Insulin Initiation and Titration in Patients

With Type 2 Diabetes

Ji Chun,1 Jodi Strong,2 and Scott Urquhart3

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■ ABSTRACT
Insulin initiation and titration can be challenging for many primary care pro-
viders who are involved in the treatment of patients with type 2 diabetes.
Despite the introduction of advanced insulin analogs and improvements in
insulin delivery devices, many patients with type 2 diabetes continue to expe-
rience suboptimal glycemic control. With an increasing number of treatment
options available, type 2 diabetes management is moving away from a “one-
size-fits-all” approach and toward individualized treatment regimens based on
particular patient needs. Given this, nurse practitioners, physician assistants,
pharmacists, and certified diabetes educators are becoming increasingly valuable
resources in busy primary care practices.

I
nsulin initiation and titration is a tively high incidence of hypogly-
challenge for many primary care cemia, remains in use today (7).
providers (PCPs) involved in the The first-generation basal insu-
treatment of patients with type 2 di- lin analogs, insulin glargine 100
abetes (1). Clinical inertia, the failure units/mL (Gla-100) and insulin
to initiate or intensify insulin thera- detemir 100 units/mL provided a
py when indicated, is a multifactorial near–24-hour glucose-lowering effect
problem resulting from barriers to with low variability in insulin action
insulin initiation and intensification, and a lower incidence of hypoglyce-
including treatment regimen inconve- mia than NPH insulin (8). The more
nience, needle phobia, and fear of hy- recently approved second-generation
poglycemia (2–5) and has important basal insulin analogs, insulin glargine
consequences for patients, significant- 300 units/mL (Gla-300) and insulin
ly increasing the risk of microvascular degludec 100 units/mL (IDeg U100)
complications such as retinopathy, or 200 units/mL (IDeg U200), with
nephropathy, and neuropathy (6). their prolonged duration of action
OptumCare Medical Group, Laguna
1 A desirable basal insulin therapy and more evenly distributed activity
Niguel, CA regimen includes an insulin analog profiles, are associated with reduced
2Ministry Medical Group, Stevens Point, WI possessing a pharmacokinetic profile incidences of hypoglycemia and sim-
3
Diabetes and Thyroid Associates, that mimics the naturally occurring ilar A1C control compared to earlier
Fredericksburg, VA basal endogenous insulin secretion basal analogs (9,10). They also provide
Corresponding author: Ji Chun, profile, which can provide adequate the advantage of once-daily dosing
cjcmedicine@gmail.com and reproducible glucose control. with reduced intra-individual vari-
https://doi.org/10.2337/ds18-0005 Basal insulin analogs from recom- ability (11).
binant DNA technology represent a Despite the introduction of insulin
©2018 by the American Diabetes Association.
Readers may use this article as long as the work
significant advancement from human analogs, refinement of insulin regi-
is properly cited, the use is educational and not NPH insulin, an intermediate- mens, and improvements in injection
for profit, and the work is not altered. See http://
creativecommons.org/licenses/by-nc-nd/3.0
acting insulin that, despite the need devices such as pens with fine-gauge
for details. for twice-daily dosing and a rela- needles, advocacy for early insulin

104 SPECTRUM.DIABETESJOURNALS.ORG
 chun et al.

initiation, and continuous titration glycemic control (18). Provider or that exists as a stable dihexameric
algorithms, many patients with type 2 clinician factors, including a lack complex that forms long soluble mul-
diabetes continue to experience poor of integrated care (20), uncertainty tihexameric chains after injection. Its
glycemic control (12). This review regarding insulin type, complexity mechanism of protraction is due to
discusses the initiation and titration of titration algorithms, and concerns binding to albumin to form bound
of insulin and ways this approach that the complexity of insulin therapy complexes, from which it dissociates
may be optimized by PCPs to help is too great to be managed in primary very slowly, thus providing a pro-
overcome clinical inertia and provide care often lead PCPs to delay insulin longed and stable delivery of insulin
patients with timely glycemic control. initiation (19). (7,25). Insulin degludec is available
in two different concentrations, with
Treatment Delays and Barriers Advanced Basal Insulin Analogs
IDeg U200 demonstrating similar
Patient and clinician factors contrib- and Fixed-Ratio Combinations glycemic control with significantly
ute to delays in adding insulin to Advanced insulin analogs and pre- lower risk of overall and nocturnal
treatment regimens or in transitioning filled pen delivery devices are helping hypoglycemia compared to Gla-100
from oral antidiabetic agents (OADs) to overcome some of the barriers to (26). Pre-filled IDeg U100 pens

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to insulin. Patient barriers are numer- insulin initiation and titration expe- contain 300 units, with a maxi-
ous and include the inconvenience rienced by some patients and PCPs. mum dose per injection of 80 units,
of insulin regimens, a need for more Gla-300, a new formulation of whereas pre-filled IDeg U200 pens
frequent self-monitoring of blood glu- insulin glargine, is available in pre- contain 600 units, with a maximum
cose (SMBG) (13,14), fear of hypo- filled pens containing 450 and 900 dose per injection of 160 units. IDeg
glycemia, weight gain, and injection units and requires only one-third of U200 provides the same dose as 100
pain. Many patients lack confidence the injection volume to deliver the units/mL basal insulin, but in half
in their ability to self-manage their same number of units as the Gla-100 the volume. As with Gla-300, a 1:1
diabetes (15–17), with emotional pen (21,22). The decreased surface total daily conversion ratio is rec-
factors such as an unwarranted sense area of the smaller injection depot ommended when transitioning from
of failure, guilt, and shame repre- leads to a slower release rate of insu- long- or intermediate-acting basal
senting some of the most significant lin, resulting in protracted and stable insulins, followed by individual dos-
barriers to insulin use (13,15,18). In delivery into the circulation (7,21,23). ing adjustments (27).
the Diabetes Attitudes, Wishes, and Gla-300 also provides the advantage A follow-on Gla-100 insulin
Needs study, 48% of patients initiat- of once-daily dosing and reduced available in the United States is a long-
ing insulin believed they had failed to intra-individual variability (22), while acting human insulin analog with
manage their diabetes correctly, 52% offering similar glycemic control and similar pharmacological/therapeutic
were worried about initiating insu- a lower risk of hypoglycemia than effects and safety profile to Gla-100
lin, and only 23% believed insulin Gla-100 (10). (28), which can be administered sub-
would help manage their diabetes (2). It is recommended that unit- cutaneously at any time of the day,
Additionally, nonscientific beliefs such to-unit conversions are used when providing 24-hour glycemic control
as the notion that insulin causes limb patients are switched from Gla-100 (29,30).
loss or kidney failure (18), lack of to Gla-300. However, it should be Two fixed-ratio combinations of
awareness of improved insulin deliv- noted that Gla-100 and Gla-300 are a glucagon-like peptide 1 (GLP-1)
ery devices (19), and concerns about not bioequivalent; therefore, when receptor agonist and a basal insulin
treatment costs are important factors switching from Gla-100 to Gla-300, analog delivered in a single injection
that influence insulin adherence (20). a higher Gla-300 dose (by ~10–18%) received approval from the U.S. Food
Among PCPs, there is often res- may be needed to maintain the same and Drug Administration in 2016
onance with patients with regard to level of glycemic control. Conversely, (30,31). GLP-1 receptor agonists pro-
fear of hypoglycemia, as well as a lack when switching from Gla-300 to vide complementary mechanisms of
of confidence in patients’ ability to Gla-100, the initial dose may need action to basal insulin by stimulat-
manage insulin therapy. Factors such to be similarly reduced to limit the ing insulin secretion from pancreatic
as a patient’s presumed unwilling- risk of hypoglycemia (24). Overall, β-cells, suppressing glucagon secre-
ness or inability to inject contribute it is advised that careful glycemic tion from α-cells, and delaying gastric
to the reluctance of PCPs to initiate monitoring and individualized dose emptying (32,33). Both combinations
insulin (16). Importantly, a lack of adjustments be made when switch- (iGlarLixi [Gla-100 and lixisenatide]
awareness of patient fears, beliefs, ing from one type of basal insulin to and IDegLira [IDeg U100 and
and expectations may affect the qual- another. liraglutide] [30,31]) demonstrate
ity of PCP-patient relationships and Insulin degludec is a novel, improved glycemic control compared
create further barriers to achieving long-acting, once-daily insulin to their individual components alone,

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with no increased risk of hypoglyce- initiation and titration. Three regimen 10–20% of the TDD according to
mia or weight gain (34–36). options should be considered: FPG values, as indicated in Figure
The fixed ratio of Gla-100 and lix- • Regimen 1: Administer one rapid- 2. For patients taking a sulfonylurea,
isenatide in iGlarLixi provides basal acting insulin injection before the dose may have to be reduced or
insulin doses of 15–60 units as a sin- the meal with the greatest carbo- discontinued during titration due to
gle daily injection corresponding to hydrate content; if the glycemic increased risk of hypoglycemia (38).
lixisenatide doses of 5–20 µg. Starting target is not met, progress to two If the A1C target is unmet, a GLP-
doses depend on previous therapy; or more rapid-acting insulin injec- 1 receptor agonist, sodium–glucose
for patients previously treated with tions before meals (basal-bolus cotransporter 2 inhibitor, dipeptidyl
lixisenatide or with a basal insulin regimen). peptidase-4 inhibitor, or prandial in-
dose of <30 units daily, the recom- • Regimen 2: Add a GLP-1 recep- sulin may be added to the treatment
mended starting dose of iGlarLixi tor agonist. If target A1C remains regimen. Two approaches to initiat-
is 15 units (which includes 5 µg lix- unmet or the regimen is not toler- ing prandial insulin may be used as
isenatide), whereas the recommended ated, patients may discontinue the follows.
starting dose for patients previously GLP-1 receptor agonist and switch • Regimen 1: Begin prandial insulin

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taking 30–60 units of basal insulin to regimen 1 or 3. at 10% of basal dose or 5 units
is 30 units (which includes 10 µg • Regimen 3: Replace basal insulin before the largest meal (basal + 1).
lixisenatide). Up or down titration with premixed insulin at a 75/25, If A1C target is unmet, progress
should occur in 2- to 4-unit incre- 70/30, or 50/50 mix twice (usu- to injections before meals 2 or 3
ments every week, based on individual ally before breakfast or dinner) (basal + 2 or basal + 3).
patient requirements (30). or thrice daily (before breakfast, • Regimen 2: Begin prandial insu-
IDegLira is provided in doses of lunch, and dinner). Basal insu- lin before each meal with a 50%
insulin ranging from 16 to 50 units, lin and GLP-1 receptor agonists basal/50% prandial ratio to achieve
corresponding to liraglutide doses should be discontinued before ini- a TDD of 0.3–0.5 units/kg, start-
of 0.58–1.8 mg. The recommended tiating premixed insulin. ing at 50% of the TDD in three
starting dose is 16 units, which can divided doses before meals.
be titrated up or down in 2-unit incre- For regimens 1 and 3, insulin
ments every 3–4 days. The pens can doses should be increased by 1–2 For both regimens, insulin should
administer doses as low as 10 units units or 10–15% until target A1C be titrated every 2–3 days until glyce-
(with 0.36 mg liraglutide), but doses and blood glucose values are met. If mic targets are met, as recommended
<16 units are only recommended as appropriate, oral agents other than in Figure 2.
temporary for down titration; patients metformin can be discontinued to
Insulin Titration Algorithms
persistently requiring <16 units/day avoid regimens that are too complex
A number of titration algorithms have
should be transitioned to a different and expensive. If the targets remain
been evaluated that aim to simplify
treatment (31). unmet, patients may switch to the
insulin titration and enable patient
alternative regimen. If hypoglycemia
Current Guidelines for Insulin
empowerment through self-titration
occurs, the cause should be investi-
Initiation and Titration
to effectively participate in the man-
gated, and, if no clear cause is found,
agement of their disease (4,39–42),
American Diabetes Association
the insulin dose should be reduced as
the details of which are summa-
Guidelines
recommended in Figure 1.
rized in Table 1. Several studies have
The American Diabetes Association American Association of Clinical demonstrated that simple algorithms
(ADA) recommends initiation of bas- Endocrinologists Guidelines for titrating basal insulin in small in-
al insulin at 10 units/day or 0.1–0.2 The American Association of Clinical crements at short intervals (e.g., ev-
units/kg/day, adjusted by 10–15% Endocrinologists (AACE) recom- ery 3 days based on the mean of three
or 2–4 units once or twice weekly to mends initiating long-acting basal self-monitored FPG values or increas-
reach a target fasting plasma glucose insulin at a total daily dose (TDD) ing by 1 unit/day) allow patients to
(FPG) in patients whose A1C remains of 0.1–0.2 units/kg for patients with achieve comparable glycemic control
uncontrolled after >3 months of triple an A1C <8% or 0.2–0.3 units/kg as with physician-directed titration
combination therapy, whose A1C is for patients with an A1C >8%, with (43–45).
>10%, whose blood glucose is >300 insulin titration every 2–3 days to Simplified self-titration algorithms
mg/dL, or who are symptomatic of reach the glycemic target (38). For have also been successfully evaluated
hyperglycemia (37). Figure 1 details those on fixed regimens, the TDD for basal-bolus regimens (46,47) and
treatment intensification recommen- may be increased by 2 units, whereas prandial regimens (48). Several stud-
dations for patients whose A1C re- for those on adjustable regimens, the ies have also revealed that, in some
mains uncontrolled after basal insulin dose should be adjusted by 1 unit or cases, certain patients can achieve

106 SPECTRUM.DIABETESJOURNALS.ORG
 chun et al.

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■ FIGURE 1. ADA-recommended approach to initiating and titrating insulin in type 2 diabetes. Reprinted with permission from
ref. 37; adapted with permission from ref. 61. ©2015 American Diabetes Association. FBG, fasting blood glucose; GLP-1RA,
GLP-1 receptor agonist; hypo, hypoglycemia.

ing the insulin dose without limit until reduction in their A1C. Furthermore,
adequate A1C control using more
an FPG of 100–130 mg/dL is reached patients are prone to experience post-
complex titration algorithms com-
(50). “Overbasalization” is said to oc- prandial hyperglycemia due to a lack
bined with regular support from
cur when FPG is uncontrolled de- of mealtime insulin as a result of
PCPs (49).
spite uptitration of basal insulin and β-cell failure. Overbasalization may
When Too Much Insulin Has the A1C target remains unmet (51). cause hypoglycemia during the day
Little Effect on Glycemic Target Since basal insulin is not designed for and evening hours (in the nonfasting
Current use of basal insulin has been postprandial coverage, patients may state) if insulin dose adjustments are
shaped by treat-to-target trials that experience hypoglycemia in the fast- based on fasting blood glucose values.
have emphasized systematically titrat- ing state without seeing any additional Increased activity levels during the day

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■ FIGURE 2. AACE-recommended approach to initiating and titrating insulin in type 2 diabetes. Reprinted with permission
from ref. 38. ©2018 American Association of Clinical Endocrinologists. BG, blood glucose; DPP-4i, dipeptidyl peptidase-4
inhibitor; GLP-1 RA, GLP-1 receptor agonist; SGLT-2i, sodium–glucose cotransporter 2 inhibitor.

can lead to hypoglycemia if too much insulin results in a marked reduction or within the target range but whose
basal insulin is given daily. in fasting hyperglycemia, and this A1C remains elevated after treatment
Therefore, it is important to ensure accounts for approximately one-third intensification with basal insulin
that patients monitor their blood glu- of total hyperglycemia in patients who should be considered for therapy that
cose values at different times of the are close to their A1C target. These effectively reduces postprandial gly-
day. This practice was derived from findings highlight the importance cemia (37).
the concept of “fix fasting first,” which of addressing both fasting and post- Managing Insulin Regimens in
developed as a consequence of fasting prandial hyperglycemia to normalize the Primary Care Setting
hyperglycemia being shown to be the glycemic exposure. It is important to gain an understand-
primary contributor to hyperglyce- A basal insulin dose >0.5 units/kg ing of a patient’s background and life-
mia at higher A1C levels in patients (37,54), a >50 mg/dL difference style before initiating insulin to ensure
taking only OADs (52). Riddle et al. between bedtime (Be) and the next that the treatment regimen takes into
(53) expanded this concept by show- morning’s (AM) SMBG value (known account the patient’s needs and pref-
ing how treatment intensification as the “BeAM value”), or an absolute erences as well as clinical characteris-
affects the relative contributions of morning glucose level <70 mg/dL tics (37,56,57). The key to successful
fasting hyperglycemia and postpran- (54) should be recognized as poten- initiation and titration of insulin is
dial hyperglycemia in patients with tial overbasalization. Increasing basal to communicate effectively the ben-
an A1C >7% taking only OADs (53). insulin to >0.5 units/kg has been efits of insulin and develop a shared
The observed changes depend on the shown to not improve A1C or mean decision-making process that enables
main effect of the treatment used. FPG and is associated with weight patients to feel confident in and in
Treatment intensification with basal gain (55). Patients whose FPG is near control of their treatment regimens,

108 SPECTRUM.DIABETESJOURNALS.ORG
 chun et al.

TABLE 1. Titration Algorithms Evaluated in Clinical Trials

Trial Study Group Comparison Group
Treat-to-target (50) Algorithm 1: Gla-100 titration Algorithm 2: NPH titration
Increase Gla-100 dose by: Increase NPH dose by:
• 8 units with FPG ≥180 mg/dL • 8 units with FPG ≥180 mg/dL
• 6 units with FPG 140–180 mg/dL • 6 units with FPG 140–180 mg/dL
• 4 units with FPG 120–140 mg/dL • 4 units with FPG 120–140 mg/dL
• 2 units with FPG ≥100–120 mg/dL • 2 units with FPG ≥100–120 mg/dL
ATLANTUS study (43) Algorithm 1: Patient self-titration Algorithm 2: Physician titration
Increase Gla-100 dose by: Increase Gla-100 dose by:
• 6–8 units with FPG ≥180 mg/dL • 2 units with FPG ≥180 mg/dL
• 4 units with FPG 140–180 mg/dL • 2 units with FPG 140–180 mg/dL

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• 2 units with FPG 120–140 mg/dL • 2 units with FPG 120–140 mg/dL
• 0–2 units with FPG ≥100–120 mg/dL • 0–2 units with FPG ≥100–120 mg/dL
PREDICTIVE study (44) Patient self-titration Standard care
• Decrease insulin detemir by 3 units with
mean FPG <80 mg/dL
• Keep insulin detemir dose the same
with mean FPG 80–100 mg/dL
• Increase insulin detemir dose by 3 units
with FPG >110 mg/dL
INSIGHT trial (45) Patient self-titration EDITION algorithm
• Increase Gla-300 dose by 1 unit/day if • Increase Gla-300 dose by:
FPG >100 mg/dL ❍❍ 3 units if SMPG value >100 and <140 mg/dL
❍❍ 6 units if SMPG value ≥140 mg/dL
• Decrease by 3 units if SMPG value
<79 mg/dL
SMPG, self-monitoring of plasma glucose.

facilitating their decision to start and knowledge and to manage patients’ may be necessary to adjust other
engage with insulin therapy. Factors expectations (58). noninsulin therapies when insulin is
to consider when initiating insulin Patients should be closely mon- added, especially agents that increase
regimens include patients’ age, daily itored during titration, and their hypoglycemia risk—namely, insulin
schedule, activity level, eating pattern, therapy should be adjusted accord- secretagogues (i.e., sulfonylureas and
social situation, cultural factors, diabe- ingly until their A1C target is glinides).
tes-related complications, comorbidi- achieved (56). Some patients may Once a stable insulin dose and
ties, preferences for self-management, require more frequent contact with adequate A1C control have been
and life expectancy (14). their PCPs (59) and diabetes man- achieved, the frequency of patient
Although it has been demonstrated agement team during titration to evaluation and monitoring should be
reduce the risk of overbasalization reviewed (59). PCPs should continue
that some patients can successfully
(60). As the target FPG is approached, to communicate with patients in a
manage their insulin regimen (43,44), smaller and less frequent insulin dose
the titration regimen must be sim- timely manner to ensure that they are
adjustments should be used to reduce persistent with treatment, successfully
ple and easy to manage and support the risk of hypoglycemia. If hypo-
both patients and PCPs in optimizing managing their disease, and kept up
glycemia occurs, its cause should to date on new guidelines, treatment
insulin therapy. Careful support and be investigated because it may be
education about available treatments options, and insulin delivery devices.
due to non–insulin-related factors
are instrumental to intensifying insu- such as a missed meal or increased Conclusion
lin therapy and should be provided to physical activity. If no cause can Multiple insulin algorithms have been
help overcome barriers such as fear of be found, the insulin dose should developed to help PCPs with insulin
injections, hypoglycemia, and lack of be reduced accordingly (59). It also initiation and titration and to enable

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