Diabetes Ther (2019) 10:1189–1204
https://doi.org/10.1007/s13300-019-0629-z
REVIEW
BE-SMART (Basal Early Strategies to Maximize HbA1c
Reduction with Oral Therapy): Expert Opinion
Sarita Bajaj . A. K. Das . Sanjay Kalra . Rakesh Sahay . Banshi Saboo . Sambit Das . M. Shunmugavelu .
Jubbin Jacob . Gagan Priya . Deepak Khandelwal . Deep Dutta . Manoj Chawla . Vineet Surana .
Mangesh Tiwaskar . Ameya Joshi . Pradip Krishna Shrestha . Jyoti Bhattarai . Bishwajit Bhowmik .
Tint Swe Latt . Than Than Aye . G. Vijayakumar . Manash Baruah . Fatema Jawad . A. G. Unnikrishnan .
Subhankar Chowdhury . Md. Faruqe Pathan . Noel Somasundaram . Manilka Sumanathilaka . Abbas Raza .
Silver K. Bahendeka . Ankia Coetzee . Sundeep Ruder . Kaushik Ramaiya . Roberta Lamptey . Charlotte Bavuma .
Khalid Shaikh . Andrew Uloko . Sandeep Chaudhary . Abdurezak Ahmed Abdela . Zhanay Akanov .
Joel Rodrı̀guez-Saldaña . Raquel Faradji . Armindo Tiago . Ahmed Reja . Leszek Czupryniak
Received: March 19, 2019 / Published online: May 17, 2019
 The Author(s) 2019
ABSTRACT several years due to its asymptomatic nature
during the initial stages. In India, 70% of diag-
The past three decades have seen a quadruple rise nosed diabetes cases remain uncontrolled. Cur-
in the number of people affected by diabetes rent guidelines endorse the initiation of insulin
mellitus worldwide, with the disease being the early in the course of the disease, specifically in
ninth major cause of mortality. Type 2 diabetes patients with HbA1c[10%, as the use of oral
mellitus (T2DM) often remains undiagnosed for agents alone is unlikely to achieve glycemic tar-
gets. Early insulin initiation and optimization of
glycemic control using insulin titration algo-
Enhanced Digital Features To view enhanced digital rithms and patient empowerment can facilitate
features for this article go to https://doi.org/10.6084/
m9.figshare.8035433. the effective management of uncontrolled dia-
betes. Early glucose control has sustained
S. Bajaj M. Shunmugavelu
Department of Medicine, MLN Medical College, Trichy Diabetes Speciality Centre (P) Ltd., Trichy,
Allahabad, India India
A. K. Das J. Jacob
Department of Medicine, JIPMER, Puducherry, India Endocrine and Diabetes Unit, Department of
Medicine, Christian Medical College and Hospital,
S. Kalra (&) Ludhiana, India
Department of Diabetes and Endocrinology, Bharti
Hospital, Karnal, India G. Priya
e-mail: brideknl@gmail.com Fortis Hospital, Mohali, India
R. Sahay D. Khandelwal
Department of Endocrinology, Osmania Medical Department of Endocrinology, Maharaja Agrasen
College and Hospital, Hyderabad, India Hospital, Delhi, India
B. Saboo D. Dutta
Diacare—Diabetes Care and Hormone Clinic, Department of Endocrinology, Diabetology and
Ahmedabad, India Metabolic Disorders, Venkateshwar Hospital, New
Delhi, India
S. Das
Department of Endocrinology, Apollo Hospitals,
Bhubaneswar, India
1190 Diabetes Ther (2019) 10:1189–1204
benefits in people with diabetes. However, insu- disease is now the ninth major cause of mor-
lin initiation, dose adjustment, and the need to tality [1]. In 1980, the estimated number of
repeatedly assess blood glucose levels are often persons with diabetes was 108 million; by 2014,
perplexing for both physicians and patients, and this figure had escalated to 422 million. The
there aremisconceptions andconcerns regarding age-standardized global prevalence of diabetes
its use. Hence, an early transition to insulin and has almost doubled, increasing from 4.7% to
ideal intensification of treatment may aid in 8.5% in the adult population, reflecting a rise in
delaying the onset of diabetes complications. associated risk factors such as obesity. In 2012,
This opinion statement was formulated by an diabetes was the direct cause of 1.5 million
expert panel on the basis of existing guidelines, deaths; additionally, by increasing the risks of
clinical experience, and economic and cultural cardiovascular and other diseases, higher-than-
contexts. The statement stresses the timely and optimal blood glucose resulted in another 2.2
appropriate use of basal insulin in T2DM. It million deaths. Of these 3.7 million deaths
focuses on the seven vital Ts—treatment initia- linked to high glocuse levels, 43% occurred in
tion, timing of administration, transportation people under 70 years of age [2].
and storage, technique of administration, targets The recent International Diabetes Federation
for titration, tablets, and tools for monitoring. (IDF) atlas predicted that the number of people
Funding: Sanofi. with diabetes will rise to 693 million by 2045. In
Africa, the number of people with diabetes is
expected to rise by 162.5% by 2045. Southeast
Keywords: Basal insulin; Degludec; Detemir; Asia is home to 19.3% (82 million adults) of the
Glargine; Hypoglycemia; Titration; Type 2 global diabetic population, and 84.5% of all
diabetes mellitus undiagnosed cases of diabetes are in low- and
middle-income countries. Nearly 45.8% of
adults with diabetes in Southeast Asia are
INTRODUCTION undiagnosed, while over two-thirds (69.2%) of
adults with diabetes in the African region are
In the past three decades, there has been a undiagnosed [3].
quadruple rise in the number of people affected Type 2 diabetes mellitus (T2DM) often
by diabetes mellitus worldwide, such that the remains undiagnosed for many years, owing to
its asymptomatic nature during the initial
M. Chawla T. S. Latt
Lina Diabetes Care and Mumbai Diabetes Research University of Medicine 2, Yangon, Myanmar
Centre, Mumbai, India
T. T. Aye
V. Surana University of Medicine 2, Myanmar Society of
Manipal Hospitals, New Delhi, India Endocrinology and Metabolism (MSEM), Yangon,
Myanmar
M. Tiwaskar
Shilpa Medical Research Centre, Mumbai, India G. Vijayakumar
Apollo Specialty Hospital and Diabetes Medicare
A. Joshi Centre, Chennai, India
Bhaktivedanta Hospital and Research Institute,
Thane, India M. Baruah
Excel Care Hospitals, Guwahati, India
P. K. Shrestha
Nidan Hospital Pvt. Ltd., Patan, Nepal F. Jawad
Journal of Pakistan Medical Association, Karachi,
J. Bhattarai Pakistan
Metro Kathmandu Hospital, Kathmandu, Nepal
A. G. Unnikrishnan
B. Bhowmik Chellaram Diabetes Hospital, Pune, India
Centre for Global Health Research, Diabetic
Association of Bangladesh, Dhaka, Bangladesh
Diabetes Ther (2019) 10:1189–1204 1191
stages, during which the body is exposed to factors for achieving the glycemic HbA1c goal as
hyperglycemia, bringing about irreversible targeted by the treating physician in adults with
organ damage [4]. In India, 70% of diagnosed type 2 diabetes requiring insulin initiation,
diabetes cases remain uncontrolled [5]. Once- titration, and/or intensification [11].
daily dosing of basal insulin with continued use Current guidelines endorse the initiation of
of one or more oral antidiabetic drugs (OADs) insulin early in the course of the disease, par-
has proven to be an effective and safe glucose- ticularly in patients with HbA1c[10%, as the
lowering treatment in most insulin-naive use of oral agents alone is unlikely to achieve
patients. It has various advantages—only one glycemic targets in patients with uncontrolled
insulin injection may be required each day, diabetes. Early insulin initiation and optimiza-
with no need to mix different types of insulin, tion of glycemic control using insulin titration
and titration can be accomplished in a slow and algorithms and patient empowerment can help
safe manner. Moreover, this combination ther- to effectively manage uncontrolled diabetes.
apy requires a lower total dose of insulin. This Self-monitoring of blood glucose (SMBG), edu-
combination approach was popularized by the cation about insulin, and the ability of those
BIDS regimen, which combines a basal insulin with diabetes to detect and manage hypo-
(BI) with a sulfonylurea (DS) [6]. glycemia can significantly facilitate this process
The ORIGIN trial showed that therapy with [12, 13].
basal insulin glargine had a neutral effect on Even though treatment with insulin is
cardiovascular outcomes and cancers while acknowledged to be the most effective treat-
permitting near-normal glycemic control and ment for T2DM, it is considered to be chal-
slowing the progression of dysglycemia [7]. lenging and time-consuming for both the
However, early glucose control has shown sus- patient and the healthcare provider [14]. Insulin
tained benefits in people with diabetes; it initiation, insulin dose adjustment, and the
reduced the risks of macro- and microvascular need for repeated assessment of blood glucose
complications [8] and even lowered the risk of levels are often perplexing for physicians and
cardiovascular complications in other trials patients owing to misconceptions and concerns
such as the Diabetes Control and Complications regarding its use [15]. Clinical inertia or thera-
Trial (DCCT) and the UK Prospective Diabetes peutic inertia, defined as a recognition of the
Study (UKPDS) [9, 10]. Studies such as GOAL problem but a failure to act, plays a role in
assessed the clinical and nonclinical predictive delayed insulin initiation and optimization and
S. Chowdhury A. Coetzee
Department of Endocrinology, IPGME&R and SSKM Division of Endocrinology, Department of
Hospital, Kolkata, India Medicine, Stellenbosch University and Tygerberg
Hospital, Society for Endocrinology, Diabetes and
Md. F. Pathan Metabolism, Cape Town, South Africa
Department of Endocrinology, BIRDEM General
Hospital, Dhaka, Bangladesh S. Ruder
Life Fourways Hospital, University of the
N. Somasundaram Witwatersrand, Cape Town, South Africa
Diabetes and Endocrine Unit, National Hospital of
Sri Lanka, Colombo, Sri Lanka K. Ramaiya
Shree Hindu Mandal Hospital, Dar e Salaam,
M. Sumanathilaka Tanzania
National Hospital of Sri Lanka, Sri Lanka College of
Endocrinologists, Colombo, Sri Lanka R. Lamptey
Korle Bu Teaching Hospital, University of Ghana
A. Raza School of Medicine and Dentistry, Accra, Ghana
Shaukat Khanum Memorial Cancer Hospital and
Research Center, Lahore, Pakistan C. Bavuma
College of Medicine and Health Science, University
S. K. Bahendeka of Rwanda, Kigali, Rwanda
Mother Kevin Postgraduate Medical School, Martyrs
University, St. Francis Hospital, Kampala, Uganda
1192 Diabetes Ther (2019) 10:1189–1204
thus poor glycemic control. It can be present at and does not involve any new study on human
the patient, physician, and system levels. This or animal subjects performed by any of the
therapeutic inertia may be initiation inertia authors.
(delayed initiation of insulin), titration inertia
(lack of dose adjustment), intensification inertia
(delayed intensification), or all three together. BE-SMART EXPERT OPINION
Reasons for this inertia may include miscon-
ceptions surrounding insulin therapy, a lack of This expert opinion is focused on the timely
motivation, and poor communication between and appropriate use of basal insulin in T2DM
patients and healthcare providers (HCPs). Apart treatment [early basal insulin initiation and
from these, a fear of weight gain, hypoglycemia, optimization, with a focus on the role of basal
and increasingly complex treatment regimens insulin supported oral therapy (BOT)]. It focuses
may also contribute to therapeutic inertia, on the seven vital Ts—treatment initiation,
thereby leading to poor glycemic control. Early timing of administration, transportation and
transition to insulin and ideal intensification of storage, technique of administration, targets for
treatment might aid in delaying the onset of titration, tablets, and tools for monitoring. The
diabetes complications. Physicians managing 7-T concept can be a useful reckoner to help
diabetes must aim to increase acceptance, per- physicians improve their understanding and
sistence, and adherence to insulin therapy by optimize the use of basal insulin early in dia-
focusing on the safety, simplicity, and conve- betes treatment along with oral antiglycemic
nience of the therapy [14, 16, 17]. agents, thereby improving outcomes.
The members of the expert panel have for-
mulated this opinion statement on the basis of Treatment Initiation
current disease concepts among physicians,
clinical experience, available research evidence, • Timely insulin initiation leads to a long-term
and economic and logistic constraints that are reduction in complications and improved
prevalent in India and other countries whose outcomes. Clinical evidence from landmark
members were involved in this panel. This trials such as the Diabetes Control and
article is based on previously conducted studies Complications Trial/Epidemiology of
K. Shaikh R. Faradji
Department of Diabetes, Faculty of Internal Clinica EnDi, RENACED Diabetes Tipo 1, Escuela de
Medicine, Royal Oman Police Hospital, Muscat, Medicina, TEC-ABC, Centro Médico ABC, Sociedad
Oman Mexicana de Nutrición y Endocrinologı́a, Mexico
City, Mexico
A. Uloko
College of Health Sciences, Bayero University, Kano, A. Tiago
Nigeria Mozambican Diabetic Association, Maputo Central
Hospital, Maputo, Mozambique
S. Chaudhary
NMC Speciality Hospital, Dubai, UAE A. Reja
Department of Internal Medicine, Addis Ababa
A. A. Abdela University, Addis Ababa, Ethiopia
Department of Internal Medicine, School of
Medicine, CHS, Addis Ababa University, Addis L. Czupryniak
Ababa, Ethiopia Department of Diabetology and Internal Medicine,
Central University Hospital, Warsaw Medical
Z. Akanov University, Warsaw, Poland
Kazakh Society for Study of Diabetes, Almaty,
Kazakhstan
J. Rodrı̀guez-Saldaña
Multidisciplinary Diabetes Center of Mexico,
Mexico City, Mexico
Diabetes Ther (2019) 10:1189–1204 1193
Diabetes Intervention and Complications Timing of Administration
Study (DCCT/EDIC) and the United King-
dom Prospective Diabetes Study (UKPDS) • Basal insulin should be injected at the
shows that early glucose control reduces the appropriate time (usually bedtime), in line
risk of both macro- and microvascular com- with the prescribing information.
plications [8, 18]. Studies have shown that • Basal insulin may, under some circum-
targeting postprandial glucose (PPG) can stances (e.g., administration by caregivers
help minimize cardiovascular risk [19, 20]. and nursing home residents), be adminis-
• ‘‘Metabolic karma’’ is a term that can effec- tered in the morning or afternoon as well,
tively explain glycemic legacy in diabetes. It preferably at the same time daily.
helps us to understand the advantages of • Basal insulin analogues provide the advan-
achieving tight glycemic and metabolic con- tage of flexibility of timing, making it simple
trol in persons with diabetes using appropri- and less intrusive. They involve only one
ately individualized patient-centric therapy injection per day and do not require adher-
[21]. ence to inflexible meal patterns, quantity,
• Early insulin initiation can help overcome and composition [25].
the glucotoxic effects of hyperglycemia and • Neutral Protamine Hagedorn (NPH)
hence facilitate ‘‘b-cell rest’’ to preserve b-cell Insulin: With NPH insulin, the preferred
mass and function, while also improving injection time is bedtime [26].
insulin sensitivity [22]. • First-Generation Basal Insulin Ana-
• Basal insulin is a convenient and effective logues (Gla-100 and Insulin Detemir):
option for insulin initiation in the majority Both of the first-generation basal insulin
of patients if it does not impact post-meal analogues are also best administered at
hyperglycemia significantly. Basal insulin bedtime. Insulin glargine can be admin-
should be initiated in a timely manner, istered anytime each day, irrespective of
preferably within 3–6 months of inadequate fasting plasma glucose (FPG) levels
control, with the optimal use of 1, 2, or 3 [25, 27, 28].
oral glucose-lowering agents (GLA) [12]. • Second-Generation Basal Insulin Ana-
• Basal insulin may be initiated at the diagno- logues (Insulin Degludec and Gla-300):
sis of diabetes if catabolic symptoms are These offer more flexibility in the timing
present and/or glycated hemoglobin of injection and can be administered at
(HbA1c) is[10% [13]. any time in the day, but they have to be
• The basal-only regime is the most conve- administered at the same time each day
nient initial insulin regimen, beginning at [29].
10 U/day or 0.1–0.2 U/kg/day, depending on • Upon realizing that a dose of basal insulin
the degree of hyperglycemia [12]. has been missed, the situation can be
• In diabetes management, it is crucial that redressed by immediately administering the
patients are involved in their treatment dose while ensuring that there is a gap of at
process. There is a need for open doctor–pa- least an 8 h between injections. Once this
tient communication to achieve good glyce- dose has been taken, the patient can return
mic control, reduce complications, and to their regular dosing schedule.
improve quality of life. Training of health- • In fasting and special populations, the
care professionals, persons living with dia- schedule for basal insulin and GLA
betes, and other caregivers as well as administration shown in Table 1 should
teamwork among all stakeholders are crucial be followed.
to achieving optimal basal insulin use In order to prevent episodes of hypoglycemia
[23, 24]. during fasts, such as during Ramadan, patients
treated with insulin and insulin secretagogues
should measure glucose before, during, and
after fasting (2–4 times daily). A reduction in
1194 Diabetes Ther (2019) 10:1189–1204
Table 1 Choice of basal insulin and GLAs in special populations
Population Special Choice of BI Titration Additional GLAs
concern
Fasting/ Hypoglycemia Gla-100/Gla-300/ Slow DPP4i/TZD/glipizide/
Ramadan degludec repaglinide
Pregnancy Safety NPH/Detemir/Glargine Early titration until Metformin
target
Elderly Hypoglycemia Gla-100/Gla-300/ Slow/weekly DPP4i/metformin/SU
degludec
BI basal insulin, DPP4i dipeptidyl peptidase-4 inhibitor, NPH neutral protamine Hagedorn, GLA oral glucose-lowering
agents, TZD thiazolidinediones, SU sulfonylureas
the dose of insulin secretagogues should be Injection Devices:
considered [30]. • Syringes and vials: Disposable plastic insulin
syringes are the most widely used devices for
Transportation and Storage insulin injection. Insulin syringes are avail-
able with 0.3-, 0.5-, 1-, and 2-ml capacities.
Transport: The cold chain should be main- Needle length and thickness have been
tained during the transportation of the vials or reduced to minimize the pain during the
cartridges of insulin [31]. injection and to prevent inadvertent intra-
muscular administration of insulin.
Storage: Insulin vials, cartridges, or pens may Pinching may be necessary for some indi-
be kept at room temperature, i.e., at 59–86 F viduals with thin skin when using the 6-mm or
(15–30 C), for 28 days or about 1 month. larger needles. A 4-mm needle is currently avail-
Insulin detemir can be stored at room tem- able for pens and a 6-mm needle is available for
perature for up to 42 days. Insulin degludec syringes. This means that there are options suit-
may be kept at room temperature for able for everyone,without theneed for pinching.
2 months. Exposure to extremes of temperature • Pen needles: Pen needles are available in
can lead to a loss of insulin effectiveness and a different lengths: 4, 5, 6, 8, and 12.7 mm.
deterioration in glycemic control. In settings Shorter and thinner needles cause less pain;
where the temperatures can be above 30 C or less penetration force can be applied with
below 2 C, it is not advisable to leave the vials thinner needles.
at room temperature, and appropriate steps for
storing them at an optimum temperature must
be taken [32]. Needle Reuse: Ideally, disposable syringes and
pen needles should be used only once, as reuse
Technique of Administration compromises sterility. Hence, a new sterile syr-
inge and needle for every injection is advised.
However, despite reuse not being recommended,
Insulin Injection Technique: Basal insulin
the practice is common. In such cases, reuse
should be injected into the subcutaneous space.
should be restricted to a maximum of 5 times, or
If injected into intramuscular space, it may
fewer if the needle causes pain. Using short- and
inadvertently behave like rapid-acting insulin.
narrow-gauge (4–5 mm 9 32G) insulin pen nee-
Studies with insulin showed an increased rate of
dles reduces pain [34].
absorption with intramuscular injection, and
this is thought to increase the risk and severity Site of Injection: The injection site should be
of hypoglycemia [33]. inspected by a physician, especially if
Diabetes Ther (2019) 10:1189–1204 1195
lipohypertrophy is already present or suspected Table 2 Recommendations for insulin injection [35]
[26]. When shifting the injection site from the
Pre-injection During injection Post-injection
habitual lipohypertrophy site to normal subcu-
taneous tissue [35], insulin dosing may be Convey the Do not inject on a Release skin fold,
reduced by 10–20%. The abdomen is the pre- benefits of tight, blanched, if raised, slowly
ferred site for soluble human insulin because insulin in a or painful skin after
absorption occurs the most rapidly there. In the positive manner fold or bruised withdrawing
case of NPH insulin, the thighs and buttocks are
or traumatic the needle
the preferred injection sites [26]. Differences in
sites
the rates of absorption at various body sites are
negligible with the newer insulin analogues. Selection of Allow topical Follow correct
Injection-Site Rotation: In order to avoid appropriate alcohol to site rotation
bumps and scar tissue on the skin, the insulin insulin site, evaporate policy
injection site should be rotated. A systematic device, needle
approach to injection-site rotation needs to be gauge, and
adopted [34]. length
The 2017 Indian recommendations for best
Use a new needle Avoid injecting at
practice in insulin injection are shown in Table 2
[35]. for each hair roots
It is important to appropriately match injection
delivery device to insulin preparation (e.g., pen Use concentrated Penetrate the skin
and cartridge as well as vial and syringe of cor- insulin if the quickly
rect strength). All stakeholders should be edu-
dose
cated about different types of basal insulins,
including biosimilar insulins, in order to avoid requirement is
inappropriate use. As far as possible, prescrip- high
tion sanctity should be maintained [35]. Use neutral pH Do not move the
insulin if pain needle
Targets for Titration occurs with immediately
acidic pH after insertion
• Titration of the insulin dose is recommended insulin
using a treat-to-target approach, wherein the
dose can be uptitrated to reach a predefined Insulin should
therapeutic goal in terms of FPG level and preferably be at
HbA1c [36]. room
• The initial basal insulin dose may be started temperature as
at 10 U/day or 0.1–0.2 U/kg/day, depending injection of
on the degree of hyperglycemia [12]. Starting cold insulin is
with a higher dose may be required in painful
persons with a high body mass index, high
HbA1c, and longer duration of diabetes or
signs of insulin resistance, such as acanthosis (5.6–7.2 mmol/L) and HbA1c B 7.0% are rea-
nigricans and/or a dorsocervical fat pad. sonable goals for most adults. Once fasting
• The recommended treat-to-target algorithm control has been achieved, oral medication or
for the initiation and titration of basal prandial insulin may be needed to achieve
insulin in basal insulin supported by oral postprandial control. Dietarymodification and
GLA therapy is elaborated in Fig. 1. portion size control isnon-negotiable andmust
• While glycemic targets should be individual- be emphasized at all stages of intensification of
ized, a FPG level of 100–130 mg/dL therapy. Titration, in dose steps of 2–4 units,
1196 Diabetes Ther (2019) 10:1189–1204
Table 3 Basal insulin dose adjustment [37]
FPG (mg/dL) (mean of Recommended dose
the three most recent adjustment (once or twice
values) a week)
\ 80 mg/dL Reduce dose by 2 units
(\ 4.4 mmol/L)
80–130 mg/dL No dose modification
(4.4–7.2 mmol/L)
131–160 mg/dL Increase dose by 2 units
(7.27–8.9 mmol/L)
161–180 mg/dL Increase dose by 4 units
(8.94–10.0 mmol/L)
[180 mg/dL Increase dose by 6 units
([ 10.0 mmol/L)
FPG fasting plasma glucose
of the three most recent values of FPG are
shown in Table 3 [37].
A simplified titration technique should be
taught and demonstrated to the patient at the
time of initiation of basal insulin. Patient-led
titration regimens have been shown to be effi-
cacious in achieving glycemic control.
• For instance, in the INSIGHT study, patient-
Fig. 1 Recommended treat-to-target algorithm for the led titration using simple titration algo-
initiation and titration of basal insulin in basal insulin rithms resulted in greater reductions in
supported oral antidiabetic therapy (BOT). $Basal insulin HbA1c than physician-led adjustment of oral
analogues such as glargine and detemir are associated with antidiabetic drugs (control) (- 1.55% vs.
a lower risk of hypoglycemia and are preferred. Where cost - 1.25%, - 17 vs. - 14 mmol/mol,
is a constraint, neutral protamine Hagedorn (NPH) can be P = 0.005). The study also showed that com-
used. In individuals at high risk of hypoglycemia, longer-
pared to the control group, patients receiv-
acting insulin analogues such as degludec or Gla-300
* ing Gla-100 were 1.68 times more likely toshould be considered. While once-daily basal insulin is
achieve two consecutive HbA1c levels
preferably administered at bedtime, it can be administered
any time of the day depending on the sociocultural B 6.5%, had lower FPG (P = 0.0001), non-
circumstances. NPH and detemir may have to be admin- high-density lipoprotein cholesterol
istered twice a day in some individuals (P = 0.02) and triglycerides (P = 0.02), and
greater increases in treatment satisfaction
should be initially performed once to twice a (P = 0.045) [38].
week until optimal control is achieved. • The AT.LANTUS trial compared an investi-
• Titration may be performed in steeper steps gator-led insulin Gla-100 initiation and titra-
if the daily requirement is[ 30 U/day. tion algorithm to that led by study subjects.
Physicians should refer to the prescribing It showed that there was a significant reduc-
information for the frequency of titration of a tion in HbA1c (from 8.9 ± 1.3% to
specific basal insulin. 7.8 ± 1.2%), with a greater decrease
• The recommended dose adjustments for (P\ 0.001) with the study subject-led
insulin dose based on the mean or lowest
Diabetes Ther (2019) 10:1189–1204 1197
algorithm (- 1.22%) than the investigator- until the glycemic target is reached [43].
led algorithm (- 1.08%) [39]. Modern sulfonylureas (glimepiride and gli-
• The Asian Treat to Target Lantus Study clazide MR) confer a lower risk of hypo-
(ATLAS) showed that self-titration with Gla- glycemia and are thus preferred over older
100 was found to statistically significantly sulfonylureas such as glibenclamide [44].
lower the mean HbA1c (by 1.40% for self- Clinical studies on the addition of sulfony-
titration vs. 1.25% for physician-led titra- lureas to basal insulin yielded the following
tion) [40]. results:
• The TAKE CONTROL study evaluated the • Basal insulin ? glimepiride: In a 24-week
self-titration and physician-led titration of prospective randomized comparative
Gla-300 in people with T2DM. Self-titration study, basal insulin in addition to glime-
was found to statistically significantly lower piride offered better efficacy, less hypo-
the mean HbA1c (by 0.97% for self-titration glycemia, and less weight gain, and
vs. 0.84% for physician-led titration) [40]. significantly reduced the insulin dose
Hence, self-titration with both Gla-100 and required (by 4.01%) [45].
Gla-300 resulted in significantly improved • Basal insulin ? metformin ? glimepiride: In
glycemic control (vs. physician-led titra- a 28-week clinical trial, metformin and
tion), without increased hypoglycemia [40]. glimepiride plus insulin glargine resulted
Titration of the basal insulin dose may be in a significant improvement in overall
done by the physician, diabetes care nurse, glycemic control as compared to other
patient, or caregiver. combinations. The decrease in HbA1c was
more pronounced with insulin glargine
Tablets plus glimepiride plus metformin than
with insulin glargine plus metformin
Combination therapies (oral therapy combined (0.49% [CI, 0.16%–0.82%]; P = 0.005)
with basal insulin or basal insulin combined (5.10 mmol/mol [CI, 1.64–8.61]; P =
with oral therapy) offer complementary mech- 0.005) and insulin glargine plus glimepir-
anisms of action that can help maximize effi- ide (0.59% [CI, 0.13%–1.05%]; P =
cacy, reach target HbA1c goals, and minimize 0.012) (5.87 mmol/mol [CI, 1.10–10.64];
adverse events [41]. P = 0.012) (overall P = 0.02) [46].
• Among the various GLAs, metformin is the
preferred initial therapy (with HbA1c • Regular monitoring is recommended, espe-
C 6.5% and FPG level C 126 mg/dL). The cially when combining with insulin secreta-
advantages of including metformin are as gogues such as sulfonylureas.
follows [41, 42]: • Thiazolidinediones, when combined with
• It is associated with less weight gain insulin, may favor weight gain and fluid
(useful in treating obese patients) retention [47].
• Usage leads to decreased hepatic glucose • Pioglitazone or rosiglitazone helps reduce
production, blood pressure, and risk of PPG levels [48].
atherothrombotic disease, thus reducing • Alpha-glucosidase inhibitors (AGIs) should
insulin requirements and blood levels of be considered as the first-line treatment in
insulin patients with controlled basal glucose con-
• Inclusion of metformin leads to increased centrations and marked postprandial hyper-
hepatic sensitivity to insulin, and it may glycemia. Mean HbA1c at week 24 was
also have a mild effect on muscular significantly decreased (by 0.7% from base-
sensitivity to insulin line) in both acarbose and voglibose patient
• When adding sulfonylureas, start the ther- groups who were previously inadequately
apy with low-dose sulfonylureas. The dosage controlled with basal insulin [49, 50].
can be increased at intervals of 2–4 weeks • Sodium-glucose cotransporter 2 (SGLT2)
inhibitors may be considered as add-ons to
1198 Diabetes Ther (2019) 10:1189–1204
Fig. 2 Protocol for managing hypoglycemia. *Symptoms or 150 mL of fruit juice or sweetened beverages such as
of hypoglycemia include excessive hunger, sweating, cola (not diet cola) can be administered. $Complex
tremors, palpitations, irritability, blurring of vision, dizzi- carbohydrate snack can include 150 mL milk, 1 bread
ness, difficulty concentrating, excessive tiredness, incoher- sandwich, 1 chapati, or 3 heaped tablespoons of cooked
ent speech, and altered sensorium/seizures; symptoms of rice. When hypoglycemia occurs prior to a meal, the meal
hypoglycemia are idiosyncratic. #15 g of glucose or sucrose should be taken immediately
Diabetes Ther (2019) 10:1189–1204 1199
metformin alongside other drugs such as • SMBG should be performed at least as often
sulfonylureas, dipeptidyl peptidase 4 (DPP-4) as insulin is administered.
inhibitors, thiazolidinedione, and basal insu- • The ideal SMBGrequirement is seven tests/-
lin. SGLT2 inhibitors are associated with day, i.e., three before and three after each
weight loss and do not increase the risk of meal andone test at3am.Asa compromise,
hypoglycemia. They have potential benefits one fasting test and three each after break-
in terms of weight loss, reduction of blood fast, lunch, and dinner daily may be more
pressure, improvements in glycemic control feasible as well as acceptable. This can be
without weight gain, and hypoglycemic risks further individualized to twice or thrice a
associated with insulin therapy [51]. week in pregnant patients as the pregnancy
• DPP-4 inhibitors are weight neutral and not advances. Two-hour post-meal monitoring
associated with an increased risk of hypo- maybe easier to remember, as this timing is
glycemia. DPP-4 inhibitors lower PPG levels routinely used [4].
by decelerating gastric emptying. They best • For patients on intensive insulin regi-
complement the action of basal insulin on mens who are on multiple doses of
fasting glucose control and help patients insulin or on insulin pumps, testing
with T2DM achieve their target HbA1c [52]. should be carried out three or more times
• In general, GLP-1 receptor agonists (GLP- daily (all pre-meals, post-meals, at bed-
1RAs) should not be discontinued with the time, and prior to exercise) [4].
initiation of basal insulin. Basal insulin and • Some patients may require testing 6–10
GLP-1RAs address various defects seen in (or more) times daily [4].
T2DM physiopathology. Basal insulin plus • Pregnant women with insulin-treated
GLP-1 receptor agonists are associated with diabetes must be advised to perform
less hypoglycemia and with weight loss SMBG on a daily basis. However, in case
instead of weight gain. However, they may be of any failure to do so, at least weekly
less tolerable and come at a greater cost. That monitoring should be encouraged [4].
said, a fixed ratio combinationofGLP-1RAand • Meal-based testing schemes such as 5- and
basal insulin isapotentiallyhelpful tool for the 7-point regimens and the staggered-fre-
treatment of patients with T2DM as a result of quency regimen can help to show the
its favorable safety and efficacy profile, espe- effect of food consumed on the rise in
cially in obese patients who are uncontrolled bloodglucose after specificmealtimes [54].
on OADs or basal insulin [12, 53]. • Monitoring hypoglycemia in patients: Severe
hypoglycemia is a common acute complica-
Tools for Monitoring and Troubleshooting tion in people with diabetes being treated
with insulin, and its incidence increases with
• Second-generation basal insulin analogues the duration of insulin therapy. A basal
(Gla-300 and degludec) are associated with insulin switch from conventional to long-
the lowest risk of hypoglycemia, which can acting or to ultra-long-acting preparations
be further reduced by implementing timely may be indicated if a particular insulin
therapy initiation, proper patient education, cannot be uptitrated due to hypoglycemia
and SMBG. Hypoglycemia and need for or glycemic variability.
monitoring is reduced with BOT as com- Physicians can refer to the hypoglycemia pro-
pared with basal bolus [24, 28]. tocol illustrated in Fig. 2.
• Regular SMBG is recommended in patients • SMBG should be performed in a pragmatic
with diabetes on multiple daily insulin manner. Once-daily FPG and structured 2-h
injections, with a history of hypoglycemia, PPG are acceptable SMBG strategies for BOT.
and with poor metabolic control with mul- Monitoring PPG levels will provide data on
tiple GLAs and/or basal insulin. the adequacy of the BOT regimen [55].
• Tools for patients: Basal insulin titration and
target achievement can be facilitated by the
1200 Diabetes Ther (2019) 10:1189–1204
use of modern technology, including ambu- can conveniently use to manage diabetes
latory glucose profiling and online apps. The [56, 57].
Hypoglycemia Awareness Questionnaire can • Risk factors for hypoglycemia can be reduced
be used by patients to monitor glucose level with the timely initiation of therapy using
changes and consult with their healthcare currently available insulin formulations and
providers [56]. Several online apps are avail- technologies (insulin pumps and monitor-
able in India, such as mySugr, OnTrack ing) and proper patient education, which
Diabetes, and MyFitnessPal, which patients should empower physicians to overcome
their inertia [24].
Summary of the 7-T concept of basal early strategies to maximize HbA1c reduction with oral therapy
Treatment initiation Begin basal insulin at 10 U/day or 0.1–0.2 U/kg/day, depending on the degree of hyperglycemia
Timing Basal insulin should be injected at the appropriate time (usually bedtime)
Under some circumstances, it may be administered at the same time daily, in the morning or
afternoon
Transportation and Insulin vials, cartridges, or pens may be kept at room temperature for 28 days to 1 month,
storage depending on the type of insulin. However, in settings where the temperatures can be above
30 C or below 2 C, it is not advisable to leave the vials at room temperature
The cold chain should be maintained during the transportation of the vials or cartridges of insulin
Technique of Basal insulin, if injected into intramuscular space, may act like rapid-acting insulin
administration The abdomen is the preferred site for soluble human insulin as it leads to the fastest absorption
Targets for titration The initial basal insulin dose may be started at 10 U/day or 0.1–0.2 U/kg/day, depending on the
degree of hyperglycemia
Titration, in steps of 2–4 units, should be initially performed once to twice a week until optimal
control is achieved
Tablets In combination with basal insulin:
- Metformin: Preferred initial therapy (with HbA1c C 6.5% and FPG level C 126 mg/dL)
- Sulfonylureas: Preferred agents where cost is a limiting factor. Begin at a low dose, but dosage can
be increased at intervals of 2–4 weeks until the glycemic target is reached. Pioglitazone or
rosiglitazone help reduce PPG levels
- AGIs: Used as the first-line treatment in patients with controlled basal glucose concentrations
and marked postprandial hyperglycemia
- DPP-4 inhibitors: Weight neutral, not associated with an increased risk of hypoglycemia, and
lowers PPG levels by decelerating gastric emptying, thus helping patients with T2DM achieve
their target HbA1c levels
- SGLT2 inhibitors: Possess potential benefits in terms of renoprotection, cardiovascular risk
reduction, weight loss, blood pressure reduction, and improvements in glycemic control without
the weight gain and hypoglycemic risks associated with insulin therapy
- GLP-1 receptor agonists: Basal insulin plus GLP-1 receptor agonists are associated with less
hypoglycemia and with weight loss instead of weight gain, but they may be less tolerable and cost
more
Diabetes Ther (2019) 10:1189–1204 1201
continued
Tools for Once-daily FPG and strategic 2-h PPG
monitoring and are acceptable SMBG strategies for
troubleshooting BOT
Hypoglycemia Awareness Questionnaire may be used by
patients to monitor glucose level changes in consultation
with their healthcare providers
Online apps, such as mySugr, OnTrack Diabetes,
MyFitnessPal, and Diabeto, can be used by patients to
manage diabetes and insulin dosing
CONCLUSION Funding. This expert opinion initiative was
funded by Sanofi India. The article processing
The selection of an appropriate insulin regimen charges and the open access fee received by the
and initiation time as well as the optimization journal for the publication of this article were
of insulin therapy are crucial to achieving sponsored by Sanofi India.
optimal glycemic control. The strength of the
current expert opinion statement is that it Medical Writing and/or Editorial Assis-
leverages clinical experience and regional tance. Editorial support was provided by
expertise and practices to adapt existing rec- Medulla Communications Private Limited,
ommendations on the basis of published evi- which was funded by Sanofi India.
dence for local contexts.
Authorship. All named authors meet the
We hope that these recommendations will
International Committee of Medical Journal
prove useful to physicians as a reference. We
Editors (ICMJE) criteria for authorship for this
envisage that these recommendations will
manuscript, take responsibility for the integrity
highlight the need for the optimization and
of the work, and gave final approval for the
early intensification of basal insulin in the
version to be published.
treatment of diabetes. The impact of these rec-
ommendations will be validated through
Disclosures. Jubbin Jacob received research
observational studies in real-life diabetes out-
funding for clinical trials from Novo Nordisk, Eli
patient practices.
Lilly and Co., Sanofi Synthelabo Pvt. Ltd., and
Biocon India Pvt. Ltd., and speaking assignments
from Novo Nordisk India, Eli Lilly India Ltd.,
ACKNOWLEDGEMENTS Sanofi Aventis India, Biocon, Lupin India, and
AstraZeneca Pharma India Ltd. Deepak Khandel-
We acknowledge the Sanofi India team—Dr. wal received a speaker honorarium from Sanofi.
Shalini Menon, Dr. Senthilnathan Mohanasun- Manoj Chawla is on the advisory board for/has a
daram, Dr. Romik Ghosh, and Dr. Amal speaker contract with/has a consultancy agree-
Mathew—for their assistance, guidance, and ment with Sanofi India, Novo Nordisk India Pvt.
expertise in convening the expert forum. The Ltd., Eli Lilly India, Boehringer Ingelheim, MSD,
information contained herein solely represents AstraZeneca Pharma India Ltd., Novartis, Eris
the views and opinions of the authors. This Lifesciences, and USV. Roberta Lamptey has
expert opinion document does not seek to rep- served as consultant/speaker/advisory board
resent the opinions and policies of or the pro- member for Sanofi, Novo Nordisk, AstraZeneca
cedures used by Sanofi. and Novartis. Sarita Bajaj, AK Das, Rakesh Sahay,
Banshi Saboo, Sambit Das, M. Shunmugavelu,
1202 Diabetes Ther (2019) 10:1189–1204
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