Management of Blood Glucose in Adults With Type 1 Diabetes Mellitus - UpToDate

1/10/22, 00:59 Management of blood glucose in adults with type 1 diabetes mellitus - UpToDate
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Management of blood glucose in adults with type 1

diabetes mellitus
Author: Ruth S Weinstock, MD, PhD
Section Editor: Irl B Hirsch, MD
Deputy Editor: Katya Rubinow, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2022. | This topic last updated: Feb 15, 2021.
INTRODUCTION
Type 1 diabetes is characterized by destruction of the pancreatic beta cells, leading to insulin
deficiency. It accounts for approximately 5 to 10 percent of cases of diabetes in the United
States, Canada, and Europe (whereas type 2 diabetes accounts for over 90 percent). It is one of
the most common chronic diseases of childhood, although type 1 diabetes may present in
adulthood. In general, the younger the age of diagnosis and the longer the duration of type 1
diabetes, the greater the likelihood that the individual will have absolute insulin deficiency with
undetectable C-peptide levels.
This topic will review the management of blood glucose in nonpregnant adults with type 1
diabetes. Management of type 1 diabetes in children, adolescents, and during pregnancy is
reviewed separately. A general discussion of the classification of diabetes, clinical presentation
and diagnosis of diabetes, and evaluation for diabetes-related complications is reviewed
separately.
● (See "Overview of the management of type 1 diabetes mellitus in children and

adolescents".)
● (See "Pregestational (preexisting) diabetes mellitus: Antenatal glycemic control".)
● (See "Pregestational (preexisting) and gestational diabetes: Intrapartum and postpartum
glucose management".)
● (See "Classification of diabetes mellitus and genetic diabetic syndromes".)
● (See "Clinical presentation, diagnosis, and initial evaluation of diabetes mellitus in adults".)
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● (See "Overview of general medical care in nonpregnant adults with diabetes mellitus".)
INTENSIVE DIABETES THERAPY
Intensive diabetes therapy includes the coordination of meals/diet and activity with insulin
replacement as physiologically as possible, which involves the frequent monitoring of glucose
levels and frequent insulin administration to match needs. It is the standard of care for patients
with type 1 diabetes.
Glycemic targets — Glycated hemoglobin (A1C) and glucose monitoring are critical for
directing therapy. For some populations, for example African Americans, the relationship
between A1C and mean glucose derived from continuous glucose monitoring (CGM) may be
different than that in White Americans. However, there is even greater variation in this
relationship within races than between them [1]. (See "Measurements of glycemic control in
diabetes mellitus", section on 'Racial/ethnic differences'.)
● Glycated hemoglobin – A1C goals in people with diabetes should be tailored to the
individual, balancing the demonstrated benefits with regard to prevention and delay in
micro- and macrovascular complications with the risk of hypoglycemia. For most adults
with type 1 diabetes, we aim for an A1C value of ≤7 percent (using an assay aligned to the
Diabetes Control and Complications Trial [DCCT] in which the upper limit of normal is 6
percent). A1C goals may be higher in people in whom the risks of tighter control outweigh
benefits. Data from the T1D Exchange Clinic Registry and from a United States electronic
health record database suggest that the majority of adults with type 1 diabetes do not
achieve an A1C goal of <7 percent, with the highest mean A1C levels observed in
adolescents and young adults ( figure 1) [2,3].
● Blood glucose – In general, for healthy, young and middle-aged adults, the target glucose
range is 70 to 180 mg/dL (3.9 to 10 mmol/L), while minimizing time in hypoglycemia (<70
mg/dL [3.9 mmol/L]) and hyperglycemia (>180 mg/dL [10 mmol/L]) and avoiding glucose
readings of <54 mg/dL (3 mmol/L) and >250 mg/dL (13.9 mmol/L) [4]. The actual mean
blood glucose levels associated with A1C levels 6.50 to 6.99 percent in type 1 diabetes are
144, 140, and 154 mg/dL fasting, pre-meals, and pre-bed, respectively [5].
● Interstitial glucose – CGMs measure interstitial glucose levels every one to five minutes.
Interstitial glucose concentrations correlate well with blood glucose results. CGM metrics
are being increasingly used to assess glycemic control. Having a time in range [70 to 180
mg/dL (3.9 to 10 mmol/L)] of 70 percent has been associated with an estimated A1C of
approximately 7 percent [6]. Additional important metrics include percent time in

hypoglycemia, coefficient of variation (CV; measure of glucose variability), and the
"glucose management indicator" (GMI), which is based on mean CGM glucose [6-8]. (See
'Monitoring blood glucose' below.)
Glycemic targets (A1C goals) are generally set higher (eg, <7.5 or <8 percent, or higher) for
older adults and those with a history of severe hypoglycemia, hypoglycemia unawareness,
comorbidities, or a limited life expectancy [9,10]. More stringent control may be indicated for
selected motivated patients with type 1 diabetes and during pregnancy. (See "Pregestational
(preexisting) diabetes mellitus: Antenatal glycemic control" and "Glycemic control and vascular
complications in type 1 diabetes mellitus", section on 'Glycemic targets'.)
Insulin replacement — For people with type 1 diabetes, the goal of insulin therapy is to
provide a physiologic profile of insulin by administration of a basal insulin (delivered by daily or
twice-daily injections of an intermediate-acting or long-acting insulin preparation or continuous
subcutaneous delivery of a rapid-acting insulin preparation via a pump) plus mealtime
(prandial) boluses of a rapid-acting or short-acting insulin ( table 1). The dose of the pre-meal
bolus is determined by the ambient blood glucose level before the meal, the size and
composition of the meal, anticipated activity levels, and trending glucose levels (when available)
from CGM. (See 'Insulin regimens' below.)
This physiologic replacement of insulin with "basal-bolus" insulin therapy should be started as
early as possible following the diagnosis of type 1 diabetes. Simpler regimens (eg, twice-daily
injections of short-acting [regular] and intermediate-acting [NPH] insulin mixed together in the
same syringe and given in fixed amounts before breakfast and dinner) are not recommended
unless the patient cannot or will not adhere to multiple injections or an insulin pump. (See
'Choice of insulin delivery' below and "General principles of insulin therapy in diabetes mellitus",
section on 'Insulin preparations'.)
The DCCT and its long-term Epidemiology of Diabetes Interventions and Complications (EDIC)
follow-up study showed that, compared with a simple insulin regimen, early aggressive insulin
therapy substantially and uniformly decreased the complications that accompany type 1
diabetes:
● The DCCT and other smaller studies demonstrated that improved glycemic control with
intensive insulin therapy in patients with type 1 diabetes mellitus led to reductions in
relatively early stages of retinopathy, nephropathy, and neuropathy by 35 to 76 percent
( figure 2 and figure 3) [11,12].
● The EDIC follow-up study from the DCCT demonstrated that improved glycemic control
with intensive insulin therapy also reduces more advanced stages of microvascular
disease, as well as cardiovascular disease and mortality [13-17].
In addition, in the DCCT, early aggressive insulin therapy helped to sustain endogenous insulin
secretion, which was associated with a lower A1C and a lower risk for severe hypoglycemia,
defined as an episode of biochemical hypoglycemia that required assistance from another to
treat [12].
What was considered "intensive therapy" in the DCCT is now considered to be standard therapy
for management of type 1 diabetes. (See "Glycemic control and vascular complications in type 1
diabetes mellitus".)
Optimal insulin therapy requires an understanding of insulin pharmacokinetics ( table 1). A

number of factors influence the pharmacokinetics of insulin, including the insulin preparation,
size of subcutaneous depot, injection technique, site of injection, alterations in subcutaneous
blood flow, and, potentially, the presence and titer of anti-insulin antibodies. These issues are
reviewed in detail elsewhere. (See "General principles of insulin therapy in diabetes mellitus".)
Monitoring blood glucose — Monitoring blood glucose is an integral part of intensive insulin

therapy in type 1 diabetes as it is necessary to direct insulin dosing.
● Blood glucose monitoring (BGM) – BGM, often called self-monitoring of blood glucose
(SMBG) requires intermittent capillary blood sampling and the use of a glucose meter.
Ideally, for individuals using SMBG, testing at home should be done at least four times
daily, before meals and at bedtime. Additional testing, two to three hours after meals and
occasionally at 3 AM (for safety), as well as before and after exercise, before driving, and
when hypoglycemia is suspected, may be indicated. (See "Glucose monitoring in the
management of nonpregnant adults with diabetes mellitus", section on 'BGM systems'.)
● Continuous glucose monitoring – CGM is useful for adults with type 1 diabetes,
especially for those who are having frequent or severe hypoglycemia and who have
developed hypoglycemic unawareness. Several generations of devices to sample glucose
continuously from interstitial fluid are available, with ongoing development in progress.
Real-time CGM devices measure and transmit glucose values automatically every five
minutes to a receiver and can alert (alarm) for hypoglycemia and hyperglycemia. There are
CGM systems that transmit glucose data to mobile phones and allow users to "share" their
data with family members, friends, and caregivers; others require the use of device-
specific receivers. The immediate feedback of glucose results allows timely intervention
for high, low, or trending glucose levels to aid management and avert serious
hypoglycemic events. CGM devices increasingly provide feedback to insulin pumps,
allowing automatic adjustments of basal rate infusions for low glucose values or trends
(low glucose suspend) and high or rising glucose levels (automated increases in basal
infusion). (See "Continuous subcutaneous insulin infusion (insulin pump)", section on
'Types of insulin pumps'.)
In addition to the real-time CGM devices, there is a commercially available "flash" or

"intermittent scanning" CGM device. This device does not require calibration. It requires
the user to pass the reader (or their smartphone) over the sensor/transmitter to visualize
the glucose readings, which are measured every minute and recorded every 15 minutes.
The first model of this device does not alarm, but the most recent model can provide real-
time alarms.
Because of reliability issues and the need for calibration for some of the devices, CGM
does not eliminate the need for at least occasional fingersticks (SMBG). (See "Glucose
monitoring in the management of nonpregnant adults with diabetes mellitus", section on
'CGM systems'.)
● Glycated hemoglobin – A1C should be tested approximately every three to six months to
assess chronic glucose control.
Diabetes education — Type 1 diabetes treatment regimens are complex and are primarily
dependent on self-care. All people with type 1 diabetes require intensive initial as well as
ongoing self-management education and support in order to manage their diabetes safely and
improve clinical outcomes and quality of life [18]. It is important to understand the effects of
diet, physical activity, and stress on blood glucose; proper use of glucose and ketone
monitoring; proper insulin injection techniques and use of insulin pump (when applicable); sick
day rules; recognition, treatment, and prevention of hypoglycemia; foot care; and strategies for
the prevention and management of complications. (See 'Follow-up' below and "Hypoglycemia in
adults with diabetes mellitus", section on 'General approach to reduce risk' and "Overview of
general medical care in nonpregnant adults with diabetes mellitus", section on 'Diabetes-
related complications'.)
Diabetes therapy will have the greatest chance for success if the person is motivated, has a
good understanding of the regimen, and is supported by family, friends, and a health care team
with sufficient enthusiasm and expertise to guide therapy, educate the patient, and to monitor
progress continuously.
Nutrition — One of the most important and difficult components of nutrition education is for
patients to learn to estimate how much carbohydrate they are about to consume at any meal or
snack. Matching insulin delivery to insulin requirements is based upon the patient
understanding the anticipated glucose excursion with meals and selecting a dose of rapid-
acting or short-acting insulin that will control postprandial blood glucose excursions. Use of
insulin-to-carbohydrate ratios can free patients from having to eat a fixed amount of
carbohydrate at particular meals. If they plan to eat less carbohydrate at a meal, they simply
decrease the dose of prandial insulin. Mobile apps are available to help individuals estimate the
carbohydrate content of their meals.
Patients vary considerably in how much insulin they need to cover a set amount of
carbohydrate. Some patients need a different "insulin-to-carbohydrate ratio" at different meals.
In addition, meals containing higher fat and protein may require different insulin delivery
profiles to prevent late postprandial hyperglycemia [19-21]. (See "Nutritional considerations in
type 1 diabetes mellitus", section on 'Advanced carbohydrate counting'.)
Physical activity — Incorporating regular physical activity into the diabetes treatment plan is
helpful to avoid or limit weight gain frequently associated with intensive insulin administration
[22]. It also has cardiovascular and other benefits. We encourage healthy adults with diabetes
to perform at least 30 minutes of moderate-intensity aerobic activity on most days of the week.
To increase adherence, the clinician should advise choosing a type of activity or exercise they
will enjoy and offer regular encouragement and suggestions for overcoming barriers to
exercise.
There are four aspects of exercise that are important to consider:
● The effect of exercise on blood glucose varies with the time of day and whether the person
is relatively hypoinsulinemic or hyperinsulinemic at that time.
● Late hypoglycemia can occur several hours after vigorous aerobic exercise, due to
repletion of muscle glycogen stores.
● The type (aerobic versus weightbearing), intensity, and duration of the exercise can affect
glycemia.
● Exercise may change the profile of insulin absorption with more rapid absorption from an
exercising limb.
Adjustments to the insulin regimen before, during, and after exercise are reviewed separately.
(See "Effects of exercise in adults with diabetes mellitus", section on 'Managing blood glucose
during exercise' and "Cases illustrating the effects of exercise in intensive insulin therapy for
type 1 diabetes mellitus".)
Psychosocial issues — Patients with type 1 diabetes often experience significant stress related
to the many self-care responsibilities to optimize glycemic control. Assessment and
management of psychosocial issues are an important component of care in patients with type 1
diabetes. Depression, anxiety (fear of hypoglycemia and hyperglycemia), and eating disorders
may develop and are associated with poor glycemic control [18,23] (see "Nutritional
considerations in type 1 diabetes mellitus", section on 'Eating disorders'). In adolescents and
young adults, comprehensive management of diabetes that addresses these psychosocial
issues can improve glycemic control and reduce hospitalization [24,25]. In adults, food
insecurity has been associated with worse glycemic control [26]. Financial difficulties, including
the inability to purchase sufficient insulin or adequate self-monitoring equipment or supplies,
can also contribute to poor glycemic control.
Challenges — Although intensive diabetes therapy (coordination of meals/diet, activity,

frequent monitoring of blood glucose, and physiologic insulin therapy replacement) has clear
benefits in adults with type 1 diabetes, it is important to consider the potential challenges
associated with this regimen:
● Great effort is required by the patient to manage and coordinate diet, activity, insulin
administration, and blood glucose monitoring. (See "Glucose monitoring in the
management of nonpregnant adults with diabetes mellitus".)
● There is a heightened risk of hypoglycemia with intensive insulin therapy. (See

"Hypoglycemia in adults with diabetes mellitus", section on 'Risk factors for
hypoglycemia'.)
● The cost of intensive diabetes therapy is greater than that of conventional treatment.
Based upon an analysis of the DCCT and costs from the early 1990s, the cost of intensive
diabetes therapy as performed in the DCCT (USD $4000 to $6000/year) was approximately
three times that of conventional treatment (one or two injections per day with minimal
SMBG) [27]. The overall cost of intensive diabetes management today varies enormously
depending on which insulin is used, whether an insulin pump is involved, frequency of
SMBG, use of CGM, and other factors. Cost remains an important barrier that may limit
use of insulin analogs, insulin pens, SMBG, CGM, and insulin pumps.
● Weight gain may occur after initiation of intensive insulin therapy, which can affect patient
compliance. (See 'Follow-up' below.)
In spite of these challenges, intensive insulin therapy is recommended for the majority of adults
with type 1 diabetes.
INSULIN REGIMENS
The basic requirements of an optimal insulin regimen include administration of a basal insulin
plus mealtime boluses of a rapid-acting or short-acting insulin. Basal insulin can be delivered by
daily or twice-daily injections of an intermediate-acting or long-acting insulin preparation or
continuous subcutaneous insulin infusion (CSII) via a pump using a rapid-acting insulin
preparation. Mealtime boluses plus additional insulin used to correct hyperglycemia are
provided by a rapid-acting or short-acting insulin ( table 1). (See "General principles of insulin
therapy in diabetes mellitus", section on 'Insulin preparations'.)
Choice of insulin delivery — The choice between multiple daily insulin (MDI) injections and
continuous subcutaneous delivery of a rapid-acting insulin preparation via a pump (CSII) is
largely a matter of patient preference, lifestyle, and cost. It should be made after both regimens
are carefully explained to the patient. CSII can be of particular benefit in adults with variable
basal requirements, unpredictable or varying schedules requiring flexible insulin dosing, and
sometimes in those who have not been able to achieve their glycemic goals on MDI.
Glycemic outcomes — Glycemic control is generally similar with MDI and CSII when using
self-monitoring of blood glucose (SMBG). The impact on hypoglycemia is less certain, with most
trials showing no difference in severe hypoglycemic events. Regardless of the mode of insulin
delivery (MDI versus CSII), clinical trials have reported improved glycemic outcomes with the
use of continuous glucose monitoring (CGM) in adults with type 1 diabetes, with similar or
lower A1C levels but less frequent hypoglycemia. Newer insulin pumps, which are integrated
with CGM systems, have features that can reduce hypoglycemia by temporarily suspending
insulin infusion ("low glucose suspend" feature). (See "Continuous subcutaneous insulin
infusion (insulin pump)", section on 'Sensor-augmented insulin pump'.)
● In the Diabetes Control and Complications Trial (DCCT), in which all supplies were free,
patients in the intensive therapy group were allowed to choose between MDI or CSII [11].
Glycemic control, frequency of severe hypoglycemia, and progression of microvascular
disease were similar with either type of insulin therapy. It should be noted that pumps
have become smaller, more reliable, and more sophisticated since the DCCT ended in
1993.
● In meta-analyses of randomized controlled trials that compared CSII with MDI, continuous
therapy resulted in slightly better glycemic control (weighted mean difference -0.2 to -0.4
percentage points), with little difference between the two groups in the rate of
hypoglycemia [28-31]. Many of the trials included in the meta-analyses used rapid-acting
insulin analogs instead of regular insulin for CSII and rapid-acting and long-acting insulin
analogs for MDI. In the 2017 and 2019 meta-analyses, which included a trial using CSII
with CGM (sensor-augmented insulin pump), there was no difference in minor or severe
hypoglycemic events; however, there was a reduction in the incidence of nocturnal
hypoglycemia with CSII [30]. Small trials comparing intensive insulin therapy using MDI
versus CSII reported no difference in quality-of-life measures between treatment groups
[32,33]. Sensor-augmented pump therapy with a suspend feature was not used in these
older studies. (See "Continuous subcutaneous insulin infusion (insulin pump)", section on
'Sensor-augmented insulin pump'.)
Risk of DKA — In some trials comparing MDI and CSII, the risk of diabetic ketoacidosis (DKA)
was higher with CSII [31]. DKA in patients using CSII is usually due to detachment or blockage
or leakage in the syringe or the infusion set or connectors, causing an interruption of insulin
infusion [34,35]. Since the subcutaneous depot is very small, any interruption in continuous
flow leads very quickly to hypoinsulinemia, hyperglycemia, and, possibly, DKA. DKA occurs more
rapidly (four versus six hours) in patients with pump malfunction who are using insulin lispro
rather than regular insulin [36]. (See "Continuous subcutaneous insulin infusion (insulin
pump)", section on 'Troubleshooting'.)
Dose adjustments and absorption — One advantage of CSII is that it allows for flexibility of
insulin dosing and adjustments. As an example, a temporary basal rate can be programmed,
such that basal rates can be reduced for aerobic activities. In addition, CSII may allow more
flexibility in the timing of meals (a relative advantage that may also pertain to MDI regimens
that use insulin analogs instead of NPH).
CSII can deliver insulin accurately in fractions of units, which can be a benefit for adults who are
very insulin sensitive. Doses as low as 0.05 units can be accurately delivered with CSII. While
these extremely small doses of insulin may not be clinically important for some adults,
nonpump insulin delivery can only provide insulin at 0.5- to 1-unit increments, which for some
patients, especially children, may not be optimal.
For adults who have gastroparesis or eat high fat and protein meals, advanced bolus features
(extended or dual-wave bolus) may help to better control the delayed or prolonged
hyperglycemia observed after meals.
In addition, insulin absorption with pump therapy appears to be less variable from day to day
[37], and therefore, blood glucose profiles may be more predictable, particularly compared with
NPH and glargine-based MDI regimens. Both the small subcutaneous depot and the constancy
of the injection site and depth for the two to three days with each catheter contribute to the
relative consistency of absorption.
Lifestyle considerations — There are patients who prefer not to wear a CSII device. Some
patients who use pumps complain that the treatment is awkward, embarrassing, or unpleasant,
particularly when sleeping or having sexual intercourse. Pump-treated patients can take off the
pump for brief periods. Doing so for one hour or less does not usually lead to loss of blood
glucose control. For longer periods (such as overnight), the patient should transition to an
intermediate-acting or long-acting basal insulin.
Although the available hybrid closed-loop devices may lower A1C modestly without an increase
(and even a decrease) in hypoglycemia, the interface between patient management of boluses
and automated basal rate control may be troublesome with numerous alarms. For some adults,
however, use of hybrid closed-loop devices may reduce fear of nocturnal hypoglycemia, thereby
decreasing anxiety and improving duration of sleep. The next generation of fully automated,
closed-loop insulin delivery devices are being designed to reduce the burden of self-care
associated with type 1 diabetes.
Cost — The costs of the pump and supplies are higher than those of insulin injection therapy
(MDI).
Multiple daily injections — Many different insulin regimens may be used in an MDI regimen.
Some of the more common ones are shown in the table ( table 2). Regardless of the type of
insulin chosen, these insulin regimens should be monitored with SMBG or use of CGM. (See
'Monitoring blood glucose' above.)
Choosing basal/prandial insulin — The choice of basal (NPH, U-100 or U-300 glargine,

detemir, or degludec) and prandial (lispro, aspart, glulisine, regular) insulin for an MDI regimen
depends upon patient preference, lifestyle, and cost concerns with variable insurance coverage
of different insulins. Owing to the convenience for patients regarding timing of prandial rapid-
acting insulin and the reduced risk of hypoglycemia, most patients use insulin analogs. Since
regular and NPH insulins are less expensive than analog insulins, some patients need to use
them for cost reasons. (See "General principles of insulin therapy in diabetes mellitus", section
on 'Insulin preparations'.)
In short-term trials, there may be a modest benefit of insulin analogs over non-analog insulin
on A1C levels. As an example, in an 18-week trial in 595 adults with type 1 diabetes randomly
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assigned to NPH/regular versus detemir/aspart, there was a small but significant difference in
A1C values (mean difference -0.22 percentage points) favoring the insulin analogs [38].
Although the patients in the analog group received a slightly higher daily dose (by 4 units) of
basal insulin, the risk of overall and nocturnal, but not severe, hypoglycemia was lower in the
analog group. Whether the basal, bolus, or both analogs were responsible for the improvement
compared with non-analog treatment is not clear. Long-term trials with diabetic complications
as endpoints are lacking.
Basal insulin options — The choice of basal insulin depends upon patient preference,
lifestyle, and cost concerns.
● Insulin glargine – In patients with type 1 diabetes, glycemic control is similar if once-daily
glargine is given before breakfast, before dinner, or at bedtime, but there is less nocturnal
hypoglycemia with breakfast administration [39].
Although many patients can achieve stable basal serum insulin concentrations with a
single daily injection of U-100 insulin glargine given in the morning or evening (regimens 3
and 4) ( table 2), this is not always the case. Some patients with type 1 diabetes achieve
better glycemic control with U-100 glargine given twice per day (regimen 5) ( table 2). U-
100 insulin glargine has a half-live of 12 hours.
Insulin glargine is also available in a more concentrated formulation (U-300 glargine),

which prolongs its duration of action and further smooths its profile. This insulin is given
once daily and can be of benefit for some adults with type 1 diabetes. Similar to insulin
degludec, U-300 insulin glargine has little peak effect and may reduce hypoglycemia in
individual patients. (See "General principles of insulin therapy in diabetes mellitus", section
on 'Basal insulin analogs'.)
● Insulin detemir – The duration of action of insulin detemir is shorter than that of insulin
glargine [40], though still somewhat longer than NPH ( table 1). In one study, a detemir
dose of 0.29 units/kg provided the same effect as 0.3 units/kg NPH but with a longer
duration of action (16.9 versus 12.7 hours, respectively) [41]. Like NPH, twice-daily
injections appear to be necessary in most patients with type 1 diabetes. Duration of action
is shorter when lower doses are used.
● Insulin degludec – Insulin degludec is a very long-acting basal insulin available in U-100
and U-200 formulations ( table 1) [42]. It is administered once daily at any time of day. In
contrast to U-100 glargine and detemir insulins, degludec may be mixed with rapid-acting
insulins without appreciably altering the kinetics of the degludec or the rapid-acting
insulin. The long-term safety profile of insulin degludec is unknown.
In meta-analyses of short-term trials comparing long-acting (glargine or detemir) with

intermediate-acting (NPH) insulin in adults with type 1 diabetes, there was little glycemic
advantage to the long-acting insulin analogs (mean difference in A1C -0.06 to -0.39 percentage
points) [43-45]. In one analysis, detemir once or twice daily and glargine once daily caused less
weight gain than NPH once daily [43]. In addition, there was a slightly lower risk of severe
hypoglycemia and nocturnal hypoglycemia with detemir once or twice daily compared with
NPH once or twice daily [45]. However, in most of the older studies, CGM data were not
available, so ascertainment of hypoglycemia was incomplete. In addition, the majority of the
studies in the meta-analysis used NPH once daily as the comparator, which is not standard
therapy for NPH considering its duration of action [43]. Therefore, the design of the studies in
the meta-analysis favored glargine.
In trials comparing insulins degludec and glargine in patients with type 1 diabetes (each in
combination with pre-meal aspart), there was similar glycemic efficacy (-0.4 percentage point
reduction in A1C), with less overall and/or nocturnal hypoglycemia with degludec, but no
significant difference in rates of severe hypoglycemia [46,47].
In a crossover trial including 501 adults with type 1 diabetes and at least one risk factor for
hypoglycemia who were randomly assigned to insulin degludec or glargine for 32 weeks and
then crossed over to the alternate regimen for an additional 32 weeks, there was a reduced rate
of overall symptomatic hypoglycemia with degludec (2200 versus 2463 episodes per 100
patient-years' exposure in the degludec and glargine groups, respectively; rate ratio [RR] 0.89,
95% CI 0.85-0.94) [48]. The rate of nocturnal symptomatic hypoglycemia was also reduced with
degludec (277 and 429 episodes per 100 patient-years' exposure, RR 0.64, 95% CI 0.56-0.73).
The absolute rate of severe hypoglycemia was only a small fraction of total episodes, but the
proportion of patients affected was approximately 7 percent lower with degludec (10.3 percent)
compared with glargine (17.1 percent). The loss-to-follow-up in this brief study was greater than
20 percent, making the results somewhat unreliable. Whether the results would apply to
patients at lower risk for hypoglycemia is not known.
Prandial insulin options — For patients with type 1 diabetes, basal insulin alone is
inadequate for good glycemic control. Prandial (pre-meal or preprandial) boluses are necessary.
Either rapid-acting insulin (lispro, aspart, glulisine) or short-acting (regular) can be given pre-
meal. Although rapid-acting insulins are more expensive than regular insulin, the convenience
for patients regarding timing of pre-meal administration and reduction in hypoglycemia
reported in some studies represent distinct advantages for patients [49-52]. Rapid-acting
insulins:
● Can be injected 10 to 15 minutes before or up to immediately after meals, whereas

regular insulin should be given 30 to 45 minutes or more before meals to optimally match
the glycemic excursions after a meal.
● Have a shorter duration of action, reducing hypoglycemia several hours after the dose is
given.
● Are particularly useful in addressing unexpectedly high blood glucose levels (eg, between
meals or in the setting of stress) because they will lower glucose levels more rapidly and
without the prolonged effect of regular insulin.
In a meta-analysis of randomized trials comparing rapid-acting insulin analogs with regular

insulin, there was only a minor benefit of insulin analogs in terms of A1C values (mean
difference approximately -0.15 percent) and no significant difference in risk of severe
hypoglycemia [53]. In two of the trials, there was a significant reduction in nocturnal
hypoglycemia with insulin analogs. CGM was not used in most of these studies, so reliable data
on reduction of severe and nocturnal hypoglycemia were not available. There are no data
examining the relative effects of insulin analogs on long-term diabetic complications. The
convenience of rapid-acting insulin compared with regular insulin should not be
underestimated.
An even faster-acting insulin aspart (with added niacinamide) has more rapid initial absorption
than insulin aspart, with a similar time to peak concentration. There is also a faster insulin
lispro. Insulin lispro as well as the faster-acting insulin lispro are available in pens in more
concentrated formulations (U-200). Regular insulin is available in a very concentrated (U-500)
formulation for injection using U-500 syringes or a U-500 regular insulin pen. U-500 regular has
a delayed peak action and a more prolonged duration of action compared with U-100 regular
insulin, and it is generally not used in type 1 diabetes. (See "General principles of insulin therapy
in diabetes mellitus".)
One inhaled insulin preparation is available, but it is rarely used [54]. Studies have shown that
inhaled insulin causes a very rapid rise in serum insulin concentration (similar to that after
subcutaneous insulin lispro and aspart, and faster than that after subcutaneous regular
insulin). However, there are dosing constraints (only available in 4-unit increments), and the
basal insulin must still be administered by injection. Inhaled insulin is contraindicated in the
presence of chronic lung disease. No study has demonstrated whether inhaled insulin can
achieve A1C levels as low as 7 percent in type 1 diabetes. Inhaled insulin is reviewed in more
detail elsewhere. (See "Inhaled insulin therapy in diabetes mellitus".)
Designing an MDI insulin regimen

● Initial total daily dose (TDD) – Most newly diagnosed patients with type 1 diabetes can
be started on a TDD of 0.2 to 0.5 units of insulin per kg per day, although many will
ultimately require 0.6 to 0.7 units per kg per day. Adolescents, especially during puberty,
as well as adults with infections or other acute medical conditions or stresses often need
more. The starting dose can be adjusted upward (or downward) every few days based
upon symptoms and blood glucose measurements.
● Basal bolus composition and timing – In designing an MDI injection regimen,

approximately 40 to 50 percent of the TDD should be given as a basal insulin, either as
once-daily degludec or U-300 glargine, once- or twice-daily U-100 glargine or detemir, or
as twice-daily intermediate-acting insulin NPH. The long-acting insulin can be given either
at bedtime or in the morning; the NPH is usually given as approximately two-thirds of the
dose in the morning and one-third at bedtime.
The remainder of the TDD is given as short-acting or rapid-acting insulin, divided before
meals. The pre-meal dosing is determined by the pre-meal glucose level, meal size and
content, glucose trends (when available from CGM), as well as activity and exercise pattern
(see "Nutritional considerations in type 1 diabetes mellitus"). Regimens that use NPH in
the morning may not require a pre-lunch dose of short-acting (regular) or rapid-acting
insulin because the peak of NPH action is occurring at that time, potentially reducing the
frequency of injections.
● Injection sites – The abdomen is the preferred site for pre-meal injections of regular
insulin because absorption is quicker from this site [55]. In comparison, the thigh or
buttock is a good site for the evening intermediate-acting insulin (NPH) dose; the slower
rate of absorption enhances the likelihood that the insulin will last through the night. The
site of injection is less important for rapid-acting or long-acting insulin analogs, and
therefore, they may be administered in the abdomen, thighs, buttock, or upper arms.
However, insulin absorption may be faster in an exercising limb. (See "General principles
of insulin therapy in diabetes mellitus".)
Because of the difference in pharmacokinetics of regular insulin (duration of action, five to eight
hours) versus rapid-acting insulin analogs (two to four hours), an increase in the dose of
intermediate-acting or long-acting insulin may be required when a patient is switched from
regular insulin to an insulin analog for the pre-meal bolus dose ( table 1). In a randomized
clinical trial of 56 patients with type 1 diabetes using variable-dose lispro or regular insulin
before meals along with twice-daily NPH insulin, A1C values were lower after 12 months (6.3
versus 6.7 percent) and hypoglycemia was less frequent (7.4 versus 11.5 episodes per month,
defined as blood glucose concentrations less than 70 mg/dL [3.8 mmol/L]) in the insulin lispro
group, but 30 percent more NPH insulin was required [56].
Continuous subcutaneous insulin infusion (insulin pump) — A variety of insulin pumps are
available, some of which "communicate" with specific CGM devices. The choice among pumps is
largely a matter of patient preference, cost, and lifestyle. Initiating insulin pump therapy is
reviewed in detail separately. (See "Continuous subcutaneous insulin infusion (insulin pump)".)
ADJUNCTIVE THERAPY NOT RECOMMENDED
Although other diabetes agents are being tested (or have been tested) in patients with type 1
diabetes, we do not recommend the use of these adjunctive therapies, owing to the absence of
long-term efficacy and safety data [57]:
● Amylin analogs – Amylin analogs, such as pramlintide, influence blood glucose levels by
slowing gastric emptying, promoting satiety, and suppressing the abnormal postprandial
rise of glucagon in patients with diabetes. Pramlintide is the only adjunctive therapy that is
US Food and Drug Administration (FDA) approved for type 1 diabetes. However, many
questions remain unanswered regarding clinical use and long-term outcomes with this
class of drug.
Pramlintide reduces A1C slightly (approximately 0.3 percentage points) with a lower
insulin dose [58,59]. It does not cause weight gain and may be associated with a modest
weight loss. Whether the putative clinical benefit balances the inconvenience of taking
more injections, the frequent gastrointestinal side effects (mild to moderate nausea and
occasional vomiting), and the substantial added expense is unclear. (See "Amylin analogs
for the treatment of diabetes mellitus".)
● Glucagon-like peptide 1 (GLP-1) receptor agonists – GLP-1 receptor agonists are not
approved by the FDA for use in type 1 diabetes. In randomized trials comparing the
addition of liraglutide or placebo to insulin therapy in patients with type 1 diabetes, the
addition of liraglutide resulted in trivially lower A1C levels (placebo-corrected reductions in
A1C of approximately 0.1 to 0.2 percentage points), lower insulin doses, and lower body
weight; however, there was an increase in symptomatic hypoglycemia and hyperglycemia
with ketosis in the liraglutide groups [60,61]. (See "Glucagon-like peptide 1-based
therapies for the treatment of type 2 diabetes mellitus".)
● Sodium-glucose co-transporter (SGLT) inhibitors – The SGLTs are a family of proteins

involved in glucose transport [62]. SGLT2 is expressed in the proximal tubule of the kidney
and mediates reabsorption of approximately 90 percent of the filtered glucose load. SGLT2
inhibitors promote the renal excretion of glucose and thereby modestly lower elevated
blood glucose levels. SGLT1 is predominantly expressed in the small intestine and
mediates the absorption of glucose; SGLT1 inhibition reduces intestinal glucose
absorption.
SGLT2 inhibitors are available for the treatment of type 2 diabetes. (See "Sodium-glucose
co-transporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus",
section on 'Glycemic efficacy'.)
Although SGLT2 inhibitors have been studied as add-on therapy to insulin in patients with
type 1 diabetes, any small benefit in reducing A1C and body weight is offset by the
increased risk for adverse effects, including diabetic ketoacidosis (DKA) [63-67]. SGLT2
inhibitors are not approved by the FDA for use in type 1 diabetes. (See "Sodium-glucose
co-transporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus",
section on 'Adverse effects' and "Diabetic ketoacidosis and hyperosmolar hyperglycemic
state in adults: Clinical features, evaluation, and diagnosis" and "Sodium-glucose co-
transporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus",
section on 'Contraindications and precautions'.)
Sotagliflozin is a dual SGLT1 and SGLT2 inhibitor that is under investigation as adjunctive
therapy in type 1 diabetes [68]. In a phase III trial, 1402 patients with type 1 diabetes
selected to be at low risk for DKA were randomly assigned to sotagliflozin or placebo in
addition to insulin therapy. After 24 weeks, the proportion of patients who achieved an
A1C <7 percent and no severe hypoglycemia or DKA was greater in the sotagliflozin group
(28.6 versus 15.2 percent) [69]. However, the rate of DKA was higher in the sotagliflozin
group (3 versus 0.6 percent), as was the frequency of dehydration and genital infections.
Of note, participants were instructed in how to mitigate the risk of ketoacidosis and were
provided with ketone testing strips and meters to measure beta-hydroxybutyrate in
addition to regular measurements during study visits. There was no difference in severe
hypoglycemia. The increased risk for treatment-related complications, especially DKA and
added expense, is not balanced by the modest lowering of A1C.
● Metformin – Metformin is a biguanide that decreases hepatic glucose output and

increases insulin-mediated glucose utilization in peripheral tissues (such as muscle and
liver). In the absence of contraindications, metformin is considered the first choice for oral
treatment in type 2 diabetes. It has been evaluated as an adjunct to insulin therapy in type
1 diabetes. In a meta-analysis of five trials comparing the addition of metformin versus
placebo or comparator in patients with type 1 diabetes, there was a significant reduction
in insulin dose but not in A1C [70]. There are no data on microvascular or macrovascular
outcomes, although a trial is underway [71]. (See "Metformin in the treatment of adults
with type 2 diabetes mellitus".)
FOLLOW-UP
● Frequency – The frequency of clinic visits and adjustments to the insulin regimen vary
based on the needs of the patient and patient/health care team preference. In general,
nonpregnant patients with type 1 diabetes are seen every three months, although stable
patients who are safely meeting their glycemic goals can be seen less frequently. During
adjustments of therapy and if patients are not meeting goals, they may need to be seen
more frequently. For some individuals, many day-to-day problems can be solved over the
telephone or via televisits or email (especially if data from devices [glucose meter, insulin
pump, continuous glucose monitors (CGM)] have been uploaded and/or blood glucose
levels have been faxed in or emailed prior to the conversation).
● Assessment of glucose patterns and insulin adjustment – At clinic visits, all devices
(glucose meters, CGM, pumps) should be downloaded and the glucose and insulin data
reviewed. The insulin regimen is adjusted based on glucose patterns, with an eye to
reducing hypoglycemia, while at the same time achieving target glucose and A1C levels.
There should be ongoing discussion and agreement on target glucose and A1C levels,
determined by the patient's age, comorbidities, history of hypoglycemia, and preference.
It is useful to review the patient's blood glucose monitoring technique, insulin injection
timing and technique, and food records. The results obtained should be discussed so that
the patient can learn how to interpret the findings and how to make appropriate
adjustments in dietary intake and insulin dose. Maintaining improved glycemic control
over the long term requires a major effort to prevent complacency and to avoid burnout.
A number of different patterns and problems can be identified during this initial period.
(See "Cases illustrating problems with insulin therapy for type 1 diabetes mellitus".)
As examples:
• Postprandial hyperglycemia – If postprandial rises in blood glucose are too high,

options include modifying the content of the diet (including more high fiber, slowly
absorbed carbohydrate, and/or reducing the amount of carbohydrate), altering the
time between when the insulin is given and the meal is started, and/or adjusting the
preprandial insulin dose. Alternatively, if it is not already being used, try replacing the
regular insulin with a rapid-acting insulin, which is absorbed and therefore acts more
rapidly than regular insulin, resulting in lower postprandial blood glucose values [72].
(See "Nutritional considerations in type 1 diabetes mellitus", section on 'Carbohydrate
consistency' and 'Prandial insulin options' above.)
• Fasting hyperglycemia – The "dawn phenomenon" is thought to result from diurnal

secretion patterns of hormones, particularly increased growth hormone at midnight to
2 AM, that tend to antagonize the actions of insulin in the early morning hours and so
raise fasting blood glucose concentrations. Basal insulin should keep glucose readings
at target when the individual is not eating, exercising, or under stress. To determine if
basal insulin dosing needs to be adjusted requires examining glucose profiles
beginning at least three to four hours after the last meal or snack and insulin bolus and
occasionally at 3 AM.
However, overnight glycemic patterns may not solely reflect basal insulin dosing. When
addressing nocturnal and fasting hyperglycemia, question the patient concerning
evening snacking and bedtime insulin bolusing for food and/or correction of
hyperglycemia. Evening or night-time snacking with insufficient coverage with rapid-
acting insulin can cause fasting hyperglycemia.
• No discernible pattern – If the blood glucose records show no consistent pattern, the
problem may be an erratic lifestyle and eating pattern. If the patient is disciplined and
consistent in the content and timing of meals, the site and timing of insulin injections,
and the timing and frequency of exercise, it is easier to interpret blood glucose
patterns and make appropriate alterations to the regimen. Compared with previous
nonphysiologic, fixed-dose regimens, current regimens provide somewhat more
flexibility in timing of meals, meal size, and composition since timing and size of doses
can be varied.
Some women need to alter the insulin dosing a few days prior to menses. Episodes of
hyperglycemia can also be caused by stress, pain, steroid medications, and acute
illnesses such as infections. Injection technique and site of insulin administration
should also be assessed.
● Managing hypoglycemia – Episodes of severe hypoglycemia (and any glucose <54 mg/dL
[3 mmol/L]) should be reviewed in detail to determine their cause and means of
prevention. Poor hypoglycemia awareness becomes more prevalent with longer duration
of type 1 diabetes and in adults with recurrent hypoglycemia [73]. It is important to screen
for and address hypoglycemia unawareness and to ensure that the patient's family or
partner is well equipped to deal with hypoglycemia. Glucagon (nasal, intramuscular, or

subcutaneous) should be available for emergency use. Education and medical
interventions, as well as the use of CGM, can help prevent life-threatening severe
hypoglycemia. (See "Hypoglycemia in adults with diabetes mellitus" and "Interactive
diabetes case 3: Hypoglycemia in a patient with type 1 diabetes".)
● Preventing weight gain – Weight gain is a common problem with insulin replacement,
especially when A1C levels are reduced substantially. Poor adherence may subsequently
be a problem in patients who intentionally omit insulin injections to lose weight or avoid
weight gain. The use of newer insulin analogs and CGM, as well as careful attention to
insulin dosing (avoiding giving too much basal insulin) may help prevent excessive weight
gain [43,74,75]. Attention should also be paid to caloric content and exercise to avoid or
limit the weight gain that commonly accompanies intensive insulin administration. (See
'Diabetes education' above.)
Patients randomly assigned to intensive insulin therapy in the Diabetes Control and
Complications Trial (DCCT) gained significantly more weight than those who received
conventional therapy (5.1 versus 2.4 kg) [22]. Higher baseline A1C values and greater
decrements in A1C during intensive therapy were both associated with greater weight
gain.
The potential importance of these findings is illustrated in a subsequent analysis of the

DCCT, in which patients were divided into quartiles based upon weight gain, from no
weight gain (first quartile) to maximal weight gain (fourth quartile) [76]. The mean body
mass index (BMI) in the fourth quartile was 31 kg/m2, placing these patients in the obesity
range. The following results were observed:
• Intensive insulin therapy resulted in similar glycemic control at follow-up (mean 6.1
years) in all the weight gain quartiles.
• Patients in the first quartile (no weight gain) had decreases in serum triglyceride, total
cholesterol, and low-density lipoprotein (LDL) cholesterol concentrations compared
with baseline, reflecting the benefits of improved glycemic control on serum lipid
concentrations in the absence of weight gain.
• Patients in the fourth quartile had a significant elevation in serum concentrations of

these lipids and in blood pressure compared with baseline. They also had higher waist-
to-hip ratios (abdominal obesity) than patients in other quartiles.
The constellation of lipid abnormalities, abdominal obesity, and hypertension is similar to

that in the central obesity-insulin resistance syndrome that is characteristic of many
patients with type 2 diabetes (see "Metabolic syndrome (insulin resistance syndrome or
syndrome X)"). Such patients are predisposed to develop coronary atherosclerosis,
although it is unproven whether control of weight gain could be important in decreasing
the risk of macrovascular complications in patients receiving intensive insulin therapy.
Excessive weight gain might detract from the demonstrated large benefit of insulin
therapy on macrovascular complications demonstrated by the DCCT/Epidemiology of
Diabetes Interventions and Complications (EDIC) study [13].
● Sick-day rules – Sick-day management is directed towards preventing hypoglycemia,

significant hyperglycemia, and diabetic ketoacidosis (DKA).
During an illness, blood glucose monitoring should be performed more frequently, eg,
every two to three hours including during the night; this may be increased to every one to
two hours if necessary. Alternatively, use of a CGM, if available, can be particularly helpful
for sick-day management.
Patients should be instructed to measure capillary or urinary ketones if the blood glucose
concentration is above 250 to 300 mg/dL (13.9 to 16.7 mmol/L) for unexplained reasons,
especially if the person feels generally unwell at the time. Ketones should be monitored
during periods of illness or stress or if there are symptoms compatible with ketoacidosis,
such as nausea, vomiting, and abdominal pain. Home testing of blood for beta-
hydroxybutyrate is available, but it is used infrequently in adults, at least in the United
States. This method permits earlier and a more quantitative detection of ketosis compared
with tests for urinary ketones, which measure acetone and acetoacetate.
The presence of ketones in the urine does not always mean that the person has
impending ketoacidosis. Ketonuria indicates that the person is in a catabolic state and is
breaking down fat, and it can occur in anyone who has a negative caloric balance while
dieting. However, in type 1 diabetes, the presence of urine ketones along with
hyperglycemia is presumptive evidence of a pathologic catabolic state more serious than
hyperglycemia alone. Under these circumstances, the person should be advised to retest
every two to three hours, take measures to keep well hydrated, and take extra insulin if
indicated. Treatment of DKA is discussed separately. (See "Diabetic ketoacidosis and
hyperosmolar hyperglycemic state in adults: Treatment".)
● Diabetes-related complications – Patients with diabetes require ongoing evaluation for

diabetes-related complications ( table 3). This topic is reviewed in detail separately. (See
"Overview of general medical care in nonpregnant adults with diabetes mellitus", section
on 'Diabetes-related complications'.)
● Special situations – Lapses in dietary control during special occasions (such as eating at a
restaurant or traveling) are to be expected. Religious fasting or major changes in activity
levels will affect glucose control. Patients should be educated so that they can adjust their
insulin regimens to prevent marked fluctuations in the plasma glucose concentration. (See
"Cases illustrating intensive insulin therapy in special situations" and "Interactive diabetes
case 9: Management of type 1 diabetes in a patient on glucocorticoid therapy".)
● Other – There are a number of other issues that should be reviewed in patients receiving
multiple daily insulin (MDI) injections or continuous subcutaneous insulin infusion (CSII). It
is often helpful to focus on one particular aspect (such as exercise, diet, or insulin-to-
carbohydrate ratios) for a few weeks and then switch to another issue. Giving the patient
written feedback on how they are doing (graphing out their changes in weight, A1C, etc)
may also be useful.
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Diabetes mellitus in
adults" and "Society guideline links: Blood glucose monitoring".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer
short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more
sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print
or e-mail these topics to your patients. (You can also locate patient education articles on a
variety of subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topics (see "Patient education: Type 1 diabetes (The Basics)" and "Patient education:
Using insulin (The Basics)" and "Patient education: Should I switch to an insulin pump?
(The Basics)")
● Beyond the Basics topics (see "Patient education: Type 1 diabetes: Overview (Beyond the
Basics)" and "Patient education: Type 1 diabetes: Insulin treatment (Beyond the Basics)"
and "Patient education: Blood glucose monitoring in diabetes (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
● We recommend intensive diabetes therapy for most adults with type 1 diabetes with the
goal of achieving glycemic control as close to the nondiabetic range as safely possible
(Grade 1A). Intensive diabetes therapy includes the coordination of meals/diet and activity
with physiologic insulin replacement, guided by frequent monitoring of blood glucose
levels or use of continuous glucose monitoring (CGM). (See 'Intensive diabetes therapy'
above and 'Insulin replacement' above.)
● Glycated hemoglobin (A1C) goals in patients with diabetes should be tailored to the
individual, balancing the demonstrated benefits with regard to prevention and delay in
microvascular complications with the risk of hypoglycemia. For adults with type 1
diabetes, we aim for an A1C value of ≤7 percent (using an assay aligned to the Diabetes
Control and Complications Trial [DCCT] in which the upper limit of normal is 6 percent) in
patients in whom the benefits outweigh the risks. Higher targets may be appropriate in
certain adults such as those who are older, have a history of severe hypoglycemia, or with
serious comorbidities. (See 'Glycemic targets' above and "Glycemic control and vascular
complications in type 1 diabetes mellitus".)
● For patients with type 1 diabetes, the goal of insulin therapy is to provide a physiologic
profile of insulin by administration of a basal level of insulin (delivered by daily or twice-
daily injections of an intermediate-acting or long-acting insulin preparation, or continuous
subcutaneous delivery of a rapid-acting insulin preparation via a pump [CSII]) and pre-
meal boluses of a rapid-acting or short-acting insulin ( table 1). The dose of the pre-meal
bolus is determined by the ambient blood glucose level before the meal, the size and
composition of the meal, anticipated activity levels, and glucose trends (if using CGM). (See
'Insulin replacement' above.)
● CGM is particularly useful for adults with type 1 diabetes who are having frequent or
severe hypoglycemia and who have developed hypoglycemic unawareness. In the absence
of CGM, blood glucose monitoring, using a glucose meter to read the test strips, should be
performed at least four times daily before meals and bed. Additional testing, two to three
hours after meals and occasionally at 3 AM, as well as before and after exercise, before
driving, and when hypoglycemia is suspected, may be indicated. A1C should be tested
regularly to assess chronic glucose control. (See 'Monitoring blood glucose' above and
"Glucose monitoring in the management of nonpregnant adults with diabetes mellitus".)
● The choice between multiple daily insulin injections (MDI) and continuous subcutaneous
delivery of a rapid insulin preparation via a pump is largely a matter of patient preference,
lifestyle, and cost. It should be made only after both regimens are carefully explained to
the patient. (See 'Choice of insulin delivery' above.)
● There are several different MDI regimens ( table 2). The choice of basal and pre-meal
bolus insulin for an MDI regimen depends upon patient preference, lifestyle, and cost.
There may be modest glycemic benefit (modest reduction in A1C and/or rate of severe
hypoglycemia) of insulin analogs over conventional insulin; the long-term effects of the
individual MDI regimens on diabetic complications are not yet known. (See 'Choosing
basal/prandial insulin' above and "General principles of insulin therapy in diabetes
mellitus", section on 'Human insulins'.)
● All patients with type 1 diabetes should receive ongoing self-management education and
support in order to improve clinical outcomes and quality of life. Insulin adjustments are a
lifelong exercise and must be made in response to glycemic (blood glucose and A1C)
control that is not meeting individualized targets. Hypoglycemia is a constant theme and
may require insulin adjustments. Changes in exercise pattern, dietary habits, weight loss,
and travel plans require adjustments in the insulin plan coincident with and not after the
changes. (See 'Diabetes education' above and 'Follow-up' above.)
ACKNOWLEDGMENT
The UpToDate editorial staff acknowledges David McCulloch, MD, who contributed to earlier
versions of this topic review.
Use of UpToDate is subject to the Terms of Use.
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aspart) versus traditional human insulins (NPH insulin and regular human insulin) in basal-
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dinner, or bedtime administration of insulin glargine in patients with type 1 diabetes.
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dynamics of the long-acting insulin analogs glargine and detemir at steady state in type 1
diabetes: a double-blind, randomized, crossover study. Diabetes Care 2007; 30:2447.
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investigating the pharmacodynamic and pharmacokinetic properties of the long-acting
insulin analog detemir. Diabetes Care 2005; 28:1107.
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insulin degludec, an ultra-long-acting basal insulin. Pharm Res 2012; 29:2104.
43. Tricco AC, Ashoor HM, Antony J, et al. Safety, effectiveness, and cost effectiveness of long
acting versus intermediate acting insulin for patients with type 1 diabetes: systematic
review and network meta-analysis. BMJ 2014; 349:g5459.
44. Sanches AC, Correr CJ, Venson R, Pontarolo R. Revisiting the efficacy of long-acting insulin
analogues on adults with type 1 diabetes using mixed-treatment comparisons. Diabetes
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management of diabetes mellitus: a meta-analysis. CMAJ 2009; 180:385.
46. Heller S, Buse J, Fisher M, et al. Insulin degludec, an ultra-longacting basal insulin, versus
insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes
(BEGIN Basal-Bolus Type 1): a phase 3, randomised, open-label, treat-to-target non-
inferiority trial. Lancet 2012; 379:1489.
47. Mathieu C, Hollander P, Miranda-Palma B, et al. Efficacy and safety of insulin degludec in a
flexible dosing regimen vs insulin glargine in patients with type 1 diabetes (BEGIN: Flex T1):
a 26-week randomized, treat-to-target trial with a 26-week extension. J Clin Endocrinol
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48. Lane W, Bailey TS, Gerety G, et al. Effect of Insulin Degludec vs Insulin Glargine U100 on
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49. Hirsch IB, Juneja R, Beals JM, et al. The Evolution of Insulin and How it Informs Therapy and
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50. Holleman F, van den Brand JJ, Hoven RA, et al. Comparison of LysB28, ProB29-human
insulin analog and regular human insulin in the correction of incidental hyperglycemia.

51. Raskin P, Guthrie RA, Leiter L, et al. Use of insulin aspart, a fast-acting insulin analog, as the
mealtime insulin in the management of patients with type 1 diabetes. Diabetes Care 2000;
23:583.
52. Rave K, Klein O, Frick AD, Becker RH. Advantage of premeal-injected insulin glulisine
compared with regular human insulin in subjects with type 1 diabetes. Diabetes Care 2006;
29:1812.
53. Fullerton B, Siebenhofer A, Jeitler K, et al. Short-acting insulin analogues versus regular
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:CD012161.
54. http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm403122.htm (Access
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92:59.
56. Lalli C, Ciofetta M, Del Sindaco P, et al. Long-term intensive treatment of type 1 diabetes
with the short-acting insulin analog lispro in variable combination with NPH insulin at
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58. Ratner RE, Dickey R, Fineman M, et al. Amylin replacement with pramlintide as an adjunct
to insulin therapy improves long-term glycaemic and weight control in Type 1 diabetes
mellitus: a 1-year, randomized controlled trial. Diabet Med 2004; 21:1204.
59. Herrmann K, Frias JP, Edelman SV, et al. Pramlintide improved measures of glycemic control
and body weight in patients with type 1 diabetes mellitus undergoing continuous
subcutaneous insulin infusion therapy. Postgrad Med 2013; 125:136.
60. Mathieu C, Zinman B, Hemmingsson JU, et al. Efficacy and Safety of Liraglutide Added to
Insulin Treatment in Type 1 Diabetes: The ADJUNCT ONE Treat-To-Target Randomized Trial.
61. Ahrén B, Hirsch IB, Pieber TR, et al. Efficacy and Safety of Liraglutide Added to Capped
Insulin Treatment in Subjects With Type 1 Diabetes: The ADJUNCT TWO Randomized Trial.
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Rev 2011; 91:733.
63. Lamos EM, Younk LM, Davis SN. Empagliflozin, a sodium glucose co-transporter 2 inhibitor,
in the treatment of type 1 diabetes. Expert Opin Investig Drugs 2014; 23:875.
64. Henry RR, Thakkar P, Tong C, et al. Efficacy and Safety of Canagliflozin, a Sodium-Glucose
Cotransporter 2 Inhibitor, as Add-on to Insulin in Patients With Type 1 Diabetes. Diabetes
Care 2015; 38:2258.
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66. Peters AL, Buschur EO, Buse JB, et al. Euglycemic Diabetic Ketoacidosis: A Potential
Complication of Treatment With Sodium-Glucose Cotransporter 2 Inhibition. Diabetes Care
2015; 38:1687.
67. http://www.fda.gov/Drugs/DrugSafety/ucm446845.htm (Accessed on June 18, 2015).
68. Sands AT, Zambrowicz BP, Rosenstock J, et al. Sotagliflozin, a Dual SGLT1 and SGLT2
Inhibitor, as Adjunct Therapy to Insulin in Type 1 Diabetes. Diabetes Care 2015; 38:1181.
69. Garg SK, Henry RR, Banks P, et al. Effects of Sotagliflozin Added to Insulin in Patients with
Type 1 Diabetes. N Engl J Med 2017; 377:2337.
70. Vella S, Buetow L, Royle P, et al. The use of metformin in type 1 diabetes: a systematic
review of efficacy. Diabetologia 2010; 53:809.
71. George P, McCrimmon RJ. Potential role of non-insulin adjunct therapy in Type 1 diabetes.
Diabet Med 2013; 30:179.
72. Zinman B, Tildesley H, Chiasson JL, et al. Insulin lispro in CSII: results of a double-blind
crossover study. Diabetes 1997; 46:440.
73. Weinstock RS, DuBose SN, Bergenstal RM, et al. Risk Factors Associated With Severe
Hypoglycemia in Older Adults With Type 1 Diabetes. Diabetes Care 2016; 39:603.
74. Polonsky WH, Anderson BJ, Lohrer PA, et al. Insulin omission in women with IDDM.
75. Biggs MM, Basco MR, Patterson G, Raskin P. Insulin withholding for weight control in
women with diabetes. Diabetes Care 1994; 17:1186.
76. Purnell JQ, Hokanson JE, Marcovina SM, et al. Effect of excessive weight gain with intensive
therapy of type 1 diabetes on lipid levels and blood pressure: results from the DCCT.
Diabetes Control and Complications Trial. JAMA 1998; 280:140.
Topic 1796 Version 53.0
GRAPHICS
Mean A1C stratified by age: A comparison of T1D Exchange and T1PCO

data
For the T1D Exchange data set, the average A1C for each year of age was plotted using the most
recent value available for each of the 16,057 participants with a recent update. Participants <4
years old were grouped at age 4, and participants >75 years old were grouped at age 75. For the
T1PCO data set, the average A1C for each year of age was plotted using the most recent value
available for a random sample of 16,000 participants. Participants >85 years old were grouped at
age 85. The lines were estimated using LOESS, a nonparametric method for estimating the
regression equation that fits a smoothing parameter. Circles represent the mean A1C for each
year of age. The gray shaded area represents the 95% CI around the smoothed LOESS line.
A1C: glycated hemoglobin; T1D: type 1 diabetes; T1PCO: Adult Type 1 Diabetes Patient
Characteristics, Disease Burden, and Clinical Outcomes in US EHR Database; LOESS: locally
estimated scatter plot smoothing.
From: American Diabetes Association. Pettus JH, Zhou FL, Shepherd L, et al. Incidences of severe hypoglycemia and
diabetic ketoacidosis and prevalence of microvascular complications stratified by age and glycemic control in U.S. adult
patients with type 1 diabetes: A real world study. Diabetes Care 2019; 42:2220. Copyright and all rights reserved.
Material from this publication has been used with the permission of American Diabetes Association.
Graphic 119046 Version 3.0
Pharmacokinetics of commonly used insulin preparations
(A) Prandial insulin

Insulin type Approximate onset of Effective peak Approximate
action duration of action*
Lispro, lispro- 15 to 30 minutes 1 to 3 hours 4 to 6 hours

aabc, aspart,
faster aspart,
glulisine¶
Regular 30 minutes 1.5 to 3.5 hours 8 hours
(B) Basal insulin

Insulin type Half-lifeΔ Effective peak Approximate
duration of action*
NPH 4.4 hours 4 to 6 hours 12 hours
Insulin glargine
U-100 12 hours No pronounced peak 20 to >24 hours
U-300 19 hours No pronounced peak 20 to >24 hours
Insulin detemir 5 to 7 hours 3 to 9 hours 6 to 24 hours◊
Insulin degludec 25 hours No pronounced peak >24 hours

(U-100, U-200)
* Glucose-lowering action may vary considerably in different individuals or within the same
individual; the duration of action is dose dependent.
¶ Lispro-aabc and faster aspart have quicker pharmacokinetic profiles than standard lispro and
aspart.
Δ In general, it takes 4 half-lives to reach steady state. Dose adjustments should not be made until
after steady state is achieved.
◊ At higher doses (≥0.8 units/kg), mean duration of action is longer and less variable (22 to 23
hours).
Strict glycemic control slows progression of

retinopathy
Cumulative incidence of progressive retinopathy in patients with

type 1 diabetes and very mild to moderate nonproliferative
retinopathy who were treated with either conventional (dashed line)
or intensive (solid line) insulin therapy for 9 years. There was an
increasing benefit of intensive therapy over time, although intensive
therapy was associated with transient worsening in the first year
(p<0.001).
Data from: Diabetes Control and Complications Trial Research Group. The effect of
intensive treatment of diabetes on the development and progression of long-term
complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329:977.
Strict glycemic control prevents moderately

increased albuminuria (formerly called
microalbuminuria) in patients with type 1 diabetes
mellitus
Cumulative incidence of moderately increased albuminuria

(formerly called microalbuminuria) in patients with type 1 diabetes
treated with either conventional or intensive insulin therapy for up
to 9 years. There was an increasing benefit of intensive therapy over
time (p<0.04).
Data from: The effect of intensive treatment of diabetes on the development and
progression of long-term complications in insulin-dependent diabetes mellitus. The
Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;
329:977.
Multiple daily insulin injections
Regimen Breakfast Lunch Dinner Bedtime
1* RA + N RA N
2¶ RA RA RA N
3 RA RA RA G or D or De
4 RA + G or D or De RA RA
5 RA + GΔ or D RA RA + GΔ or D
Rapid-acting analog (lispro, aspart, or glulisine) can be replaced with regular insulin.
RA: any rapid-acting analog (lispro, aspart, or glulisine); N: NPH (neutral protamine
hagedorn) insulin; G: glargine; D: detemir; De: degludec.
* A small dose of RA may be needed at lunch, depending upon the carbohydrate content of lunch.
¶ If RA is used and there are >4 hours between breakfast and lunch, lunch and dinner, or dinner and
bedtime, another regimen should be used.
Δ U-300 insulin glargine is generally not administered twice daily, as it has a flatter and more
prolonged duration of action than U-100 insulin glargine.
Monitoring in patients with diabetes mellitus
Intervention Frequency Notes
History and physical examination
Height, weight, and Every visit

BMI
Smoking cessation Every visit For smokers only.

counseling
Blood pressure Every visit Individualize goal blood pressure (eg, <130/80
mmHg if at high cardiovascular risk; <140/90
mmHg if at lower risk).*
Dilated eye Annually¶ Begin at onset of type 2 diabetes, 3 to 5 years

examination after onset of type 1 diabetes. Examine yearly (or
more frequently) if retinopathy present, every 2
to 3 years if there is no evidence of retinopathy.
Comprehensive foot Annually Every visit if peripheral vascular disease or

examination neuropathy.
Dental examination Annually Periodontal disease is more severe and may be

more prevalent in patients with diabetes.
Laboratory studies
Lipid profile Initially, as indicated In people <40 years of age without dyslipidemia
and not on cholesterol-lowering therapy, testing
may be infrequent (eg, every 5 years).
A1C Every 3 to 6 months Goal ≤7% (may be lower or higher in selected

patients).
Basic metabolic Annually Includes electrolytes, BUN, creatinine, calcium,

profile and glucose. In the presence of chronic kidney
disease, may need to measure more often.
Urinary albumin-to- Annually Begin 3 to 5 years after onset of type 1 diabetes

creatinine ratio and at diagnosis in patients with type 2 diabetes;
protein excretion should also be monitored if
persistent albuminuria is present.
Vaccinations
Pneumococcus
PPSV23 1 dose, ages 19 to 64 Once the patient is ≥65 years (and ≥1 year after
years PCV13 and >5 years after previous dose of
PPSV23), give a second dose of PPSV23.
Revaccinate every 10 years.
PCV13 1 dose at age ≥65 Once the patient is ≥65 years (and ≥1 year after
years PPSV23), give PCV13.
Influenza Annually
SARS-CoV-2 (COVID- 3-dose series Follow changing guidelines, with type 2 diabetes
19) having markedly increased risk of complications
from COVID-19 risk and type 1 diabetes having
lesser increased risk of complications from
COVID-19.
Hepatitis B 3-dose series Administer to unvaccinated adults who are ages

19 to 59 years. For older patients, administer
based upon risk of acquiring hepatitis B,
including the need for assisted blood glucose
monitoring and the likelihood of an adequate
immune response to vaccination.
Provide other routine vaccinations for adults with diabetes according to age-related
recommendations.
Education, self-management review
Annually More often at onset of diabetes and when there

is a change in regimen.
BMI: body mass index; A1C: glycated hemoglobin; BUN: blood urea nitrogen; ASCVD: atherosclerotic
cardiovascular disease.
* When manual auscultatory method is used to measure blood pressure. High cardiovascular risk
includes those with existing ASCVD or 10-year ASCVD risk ≥15%. Lower cardiovascular risk includes
those with 10-year ASCVD risk <15%.
¶ Less frequent screening (every 2 to 3 years) may be appropriate for some patients (eg, patients
with little or no retinopathy and near-normal A1C levels).
Contributor Disclosures
Ruth S Weinstock, MD, PhD Grant/Research/Clinical Trial Support: Boehringer Ingelheim [Diabetes]; Eli
Lilly [Diabetes]; Insulet [Diabetes]; Kowa Research Institute [Diabetes]; Medtronic [Diabetes]; Novo Nordisk
[Diabetes].
All of the relevant financial relationships listed have been mitigated. Irl B Hirsch,
MD Grant/Research/Clinical Trial Support: Beta Bionics [Diabetes]; Insulet Corporation [Diabetes].
Consultant/Advisory Boards: Abbott [Diabetes]; GWave [Diabetes]; Lifescan [Diabetes]; Roche [Diabetes].
All of the relevant financial relationships listed have been mitigated. Katya Rubinow, MD No relevant
financial relationship(s) with ineligible companies to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
Conflict of interest policy

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Management of blood glucose in adults with type 1

● (See "Overview of the management of type 1 diabetes mellitus in children and

INTENSIVE DIABETES THERAPY

approximately 7 percent [6]. Additional important metrics include percent time in

Optimal insulin therapy requires an understanding of insulin pharmacokinetics ( table 1). A

Monitoring blood glucose — Monitoring blood glucose is an integral part of intensive insulin

In addition to the real-time CGM devices, there is a commercially available "flash" or

There are four aspects of exercise that are important to consider:

Challenges — Although intensive diabetes therapy (coordination of meals/diet, activity,

● There is a heightened risk of hypoglycemia with intensive insulin therapy. (See

Choosing basal/prandial insulin — The choice of basal (NPH, U-100 or U-300 glargine,

Insulin glargine is also available in a more concentrated formulation (U-300 glargine),

In meta-analyses of short-term trials comparing long-acting (glargine or detemir) with

● Can be injected 10 to 15 minutes before or up to immediately after meals, whereas

In a meta-analysis of randomized trials comparing rapid-acting insulin analogs with regular

Designing an MDI insulin regimen

● Basal bolus composition and timing – In designing an MDI injection regimen,

ADJUNCTIVE THERAPY NOT RECOMMENDED

● Sodium-glucose co-transporter (SGLT) inhibitors – The SGLTs are a family of proteins

● Metformin – Metformin is a biguanide that decreases hepatic glucose output and

• Postprandial hyperglycemia – If postprandial rises in blood glucose are too high,

• Fasting hyperglycemia – The "dawn phenomenon" is thought to result from diurnal

partner is well equipped to deal with hypoglycemia. Glucagon (nasal, intramuscular, or

The potential importance of these findings is illustrated in a subsequent analysis of the

• Patients in the fourth quartile had a significant elevation in serum concentrations of

The constellation of lipid abnormalities, abdominal obesity, and hypertension is similar to

● Sick-day rules – Sick-day management is directed towards preventing hypoglycemia,

● Diabetes-related complications – Patients with diabetes require ongoing evaluation for

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

SUMMARY AND RECOMMENDATIONS

Use of UpToDate is subject to the Terms of Use.

Diabetes Care 1996; 19:1426.

Mean A1C stratified by age: A comparison of T1D Exchange and T1PCO

Graphic 119046 Version 3.0

Pharmacokinetics of commonly used insulin preparations

(A) Prandial insulin

Lispro, lispro- 15 to 30 minutes 1 to 3 hours 4 to 6 hours

Regular 30 minutes 1.5 to 3.5 hours 8 hours

(B) Basal insulin

NPH 4.4 hours 4 to 6 hours 12 hours

U-100 12 hours No pronounced peak 20 to >24 hours

U-300 19 hours No pronounced peak 20 to >24 hours

Insulin detemir 5 to 7 hours 3 to 9 hours 6 to 24 hours◊

Insulin degludec 25 hours No pronounced peak >24 hours

Graphic 130874 Version 1.0

Strict glycemic control slows progression of

Cumulative incidence of progressive retinopathy in patients with

Graphic 61305 Version 8.0

Strict glycemic control prevents moderately

Cumulative incidence of moderately increased albuminuria

Graphic 73143 Version 8.0

Multiple daily insulin injections

Regimen Breakfast Lunch Dinner Bedtime

Graphic 69575 Version 7.0

Monitoring in patients with diabetes mellitus

Intervention Frequency Notes

History and physical examination

Height, weight, and Every visit

Smoking cessation Every visit For smokers only.

Dilated eye Annually¶ Begin at onset of type 2 diabetes, 3 to 5 years