The grading system used for recommendations:

The grading system uses A, B, C, or E to show the evidence level that supports each recommendation.

ABSTRACT

Insulin therapy is critical for people with type 1 diabetes (T1D). Although oral antidiabetic drugs (OADs) remain the mainstay of treatment for people with type 2 diabetes (T2D) in the early stages, insulin therapy becomes essential as the disease progresses to sustain life. Whilst there are guidelines and consensus statements from reputed institutions and medical bodies pertaining to diabetes mellitus (DM), there is not a dedicated guideline or consensus statement that is based on an evidence-based grading system that deals exclusively with the “Practical Approach to the Initiation, Titration and Intensification of Insulin Therapy in Adults with Diabetes in the Indian Context”, guiding general physicians and general practitioners. Hence, this consensus statement uses the modified Delphi method.

The Association of Clinical Endocrinologists is a non-profit, non-commercial body registered in India, that serves as a platform for like-minded Endocrinologists who aspire to work for the cause of the science of Diabetes and Endocrinology, its utility and application for the betterment of the health of the people and the country. The authors request the readers to please do not confuse this Association of Clinical Endocrinologists with the American College of Endocrinology/American Association of Clinical Endocrinologists (ACE/AACE) of the United States of America (USA).

Keywords: insulin therapy, diabetes mellitus, hyperglycemia, hypoglycemia, type 1 diabetes (T1D), type 2 diabetes (T2D)

Introduction

Diabetes mellitus (DM) is a chronic disease that affects 537 million people worldwide [1]. Globally, 150–200 million individuals depend on insulin, but this number is probably underestimated [2]. Insulin therapy is critical for people with type 1 diabetes (T1D). Although oral antidiabetic drugs (OADs) remain the mainstay of treatment for people with type 2 diabetes (T2D) in the early stages, insulin therapy becomes essential as the disease progresses to sustain life [3]. In India, it is estimated that approximately 4 out of every 10 people with T2D use insulin, either alone or in combination with OADs [4].

Rationale

The vast majority of the people with DM are managed by general practitioners and family physicians, most of them practicing in areas with less-than-ideal healthcare facilities in India. Whilst there are guidelines and consensus statements from reputed institutions and medical bodies pertaining to DM, there is not a dedicated guideline or consensus statement that deals exclusively with the “Practical Approach to the Initiation, Titration and Intensification of Insulin Therapy in Adults with Diabetes in the Indian Context”, guiding general physicians and general practitioners. Hence, this consensus statement uses the modified Delphi method.

Methodology

The current analysis used a three-step modified Delphi method to establish the consensus. Delphi approaches are organized group communication methods where professionals assess complicated issues with inadequate and ambiguous knowledge through an iterative procedure. The distinguishing characteristic is that each new questionnaire includes the aggregated group responses from earlier ones, allowing the experts being questioned to review and, if necessary, revise their conclusion statements [5]. In the last few decades, the Delphi techniques have played a crucial role in the development of best practice guidelines utilizing collective intelligence in situations when research is scarce, ethical, and logistically challenging, or the data is contradictory. However, much variation has been seen in attempts to evaluate the quality standard of Delphi investigations, and the details of the methodology are typically ambiguous [6]. Thorough use of scientific research methods, such as the Delphi Panel approach, enables high-quality, scientific expert surveying [7].

There are many forms of Delphi techniques such as the modified Delphi, policy Delphi, and the real-time Delphi [8].

Modified Delphi method

The modified Delphi technique involves gathering information initially using questionnaires and then conducting a formal in-person meeting, that maximizes the advantages [9].

The insights or expert opinions for the current analysis were sought using a 3-step modified Delphi method to enable members of the Association of Clinical Endocrinologists to pool their knowledge and develop recommendations that would facilitate a general physician or general practitioner to address various challenges and barriers and that may aid in proper utilization of insulin therapy in India.

This modified Delphi method comprised 2 email-based questionnaire rounds followed by a consensus physical meeting to allow direct interaction between the experts in the final round, which allowed panel members to clarify their points from the previous rounds and also present arguments to justify their points of view (Fig. 1).

Figure 1. The Modified Delphi Technique Followed

The initial stage was the development of recommendation statements following a comprehensive literature review using PubMed and other online resources for clinical studies, existing guidelines, review articles, consensus statements, and national and international standards on insulin therapy in adults with diabetes. The relevant data was retrieved and reviewed, recommendation statements were developed and compiled into a Microsoft Excel sheet.

The process of developing the recommendations

Consensus statements by highly reputed medical bodies like the American Diabetes Association (ADA) may not suit the Indian milieu due to a variety of reasons including practicality, affordability and the healthcare ecosystem being completely different in India compared to the Western world. While taking the ADA, National Institute for Health and Care Excellence (NICE), European Association for the Study of Diabetes (EASD), The International Society for Pediatric and Adolescent Diabetes (ISPAD), American Association of Clinical Endocrinologists (AACE) guidelines and other peer-reviewed evidence-based guidelines and consensus statements into consideration, the expert panel comprising 16 practicing Endocrinologists from the Association of Clinical Endocrinologists has drafted new recommendations with specific consideration for the Indian milieu keeping in mind the resources available to the general physician or a general practitioner.

Round 1

The recommendation statements were circulated to the panel members through email along with an explanation of the analysis, objectives, and instructions. The questionnaire was presented in a tabular format with columns beside the statements for addition of responses. The experts had to choose “Yes” for “Agree” or” “No” for “Disagree” for each statement and were free to add comments and suggestions in the specified column if required. Anonymity of the answers and comments was maintained all through the process. Statements with at least 80% agreement were considered to have reached concordance and those that did not reach concordance were modified as per the panel’s inputs and recirculated in Round 2.

Round 2

The statements that did not reach concordance in Round 1 were circulated among the experts by email. The responses were collected and analyzed in the same manner as in Round 1. Statements not reaching 80% concordance were retained for discussion in Round 3. In the current analysis, 19 statements did not reach 80% concordance which were brought for further discussion to Round 3.

Round 3

Round 3 was a direct interaction round among the experts in person with one member acting as the facilitator in a physical meeting. The panelists were encouraged to discuss the statements until an agreement was reached to modify, eliminate, or retain the statement in the recommendations.

Statistical methods

The responses obtained for each statement were subjected to descriptive statistics, i.e., percentage of response to each consensus statement. 80% agreement for each consensus statement was considered as a standard to be included as a recommendation and statements that did not achieve 80% agreement were recirculated for further discussion and were accepted with iterations.

In the current analysis, of 214 recommendation statements circulated through email in Round 1, 80% concordance was achieved for 195 recommendation statements. Therefore, the remaining 19 recommendations were recirculated in Round 2 but, could not achieve 80% concordance. Hence, a Round 3, physical meeting was conducted with the experts to resolve and obtain consensus on these 19 recommendations, along with all other recommendations.

Need for insulin

Insulin therapy is crucial for people with T1D because the hallmark of the condition, the beta-cell function is nearly absent or diminished. Insulinopenia can cause hyperglycemia, tissue catabolism, hypertriglyceridemia, ketoacidosis, and other metabolic disturbances. For the first six or seven decades following the discovery of insulin, severe metabolic decompensation was avoided with once- or twice-daily injections. However, over the past three decades, evidence has shown that a more intensive insulin regimen, such as multiple daily insulin injections (MDI) or continuous subcutaneous insulin infusion (CSII) via an insulin pump, offers the best compromise between effectiveness and safety for people with T1D [10]. The Diabetes Control and Complications Trial (DCCT) demonstrated that MDI of intensive therapy with short-acting (regular) and intermediate-acting human insulins or CSII decreased glycated hemoglobin (HbA1c) and were linked to better long-term outcomes [11].

People with T2D who fail to achieve or maintain HbA1c levels over time, even with multiple OADs, will eventually require insulin therapy [12]. However, it is equally crucial to make sure that insulin is started right away once the best combinations of OADs have failed to control blood glucose levels.

Healthcare providers (HCPs) should refrain from using insulin as a threat, a sign of failure, or a punishment, and instead should regularly and objectively explain to people the progressive nature of T2D. Educating to self-titrate insulin doses based on blood glucose monitoring (BGM) improves glycemic control in people with T2D who are initiated on insulin [13]. Structured comprehensive education on diet, hypoglycemia prevention and treatment, self-monitoring of blood glucose (SMBG), and other topics are crucial in any person using insulin [10].

Most guidelines advise people with high HbA1c levels at the time of presentation to begin short-term insulin therapy as soon as possible [10, 14, 15]. According to landmark trials from the previous decade, intensive glycemic control should be practiced in the early stages of diabetes, preferably within the first four years of diagnosis [16]. The traditional practice of delaying insulin therapy until a sustained inability of dietary changes and oral medications to achieve glycemic control has been changed in the past ten years to include insulin therapy much earlier, frequently in conjunction with OADs or glucagon-like peptide 1 receptor agonists (GLP-1RA). In people with T2D, the decision to use injectable therapy is influenced by clinical, pharmacological, and psychosocial factors [14]. In the Indian context, it is also important to consider factors like price, quality, cold chain maintenance, and ongoing availability of insulin preparations and delivery devices [14].

Indications of insulin

Some of the indications of insulin include people with T1D, newly diagnosed T2D with HbA1c > 10%, or catabolic/osmotic symptoms, when oral antidiabetic medications are contraindicated or failed to achieve goals, and need for flexible therapy, in persons with acute illness or surgery, pregnancy, glucose toxicity [3].

Recommendations

Indications of insulin

Classification of insulins

Based on their molecular structure, insulins are classified as human insulins and insulin analogs (Fig. 2) [3]. The insulin that is currently used is recombinant insulin, which is either directly derived from native human insulin or created by structurally altering the amino acid sequence of the insulin molecule (insulin analog). The main differences between human insulin and insulin analogs are in the pharmacokinetic parameters and propensity for adverse effects. When regular human insulin is injected subcutaneously (SC), it takes some time for it to break down into its monomer form and enter the bloodstream. Because of this, regular human insulin frequently fails to control postprandial glycemic excursions and tends to result in delayed hypoglycemia. The use of insulin analogs and their combinations significantly reduces these issues [17].

Figure 2. Classification of Insulin (Adapted from [10])

DNA — deoxyribonucleic acid; IDegAsp — insulin degludec + insulin aspart

There are three characteristics of insulin that are relevant in clinical use [18]:

Human insulins

Human insulins are manufactured by using recombinant deoxyribonucleic acid (DNA) technology. Human insulins are classified as [3]:

The onset, peak, and duration of action of different kinds of human insulins are summarized in Table 1.

Insulin analogs

Insulin analogs were developed by modifying the amino acid sequence for better management of fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) levels with minimal hypoglycemic risk. Based on their pharmacokinetic characteristics, insulin analogs are classified as rapid-acting insulin analogs (RAA), long-acting insulins (LAA) analogs, ultra-long-acting insulin analogs (ULAA), and pre-mix analog preparations [10].

The onset, peak, and duration of different kinds of analog insulin are summarized in Table 2.

Insulin regimens

Initiating and titrating insulins in people with T1D

It is of paramount importance to acknowledge that the choice of insulin regimen and the initiation, titration, and intensification doses of any insulin regimen instituted for any person with diabetes are based on multiple factors including the type of diabetes, HbA1c, current blood glucose readings, age, body weight, pregnancy and lactation, comorbidities, concurrent medication use, hypoglycemia risk, knowledge and skills of the HCP, the person’s lifestyle, awareness, affordability and choices of the person and the limitations of the healthcare system [10, 19]. The insulin regimens and doses suggested in this guideline for initiation, titration, and intensification are a rough guide only and due clinical discretion of the HCP is mandatory whilst individualizing insulin treatment.

Basal-bolus regimen (BBR) is the most preferable regimen in people with T1D [22]. Insulin regimens should be customized to the individual’s age, general health, lifestyle, treatment objectives, hypoglycemia awareness status, medication adherence, and ability to self-manage. Social and economic factors should also be considered [10].

Basal insulin dosage is estimated based on weight and is normally initiated at 0.1 to 0.2 units/kg body weight/day [10] and then up-titrated based on glycemic values, with typical doses ranging from 0.2 to 1.0 units/kg body weight/day. Short-acting insulins should be added for PPG control [13, 15]. Patient education programs such as dose adjustment for normal eating (DAFNE) which enable those with T1D to understand the principles of carbohydrate (CHO) counting and self-adjust insulin doses need to be encouraged [23]. Premix insulin regimens are sub-optimal but can be used where a person with T1D prefers these over BBR [10].

Initiating and titrating insulins in people with T2D

The initial regimen of insulin therapy is based on the person’s age, clinical features, glucose profile, risk of hypoglycemia, cost, and person’s preference. Either basal insulin or premix insulin can be considered as an initial insulin regimen in people with T2D [12]. When FPG is high, consider initiating insulin therapy with basal insulin. When both FPG and PPG are high, one may consider initiating insulin therapy with premix insulin [10]. BBR is the initial insulin regimen in acutely unwell and hospitalized people with T2D, women with T2D planning pregnancy when other regimens do not achieve optimal glycemic control, and in people with challenging lifestyles [15]. Analog insulins may be preferred over human insulins as they possibly reduce the risk of hypoglycemia and are flexible to use [10]. However, economic considerations must be taken into account.

Structured education and training should be provided for all insulin users regarding storage, administration, SMBG/continuous glucose monitoring (CGM), dose adjustment, hypoglycemia prevention, and treatment strategies. Concordance with insulin usage should be evaluated at regular intervals [10].

Insulin doses should be titrated regularly at least once a week, but more frequently if required [24]. FPG levels and PPG levels should be aimed at 80–130 mg/dL and 140–180 mg/dL respectively in the majority of people with T2D [24, 25]. These targets can be individualized, based upon the risk of hypoglycemia and the need for glycemic control. Initially, titration should be done to control FPG, followed by PPG for prandial insulin with the highest glycemic fluctuation, in a sequential order [25].

Insulin intensification should not be delayed for individuals not meeting treatment goals. Therapy intensification is recommended for those whose HbA1c is still uncontrolled following basal insulin introduction and titration [10]. The advantages and disadvantages of various insulin regimens are discussed below in Table 3 [26].

Recommendations

Insulin therapy in people with T1D

Insulin initiation in people with T2D

Insulin titration in people with T2D

Simplifying insulin initiation in the context of Indian realities

Since T2D is a progressive condition, most people will eventually require treatment intensification. This generally entails gradually introducing a new glucose-lowering medication or moving to a more complex insulin regimen [27]. Complex treatment regimens may be more physiological and flexible but might result in an increased risk of hypoglycemia and a high treatment load, which can have a poor influence on both therapeutic adherence and overall quality of life (QoL). Treatment simplification strives to decrease individual treatment burdens while maintaining therapeutic efficacy and safety. Although there is evidence that simplifying insulin treatment can result in efficient glycemic control without jeopardizing therapeutic efficacy or safety, it is not commonly implemented in clinical practice [27].

The term “simplification” is seen to be the most appropriate to describe reducing the number of insulin injections (including termination) and modifying the treatment plan to each individual’s circumstances. Therefore, individuals with T2D who are on a complex insulin therapy regimen should be assessed frequently and insulin regimen simplification should be considered with the goal of improving clinical outcomes like risk of hypoglycemia and QoL [10, 27].

Barriers to insulin initiation

Even though the majority of practitioners consider the start of insulin therapy to be crucial to the management of T2D, many view it as the “last option” and report that their patients are hesitant to accept this treatment [28]. The unwillingness to initiate insulin therapy might be due to physician-related, patient-related, or system-related barriers [28].

Physician-related barriers may include their lack of knowledge of updated guidelines, experience of insulin therapy, beliefs and attitudes towards insulin and diabetes management, side effects of insulin therapy (e.g., hypoglycemia and weight gain), and perceptions of patients’ attitudes towards insulin therapy (patient’s adherence, and wish to prolong non-insulin therapy) [29].

Patient-related barriers include fear of needle and injection phobia, hypoglycemia and weight gain, negative effects of therapy on occupation and social life, the difficulty of administering injections, perceptions of personal failure in self-management, and the effectiveness of therapy [29].

System-related barriers include limited access to education, limited training of providers in injection techniques, overburdened workload among providers, and poor adherence [30].

Recommendations

Basal insulin regimen

Basal insulin includes human NPH insulin, LAA, ULAA, and also continuous RAA insulin delivery via an insulin pump [10]. Basal insulin regulates hepatic glucose production by maintaining a steady quantity of insulin in the background [24]. Presently, the Indian market offers NPH, glargine U100 and U300, detemir, and insulin degludec. Basal insulin analogs have a longer duration of action with flatter, more constant plasma concentrations and activity profiles than NPH insulin [10]. LAA, such as glargine is currently the most widely used basal insulin after NPH. LAA is followed by the ULAA basal insulin analogs, such as insulin degludec and U300 glargine [10].

ULAA has documented a lower incidence of overall and nocturnal hypoglycemia, a longer duration of action, and a stable profile in comparison to LAA basal insulin analogs (glargine and detemir). Despite offering an equivalent level of glycemic control, LAA basal insulin analogs have been found to have a lower risk of hypoglycemia than NPH insulin [31]. Advantages of ULAA such as U300 glargine and degludec include a flat peakless profile, low variability, once-daily (OD) dosing, variable time of administration, and a reduced risk of nocturnal hypoglycemia [24].

Initiation of basal insulins

It is recommended to initiate basal insulin dosage at 6–8 units/day or 0.1 to 0.2 units/kg body weight/day if HbA1c is ≤ 8% and 8–10 units/day or 0.2 to 0.3 units/kg body weight/day if HbA1c is > 8% (Fig. 3) [32]. Lower and higher doses [33] than these may be needed based on individual clinical case scenarios.

Figure 3. Steps for Initiation, Titration, and Intensification of Basal Insulin

*If not on antidiabetic agents like GLP-1RA, SGLT-2i, DPP4i consider these agents; **See Figure 5 for titration of bolus insulin; ***Total basal + bolus dose if converted from basal plus regimen; #Premix/co-formulation

BG — blood glucose; BBR — basal-bolus regimen; DPP4i — dipeptidyl peptidase-4 inhibitors; GLP-1RA — glucagon-like peptide 1 receptor agonist; FPG — fasting plasma glucose; HbA1c — glycated hemoglobin; , SGLT-2i — sodium glucose co-transporter 2 inhibitors; TDD — total daily dose

Titration

The active titration period is defined as the time period when the physician adjusts the basal insulin dose. This period usually lasts up to 12 weeks after starting insulin therapy. Ideally, the maximum reduction in HbA1c and FPG should be achieved by week 12 after starting insulin therapy, and a minimal reduction should be seen after 12 weeks [34].

The recommended target for titration is FPG of 80–130 mg/dL usually. It is recommended to titrate the dose at least once a week, but more frequently based on FPG [24, 25]. The dose can be modified based on the lowest/mean value of the three most recent FPG values [24]. The dose may be reduced by at least 20% for individuals reporting hypoglycemia (< 70mg/dL) [32] unless there is an identifiable and modifiable one-off cause for that episode of hypoglycemia. Insulin therapy should be intensified, in case they fail to achieve glycemic goals even after optimal dose titration. In the Indian context, this regimen may be a simple and effective method for most people. Where possible, the insulin dose can also be titrated 2 units every 3 days [24, 32]. Upon titration, if FPG is 80–130 mg/dL, no adjustments are recommended. If FPG is 131–160 mg/dL, 161–200 mg/dL, ≥ 201 mg/dL it is recommended to increase the basal dose by 2 units, 4 units, and 6 units respectively [24, 32]. Consider reviewing other OADs and GLP-1RA, during the titration if these haven’t been optimized already.

If the glycemic goals are not met after optimizing OADs, either add 1 prandial insulin before the largest meal at 4 units or 0.1 units/kg body weight, whichever is less, i.e., change to the basal plus regimen, or opt for premix/co-formulation insulin twice daily (BID) (at breakfast and dinner) and divide the current basal dose into 60% at breakfast and 40% at dinner [24]. If the glycemic goals are not met by premix or co-formulation insulin BID, change to premix/co-formulation insulin thrice daily (TID) (breakfast, lunch, and dinner). If the glycemic goals are still not met, consider switching to BBR [10].

Recommendations

Premix regimen

Once daily premix/co-formulation insulin regimen

Premix insulin therapy is appropriate for people who are unable to calculate CHOs or have constant eating patterns and a predictable lifestyle. To attain the target HbA1c values, insulin therapy can be started with premix insulin OD and then intensified to BID or TID [35].

Premix insulins are indicated in people with T2D who did not attain glycemic targets with OADs or basal/basal plus insulin, and people with T1D (need to initiate with at least BID premix) [35].

If HbA1c ≤ 8, OD premix insulin can be initiated at 6–8 units with the largest meal of the day.

The recommended target for titration is a pre-meal value of 80–130 mg/dL [24, 32]. The dose can be titrated at least once a week, but more frequently based on pre-dinner or pre-breakfast values [34]. It is recommended to modify the dose based on the lowest/mean value of the three most recent pre-breakfast/pre-dinner glucose values [34]. Premix analogs can be given immediately before or after the meal, while human premix insulins need to be given 30 minutes before the meal [20]. For individuals reporting hypoglycemia (< 70 mg/dL), it is recommended to reduce the dose by 20% unless there is an identifiable and modifiable one-off cause for that episode of hypoglycemia [10, 32]. Premix analog insulins/co-formulations have a lower risk of hypoglycemia, and better safety, flexibility, and convenience compared to human premix or co-formulation [10].

Breakfast dose adjustments are titrated based on pre-dinner values. No dose adjustments are recommended if the pre-dinner values are ≤ 140 mg/dL. If pre-dinner values are between 141–180 mg/dL, can increase the dosage by 2 units. It is recommended to increase the dosage by 4 units and 6 units if the pre-dinner values are between 181–220 mg/dL and ≥ 221 mg/dL respectively.

Dinner dose adjustments are titrated based on pre-breakfast values. No dose adjustments are recommended if the FPG values are between 80–130 mg/dL. If FPG values are between 131–160 mg/dL, it is recommended to increase the dosage by 2 units. It is recommended to increase the dosage by 4 units and 6 units if the FPG values are between 161–200 mg/dL and ≥ 201 mg/dL respectively.

Recommendations

Twice daily premix/co-formulation insulin regimen

When BID premix/co-formulation is necessary and insulin is initiated in an insulin-naïve person, it is recommended to initiate BID premix/co-formulation at 12–16 units or higher doses and divide the total daily dose (TDD) as 60% at breakfast and 40% at dinner.

The recommended target for titration is a pre-meal value of 80–130 mg/dL. It is recommended to titrate the dose at least once a week, but more frequently based on pre-dinner and pre-breakfast values [24]. The dose can be modified based on the lowest/mean value of the three most recent pre-breakfast/pre-dinner glucose values. It is recommended to reduce the dose by 20% for individuals reporting hypoglycemia (< 70 mg/dL) unless there is an identifiable and modifiable one-off cause for that episode of hypoglycemia [10, 24].

Breakfast dose adjustments are made based on pre-dinner values. No dose adjustments are recommended if the pre-dinner values are ≤ 140 mg/dL. If pre-dinner values are between 141–180 mg/dL, one may increase the breakfast dosage by 2 units. It is recommended to increase the dosage by 4 units and 6 units if the pre-dinner values are between 181–220 mg/dL and ≥ 221 mg/dL respectively.

Dinner dose adjustments are titrated based on pre-breakfast values. No dose adjustments are recommended if the FPG values are between 80–130 mg/dL. If FPG values are between 131–160 mg/dL, it is recommended to increase the dosage by 2 units. It is recommended to increase the dosage by 4 units and 6 units if the FPG values are between 161–200 mg/dL and ≥ 201 mg/dL respectively.

If the glycemic targets are not met and the target HbA1c is not reached even after 3 months, one may intensify premix/co-formulation from OD to BID and BID to TID. While intensifying from OD to BID, it is recommended to increase the TDD by 10% and split it into 60% at breakfast and 40% at dinner, and keep it titrating till glucose values are achieved.

Recommendations

Thrice daily premix/co-formulation insulin regimen

While intensifying from BID to TID, if pre-dinner values are above target, one may initiate 4–6 units at lunch and reduce the morning dose by 10% [35]. Whenever TID premix is considered, it is recommended to prefer 50/50 over 30/70 premix insulin (Fig. 4) [14].

Figure 4. Steps for Initiation, Titration, and Intensification of Premix/Co-Formulation Insulin

When BID changed to TID consider changing 30/70 premix to 50/50 premix

**Breakfast insulin dosage is adjusted based on pre-lunch glucose values; lunch insulin dosage is adjusted based on pre-dinner values; and dinner isulin dosage is adjusted based on FPG values; #Premix/co-formulation

BG — blood glucose; BBR — basal-bolus regimen; BID — twice-daily; FPG — fasting plasma glucose; HbA1c — glycated hemoglobin; OD — once-daily; T2D — type 2 diabetes; TDD — total daily dose; TID — thrice-daily

The recommended target for titration is a pre-meal target of 80–130 mg/dL. For titrating TID premix/co-formulation, breakfast insulin dosage is adjusted based on pre-lunch glucose values, lunch insulin dosage is adjusted based on pre-dinner values, and dinner insulin dosage is adjusted on FPG values [24].

It is recommended to titrate the dose at least once a week, or more frequently based on fasting, pre-lunch, and pre-dinner values. The dose can be modified based on the lowest/mean value of the three most recent pre-breakfast/pre-lunch/pre-dinner values [24].

Recommendations

Basal plus insulin regimen

A “basal plus” method is the addition of a single prandial insulin injection to the already used basal regimen before the main meal or the meal commensurate with the highest PPG [36]. This regimen has proven to be an effective way to intensify insulin therapy before implementing a full BBR or in lieu of BBR [10, 14, 32]. Careful patient evaluation and scheduling are necessary due to the complicated nature of this regimen. This regimen is best suited for those with T1D and T2D who are younger, extremely motivated, energetic, and have diverse eating habits [37]. Basal plus regimen is a step-by-step approach to basal insulin intensification that can lead to BBR prescription if necessary.

This can be initiated by starting a short-acting insulin at a dose of 4 units or 0.1 unit/kg body weight (whichever is lower), with the main meal of the day, while continuing the existing basal insulin [10].

The recommended target for basal dose titration is FPG of 80–130 mg/dL. The prandial insulin dose is recommended to be titrated once a week, but more frequently if required, based on the 2-hour PPG value [24]. For individuals reporting hypoglycemia (< 70 mg/dL), it is recommended to reduce the dose by at least 20% [10, 32].

Recommendations

Basal-bolus regimen

Basal-bolus regimen is used when basal insulin alone does not achieve target glycemic control. It almost replicates the natural production of insulin by the pancreas. A long-acting insulin is used as basal insulin to control fasting/pre-meal glucose and short-acting insulin as bolus is administered with each meal to control PPG excursions. To achieve the desired level of glycemic control with this regimen, frequent and active SMBG, understanding of the insulin-CHO ratio and correction factors, and titration of the insulin are required [37].

BBR is indicated in people who fail to achieve glycemic targets with basal/basal plus/premix/co-formulation insulin regimens with or without OADs, people with T1D, [10] secondary diabetes, and those with frequent hypoglycemia with premix/co-formulation insulins.

To initiate this regimen in insulin naïve people, it is recommended to calculate the total insulin dose as 0.5 units/kg body weight for people with T1D [38] and 0.2–0.3 units/kg body weight for people with T2D [32]. It is recommended to divide TDD into 40% as basal insu­lin given usually at bedtime and 60% as prandial insulin divided into 3 doses at each meal.

To initiate this regimen in people switching from other insulin regimens (basal/basal plus/premix/co-formulation), an increase in TDD by 10% may be considered and then, divide TDD into 40% as basal insulin given usually at bedtime and 60% as prandial insulin divided into 3 doses at each meal (Fig. 5).

Figure 5. Steps for Initiation, Titration, and Intensification of Basal-Bolus Insulin

The recommended target for titration of the prandial component is a 2-hour PPG value of ≤ 180 mg/dL. The recommended target for titration of basal components is a FPG value of 80–130 mg/dL. It is recommended to titrate the dose at least once a week, or more frequently based on FPG and PPG values for basal and bolus insulins respectively [24].

It is recommended to address the FPG first, this is typically best accomplished with a bedtime basal insulin dosage (‘Fix Fasting First’) [39].

It is recommended to modify the dose based on the lowest/mean value of the three most recent FPG values [24]. A lower starting dose, slower titration, and higher glucose targets may be recommended for those people at higher risk of hypoglycemia.

The TDD of basal and/or prandial insulin can be reduced by 20% if the blood glucose level is consistently < 70 mg/dL. FPG and PPG readings are considered for dose adjustments so that basal and prandial insulins are adjusted accordingly.

While titrating basal insulin, no dose adjustments are recommended if the FPG levels are between 80–130 mg/dL. If the FPG values are between 131–160 mg/dL, it is recommended to increase the dosage by 2 units, and if FPG values are between 161–200 mg/dL and ≥ 201 mg/dL, increase the dosage by 4 units and 6 units respectively.

While titrating prandial insulin, no dose adjustments are recommended if the 2h PPG levels are ≤ 180 mg/dL. If the PPG values are between 181–200 mg/dL, it is recommended to increase the dosage by 1–2 units. It is recommended to increase the dosage by 2–3 units and 3–4 units if the PPG values are between 201–220 mg/dL and ≥ 221 mg/dL respectively.

Recommendations

Insulin injection technique

Insulin must be administered properly into the appropriate tissue. Although insulin therapy remains the cornerstone of diabetes management, the skill of injecting insulin is not properly understood by many users and even some HCPs. A proper insulin injection technique should consider appropriate injection sites in the body, injection technique, rotating injection sites, caring of injection sites, and avoiding intramuscular (IM) insulin administration [40].

Insulin delivery devices

Insulin syringes were the most popular method for delivering SC insulin. The capacity and type of the syringe is chosen based on the dose and concentration of insulin [40]. Other things to consider when choosing an insulin syringe are needle gauge and needle length, as larger needles increase the risk of IM injections [40].

Insulin syringes may be utilized for insulin delivery considering individual and carer preferences, insulin type, dosage regimen, cost, and dexterity. It is advised not to draw insulin with syringes from insulin cartridges/penfills/pens. The best suggested needle length for an insulin syringe is 6 mm [40]. Needles longer than 6 mm for adults or teenagers are not advisable.

Glass syringes should be replaced with plastic fixed-needle syringes that have less dead space and are intended for single use [41]. Many people reuse insulin needles for a variety of reasons, including cost considerations [40]. The manufacturers do not advise this, as there is a link between lipohypertrophy (LH) and needle reuse. The reuse of needles triggers more pain at the injection site.

Insulin pens are prefilled cartridges of insulin that are devised to make injections easier and more flexible. They eliminate the need to extract insulin from a vial; they may be especially beneficial for insulin delivery when away from home, at school, or on a holiday. While using a pen, it is recommended to count from 1 to 10 before removing the needle, to allow time for any air bubble in the cartridge to expand [19]. Wherever possible, usage of insulin pens is recommended over syringes due to convenience, accuracy of dosage, and safety reasons [42].

There are two main categories of insulin pens: disposable and durable. Disposable insulin pens are prefilled with insulin and are thrown away once they are empty [40]. Insulin pens are only permitted for single-person usage. Individuals should never share their insulin pen cartridges with others so as to avoid the risk of biological contamination in the pen cartridges even if a new needle is used [40].

Insulin pens may be considered as a better option than syringes for people with vision impairment or dexterity issues, children, and elderly people to ease the administration of accurate insulin doses. A 4 mm needle is recommended to be used with pens [40]. When compared to the traditional vial/syringe, the scale on insulin pens is simpler to read.

Disposal

Proper disposal of used insulin vials and syringes is mandatory [15, 19]. Ideally, they should be disposed off in sharps containers that have been carefully labeled and are available for sale in pharmacies and a few diabetes centers. Ideally, the needle may be taken out and rendered unusable using specialized needle clippers (like a safe clip) [19]. Syringes with removed needles can be disposed off in tins or opaque plastic containers [19]. People with diabetes and their family members who improperly dispose sharp objects are at risk of needle-stick injuries among themselves, domestic waste handlers, and the community [43]. HCPs ought to take responsibility for educating people about proper disposal and spreading awareness about it. In case of unavailability of sharp bins, needles should be gathered in a sturdy cardboard or glass container, or used soft drink tin, sealed and marked, and sent to the nearest healthcare facility.

According to a research study in New Delhi, 84.1% of people with diabetes put sharps right into their residential garbage containers [44]. The results of a recent worldwide injection technique questionnaire (ITQ) study, which included 7.6% of subjects from India, revealed that a significant amount of used sharps still end up in household garbage [45]. Improper disposal techniques resulted in sharps injuries in the community in 8.6% of the overall population [45].

Insulin concentrations

Insulins are available in the strengths of U40 and U100 concentrations in India. U100 means 100 units of insulin in 1 mL. U200 and U300 insulins are also available, but exclusively in the form of a pen. To minimize dosage problems, it is mandatory to use a U40 syringe for U40 insulin and a U100 syringe for U100 insulin vials [40].

Intravenous (IV) syringes should never be used for insulin delivery [40]. The date of opening the vial should be recorded with a black/marker pen, and it should be utilized usually within 28 days [46].

Most of the concentrated insulins, such as lispro U200, regular insulin U200, and regular insulin U500, were developed to overcome severe insulin resistance and satisfy the demands of a substantial supply of insulin. Concentrated U300 basal insulin glargine offers the advantages of low injection volume leading to less pain, low variability, and lesser risk of overall hypoglycemia, including nocturnal hypoglycemia, and can be prescribed as an alternative to U100 basal insulin [47].

Injection sites

The abdomen, thigh, and buttocks were suggested as the most common injection sites [10]. After the insulin has been injected, the person should count slowly till 10 and then withdraw the needle from the skin [3]. Insulin administration through SC tissue is most often employed in ambulatory persons. Additional methods include IV infusion which is only used in cases of DKA, HHS, when insulin administration is indicated in a nothing-by-mouth (NBM) scenario, in the emergency and intensive care unit (ICU) setting, to name a few [40]. IM insulin is almost never advised, due to erratic absorption, and risk of hypoglycemia and may be rarely considered in exceptional circumstances only [48].

Injection site rotation

Injections should be switched between sites systematically to maintain a healthy injection site so as to improve insulin absorption and lower the risk of LH [40]. LH occurs when there is an accumulation of SC fat at the injection site as a result of insulin’s adipogenic effects [40]. LH can cause irregular insulin absorption, increased glycemic variability, and unexplained hypoglycemia episodes. It manifests as soft or rubbery fatty swellings at the site of repeated insulin injections [40].

An alternative efficient strategy to rotate the injection site is to split the injection site into quadrants (abdomen) or halves (thighs, and buttocks). After using one quadrant or half for a week, switch to the next one in either a clockwise or an anticlockwise direction. Adolescents should use the abdominal area most often [40].

The distance between the new injection site and the previous injection site should be at least 1 cm [48]. Avoid injecting in areas with infections, edema, or LH. Injection sites should be examined by the HCPs at least once a year and preferably at every visit [48]. Education regarding correct injection site rotation and how to spot and stay away from areas of LH should be provided to individuals and/or their carers [48].

Needle length

Ideally, a 6 mm needle should be used with syringes and a 4 mm needle should be used with pens [40, 43]. In teenagers or adults who are slender to normal weight, a syringe needle injection should always be administered into a raised skinfold at 90° [40].

Ideally insulin needle should be used only once. If reusing the needle is intended, which is not ideal, it must be thoroughly recapped after each use. The needle should never be cleaned or washed and needles should be changed after a maximum of 3–4 uses, to avoid needle infection [3]. It is recommended to follow the correct site rotation policy.

Storage and transport

Insulin should preferably be stored in a cool (< 30°C) and dark environment, as per the manufacturer’s recommendations [40]. The ideal temperature for transporting insulin should be between 2 and 8°C [3]. Insulin vials can be kept in a pot with sand if refrigeration is not available [49].

Insulins’ potency and efficiency can be diminished when they are exposed to direct sunlight or high temperatures. Excessive agitation should be avoided to avoid potency loss, clumping, frosting, or precipitation. As a result, it is crucial to maintain the temperature while transporting [40, 49].

If refrigeration is not available, insulin should be kept cool for example, in an earthenware pot of water (inside a ziplock plastic bag), thermos flasks, or ice bags. Various unconventional methods of insulin storage include pot-in–pot refrigerators or the Zeer pot, mud pots, goat skin pots filled with water, vegetable gourds filled with water, and buckets filled with wet sand [50]. Regular insulin should not be used if it appears hazy. Cloudy insulin should not be used if it cannot be re-suspended [40, 49]. Regardless of where it is kept, opened insulin has a shelf life of 28 days and it needs to be discarded after that [46]. Before administering insulin, it should be taken out of the refrigerator and allowed to reach room temperature. ‘Never freeze insulins’ is the dictum [3, 40].

Insulin stability

Used vials can be stored in a clean plastic box and out of direct sunlight for six weeks at room temperature (20–25°C), or four weeks if the temperature rises to 30°C. Insulin can degrade or be converted to larger molecular weight components if it is stored at higher temperatures [43]. According to Pendsey et al., the insulin that has not been refrigerated may be thermostable for up to two months, and in some cases up to four months [51].

The steps for using an insulin syringe and vial

Recommendations

Insulin delivery devices

Insulin concentrations and strength

Insulin transport and storage

Injection sites

Injection site rotation

Needle length

Needle stick injuries

Disposal of needles

Hypoglycemia

Hypoglycemia is a major challenging event during the glycemic management of a person with diabetes. Level 1 hypoglycemia is termed when blood glucose is ≥ 54 mg/dL and < 70 mg/dL. Level 2 hypoglycemia is when the blood glucose is < 54 mg/dL and level 3 hypoglycemia is when a severe incident is defined by changed mental or physical status needing help for treatment of hypoglycemia (Fig. 6) [52].

Figure 6. Classification of Hypoglycemia (Adapted from [52])

Hypoglycemia symptoms include shakiness, anger, disorientation, tachycardia, and hunger. For people with diabetes, hypoglycemia symptoms can be uncomfortable or scary. Hypoglycemia at level 3 might result in unconsciousness, seizures, coma, or even death. At each visit, doctors should assess the person’s risk of hypoglycemia, especially if they are on insulin [53].

It is worth considering insulin analogs for managing blood glucose in people with T1D or T2D who frequently experience severe hypoglycemia with human insulin [54]. People who experience frequent episodes of hypoglycemia require periodic SMBG (3 times or more per day) or CGM. Additional suggestions include checking the injection site often (irregular absorption can cause hypoglycemia), adjusting the insulin dose before and after activity, and making sure a CHO supplement and glucometer are readily available [25]. Compared to previously established basal analogs (detemir and glargine U100), ULAA basal analogs (degludec, and glargine U300), have more physiological basal profiles and fewer risks of nocturnal and overall hypoglycemia [10]. It is important to advise people to report to their doctor about episodes of hypoglycemia.

Management of hypoglycemia

The management of hypoglycemia is summarized in Figure 7. Most episodes of hypoglycemia can be self-treated by ingestion of glucose or CHO-containing juices, soft drinks, candy, other snacks, or a meal. A good amount of CHOs (15–20 g) can be given again in 15–20 minutes if necessary [55]. Since the glycemic response to oral glucose is transient, it is often advised to consume a larger snack or meal soon after the plasma glucose level is corrected to the normal range with oral glucose. When a hypoglycemic person is unable to consume CHOs orally, or in case of severe hypoglycemia, IV glucose or glucagon injection IM or SC is necessary [52].

Fast-acting CHOs should be given to people when their blood glucose falls below the normal range, which is < 70 mg/dL. Although pure glucose ingestion is preferred to correct hypoglycemia, any form of CHO that contains glucose is recommended to raise blood glucose levels rapidly [52].

When someone is unable or unwilling to take glucose or foods orally, hypoglycemia can be treated using glucagon injection IM or SC. Both the person and their caretakers (family members, roommates, school personnel, childcare providers, institution staff, or co-workers, etc.), should be primed about the usage of glucagon which includes glucagon storage and how to give it [52].

For treating hypoglycemia with IV glucose, the use of 5%, 10%, or 25% glucose solutions is preferable over the use of 50% glucose, because, the use of hyperosmolar solutions increases the risk of extravasation damage [56].

In order to reduce hypoglycemia, education on hypoglycemia avoidance, re-evaluation, and treatment regimen adjustments should be made [52]. Precipitating causes need to be investigated at the earliest opportunity and appropriately managed. Education about hypoglycemia prevention and treatment should be part and parcel of every visit of the person by the doctor [55].

Impaired awareness of hypoglycemia

Impaired awareness of hypoglycemia (IAH) is a common side effect of insulin treatment. Around 50% of insulin-treated people with T1D and T2D exhibit hypoglycemia unawareness, and 15–25% have a persistent IAH [57]. Identifying or recognizing a hypoglycemic event by the person is the first step in making HCPs aware of hypoglycemia [58].

Less stringent blood glucose targets, such as a three-month duration without hypoglycemia, as well as instruction on a CSII and CGM, are advised to lower the risk of developing severe hypoglycemia and to try to regain hypoglycemic consciousness [59].

Recommendations

Blood glucose monitoring

Individual glucose monitoring is a valuable tool for the self-management of diabetes, which allows people to evaluate their individual response to therapy and assess whether glycemic targets are being safely achieved. It also provides guidance on dietary changes, physical activity, and medication modification, especially for insulin users. It can help people to improve glucose control, reduce hypoglycemia, and boost self-efficacy [42]. Monitoring blood glucose levels and identifying trends will enable prompt and appropriate modifications to insulin dose, dietary intake, and physical activity management which are the most crucial components of diabetes care. To identify these trends, tools like SMBG using glucometers and CGM can be used [60]. Where glucometers are not available for the individuals due to any reason, at least lab glucose checks are recommended in lieu of glucometer checks.

Self-monitoring of blood glucose

Self-monitoring of blood glucose is the simplest and may be the most useful technique for evaluating the efficacy and safety of glycemic management. SMBG refers to the monitoring and recording of blood glucose levels throughout the day by the person and/or caretaker at home or in a healthcare center [61]. The measured blood glucose levels assist individuals and clinicians in planning proper lifestyle (diet, exercise, and medication) changes.

To ensure that data is used effectively and quickly, both the person with diabetes and the HCPs must examine and analyze data that is recorded using a glucometer. People with diabetes should be educated on how to use BGM data to modify their dietary intake, physical activity levels, or drug therapy to achieve specific goals [61]. Proactive control of diabetes with SMBG can enhance therapeutic results and lower morbidity and mortality [62].

Figure 7. Management of Hypoglycemia (Adapted from [55])

*1 mg IM/SC glucagon injection is a useful alternative to treat hypoglycemia. Monitor for rebound hyperglycemia in T2D after glucagon injection. Review antidiabetic medications and triggers of hypoglycemia

BG — blood glucose; CGM — continuous glucose monitoring; IM — intramuscular; IV — intravenous; SC — subcutaneous; T2D — type 2 diabetes

Continuous glucose monitoring

A CGM predicts blood glucose levels by monitoring the concentration of glucose in the interstitial fluid using a sensor implanted directly beneath the skin [63]. Time in range (TIR) is a useful metric of CGM for glycemic control and glucose patterns, and it correlates well with HbA1c [64]. However, people using CGM devices must have access to a glucometer at all times [42]. The guidance on CGM targets for the assessment of glycemic control among various groups is discussed in Table 4.

The worldwide agreement on TIR offers recommendations for common CGM measurements (Fig. 8) and things to keep in mind when using them in clinical interpretation and treatment [65]. Time above range (TAR) and time below range (TBR) are additional helpful metrics for adjusting insulin doses and re-evaluating the treatment strategy. According to the most recent advanced technologies and treatments for diabetes (ATTD) international TIR consensus 2019, most people with T2D should aim to spend > 70% of their time per day (approx. > 17 h) in TIR (70–180 mg/dL), < 4% in TBR (< 70 mg/dL) and < 25% of the time per day in TAR (> 180 mg/dL) [66].

BGM and CGM can help manage medications, guide medical nutrition treatment, encourage physical activity, and prevent hypoglycemia [42]. The CGM measures TIR (including TAR and TBR) and gives insights for a more individualized diabetes treatment plan [64]. These indicators are now being incorporated into clinical practice.

In those who can afford, the use of CGM devices should be considered as soon as diabetes is diagnosed and insulin therapy is initiated [67]. This relieves the strain of regular BGM and enables close monitoring of glucose levels with adjustments to insulin dose and lifestyle changes.

CGMs are classified into two types based on data type: “real-time” and “flash.” Real-time CGMs (rtCGM) send glucose readings every 1–5 minutes over Bluetooth to a chosen receiver, mobile, or insulin pump. Flash CGMs, also known as intermittently scanned CGMs (isCGM) record glucose concentrations every 1–15 minutes, but downloads the data only to the designated reader when the user “flashes” the near field communication tag, at a point where the past 8 hours of data is retrieved [63].

Professional CGMs are CGM devices that are attached to a person with diabetes at the doctor’s clinic under remote control and worn for a specific amount of time (generally 7–14 days). The data is utilized to evaluate glycemic trends and patterns. Unlike rtCGM and isCGM devices, these are clinic-based and are not owned by the people [42].

Recommendations

Insulin pump

CSII commonly known as insulin pumps are devices that deliver RAA throughout the day in order to regulate blood glucose levels. A CSII or insulin pump attempts to replicate pancreatic activity [68].

Factors to take into account when starting pump therapy in people with diabetes include affordability, assessment of the person’s and their family’s readiness, selection of the pump type and initial pump settings, individual/family education on potential pump complications, transition from BBR, and introduction of advanced pump settings [42].

Insulin pumps are safe and efficient in young people with T1D to achieve their desired glycemic results while lowering their risk of hypoglycemia and DKA, enhancing their QoL, and avoiding long-term consequences [42].

CSII, an alternative to BBR, has been linked to better long-term results in intensive insulin treatment for T2D glycemic control [69]. Adults with severe hypoglycemia were less likely to experience severe episodes while receiving CSII through pump treatment.

Recommendations

Intravenous insulin infusion

Intravenous insulin infusion is useful in people who are critically ill, in hyperglycemic emergencies, those with uncontrolled hyperglycemia on SC insulin regimens, and during the perioperative phase, people with NBM status or during labor [17]. There are no absolute contraindications to using IV insulin infusion, and the important precaution to take is to avoid hypoglycemia. Hypokalemia is a potential problem during usage of IV insulin; hence serum potassium levels need to be monitored and replaced appropriately. IV insulin has a rapid onset of action and a very short half-life, allowing its dose to be easily titrated in response to changing blood glucose levels [17].

In hospitalized people, insulin is the quickest and most effective medication for attaining glycemic control.

Indications of IV insulin

The majority of hospitalized people, with and without serious illnesses should maintain a blood glucose target of 140–180 mg/dL. In cases where a lower target of 110–140 mg/dL may be achieved without causing significant hypoglycemia, such tight glucose targets may be considered [70]. On the other hand, for terminally ill people, people with significant comorbidities, and people in situations where frequent BGM is not practical or if one is concerned about hypoglycemia, one may accept a target of < 250 mg/dL [70]. Less severe insulin regimens are more suitable in these people to reduce glucosuria, dehydration, and electrolyte abnormalities. The use of a sliding scale SC insulin regimen is strongly discouraged in the inpatient hospital setting [70].

Ideally, BBR is the treatment of choice in non-ICU hospital settings. For the majority of noncritically ill hospitalized people who receive appropriate nourishment, an insulin regimen including basal, prandial, and correction components is the optimal course of treatment. Usually, all OADs have to be stopped and insulin is initiated at a very low threshold in hospitalized people. Few selective DPP4i may be continued where appropriate considering other comorbidities [70].

Transition from intravenous to subcutaneous insulin

A transition procedure is advised when stopping IV insulin since it is linked to decreased morbidity [70]. It may be appropriate to consider administering a person with T1D or T2D, a dose of SC basal insulin 2 hours before transitioning from an IV infusion to an SC regimen due to the short half-life of IV insulin and the delayed onset of action of SC basal insulin. Initiating SC basal insulin before stopping an IV insulin may help reduce hyperglycemia [71]. The insulin dosage is best determined based on the insulin infusion rate during the last 6 hours when stable glycemic objectives were met [72]. Usually, the last 6 hours’ IV insulin administered is multiplied by 4 to get the total SC insulin that is required over 24 hours. Of the total calculated daily SC insulin requirement, 40% is given as basal SC injection, and the rest 60% is divided into three doses of bolus SC insulin injections over a span of 24 hours. Whilst calculating this, other factors such as the IV fluids that were being administered such as IV dextrose, any inotropes, or corticosteroids that were being administered, need to be taken into consideration. There needs to be an overlap of 30 minutes of IV insulin, after SC bolus insulin is given while transitioning from IV to SC insulins [17].

Hypoglycemia is a crucial consequence that has to be minimized during hospitalization due to dysregulated metabolism and/or diabetes treatment. Each hospital should thus establish and put into practice a hypoglycemia prevention and management plan. If a person’s blood glucose level is < 70 mg/dL, a standardized hospital-wide, hypoglycemia treatment strategy ought to be in place [73]. Additionally, every person should have their unique strategy created for both avoiding and managing hypoglycemia [74].

Recommendations

Insulin therapy in special populations

Pregnancy

All women of reproductive age with diabetes should be advised about the necessity of reaching and maintaining euglycemia as safely as possible prior to conception and throughout pregnancy. Family planning should be discussed, and effective contraception advice should be provided until a woman’s treatment regimen and HbA1c are optimal for pregnancy. Preconception counselling should emphasize the significance of obtaining glucose levels as near normal levels as safely achievable, preferably HbA1c < 6.5%, to lower the risk of congenital abnormalities, preeclampsia, macrosomia, premature birth, and other problems [74].

Prior to pregnancy, all drugs that are risky in pregnancy should be discontinued, including OADs [74]. When corticosteroids are used in pregnancy for fetal lung maturation or any other indication, BGM and proactive optimization of glycemic control using insulin are mandatory [75]. Insulin is the drug of choice for treating hyperglycemia in pregnancy [3, 74]. Metformin can be used in certain circumstances where clinically appropriate [3].

While GDM is the primary cause of hyperglycemia found in pregnancy, preexisting T1D and T2D account for most of the remaining [25]. Glucose targets for pregnant women with diabetes are FPG < 95 mg/dL, 1-hour PPG < 140 mg/dL, and 2-hour PPG < 120 mg/dL, whilst avoiding hypoglycemia. HbA1c should be used as a supplementary indicator of glycemic control during pregnancy [74]. CGM when used in conjunction with pre and postprandial BGM, aids in the achievement of glycemic control in GDM [74].

It is recommended to initiate insulin along with lifestyle changes if nutrition treatment or a meal plan fails to help women with GDM achieve their blood glucose goals, usually within two weeks of starting them [76]. As insulin does not cross the placenta significantly, it is the preferred medication for treating hyperglycemia in GDM. When compared to regular in-person treatment alone, telehealth consultations in addition, for pregnant women with GDM may enhance outcomes [74]. Both insulin aspart and insulin lispro have been demonstrated to be safe and effective for usage during pregnancy [77]. BBR or insulin pump technologies can be used for T1D-complicated pregnancy. BBR is the regimen of choice; however, a premix regimen can be considered in a resource-constrained setting. Information on available insulin analogs and associated pregnancy categories are summarized in Table 5.

Insulin is the drug of choice for people with preexisting T1D and T2D in pregnancy as it does not cross the placenta, in significant quantity. Structured education about the prevention, detection, and treatment of hypoglycemia is vital before, during, and after pregnancy, in people with diabetes and their family members [74]. In a meta-analysis of three available RAA (insulin lispro, aspart, and glulisine, respectively) in pregnant women with T1D or GDM, insulin lispro, and insulin aspart were found to be safe and effective for both mother and fetus, with glycemic control at least as good as with regular human insulin [78]. Women with diabetes planning pregnancy or who have become pregnant should be counselled on the risk of development and/or progression of diabetic retinopathy [74].

Frequent SMBG is necessary to guide the treatment of GDM. To achieve ideal glycemic targets, ADA recommends performing SMBG four times daily, (one fasting and 3 tests post breakfast, post lunch, and post dinner) in both GDM and pre-existing T1D and T2D. However, individuals with pre-existing T1D or T2D should monitor their blood glucose levels pre-prandial also, i.e., seven tests each day, (one fasting, three before and three after each meal) [74].

CGM, when used in conjunction with pre and post-meal BGM, can aid in achieving the glucose targets in pregnant women with diabetes. rtCGM when used in addition to BGM, helps to lessen macrosomia and newborn hypoglycemia in pregnancies complicated by T1D. It is not recommended to utilize standard estimates of HbA1c or glucose control indicator calculations during pregnancy [74].

Insulin resistance decreases significantly, immediately after childbirth. Hence, insulin requirements must be monitored carefully and insulin doses should be reduced in those with pre-existing DM or even stopped in those with GDM [74].

For mothers with prior GDM, breastfeeding lowers their chance of acquiring T2D [74]. A change in insulin dosage may be necessary since nursing might cause nocturnal hypoglycemia.

Breastfeeding women should be encouraged to follow an individualized diet. It is important to ensure that women with diabetes previously treated with insulin, understand that they are more likely to have hypoglycemia in the postpartum period, particularly if they are breastfeeding, and encourage them to have a snack between meals.

Recommendations

the risk of development and/or progression of diabetic retinopathy. B

I. Glucose targets for pregnant women with diabetes are FPG < 95 mg/dL, 1-hour PPG < 140 mg/dL, and 2-hour PPG < 120 mg/dL, whilst avoiding hypoglycemia. B

J. HbA1c is slightly lower in pregnancy; the ideal target in pregnancy is < 6% if it can be achieved without significant hypoglycemia. The target may be relaxed to < 7% in certain cases to prevent hypoglycemia. B

K. HbA1c targets in diabetes and pregnancy can be facilitated by CGM. B

L. Insulin is the drug of choice for treating hyperglycemia in GDM. Metformin can be used in certain circumstances where clinically appropriate. A

M. All insulins can be used in pregnancy. However, class B insulins are preferred over class C, class D. C

N. Regular insulin or RAA may be used in women with preexisting diabetes to improve PPG. B

O. BBR is the regimen of choice. However, premix can be considered in resource-constrained settings. B

P. In a pregnancy complicated by T1D, either BBR or insulin pump technology can be recommended. A

Q. When corticosteroids are used in pregnancy for fetal lung maturation or any other indication, BGM and proactive optimization of glycemic control using insulin is mandatory. E

R. In women with diabetes poorly controlled on BBR, consider initiation of CSII, ideally at preconception. A

S. An ideal SMBG would be seven tests each day, one fasting, three before and three after each meal. If this is not possible, encourage one fasting test, and three tests, that are performed daily two hours after breakfast, lunch, and dinner. C

T. Insulin resistance lowers significantly immediately following delivery, and insulin requirements must be monitored and reduced or stopped as appropriate in the postpartum period. C

U. Educate women with insulin-treated pre-existing diabetes about their higher risk of hypoglycemia in the postpartum period, particularly while breastfeeding, and advise them to have a snack between meals. B

Elderly

Diabetes is a highly heterogeneous condition and a major health concern among the elderly. Regular evaluations of the medical, psychological, functional, and social domains are necessary for managing diabetes in older persons [80]. When evaluating older persons who have diabetes, it is crucial to correctly classify the type of diabetes, as well as other elements including its duration, the presence of complications, other comorbidities, and treatment-related concerns like hypoglycemia and anxiety. Screening for diabetes complications in older persons should be tailored to each individual and repeated regularly as the findings of screening tests may influence targets and treatment methods [80].

Episodes of hypoglycemia should be identified and treated during every visit. Older persons are more likely to have hypoglycemia for a variety of reasons, including insulin deficiency, which necessitates insulin treatment, and growing renal insufficiency. CGM is advised for older people with T1D and T2D to lessen hypoglycemia and to enhance glycemic outcomes and reduce glucose variability [80].

Elderly adults with no coexisting chronic illnesses as well as unimpaired cognitive function and a good functional status may aim for stringent glycemic goals (HbA1c < 7.0–7.5%) if achievable without hypoglycemia. Older adults with multiple coexisting chronic illnesses, cognitive impairment, or functional dependence should have less stringent goals (HbA1c < 8.0%). Glycemic targets may be reduced for the elderly as part of individualized therapy [80].

It is important to avoid overtreating elderly persons with diabetes. It is advised that complex treatment regimens (particularly insulin) are simplified to lower the risk of hypoglycemia and for convenience. Polypharmacy needs to be avoided, wherever feasible, to reduce pill burden, drug interactions, and cost [80].

The usage of pens over syringes and analog insulins over human insulin needs to be considered for safety, flexibility, and convenience in the geriatric population. Telemedicine consultations offer convenience and continuity of care for diabetes, especially for the elderly, similar to pregnancy. Costs of care need to be considered when designing treatment plans, to limit cost-related obstacles to adherence [80].

Recommendations

Insulin therapy during fasting

Many people with diabetes fast for religious reasons, increasing the risk of severe hypoglycemia. Insulin resistance/deficiency during fasting might result in excessive glycogen breakdown and increased gluconeogenesis [81]. When using insulin therapy during religious fasting, the person must be informed about the hazards associated with fasting, made familiar with SMBG, follow the recommended diet, engage in safe exercise, and modify their insulin doses accordingly [82]. People with T2D on intensive insulin therapy should be advised to refrain from fasting.

Individuals with a history of DKA, recurrent hypoglycemia, hypoglycemic unawareness, people on complex insulin regimes, people with end-organ damage, individuals with suboptimal glycemic control, pregnant and lactating women, people with T1D, and elderly individuals should be discouraged from fasting [82]. Individualized physician recommendations for changing the dose and timing of insulin injections during the fasting interval should be followed.

During fasting, frequent SMBG or CGM is indicated to reduce the risk of hypoglycemia and detect episodes of hyperglycemia. Planning meals with low glycemic index CHOs that include fruits, vegetables, and lean meats is necessary during fasting days. Sweets, sweetened beverages, and fried meals should be avoided [83].

CHO counting during meals assists in optimizing the dosage of insulin administration. During non-fasting hours, it is recommended to stay hydrated by sipping water and other non-sweetened beverages frequently. If hypoglycemia develops, the person should be advised to break the fast immediately, irrespective of the time [83]. Structured patient education about BGM, nutritional advice, exercise advice, medication dosage and timing, adjustments, symptoms of complications, and how to treat them is recommended [83].

Recommendations

Sick day management

Sickness is frequently associated with elevated blood glucose levels and an increased risk of ketoacidosis in those with T1D and others with DM who are insulin-dependent [49]. Insulin requirement increases significantly during acute sickness which eventually requires increased frequency of BGM. Depending on their glucose levels, people may require RAA, every 2 to 4 hours [25]. Additionally, ketone testing during sickness may aid in the management of individuals suffering from acute vomiting or hyperglycemia. It is critical to recognize the early signs and symptoms of DKA to prevent it [25]. Individuals and/or carers who suspect it should contact their doctor as soon as possible.

During an illness, the following are important to remember in those with T1D and others with DM who are insulin dependent. Check blood glucose levels periodically at least every four hours or more frequently if necessary. If blood glucose levels are consistently high (> 250 mg/dL) or if the person has vomiting, stomach discomfort, or rapid breathing, it is recommended to check for blood or urine ketones [49]. The person should be sent to the hospital right away if they have high ketones (> 17.43 mg/dL)/diarrhea more than three times in 24 hours or a temperature above 101°C for 24 hours [49].

In case of low blood glucose levels, a small dosage of glucagon or consuming CHOs and/or juices regularly is recommended. To maintain adequate calorie intake, drinking more calorie-free liquids, semi-solid meals, and beverages, such as thin soups, milk, buttermilk, or fresh lime juice, should be encouraged [49]. However, individuals should be encouraged to eat normally if they can tolerate it. Insulin doses may be lowered but should not be skipped entirely. Never stop insulin completely, especially basal insulin, as this is a typical error. If in doubt about managing during sick days, it is recommended to seek an expert opinion immediately [49].

Recommendations

Safety precautions for insulin users who drive

Disclaimer: It is strongly advised that individuals with diabetes should strictly adhere to the law of the land and follow their clinician’s advice. These recommendations here are only a guide made based on the best available clinical evidence and consensus of the Association of Clinical Endocrinologists group.

The ability to drive safely in people with diabetes may be hampered by its symptoms or consequences, which can affect driving fitness in a variety of ways, including but not limited to hypoglycemia, hyperglycemia, vision impairment, peripheral neuropathy, and other diabetes problems. Furthermore, driving necessitates a high metabolic demand, which may lead to hypoglycemia episodes in individuals with diabetes which might result in driving errors and road traffic accidents [84]. Hence, precautions ought to be taken to protect themselves, co-passengers, and other road users.

People with diabetes should be advised to always have their glucometer, blood glucose strips, or CGM with them. It is recommended to check their blood glucose levels before the trip and for every two hours after they start driving. Frequent testing may be essential if there is a higher risk of hypoglycemia for any reason, such as after physical exercise or a change in meal schedule. If the blood glucose values are ≤ 90 mg/dL, it is recommended to advise them to have a snack. “Never drive if blood glucose is in the hypoglycemic range or if the person feels hypoglycemic” should be the dictum [85].

It is recommended to always maintain an emergency supply of fast-acting CHOs, such as glucose, or sweets, or chocolates, in the vehicle. The person needs to be advised to consume regular meals and snacks and take breaks during long journeys. It is recommended to always avoid alcohol while driving [85].

Recommendations

Alcohol and insulins

People with diabetes who consume alcohol should be advised to avoid or limit alcohol intake [55]. Alcohol intake is associated with risks such as weight gain, hyperglycemia (for those who consume excessive quantities of CHO-rich drinks), and hypoglycemia (especially for those taking insulin or insulin secretagogue therapy) [86].

Individuals with diabetes should be educated about the indications, symptoms, and self-management of delayed hypoglycemia after drinking alcohol, especially spirits, and if they are on insulin or insulin secretagogues [87]. It is also important to emphasize the need of glucose monitoring after consuming alcoholic drinks in order to limit the risk of hypoglycemia [86].

Recommendations

Others

People with both diabetes and hepatic impairment are more likely to be seen in clinical practice as they are at risk of developing non-alcoholic fatty liver disease (NAFLD). NAFLD and T2D frequently coexist, raising the risk of dangerous hepatic and extra-hepatic effects.

Individuals with hepatic impairment who need insulin treatment should select regimens with a reduced risk of hypoglycemia. Insulin analogs should be considered in people with T2D and hepatic impairment for enhanced glycemic control with minimal risk of hypoglycemia [25].

People with diabetes and chronic kidney disease (CKD) have a biphasic pattern in their insulin needs. In the early stages, more insulin is required to establish glycemic control due to insulin resistance, but as advanced renal failure progresses and creatinine clearance falls < 50 mL/min, insulin need decreases or, in extreme cases, insulin may have to be even stopped [88].

CKD risk and progression can be reduced by optimizing blood glucose and regulating blood pressure. All insulins are regarded as safe across the CKD spectrum [25]. However, ultralong and ultrashort-acting insulins are preferred for safety, flexibility, and convenience. Nevertheless, with decreasing estimated glomerular filtration rate (eGFR) readings, insulin dosages in CKD might have to be decreased [89]. Among basal insulins, detemir and glargine appear to be safe and effective and among prandial insulins, both regular insulin and RAA appear to be safe and efficacious [25].

In CKD people with glomerular filtration rate (GFR) between 15–60 mL/min and < 15 mL/min, prompt adjustments with a reduction to 75% and 50% in insulin TDD respectively are often necessary. However, in people with GFR > 60 mL/min, no dose modifications may be needed [25].

People on dialysis are at an increased risk considering glucose fluctuations. It may be required to lower the basal insulin dosage by up to 25% on days of hemodialysis (HD) to avoid hypoglycemia [90]. People undergoing HD are usually advised to avoid short-acting insulins during and immediately before HD [91].

During peritoneal dialysis (PD), insulin may be administered SC, or along with the dialysis fluid. If insulin is administered along with dialysate, an increase of up to 30% may be necessary to minimize the effects of dextrose absorption for the PD fluids and for the loss of tubing and dilution [90]. Hence, the lowest possible dialysate dextrose concentration should be used as a PD fluid as much as possible [92].

Overall, a lacune exists in the literature concerning recommendations for adjusting insulin therapy when initiating HD or PD, or when switching between the two.

The link between insulin and cardiovascular disease (CVD) is complicated. People with diabetes are more likely to develop CVD and its related clinical consequences. Premix insulins are more successful in lowering PPG than basal insulin analogs [15]. The insulin regimen selected should be individualized and based on the severity of hyperglycemia, the risk of hypoglycemia, and the possibility of interventional operations in the near future. If the glycemic objective is not met after adding basal insulin, a basal plus/premix regimen should be explored before moving on to a BBR [25].

People with T2D who are receiving combination treatment with premix insulin analogs and OADs should be closely evaluated for signs and symptoms of heart failure (HF), weight gain, and edema, and quick clinical intervention is advised if cardiac symptoms worsen [15]. Wherever appropriate, concomitant SGLT2i and/or GLP-1RA use along with insulins helps reduce the TDD of insulin, lessen weight gain and hypoglycemic episodes.

An acceptable step-by-step method for the management of late PTDM is lifestyle change followed by OADs and insulin. People with acute post-transplant hyperglycemia, however, should be managed in the opposite order from how it appears above [25]. Insulin is the drug of choice for the management of hyperglycemia, PTDM [10]. During the initial few months following transplantation, insulin treatment should be favored [25].

In general, less than 1% of individuals who receive immunotherapy develop new-onset DM [25]. Insulin is recommended as the preferred treatment for these individuals [25].

GIH and glucocorticoid-induced diabetes are linked to higher rates of mortality and morbidity and may have exacerbated long-term microvascular and macrovascular risks. The co-existence of inflammatory disorders and GIH further increases the risk of CVD. The coronavirus disease 2019 (COVID-19) pandemic has increased the clinical importance of glucocorticoid treatment by increasing the number of hospital admissions for acute viral infection. It has been demonstrated that COVID-19 increases the incidence of hyperglycemia and is linked to greater incidences of DKA, HHS, and new-onset diabetes. All patients undergoing high-dose glucocorticoid medication should have BGM for at least 48 hours after cessation of glucocorticoid treatment, and SC insulin therapy should be initiated as needed. The type of glucocorticoid and duration of action must be considered in determining insulin treatment regimens. For individuals who are on higher doses of glucocorticoids, an increase in the dosage of prandial and correctional insulin may be needed in addition to basal insulin [93]. The dose of correctional insulin is based on the dose of the administered glucocorticoid and the weight of the person [94].

Recommendations

Future of insulins

The use of insulin therapy is crucial in the management of DM. SC injection is still the most common method for administering insulin. However, because of the short half-life of insulin, a person must endure many injections throughout the day to effectively regulate their blood glucose levels. This results in significant inconvenience and low compliance. Numerous initiatives have been attempted to enhance insulin administration, including the development of non-invasive routes, which mainly include buccal, oral, pulmonary, nasal, and transdermal systems [95]. We are expecting the launch of newer insulins in India soon which are already available in the USA and Europe but not yet available in India.

On the other side, “biosimilar” refers to a protein molecule that is a perfect duplicate of already-existing insulin with the same amino acid sequence (except for small alterations in therapeutically relevant components) and no appreciable differences in efficacy and safety [15].

The advantage of biosimilar insulins is their low cost which makes them affordable for the majority. However, immunogenicity is a concern [96]. When switching from one kind of insulin to another insulin that are identical (biosimilar), it is recommended to carry out a dosage titration, always starting with a lower dose and up-titrating it to minimize hypoglycemia, with BGM [15].

Article information

Data availability statement

The initial stage was the development of recommendation statements following a comprehensive literature review using PubMed and other online resources for clinical studies, existing guidelines, review articles, consensus statements, and national and international standards on insulin therapy in adults with diabetes. The relevant data was retrieved and reviewed, recommendation statements were developed and compiled into a Microsoft Excel sheet.

While taking the American Diabetes Association (ADA), National Institute for Health and Care Excellence (NICE), European Association for the Study of Diabetes (EASD), The International Society for Pediatric and Adolescent Diabetes (ISPAD), American Association of Clinical Endocrinologists (AACE) guidelines and other peer-reviewed evidence-based guidelines and consensus statements into consideration, the expert panel comprising 16 practicing endocrinologists from the Association of Clinical Endocrinologists has drafted new recommendations with specific consideration for the Indian milieu keeping in mind the resources available to the general physician or a general practitioner.

Funding

Supported by an unrestricted educational grant from Cipla. Apart from the sponsorship, Cipla had no role in the development of this guideline and their drugs were not/will not be given any preferences.

Authors contributions

Ravi Sankar Erukulapati: prime author; lead of the Consensus Group, coordinated the entire process, drafted recommendation statements for rounds 1, 2, and 3.

Ravi Sankar Erukulapati and Murali Ganguri participated in the drafting of recommendation statements for rounds 1, 2, and 3.

All authors participated in rounds 1, 2, and 3 of modified Delphi process.

All authors participated in writing up the Consensus document.

Editorial assistance from Dr. Subhadra Polisetti, Dr. Satya Parvathi K, and Dr. Vamsi Krishna Kolukula from Medswan Global Healthtech Private Limited.

Acknowledgments

All the members of the Consensus Group are practicing clinicians who have had various professional engagements with numerous pharmaceutical companies across the world over the past several years. Editorial assistance was provided by Dr. Subhadra Polisetti, Dr. Satya Parvathi K, and Dr. Vamsi Krishna Kolukula from Medswan Global Healthtech Private Limited, along with Dr. Santhosh Olety Sathyanarayana.

Conflict of interest

The authors declare no conflict of interest.