RSSDI consensus recommendations on insulin therapy in the management of diabetes
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The Research Society for the Study of Diabetes in India (RSSDI) has regularly updated its Clinical Practice Guidelines on various aspects of diabetes. The pharmacotherapeutic management of diabetes involves a plethora of agents targeting different aetiopathogenic mechanisms administered orally or via injections as well as insulin. While most people with type 1 diabetes need complete insulin replacement therapy with multiple-daily subcutaneous injections of insulin or a continuous subcutaneous insulin infusion pump, patients with type 2 diabetes may also need insulin as and when needed, especially owing to the declining beta cell function due to the progressive nature of their diabetes. To date, various insulin regimens including basal-bolus, split-mixed, premix, and prandial therapy are available which can be individualized based on the patient profile though their prescription is often perceived as complex for management of diabetes, forming a major barrier in the acceptability of insulin. In order to provide physicians with a simple guidance on different aspects of insulin use including choosing the right insulin and regime to match the individual patient, the RSSDI for the first time has formulated this guideline on insulin therapy using simple algorithms for insulin initiation as well as titrations based on a systematic literature search of new clinical evidences on all aspects of insulin use. Insulin therapy is hereby proposed as easy to initiate and maintain, efficacious, and a safer option which when administered appropriately can almost mimic physiological insulin secretion in diabetic patients and help them achieve target glucose control and minimize complications while improving their quality of life.
KeywordsInsulin Diabetes Premix Basal Regular insulin
In 2017, diabetes mellitus has affected 425 million people globally, and without effective prevention and management, the number of people with diabetes is projected to rise to 629 million by 2045 . India has become a diabetes capital of the Southeast Asian region, with an estimated 74 million people, aged 18–99 years, having diabetes and premature mortality of 50.7% (20–79 years) . A population-based cross-sectional study estimating the national prevalence of diabetes and prediabetes in India reported an overall prevalence of 7.3% . In 2019, the TIGHT study by Borgharkar and Das involving 55,639 eligible patients’ records reported uncontrolled glycated hemoglobin (HbA1c) ≥ 7% in nearly 76.6% of patients. Sixty-two percent of these patients had HbA1c between 7 and 8% (53–64 mmol/mol). One-third of the study population had microvascular complications, predominantly neuropathy. Glycemic control from the combination of oral antidiabetic drugs (OADs) with or without insulin varied between 14.2% and 24.8% .
Although OADs remain the mainstay of treatment for early stages of type 2 diabetes mellitus (T2DM), insulin therapy becomes inevitable as the disease advances to sustain life. In India, it is estimated that about 4 of 10 patients with T2DM are using insulin, either alone or in combination with OADs [5, 6]. Proper insulin injection technique is also vital to achieving glycemic control by ensuring appropriate delivery to the subcutaneous tissues and avoiding complications . Nonetheless, insufficient knowledge of insulin use can result in poor acceptance, adherence, and outcome of therapy .
The objective of this report is to develop a consensus for use of insulin therapy in the management of Indian diabetes patients based on critical review of scientific evidence published in peer-reviewed journals and clinical expertise and experience as shared by experts. It will provide an objective snapshot of consensus practices both in type 1 diabetes mellitus (T1DM) and T2DM regarding insulin initiation and titration, parameters to be monitored during therapy, use in special populations, management of adverse effects, and strategies to overcome the various barriers to support adherence to insulin therapy.
A steering committee involving experienced diabetologists and endocrinologists across India across India was constituted by RSSDI. The steering committee deliberated and defined the scope of the recommendations. Four expert panels, each comprising of one steering committee member acting as a coordinator, and several national experts were formed. The panels reviewed all available evidence—national and international—to formulate the recommendations.
All the available scientific literature was reviewed. In paucity of published literature on various aspects, the panel formulated the recommendations on the basis of clinical acumen and experience, judgement, and consensus. These recommendations were then reviewed by the steering committee which was subsequently finalized by the writing group as a draft consensus document.
The Indian evidence published between 1990 and 2019 was used to decide on the analytical re-evaluation of recommendations proposed by RSSDI 2019. The relevant Indian literature was obtained from keyword-based searches of indexed literature including articles published in the International Journal of Diabetes in Developing Countries (IJDDC). Other relevant sources included RSSDI Textbook of Diabetes (third edition), Journal of Association of Physicians of India (JAPI), and the personal experience as shared by authors. In the absence of Indian literature, Asian/global evidence was considered.
Insulin secretion and physiology
Insulin secretion in patients with diabetes
After it was reported by Lang and Bingley that healthy individuals have oscillating plasma insulin levels, patients with T1DM and T2DM were indicated to have an altered pattern of pulsatile insulin release [12, 13]. Patients with T2DM can be characterized by increased insulin resistance with decreased glucose clearance rate, manifesting as a decreased and impaired early-phase insulin secretion while patients with T1DM have an absolute or near absolute deficiency of insulin secretion .
The insulin receptor and mechanism of action
Exogenous insulins and its classifications
Structure and PK details of various insulins
Onset of action
Peak action time
Duration of action
~ 30 min
l-Arginine (stabilising agent) and niacinamide (accelerated initial absorption after SC inj.) have been added
Reversal of amino acid proline at B28 and lysine at B29
~ 15 min
Replacing proline at B 28 with aspartic acid
Replacing asparagine with lysine at B3 and glutamic acid with lysine at B29
~ 55 min
~ 6 h
Isophane insulin; NPH
Neutral protaminated insulin
Up to 24 h
Asparagine replaced with glycine at A21 and two arginine amino acids added at position B31 and B32
4 h (peak not pronounced)
Up to 24 h
Up to 36 h
Myristic acid acylation to the lysine residue on position B-29 and deletion of threonine from B30
3–9 h (peak not pronounced)
Up to 24 h
Deletion of threonine at B30 and addition of 16-carbon fatty acid to lysine at B29 via a γ-l-glutamic acid linker
Up to 48 h
Premixed human insulin
70% isophane insulin and 30% Regular insulin
Human mixtard 50:50
Soluble insulin 50% and isophane insulin 50%
Up to 24 h
Premixed insulin analogues
75% neutral protaminated insulin lispro and 25% insulin lispro
Up to 24 h
50% neutral protaminated insulin lispro and 50% insulin lispro
Up to 24 h
70% protaminated insulin aspart and 30% insulin aspart
Up to 24 h
50% soluble and 50% protamine-crystallised insulin aspart
Up to 16 h
70% insulin degludec and 30% insulin aspart
> 24 h
Each mL contains 100 units insulin glargine and 33 mcg lixisenatide
This fixed ratio has no impact on the PK of IGlar. After SC administration, IGlar showed no pronounced peak and median tmax of lixisenatide was in the range of 2.5 to 3.0 h
Each mL contains 100 units of insulin degludec and 3.6 mg of liraglutide
The PK of IDeglu and liraglutide were not affected when administered as fixed ratio (100/3.6). Steady-state concentrations of IDeglu and liraglutide are reached after 2–3 days of daily administration
Basal insulins (intermediate- and long-acting insulins)
Mechanisms contributing to sustained duration of action for basal insulins
Mechanism contributing to sustained duration of action
Multi-hexamer formation at the site of injection
Insulin degludec/insulin aspart (IDegAsp) is a first soluble co-formulation comprising of both basal and bolus insulin components with favorable PK profile as compared with previously available biphasic insulin preparations. IDegAsp has shown noninferiority in controlling HbA1C as compared with currently available basal and premixed insulins in once- and twice-daily dosing. Additionally, the risk of hypoglycemia is also reduced. The favorable pharmacological profile is seen as offering distinct clinical benefits over the conventional premixed insulin suspensions .
Numerous studies are currently underway that will confirm the efficacy and safety of combining basal insulin to GLP1R agonists. This combination is expected to provide enhanced glycemic control by regulating both fasting and postprandial plasma glucose albeit to a lesser extent. This combination helps promote weight loss and has a lower risk of hypoglycemia (Table 1).
Bolus insulins/rapid-acting/prandial insulins (insulin lispro, insulin aspart, and insulin glulisine)
The rapid-acting insulin was developed to provide more rapid absorption than regular human insulin, thereby reducing postprandial glucose excursions effectively. Four rapid-acting insulin analogs, namely lispro, aspart, glulisine, and FiAsp (faster-acting aspart), have so far been developed and introduced into the clinical practices. These analogs can be administered before meals to mimic the endogenous postprandial insulin surge (Fig. 6). All these analogs were developed by making modifications in the amino acid sequence. These modifications decreased the tendency of insulin chains to form dimers and hexamers, thus increasing their bioavailability .
Premix insulins (including biphasic insulins)
Premixed insulins, consisting of rapid- or short-acting and intermediate- or long-acting insulins, were developed to take care of both the basal and meal-related insulin requirements and, at the same time, reduce the number of daily injections. Indeed, the concept of the ideal formulation to more closely mimic physiological endogenous insulin secretion had not been possible until recently, as the basal insulin could not be mixed with other insulins. Therefore, in premixed insulin preparation, a part of rapid-acting insulin has protamine to convert it to intermediate-acting insulin. This challenge of mixing has been conquered by developing an IDegAsp as the first soluble co-formulation. Biphasic human insulin contains various proportions of insulin with a protamine counterpart. The most commonly available premixed insulins including biphasic human insulin (30% regular human insulin and 70% protamine regular human insulin), biphasic insulin lispro (Humalog Mix25; 75 protaminated/25 normal and Humalog Mix 50; 50 protaminated/50 normal) and biphasic insulin aspart 30 (BIAsp 30; 70 protaminated/30 normal). Compared with human premixed insulins, the biphasic insulin analogs have a more rapid onset of action (5–15 min) with an earlier peak observed in 1–2 h for the first component and a relatively steady second component lasting up to 16 h [25, 26]. These features result in improved PD effect, with clinically favorable biochemical and physiological antihyperglycemic effects in vivo (Fig. 6) .
Choosing the right insulin and individualizing therapy for adults with T1DM
Both basal-bolus injection therapy and CSII are considered the standard of care for patients with T1DM. The insulin regimens should be tailored, taking into account the individual’s age, general health, lifestyle, treatment goals, hypoglycemia awareness status, adherence to treatment, and ability for self-management. Social and financial aspects also should be considered.
Conventional insulin regimen
Summary of clinical evidences for insulin regimens in management of T1DM
De Leeuw et al., 2005
12-month multicentre, open-label, parallel-group study
IDet vs. NPH, with insulin aspart at mealtimes
Total 308 patients (2:1) received insulin detemir or NPH insulin before breakfast and dinner twice daily
• No difference between treatments in terms of HbA(1c), FPG, or 9-point blood glucose profiles
• 32% lower risk of nocturnal hypoglycemia with IDet (p = 0.02)
• Mean BW was lower with IDet vs. NPH (p < 0.001).
Birkeland et al., 2011
16-week, randomized, open-label trial
IDeg(A) vs. IDeg(B) vs. insulin glargine (IGlar), with mealtime insulin aspart
SC injections of IDeg(A) (600 μmol/L; n = 59) vs. IDeg(B) (900 μmol/L; n = 60), vs. insulin glargine (IGlar; n = 59), all given once daily in the evening
• No difference between IDeg(A), IDeg(B), and IGlar in terms of HbA1c (7.8 ± 0.8%, 8.0 ± 1.0%, and 7.6 ± 0.8%), and FPG (8.3 ± 4.0; 8.3 ± 2.8; and 8.9 ± 3.5 mmol/L, respectively)
• Compared with IGlar, risk of hypoglycemia
• 28% lower with IDeg(A) (RR, 0.72 [95% CI 0.52–1.00])
• 10% lower for IDeg(B) (RR, 0.90 [0.65–1.24])
Heise et al., 2012
Randomized single-center, parallel-group, double-blind trial
Insulin degludec (IDeg) vs. insulin glargine (IGlar)
54 subjects underwent a 24-h euglycemic glucose clamp on the 6th, 9th, and 12th days of treatment with 0.4 U/kg of IDeg or IGlar once daily.
• Compared with IGlar, the day-to-day variability in glucose-lowering effect was four times lower with IDeg (AUC (GIR, 0–24 h, SS), CV 20% vs. 82%) and for the last 22 h (AUC (GIR, 2–24 h, SS))
Tricco et al., 2014
Systematic review and network meta-analysis
Review of 39 studies involving 27 RCT and 7496 pts for safety, efficacy and cost-effectiveness of long-acting insulins
• IGlar OD, IDet OD, and IDet OD/BD significantly reduced HbA1c compared with NPH OD (26 RCTs, − 0.39%, 95% CI − 0.59 to − 0.19%; − 0.26%, − 0.48 to − 0.03%; and − 0.36%, − 0.65 to −0.08%; respectively) with less risk of hypoglycemia and weight gain
Laranjeira et al., 2018
Systematic reviews and update existing reviews
LAIAs vs. NPH
11 systematic reviews with 25 trials
• Compared with NPH, LAIAs were more efficacious in reducing
• Nocturnal hypoglycemia episodes (RR 0.66; 95% CI 0.57; 0.76)
• A1C (95% CI 0.23; 0.12)
• No significance was found related to severe hypoglycemia (RR 0.94; 95% CI 0.71; 1.24)
Multiple daily injections or basal-bolus insulin regimen
36-week randomized open-label two-period crossover trial
IGlar vs. NPH with insulin aspart at mealtimes
60 pts received 16 weeks’ treatment with either once-daily IGlar or twice-daily NPH insulin after 4-week run-in
• Compared with NPH, IGlar showed significant reduction in HbA1c (8.07% vs. 8.26%; p = 0.04) and FPG (p = 0.002)
• No differences in hypoglycemia rate (p = 0.63), weight (p = 0.45), or lipid profile (p = 0.18)
• Patient satisfaction was greater with IGlar (DTSQ, p = 0.001)
Prospective treatment, open-label, crossover study
Insulin glulisine alternating with aspart prior to a prescribed breakfast
Thirteen prepubertal children received insulin glulisine alternating with insulin aspart with a fixed amount of carbohydrate (45, 60, or 75 g) for 20 days
• Compared with aspart, mean increase in 2-h PPBG was higher in glulisine (+ 98.6 ± 66.9 vs. + 113.5 ± 65.2 mg/dL; p = 0.01)
• BG remained higher at 4 h (glulisine 141.9 ± 36.5 mg/dL, aspart 129.0 ± 37.0 mg/dL) (p = 0.04).
Yanagisawa et al., 2014
Prospective, open-label, 24-week study
Replacement of short-acting insulin with glulisinealongwithIGlar
In 59 pts (49 T1DM and 10 T2DM) with uncontrolled BG, short-acting insulins [aspart (n = 19), lispro (n = 37) and regular human insulin (n = 3)] were replaced with insulin glulisine
• Switching to glulisine insulin for 24 weeks significantly decreased level of HbA1c, prevented vascular damage, and improved treatment satisfaction
Agesen et al. 2016
2-year investigator-initiated multicentre, prospective, randomized, open, blinded endpoint (PROBE) trial (n = 114)
Reduction of non-severe hypoglycemia events with insulin analogues in patients with recurrent severe hypoglycemia
Using a balanced crossover design, 114 patients were randomized to basal-bolus therapy based on analogue (IDet/Asp) or NPH/regular human insulins
• Analogue-based treatment resulted in a 6% (2–10%; p = 0.0025) overall relative risk reduction of non-severe hypoglycemia
Continuous subcutaneous insulin infusion or insulin pump therapy
A systematic review and meta-analysis
CSII vs. MDIs
Review of 25 RCTs comparing CSII and MDIs for their effect on HbA1c, and hypoglycemic events
• Compared with MDIs, CSII showed significant reduction in HbA1c (MD 0.37; 95 % CI, 0.24–0.51)
The DIAMOND Randomized Trial
CSII vs. continuing MDI in adults using CGM
75 adults using CGM were randomized to CGM plus CSII or CGM + MDI (control) and surveyed at baseline and 28 weeks.
• Compared with controls, CGM + CSII group showed a significant reduction in QoL from baseline (− 0.02 ± 0.05 difference in difference [DiD])
• Total per-person 28-week costs were $8272 (CGM + CSII) vs. $5623 (CGM + MDI)
A meta-analysis of RCTs
CSII vs. MDI
CSII vs. MDI in children with T1DM
• Compared with MDI, CSII showed significantly reduction in HbA1c (p = 0.007)
• No difference between groups in HbA1c change, TDD, TDD change, and incidence of ketoacidosis and severe hypoglycemia
Pragmatic, multicenter, open-label, parallel-group, RCT and economic evaluation
CSII vs. MDI
Start treatment with CSII or MDI within 14 days of diagnosis
No difference between CSII and MDI (60.9 mmol/mol vs. 58.5 mmol/mol, p = 0.09) in achieving HbA1c thresholds
A systematic review and network meta-analysis
Evaluation of closed-loop (CL) systems in the glycemic control
Review of 25 RCTs comparing glycemic control in CL (either single- or dual-hormone) with CSII
• The CL group was associated with significantly
- Higher percentage of time spent in the target glycemic range (mean (SD), 67.59% (8.07%)
- Lower percentages of time in hyperglycemia (MD 3.01%, 95% CI [1.68, 4.34%]) and hypoglycemia (MD 0.67%, 95% CI [0.21, 1.13%])
• Mean glucose was also decreased in the CL group (MD 0.75 mmol/L, 95% CI [0.18–1.33])
Systematic review and meta-analysis of RCTs 40 studies with 1027 participants)
Evaluation of artificial pancreas treatment
Artificial pancreas system vs. type of insulin-based treatment
• Higher time was spent in the near normoglycemic range (3.9–10.0 mmol/L) with artificial pancreas use, both
- Overnight (weighted mean difference 15.15%, 95% confidence interval 12.21 to 18.09%) and
- Over a 24-h period (9.62%, 7.54 to 11.7%)
36-h pilot study
Feasibility of artificial pancreas strategy
To validate the ARG algorithm, five T1DM subjects were enrolled
Time spent in range was 70–250 mg/dL, 94.7%; in range 70–180 mg/dL, 82.6%; < 70 mg/dL, 4.1%; and < 50 mg/dL, 0.2%
During the last night, the time spent in range was 70–250 mg/dL, 95%; in range 70–180 mg/dL, 87.7%; < 70 mg/dL, 5.0%; and < 50 mg/dL, 0.0%.
No severe hypoglycemia and serious adverse events were reported
Multiple daily injections or basal-bolus insulin regimen
Intensive insulin therapy involves three or more insulin injections per day or insulin pump therapy. The goals are to provide better glycemic control and reduce the development and progression of microvascular and macrovascular complications . Evidence derived from studies that compared various insulin regimens for T1DM is presented below (Table 3) [36, 37, 38, 39].
Establishing a total daily dose of insulin
The first step of initiating the treatment with insulin in patients with newly diagnosed T1DM includes establishing a total daily dose, insulin sensitivity factors for correction doses, and insulin to carbohydrate ratio. This dose can vary from 0.3 to 1.5 units/kg/day, depending on the individuals. However, a good initial dose is ~ 0.5 units/kg/day. After determining the total daily dose (TDD) of insulin, it is divided by half which establishes the basal and bolus requirements. According to the thumb rule, the basal insulin should be about half of TDD of insulin, and the mealtime insulin should make up the other half.
For example, if a person is weighing 50 kg, the typical TDD of insulin would be 50 kg × 0.5 units/kg = roughly 25 units/day. The basal insulin dose would be roughly 12 units and bolus insulin total would be 12 units (divided among three meals, see below).
U-100 glargine and detemir should be administered once or twice daily as they are long-acting insulin analogs whereas insulin degludec or U-300 insulin glargine can be administered once a day as they are ultra-long-acting insulin analog .
Using prandial insulin
Establishing insulin to carb ratio
In T1DM, using basal and prandial analogs together helps in achieving the greatest therapeutic benefit. The administration of pre-meal insulin requires the patient to know their present blood glucose level and the estimated amount of carbohydrates present in the meal. Initially, the amount of prandial insulin can be determined by approximating the percentage of calories consumed at each meal. Later on, patients can alter the prandial dose by estimating the carbohydrate component of each meal or a snack [41, 42].
A person who takes a total of 40 units of insulin/day (both basal and prandial combined) will need 1 unit of rapid-acting prandial insulin for every 12.5 g carbohydrate (500/40 = 12.5 g of carbohydrate covered by 1 unit of insulin, using the above formula).
Calculating the carb ratio (alternative method)
Sum of all carbohydrates consumed in a day/total units of prandial insulin taken that day, using an average over 3 days.
Using extra carbohydrates to raise low blood sugars or cover increased physical activity
If the recent dose is taken within 1–2 h
Nausea or vomiting
Calculating correction dose/insulin sensitivity factor
Insulin sensitivity factor or correction dose is referred to as the number of milligrams per deciliter (mg/dL) by which blood sugar levels fall when a person takes 1 unit of insulin. The “1500 rule” for short-acting regular insulin (divide 1500 by daily insulin dose for mg/dL, 83 for mmol/L) and “1800 rule” for rapid-acting insulin (divide 1800 by daily insulin dose for mg/dL, 100 for mmol/L) should be followed. These methods are widely used to calculate “the correction factor” or “insulin sensitivity factor,” i.e., the glucose-lowering effect of 1 unit of insulin [41, 43]. The correction dose can be used for elevations of blood glucose that occur in-between the meals. And can be utilized in patients who had not taken an injection of rapid-acting insulin over the past 2–4 h (insulin on-board).
For example: If a person takes 60 units per day and has a blood glucose of 240 mg/dL before the meal, an extra dose of 3 units will lower the blood glucose level by an additional 90 mg/dL with rapid-acting insulin or 75 mg/dL with short-acting insulin. In the same way, units can be subtracted from the pre-meal dose if the blood glucose level is low.
1. ISF = 1800/60 (TDD) = 30; 1 unit of rapid-acting insulin will decrease glucose by 30 points; 1500/60 = 25; 1 unit of short-acting insulin will decrease glucose by 25 points.
2. 240 mg/dL (actual glucose level) − 120 mg/dL (target glucose level) = 120; this is the excess glucose, that is, the value that is above target and that needs to be corrected.
3. 120/30 (ISF) = 4 for rapid-acting; 120/25 = 4.8 for short-acting insulin; dividing the excess glucose by the ISF will provide the amount of correction insulin units that are required to bring down the glucose to target.
Putting it all together—combining the carb ratio and ISF
For example: An individual with a carb ratio of 1:10 and ISF of 1 unit/40 mg/dL, prior to a meal of 50 g carbohydrates and a pre-meal blood glucose of 210 mg/dL and target of 120 mg/dL, would take the following steps to administer the appropriate amount of prandial insulin as follows:
1. To cover carbohydrate intake: 50 g/10 g per unit = 5 units
2. Correction dose: 210 mg/dL (actual glucose) − 120 mg/dL (target glucose) = 90 mg/dL. ISF is 90/40 = 2.25 units to correct.
3. Total amount of prandial insulin: 5 (routine dose) + 2.25 (correction) = 7.25 units
Insulin titration and pattern adjustments
The most important aspects of diabetes management are reviewing blood glucose and recognizing patterns that will allow timely and appropriate adjustments in insulin dose, food intake, and managing physical activity. Recognizing patterns can be done by using tools such as self-monitoring of blood glucose (SMBG) with information obtained through download software or logbooks and continuous glucose monitoring (CGM) data [40, 43].
Continuous subcutaneous insulin infusion or insulin pump therapy
An external pump-based CSII results in better glycemic control as compared with MDIs of insulin allowing greater flexibility in routine activities. Modern-day insulin pump therapy can effectively address the disadvantages of inflexibility . Pieces of evidence that compared CSII and MDI for T1DM are presented below (Table 3) [45, 46, 47, 48].
Fundamental differences between CSII and MDI
Titration of basal doses
Practically speaking, the most important aspect of insulin dosing is to provide the correct amount of basal rate. Incorrect basal dosing leads to suboptimal bolus doses and the correction doses. Too high basal dosing is the commonest error observed in CSII therapy which results in hypoglcemia even with the smallest of correction doses. The flexibility of dosing and titration of basal doses is one of the greatest advantages of CSII [40, 43].
Depending on each patient’s needs, the basal dose can be titrated throughout the day. This is usually done in a systemic manner using the “basal checks” approach. The following conditions such as last meal and/or insulin bolus should have occurred at least 4 h prior to starting the assessment; fat and protein restriction in the last meal and avoiding exercise and alcohol should be met before performing the basal check.
Additionally, assessment should not be performed if there is a prior hypoglycemic episode earlier in the day or there is an intercurrent illness .
Nighttime basal rate
As a best practice, initiation should be done by addressing the overnight basal rate. A bedtime glucose range within the target is the pre-requisite for performing the overnight basal assessment. Any nutritional intake is restricted and the patient is asked to measure glucose levels at bedtime, at midnight, at 3 AM, and upon awakening. This is done to assess for changes in glucose profile (the use of a CGM obviously makes this exercise much easier). Additionally, any hypoglycemic symptoms also warrant the checking of blood glucose levels. The assessment is stopped in case of hypoglycemia or when glucose level rises above the target. A variation of ≤ 30 mg/dL in glucose levels on either side from bedtime to morning (upon awakening) is usually acceptable. However, glucose changes > 30 mg/dL warrant adjustments in basal rates which are generally in the range of 10–20% in insulin dose 2 h before the observed rise or fall in glucose levels. In general, a change in a basal dose takes 2 to 4 h to result in a change in blood glucose [40, 49].
Daytime basal rates
A skipped mealtime period (pre-breakfast to pre-lunch, pre-lunch to pre-dinner, and pre-dinner to bedtime) is evaluated to check the day time basal rates. For instance, to check the “pre-breakfast to pre-lunch” time segment, breakfast is skipped following which glucose levels are checked at 1–2-h intervals for the duration of that time segment. Any hypoglycemic symptom also mandates the checking of glucose levels.
Tracking of insulin on-board
Insulin dose calculator
The insulin pump facilitates the setting of insulin to carbohydrate ratios and insulin sensitivity with corresponding target glucose values can be fixed and changed as and when required. Based on the glucose levels and anticipated carbohydrate amount to be consumed entered by the patient, the insulin pump calculates the insulin dose. This again is a big advantage over MDI which requires manual calculations to arrive at an optimal dose [40, 50].
Modifications to bolus delivery
Individual bolus doses that are administered over a slightly extended period can be obtained by appropriately programming the pumps. Patients with delayed gastric emptying as seen in gastroparesis or those on pramlintide can be benefitted from this feature of CSII [40, 50, 51].
Temporary basal rates
The insulin pump also facilitates the setting of the temporary basal rates which are required in certain situations. Intercurrent illness—requiring an increased insulin requirement or alternatively during exercise—requiring a reduction in insulin dose can be managed by setting temporary basal rates [40, 50].
Sensor-augmented insulin pump therapy
The sensor-augmented insulin pump (SAP) is an insulin pump with a CGM sensor that transmits the glucose readings to the insulin pump . Based on the findings accumulated through 2013, The German Diabetes Association developed recommendations for use of CGM in T1DM. The Endocrine Society, the National Institute for Health and Care Excellence (NICE), the International Society for Pediatric and Adolescent Diabetes (ISPAD), the American Association of Clinical Endocrinologists/American College of Endocrinology, and the American Diabetes Association have published recommendations regarding clinical indications for use of CGM . In 2016, El-Laboudi et al. reported that the use of CGM resulted in a dramatic and significant reduction in both HbA1c and mean glucose with highly significant improvements in hypoglycemia . Mazze indicated that one needs about 15–30 days of CGM to obtain a stable pattern for the ambulatory glucose profile [55, 56]. Dunn and Crouther also reported that 14 days provides a good snapshot . Xing et al. recommended the use of at least 12–15 days of data to ensure that results would be correlated with results based on a 3-month study to characterize the overall level of glycemic control, mean glucose, coefficient of variation of glucose (%CV), and percentages of glucose values within the hypoglycemic, hyperglycemic, and target ranges .
Moving close to the artificial pancreas
In patients with T1DM, a newer concept of an artificial pancreas, or closed-loop (CL) system, can be helpful. This technology works to deliver insulin in response to blood glucose levels. The closed-loop system works by integrating three distinct systems which work in close coordination to maintain euglycemia: (1) CGM sensor that measures blood glucose levels and sends data to a computer; (2) an algorithm that calculates the amount of insulin needed and instructs the pump to deliver it; (3) an insulin delivery device, such as an insulin pump. This enables minimum human input which removes subjectivity from the treatment regimen. Numbers of evidences evaluated the artificial pancreas, or “closed-loop (CL) system,” for T1DM is presented below (Table 3) [59, 60, 61].
Non-insulin treatments for T1DM
Recommendations from RSSDI for insulin therapy in patients with T1DM
• MDIs of prandial and basal insulin or CSII have proved to be effective and safe treatment for people with T1DM.
• Basal-bolus insulin therapies are considered as the standard regimen for the management of diabetes in T1DM.
• Basal insulin dosage is estimated based on weight and is normally initiated at 10 U or 0.1–0.2 U/kg/day and then up-titrated based on glycemic value, with typical doses ranging from 0.2 to 1.0 units/kg/day.
• Regular insulin should be added for postprandial glucose control. Rapid-acting insulin analogs also can be used as it reduces hypoglycemia risk.
• Premixed insulin analogs help in reducing the HbA1c levels, controlling the PPG levels, and can also be used in adolescents in case of unavailability of other insulins.
• Individuals with T1DM should be educated regarding matching prandial insulin doses to carbohydrate intake, pre-meal blood glucose levels, and anticipated physical activity.
Summary of clinical evidences for non-insulin regimens in management of T1DM
A randomized, two-way crossover study
Amylin analog pramlintide and insulin vs. placebo and insulin
Regular human insulin was delivered with pramlintide or placebo using separate infusion pumps in a fixed ratio (9 μg/unit) over a 24-h period
• Compared with placebo, pramlintide showed reduction in
- Mean 24-h glucose (8.5 vs. 9.7 mmol/L; p = 0.012)
- Glycemic variability
- Postprandial glucagon
Two parallel studies were conducted
Pramlintide vs. liraglutide
Participants underwent mixed-meal tolerance tests (MMTTs) before and after 3 to 4 weeks of treatment with either pramlintide (n = 8) or liraglutide (n = 10)
• Compared with baseline,
- Pramlintide reduced the peak increment in glucagon from 32 ± 16 to 23 ± 12 pg/mL (p < 0.02)
- Liraglutide had no effect on plasma glucagon
A 52-week, double-blind, treat-to-target trial
Liraglutide added to treat-to-target insulin
1398 adults (3:1) received once-daily SC injections of liraglutide (1.8, 1.2, or 0.6 mg) or placebo added to insulin
• Liraglutide added to treat-to-target
- Insulin reduced
- HbA1c levels,
- Total insulin dose,
- Body weight
• However, it was accompanied by increased rates of
- Symptomatic hypoglycemia
- Hyperglycemia with ketosis
A 12-week randomized, placebo-controlled, double-blind, parallel-group study
Evaluate of liraglutide on counter-regulatory responses and GE rate during hypoglycemia
20 patients (1:1) received liraglutide 1.2 mg once daily or placebo as add-on to insulin treatment
• No difference between groups in
- GE rates (p = 0.96),
- Glycemic recovery,
- Counter-regulatory hormone responses,
- Systolic blood pressure,
- GLP-1 responses, and
- PP responses
• Liraglutide increased heart rate from 69 ± 4 to 80 ± 5 beats/min (p = 0.02)
Dube et al., 2018
A crossover, double-blinded, 24-week intervention study
Liraglutide added to basal/bolus insulin
15 participants (1:1) received placebo or liraglutide for 24 weeks including a 1-month titration period from 0.6 to 1.2 to 1.8 mg, in addition to their insulin
Liraglutide + basal/bolus insulin improved the anthropometric and metabolic profiles without an increase in hypoglycemia
12-month double-blind RCT
Metformin vs. placebo
Metformin (up to 1 g twice a day) or placebo in children
- Improved glyceryl trinitrate mediated dilatation by 3.3 percentage units (p = 0.03)
- HbA1c at 3 months (p = 0.001)
- Reduced insulin dose by 0.2 U/kg/day (95% CI 0.1, 0.3, p = 0.001)
Sick day management for patients with T1DM
Recommendations from RSSDI for sick day management for patients with T1DM
• In times of illness and decreased oral intake, advise the patient the following:
o Do not omit insulin.
o Frequent blood glucose monitoring at least every 3–4 h and often every 1 to 2 h (in critically ill patients) is essential.
o In patients experiencing acute illness, aim for a blood glucose levels between 140 and 180 mg/dL (8 and 10 mmol/L) and blood ketones should be below 0.6 mmol/L.
o The insulin dose often needs to be decreased when there is gastroenteritis due to limited oral intake and/or malabsorption to prevent hypoglycemia; however, one must ensure adequate basal insulin delivery to prevent hyperglycemia and hyperketonemia due to insulin deficiency.
o Hypoglycemia with hyperketonemia, which may occur in the setting of GI illness or starvation, requires administration of insulin along with carbohydrate intake.
o Maintaining hydration is essential in every patient with diabetes during an acute illness; oral fluids with or without sugar should be consumed depending on the glucose level; consider timely initiation of IV fluids if the patient is unable to drink.
Choosing the right insulin and individualizing therapy for adults with T2DM
When to start insulin in patients with T2DM
Recommendations from RSSDI regarding situations when insulin therapy may be indicated or should be considered
• T2DM patients who fail to achieve glycemic targets with current OADs, or cannot tolerate current OADs, or those who need more flexible therapy
• When adequate glycemic control is not obtained, in patients with myocardial infarction, stroke, or decompensated hepatic or renal insufficiency, or those who had major surgery
• Acute hyperglycemia, DKA/hyperglycemic-hyperosmolar state/lactic acidosis
• Pregnancy and lactation
• Diabetes patients on steroid therapy
• Insulin therapy is indicated for a short period of time in cases of acute illness or surgery, and glucose toxicity
Advantages of early use of insulin in T2DM and newly diagnosed T2DM patients
Conventional stepwise therapy approach in T2DM involves addition of antidiabetic agents one-by-one in a sequential fashion to control glucose levels. This may expose T2DM patients to prolonged periods of hyperglycemia of even up to 8 years . The progressive deterioration of pancreatic insulin secretory function was such that after 3 years, only about half of patients could attain the HbA1c levels below 7% with monotherapy, and by 9 years, this declined to approximately 25% . Compared with OADs, intensive insulin therapy causes rapid improvement in β cell functions of treatment-naïve T2DM patients, thereby helping maintain long-term normoglycemia, thus supporting the rationale for early initiation of insulin in T2DM.
Current ADA guidelines recommend early introduction of insulin if there is evidence of ongoing catabolism (weight loss), if symptoms of hyperglycemia are present, or when A1C levels (> 10% [86 mmol/mol]) or blood glucose levels (≥ 300 mg/dL [16.7 mmol/L]) are very high . The 6-year-long Outcome Reduction with Initial Glargine Intervention (ORIGIN) study has reported a stable pattern of glycemic control while other studies have reported the beneficial effects on β cell functions in patients with T2DM who were on early insulin therapy in combination with OADs [71, 72, 73]. In 2018, a prospective observational study by Mokta et al. looking at use of insulin therapy in symptomatic newly diagnosed T2DM Indian adults (HbA1c > 9%) reported a significant improvement in fasting plasma glucose (FPG), postprandial plasma glucose (PPPG), and A1C as well as β cell function after 8 weeks of therapy . Another recent Indian study by Madnani et al. also reported long-term good glycemic control and improved beta functions (which is sustained up to 2 years) after short-term insulin therapy (4–6 weeks) in treatment-naïve patients with type 2 diabetes .
To date, no studies have examined the comparative effectiveness of the stepwise addition of insulin therapy over time versus early therapy in combination with OADs.
Total daily dose of insulin
Stage of puberty
Duration and phase of diabetes
State of injection sites
Nutritional intake and distribution
Blood glucose levels and glycated hemoglobin
Initiation insulin algorithm for patients with T2DM
The current ADA guidelines strongly advocate a “patient-centered approach” to the treatment of T2DM and suggest that the individualization of treatment is the “cornerstone of success.” A diabetic meal plan matches calories from foods (carbohydrates, proteins, and fats or oils) to individual body activity and insulin levels. This approach should focus on matching the supply of insulin to the regular exercise/diet patterns of patients and follow-up with regular SMBG [28, 79].
Insulin regimens for T2DM
Basal insulin regimen
Steps for initiating basal insulin
Total daily dose
Step 1. Initiation with basal insulin*
A1C < 8%
A1C > 8%
Step 2. Titration#
(every 2–3 days to reach glycemic goals)
Increase by 2 U/day
FPG > 180 mg/dL
Add 4 U
FPG 140–180 mg/dL
Add 2 U
FPG 110–139 mg/dL
Add 1 U
Step 3. Monitor for hypoglycemia
BG < 80 mg/dL
Reduce by 10 to 20%
BG < 56 mg/dL
Reduce by 20 to 40%
Bolus-only insulin regimen
In 2011, a meta-analysis involving 16 randomized controlled trials and 7759 T2DM patients found a higher rate of achieving the HbA1c target with biphasic or prandial insulin compared with basal insulin . The onset 2 trial which compared fast-acting insulin aspart (faster aspart) and insulin aspart (IAsp) in inadequately controlled T2DM patients reported confirmed noninferiority in reducing HbA1c and change from baseline in HbA1c. Both faster aspart and IAsp improved PPG level; though, the PPG increment was statistically significant in favor of faster aspart after 1 h (p = 0.0198), but not after 2–4 h. No difference between groups was reported regarding the change from baseline in fasting plasma glucose, overall severe hypoglycemia rates, and body weight (rate ratio [RR] [95% CI] 1.09 [0.88; 1.36]) .
Premix insulin regimen
Combination of oral hypoglycemic agents with insulin
Weight gain and increased episodes of hypoglycemia preclude the use of exclusively insulin-based regimes in poorly controlled T2DM patients . In 2019, a systematic review, network meta-analysis, and cost-effectiveness analysis evaluating the comparative efficacy and safety of lixisenatide combined with basal insulin versus intensive premix insulin (premix) in patients with T2DM inadequately controlled by basal insulin reported similar HbA1c reduction compared with premix insulin, accompanied by lower risk of hypoglycemia and greater body weight reduction . Recently, Castellana et al. conducted a systematic review and meta-analysis to compare the effects of GLP-1RA/insulin combinations versus BP/BB. Compared with BP/BB, GLP-1RA/insulin combinations were associated with a similar HbA1c reduction (Δ = − 0.06%; 95% confidence interval [CI], − 0.14 to 0.02; p = 0.13; I2 = 52%), greater weight loss (Δ = − 3.72 kg; 95% CI, − 4.49 to − 2.95; p < 0.001; I2 = 89%), and lower incidence of hypoglycemic events (relative risk [RR] = 0.46; 95% CI, 0.38 to 0.55; p < 0.001; I2 = 99%). The daily insulin dosage among GLP-1RA/insulin users was 30.3 IU/day (95% CI, − 41.2 to − 19.3; p < 0.001; I2 = 94%), lower than with BP/BB. No difference was found for discontinuation due to lack of efficacy . In 2011, a meta-analysis involving 11 prospective randomized controlled trials and 2171 adults with uncontrolled T2DM reported significant efficacy/safety benefits following the addition of insulin glargine to metformin monotherapy at an earlier treatment stage over regimens including SU . In 2014, a Korean study reported a significant improvement in overall glycemic control with combination therapy of metformin and glimepiride plus glargine insulin compared with the other combinations. However, risk of hypoglycemia and the weight gain did not significantly differ among the treatment groups .
The Prospective Pioglitazone Clinical Trial in Macrovascular Events study (PROactive) evaluated the use of pioglitazone in combination with insulin treatment. A lasting improvement in glycemic control with a rapid and sustained decrease in insulin doses was observed as compared with the placebo group . More patients with poorly controlled T2DM despite high doses of insulin in the pioglitazone plus insulin group showed the maximum reduction in HbA1C. In 2009, a systematic review and meta-analysis involving eight randomized controlled trials comparing pioglitazone as an add-on therapy to insulin and the same insulin regimen reported small advantage of HbA1c reductions following the addition of pioglitazone but at the cost of weight gain and increased hypoglycemia . Add-on therapy of sodium-glucose cotransporter-2 inhibitor (SGLT2i) and dipeptidyl peptidase 4 (DPP4) inhibitors with insulin reported a significant improvement in glycemic control as compared to insulin alone without increasing hypoglycemia events [100, 101].
Recommendations from RSSDI for insulin initiation in patients with T2DM
▪ “Providers should avoid using insulin as a threat or describing it as a sign of personal failure or punishment.”
▪ As newer and effective OADs have been made available, it is recommended to consider insulin in cases where patient fails to achieve or maintain A1C levels after administration of three OADs; out of which one should be a newer agent or if patient is intolerant to any individual agent or combination of agents.
▪ Though there are several new oral agents available, their glucose-lowering potential is relatively less when compared with insulin and hence, insulin should never be delayed if A1c remains high.
▪ When there is evidence of glucose toxicity and lipotoxicity and if the HbA1c is more than 10% at the time of diagnosis, a short course of insulin for about a month can be considered.
▪ Involvement of patient and physician is important in making a decision regarding the therapeutic choice of regimen, preparation, and delivery device.
▪ The initial regimen of insulin therapy based upon patient’s age, clinical features, glucose profile, risk of hypoglycemia, and patient preference includes OD basal insulin, premixed/co-formulation insulin, or BID premixed insulin, either alone or in combination with other OADs. Also, basal insulin, either alone or in combination with GLP-1 analogs in same pen device can be used.
▪ Individuals suffering from severe hyperglycemia and life-threatening or organ/limb-threatening clinical situations will require basal-bolus insulin regimens.
▪ Analog insulins may be preferred over human insulins as they possibly lower the risk of nocturnal and symptomatic hypoglycemia; however, economic considerations must be taken into account.
– Timing of insulin and meals should be matched.
– Patients who are initiating insulin therapy should be educated about SMBG and preventive measures regarding hypoglycemia.
▪ Guidance should be provided regarding dose adjustments, administration, storage, and other practical aspects of insulin.
Titration for insulin therapy in T2DM
Summary of published evidence for dosing and titration
Author and study population
Target and SMPG value
Titration algorithm followed
Kennedy et al. 2006
N = 7893
FPG ≤ 100 mg/dL
Titration based on mean FPG (mg/dL) over previous 2–4 days
Insulin glargine, 10 U/day
• 100–119 → + 0–2 U
• 120–139 → + 2 U
• 140–159 → + 4 U
• 160–179 → + 6 U
• ≥ 180 → + 8 U
• < 70 → dose reduced to previous level
Severe hypoglycemia → stop upward titration for 1 week
Meneghini et al. 2007
N = 5604
FPG 80–110 mg/dL
Titration based on mean FPG (mg/dL) over previous 3 days
Insulin Detemir: 0.32–0.34 U/kg
• < 80 → − 3 U
• 80–110 → no change
• > 110 → + 3 U
Franek et al. 2015
N = 394
FPG 70–90 mg/dL
Titration based on mean FPG (mg/dL) over previous 3 days
IDegAsp: 06 U/twice daily
• < 56 → − 4 U (if dose > 45 units, reduced by 10%)
• ≤ 70 → − 2 U (if dose > 45 units, reduced by 5%)
• ≤ 90 → no change
• < 126 → + 2 U
• < 144 → + 4 U
• < 162 → + 6 U
• ≥ 162 → + 8 U
Fahrbachet al. 2008
N = 2000
FPG 80–109 mg/dL
Titration based on mean FPG (mg/dL) over previous 3–7 days
Lispro: 10 U/twice daily
• < 80 → − 2 U
• 80–109 → no change
• 110–139 → + 2 U
• 140–179 → + 4 U
• ≥ 180 → + 6 U
Recommendations from RSSDI for insulin titration in patients with T2DM
• Insulin regimen should be initiated as defined in the algorithm, using a self-titration regimen and increasing the dose by 2–4 U every 3 days or biweekly or with more frequent contact with a healthcare professional.
• Pre-meal glucose levels and PPG levels should be aimed between 80 and 130 mg/dL and between 140 and 180 mg/dL respectively. These targets can be individualized, based upon the risk of hypoglycemia and the urgency for glycemic control.
• Titration should be performed at regular and short intervals, as guided by the physician or trained paramedical staff to achieve glycemic goals without causing hypoglycemia.
• Initially titration should be done to control fasting blood sugar level, followed by post-meal value for prandial insulin with the highest glycemic excursion in sequential order.
Intensification for insulin therapy in T2DM
Recommendations from RSSDI for insulin intensification in patients with T2DM
▪ Insulin therapy should be intensified in case patients fail to achieve glycemic goals even after optimal dose titration.
▪ Options to be considered during intensification:
– Prandial insulin can be added to basal insulin (basal plus or basal-bolus), starting with largest meal of the day
– Premix insulin should be administered twice daily or thrice daily (rarely)
– Insulin co-formulation-based regimen can be followed
– Addition of GLP-1 analogs
o Intensification strategy can be based upon various factors such as dietary pattern, lifestyle, risk of hypoglycemia and weight gain, affordability, and patient preference.
• Basal plus regimen is a stepwise approach used for insulin intensification, leading to basal-bolus prescription. It is associated with lesser risk of hypoglycemia and weight gain than basal-bolus regimen.
• Both premix insulin therapy and co-formulation insulins are acceptable methods of intensification; however, co-formulation insulin offers lower risk of hypoglycemia and nocturnal hypoglycemia. These preparations are also free of resuspension errors.
Steps for intensification of insulin therapy
• Given preferably before dinner to achieve adequate suppression of HGP
• Target: FPG < 120
• Initiate with 10 U at bedtime and check FBSL
• Increase dose by 1 U/day or 3 U every 3 days by patient self-titration until target FBSL is achieved
• Initiate along with meal with highest glycemic excursion
• Start with 4 U and increase by 1 U/day or 3 U/3 days till PPBG < 180
• Next meal with highest glycemic excursion should be titrated similarly
• Full basal-bolus can be considered for effective prandial control after all meals
• Calculate the total dose
• Start with 6 U BID day for analogs and 2/3rd dose in morning and 1/3rd dose in evening for human insulins
• Titration can be done for morning dose based on pre-dinner values and for evening dose based on FBG
• Titration can be done by 1 U/day or 3 U/day to achieve required BG targets
Diabetes in pregnancy
A steady increase in the prevalence of diabetes in pregnancy has been witnessed in the past few years, especially in developing countries like India. Gestational diabetes mellitus (GDM) is the main cause of diabetes seen in pregnancy while the remaining cases are of preexisting T1DM and T2DM. As compared with women from other parts of the world, it is observed that Indian women have 11 times more risk of developing GDM. The prevalence of GDM in India varies in different regions with a reported prevalence of 3.8% in Kashmir, 9.5% in Western India, 6.2% in Mysore, and 22% in Tamil Nadu .
Glycemic targets in pregnancy
Ideally, the A1C target in pregnancy is 6% (42 mmol/mol) if this can be achieved without significant hypoglycemia, but the target may be relaxed to 7% (53 mmol/mol) if necessary to prevent hypoglycemia .
Insulin in women with GDM
Recommendations from RSSDI for insulin therapy in women with GDM
• Pharmacological therapy should be initiated in women with GDM if they fail to achieve blood glucose targets within 2 weeks of initiation of nutritional therapy and exercise.
• As insulin does not cross the placenta, it is the preferred agent in women with GDM.
• Insulin aspart/lispro may be preferred over human insulin for better postprandial control.
• NPH or insulin detemir can be used for basal insulin requirements.
Insulin in pregnant women with preexisting T1DM and T2DM
Recommendations from RSSDI for insulin therapy in pregnant women with preexisting T1DM and T2DM
• Insulin is considered more suitable over oral agents in women with preexisting diabetes as they are unable to overcome the insulin resistance in T2DM as well as cross the placenta, and are ineffective in T1DM.
• An individualized insulin regimen and glycemic targets by basal-bolus injection therapy should be provided to every individual pregnant woman with preexisting diabetes.
• Regular insulin or rapid-acting analogs may be used in women with preexisting diabetes to improve postprandial blood glucose.
• Detemir or glargine may be used in women with preexisting diabetes as an alternative to NPH and is associated with similar perinatal outcomes.
• Women with T1DM and insulin-treated T2DM who receive antenatal corticosteroids to improve fetal lung maturation should follow a protocol that increases insulin doses proactively to prevent hyperglycemia.
Insulin dosing in pregnancy
The CDAPP Sweet Success program offers some guidance on adjustments, suggesting changes by 2–4 units (∼ 10%) in short- and intermediate-acting insulins every 2–3 days. Women with GDM or T2DM rarely have hypoglycemia unawareness. Therefore, the most aggressive adjustments can safely be made in this population. In practice, adjustments can be made every couple of days until control is attained if personnel and time allow .
In the case of aggressive titration, it is difficult to adjust the dose of new long-acting insulin analogs as rapidly as with NPH. Insulin detemir can be safely titrated every 3 days by 3 units in non-pregnant patients. However, insulin glargine U-100 has two suggested options for dosing adjustments in non-pregnant patients: either by 1 unit every day or by 2 units every 3 days. Insulin glargine U-300 should only be adjusted every 3–4 days .
Monitoring during pregnancy
Recommendations from RSSDI for SMBG during pregnancy
• Ideal SMBG is seven tests/day, i.e., three before and three after each respective meal and one test at 3 AM. If this is not practicable, other approach should be encouraged which includes one fasting test and three tests each 1 h after breakfast, lunch, and dinner daily may be done, which can further be individualized to twice or thrice a week as the pregnancy advances.
Monitoring of blood glucose
Recommendations from RSSDI for SMBG
• SMBG should be accessible on an ongoing basis to patients using insulin therapy.
• Regular SMBG is recommended for patients who are on MDI insulin therapy, pre-gestational/GDM on insulin, history of hypoglycemia unawareness, brittle diabetes, or with poor metabolic control on multiple oral antidiabetic agents (OADs) and/or basal insulin.
• Patients on intensive insulin regimens who are on multiple doses of insulin or on insulin pumps should be tested three or more times daily (all pre-meals, post-meals, bedtime, prior to exercise).
Insulin therapy during lactation
Recommendations from RSSDI for insulin therapy during lactation
• An individualized diabetes diet for breastfeeding mothers should be encouraged.
• Early neonatal feeding as well as high-intensity breastfeeding should be encouraged in women with preexisting diabetes and GDM.
• Explain to women with insulin-treated preexisting diabetes that they are at increased risk of hypoglycemia in the postnatal period, especially when breastfeeding, and advise them to have a meal or snack available before or during feeds.
Insulin therapy in other special population
Insulin therapy in elderly
Recommendations from RSSDI for insulin therapy in elderly
• Strategies should be used strictly to prevent hypoglycemia in geriatric patients with diabetes and multiple comorbidities which include the choice of antihyperglycemic therapy and less stringent glycemic goals.
• Deintensification of complex regimens is recommended to lower the risk of hypoglycemia, if it can be achieved within the individualized A1C target.
• Use of premixed insulin and prefilled insulin pens should be encouraged in geriatric population to minimize dosing errors and to potentially improve glycemic control.
• Frequency of hypoglycemic events can be lowered in older people using basal or premix analogs instead of NPH or human 30/70 insulin.
• Overtreatment of diabetes should be avoided in older adults.
Chronic kidney disease
Glycemic targets for renal patients
2-h PPBG (mg/dL)
Normal GFR, microalbuminuria +
Pre-dialysis (CrCl < 10)
Post renal transplant
In non-critical care situation, the preferred insulin is short-acting insulin analog over regular insulin. Patients with normal eGFR and albuminuria or transplant recipients may need tighter control albeit without the risk of hypoglycemia . MDI insulin therapy with rapid-acting insulin analogs is ideal for patients with advanced CKD (eGFR < 30 mL/min) to deal with poor and unpredictable food intake, nausea, and vomiting. For those with eGFR between 30 and 60 mL/min, MDI insulin therapy with one to two basal insulin injections and two to three rapid-acting insulins (preferably analogs) may be required .
Insulins lispro, aspart, and glulisine are short-acting insulin analogs with very similar PK profiles. In the diabetic population with ESRD undergoing hemodialysis, lispro insulin provided better glycemic control and improves quality of life [148, 149]. A study in patients with T2DM and severe renal insufficiency suggested that insulin glulisine can effectively suppress postprandial hyperglycemia without prolonged hypoglycemic action . Further, the PK of short-acting insulin aspart was not affected in a clinically significant manner by renal impairment, hepatic impairment, or BMI .
In 2012, a study bt Niafer et al. reported safety and good tolerance of insulin glargine added to regular insulin in patients with T2DM and diabetic nephropathy . Another study by Kulozik and Hasslacher reported low-dose requirements of insulin glargine and detemir in T1DM patients with renal dysfunction. The insulin dose requirements were 29.7% lower in glargine-treated patients and 27.3% lower in detemir-treated patients at a GFR of < 60 mL/min compared with the dose requirements at an eGFR of > 90 mL/min . A subgroup analysis of the ORIGIN data has identified CKD (in both mild and moderate stages) as a significant risk factor for macrovascular complications in people with early dysglycemia. Moreover, these results were not impacted by the use of basal insulin glargine compared with standard treatment . AWARD-7, a multicentre, open-label trial, compared dulaglutide in two different doses to insulin glargine in patients with T2DM and moderate-to-severe CKD (n = 577). The effect on glycemic control of once-weekly dulaglutide was noninferior to that achieved with insulin glargine. Lesser declines in eGFR were also noted with dulaglutide in this study [155, 156]. A study evaluating the PKs of insulin degludec in 30 patients (n = 6 per group) with normal renal function; mild, moderate, or severe renal impairment; or end-stage renal disease (ESRD) undergoing hemodialysis reported no need for dose adjustment in patients with impaired renal functions .
A meta-analysis of non-randomized clinical trials conducted in 2015 by Almalki and coworkers found adequate and superior glycemic control with the use of intraperitoneal (IP) insulin compared with treatment with conventional subcutaneous insulin. However, IP insulin adversely affected plasma lipid profile, possibly contributing to increased CV risk. The authors of this review suggested need for further studies to assess the long-term safety of this approach . Analysis of the SAIL patient-linked dataset reported a linear association between CKD severity and insulin use; however, approximately 54% in the severe CKD group received insulin .
Recommendations from RSSDI for patients with CKD
• CKD risk and progression can be minimized by optimizing blood glucose and controlling blood pressure.
• All insulins are considered safe across the spectrum of CKD. However, insulin doses in CKD may need to be reduced with lower eGFR levels.
• Prompt adjustments with reduction to 75% and 50% are often necessary in insulin TDD depending on the GFR between 15 and 60 mL/min and < 15 mL/min, respectively. However, no dose modification is suggested in patients with GFR > 60 mL/min.
• Doses of oral agents may be modified based on eGFR calculation where necessary.
• Among basal insulins, insulins detemir and glargine appear to be safe and effective.
• Among prandial insulins, both regular insulin and rapid-acting insulin analogs appears to be safe and effective.
• Rapid-acting insulin analog/basal insulin analog may be preferred over conventional insulin.
Insulin therapy during religious fasts including Ramadan
Recommendations from RSSDI for Insulin therapy during religious fasts including Ramadan
• T2DM patients on intensive insulin therapy should abstain from fasting.
• Physician suggestions should be taken into consideration regarding the change in dose and timing of insulin injections during fasting period.
• Use of rapid-acting insulin analogs may be preferred in patients with T2DM who fast during Ramadan over regular human insulin due to lower risk of hypoglycemia and postprandial glucose excursions.
Insulin therapy in CVD patients
Guidelines are inconclusive regarding the use of insulin in patients with cardiovascular disease (CVD). The relationship between insulin and CVD is complex. Patients with diabetes are at increased risk for CVD and associated clinical complications. Large clinical studies, such as the Veterans Affairs Diabetes Trial (VADT), Action in Diabetes and Vascular Disease-PreterAx and DiamicroN Controlled Evaluation (ADVANCE), and Action to Control Cardiovascular Risk in Diabetes (ACCORD) trials, have shown mixed results for CV outcomes [170, 171, 172]. The VADT found no difference between the intensive group and the standard therapy group for a time to the first major CV event, though more frequent hypoglycemic events were noted in the intensive group (17.6 vs. 24.1%) . The ACCORD trial also found no significant reduction in major CV events with intensive therapy . In the ADVANCE trial, intensive glucose control significantly reduced both major macrovascular and microvascular events in patients with T2DM .
The ORIGIN trial has reported a neutral effect of insulin glargine on CV outcomes; though, it increased hypoglycemia and weight gain . In 2018, the DEVOTE trial demonstrated that ultra-long-acting insulin analogs like insulin degludec were comparable with that of insulin glargine U100 concerning CV outcomes in patients with T2DM; though, the risk for severe hypoglycemia was less with insulin degludec. Thus, insulin degludec might be preferred in those with CVD, those at risk for severe hypoglycemia, and/or those with CKD .
Recommendations from RSSDI for insulin therapy in CVD patients
• In case there is inadequate control with OADs, the addition of basal insulin shall be considered.
• If the glycemic goal is not achieved after the addition of basal insulin, then a basal plus/premix regimen may be considered before proceeding to a basal-bolus insulin regimen.
Insulin therapy in hepatic impairment
ADA 2007 guidelines have highlighted the importance of insulin and suggested frequent dose titrations and glucose monitoring in patients with T2DM and chronic liver disease (CLD) . Indian consensus 2017 recommends newer insulin analogs as their PK remains unaltered in CLD patients and also has a low risk of hypoglycemia. It also suggested that the dose should be titrated frequently in CLD patients . Expert opinion by Scheen et al. mentions that insulin does not exert hepatotoxic effects and can be used in all stages of CLD . However, in cirrhotic patients, the dose should be carefully adjusted with frequent blood glucose monitoring for optimal glycemic control without hypoglycemia. Insulin may be the safest agent and dose adjustment should be individualized. Insulin therapy can be used in all stages of CLD although clinical studies are scarce. No single study reports extensive experience with insulin analogs in CLD patients . In one study examining the effect of hepatic impairment on the PKs of insulin degludec, a single subcutaneous dose of 0.4 U/kg insulin degludec was administered to 24 individuals (allocated to four groups based on their hepatic impairment level). The results showed no difference in maximum insulin degludec concentration (C max), area under the 120-h serum insulin degludec concentration-time curve (AUC0–120), and apparent clearance (CL/F) for individuals with impaired versus normal hepatic function . Another study by Holmes et al. examining the effect of hepatic impairment on the PKs of insulin aspart reported no correlation between the degree of hepatic impairment and any PK variable . Insulin detemir was found less efficacious in two patients with significant NAFLD and hypertriglyceridemia. In such patients, very high dose is required to achieve glycemic control .
Recommendations from RSSDI for insulin therapy in hepatic impairment
• Use of insulin analogs should be considered in T2DM patients with hepatic impairment for improved glycemic control with low risk of hypoglycemia.
Insulin therapy in hospitalized patients
Initial and maintenance insulin dosing protocol
Initial infusion dosing
Maintenance infusion dosing
0.1 U/kg body wt
↑BG from prior BG
BG ↓ < 30 mg/dL from prior BG
BG ↓> 30 mg/dL from prior BG
Infusion initiation (U/h)
BG divided by 100
↑rate 3 U/h
↑rate 3 U/h
↑rate 2 U/h
↑rate 2 U/h
Rate adjustment (monitor BG hourly)
↑rate 1 U/h
↑rate 1 U/h
BG ↓> 30 mg/dL
Same infusion dose
BG ↓< 30 mg/dL
Increase infusion dose
↓rate by 50%
↓rate by 50%
BG ↑above baseline BG
Increase infusion dose
Hold insulin, give 25% dextrose (100 − BG) × 0.8**
Recommendations from RSSDI for insulin therapy in hospitalized patients
• For majority of critically ill patients in ICU, insulin infusion should be used to control hyperglycemia.
• BG > 180 mg/dL should trigger insulin initiation.
• Once IV insulin started, glucose level should be maintained between 140 and 180 mg/dL.
• The exact protocol is probably less important; what is important is its presence in an institution and adaptation to the individual hospital needs.
• The protocol in Table 7 above may be adapted as recommended by RSSDI inpatient hyperglycemia guidelines 2016.
• Discontinuation of IV insulin often leads to rebound hyperglycemia. Hence, intravenous to subcutaneous insulin transition should be made carefully and only after it is evident that the patient exhibits stable glycemic control.
• Transition is more likely to be successful if blood sugar levels are between 140 and 180 mg/dL with constant insulin drip rate.
• It should be ensured that there is continuity between IV insulin infusion and the first dose of SC insulin.
• The total daily insulin requirement calculation can be best ascertained during a time interval of 4–6 h during which the blood glucose values are at goal and IV insulin rates are not particularly elevated or variable.
• Regular insulin or rapid-acting analogs should be used for the bolus/prandial insulin and the supplemental insulin. The basal insulin requirement should be met using NPH or insulin detemir, glargine, or degludec.
Driving and insulin-treated diabetes
Recommendations from RSSDI for driving and insulin-treated diabetes
• Healthcare professionals should educate the insulin-treated drivers about the risk of severe hypoglycemia.
• Blood glucose level should be monitored no more than 30 min before each drive and at least as often as once every 2 h of a journey.
• Blood glucose level ≥ 90 mg/dL could be considered as a safe level for driving.
Post-transplantation diabetes mellitus (PTDM or NODAT)
Recommendations from RSSDI for PTDM or NODAT
• Insulin therapy should be preferred during the first 1–2 months of time period after transplantation.
• Management of late-PTDM should be done in an appropriate way such as lifestyle modification > oral antidiabetic therapy > insulin.
Post-immunotherapy new-onset diabetes
Recommendations from RSSDI for PINOD
• Insulin be the drug of choice in this form of insulinopenic diabetes
• Metformin should be used, provided it is not contraindicated and is well-tolerated
General considerations for insulin therapy
Compatibility of insulin with various IV fluids
Insulin concentrations and strengths
Recommendations from RSSDI for insulin concentrations and strength
• Concentrated basal insulin offers the advantages of low injection volume leading to less pain, low variability, and lesser risk of hypoglycemia and can be prescribed as an alternative to U100 basal insulin.
• In those patients requiring very high units of insulin, pump therapy should be considered as one of the best options if eligible and affordable.
• High-concentration short-acting insulin can be administered in people who have severe insulin resistance and need higher doses of insulin in a single injection.
Insulin delivery devices
Recommendations from RSSDI for insulin delivery devices
• Insulin syringes or pens may be used for delivery with consideration of patient’s preference, type of insulin, dosing regimen, cost, and self-management capabilities.
• Insulin pens may be preferred due to accuracy of dosing and convenience of injection.
• Delivery of insulin via insulin pens or injections may be considered for people with vision impairment or dexterity issues to facilitate the administration of accurate insulin dose.
Insulin transport and storage
Forum for Injection Technique and Therapy Expert Recommendations (FITTER) India 2017 recommends following specific storage conditions provided by the manufacturer for insulin, though ideally should be stored in a cool (below 30 °C) and dark place . East Africa Diabetes Study Group (EADSG) guidelines recommend a temperature range of 2–8 °C for the suitable container used for transport of insulin. Exposure of insulins to temperatures outside the recommended ranges can reduce their potency and effectiveness. Therefore, maintaining the cold chain is very important while transporting insulin from the production facility to the distributor’s storage facility . If refrigeration is not available, unopened insulin vials may be stored in a pot with sand or may be submerged in water . Contamination of insulin and resultant abscesses at the injection site is a known complication if the cold chain is not properly maintained.
Recommendations from RSSDI for insulin transport and storage
• Specific storage conditions provided by the manufacturer in the package inserts should be followed.
• If no extremes of temperatures are envisaged, transporting insulin from a health facility to home transportation can be done without an icepack. If uncertainty exists about an exposure to high temperatures (> 30 °C), it is advised to transport insulin on an ice pack.
• Insulin vials can be transported by submerging in water or keeping insulin in a pot with sand, if refrigerator is unavailable.
Recommendations from RSSDI for injection sites
• Abdomen, thigh, buttock, and upper arm are the recommended infusion and injection sites.
Injection site rotation
According to FITTER India, the systematic rotation of insulin injection sites should be done to optimize insulin absorption, maintain healthy injection sites, and reduce the risk of lipohypertrophy (LH) . To avoid glucose variability, the same site at the same time each day and injection site rotation should be practiced to avoid glucose variability and LH (same time same site rule) .
Recommendations from RSSDI for injection site rotation
• Systematic switching of the injections from one site to another site and within the injection site helps in maintaining healthy injection sites, optimize insulin absorption, and reduce the risk of LH.
• The difference between new injection site and previous injection site should be at least 1–2 cm.
• Site rotation scheme should be reviewed by the healthcare professionals with the patient at least once a year.
FITTER India recommends the use of a 4-mm needle with pens and a 6-mm needle with syringes. Injections with syringe needle should always be given into a lifted skinfold at 90 in children ≥ 6 years old, adolescents, or slim to normal-weight adults .
A 4-mm needle is considered the safest needle for all diabetic people regardless of age, sex, ethnicity, or BMI, with little risk of IM or intradermal injection .
Recommendations from RSSDI for needle length
• 4-mm needle with pens and 6-mm needle with syringes should be used in children, adolescents, and adults.
• In children, extremely lean and elder patient’s skinfold is required when using 5- and 6-mm needle, but in children, adolescent, and adults, an injection angled at 45° is required while using 6-mm needle.
• In adults, injection into limbs and slim abdomen warrants the need for a skinfold with needles longer than the 5 mm.
• Shorter needle should be inserted perpendicularly to the skin surface.
Injection site complications
Common complications of subcutaneous insulin injection include LH. Other frequently encountered local allergic reactions to insulin are usually erythema, pruritus, and induration .
Lipoheypertrophy, a rubbery swelling in the subcutaneous (SC) tissue, is a common complication of insulin therapy. In 2018, a systematic review and meta-analysis involving 26 studies and 12,493 participants found 38% pooled prevalence levels of lipoheypertrophy (LH) among insulin-injecting diabetes patients. Higher prevalence was found among patients with T2DM as compared with patients with T1DM (49%, 95% CI 23–74% vs. 34%, 95% CI 19–49%) . In 2018, two Indian studies reported more than 60% of their prevalence among insulin users [208, 209]. FITTER India recommends regular inspection of injection site, single use of needle, proper injection site rotation, use of larger injection zones, and avoiding repeated use of the same site to prevent the development of LH. For management, it recommends a decrease in insulin dose when shifting to normal SC tissue and regular inspection by both HCPs and patients with diabetes .
Pahuja et al. found that out of 68% of patients who had LH, only 26% always rotated injection sites and 16% changed needles more than half of the time in the week. Further, 77% of patients with LH were unaware of the condition. Furthermore, it was associated with an increased duration of diabetes and insulin injection therapy and a higher insulin dose per day (each p < 0.05) .
Recommendations from RSSDI for LH
• Regular inspection and palpation of insulin sites should be performed.
• Reuse of needles and injection site should be avoided.
• Follow correct site rotation policy.
• Decrease in the insulin dose is required before switching site of injections from LH to normal tissue, but it varies from one individual to another and should be monitored by frequent blood glucose measurements.
Bleeding and bruising
Recommendations from RSSDI for bleeding and bruising
• Local bruising and bleeding do not affect the clinical outcomes or the absorption of insulin.
• In case bleeding and bruising are frequent, the injection technique should be carefully assessed and presence of a coagulopathy, use of anticoagulant, or antiplatelet agents should be checked.
Needle stick injuries
Recommendations from RSSDI for NSIs
• Healthcare professionals should be trained and educated on how to minimize risk, by following optimal technique and using available safety devices.
• Short needles should be used to avoid local bruising and bleeding.
• Needles should not be reused.
Diet/exercise and alcohol
ADA guidelines 2019 recommend education for people with T1DM and T2DM on how to use carbohydrate, fat, and protein content of food to determine mealtime insulin dosing. Alcohol consumption may increase the risk for hypoglycemia in people with diabetes, especially if taking insulin or insulin secretagogues; hence, guidelines also recommend education and awareness about recognition and management of delayed hypoglycemia in people consuming alcohol .
Evening-time exercise is a frequent cause of severe hypoglycemia in T1DM, fear of which deters participation in regular exercise. In 2015, Campbell et al. have demonstrated that exercise-induced hypoglycemia can be avoided, without exposure to hyperglycemia, when people with T1DM employ a combined basal-bolus insulin reduction and low GI carbohydrate feeding strategy. This strategy does not significantly augment ketonemia or cause other metabolic disturbances . Several other studies have also demonstrated that it is possible to achieve euglycemia early after exercise by making mealtime adjustments to both rapid-acting insulin administration and postexercise carbohydrate composition. Postexercise hyperglycemia, following high-intensity interval training (HIIT) in patients with T1D, is also largely underrecognized by the clinical community and generally undertreated. Recently, the FIT study conducted by Aronson et al. comparing four multipliers (0, 50, 100, or 150%) of an individual’s insulin correction factor (ICF) to treat post-HIIT hyperglycemia reported optimal plasma glucose (PG) reduction, with minimal hypoglycemia, in the 100 and 150% correction arms .
In patients with unstable T2DM on insulin, the use of low carbohydrate dietary approaches, including ketogenic diets, may cause hypoglycemia, complicating the matching of glucose self-monitoring to medical supervision of insulin dose adjustment. If the blood glucose level is < 72 mg/dL (4.0 mmol/L) and the patient is symptomatic and awake and can swallow, manage according to the rule of 15 (provide 15 g of quick-acting carbohydrate; wait 15 min and repeat blood glucose check; if the patient’s next meal is more than 15 min away, provide some longer-acting carbohydrate) .
Recommendations from RSSDI for diet/exercise and alcohol
• Individuals diagnosed with T1DM and T2DM should be taught on how to use carbohydrate, fat, and protein counting to determine mealtime insulin dosing to improve glycemic control.
• Carbohydrate sources high in protein should be avoided in individuals with T2DM to treat or prevent hypoglycemia as ingested protein increases insulin response without increasing plasma glucose concentrations.
• Adults with diabetes are advised moderate alcohol intake (no more than one drink per day for adult women and no more than two drinks per day for adult men).
• Diabetic patient taking insulin or insulin secretagogues may be put to increased risk of hypoglycemia due to consumption of alcohol. Therefore, education and awareness regarding the recognition and management of delayed hypoglycemia are important.
Managing insulin resistance
ADA 2019 guidelines recommend aerobic and resistance exercises regularly regardless of diabetes type to decrease insulin resistance. Aerobic activity bouts should ideally last at least 10 min, with the goal of 30 min/day or more, most days of the week for adults with T2DM.
Recommendations from RSSDI for managing insulin resistance
• Aerobic and resistance exercises should be performed regularly irrespective of diabetes type to decrease insulin resistance.
Hypoglycemia, weight gain, and other safety and psychosocial aspects
Hypoglycemia with insulin therapy
Classification of hypoglycemia
Hypoglycemia alert value (level 1)
≤ 70 mg/dL (3.9 mmol/L)
Sufficiently low for treatment with fast-acting carbohydrate and dose adjustment of glucose-lowering therapy
Clinically significant hypoglycemia (level 2)
< 54 mg/dL (3.0 mmol/L)
Sufficiently low to indicate serious, clinically important hypoglycemia
Severe hypoglycemia (level 3)
No specific glucose threshold
Hypoglycemia associated with severe cognitive impairment requiring external assistance for recovery
Hypoglycemia was found to be less frequent and less severe in patients with T2DM compared with patients with T1DM. The DCCT-like Kumamoto study reported only slight increase in mild hypoglycemia after intensive insulin therapy in T2DM patients . However, the UKPDS study reported symptomatic hypoglycemia in about 30%, but severe hypoglycemia in only about 2% of diabetic patients . Three studies in T2DM, The VADT, the ACCORD, and the ADVANCE trials, have greatly improved understanding between T2DM and cardiac risk [170, 171, 172]. The ACCORD and the ADVANCE trials have proved what seems to be a favorable adaptation to tighter glycemic control, likely due to episodic moderate hypoglycemia.[171, 172]
Recommendations from RSSDI for hypoglycemia with insulin therapy
• Consider insulin analogs to manage blood glucose in adults with T1DM or T2DM who have frequent severe hypoglycemia with human insulin.
• Periodic SMBG (≥ 3 times a day, preferably after meals) is necessary in patients who have frequent episodes of hypoglycemia.
• Other recommendations: regular checkup of injection site (erratic absorption can induce hypoglycemia), taking recommended doses at mealtimes, appropriate insulin dose adjustments before and after exercise, and ensuring easy accessibility of carbohydrate supplement and glucometer.
• Degludec and glargine U300 are newer long-acting basal analogs compared with existing basal analogs, detemir, and glargine U100, respectively, with more physiological basal profiles and provide a lower risk of nocturnal hypoglycemia.
• Insulin infusion pump therapy and CGM are useful adjuncts to the management of T1DM.
Impaired hypoglycemic awareness
Impaired awareness of hypoglycemia (IAH) is a frequent complication of insulin therapy. Approximately 50% insulin-treated patients with T1DM and T2DM report hypoglycemia awareness, and 15–25% of patients have a permanent IAH . In patients with T1DM, degludec significantly lowered rates of confirmed nocturnal hypoglycemia when compared with glargine U100 (estimated rate ratio [degludec/glargine] = 0.75, 95% CI, 0.60–0.94). As compared with detemir, a 33% lower rate of nocturnal hypoglycemia was observed (estimated rate ratio [degludec/detemir] = 0.67, 95% CI, 0.51–0.88) [229, 230]. Pooled patient-level data for self-reported hypoglycemia from randomized controlled phase III trials in individuals with T2DM and T1DM further confirm a lowering of nocturnal hypoglycemia risk with insulin degludec compared with glargine . However, the randomized head-to-head BRIGHT trial reported comparable rates of hypoglycemia with both Gla-300 and IDeg-100 insulin during the full study period but lower in favor of Gla-300 during the titration period . A single study showed a clinical benefit at less than or equal to 6 months of education and relaxation of BG targets compared with insulin lispro/glargine in people with T1DM and IAH for QoL (DQOL). However, the evidence showed clinical harm of education and relaxation of BG targets for HbA1c, and the number of patients with altered hypoglycemia awareness.
Recommendations from RSSDI for IAH
• The following strategies may be considered to eliminate the risk of severe hypoglycemia and to attempt to regain hypoglycemia awareness:
o Less stringent blood glucose targets with avoidance of hypoglycemia for up to 3 months
o Education regarding CSII or sensor-augmented pump or CGM and follow-up for T1DM
Impaired awareness of hypoglycemia: clinical evidences
Score system used for IAH
Prospective case series (9–12-month follow-up)
n = 95 T1DM
n = 74 normal awareness, n = 21 IAH
Gold score ratings used to define IAH (≥ 4)
3 times higher incidence of severe hypoglycemia was found in patients with IAH
Retrospective case series
n = 422 completers
IAH (gold): 20.5%
Severe hypoglycemia: 18.5% at least one event in past 6 months
46% who reported SH episode in past 6 months also reported IAH; only 7% had intact awareness
Prospective case control study (4-week follow-up)
n = 38
T1DM normal awareness (n = 19) patients and IAH (n = 19) patients
IAH patients vs. normal awareness:
NS difference in total no. of symptomatic hypoglycemic episodes
Higher annual prevalence of SH: 53% vs. 5%
SS higher incidence of severe events (p = 0.001).
Weight gain with insulin therapy
ADA guidelines recommend considering the effect of glucose-lowering medications on the weight of overweight or obese patients with T2DM before choosing the medicines. It has been suggested to minimize the use of medications whenever possible for comorbid conditions that are associated with weight gain. Weight gain with insulin therapy can be limited. Using the insulin formulations judiciously and using “insulin-sparing” agents such as metformin, GLP-1RAs, and SGLT-2i in T2DM will be a suitable approach.
Recommendations from RSSDI for weight gain with insulin therapy
• In obese patients with T2DM, selection of antihyperglycemic agents should be based on their effect on weight.
• Whenever possible, minimize the use of medications associated with weight gain.
Hypersensitivity reactions/allergy to insulin
Insulin allergy is a rare complication with a prevalence rate of around 2.4% in patients suffering from T1DM and T2DM . Out of the 17 cases reported previously, six cases reported initial reaction to lispro, five to detemir, five to aspart, and one to glulisine. According to the literature published earlier, around 88.2% of the cases reported insulin allergy in patients with T2DM and only two of the cases occurred in patients with T1DM (11.8%). There was variability in the reactions presented by the patients ranging from a few days in one case to a few years in others .
Insulin hypersensitivity and management: clinical evidences
Age/gender/type of diabetes
Duration of therapy prior to reaction
Confirmatory tests perfomed
Aujero et al. 2011
Discontinue detemir; further management not discussed
Switched to glargine
Sola-Gazagnes et al.
Discontinue detemir; further management not discussed
Xiong et al.
Skin prick test
Discontinued novorapid; switched to novolin 30R
Oray et al.
Localized and systemic
Basal insulin glargine and nateglinide treatments
Andrade et al.
Skin prick testing, antibody
Switched to oral therapy
Watanabe et al.
Intradermal testing, antibody
Switched to glulisine
Heinzerling et al.
Intradermal testing, antibody
Immunotherapy with regular insulin and antihistamine
Use of a desensitization strategy (35%)
Conversion to other non-insulin therapeutic options (23.5%)
Conversion to an alternative insulin (12%)
Use of immunotherapy (6%)
Recommendations from RSSDI for hypersensitivity reactions/allergy to insulin
• Intradermal testing (IDT) has been suggested as a more accurate assessment for identifying an insulin hypersensitivity reaction.
• When performing confirmatory testing, reactions to common human insulin analog (HIA) excipients should also be assessed in order to rule out hypersensitivity to individual excipients.
• Management of HIA hypersensitivity reactions can be done with the help of insulin desensitization protocols.
• Patient’s scenario should be taken into account before switching to other management strategies.
• A discussion with patient regarding treatment plan, including reassurances about the trial and error process and emphasizing the importance of conducting a rechallenge with the offending agent to assist in identifying the cause.
Diabetic ketoacidosis and hyperosmolar hyperglycemic state
RSSDI treatment algorithm recommends administration of an intravenous bolus dose of 0.1 U/kg, followed by continuous intravenous infusion of insulin at the rate obtained by dividing the current blood glucose value with a factor of 100. The necessity of the initial bolus has been called into question by one study that demonstrated no differences in outcomes or hypoglycemia risk among a group of 157 patients who either did or did not receive an initial insulin bolus. Several studies have shown that insulin administration and force hydration result in a fairly predictable decrease in plasma glucose concentration at a rate of 65–125 mg/dL/h. The insulin rate should be decreased to 0.05 U/kg/h and dextrose should be added to the intravenous fluids when the plasma glucose concentration reaches ~ 11.1–13.9 mmol/L. The insulin infusion rate should be adjusted to maintain a plasma glucose level of 8.3–11.1 mmol/L until ketoacidosis is resolved, as indicated by normalization of venous pH and anion gap. Insulin infusion should be continued among patients with hyperosmolar hyperglycemic state (HHS) until mental obtundation and the hyperosmolar state are corrected .
Recommendations from RSSDI for patients with DKA and HHS
• Protocol for management of DKA or HHS: fluid resuscitation, avoidance of hypokalemia, insulin administration, avoidance of rapidly falling serum osmolality, and search for precipitating cause
• Short-acting intravenous insulin infusion of 0.10 units/kg/h should be used in adults with DKA.
• The insulin infusion rate should be maintained until the resolution of ketosis occurs which can be measured by normalization of the plasma anion gap and venous pH.
• Intravenous dextrose should be started when plasma glucose concentration falls to14.0 mmol/L in order to avoid hypoglycemia.
Barriers and myths concerning insulin
Recommendations from RSSDI for barriers and myths concerning insulin
• Education is considered the cornerstone of interventions to address both clinician and patient barriers regarding initiation and intensification of insulin therapy.
• Need to encourage clinicians to establish and foster strong relationship with diabetes educators who have the knowledge, skills, and potential to support their patients during intensification of insulin therapy.
• Diabetes educator and clinicians should focus on the availability of long- and short-acting analogs and premixed formulations when possible, insulin delivery devices, weight gain and other side effects, dose flexibility, and cost.
• Use of pen devices is widely accepted and is associated with greater persistence and improvement in patient outcome.
• To provide education to patients and family members/caregivers is an ongoing need, beginning with conversations before initiation, at the time of initiation, and when dose intensification of insulin is required.
Barriers and myths concerning insulin
Fear of injection and needle
Anxiety, fear and pain reducing strategy
Limited access to education
Monitoring of therapy
Limited training of providers in injection technique
Fear of weight gain
Fear of weight gain
Overburdened workload among providers
Fear of hypoglycemia
Patient’s adherence, and wish to prolong non-insulin therapy
Summary of the articles evaluated the barriers
Sample and setting
Tools and outcome measures
Results and conclusions
Raj et al. (2018)
Open-label, multicentric, real-world data
To understand the barriers and behaviors of insulin therapy among T2DM pts in India from a real-world setting
3192 (30.6%) pts receiving insulin therapy have moved on to various therapies observed over 9 months
Data analysis of 3192 pts to understand the reasons for shift in therapy
Barriers for initiating insulin therapies were hypoglycemic episodes (25.9%), stress (17.1%), fear of injection (10.3%), and cost (7.4%)
Education and empowerment (stress, fear of injection and cost) through shared decision-making allow patients’ preferences to be presented
Alberti et al. (2002)
To identify a broad set of attitudes, wishes, and needs among both people with diabetes and care providers
5104 pts with T2DM and diabetes care providers (nurses = 1122; physicians = 2705)
Patients on insulin therapy in India expressed concern over hypoglycemia (25–55%) and weight gain (40%)
Strategy to bridge the barrier
• Raise awareness and advocacy
• Educate and mobilize people with diabetes and those at risk
• Train healthcare providers and enhance their competencies
• Provide practical tools and systems.
• Drive policy and healthcare systems change.
Patel et al. (2012)
To identify healthcare professionals’ perspectives on delaying insulin initiation for T2DM patients in a multi-ethnic setting
14 healthcare professionals (general practitioners, specialists and nurses)
Conducted in the UK
Semi-structured, face-to-face, interviews
Barriers for initiating insulin therapy for South Asian diabetic patients could be over-accentuated by the presence of language barrier and the lack of patients’ understanding about the disease and its therapy. South Asian patients seem to be more likely to be negatively influenced by observations and experiences about insulin treatment within their community
Lakkis et al. (2013)
To investigate family physicians’ attitudes towards insulin therapy in T2DM patients in Middle Eastern Arab countries
122 family physicians
Conducted in Middle Eastern Arab countries
Online questionnaire-based survey
73.6% of family physicians chosen to delay insulin initiation until it is absolutely necessary 64% of family physicians reported hesitancy to start insulin mostly due to apparent patient reluctance
Biosimilar is a protein molecule which is a duplicate copy of already existing insulins having an identical amino acid sequence (not withstanding minor variations in clinically active components) and with no significant differences in efficacy and safety. European Union guidelines have stated that for manufacturing biosimilar insulins, their safety and efficacy profile should be similar to those of the original insulin formulation . In 2018, a systematic review was carried out which compared Basalog, LY2963016, Basalin, and MK-1293 with Lantus while SAR342434 with Humalog with respect to their efficacy and safety . Various clinical studies suggested similar clinical efficacy, immunogenicity and adverse events.
Recommendations from RSSDI for biosimilar insulins
• Dose titration should be advised before switching from original insulin to biosimilar insulin starting with a reduced dose and to up-titrate to avoid hypoglycemia.
Various human insulin and analogue insulin sold in India
Analog insulin (glargine)
Insugen R, 30/70,50/50, N (Biocon)
Basalog (Biocon; India launch year: 2009)
Humstard 30/70 (Zydus)
Basugine (Lupin (Synox); India launch year: 2013)
Humarap (Abbott, Cadila)
Glaritus (Wockhardt; India launch year: 2009)
Lupisulin-R, M30, M50, N (Lupin: India)
Basaglar (Eli Lilly/Cipla; India launch year: 2018)
Recosulin-R, 30/70, 50/50, N (Shreya Life Sciences: India)
Human Fastact (Eli Lilly and Company: India)
Mixact 30/70 (Novo Nordisk)
USV discontinued Wosulin R, 30/70, 50/50, N (Wockhardt; India launch year: 2003)
Classification of “smart” insulins
Protein-binding ligand (lectin)
• Concavalin A was used to bind to glycosylated insulin, which retained its bioactivity
• This insulin ligand complex released insulin upon being stimulated by ambient hyperglycemia to dissociate
Bulk hydrogel matrix
• Used glucose oxidase as a glucose-sensing mechanism
• Glucose oxidase swell in response to hyperglycemia
• This stimulates entrapped glucose to break down and activate insulin
Phenyl boronic acid
• Glucose-sensitive self-regulated insulin delivery
Nanotechnology-based smart insulins
• Release of insulin depends on glycemic levels
Microgel (smart sponge)
• Regulated insulin release in response to ambient glycemia
• Glucose-mediated insulin delivery
Development of non-injectable insulin products
Technosphere insulin (TI) is an alternative to subcutaneous prandial insulin which is delivered in a compact handheld inhaler device and has been approved in the USA by the Food and Drug Administration (FDA) for the treatment of individuals with T1DM and T2DM .
Inhaled insulin is available in the form of a freeze-dried powder of recombinant human insulin adsorbed onto fumaryl diketopiperazine and form microparticles for inhalation. It has a limited duration of action which lasts for approximately 2–3 h during which it rapidly gets absorbed within 12–15 min of inhalation with a peak action of approximately 53 min. The action profile of TI is similar to that of rapid-acting insulin .
A breath-powered device is used for the delivery of technosphere insulin which converts the powder formulation into lightweight particles and causes dispersion. The drug completely gets cleared from the lungs after 12 h of absorption. Clinical evidences in individuals with T2DM, CV safety outcomes, and long-term surveillance are required . Afrezza, an inhaled form of rapid-acting insulin developed by using a technosphere technology, has been approved by the FDA in 2014. This insulin has safer PK profile in comparison with previously failed inhaled form of insulin (Mohanty, 2017: 28571200).
The most common route for insulin administration has been the subcutaneous route, but in the last few years, efforts have been made to change the route of administration from subcutaneous to an oral route .
There are several barriers such as physical barrier, the enzymatic barrier, and the instability of insulin in the gastrointestinal tract for the oral administration of insulin. But recent studies have summarized various nanotechnology-based strategies for the development of insulin delivery by the oral route .
Apart from being a non-injectable route of administration, oral insulin also depicts physiological insulin extraction as it directly enters the portal circulation and promotes increased uptake of net hepatic glucose production [262, 263].
Oral insulin replicates the exact secretion of exogenous insulin from the pancreas. After getting absorbed by the intestinal walls, it reaches in higher concentration into the liver through the portal vein.
Initiation of some innovative approaches such as mucoadhesive polymers, absorption enhancers, protease inhibitors, and particulate carrier systems has boosted the scope of research in delivering insulin orally by counteracting the naturally existing hurdles and harsh conditions of the GIT. Funding, on the other hand, has always been a paramount limitation to obtain thorough PK and pharmacodynamic data in animals and humans and possible long-term side effects of the newly introduced oral insulin candidates [262, 263].
In the past few years, buccal mucosa has been found to be a promising delivery route for administration of insulin as it has a rich vasculature, immobile mucosa, and anexpanse of smooth muscle .
Avoids presystemic metabolism of insulin
Protects stomach from the direct contact of acid labile insulin
Less enzymatic activity
Improves patient compliance as it eliminates the pain caused by injections
Oral-lyn (Generex Biotechnology Corporation, Toronto, Canada) is currently the only buccal insulin available which can be administered along with food and is licensed for use in countries such as Southeast Asia, Africa, and South America. It is also currently enrolled in an FDA-approved Investigational New Drug Treatment program with a phase III trial planned [264, 265].
Oral-lyn is a proprietary liquid formulation of human recombinant insulin which can be administered through a spray device. This spray device delivers aerosol at high velocity (~ 100 mph) and is further absorbed by the mucosal lining of the oral cavity. Each puff delivered is equivalent to 1 unit of insulin absorbed into the systemic circulation [264, 265].
As it is absorbed quickly from the vascular oral mucosa, a decrease in the glucose activity can be seen within 5 min, showing a peak insulin action at around 30 min, and a duration of action is of 2 h (shorter than subcutaneous human insulin) [264, 265].
It has been seen that glycemic efficacy of both Oral-lyn and regular human insulin is comparable in individuals with T1DM receiving twice-daily basal insulin analog . It was observed that when Oral-lyn was added to oral glucose-lowering agents in individuals with T2DM with inadequate glycemic control, there was a great reduction in postprandial glucose levels within 2 h as compared with oral glucose-lowering agents. Comparative studies with insulin analogs in T2DM have not yet been carried out.
Occasional mild, self-limiting dizziness is some of the side effects observed in some of the clinical studies. Insulin spray formulation may significantly impact treatment compliance . However, more clinical studies are needed to inform glycemic durability, safety, and tolerability.
Insulin has been the most effective and durable hypoglycemic agent for the management of diabetes. Early treatment intensification with insulin in those who fail to achieve glycemic goals is important for reducing complications in the Indian population with wide ethno-geographic differences. We hope that adoption of these consensus recommendations will simplify the understanding of insulin therapy among clinicians and help better healthcare delivery to people with diabetes.
The authors would like to acknowledge the significant contribution made by the extended expert panel: Aravind SR, Banarjee S, Bhansali A, Chandalia HB, Das S, Gupta OP, Joshi S, Kumar A, Kumar KM, Madhu SV, Mittal A, Mohan V, Munichhoodappa C, Ramachandran A, Sahay BK, Sai J, Seshiah V, Zargar AH. Authors also acknowledge WorkSure India for assistance in medical writing and editing.
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