You may delay, but time will not. Beta cells lost are never found again: a case for timely initiation of basal insulin in type 2 diabetes

3.1. Common barriers to initiation of basal insulin

Barriers to starting insulin therapy are multifactorial and can be specific to the person with T2D, the HCP, the healthcare system, and/or the regimen itself. Many people have misconceptions or receive misinformation suggesting that prolonged use of insulin (rather than prolonged hyperglycemia) causes adverse outcomes. Psychological insulin resistance has been described by numerous groups and “typically represents a complex of beliefs about the meaning of insulin therapy, poor self-efficacy concerning the skills needed for insulin therapy, and a lack of accurate information,” all of which can culminate in a reluctance to initiate insulin. Reports suggest that many HCPs wait to prescribe insulin until it is absolutely necessary, citing concerns over weight gain and hypoglycemia. In particular, a misplaced sense of having failed to control T2D with oral therapies can result in reluctance to start insulin. Perhaps one of the most concerning misconceptions, from both HCPs and people with T2D alike, is the belief that if noninsulin therapies are adhered to, insulin therapy can be delayed indefinitely. One survey showed that 40% of primary care physicians agreed or strongly agreed that most patients would not need to progress to insulin therapy if they followed physician recommendations, and 41% disagreed or strongly disagreed that most patients will eventually need to go on insulin regardless of how well they adhere to their treatment regimen.

3.2. Cost as a barrier to initiation of insulin

Historically, cost and affordability have been significant barriers to initiation of insulin; however, with recent changes due to the Inflation Reduction Act in the United States, costs can be lowered and out-of-pocket costs capped for people aged ≥65 years enrolled in Medicare. Further, because of recent moves by manufacturers to significantly reduce the cost of insulin in the United States, improvements in insulin affordability are now set to be expanded to all people who require insulin, beginning in early 2024. It remains noteworthy that a real-world study confirming improved glucose control with the longer-acting basal insulin, Gla-300 versus long-acting basal insulins revealed that healthcare resource utilization, namely, all-cause and diabetes-related hospitalizations and all-cause, diabetes-related, and hypoglycemia-related emergency department visits, were all significantly lower for Gla-300 than for long-acting analogs.

4.1. Insulin as initial therapy

When considering insulin as initial therapy for T2D, the ADA Standards of Care state that “it is common practice to initiate insulin therapy for patients who present with blood glucose levels ≥300 mg/dL (16.7 mmol/L) or A1C > 10% (86 mmol/mol) or if the individual has symptoms of hyperglycemia (i.e. polyuria or polydipsia) or evidence of catabolism (weight loss).” Newly added guidance states that in this population, initiation of insulin should be considered regardless of background glucose-lowering therapy or disease stage. The ADA/European Association for the Study of Diabetes (EASD) guidelines state that “in specific circumstances, insulin may be the preferred agent for glucose lowering, specifically in the setting of severe hyperglycemia (A1C > 10%), particularly when associated with weight loss or ketonuria/ketosis and with acute glycemic dysregulation.”

4.2. Insulin in combination with other antihyperglycemic agents

In general, guidelines recommend that insulin should be added to existing antihyperglycemic therapy when glycemic targets are not met. Recognizing the balance of A1C control with safety, all guidelines recommend that A1C targets should be individualized according to patient characteristics. The 2024 ADA Standards of Care now state that “early combination therapy can be considered in adults with type 2 diabetes at treatment initiation to shorten time to attainment of individualized treatment goals.” The International Consensus on Use of Continuous Glucose Monitoring recommends the use of time in range (TIR) as a key measure of short-term glycemic control. A decrease in TIR has been shown to be associated with an increased risk for microvascular events, macrovascular events, and mortality. The 2024 ADA Standards of Care state that glycemic status should be assessed “by A1C and/or appropriate continuous glucose monitoring (CGM) metrics at least two times a year and more frequently for individuals not meeting treatment goals.”

4.3. Which individuals benefit from insulin therapy?

Another approach to assigning insulin therapy is to consider patient groups who would benefit from such treatment. The “Rationale for Timely Insulin Therapy in Type 2 Diabetes Within the Framework of Individualized Treatment: 2020 Update” suggests that the following groups of people have “patient-centered indications of timely initiation of insulin treatment”: those with severe insulin-deficient diabetes, severe autoimmune diabetes, early manifestation of diabetes-related complications (retinopathy, nephropathy) with A1C out of target despite dual or triple therapy, older adults with sarcopenia or cachexia, and those with symptoms of “high sugar” (weakness, infections, dermatological problems, erectile dysfunction, nocturia).

5.1. Understanding patient preference

It is also important to assess patient preference and satisfaction, and to discuss these before starting basal insulin. It is well published that many people prefer oral to injectable therapy; however, another study has shown that people using basal insulin report greater satisfaction than those using other medications. Age is an important factor; older people are a very heterogeneous group in terms of physical fitness, mental fitness, comorbidities, and social setting, so treatment must be tailored accordingly. Complexity and flexibility of treatment regimens also affect preferences, as can other treatments, overall health, and personal circumstances. The perceptions that HCPs have can sometimes be very different from actual patient preference; this disconnect needs to be rectified in order for shared decision-making to be successful.

5.2. Anticipating and addressing potential barriers to initiation of insulin

Before prescribing insulin, it is pertinent to anticipate potential barriers to initiation, for example fear of hypoglycemia, weight gain, or injections. This is best done by engaging with the patient and asking open-ended questions (see Figure 3). It may be helpful to use the insulin treatment appraisal scale (ITAS), which is a 20-statement questionnaire answered on a 5-point Likert scale. Ahead of the requirement for insulin therapy, it is important to provide education on home glucose/continuous glucose monitoring use and interpretation to empower people to interpret numbers, reach goals, recognize trends, and avoid hypoglycemia. Preconceived notions that insulin pen needles are the same size as those used for phlebotomy can be addressed through review of the injection pen, performing dummy injections, and doing the first injection in the office.

5.3. Providing education on key topics

While it is important to acknowledge that severe hypoglycemia and weight gain are significant harms, it should be emphasized that these risks are highest when insulin therapy is used incorrectly. The ADA Standards of Care recommend that “glucagon should be prescribed for all individuals taking insulin or at high risk for hypoglycemia. Family, caregivers, school personnel, and others providing support to these individuals should know its location and be educated on how to administer it.” Education on hypoglycemia awareness is essential, as hypoglycemia unawareness is common, particularly as hypoglycemia symptoms can vary significantly. Per the ADA, Level 1 hypoglycemia is typically defined as fasting plasma glucose (FPG) <70 mg/dL. If hypoglycemia symptoms are present, corrective treatment should not be delayed while waiting for a result. People with T2D need to know how to apply the “15–15 Rule,” which means consuming 15 grams of carbohydrate to raise blood glucose and checking after 15 minutes, repeating if blood glucose remains below 70 mg/dL. Providing information on appropriate carbohydrate sources, such as glucose tablets, juice, or regular soda, is important. It is also crucial to advise that carbohydrates high in fiber or containing fat should be avoided when treating hypoglycemia because they slow down sugar absorption. The 2024 ADA Standards of Care state that “all individuals taking insulin or at risk for hypoglycemia should receive structured education for hypoglycemia prevention and treatment.” Additionally, the use of CGM is recommended for individuals at high risk for hypoglycemia.

5.4. Other considerations

Insulin is rarely contraindicated, but because insulin preparations contain cresol, insulin should not be administered to individuals with cresol sensitivity. Caution is needed when administering insulin to individuals experiencing vomiting and diarrhea, as insulin could exacerbate hypokalemia. Concomitant antihyperglycemic therapies should also be assessed. For people at risk of hypoglycemia or weight gain, basal insulin can be used successfully alongside metformin, GLP-1 RAs, or SGLT2 inhibitors.

6.1. Initial dose

Many people with T2D do not understand the connection between fasting plasma glucose (FPG) and insulin dosing; therefore, clearly defining the starting dose, target FPG, expected final dose, and the expected time to reach this dose can help immensely. Basal insulin is routinely started at a dose of 10 U/day or 0.1–0.2 U/kg/day, but can be increased to 15 U/day for people who are overweight and/or have very high A1C. Target FPG is typically 120 or 130 mg/dL, although for older adults, a less stringent goal of 130 or 140 mg/dL is often employed. Recommended starting doses vary for different insulins, so individual product labels should be consulted.

6.2. Titration algorithms

It is important to educate that different titration approaches (HCP-led or self-titration) can be used depending on preference and ability. Standardized treat-to-target titration algorithms provide an easy approach. One such algorithm (Table 2) was developed based on the AT.LANTUS trial. If people find algorithms difficult to adhere to, simplified algorithms or technology-assisted dose adjustments can be used. A simple approach is to increase the dose by 1 U per day or by 2–4 U once or twice per week until FPG levels are within the target range or the dose exceeds 0.5 U/kg/day.

6.3. Adjustment of other antihyperglycemic medications

When starting basal insulin, doses of other antihyperglycemic medications may need to be adjusted as the insulin dose is increased. Metformin, GLP-1 RAs, and SGLT2 inhibitors are usually continued, while sulfonylurea therapies are generally stopped to reduce the risk of hypoglycemia. The 2024 ADA Standards of Care specifically state that to minimize the risk of hypoglycemia and treatment burden when starting insulin therapy, the need for and/or dose of glucose-lowering agents with higher hypoglycemia risk (i.e., sulfonylureas and meglitinides) should be reassessed. Discontinuing sulfonylureas may require an increase in basal insulin dose. Thiazolidinediones are generally stopped in people with heart failure due to the increased risk of edema in these individuals.

6.4. Avoiding overbasalization

After successfully initiating basal insulin, HCPs need to be aware of overbasalization. For example, if the basal insulin dose exceeds 0.5 U/kg/day, if the bedtime–morning glucose differential is high (≥50 mg/dL), if glucose variability is high, or if hypoglycemia occurs, therapy should be reevaluated, and the use of additional agents to manage postprandial glucose excursions should be considered. The concept of overbasalization should be explained clearly to people with T2D, paying particular attention to the relationship between FPG and the required dose.

7.1. Differences between long-acting and longer-acting basal insulin analogs

Studies have shown that the longer-acting basal insulin analogs have a longer duration of action (>24 versus ≤24 h) and more stable glucose profiles with less daily and day-to-day variability compared to long-acting analogs, which means a lower risk of hypoglycemia. However, they still need to be administered daily. Two longer-acting analogs—Gla-300 and IDeg U200—deliver the same dose of insulin in smaller volumes than Gla-100 or IDeg U100, offering more concentrated formulations. Gla-300 delivers insulin in a third of the volume of Gla-100, and IDeg U200 in half the volume of IDeg U100. These analogs, used with high-capacity insulin pens that deliver up to 160 U per injection, provide a simplified delivery for individuals requiring higher doses. However, a recent study indicated underuse of high-capacity insulin pens, particularly in primary care.

New developments in insulin include once-weekly insulin icodec, although it has yet to receive regulatory approval. A phase 2 study showed comparable efficacy to Gla-100, though there was a higher incidence of hypoglycemia with icodec. Further, the ONWARDS 4 phase 3a study compared icodec with Gla-100 in a basal–bolus regimen and found similar improvements in glycemic control. Switching from a previous basal insulin to either icodec or IDeg was also studied, with icodec showing superiority in A1C reduction, though there was a modest weight gain associated with icodec compared to IDeg, and slightly higher rates of hypoglycemia.

8.1. Benefits of shared decision-making

It is well known that people who play an active role in their healthcare have improved outcomes compared to those who do not. The benefits of adopting a shared decision-making approach between people with T2D and HCPs are well documented, and this approach is particularly useful for conditions like T2D, where treatment has a significant impact on daily life. However, HCPs often underestimate the emotional toll of living with T2D. While depression is common in people with T2D, diabetes distress is distinct from depression or anxiety. The 2024 ADA Standards of Care recommend that both individuals with diabetes and their caregivers or family members be screened for diabetes distress at least annually, with more frequent checks when treatment targets are unmet, during transitions, or in the presence of diabetes complications.

Managing diabetes should not be solely the responsibility of the primary care physician or provider. Involving the broader healthcare team, allowing patients to determine their readiness to start insulin, and framing insulin as a natural part of T2D progression (rather than a failure) can aid in insulin acceptance and empower patients to effectively manage their condition.

8.2. Use of diabetes self-management education and support

Studies show that diabetes education significantly influences treatment satisfaction and improves A1C outcomes. People who receive diabetes self-management education and support (DSMES) are more likely to receive care that aligns with guidelines, adhere to treatment, and incur lower costs. Despite this, referral rates remain low. An algorithm for identifying and referring T2D patients to DSMES programs has been outlined by several leading diabetes and healthcare organizations. The algorithm highlights five principles: (1) patient engagement, (2) information sharing for self-management, (3) psychosocial and behavioral support, (4) therapy integration, and (5) coordinated care.

The algorithm also identifies four critical times for DSMES referral: at diagnosis, annually, when complicating factors arise, and during care transitions. The 2024 ADA Standards of Care further specify five critical points: at diagnosis, when treatment goals are unmet, annually, when complications develop, and during transitions in life and care. To successfully manage T2D, timely DSMES referrals are essential.