Insulin is necessary in type 2 diabetes mellitus (T2DM). Since the UK Prospective Diabetes Study (UKPDS), it has been known that the progressive deterioration of insulin secretion over time leads to the failure of non-insulin therapies, necessitating insulin intensification in patients with T2DM (1) ( Figure 1 ). Insulin treatment in T2DM is well-established and considered a safe and effective therapy, particularly in specific clinical situations. More recently, certain patient subgroups, notably those with severe insulin deficiency (SIDD), have been identified that potentially require early insulinization, since they are associated with poor glycemic control and a higher risk of microvascular complications (2).

Current recommendations advise initiating insulin when nutritional therapy and physical exercise, along with other non-insulin medications, fail to achieve control objectives (3–5). However, these therapeutic guidelines identify specific clinical situations where insulinization is a preferred option. It is now acknowledged that insulinization should begin with the addition of basal insulin to the patient’s existing treatment and, if necessary, progress by gradually introducing prandial insulin. However, there are various barriers to insulin therapy, on the part of both patients and healthcare professionals, which unjustifiably delay the initiation of insulinization or influence patients’ non-adherence to insulin treatment (6). Undoubtedly, the daily administration of one or more doses of insulin represents one of the most significant barriers to insulin treatment.

This review analyzes various aspects related to insulin treatment in T2DM, with a special emphasis on current barriers to the initiation of insulinization. Additionally, potential solutions are introduced to reduce barriers to timely insulin initiation and thereby contribute to achieving and maintaining control objectives in T2DM.

The main pathophysiological defects underlying the onset and progression of T2DM are pancreatic β-cell insufficiency and insulin resistance, primarily in skeletal muscle, liver, and adipose tissue. The release and action of insulin must precisely meet metabolic demands. Therefore, both the molecular mechanisms involved in insulin synthesis and secretion, as well as tissue-level responses, are crucial for adequate glycemic control. Additionally, other defects in multiple organs that may contribute to the development of T2DM have been identified. This perspective was postulated by DeFronzo in 2009 and is known as the ominous octet (7).

Not all individuals with T2DM will require insulin treatment. In many cases, good metabolic control can be achieved through lifestyle changes, nutritional therapy, and non-insulin hypoglycemic agents. However, despite the numerous pharmacological options available today, insulin remains a necessary, effective, and safe treatment, particularly in specific clinical situations, as described below (8, 9) ( Figure 2 ).

The consensus report from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD), titled “Management of Hyperglycemia in Type 2 Diabetes”, recommends a holistic, multifactorial, and patient-centered approach to diabetes care. Specific factors influencing treatment choice include individualized glycemic and weight goals, cardio-renal protection, underlying physiological factors, side effects, access, cost, and availability (3). The progressive nature of T2DM often necessitates the initiation of insulin therapy. This scenario should be explained to patients, avoiding the use of insulin as a threat or portraying it as a sign of failure. Instead, emphasis should be placed on the utility and importance of insulin in maintaining glycemic control once the disease progression renders other medications less effective. Currently, basal insulin is considered the preferred regimen following the failure of non-insulin antidiabetic drugs (3).

Determining the appropriate timing for insulin therapy initiation in people with T2DM is challenging. Traditionally, many clinical practice guidelines recommended introducing insulin based on a specific HbA1c value. However, recent consensus statements for hyperglycemia treatment in T2DM by the ADA and EASD (3) make it clear that the HbA1c target for each patient should be individualized based on multiple parameters, including the risk of hypoglycemia. This patient-centered, multifactorial approach means that a single HbA1c value cannot be considered an adequate indicator of the need to start insulin therapy. The timing for initiating this therapy will depend on each patient’s characteristics, including age, duration of diabetes, weight, risk of hypoglycemia, etc. (3).

Clinical practice guidelines establish criteria to help decide when to initiate insulin therapy ( Table 1 ). According to the American Association of Clinical Endocrinology (AACE), insulinization should be initiated when therapy, including lifestyle modifications and non-insulin medications, fails to achieve glycemic control goals, or whenever a patient, whether previously exposed to insulin or not, presents symptoms of hyperglycemia. Specifically, AACE indicates that patients with HbA1c >10%, symptomatic with polyuria, polydipsia, or polyphagia, will benefit more from starting insulin (4). However, if they have few symptoms or no significant symptoms, these patients can initiate therapy with maximum doses of two or three non-insulin medications (4). This guideline also recommends using insulin in patients who need to intensify glycemic control and are already receiving three to four non-insulin medications (27). The ADA/EASD positioning in 2023 considers that in patients with insufficient glycemic control despite the use of three non-insulin antidiabetic drugs in combination, insulinization should be considered. It also contemplates early introduction of insulin if there is evidence of acute decompensation with weight loss, ketonuria/ketosis, or other symptoms of hyperglycemia, or when HbA1c levels are >10% or blood glucose levels are ≥300 mg/dL. In some cases, as glucotoxicity resolves, it may be possible to simplify the insulin regimen and/or suspend insulin and reintroduce a combination of non-insulin medications.

In the document “Comprehensive Approach to People with T2DM” prepared by the Diabetes Knowledge Area of the Spanish Society of Endocrinology and Nutrition (SEEN), insulin use is recommended when the combination of lifestyle changes (including weight loss with medical-surgical therapy) and non-insulin therapies fails to achieve the individualized control goal (26). Likewise, as mentioned earlier, insulin will be the treatment of choice for patients with T2DM during pregnancy, in patients with intercurrent diseases, or in steroid treatment causing marked hyperglycemia, or in those in whom, due to circumstances (renal or hepatic insufficiency, adverse effects, etc.), the use of non-insulin drugs is contraindicated.

Once the decision to introduce insulin treatment has been made, basal insulin is the most suitable option. The decision to maintain other antidiabetic drugs should be assessed individually, considering that they may provide better control and reduce insulin requirements, which is associated with less weight gain. In the “Consensus on Insulin Treatment in T2DM” published by the Consensus and Clinical Guidelines Working Group of the Spanish Society of Diabetes (SED), it is recommended to continue treatment with metformin, dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors), GLP-1 RAs, and/or sodium-glucose cotransporter-2 inhibitors (SGLT-2 inhibitors) and consider stopping or reducing sulfonylurea/meglitinide treatment to decrease the risk of hypoglycemia and pioglitazone due to the increased risk of heart failure associated with this combination (5).

The main action of basal insulin is to reduce excessive hepatic glucose production and decrease overnight and between-meal hyperglycemia (3). Initial doses can be estimated based on body weight (0.1 to 0.2 U/kg/day) and the degree of hyperglycemia (for an HbA1c >8%, 0.2 to 0.3 U/kg/day may be considered), with individualized titration during the first few days or weeks (4). Special attention should be paid to the pharmacokinetic and pharmacodynamic profiles of available insulins, and the dose and timing should be adapted to each individual’s needs. Numerous insulin formulations are available, and therapy advances aim to better mimic physiological patterns (3). Scientific evidence indicates that the use of long-acting insulin analogs such as detemir, glargine U100-U300, or degludec is preferable to human insulins with protamine like neutral protamine Hagedorn (NPH) insulin due to their lower risk of hypoglycemia and greater flexibility in administration timing (3).

When using insulin in patients with T2DM, awareness of the potential risk of overt basalization is crucial. Clinical signs that may indicate overt basalization include a basal dose exceeding 0.5 U/kg/day, a significant difference (>50 mg/dL) between nighttime and basal glucose, the presence of hypoglycemia, and elevated glycemic variability. If a situation of overt basalization is identified, the patient should be reassessed to further individualize therapy (3).

Many people with T2DM may eventually need prandial insulin in addition to basal insulin to achieve glycemic goals. If the individual is not yet on treatment with a GLP-1 RAs, initiating it before prandial insulin should be considered to minimize the risks of hypoglycemia and weight gain associated with intensive insulin therapy (3). For those who ultimately require prandial insulin, it is a safe approach to initiate treatment with a dose of 4 units or 10% of the basal insulin amount at the most important meal, with higher carbohydrate content, or the one with the greatest glycemic excursion. The prandial insulin regimen should be subsequently adjusted according to individual needs.

For most patients receiving insulin, aiming for an HbA1c of 7% to 7.5% is recommended, but glycemic goals should be individualized. In addition to HbA1c, insulin titration requires the use of multiple glycemic parameters, including fasting glucose, pre-meal or 1.5-2-hour postprandial glucose, and, when available, continuous glucose monitoring (CGM) data including time in range (TIR), time below range (TBR), and glucose management indicator (GMI) (28). In general, fasting and pre-meal glucose targets should be <110 mg/dl without hypoglycemia, and postprandial glucose targets should be <180 mg/dl, although they should be individualized based on comorbidities and each person’s clinical status (27). If available, the use of CGM in people treated with insulin is recommended to optimize glycemic control and minimize hypoglycemia (28).

Insulin therapy remains the cornerstone of treatment for many individuals with T2DM. However, more recent therapies have emerged to circumvent some undesirable effects associated with its use. Consequently, insulin treatment is sometimes reserved for patients with a longer disease duration or when other non-insulin therapies prove unsuccessful. Moreover, the effectiveness of insulin treatment depends significantly on its appropriate use, the careful selection of patients, training in dose adjustment based on intake, activity, or weight, and proper dose titration to achieve acceptable and safe glucose levels (29). The primary advantage of insulin use lies in its effectiveness across a wide range of patients and various glycemic control targets (30).

Nevertheless, there are still various barriers to initiating insulin treatment in individuals with T2DM, which are detailed below ( Table 2 ).

The development of insulin formulations has been constant in recent years, with notable advances such as insulin purification to reduce antibody production and allergic reactions, changes in basal insulins to delay absorption and cover 24-hour needs with a single injection, and adjustments in prandial insulins to accelerate absorption and better control postprandial hyperglycemia (42). Clinical guidelines suggest early use of GLP-1 RAs and SGLT-2 inhibitors, in combination with metformin, irrespective of the initial HbA1c, due to their cardiovascular benefits and preservation of renal function (3, 4). Despite improvements in treatment and glucose monitoring, only 55.8% in the United States (43) and 56% in Spain (44) achieve glycemic goals. Therefore, insulin will be necessary for many patients as complementary therapy to achieve and maintain glycemic targets.

This article has outlined various barriers to initiating insulin therapy, including the need for subcutaneous administration of one or more injections per day, weight gain, and various psychosocial factors complicating patients’ adoption of insulin therapy (45). These barriers, among other factors, contribute to therapeutic inertia in initiating and intensifying insulin treatment and to patients’ non-adherence to insulin therapy (46).

In this regard, the constant evolution of insulin administration tools over the past 100 years has represented a pivotal advancement in the endeavor to overcome these barriers. The use of insulin pens has changed the lives of millions of people who suffer from diabetes as they are safe, simple to use, convenient, efficient, and less painful than conventional vials and syringes (47).

Also, the recent development of weekly-administered insulins, by reducing injection frequency, could contribute to improved adherence to insulin therapy, patients’ quality of life, and better acceptance and satisfaction with treatment. For example, weekly-administered GLP-1 RAs have demonstrated greater efficacy, higher adherence, and greater treatment satisfaction compared to daily-administered agonists (48, 49).

Currently, there are two weekly-administered basal insulins in various stages of clinical development: icodec insulin and BIF basal insulin (insulin efsitora alfa; LY3209590). Icodec insulin is an insulin analog with three amino acid changes compared to human insulin and a 20C fatty acid chain attached to amino acid B29 through a hydrophilic bond. These changes facilitate strong binding to circulating albumin, reduced enzymatic degradation, and attenuated clearance after receptor binding (50). Icodec insulin has been evaluated in various phase 3 studies in patients with T2DM and type 1 diabetes, included in the ONWARDS program (51–56). BIF basal insulin is a fusion protein of an insulin chain with the extended-action IgG Fc fragment (IgG2Fc). This fusion allows for very slow clearance and weekly administration (57). Currently, this insulin has completed phase 2 of clinical development and is entering phase 3. The longer half-life of basal insulins is associated with lower peak-valley fluctuations and potentially lower risk of hypoglycemia, although with a longer time to reach a stable level after initiating or changing doses (58) ( Figure 3 ). A recent meta-analysis of icodec insulin in patients with T2DM, including only the 3 phase 2 studies, showed a significant reduction in HbA1c, albeit of smaller magnitude (-0.20%; 95% CI: -0.33, -0.07%; P=0.002), with an increase in TIR (+6.6%), without a significant increase in hypoglycemia compared to glargine U100 insulin (59). However, the use of weekly insulins has not yet received regulatory approval, and there is a need for real-world studies to demonstrate whether their use facilitates insulinization, improves adherence, and enhances patients’ quality of life.

In summary, while insulin is necessary in T2DM and is an effective and safe therapy, there are still barriers to initiating insulin therapy. The future introduction of weekly-administered basal insulins that reduce injection frequency may help overcome some of these barriers by lessening therapeutic inertia and increasing treatment adherence. These new insulins, by enabling earlier introduction of insulin, could result in an earlier reduction in HbA1c without an increased risk of hypoglycemia and contribute to preventing the onset or progression of chronic diabetes complications.

AS-P: Writing – original draft, Writing – review & editing. AE: Writing – original draft. AB: Writing – original draft. FA-B: Writing – original draft, Writing – review & editing.