Introduction
BE-SMART Expert Opinion
Treatment Initiation
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Timely insulin initiation leads to a long-term reduction in complications and improved outcomes. Clinical evidence from landmark trials such as the Diabetes Control and Complications Trial/Epidemiology of Diabetes Intervention and Complications Study (DCCT/EDIC) and the United Kingdom Prospective Diabetes Study (UKPDS) shows that early glucose control reduces the risk of both macro- and microvascular complications [8, 18]. Studies have shown that targeting postprandial glucose (PPG) can help minimize cardiovascular risk [19, 20].
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“Metabolic karma” is a term that can effectively explain glycemic legacy in diabetes. It helps us to understand the advantages of achieving tight glycemic and metabolic control in persons with diabetes using appropriately individualized patient-centric therapy [21].
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Early insulin initiation can help overcome the glucotoxic effects of hyperglycemia and hence facilitate “β-cell rest” to preserve β-cell mass and function, while also improving insulin sensitivity [22].
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Basal insulin is a convenient and effective option for insulin initiation in the majority of patients if it does not impact post-meal hyperglycemia significantly. Basal insulin should be initiated in a timely manner, preferably within 3–6 months of inadequate control, with the optimal use of 1, 2, or 3 oral glucose-lowering agents (GLA) [12].
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Basal insulin may be initiated at the diagnosis of diabetes if catabolic symptoms are present and/or glycated hemoglobin (HbA1c) is > 10% [13].
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The basal-only regime is the most convenient initial insulin regimen, beginning at 10 U/day or 0.1–0.2 U/kg/day, depending on the degree of hyperglycemia [12].
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In diabetes management, it is crucial that patients are involved in their treatment process. There is a need for open doctor–patient communication to achieve good glycemic control, reduce complications, and improve quality of life. Training of healthcare professionals, persons living with diabetes, and other caregivers as well as teamwork among all stakeholders are crucial to achieving optimal basal insulin use [23, 24].
Timing of Administration
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Basal insulin should be injected at the appropriate time (usually bedtime), in line with the prescribing information.
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Basal insulin may, under some circumstances (e.g., administration by caregivers and nursing home residents), be administered in the morning or afternoon as well, preferably at the same time daily.
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Basal insulin analogues provide the advantage of flexibility of timing, making it simple and less intrusive. They involve only one injection per day and do not require adherence to inflexible meal patterns, quantity, and composition [25].
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Neutral Protamine Hagedorn (NPH) Insulin: With NPH insulin, the preferred injection time is bedtime [26].
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Second-Generation Basal Insulin Analogues (Insulin Degludec and Gla-300): These offer more flexibility in the timing of injection and can be administered at any time in the day, but they have to be administered at the same time each day [29].
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Upon realizing that a dose of basal insulin has been missed, the situation can be redressed by immediately administering the dose while ensuring that there is a gap of at least an 8 h between injections. Once this dose has been taken, the patient can return to their regular dosing schedule.
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In fasting and special populations, the schedule for basal insulin and GLA administration shown in Table 1 should be followed.Table 1Choice of basal insulin and GLAs in special populationsPopulationSpecial concernChoice of BITitrationAdditional GLAsFasting/RamadanHypoglycemiaGla-100/Gla-300/degludecSlowDPP4i/TZD/glipizide/repaglinidePregnancySafetyNPH/Detemir/GlargineEarly titration until targetMetforminElderlyHypoglycemiaGla-100/Gla-300/degludecSlow/weeklyDPP4i/metformin/SU
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Transportation and Storage
Technique of Administration
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Syringes and vials: Disposable plastic insulin syringes are the most widely used devices for insulin injection. Insulin syringes are available with 0.3-, 0.5-, 1-, and 2-ml capacities. Needle length and thickness have been reduced to minimize the pain during the injection and to prevent inadvertent intramuscular administration of insulin.
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Pen needles: Pen needles are available in different lengths: 4, 5, 6, 8, and 12.7 mm. Shorter and thinner needles cause less pain; less penetration force can be applied with thinner needles.
Pre-injection | During injection | Post-injection |
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Convey the benefits of insulin in a positive manner | Do not inject on a tight, blanched, or painful skin fold or bruised or traumatic sites | Release skin fold, if raised, slowly after withdrawing the needle |
Selection of appropriate insulin site, device, needle gauge, and length | Allow topical alcohol to evaporate | Follow correct site rotation policy |
Use a new needle for each injection | Avoid injecting at hair roots | |
Use concentrated insulin if the dose requirement is high | Penetrate the skin quickly | |
Use neutral pH insulin if pain occurs with acidic pH insulin | Do not move the needle immediately after insertion | |
Insulin should preferably be at room temperature as injection of cold insulin is painful |
Targets for Titration
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Titration of the insulin dose is recommended using a treat-to-target approach, wherein the dose can be uptitrated to reach a predefined therapeutic goal in terms of FPG level and HbA1c [36].
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The initial basal insulin dose may be started at 10 U/day or 0.1–0.2 U/kg/day, depending on the degree of hyperglycemia [12]. Starting with a higher dose may be required in persons with a high body mass index, high HbA1c, and longer duration of diabetes or signs of insulin resistance, such as acanthosis nigricans and/or a dorsocervical fat pad.
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The recommended treat-to-target algorithm for the initiation and titration of basal insulin in basal insulin supported by oral GLA therapy is elaborated in Fig. 1.×
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While glycemic targets should be individualized, a FPG level of 100–130 mg/dL (5.6–7.2 mmol/L) and HbA1c ≤ 7.0% are reasonable goals for most adults. Once fasting control has been achieved, oral medication or prandial insulin may be needed to achieve postprandial control. Dietary modification and portion size control is non-negotiable and must be emphasized at all stages of intensification of therapy. Titration, in dose steps of 2–4 units, should be initially performed once to twice a week until optimal control is achieved.
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Titration may be performed in steeper steps if the daily requirement is > 30 U/day.
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The recommended dose adjustments for insulin dose based on the mean or lowest of the three most recent values of FPG are shown in Table 3 [37].Table 3Basal insulin dose adjustment [37]FPG (mg/dL) (mean of the three most recent values)Recommended dose adjustment (once or twice a week)< 80 mg/dL (< 4.4 mmol/L)Reduce dose by 2 units80–130 mg/dL (4.4–7.2 mmol/L)No dose modification131–160 mg/dL (7.27–8.9 mmol/L)Increase dose by 2 units161–180 mg/dL (8.94–10.0 mmol/L)Increase dose by 4 units> 180 mg/dL (> 10.0 mmol/L)Increase dose by 6 units
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For instance, in the INSIGHT study, patient-led titration using simple titration algorithms resulted in greater reductions in HbA1c than physician-led adjustment of oral antidiabetic drugs (control) (− 1.55% vs. − 1.25%, − 17 vs. − 14 mmol/mol, P = 0.005). The study also showed that compared to the control group, patients receiving Gla-100 were 1.68 times more likely to achieve two consecutive HbA1c levels ≤ 6.5%, had lower FPG (P = 0.0001), non-high-density lipoprotein cholesterol (P = 0.02) and triglycerides (P = 0.02), and greater increases in treatment satisfaction (P = 0.045) [38].
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The AT.LANTUS trial compared an investigator-led insulin Gla-100 initiation and titration algorithm to that led by study subjects. It showed that there was a significant reduction in HbA1c (from 8.9 ± 1.3% to 7.8 ± 1.2%), with a greater decrease (P < 0.001) with the study subject-led algorithm (− 1.22%) than the investigator-led algorithm (− 1.08%) [39].
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The Asian Treat to Target Lantus Study (ATLAS) showed that self-titration with Gla-100 was found to statistically significantly lower the mean HbA1c (by 1.40% for self-titration vs. 1.25% for physician-led titration) [40].
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The TAKE CONTROL study evaluated the self-titration and physician-led titration of Gla-300 in people with T2DM. Self-titration was found to statistically significantly lower the mean HbA1c (by 0.97% for self-titration vs. 0.84% for physician-led titration) [40]. Hence, self-titration with both Gla-100 and Gla-300 resulted in significantly improved glycemic control (vs. physician-led titration), without increased hypoglycemia [40].
Tablets
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Among the various GLAs, metformin is the preferred initial therapy (with HbA1c ≥ 6.5% and FPG level ≥ 126 mg/dL). The advantages of including metformin are as follows [41, 42]:
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It is associated with less weight gain (useful in treating obese patients)
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Usage leads to decreased hepatic glucose production, blood pressure, and risk of atherothrombotic disease, thus reducing insulin requirements and blood levels of insulin
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Inclusion of metformin leads to increased hepatic sensitivity to insulin, and it may also have a mild effect on muscular sensitivity to insulin
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When adding sulfonylureas, start the therapy with low-dose sulfonylureas. The dosage can be increased at intervals of 2–4 weeks until the glycemic target is reached [43]. Modern sulfonylureas (glimepiride and gliclazide MR) confer a lower risk of hypoglycemia and are thus preferred over older sulfonylureas such as glibenclamide [44]. Clinical studies on the addition of sulfonylureas to basal insulin yielded the following results:
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Basal insulin + glimepiride: In a 24-week prospective randomized comparative study, basal insulin in addition to glimepiride offered better efficacy, less hypoglycemia, and less weight gain, and significantly reduced the insulin dose required (by 4.01%) [45].
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Basal insulin + metformin + glimepiride: In a 28-week clinical trial, metformin and glimepiride plus insulin glargine resulted in a significant improvement in overall glycemic control as compared to other combinations. The decrease in HbA1c was more pronounced with insulin glargine plus glimepiride plus metformin than with insulin glargine plus metformin (0.49% [CI, 0.16%–0.82%]; P = 0.005) (5.10 mmol/mol [CI, 1.64–8.61]; P = 0.005) and insulin glargine plus glimepiride (0.59% [CI, 0.13%–1.05%]; P = 0.012) (5.87 mmol/mol [CI, 1.10–10.64]; P = 0.012) (overall P = 0.02) [46].
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Regular monitoring is recommended, especially when combining with insulin secretagogues such as sulfonylureas.
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Thiazolidinediones, when combined with insulin, may favor weight gain and fluid retention [47].
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Pioglitazone or rosiglitazone helps reduce PPG levels [48].
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Alpha-glucosidase inhibitors (AGIs) should be considered as the first-line treatment in patients with controlled basal glucose concentrations and marked postprandial hyperglycemia. Mean HbA1c at week 24 was significantly decreased (by 0.7% from baseline) in both acarbose and voglibose patient groups who were previously inadequately controlled with basal insulin [49, 50].
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Sodium-glucose cotransporter 2 (SGLT2) inhibitors may be considered as add-ons to metformin alongside other drugs such as sulfonylureas, dipeptidyl peptidase 4 (DPP-4) inhibitors, thiazolidinedione, and basal insulin. SGLT2 inhibitors are associated with weight loss and do not increase the risk of hypoglycemia. They have potential benefits in terms of weight loss, reduction of blood pressure, improvements in glycemic control without weight gain, and hypoglycemic risks associated with insulin therapy [51].
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DPP-4 inhibitors are weight neutral and not associated with an increased risk of hypoglycemia. DPP-4 inhibitors lower PPG levels by decelerating gastric emptying. They best complement the action of basal insulin on fasting glucose control and help patients with T2DM achieve their target HbA1c [52].
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In general, GLP-1 receptor agonists (GLP-1RAs) should not be discontinued with the initiation of basal insulin. Basal insulin and GLP-1RAs address various defects seen in T2DM physiopathology. Basal insulin plus GLP-1 receptor agonists are associated with less hypoglycemia and with weight loss instead of weight gain. However, they may be less tolerable and come at a greater cost. That said, a fixed ratio combination of GLP-1RA and basal insulin is a potentially helpful tool for the treatment of patients with T2DM as a result of its favorable safety and efficacy profile, especially in obese patients who are uncontrolled on OADs or basal insulin [12, 53].
Tools for Monitoring and Troubleshooting
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Second-generation basal insulin analogues (Gla-300 and degludec) are associated with the lowest risk of hypoglycemia, which can be further reduced by implementing timely therapy initiation, proper patient education, and SMBG. Hypoglycemia and need for monitoring is reduced with BOT as compared with basal bolus [24, 28].
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Regular SMBG is recommended in patients with diabetes on multiple daily insulin injections, with a history of hypoglycemia, and with poor metabolic control with multiple GLAs and/or basal insulin.
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SMBG should be performed at least as often as insulin is administered.
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The ideal SMBG requirement is seven tests/day, i.e., three before and three after each meal and one test at 3 am. As a compromise, one fasting test and three each after breakfast, lunch, and dinner daily may be more feasible as well as acceptable. This can be further individualized to twice or thrice a week in pregnant patients as the pregnancy advances. Two-hour post-meal monitoring may be easier to remember, as this timing is routinely used [4].
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For patients on intensive insulin regimens who are on multiple doses of insulin or on insulin pumps, testing should be carried out three or more times daily (all pre-meals, post-meals, at bedtime, and prior to exercise) [4].
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Some patients may require testing 6–10 (or more) times daily [4].
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Pregnant women with insulin-treated diabetes must be advised to perform SMBG on a daily basis. However, in case of any failure to do so, at least weekly monitoring should be encouraged [4].
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Meal-based testing schemes such as 5- and 7-point regimens and the staggered-frequency regimen can help to show the effect of food consumed on the rise in blood glucose after specific mealtimes [54].
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Monitoring hypoglycemia in patients: Severe hypoglycemia is a common acute complication in people with diabetes being treated with insulin, and its incidence increases with the duration of insulin therapy. A basal insulin switch from conventional to long-acting or to ultra-long-acting preparations may be indicated if a particular insulin cannot be uptitrated due to hypoglycemia or glycemic variability.
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SMBG should be performed in a pragmatic manner. Once-daily FPG and structured 2-h PPG are acceptable SMBG strategies for BOT. Monitoring PPG levels will provide data on the adequacy of the BOT regimen [55].
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Tools for patients: Basal insulin titration and target achievement can be facilitated by the use of modern technology, including ambulatory glucose profiling and online apps. The Hypoglycemia Awareness Questionnaire can be used by patients to monitor glucose level changes and consult with their healthcare providers [56]. Several online apps are available in India, such as mySugr, OnTrack Diabetes, and MyFitnessPal, which patients can conveniently use to manage diabetes [56, 57].
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Risk factors for hypoglycemia can be reduced with the timely initiation of therapy using currently available insulin formulations and technologies (insulin pumps and monitoring) and proper patient education, which should empower physicians to overcome their inertia [24].
Treatment initiation | Begin basal insulin at 10 U/day or 0.1–0.2 U/kg/day, depending on the degree of hyperglycemia |
Timing | Basal insulin should be injected at the appropriate time (usually bedtime) |
Under some circumstances, it may be administered at the same time daily, in the morning or afternoon | |
Transportation and storage | Insulin vials, cartridges, or pens may be kept at room temperature for 28 days to 1 month, depending on the type of insulin. However, in settings where the temperatures can be above 30 °C or below 2 °C, it is not advisable to leave the vials at room temperature |
The cold chain should be maintained during the transportation of the vials or cartridges of insulin | |
Technique of administration | Basal insulin, if injected into intramuscular space, may act like rapid-acting insulin |
The abdomen is the preferred site for soluble human insulin as it leads to the fastest absorption | |
Targets for titration | The initial basal insulin dose may be started at 10 U/day or 0.1–0.2 U/kg/day, depending on the degree of hyperglycemia |
Titration, in steps of 2–4 units, should be initially performed once to twice a week until optimal control is achieved | |
Tablets | In combination with basal insulin: |
- Metformin: Preferred initial therapy (with HbA1c ≥ 6.5% and FPG level ≥ 126 mg/dL) | |
- Sulfonylureas: Preferred agents where cost is a limiting factor. Begin at a low dose, but dosage can be increased at intervals of 2–4 weeks until the glycemic target is reached. Pioglitazone or rosiglitazone help reduce PPG levels | |
- AGIs: Used as the first-line treatment in patients with controlled basal glucose concentrations and marked postprandial hyperglycemia | |
- DPP-4 inhibitors: Weight neutral, not associated with an increased risk of hypoglycemia, and lowers PPG levels by decelerating gastric emptying, thus helping patients with T2DM achieve their target HbA1c levels | |
- SGLT2 inhibitors: Possess potential benefits in terms of renoprotection, cardiovascular risk reduction, weight loss, blood pressure reduction, and improvements in glycemic control without the weight gain and hypoglycemic risks associated with insulin therapy | |
- GLP-1 receptor agonists: Basal insulin plus GLP-1 receptor agonists are associated with less hypoglycemia and with weight loss instead of weight gain, but they may be less tolerable and cost more | |
Tools for monitoring and troubleshooting | Once-daily FPG and strategic 2-h PPG are acceptable SMBG strategies for BOT |
Hypoglycemia Awareness Questionnaire may be used by patients to monitor glucose level changes in consultation with their healthcare providers | |
Online apps, such as mySugr, OnTrack Diabetes, MyFitnessPal, and Diabeto, can be used by patients to manage diabetes and insulin dosing |