Most practice guidelines recommend the use of longacting or pre-mixed insulin at the initiation of insulin therapy in type 2 diabetes, especially in patients not achieving glycaemic goals. Nonetheless, there are some specific indications where basal bolus insulin is the preferred regimen for insulin initiation. These include the "5S" situations - 'Severe' hyperglycaemia, 'Symptomatic' diabetes, 'Sick' diabetes (acute or chronic comorbidity), 'Special' situations (pregnancy, childhood, adolescence) and 'Secondary' diabetes (pancreatic, drug-induced, endocrine disorders). This review describes a practical approach to initiation and follow up of basal bolus insulin regimens.
Keywords: diabetes, insulin, basal-bolus insulin regimen, multiple subcutaneous insulin injection (MSII), insulin regimen.
Diabetes is a heterogeneous condition, which requires an individualized, patient-centered approach to management. While diabetes is characterized by multiple pathophysiological defects often described as the ominous octet, defects in β-cell function and insulin secretion occur very early, even before the diagnosis of diabetes, and progress over time.1 Therefore, a large majority of individuals eventually require insulin therapy in the longterm as the disease progresses to irreversible β-cell insufficiency.2 In addition, insulin may also be required for short term during periods of acute hyperglycaemia, glucotoxicity or inter current illness that are characterized by transient or partially reversible β-cell insufficiency.2 The choice of therapeutic regimen is guided by individual patient requirements and may vary over time. Treatment needs to be tailored for the individual, based on his/her glycaemic status and duration of diabetes, anthropometric parameters, risk of hypoglycaemia, comorbidities and concomitant illness, dietary habits and lifestyle, self-care capabilities and socio-economic factors.3,4
Limitations of current recommendations
Consensus statements and recommendations do offer a framework to help choose appropriate therapeutic interventions.3-6 It must be noted, however, that these guidelines are not a substitute for clinical skills and acumen. In general, these documents assume that they are dealing with adult, non-pregnant, otherwise healthy individuals, who are in regular contact with diabetes care services. Critical analysis of the levels of HbA1c to classify severity of hyperglycaemia in order to triage patients for the choice of initial therapy, used by guideline authors, would seem to suggest that levels ≥10.0% are a rare occurrence. The authors of these recommendations also assume that there is no acute complication or comorbidity which needs to be addressed, and no concomitant intake of medication which may influence choice of glucose lowering therapy. Adherence to lifestyle modification is assumed. Reality, however, is different, particularly for the Afro Asian physician who deals with diabetes.7 The developing countries of Africa and South-East Asia have a huge burden of undetected diabetes associated with high morbidity and mortality. Compounded by unique socio-cultural and economic factors, this creates a significant challenge for healthcare providers.8 The busy medical care provider deals with not only healthy adults, but with sick persons, children, adolescents and antenatal or lactating women as well. Many persons who should ideally be admitted in an indoor care facility are treated on an outdoor basis in the real world.
A significant proportion of patients present late, with severe hyperglycaemia or symptoms of uncontrolled diabetes such as weight loss and osmotic symptoms. Others present with symptoms suggestive of complications including sensory neuropathy, autonomic neuropathy, cardiovascular or cerebrovascular disease, renal impairment, visual impairment and / or musculoskeletal dysfunction.9-11 Acute comorbidity, such as infectious disease, dehydration, electrolyte imbalance or organ dysfunction, complicate the presenting picture in many cases. Clinical situations which warrant use of glucose- modifying drugs, such as glucocorticoids and immunosuppressants, are notuncommon. The Afro Asian diabetes care physician, therefore, wears two hats simultaneously: that of an acute care provider, and that of a chronic care delivery expert.
Though extensive (and sometimes, conflicting) guidance is available regarding the management of hyperglycaemia from a chronic or long-term perspective, there is inadequate literature to guide the management of 'acute diabetes'. Though optimal means of in-patient glycaemia management are also published,12 the outdoor management of persons with diabetes who are symptomatic or "sick" has been ignored. One reason may be the relative preponderance of such patients in Third World countries, which have not been able to put forward their perspective of diabetes in international literature. A significant proportion of these sick patients continue to be managed in outdoor facilities with little to guide the clinician.
Diversity of insulin regimens
Several different insulin formulations are currently available and insulin regimens can vary from basal alone, basal plus, premixed or basal bolus regimens. Conventional and recent hyperglycaemia management guidelines support the use of basal insulin or premixed insulin as initial therapy, and basal plus, premixed or basal bolus as an intensification option in the long-term management of hyperglycaemia.13,14 All these have their own place in the management of diabetes. Each insulin regimen has its advantages and short-comings and the choice of insulin formulation and insulin regimen needs to be individualized from person to person and may vary from time to time in the same individual. Such a wide variety of choices allows the astute clinician to match the appropriate insulin to the patient's biomedical needs, lifestyle, and personal preferences.
Basal bolus regimen
The normal physiological pattern of insulin secretion is characterized by a continuous basal secretion of insulin by the pancreas to suppress hepatic glucose production overnight and between meals, and a bolus secretion following ingestion of meals or snacks, that allows for increased peripheral uptake of glucose.11 This is depicted in figure.
In general, basal insulin constitutes approximately 40-50% of total daily insulin secretion and prandial insulin in each meal is 10-20% of total insulin, depending on the carbohydrate and calorie content of the meal.15 The basal-bolus regimen, or multiple subcutaneous insulin injection (MSII), consists of one (but sometimes two) basal injection, along with bolus injections of short-acting or rapid-acting insulin with each meal. While the basal insulin controls fasting glycaemia, rapid acting shots of insulin deliver prandial insulin for meal-related glucose control. Some preparations of insulin which can be used as part of a bas al bolus regimen are listed in Table -1.
The basal-bolus insulin regimen is intended to replicate the insulin dynamics of basal and prandial components and can be considered the most physiological replacement strategy after continuous subcutaneous insulin injection (CSII).16 It is also the most effective insulin regimen that provides both basal and prandial glycaemic control, helps attain glycaemic control rapidly and can be tailored to suit varying severity of hyperglycaemia. The basal bolus regimen offers the convenience of flexibility in meal timing and composition and can be adjusted to individual's activity levels.15 However, the basal-bolus regimen entails the burden of multiple daily insulin injections, and a need for more frequent self-monitoring of blood glucose (SMBG). Use of rapid acting and long acting insulin analogues is associated with a more physiological insulin delivery and a lower risk of hypoglycaemia including nocturnal and severe hypoglycaemia and better postprandial glucose control.3 But cost considerations and availability issues in developing countries limit the use of insulin analogues. Conventional insulins continue to be the most prescribed insulins in Afro-Asian countries and are used most commonly in the basal-bolus regimen as well.
Indications for basal-bolus insulin
The indications for initiation of basal bolus insulin are listed in Table-2 and are described as the 5S indications.
Any clinical situation that requires prompt and early resolution of hyperglycaemia, with minimal variability, are candidates for basal bolus therapy. Such indications may occur at any time in the natural history of diabetes. Insulin may have to be started de novo as basal-bolus therapy or an existing insulin regimen may be intensified to basal- bol us w henever th ought appropriate. As an initial therapy, basal bolus insulin is indicated in persons with severe hyperglycaemia, significant symptoms of diabetes, and acute or chronic complications which require early addressal of hyperglycaemia. This would also include comorbid conditions which will not recover optimally unless glycaemia is instituted, and special situations including hyperglycaemic states in pregnant and lactating women. Infections are a commonly encountered comorbid condition in diabetes.17 Infections have a bidirectional relationship with glycaemic control. Poor glycaemic control precipitates infections and contributes to non-resolution of existing infection. Such infection, in turn, leads to uncontrolled hyperglycaemia, and is a cause of refractory diabetes. Just as undetected focus of infection must be searched for as a part of management poorly of controlled diabetes, poorly managed diabetes must be corrected for the infection to respond to routine medical and/or surgical intervention.
Table-3 details clinical situations when basal bolus insulin should be considered in the management of diabetes with concomitant infection. We use the mnemonic STRIFE to share these indications with colleagues. Basal bolus insulin should be initiated in situations of STRIFE, i.e., Severe hyperglycaemia / variability, Threat to life/ limb/organ, Resistant/ recurrent infection, major planned Interventions, impaired organ Function (cardiac, renal, hepatic) and excessive Expense of therapy/impact on quality of life.
Calcutation of initial dose and titration
When initiating basal-bolus insulin, the healthcare provider must first estimate the Total Daily Dose (TDD) of insulin. This depends on several factors, including the severity of hyperglycaemia, expected nutritional and caloric intake, concomitant acute medical or surgical conditions including infections, concomitant use of medications such as glucocorticoids that may lead to increased insulin requirements, comorbidities such as renal or hepatic impairment and the individual's risk for hypoglycaemia. The diabetes literacy/numeracy of the patient, and his/her willingness/ability to self-monitor blood glucose and titrate insulin doses accordingly also influence the initial dose of insulin. An estimated total daily dose of 0.3 to 1.0 U/kg/day can be prescribed when basal bolus insulin is initiated.18
Table-4 provides guidance in calculation of initial total daily dose (TDD). However, it must be remembered that the actual dose requirements may vary from individual to individual and rapid titration of both basal and bolus insulin will be needed to achieve optimal therapeutic targets. The distribution of basal and bolus insulin is usually 40- 50% basal, and 50-60% divided as prandial insulin boluses with meals. The prandial insulin bolus varies from 10-20% per meal depending on the carbohydrate content of the meal. The doses of both basal and prandial components are titrated based on regular SMBG, to achieve predetermined targets for fasting, pre-prandial and postprandial glucose levels. Basal insulin should be titrated once or twice a week to a fasting plasma glucose target of 80-130 mg/dl. The frequency of titration for basal insulin would depend on the pharmacokinetic properties of the insulin formulation being used. Since ultra-long acting insulins such as Degludec and Glargine U-300 take 3-5 days to achieve a steady state, rapid daily titrations should be avoided. Prandial doses of insulin are titrated based on post-prandial glucose values and the carbohydrate intake during the respective meal.
Box-1 provides a case vignette discussing the initiation of basal-bolus insulin regimen and dose titration in a hypothetical patient.
The indication for basal bolus insulin informs the duration of this mode of treatment. Patients with severe or symptomatic type 2 diabetes may respond to less intensive therapy with insulin and/ or oral glucose lowering drugs, once the initial glucotoxicity and metabolic derangement is corrected. Those with acute or subacute comorbidity, such as infection, can be weaned off insulin once the infection is cured. If basal bolus insulin is initiated for renal or hepatic impairment, or for a physiological state such as pregnancy or lactation, it must be continued until this state is resolved. Changes in the comorbid health status, or in concomitant medication and nutritional status, should prompt a review of the glucose-lowering strategy. This clinical review should focus on choice of therapeutic regimen, insulin preparations, and insulin dosage and insulin technique as well.
Basal bolus insulin is associated with a risk of hypoglycaemia. This is especially so with human insulinbased regimens. A basal bolus prescription, therefore should be accompanied by detailed counseling of the patient and his/ her caregivers. Insulin technique, glucose monitoring, and hypoglycaemia prevention, detection and management must be explained in detail. The insulin dosage should be kept to a minimum, provided that glycaemic targets are met. Patients should be reminded that insulin is not a substitute for lifestyle modification; rather, it is an add-on to a healthy life. Regular medical supervision is required to ensure that adverse events are minimized.
This communication details the place of basal bolus insulin in diabetes management, focusing on its usage as a regimen for initiation of injectable therapy. Understanding of the indications for basal bolus insulin, and its pragmatic usage, will allow achievement of glycaemic goals and optimization of overall health. We would like to reiterate that this is not a prescriptive guideline or recommendation. It is an experience-based guide to the rational use of insulin in complex clinical situations. Each patient is unique, and so is each clinical challenge. In addition, diabetes is a dynamic disease and the therapeutic regimen needs to be revised from time to time, based on current clinical condition of an individual. We hope that this discussion encourages good clinical sense in diabetology.
1. Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009 ;58:773-95.
2. Kalra S, Gupta Y. Beta-cell Insufficiency. Eur Endocrinol. 2017;13:51 53.
3. Davies MJ, D'Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41:2669-2701.
4. Bajaj S. RSSDI clinical practice recommendations for the management of type 2 diabetes mellitus 2017. Int J Diabetes Dev Ctries. 2018 Mar;38(Suppl 1):1-115.
5. Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, et al. Consensus statement by the american association of clinical endocrinologists and american college of endocrinology on the comprehensive type 2 diabetes management algorithm - 2017 executive summary. Endocr Pract. 2017 ;23:207-238.
6. Aschner P. New IDF clinical practice recommendations for managing type 2 diabetes in primary care. Diabetes Res Clin Pract. 2017; 132:169-170.
7. Kalra S, Megallaa MH, Jawad F. Patient-centered care in diabetology: From eminence-based, to evidence-based, to end user-based medic i ne. I ndian J Endocr inol Me tab. 2 01 2; 16 :8 71 -2.
8. Cho NH, Shaw JE, Karuranga S, Huang Y, da Rocha Fernandes JD, Ohlrogge AW, et al. IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract. 2018 ; 138:271-281.
9. Mohan V, Sandeep S, Deepa R, et al. Epidemiology of type 2 diabetes: Indian scenario. Indian J Med Res. 2007; 125:217-230.
10. Unnikrishnan R, Anjana RM, Deepa M, et al. ICMR-INDIAB Collaborative Study Group. Glycemic control among individuals with self-reported diabetes in India--the ICMR-INDIAB Study. Diabetes Technol Ther. 2014;16:596-603.
11. Peer N, Kengne AP, Motala AA, Mbanya JC. Diabetes in the Africa Region: an update. Diabetes Res Clin Pract. 2014 ;103:197-205.
12. Umpierrez GE, Hellman R, Korytkowski MT, Kosiborod M, Maynard GA, Montori VM, et al. Endocrine Society. Management of hyperglycemia in hospitalized patients in non-critical care setting: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2012 Jan;97:16-38.
13. Silver B, Ramaiya K, Andrew SB, Fredrick O, Bajaj S, Kalra S, et al. EADSG Guidelines: Insulin Therapy in Diabetes. Diabetes Ther. 2018 ;9:449-492. doi: 10.1007/s13300-018-0384-6.
14. Kalra S, Thai HQ, Deerochanawong C, Su-Yen G, Mohamed M, Latt TS, et al. Choice of Insulin in Type 2 Diabetes: A Southeast Asian Perspective. Indian J Endocrinol Metab. 2017;21:478-481.
15. Donner T. Insulin - Pharmacology, Therapeutic Regimens And Principles Of Intensive Insulin Therapy. [Updated 2015 Oct 12]. In: De Groot LJ, Chrousos G, Dungan K, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK278938/
16. Hirsch IB, Farkas-Hirsch R, Skyler JS. Intensive insulin therapy for treatment of type I diabetes. Diabetes Care. 1990;13:1265-83.
17. Atreja A, Kalra S. Infections in diabetes. J Pak Med Assoc. 2015;65:1028-30.
18. Khazai NB, Hamdy O. Inpatient Diabetes Management in the Twenty-First Century. Endocrinol Metab Clin North Am. 2016 ;45:875-894.