Accepted Manuscript

Title: Evidence-based recommendations for insulin

intensification strategies after basal insulin in type 2 diabetes

Authors: Sujoy Ghosh, A.G. Unnikrishnan, Banshi Saboo,

Jothydev Kesavadev, S.R. Aravind, Sarita Bajaj, Rajesh
Rajput, Krishna Seshadri, Narsingh Verma, Arvind Gupta,
Brij Mohan Makkar, Mihir Saikia, Shailaja Kale, Suresh
Damodaran, Ashish Dengra, T.K.M. Eashwar, Anuj
Maheshwari, Sharad Pendsey, Sanjeev R. Phatak, Surendra
Kumar Sharma, Surya Kumar Singh, A. Ramachandran,
Abdul H. Zargar, Shashank R. Joshi, Shaukat M. Sadikot

PII: S1871-4021(17)30057-7
DOI: http://dx.doi.org/doi:10.1016/j.dsx.2017.03.045
Reference: DSX 751

To appear in: Diabetes & Metabolic Syndrome: Clinical Research & Reviews

Please cite this article as: Ghosh Sujoy, Unnikrishnan AG, Saboo Banshi, Kesavadev
Jothydev, Aravind SR, Bajaj Sarita, Rajput Rajesh, Seshadri Krishna, Verma Narsingh,
Gupta Arvind, Makkar Brij Mohan, Saikia Mihir, Kale Shailaja, Damodaran Suresh,
Dengra Ashish, Eashwar TKM, Maheshwari Anuj, Pendsey Sharad, Phatak Sanjeev
R, Sharma Surendra Kumar, Singh Surya Kumar, Ramachandran A, Zargar Abdul H,
Joshi Shashank R, Sadikot Shaukat M.Evidence-based recommendations for insulin
intensification strategies after basal insulin in type 2 diabetes.Diabetes and Metabolic
Syndrome: Clinical Research and Reviews http://dx.doi.org/10.1016/j.dsx.2017.03.045

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 1

Title page

Type of article: Review

Title: Evidence-based recommendations for insulin intensification strategies after basal insulin

in type 2 diabetes

Running title: Insulin intensification strategies in type 2 diabetes

Sujoy Ghosha,*, AG Unnikrishnanb, Banshi Sabooc, Jothydev Kesavadevd, Aravind SRe, Sarita

Bajajf, Rajesh Rajputg, Krishna Seshadrih, Narsingh Vermai, Arvind Guptaj, Brij Mohan

Makkark, Mihir Saikial, Shailaja Kalem, Suresh Damodarann, Ashish Dengrao, TKM Eashwarp,

Anuj Maheshwariq, Sharad Pendseyr, Sanjeev R Phataks, Surendra Kumar Sharmat, Surya Kumar

Singhu, A. Ramachandranv, Abdul H Zargarw, Shashank R Joshix, Shaukat M Sadikoty

Affiliations:

a Department of Endocrinology and Metabolism, Institute of Post-Graduate Medical

Education and Research, Kolkata, India
b Chellaram Diabetes Institute, Pune, India
c DiaCare, Ahmedabad, Gujarat, India
d Jothydev’s Diabetes & Research Center, Trivandrum, India
e Diacon Hospital, Bangalore, India
f Department of Medicine, Motilal Nehru Medical College, Allahabad, India
g Department of Endocrinology, Pandit Bhagwat Dayal Sharma Post Graduate Institute of
Medical Sciences, Rohtak, India
h Department of Endocrinology and Metabolism, Shri Rama Chandra University, Chennai,
India
i King George's Medical University, Lucknow, India
j Jaipur Diabetes Research Center, Jaipur, India
k Diabetes & Obesity Center, New Delhi, India
l Gauhati Medical College, Guwahati, India
m Orange Diabetes Foundation, Pune, India
 2

n Consultant Endocrinologist, Coimbatore, India

o Mahi Diabetes & Thyroid Care and Research Center, Jabalpur, India
p Ideas Diabetes Center, Rajkot, India
q Department of Medicine, Babu Banarasi Das University, Lucknow, India
r Diabetes Clinic and Research Center, Nagpur, India
s Consultant Diabetologist, Sumeru Center, Ahmedabad, India
t Galaxy Specialty Center, Jaipur, India
u Department of Endocrinology and Metabolism, Institute of Medical Sciences, Banaras
Hindu University, Varanasi, India
v India Diabetes Research Foundation, Chennai, India
w Advanced Center for Diabetes and Endocrine Care, Srinagar, India
x Lilavati and Bhatia Hospital and Grant Medical College, Mumbai, India.
y Diabetes India, Mumbai, India
* Corresponding author

Dr. Sujoy Ghosh,

Department of Endocrinology and Metabolism at IPGME, Kolkata, India.
Email ID: drsujoyghosh2000@gmail.com
Conflict of interest: There are no conflicts of interest
Abstract
Over the time due to progressive nature of diabetes, proactive intensification of the existing insulin
therapy becomes imminent as it minimizes patients' exposure to chronic hypo/hyperglycemia and
reduces weight gain while achieving individualized glycemic targets. This review focuses on the
strength of evidence behind various options for intensification, primarily the insulins as also the
GLP-1 analogs. The recommendations presented here are meant to serve as a guide for the
physician managing type 2 diabetes patients requiring insulin intensification upon failing of basal
insulin therapy.

Abbreviations: PPG: Postprandial Glucose

EXECUTIVE SUMMARY

Evidence based recommendations for insulin intensification strategies after basal insulin in type 2
diabetes
 3

A. When to intensify after basal insulin?

A1. Timely intensification of insulin therapy is recommended when patients fail to achieve HbA1c
targets with basal alone therapy after 3-6 months of basal insulin titration. (Grade A; EL 1).
A2. It is important to initially optimize basal insulin (adequate up titration targeting FPG to target).
After adequate optimization, if HbA1c/post prandial plasma glucose (PPG) remains above target,
despite normal fasting plasma glucose (FPG) or with basal insulin dose exceeding 0.5 U/Kg/day,
consider intensification of therapy. (Grade A; EL 1)
B. What are the options for intensification after basal?
B1. Add prandial insulin: basal plus, basal bolus
B2. Switch to premix regimen
B3. Switch to insulin coformulation regimen
B4. Add GLP-1 receptor agonists: basal + GLP-1 receptor antagonist
B1. Basal plus/ basal bolus regimen
 Basal plus regimen is an effective alternative to basal bolus with appropriate patient
selection and may help to overcome clinical inertia linked to insulin intensification. It is
associated with lesser hypoglycemia and weight gain than basal bolus. (Grade A; EL 1)
 Prandial insulin may begin with one of the below method depending on the patients
characteristics. (Grade A; EL 4)
a. a fixed single bolus dose of 4-6 units administered with the largest meal of the day or
the meal with largest post-prandial glucose excursion or
b. a dose defined based on levels of PPG (Glucose value in mmol/L divided by 2 or in
mg/dl divided by 18x2)
c. dose based on previous basal dose (10% of basal dose) or
d. patient’s weight (0.05 U/kg)
 Initiate basal plus regimen by adding prandial insulin to the meal with largest post-prandial
glycemic excursion i.e. the main meal. (Grade A; EL 1)
 The strategy for further titration of basal plus regimen, among those which have been
published and are made available for physicians and patients, should be selected depending
on needs of patients and their individual preferences along with proper patient education
and ability to self-titrate their insulin doses. (Grade A; EL 4)
 4

B2. Premix regimen: Premix as intensification of insulin therapy is an acceptable alternative in

patients though limited by lack of flexibility often associated with weight gain and day-time
hypoglycemia. (Grade A; EL 1)
B3. Coformulation insulin regimen
 Coformulation is an acceptable alternative in patients though limited by lack of flexibility
and has added advantage of lesser risk of weight gain and day-time hypoglycemia than
premix insulin. (Grade A; EL 1)
 Coformulation was not non-inferior to basal bolus. (Grade A; EL 1)
B4. GLP-1 receptor agonists
 Adding a GLP-1 (glucagon like peptides-1) receptor agonist (RA) to basal insulin may be
tried as an effective option in patients requiring basal intensification, with low risk of
hypoglycemia and additional benefit of weight loss. The class is associated with an increase
in gastrointestinal (GI) side effects to which tolerance develops over time. (Grade A; EL
1)
 Prandial GLP-1 RA added to basal insulin provide the advantage of lesser hypoglycemia
risk compared to basal plus and basal bolus and reduction in weight. (Grade A; EL 1)

Keywords: Basal plus; insulin intensification; hypoglycemia; GLP-1; recommendations

1. Introduction

1.1. Burden of disease

The prevalence of diabetes is rising worldwide making it a global epidemic. According to the
International Diabetes Federation (IDF) the global epidemic has reached 415 million people in
2015 and is expected to reach 642 million by the year 2040. Similarly, the statistics from the South
East- Asia region of IDF, estimated 78.3 million adults with diabetes and 42.2 million people with
impaired glucose tolerance (IGT) in 2015 [1]. Type 2 diabetes is a chronic progressive disease
characterized by insulin resistance and declining beta-cell function resulting in inadequate insulin
secretion [2]. Evidence based on clinical investigations and observations suggests that by the time
diabetes is diagnosed, the patient would have lost approximately 80% of normal beta-cell function
 5

and which continues to decline with diabetes progression [3]. The deterioration of glycaemic
control usually begins with initial reduced first-phase insulin repose post-meal, resulting in post-
prandial hyperglycaemia followed by fasting hyperglycemia as a consequence of increased
nocturnal hepatic glucose production [4].

1.2. Importance of good glycemic control

Evidence from large interventional studies indicates that achieving and maintaining near-normal
glycemic levels through aggressive management substantially reduces the risk for micro- and
macro-vascular complications in both type 1 and type 2 diabetes [5–8]. Each 1% reduction in
glycated haemoglobin (HbA1c) was found to be associated with a 37% reduction in microvascular
complications (P < 0.0001), 14 % reduction in myocardial infarction (MI) (P < 0.0001), 21%
reduction for any endpoint related to diabetes (P < 0.0001) and 21% reduction in deaths related to
diabetes (P < 0.0001) [6]. Data from such landmark studies have led the American Diabetes
Association (ADA)/European Association for the Study of Diabetes (ADA/EASD) and IDF
guidelines to propose an HbA1c target of <7.0% [9]. The American Association of Clinical
Endocrinologists (AACE), on the other hand, recommends stringent HbA1c targets of ≤ 6.5% for
patients without concurrent illness and low risk of hypoglycemia, emphasizing the importance of
early intensive glycemic control [1,10]. In this context, the therapies that aim at ‘treating to target’
specific HbA1c goals may facilitate better achievement of recommended standards of diabetes
care [11]. Such an approach is not only likely to achieve safer glucose targets, but also prevent
associated complications when treatment is promptly initiated and adjusted as per the need of the
patient [12].

1.3. Need for early insulin initiation and intensification

Depending on disease progression, the therapy can be intensified by the addition of two or more
pharmacological agents [13]. The percentage point reductions in HbA1c typically achieved by oral
anti-diabetic drugs (OADs) are 0.8% to 2.0% [14]. Nevertheless, the majority of patients (>50%)
fail to achieve target glucose levels even with maximal doses of monotherapy [15] eventually
requiring further intensification of therapy [16]. The natural history of diabetes suggests that over
a period of time any/all oral antidiabetic drugs (OADs) will fail to achieve adequate glycemic
control and insulin will have to be initiated. The benefit of initiating insulin at an earlier versus
later treatment stage has been demonstrated in recent pooled analysis of 11 prospective randomized
 6

clinical trials (RCTs) involving 2171 adults with uncontrolled type 2 diabetes [17]. Indian
epidemiological data on patients reaching the goal, as seen from the large IDMPS study with 994
patients from India, showed that only 25.9% of the patients could achieve it [18]. One of the
reasons for the same is a lack of intensive control during early phases of the disease.

Initiating insulin therapy with long-acting basal insulin with background OAD therapy is
considered to be an easy and effective means to initiate insulin therapy, by addressing fasting and
to some extent post-prandial control in type 2 diabetes [19–21]. While basal insulin can control
the fasting (inter-meal) glucose level as also to some extent the PPG at initiation, the post-prandial
readings rise over a period of time. At this point basal insulin is insufficient and add-on therapies
are required. Several add-on options are available - adding a rapid acting insulin before one meal
(basal plus), rapid acting before all meals (basal bolus), injectable incretin therapy, and
optimization with more oral agents.

Several important issues will have to be considered when we interpret data published from clinical
trials involving all the insulins, and GLP-1 analogues during the course of diabetes. Firstly it is
important to remember that during the course of diabetes (its natural history), a patient will become
more and more insulinopaenic as the disease progresses. Hence at the time of failure of OADs, a
patient may have only deficiency of basal insulin and gradually have a progressive decline in
prandial insulin secretion. Hence not surprisingly initially after OAD failure patient may respond
adequately to basal insulin therapy. Gradually the patient may then need prandial insulin support,
which may initially be for one/predominant meal followed by a time when even more intensive
basal with multiple prandial insulin shots may be required. It is, therefore, important to remember
the patient population selected for a particular study may only represent patients in a particular
phase of the natural history of type 2 diabetes. Hence not surprisingly some studies might
demonstrate non-inferiority of a basal plus in a certain patient population as compared to basal
bolus.

Additionally, it is very important to know the insulin action profile of all the insulins and GLP-1
analogues. Most of the times, an astute clinician will be able to predict clinical response and
clinical trial results from the PK/PD of the drug regimens and trial design. The end points of all
trial data included should not only include the glycemic end points (which is usually equal in treat
to target studies), but also evaluate hypoglycemia rates and weight changes and if available other
 7

parameters like quality of life and ease of administration and patient satisfaction. Hence
interpretation of trial data should be made rationally by the reader, without biases and in the light
of population of patients selected and all the other caveats mentioned.

While this manuscript will discuss all available options, the focus is on insulin based options with
an attempt to adopt protocols used in various clinical trial settings and then adapt them to the real-
life setting- to provide simple guidelines to a practicing physician. The purpose of this consensus
statement is to provide guidance on timely intensification and adapting stepwise approach in type
2 diabetes management.

2. Methodology

A systematic review of literature was conducted to provide the best possible evidence base for the
use of basal plus/bolus in the management of type 2 diabetes. Existing guidelines, meta‐analyses,
systematic reviews, key cited articles relating to diabetes management were reviewed and
recommendations were framed. Recommendations for each section of the consensus statement
were discussed by the expert panel and where there was little or no evidence, the panel relied on
experience, judgment and consensus to make their recommendations. The current consensus is
developed in accordance with the AACE protocol for standardized production of clinical practice
guidelines [22]. Recommendations are based on clinical importance (graded as A: strongly
recommended, B: intermediate, C: weak and D: not evidence based) coupled by four intuitive
levels of evidence (1 = ‘at least one RCT or meta-analysis of RCTs’, 2 = ‘at least one non-
randomized or non-controlled, prospective epidemiological study’, 3 = ‘cross-sectional or
observational or surveillance or pilot study’ and 4 = ‘existing guideline or consensus expert
opinion on extensive patient experience or review’) (Table 1).

This review will focus on the strength of evidence behind the various options for intensification,
primarily the insulins as also the GLP-1 analogs. We have not included the oral options for
intensification, considering patients with long-standing diabetes wherein evidence with these
agents after insulin is low.

3. Insulin initiation

The objective of insulin initiation is to mimic normal physiologic insulin secretion while
maintaining patient compliance without hypoglycemia. Basal insulin is the most commonly used
 8

insulin for initiation in combination with oral antidiabetic agents [9,23] The selection of
appropriate insulin regimen will depend on several factors including type and duration of diabetes,
HbA1c levels, current therapy, comorbidities and individual needs. In addition, factors such as
age, the number of injections, hypoglycemia, weight gain and frequency of monitoring should also
be considered [23,24]. When PPG remains uncontrolled by OADs, premix is a suitable alternative
for initiation [23,25,26]. Several treatment guidelines recommend early initiation of insulin
therapy [9,10,27,28] .
Treatment choices should be tailored to the needs of individual patient. There are several types of
basal insulins which are commonly used and recommended as first choice for initiation with orals
antidiabetic agents - NPH, glargine, detemir and degludec [29]. The aim of basal insulin therapy
in type 2 diabetes is to provide supplemental insulin to suppress hepatic glucose output and keep
fasting hyperglycemia under control [29].
4. Insulin intensification

4.1. Need to stop basal insulin titration and intensify meal-time insulin
Insulin intensification is essential to minimize patients’ exposure to chronic hyperglycemia albeit
not exacerbating the risk of hypoglycemia, while achieving individualized glycemic targets. After
an initial period of normal HbA1c, normal fasting and post-meal glucose levels- when the post
prandial glucose increases >140 mg/dl and the HbA1c levels rise to >7%, then despite a normal
fasting glucose level of < 110 mg/dl then basal insulin will no longer suffice and intensifying
insulin is a must [9].

Patient close to but not at target (HbA1c < 7%) or those using high doses of basal insulin without
success (> 0.5 U/kg) or those who are at increased risk of nocturnal hypoglycemia preventing
further titration of basal insulin doses need intensification of basal insulin [30].

4.2. Intensification options of basal insulin therapy

Intensification of existing basal insulin therapy may be achieved by directly initiating on basal
bolus regimen or first by addition of one rapid-acting insulin with one of the daily meals (basal
plus regimen) or switching to premixed or coformulations insulins with two daily meals [9] and
if still not under control, then finally addition of rapid-acting insulins injections with two-three
daily meals (basal-bolus). Recently other methods have been introduced like oral agents and
 9

GLP-1 receptor agonists, as a trial before initiation of rapid acting or switching to premix
insulins. Table 2 gives us the various options after basal insulin and table 3 provides the time-
action profiles of the insulin options and of the different GLP-1 analogs.

4.3. Regimen for intensification with prandial insulin

4.3.1. The basal plus regimen
Clinical inertia has been shown to be a significant barrier in intensification [31]. A relatively newer
approach is to adopt the basal plus regimen for intensification. This approach allows for more
gradual intensification of insulin therapy to full basal-bolus therapy if glycemic targets are not
achieved. Several studies have investigated the step-by-step approach with the basal-plus for
insulin intensification and delays progression to a full basal-bolus insulin replacement therapy for
many individuals [32]. Fig.1 describes an overall strategy for insulin initiation and intensification
with beta-cell function.

Addition of short-acting regular human insulin or rapid-acting insulins analogues (RAIAs) such as
glulisine, aspart and lispro before main meals is the simplest initial intensification step [33]. The
RAIAs should be preferred over regular human insulin as they mimic more closely to physiological
insulin profile [34–36] with faster absorption, lower pharmacokinetic and pharmacodynamic
variability and lower risk of hypoglycemia than human insulins [37–39]. The faster glucose
lowering effect of RAIAs allows them to be dosed just before a meal or even after a meal when
post-prandial glycemic excursions are high. This provides a significant convenience advantage in
patients relative to regular human insulin which requires administration 30-45 mins prior to meals
[40]. Most, if not all of the studies of basal plus insulin therapy have been conducted by adding
glulisine to a background of glargine therapy. However, there is no evidence to suggest that the
addition of lispro or aspart to the background of glargine or degludec would be in anyway different
from the glulisine add on as a bolus to the background of glargine therapy.

In a 6-month “Proof-of-Concept” (POC) study, basal insulin was titrated to optimize FPG before
initiating and titrating prandial insulin in type 2 diabetes patients uncontrolled on basal + OADs.
After 3 months, reduction in HbA1c was significantly higher in basal plus group than in the basal
only group (-0.37 vs. -0.11%; P = 0.0290) with significantly higher number of patients reaching
target HbA1c [41]. Overall, the results from basal plus studies (Table 4) indicated that, in patients
failing to achieve desired glycemic targets with basal + OADs, the approach with a single prandial
 10

injection (basal plus) is more effective, convenient and safe option when intensifying insulin
therapy in type 2 diabetes patients.
The timing of prandial insulin administration is necessary for better efficacy and safety in patients
with type 2 diabetes intensified to basal plus/bolus from existing insulin regimen. A 48-week
STEPwiseTM study investigated the sequential addition of prandial rapid acting/analog insulin to
the largest meal (titration based on premealglucose values [SimpleSTEP]) compared to the meal
with largest prandial glucose (titration based on post-meal values [ExtraSTEP]) [42]. At study end,
both the strategies were associated with similar reductions in HbA1c with no significant difference
hypoglycemia, weight gain or treatment satisfaction. The proportion of patients reaching target
HbA1c <7% was similar between the groups (31% and 27%, respectively, P =0.74). Overall, the
study concluded that both SimpleSTEP and ExtraSTEP were equally effective strategies for the
step-wise addition of bolus insulin in type 2 diabetes patients uncontrolled on basal + OADs.

The Orals Plus Apidra and LANTUS (OPAL) study comparing basal plus to basal alone in 393
type 2 diabetes patients demonstrated significant improvement in mean HbA1c levels with
addition of single dose of prandial insulin (at breakfast or at main mealtime) to basal insulin
compared to basal insulin alone (adjusted HbA1c mean difference (95% CI): 0.0481% (-0.115 to
0.211); P < 0.0001 for equivalence) [43]. In both OPAL and POC studies, the rates of
hypoglycemia and weight changes were comparable between the treatment groups suggesting that
basal plus regimen was effective in reducing HbA1c without increased risk of hypoglycemia.

Another 52-week trial that examined the effect of post-prandial versus pre-prandial insulin
administration on weight and glycemic control in type 2 diabetes patients on basal therapy showed
that prandial insulin administered either before or after meals achieved similar glycemic control
(7.04% vs. 7.16%; P = NS) with no significant difference in the risk of hypoglycemia or weight
change [44].

Self-monitoring of blood glucose (SMBG) is a useful tool that aids in improving glycemic control
and indirectly dictates the success of therapy in patients initiated on insulin regimen [10,45].
Before intensifying basal therapy by adding pre-meal prandial insulin, performing SMBG 2 hours
after meals for a period of up to 1 week will help to identify and target meal with largest post-
prandial glycemic excursion [46]. This approach facilitates timely and appropriate stepwise
adjustments of insulin doses in response to fasting and prandial blood glucose values and in turn
 11

achieves optimal therapeutic outcomes in patients at increased risk of hypoglycemia. Clinical

experience suggests that insulin self-titration interventions based on structured SMBG
significantly improve glycemic control with no increase in incidence of hypoglycemia or body
weight gain in poorly controlled insulin-treated type 2 diabetes patients [47].

Usually, bolus insulin dose is initiated and adjusted based on the PPG levels with recommended
target of <160-180mg/dl [1,45]. Therefore a patient initiating basal plus strategy, may begin with
a single bolus dose of 4-6 units administered with the largest meal of the day or the meal with
largest post-prandial glucose excursion [23,48]. Subsequently, prandial insulin dose may be
adjusted to achieve 2 hour PPG levels <180mg/dl [45]. Finding an appropriate dose for bolus
insulin initiation is critical when initiating basal plus strategy. To start with, bolus insulin dose
may be calculated using

1) fixed dose method or

2) a dose may be defined based on
a. levels of PPG or
b. previous basal dose or
c. patient’s weight [49]
The ADA EASD 2016 guidelines mention, 4 units per day or 10% of basal dose or 0.1 unit/kg
based on body weight. Dosing prandial insulin, particularly RAIAs, with small fixed dose as
opposed to dosing based on planned carbohydrate intake (flexible dosing) and blood glucose
levels, is the most effective and simplest method to avoid hypoglycemia while reducing the
complexity of basal bolus regimen [50]. Several titration schemes have been published and are
made available for physicians and patients to choose from depending on needs of patients and their
individual preferences. Further titration and adjustments of prandial doses may be achieved with
fixed dose increments every 7 days based on pre-meal SMBG values [49]. Simple algorithm based
steps in the intensification of basal insulin are described in Appendix I.

When initiating basal plus regimen, the patients may be continued on the previous basal insulin
dose. However, if the selected main meal for bolus insulin is dinner, it is desirable to reduce the
basal insulin dose by 10% in order to avoid nocturnal hypoglycemia [49].

Another common concern when implementing basal plus regimen is whether to continue or
discontinue OADs. In general, OADs used in combination with basal insulin, particularly insulin
 12

sensitizers (biguanide and thiazolidinediones) may also be continued with basal plus regimen.
However, in patients using insulin secretogogues (sulfonylureas and glinides), it is desirable to
monitor and if required modify the dose to avoid to increased risk of hypoglycemia and weight
gain [51]. Conversely, discontinuing these agents may result in substantial increase in insulin doses
[52]. In any case, it is recommended that the treatment regimen should be individualised according
to the needs and preference of the patient while initiating or intensifying existing antidiabetic
regimen accordingly [9].

4.3.2. Sequential intensification after basal plus

Several strategies for effective treatment intensification have been investigated in patients
inadequately controlled on basal plus regimen. The OSIRIS (Opposing Step-by-step Insulin
Reinforcement to Intensified Strategy) study was designed to evaluate the efficacy of stepwise
intensification of prandial insulin to a straightforward basal-bolus regimen in 811 type 2 diabetes
patients poorly controlled on basal + OADs [33]. The authors concluded that compared to full
basal bolus strategy, stepwise intensification was equally effective in HbA1c reduction but with
significantly lower hypoglycemia risk and better patient satisfaction. Another study that compared
basal plus to basal bolus regimen in general medical and surgical patients with type 2 diabetes
showed that basal plus regimen with glargine once daily plus corrective doses with glulisine insulin
before meals is as effective as standard basal-bolus regimen in achieving glycemic control (P =
0.16) with no difference among the groups in the frequency of severe hypoglycemia (<40 mg/dL;
P = 0.76) [53]. A sample patient information sheet guiding self-titration of basal and/or bolus
insulin therapy can be found in Appendix II. Also a guide to carbohydrate counting, which is
recommended in patients with variable carbohydrate intake from meal to meal and day to day, is
explained in Appendix III.

4.4. Premix insulin as an alternative approach for intensification

The current ADA/EASD guidelines recommend that if the HbA1c is still above the glycemic target
with basal insulin, one may consider proceeding through stepwise intensification to basal bolus
regimen, or to a less flexible alternative regimen of twice-daily premixed insulin which may be
eventually progressed to basal bolus when identified unsuccessful in attaining optimal glycaemic
control [9]. Premixed insulins regimens provide optimal glycemic control with a relative
convenience of fewer number of insulin injections [54]. However due to fixed-ratio combinations
 13

of rapid- and basal-acting insulins, they are limited by inability to titrate the shorter- from the
longer-acting component of these formulations [55] often resulting in weight gain and day-time
hypoglycemia besides requiring strict lifestyle changes [19,56]

The studies mentioned below have compared the role of premix versus basal plus approach for
intensification (Table 5). A 60-week “All to Target” study compared basal plus (once daily
glargine + once daily glulisine), basal bolus (once daily glargine + thrice daily glulisine) and twice
daily premixed insulin (biphasic aspart 70/30).The insulin glargine-based regimens differed
significantly from Premix (Basal plus vs. PM, P =0.025; Basal bolus vs. PM−2, P =0.0309) but
not between one another (P = 0.918) in the primary endpoint of patients reaching HbA1c <7%.
Basal plus and basal bolus were superior to premixed insulin in attaining <7.0% at 60weeks (39%
(75/191), 49% (92/189) and 45% (86/191) with PM−2, G+1, and G+3.) [57]. The rates of
hypoglycemia as confirmed with plasma glucose <50.4 mg/dL (<2.8mmol/L) was 40% higher with
premixed insulins compared to basal plus or basal bolus [adjusted incidence: 46 (P = 0.0087) vs.
33 (P = 0.0045) and 31.5%, respectively]. Similarly, the event rates were two-times higher with
premixed insulin than basal plus or basal bolus groups (1.9 vs. 0.8 and 0.9, respectively;
P  ≤  0.0001). The findings from this study indicate that stepwise basal prandial regimens are as
effective as premixed insulin and are associated with less hypoglycemia in type 2 diabetes patients
uncontrolled in basal alone therapy. The GALAPAGOS study compared insulin glargine
(±glulisine) versus premixed insulin for management of 923 insulin-naïve type 2 diabetes patients
uncontrolled on OADs. Glargine (±glulisine) and premix strategies resulted in similar percentages
of well-controlled patients (33.2% versus 31.4%, respectively) (P = 0.56) [58]. The LanScape
study also demonstrated non-inferiority of basal plus ( insulin glargine + glulisine ) to premixed
regimen (biphasic aspart) [59]. In another recent trial, glargine + insulin lispro was found to be
similar to premix insulin lispro [60].
Premix insulins also have been studied as an alternative to a full basal bolus regimen in patients
uncontrolled on OADs, with or without basal insulin [48]. The study showed that twice-daily
premix insulins may be an attractive treatment option for patients who require a simpler, though
less flexible, approach compared with a full basal bolus regimen. Based on the results from these
studies, intensification of twice-daily premix insulin regimens by adding a mid-day bolus insulin
dose can provide additional improvements in glycemic control. However, basal insulin followed
by intensification to a full basal bolus regimen can provide similar glycemic control with less
 14

hypoglycemia and weight gain. Adding either a third injection of premix insulin at lunch, or a
rapid-acting analogue to ongoing twice daily premix therapy, might be a temporary way of
intensifying treatment. If treatment goals are achieved and the patient neither requires nor wants
more flexibility or a fourth injection, then this might be a longer-term solution. Transitioning from
either premix approach to full basal bolus therapy would ultimately provide patients with more
flexibility in terms of timing of insulin administration and food intake.
4.5. Coformulation insulins an alternative approach for intensification
The Insulin degludec/insulin aspart (IDegAsp) provides both basal and prandial insulin coverage
with in a single injection, benefiting patients who require prandial coverage inaddition to their
basal insulin. Furthermore, the IDegAsp components remain separate following subcutaneous
(SC) injection, preserving their distinct basal and prandial effects at different dose levels and at
steady state [61]. There are no trials comparing IDegAsp once or twice daily vs basal plus therapy
at present. When insulin-naïve people were randomized to IDegAsp or BIAsp 30 twice daily,
HbA1c change was similar (and non-inferior) at 26 weeks [62]. However, IDegAsp showed
superior reduction in FPG, and 9-point self-monitored plasma glucose (SMPG) profiles revealed
that SMPG values were lower for IDegAsp than BIAsp 30 before breakfast, 90 min after breakfast,
and before breakfast the following day. IDegAsp also demonstrated less hypoglycemia
nocturnally.

Use of IDegAsp compared with BIAsp 30 (both twice daily) in people already using insulin was
explored in 26-week, randomized, open-label, treat-to-target trials, one in a global and one in an
Asian population [63,64]. For glucose-lowering (difference in change from baseline in HbA1c
after 26 weeks), the results were similar, with similar and non-inferior HbA1c levels between
treatments in both trials and better FPG in both trials (Table 6); this was on a lower daily insulin
dose with IDegAsp (−11% and−21% compared with BIAsp 30). For the global trial, hypoglycemia
rates were clearly better on IDegAsp than BIAsp 30, driven by very much lower nocturnal rates
(Table 6). The use of premixed insulin is more common in Asia, and trial results in this population
may reflect the experience of the patient and physician in administering this regimen in an optimal
manner [64]. For the Asian population, treatment with IDegAsp led to numerically fewer episodes
of nocturnal hypoglycemia, although there was not enough power to confirm this statistically,
whereas any-time hypoglycemia was unchanged. Vaag and colleagues performed a combined
analysis of the two trials; the rates of overall confirmed, nocturnal confirmed, and severe
 15

hypoglycemic events were lower with IDegAsp, particularly during the maintenance period (Table
6) [64]. Similar findings were reported when this combined analysis was restricted to participants
who achieved HbA1c <7.0% (<53 mmol/mol) by the end of the trial, indicating achievement of
optimal glycemic targets as recommended by clinical guidance [65].
In a study by Rodbard et al,the use of IDegAsp given twice daily showed final HbA1c comparable
to the one achieved with IDeg once daily plus mealtime IAsp (2–4 injections daily) (Δ%HbA1c
from baseline−1.31 and−1.50%, NS) and non-inferiority for IDegAsp was not achieved. [66]. No
significant differences were observed in the proportion of patients achieving HbA1c <7.0% (56.5
and 59.6%, respectively). IDegAsp treatment resulted in a significantly lower total daily insulin
dose, a smaller change in body weight, numerically lower rates of confirmed hypoglycemia (self‐
reported plasma glucose <3.1 mmol/l; rate ratio 0.81; P = non‐significant), and nocturnal
confirmed hypoglycemic episodes (rate ratio 0.80; P = non‐significant) versus IDeg+IAsp.

4.6. GLP-1 receptor agonists for intensification

Glucagon-like peptide-1 receptor agonists are an important candidate class for addition to basal
insulin because of the differing mechanisms of action and, particularly in the case of the short-
acting GLP-1 RAs, complementary physiologic effects between the two agents. The principal
effect of basal insulin is on FPG via inhibition of hepaticglucose production. The GLP-1 RAs can
also lower FPG (particularly the long-acting formulations), but they also affect PPG and meal-
related glucose oscillations, which is particularly true for the short-acting formulations [67] (see
Table 7). While basal insulin may induce ‘rest of β-cell function’, GLP-1 RAs stimulate
endogenous insulin secretion and inhibit glucagon secretion in a glucose dependent manner
without causing β-cell overload. They also have a significant potential for inducing β-cell survival
and protection from pro-apoptotic actions of cytokines and fatty acids [67]. Preclinical
investigation has shown that lixisenatide may protect pancreatic β cells from apoptosis. When
administered alone, it reduced the number of apoptotic cells by 50–60%; an 80% reduction was
seen when lixisenatide and insulin glargine were added together, suggesting a synergistic effect on
β-cell survival [68,69]. Importantly, insulin therapy is known to increase the risk of hypoglycemia
whereas, treatment with GLP-1RAs is associated with a relatively low propensity to hypoglycemia
because of glucose-dependent effects on α and βcells. Furthermore, insulin therapy is associated
with weight gain while GLP-1 RA therapy is associated with favourable weight effects [1,67]. In
the Get-Goal-duo 2 trial [70], Rosenstock and colleagues tested lixisenatide plus basal insulin
 16

versus insulin glulisine either as basal plus or basal bolus regimen. Lixisenatide plus insulin
glargine was noninferior to basal plus and basal bolus for HbA1c reductions and was statistically
superior for changes in body weight compared with basal bolus (-2.0 Kg, 95% CI, –2.59 –1.40).
Hypoglycemia was also less frequent in the lixisenatide arm compared to basal plus/ basal bolus
arm.

GLP-1 receptor analogues have complementary mechanism of action that controls PPG excursion
by inhibiting glucagon secretion, or suppressing appetite, or by delaying gastric emptying [71].
Therefore, coformulation of basal and GLP-1 receptor analogues could offer a safe and effective
alternative to basal–bolus insulin [72]. Numerous trials have evaluated the efficacy and safety of
this coformulation. In the LixiLan-O randomized trial, a titratable fixed-ratio combination of
insulin glargine plus lixisenatide compared to each of the monocomponents had achieved
meaningful HbA1c reduction (−1.6%, −1.3%, −0.9%, respectively for IGlar-Lixi, IGlar and Lixi).
Further, significantly more patients attained target HbA1c <7% with IGlar-Lixi (74%) versus IGlar
(59%) or Lixi (33%) (P < 0.0001 for all). Furthermore mean body weight was decreased
significantly (P < 0.0001) with IGlar-Lixi compared to their monocomponents with similar
hypoglycemic episodes with IGlar [73]. The LixiLan-L randomized trial compared the efficacy
and safety of IGlar-Lixi, a novel, titratable, fixed-ratio combination of insulin glargine (IGlar) (100
units) and lixisenatide, with IGlar in patients with type 2 diabetes inadequately controlled on basal
insulin. A significant change in reduction of HbA1c (-1.1% vs. -0.6%, P < 0.0001) and body
weight (-0.7 Kg vs +o.7 Kg, P < 0.0001) was observed with IGlar-Lixi compared to IGlar alone.
Further more patients attainted target HbA1c in IGlar-Lixi arm (55% vs 30%) with similar
incidence of hypoglycemic episodes [74]. In the LixiLan Proof-of-Concept trial, IGlar-Lixi
achieved statistically significant reductions to near-normal HbA1c levels ([95% CI] difference: -
0.17% [-0.31, -0.04] {-1.9 mmol/mol [-3.4, -0.4]}; P = 0.01) with weight loss (-1 Kg vs +0.5 kg;
P < 0.0001) and similar hypoglycemic risk (∼25% in each group) compared with insulin glargine
alone, in type 2 diabetes patients inadequately controlled on metformin [75]. Similarly in DUAL-
1 trial, IDegLira compared to its monocomponents provided improved glycaemic control in
insulin-naive patients (Gough SC et al. 2014; Gough SC et al. 2015). Similar results were observed
in DUAL-II and DUAL-V trials with IDegLira achieving greater glycemic control in comparison
to IDeg and IGlar alone; however, a more number of non-serious gastrointestinal complications
were observed with IDegLira patients in DUAL-V trial [76,77]. Fremantle et al indirectly
 17

compared the efficacy of IDegLira versus alternative strategies for intensification of basal insulin
in a multivariable comparison. The analyses showed a consistent pattern of efficacy for IDegLira,
with results that were generally significantly better than those obtained with basal-bolus or up-
titrated basal insulin therapy. Results were generally similar to those obtained by adding a GLP-1
RA to basal insulin, and were achieved with a similar dose of basal insulin but lower dose of
liraglutide with IDegLira versus liraglutide added to basal insulin. Apart from hypoglycemia
(which were significantly lower with IDegLira), safety was not specifically considered in this
analysis. These indirect results indicate that fixed ratio combination of basal insulin and GLP-1
RAs may offer a useful treatment alternative for patients with type 2 diabetes who have failed to
achieve glycemic control using basal insulin therapy [78]. In a nut shell, coformulation of basal
insulin–GLP-1 receptor analogues demonstrated a robust glycaemic control with the additional
benefits like lower doses of insulin needed to achieve target HbA1c, relatively low risk of
hypoglycaemia with no weight gain [71,73,75,79]

5. Choice of therapy based on patient type and other factors

As mentioned earlier the various options that have emerged in relation to the standard basal bolus
regimen have been studied in differing patient populations. Hence choosing the right patient may
play a vital role in achieving the desired results in terms of both efficacy and safety.

Selection of an appropriate candidate for insulin intensification :

5.1. With basal plus therapy [49]

The table 8 provide some guidance on choosing the appropriate patient for basal plus regimen

5.2. With Premix therapy

Broadly, the reasons to consider premix insulin include convenience of lesser injections, and the
ability to intensify treatment up to thrice daily if needed. Being biphasic in nature, hypoglycemia
and weight gain may be expected and also frequent need for monitoring, accordingly patient
preferences may be considered [57,58]. It is preferred in patients who follow predictable lifestyle
and meal patterns.

5.3. With insulin coformulation

Similar to premix, there is the factor of convenience of lesser injections. There is lesser risk of
hypoglycemia compared to premix seen though not significantly different in Asian population
 18

[64]. Patient concerned about potential weight gain need to be informed on the risk of weight gain
which is similar to that seen with premix in Asians [64]. Being a fixed combination there will be
frequent need for monitoring and dose adjustments will be required.

5.4. With basal plus GLP-1 RA therapy

Certain patients may be better suited to the addition of GLP-1 RA therapy rather than prandial
insulin, such as: (i) those concerned about potential weight gain with intensification of insulin
therapy, or overweight and obese patients; (ii) patients at particular risk from hypoglycemia,
including elderly or frail patients; and (iii) patients who are not comfortable with self-
administering multiple daily injections and unskilled at monitoring their plasma glucose levels.
However, if a patient has a contraindication to GLP-1 RAs, has an HbA1c much higher than target,
or experiences a particular adverse reaction to GLP-1 RA treatment, addition of prandial insulin
may suit them better, although will usually require intense SMBG. In patients treated with basal
insulin and in cases where the glycemic profile shows a clear predominance of prandial
hyperglycemia, a regimen with a more specific action against this abnormality could prove useful
[80]. Studies have shown that the prandial GLP-1 RA lixisenatide confers glycemic control in
patients regardless of duration of disease [67–69]. This means that patients with type 2 diabetes
with declined β-cell function, such as those with long-standing disease, may also benefit from the
addition of a GLP-1 RA to basal insulin. Potentially relevant to this concept, post-hoc analyses of
the Get Goal clinical trial programme have demonstrated the efficacy and tolerability of
lixisenatide in elderly patients [67]. Table 9 summarizes information based on the patient
population studied in the different trials and may help provide some guidance selecting various
insulin intensification strategies. In addition to the aspects described below, the cost of the therapy
would also play a role in deciding the suitable option.

6. Conclusion

Addition of basal insulin to previous therapy is considered the most effective and simplest way to
initiate insulin therapy. Over time, due to progressive nature of diabetes, proactive intensification
of the existing insulin therapy becomes imminent as it minimizes patients' exposure to chronic
hyperglycemia, while achieving individualized glycemic targets.
 19

Although several treatment guidelines are available to assist physicians and patients in step-by-
step process of advancing insulin therapy, choosing the best regimen is still debatable. Based on
the available clinical evidence in this consensus statement we attempted to identify trends suitable
for use of basal plus/ bolus therapy as also the alternatives of premix, and newer therapies like
coformulations and GLP-1 receptor agonists in patients with type 2 diabetes.
The recommendations presented here meant to serve as a guide for patients requiring insulin
intensification upon failing of basal insulin therapy. Finally, tailoring the insulin regimen to suit
the needs of the patients will increase the success of therapy.
Acknowledgements: The authors acknowledge Sanofi INDIA for supporting this initiative with

an academic grant and Jeevan Scientific Technology Limited (Hyderabad, India) for editorial

assistance in the development of this manuscript.

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Fig. 1. Insulin initiation and intensification vs. beta-cell function
 Appendix I: Simple algorithm based steps for intensifying basal insulin.

References:

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management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the
initiation and adjustment of therapy: a consensus statement from the American Diabetes
Association and the European Association for the Study of Diabetes. Diabetologia.
2009;52:17-30.
[2] Nicolucci A, Del Prato S, Vespasiani G. Optimizing insulin glargine plus one injection of
insulin glulisine in type 2 diabetes in the ELEONOR study: similar effects of telecare and
 conventional self-monitoring of blood glucose on patient functional health status and
treatment satisfaction. Diabetes Care. 2011;34:2524-6.
[3] Mooradian AD, Bernbaum M, Albert SG. Narrative review: a rational approach to starting
insulin therapy. Ann Intern Med. 2006;145(2):125-34.
[4] Riddle MC, Rosenstock J, Gerich J. The treat-to-target trial: randomized addition of glargine
or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care.
2003;26(11):3080-6.
[5] Janka HU, Plewe G, Riddle MC, Kliebe-Frisch C, Schweitzer MA, Yki-Jarvinen H.
Comparison of basal insulin added to oral agents versus twice-daily premixed insulin as
initial insulin therapy for type 2 diabetes. Diabetes Care. 2005;28:254-9.
[6] Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, et al. Intensive insulin
therapy prevents the progression of diabetic microvascular complications in Japanese
patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year
study. Diabetes Res Clin Pract. 1995;28(2):103-17.
[7] Yki-Jarvinen H, Juurinen L, Alvarsson M, Bystedt T, Caldwell I, Davies M, et al. Initiate
Insulin by Aggressive Titration and Education (INITIATE): a randomized study to compare
initiation of insulin combination therapy in type 2 diabetic patients individually and in
groups. Diabetes Care. 2007;30(6):1364-9.
[8] Meneghini L, Koenen C, Weng W, Selam JL. The usage of a simplified self-titration dosing
guideline (303 Algorithm) for insulin detemir in patients with type 2 diabetes--results of the
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Appendix II: Patient information sheet
Appendix III

Carbohydrate counting

It is recommended in patients with variable carbohydrate intake from meal to meal and day to day.
It is an alternate method to dosage algorithms for determining prandial insulin doses providing
greater flexibility in meal planning. It involves counting of total amount of carbohydrate offered
rather than on specific calorie content at each meal. Such an approach would facilitate matching
the prandial insulin dose to the amount of carbohydrate consumed for effective glycemic
management

Carbohydrate counting and bolus insulin dose adjustmenta

Meal time dose Mealtime glucose values below Mealtime glucose values above
targetb targetc
1 U/20g CHO Decrease to 1 U/25g CHO Increase to 1 U/15g CHO
1 U/15g Decrease to 1 U/20g Increase to 1 U/105g
1 U/10g Decrease to 1 U/15g Increase to 2 U/15g
2 U/15g Decrease to 1 U/10g Increase to 3 U/15g
3 U/15gd Decrease to 2 U/15g Increase to 4 U/15g
CHO: carbohydrate
a
Each patient in the carb count group was also given a schedule for a mealtime insulin glulisine
correction dose to add a few units if high or subtract a few units if low.
b
If more than one-half of the mealtime blood glucose values for the week were below target.
c
If more than one-half of the mealtime blood glucose values for the week were above target.
d
Increase mealtime insulin as needed following this pattern.
Tables
Table 1
Evidence Rating and Recommendation Grading According to the AACE Protocol for Production
of Clinical Practice Guideline [22].
Evidence Semantic descriptor (Reference methodology) Grades Recommendation
level
1 Meta-analysis of randomized controlled trials, A Strong
randomized controlled trials,
2 Meta-analysis of non-randomized prospective or B Intermediate
case-controlled trials, systemic literature review,
non-randomized controlled trial, Prospective cohort
study, retrospective case-control study
3 Cross-sectional study, single case reports, C Weak
consecutive case series, surveillance study
(registries, surveys, epidemiologic study,
retrospective chart)
4 Mathematical modelling of database, no evidence D Not evidence
(theory, opinion, consensus, review, or preclinical based
study)

Table 2
Insulin intensification therapies and regimens
Therapies Regimen

Add Prandial insulin Basal Plus, Basal bolus

Switch to Premix Premix Regimen
Switch to insulin Coformulation Coformulation Regimen
Add GLP-1 receptor agonists Basal + GLP-1RA
GLP-1, glucagon like peptide-1; GLP-1RA, glucagon like peptide-1 receptor agonist
Table 3a
Options for prandial intensification and the time-action profiles of the intensification options [81]
Insulin Type Action Onset Peak Duration
(trade name) FPG/PPG
Bolus (prandial) Insulins

Rapid-acting insulin PPG 5-15 min 1-2 hr 3-4 hr

analogues: Insulin aspart/
Insulin glulisine / Insulin
lispro / Insulin lispro U200

Short-acting insulins: Insulin PPG 30-60 min 2-4h 6-8 h

regular

Mixed insulins

30/70 Premix: Biphasic PPG and 15 min 0.5 to 1 hr 16 hr

aspart, Biphasic lispro, FPG
Biphasic human insulin

Insulin Coformulation
 Insulin degludec + Insulin PPG and 10 min No peak > 24 hr
aspart (IDegAsp) FPG

FPG, fasting plasma glucose; PPG, post prandial glucose

Table 3b
Classification of GLP-1 RA, new option for prandial intensification[31]
GLP-1 analogs Action on FPG and PPG Dosing
Lixisenatide PPG>> FPG Once daily
Exenatide PPG>> FPG Twice daily
Liraglutide FPG and PPG Once daily
Dulaglutide FPG >> PPG Once weekly
Exenatide LAR FPG >> PPG Once weekly
FPG, fasting plasma glucose; PPG, post prandial glucose
Table 4
Clinical trials investigating the stepwise addition of bolus insulin to basal insulin
Trial Durat Trial arms Popul HbA Target Propor Severe Weig
ion of ation 1c HbA1c tion hypoglyc ht
rando size chan [mmol/ achiev emia chan
mize ge mol ing rate ge
d (%) (%)] target (events/ (kg)
treat HbA1 patient-
ment c (%) year)
perio
d
OPAL 24 Insulin glargine + 162* - ≤ 48 (≤ 27.8 0.01 ± +1.0
study week OADs + insulin 0.36 6.5) 0.15‡
[43] s glulisine at breakfast †
Insulin glargine + 154* - ≤ 48 (≤ 33.8 0.04 ± +0.9
OADs + insulin 0.31 6.5) 0.30§
glulisine at main †
mealtime
‘Proof 3 Insulin glargine + 51* - < 53 (< 8.8 0.2 ± 1.1 -0.4
of mont OADs 0.11 7)
Conce hs †
pt’ Insulin glargine + 45* - < 53 (< 22.4 0.0 ± 0.0 +0.7
study OADs + insulin 0.37 7)
[41] glulisine at main †
mealtime
1.2.3. 24 Insulin glargine + 115ǁ - < 53(< 30 0.28 +3.8†
study week OADs + once daily 0.44 7)
[82] s Insulin glulisine †

Insulin glargine + 113ǁ - < 53 (< 33 0.89** +4.1†

OADs + twice daily 0.36 7)
Insulin glulisine †
 Insulin glargine + 115ǁ - < 53 (< 46 0.64 +3.9†
OADs + thrice daily 0.43 7)
Insulin glulisine †
OSIRI 12 Insulin glargine + 144* - NA NA NA +2.03
S mont metformin + thrice- 0.72 ±
study hs daily insulin glulisine ± 3.21
[32] 1.25
†
Insulin glargine + 197* - NA NA NA +1.30
metformin + stepwise 0.47 ±
addition of insulin ± 3.17
glulisine (1-3 times 1.05
daily)†† †
Insulin glargine + 123* - NA NA NA +1.90
metformin + 0.40 ±
sulphonylurea + ± 3.38
stepwise addition of 1.11
insulin glulisine 1-3 †
times daily)††
STEP 3* Insulin detemir + 150 -1.1 < 53 (< 31 0.04‡‡ +2.7
Wise 12 OADs + stepwise ± 1.1 7) ±
[42] week addition of insulin 3.9§§
s aspart to largest meal
treat based on pre-meal
ment glucose values):
perio Simple STEP
ds Insulin detemir + 146 -1.3 < 53 (< 27 0.01‡‡ +2.0
OADs + stepwise ± 1.2 7) ±
addition of insulin 3.8§§
aspart to meal with
largest prandial
glucose increment
(based on post-meal
 glucose values): Extra
STEP
ELEO 24 Insulin glargine + 126ǁǁ -0.7 < 53 (< 54.8 0.02 +0.4 ± 5.1
NOR week metformin + once ± 7)
[83] s daily insulin glulisine 0.06
titrated using SMBG †
Insulin glargine + 115ǁǁ -0.7 < 53 (< 45.2 0.04 +0.4 ± 3.4
metformin + once ± 7)
daily insulin glulisine 0.06
titrated using telecare †
All To 60 Twice-daily premixed 192 -1.8 < 53 (< 39 0.2 ± NA
Target week insulin ± 0.1 7) 0.1***
[84] s (70/30 protamine
aspart/
aspart) + 2-3 OADs
Insulin glargine + 189 -2.1 < 53 (< 49 0.1 ± NA
once-daily ± 0.1 7) 0.0***
glulisine + 2-3 OADs
Insulin glargine + 191 -2.2 < 53 (< 45 0.2 ± NA
stepwise addition of ± 0.1 7) 0.1***
insulin glulisine + 2-3
OADs
*Per-protocol population; †Adjusted mean change from baseline; ‡Safety population n = 196; §Safety population n = 197; ǁ Modified
intention-to-treat population; Safety population n = 115; **Safety population n = 113; ††The first dose of insulin glulisine was added
to the meal with the highest post-prandial glucose excursion; ‡‡Major hypoglycemic episodes-patients unable to treat the episode
themselves; §§Data expressed as mean ± standard deviation; ǁǁ Intention-to-treat population; Last observation carried forward; ***Data
expressed as adjusted event-rates per patient/year ± standard error.
ELEONOR, Evaluation of Lantus Effect on Optimization of Use of Single Dose Rapid Insulin; NA, data not available; OAD, oral
antidiabetic drug; OPAL, Orals Plus Apidra and Lantus; OSIRIS, Opposing Step-by-Step Insulin Reinforcement to Intensified Strategy;
SMBG, self-monitoring of blood glucose.
Table 5
Premix versus Basal plus/ bolus: Baseline demographics and efficacy/safety results
Trial GALAPAGOS Riddle et al. [57] LanScape Tinahones Tinahones
[58] [59] et al. [60] et al. [85]
Baseline characteristics for insulin intensification trials
Sample Patients with Aged Aged 18- Aged C18 Aged C20
T2D 30–80 years; 75 years and B75 years with
diagnosed C2 years’ with a years T2D;
[1 year; aged history of diagnosis with T2D; BMI\30
C35 years T2D; BMI of T2D; HbA1c kg/m2;
\45 kg/m2; HbA1c C7.5% HbA1c
HbA1c[7.5% C7.5% and C7.0% and
at screening (C58.5 B10.5%; B10.0%;
mmol/mol) BMI FPG\130
and B11%; B45 kg/m2; mg/dL
BMI B40 FPG
2
kg/m B6.7
mmol/L
Duration of 24 weeks 60 weeks 24 weeks 24 weeks 24 weeks
randomized
treatment
Trial arms (1) Insulin Insulin glargine (1) Insulin (1) Insulin (1) Insulin
glargine OD +0–1 glargine glargine glargine OD
OD ± insulin injections of OD + OD + + insulin
glulisine OD insulin glulisine ± insulin insulin glulisine OD
+metformin ± OADs glulisine lispro OD ± or
insulin (metformin, OD ± metformin BID ±
secretagogue Secretagogues metformin ± OADs
(2) Premix [sulfonylurea or (2) Premix pioglitazone (metformin,
insulin (both meglitinide] and insulin (2) Insulin sulfonylurea,
30/70 and thiazolidinediones aspart lispro low meglitinide,
25/75) OD or [pioglitazone (30/70) mixture or
BID + only]) BID ± (25/75) BID a-
metformin ± (2) Insulin metformin ± glucosidase
insulin glargine OD + 0– metformin inhibitors)
secretagogue 3 injections of ± (2) Premix
insulin glulisine ± pioglitazone insulin
OADs aspart
(3) Premix insulin (30/70) BID
aspart (30/70) ± OADs
BID ± OADs
Sample size 923a 582b 334b 476a 160a
Age, years 56.3 (9.2) 54.1 Basal plus: 57.5 (9.5) Basal plus:
(10.1) 61.6 59.45
(8.0) (10.03)
Premix: Premix:
61.6 (8.9) 59.50
(8.72)
Gender, male, 51 43.1 72.4 45 50
% 72.6 47.56

Duration of 8.9 (5.9) 9.3 (6.14) 12.9 (6.2) 11.7 (7.3) 15.17 (6.77)
diabetes, years 13.0 (6.6) 16.19 (6.42)
Mean HbA1c, 8.7 (0.9) 9.4 (1.6) [79.2] 8.6 (0.9) 8.6 (0.8) 8.31 (0.74)
% (SD) [71.6] [70.5] [70.5] [67.3]
[mmol/mol] 8.6 (0.9) 8.48 (0.74)
[70.5] [69.2]
Weight, kg 75.8 (13.7) 96.9 (20.2) 91.5 (15.7) 78.6 (15.4) 64.94 (9.39)
90.8 (15.4) 63.90 (9.77)
BMI, kg/m2 28.4 (4.5) 33.2 (5.80) 31.2 (4.1) 29.6 (5.1) 24.71 (2.71)
31.0 (4.3) 24.35 (2.67)
Efficacy and safety endpoints in insulin initiation trials
Target HbA1c <7% (<53 <7% (<53 <7% (<53 ≤6.5% ≤6.5%
mmol/mol) mmol/mol) mmol/mol) (<47.5 (<47.5
mmol/mol) mmol/mol)
and <7% and<7%
(<53 (<53
mmol/mol) mmol/mol)

Basal plus vs. -1.48/- 1.64 -2.3/- 2.0 (non- -1.00/- -1.08/- 1.30 -0.91/-1.07
premix HbA1c (P<0.01) inferiority 1.22 (non- (P<0.05) (NS)
reduction from confirmed) inferiority
baseline (%) confirmed
at
predefined
margin of
0.4%)
Basal plus vs. 43.2/52.6 39/49 (P<0.05) 20.6/27.9 ≤6.5% ≤6.5%
premix (P<0.01) (NS) (<47.5 (<47.5
Proportion mmol/mol): mmol/mol):
achieving data not 14.10/14.63
target HbA1c reported (NS)
(%) <7% (<53 <7% (<53
mmol/mol): mmol/mol):
33.3/29.27
(NS)
Basal plus vs. PG ≤3.1 PG≤2.8 mmol/L: BG<3.3 PG ≤3.9 BG ≤3.8
premix overall mmol/L: 0.8/1.9 (P<0.01) mmol/L: mmol/L: mmol/L
hypoglycemia 1.20/2.93 PG≤3.9 mmol/L: 15.3/18.2 (≤70
(events/patient- (P<0.01) 7.1/12.2 (P<0.01) (NS) mg/dL):
year) PG ≤3.9 Baseline to
mmol/L: week 12:
4.85/8.37 818/375a
(P<0.01) (P<0.05)
Week 12 to
week 24:
152/386a
(NS)

Basal plus vs. PG ≤3.1 – BG<3.3 PG ≤3.9 BG ≤3.8

premix mmol/L: mmol/L: mmol/L: mmol/L
Nocturnal 0.35/1.03 5.7/3.6 1.82/1.54 (≤70
hypoglycemia (P<0.01) (P\0.05) (NS) mg/dL):
(events/patient- PG ≤3.9 Baseline to
year) mmol/L: week 12:
1.14/2.28 86/61a (NS)
(P<0.01 Week 12 to
week 24:
22/57a (NS)

Basal plus vs. 1.3/1.7a 0.1/0.2 (NS) BG<2 16.51/13.07 PG<2

premix mmol/L: (NS) mmol/L
severe 7.6/5.5b 0/0.04 (NS) (<36
hypoglycemia mg/dL):
(events/patient- Baseline to
year) week 12:
1/0a (NS)
Week 12 to
week 24:
 1/1a (NS)

Basal plus vs. +1.1/ +1.4 +5.2/+6.9 (NS) +2.1/+ 2.5 +0.50/+1.13 +1.22/ +1.05
premix (NS) (NS) (P<0.05) (NS)
Body weight
change (kg)
BG, blood glucose; HbA1c, glycated hemoglobin; PG, plasma glucose; NS, not significant
a Reported as number of events
b Reported as percentages and not analyzed statistically
c Nocturnal hypoglycemia was defined as any hypoglycemic event that occurred between bedtime and waking
d Severe hypoglycemia was defined as a hypoglycemic event that necessitated third-party assistance, in addition to rapid recovery
after taking oral or parenteral carbohydrate/ glucagon with or without glucose measurement

Table 6
Clinical studies of coformulation vs premix insulin
Study Population/ Study n Study Glucose-lowering Hypoglycemia
background therapy/ duration difference (95% Percent people [rate]
therapy dose (weeks) CIs)* or rate ratio (95%
frequency CIs)
HbA1c FPG Any-time Nocturnal
(%- (mmol/L)
units)
Franek Insulin- IDegAsp, 197 26 0.0 (- -0.4 (- 0.46 0.25
E et al., naïve bd 197 0.1, 0.1, - (0.35, (0.16,
2014 (metformin) BIAsp 0.2) 0.7)‡ 0.61) 0.38)
[62] 30, bd
Fulcher Insulin- IDegAsp, 224 26 -0.0 (- -1.1 (- 0.68 0.27
G et al., treated bd 222 0.2, 1.5, -0.8) (0.52, (0.18,
2014 (+OGLDs) BIAsp 0.1) −0.89) 0.41)
[63] 30, bd
Kaneko Insulin- IDegAsp, 282 26 0.1 (- -1.1 (- 1.00 0.67
S et al., treated bd 142 0.1, 1.4, -0.7) (0.76, (0.43,
2015 (metformin) BIAsp 0.2) 1.32) 1.06)
[64] 30, bd

Vaag A Insulin- IDegAsp 504 26 0.0 (- -1.1 (- Rate Rate

et al., treated BIAsp 30 364 0.1, 1.4, -0.9) difference difference
2013 (composite 0.1) −19% −57%
[65] analysis) (post- (post-
titration titration
−31%§) −62%§)
Rodbard Insulin- IDegAsp 138 26 0.2 (- -0.3 (- 0.81 0.80
HW et treated bd 136 0.0, 1.0, 0.3) (0.61, (0.50,
al., (basal only) IDeg od 0.4) 1.07) 1.29)
2014 (OGLDs) +IAsp
[66] ×2-4/day
Table 7
Glycemic parameters from clinical studies combining glucagon-like peptide-1 receptor agonists
and basal insulin
Trial Treatment Patients Mean FPG Mean PPG Mean body
name/Author arms (%) change from change from weight
Study and achieving baseline, baseline, change from
duration BGD HbA1c mmol/L mmol/L baseline, kg
≤7.0%
Buse et al., Exenatide 60 (51, 69) -1.6 (-1.9, - NR -1.78 (-2.48, -
2011 1.3) 1.08)
[86] Placebo 35 (25, 45) -1.5 (-1.8, - NR 0.96 (0.23,
30 weeks 1.2) 1.70)
BGD 25 (12, 39); -0.1(-0.52, NR -2.74 (-3.74, -
p<0.001 0.32); p=0.63 1.74);
p<0.001
GetGoal-L Lixisenatide 35.6 -0.42 -7.96 -0.38
Asia; Seino
et al., 2012 Placebo 5.2 0.25 -0.14 0.06
[87] BGD 30.4; -0.67; (-8.89, - -0.44 (-0.925,
24 weeks p<0.0001 p=0.0187 6.77); 0.061);
p<0.0001 p=0.0857
GetGoal- Lixisenatide 56 0.3 (0.2) -3.1 (0.5) 0.3 (0.3)
Duo1; Placebo 39 0.5 (0.2) 0.1 (0.5) 1.2 (0.3)
Riddle et al., BGD 17; -0.1 -3.2 -0.89
2013b [88] p=0.0001 (-0.5, 0.2); (-4.0, -2.4); (-1.4, -0.4);
24 weeks p=0.5142 p<0.0001 p=0.0012
GetGoal-L; Lixisenatide 28.3 -0.6 (0.2) -5.5 (0.5) -1.8 (0.2)
Riddle et al., Placebo 12.0 -0.6 (0.3) -1.7 (0.5) -0.5 (0.3)
2013a [89] BGD 16.3; -0.1 -3.8 -1.3
24 weeks p<0.0001 (-0.6, 0.4); (-4.7, -2.9); (-1.8, -0.7);
p=0.7579 p<0.0001 p<0.0001
BEGIN: Liraglutide 58.0 -0.14 -0.8* -2.8
VICTOZA (3.8)
ADD-ON; Insulin aspart 44.9 -0.04 -1.0* 0.9 (2.5)
Mathieu et QD
al., BGD p=NS -0.1; p=NS -3.75
2014 [90] 28 p=NS (-4.70, -
weeks 2.79);
p<0.0001
Values in parentheses are 95% confidence intervals or standard error. These were not reported in
all studies. *Meal with largest decrease from baseline; BID, twice daily; FPG, fasting plasma
glucose; GLP-1 RA, glucagon-like peptide-1 receptor agonist; NS, non-significant; NR, not
reported; PPG, post prandial plasma glucose; QD, once daily.
Table 8
Patient selection for basal plus regimen
Clinical Situation
Patients on basal insulin ± oral agents with an
A1c between 7.0% and 8.0%
Patients treated with 2 or 3 oral agents and a
high A1c >8.5-9.0%
Patients on basal insulin ± oral agents with an
A1c >8.5 % who are reluctant to start basal
bolus therapy
Patients previously treated with premixed
insulin twice daily
Patients starting corticoid therapy for other
concomitant diseases
Comments
Ideal candidates. A high percentage will
achieve an A1c ≤ 7%
After optimized titration of basal insulin,
addition of increasing injections of prandial
insulin will be necessary to reach an A1c ≤
7%
Basal plus should be considered as a
transitional therapy to progress steeply to
basal-bolus therapy, which will be necessary
for most patients in this clinical situation.
For those with frequent hypoglycemia
episodes and/or irregular glycemic profiles,
basal plus will offer an alternative
May be a valuable alternative to achieve
stable daily glycemic profiles, especially at
lunch and dinner.

Table 9
Insulin intensification options: Efficacy, flexibility, convenience, hypoglycemia and weight gain
Intensific Efficacy Flexibility Convenience Hypoglycemia and
ation weight gain
options
Basal High efficacy High in Inconvenienc Hypoglycemia and
bolus flexibility e of multiple weight gain lesser than
(BB) injections and premix but greater than
need for BP/B+GLP-1
frequent
monitoring
Basal plus Non-inferior to High in Moderate Lower hypo and weight
(BP) basal bolus if flexibility convenience gain than PMX/CF/ BB
initiated early, as 2 injections
however inferior to Needs
basal bolus as monitoring
disease progresses though less
frequent than
BB
Switch Inferior to basal Low in Moderate Increase in hypo and
from bolus when flexibility convenience weight gain than
Basal to initiated late as 2 injections BP/CF/BB
Premix Needs
(PMX) monitoring
Switch Inferior to basal Low in High Lower hypo and weight
from bolus when flexibility Convenience gain than PMX
basal to initiated late as 1 injection
Insulin Needs
co- monitoring
formulati
on (CF)
Basal + Non inferior to High in Moderate to Lower hypo and weight
GLP-1 basal bolus if flexibility high gain than PMX/CF/ BB/
RA initiated early convenience BP
as 1 /2
injection
Less frequent
need for
monitoring