Starting insulin in patients with type 2 diabetes: An individualized approach
ABSTRACTBecause type 2 diabetes mellitus is a progressive disease, most patients eventually need insulin. When and how to start insulin therapy are not one-size-fits-all decisions but rather must be individualized. This paper reviews the indications, goals, and options for insulin therapy in type 2 diabetes.
KEY POINTS
- In deciding a patient’s hemoglobin A1c goal and whether it is time to start insulin therapy, one should take into account the patient’s age, life expectancy, concurrent illnesses, risk of hypoglycemia, and other factors.
- When the target hemoglobin A1c is not achieved with metformin or a two-drug regimen that includes metformin, the American Diabetes Association recommends adding a daily dose of basal insulin.
- Eventually, preprandial bolus doses may need to be added to the insulin regimen to control postprandial blood glucose levels and hemoglobin A1c.
WHEN SHOULD INSULIN BE STARTED?
Physicians should consider the needs and preferences of each patient and individualize the treatment. The most recent recommendations from the ADA5 stress the importance of a patient-centered approach, with multiple factors taken into account. These include the patient’s attitude, expected compliance with treatment, risk of hypoglycemia, disease duration, life expectancy, and comorbidities, and the side effects of oral medications and insulin.
Compared with previous guidelines, there are fewer rules on how and when to start insulin therapy. But absolute and relative indications for insulin therapy should be considered in patients with the following:
Absolute indications for insulin
- Ketoacidosis or catabolic symptoms, including ketonuria
- Newly diagnosed type 2 diabetes with pronounced hyperglycemia (glucose ≥ 300 mg/dL or hemoglobin A1c ≥ 10.0%) with or without severe symptoms, including weight loss, polyuria, or polydipsia10
- Uncontrolled type 2 diabetes mellitus despite using one, two, or more oral antidiabetic drugs or glucagon-like peptide 1 (GLP-1) receptor agonists
- Gestational diabetes
- Preference for insulin.
Relative indications for insulin
- Hospitalized for surgery or acute illnesses
- Advanced renal or hepatic disease
- Inability to afford the cost or tolerate the side effects of oral antidiabetic drugs and GLP-1 receptor agonists.
Depending on the situation, blood glucose is measured fasting, before meals, or after meals after initiating or adjusting insulin regimens (Table 2).
WHAT ARE THE INSULIN REGIMENS?
Basal insulin
In the early stages of type 2 diabetes, metformin alone or in combination with another oral antidiabetic drug or with a GLP-1 receptor agonist is often used along with healthy eating, weight control, and increased physical activity.
When the target hemoglobin A1c cannot be achieved with one or two noninsulin drugs, the ADA suggests basal insulin be added to metformin or a two-medication regimen that includes metformin (Table 3). However, recent evidence suggests that combining a GLP-1 receptor agonist with basal insulin, in a regimen without metformin, is safe and improves glycemic control without hypoglycemia or weight gain.11
While a total daily dose of insulin of 0.1 to 0.2 units/kg could be initially used in patients with a hemoglobin A1c level less than 8%, a higher dose of 0.2 to 0.3 units/kg is required if the hemoglobin A1c level is between 8% and 10%. The dose can be titrated once or twice weekly if the fasting glucose is above the target level (usually < 130 mg/dL). If hypoglycemia develops (glucose < 70 mg/dL), the insulin dose should be reduced by 10% to 20%.10
Available basal insulins include glargine, detemir, and neutral protamine Hagedorn (NPH) (Table 4).12–14 Because glargine and detemir offer better pharmacokinetic properties, less variability in response, and less risk of hypoglycemia, they are preferred over NPH. Glargine has a relatively constant plasma concentration over 24 hours, allowing once-daily dosing at any time during the day (Figure 1).15 The dose should be taken at the same time every day. Detemir and NPH are usually taken once or twice daily.
Patients treated once daily should take the dose with the evening meal or at bedtime. Patients who require a twice-daily regimen can take the first dose with breakfast and the second one with the evening meal, at bedtime, or 12 hours after the morning dose.
The randomized Treat-to-Target trial,16 in 756 patients, showed that both glargine and NPH, when added to oral therapy in patients with type 2 diabetes, achieve the target hemoglobin A1c, but NPH is associated with more episodes of nocturnal hypoglycemia. Similar results were found when NPH was compared with detemir insulin.17
A Cochrane review18 suggested that glargine and detemir are similar in efficacy and safety. However, detemir often needs to be injected twice daily, in a higher dose, and is associated with less weight gain. Furthermore, a meta-analysis of 46 randomized clinical trials19 showed that the weight increase at 1 year is less in patients treated with basal than with twice-daily or prandial regimens.
A noninterventional longitudinal study20 in 2,179 patients newly started on insulin showed that the mean weight increase at 1 year was 1.78 kg, and 24% of patients gained more than 5 kg. However, the factors independently associated with the weight gain were a higher hemoglobin A1c at baseline, a higher insulin dose at baseline and at 1 year, and a lower baseline body mass index, but not the type of insulin regimen.
Currently, a new class of ultralong-acting basal insulins is being studied. Insulins in this class are approved in other countries, but the US Food and Drug Administration requires additional data for approval. Ultralong-acting insulins are expected to reduce the risk of hypoglycemia, specifically the risk of nocturnal episodes. Also, given their longer duration of action and stable steady-state pharmacokinetics, they will offer flexibility in the dose timing.21
