing the basal insulin dose by 2 units every 3 days, with a goal of obtaining the patient's individualized fasting plasma glucose target without hypoglycemia.2

Conclusion
Even with the many new pharmacologic developments of oral and non-insulin injectable medications for the treatment of T2DM, insulin therapy remains a standard and effective treatment for achieving glycemic control. The indications for insulin therapy are varied and range from beta cell failure late in T2DM to severe hyperglycemia at the initial clinical presentation and subsequent diagnosis. The main advantage of insulin over other glucose lowering medications is that insulin lowers glucose in a dose dependent manner to almost any glycemic target, as limited by hypoglycemia. With newer insulin analogs, the benefits of insulin treatment should be more obtainable with minimal risk of hypoglycemia when prescribed appropriately and tailored to the individual needs of the patient.

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Question
According to the most recent consensus guidelines published by the ADA and the EASD, which of the following best describes how to initiate basal insulin in a patient with T2DM?
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Correct answer: B

Rationale: The most recent consensus guidelines published by the ADA and the EASD recommend the initiation of basal insulin in patients whose A1C is above target despite dual/triple therapy.2 Starting doses can be weight-based (0.1-0.2 units/kg/day) or empirical (10 units/day).2 Patient self-titration is more effective according to the new consensus guidelines. Providers are encouraged to choose an evidence-based titration algorithm.

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