PHARMACOLOGICAL
THERAPY FOR TYPE 1 DIABETES
Recommendations
Most people with
type 1 diabetes should be treated with multiple-dose insulin
injections (three to four injections per day of basal and prandial
insulin) or continuous subcutaneous insulin infusion. A
Consider
educating individuals with type 1 diabetes on matching prandial
insulin dose to carbohydrate intake, premeal blood glucose, and
anticipated activity. E
Most individuals
with type 1 diabetes should use insulin analogs to reduce
hypoglycemia risk. A
Individuals who
have been successfully using continuous subcutaneous insulin
infusion should have continued access after they turn 65 years of
age. E
Insulin Therapy
Insulin is the
mainstay of therapy for individuals with type 1 diabetes. There are
excellent reviews to guide the initiation and management of insulin
therapy to achieve desired glycemic goals. Although most studies of
multiple-dose insulin versus pump therapy have been small and of
short duration, a systematic review and meta-analysis concluded that
there are minimal differences between the two forms of intensive
insulin therapy in A1C (combined mean between-group difference
favoring insulin pump therapy 20.30% [95% CI 20.58 to 20.02]) and
severe hypoglycemia rates in children and adults. A large randomized
trial in patients with type 1 diabetes with nocturnal hypoglycemia
reported that sensor-augmented insulin pump therapy with the
threshold suspend feature reduced nocturnal hypoglycemia, without
increasing glycated hemoglobin values. Intensive management through
pump therapy/continuous glucose monitoring and active patient/family
participation should be strongly encouraged. Selected individuals who
have mastered carbohydrate counting should be educated that fat
increases glucose concentrations and insulin requirements.
The Diabetes Control
and Complications Trial (DCCT) clearly showed that intensive insulin
therapy (three or more injections per day of insulin) or continuous
subcutaneous insulin infusion (CSII) (insulin pump therapy) was a key
part of improved glycemia and better outcomes. The study was carried
out with short-acting and intermediate-acting human insulins. Despite
better micro-vascular, macro-vascular, and all-cause mortality
outcomes, intensive insulin therapy was associated with a high rate
of severe hypoglycemia (62 episodes per 100 patient-years of
therapy). Since the DCCT, a number of rapid-acting and long-acting
insulin analogs have been developed. These analogs are associated
with less hypoglycemia in type 1 diabetes, while matching the A1C
lowering of human insulins.
Rapid-acting inhaled
insulin used before meals in type 1 diabetes leads to inferior A1C
lowering when compared with aspart insulin, with less hypoglycemia
across all A1C target categories.
Postprandial
glucose excursions can be better controlled by adjusting the timing
of prandial (bolus) insulin dose administration. The optimal time to
inject prandial insulin varies, based on the type of insulin injected
(regular, rapid-acting analog, inhaled, etc.), the measured blood
glucose level, timing of meals, and carbohydrate consumption.
Recommendations for prandial insulin dose administration should
therefore be individualized.
Suggested
citation: American Diabetes Association. Approaches to glycemic
treatment. Sec. 7. In Standards of Medical Care in Diabetesd2016.
Diabetes Care 2016;39(Suppl. 1):S52–S59 © 2016 by the American
Diabetes Association. Readers may use this article as long as the
work is properly cited, the use is educational and not for profit,
and the work is not altered.
Recommended therapy
for type 1 diabetes consists of the following:
Multiple-dose
insulin injections (three to four injections per day of basal and
prandial insulin) or CSII therapy.
Match prandial
insulin to carbohydrate intake, premeal blood glucose, and
anticipated physical activity.
For most patients
(especially those at elevated risk of hypoglycemia), use insulin
analogs.
For patients with
frequent nocturnal hypoglycemia, recurrent severe hypoglycemia,
and/or hypoglycemia unawareness, a sensor-augmented low glucose
threshold suspend pump may be considered.
Pramlintide
Pramlintide, an
amylin analog, is an agent that delays gastric emptying, blunts
pancreatic secretion of glucagon, and enhances satiety. It is a U.S.
Food and Drug Administration (FDA)-approved therapy for use in
adults with type 1 diabetes. It has been shown to induce weight loss
and lower insulin dose. Concurrent reduction of prandial insulin
dosing is required to reduce the risk of severe hypoglycemia.
Pancreas and Islet
Cell Transplantation
Pancreas and islet
cell transplantation have been shown to normalize glucose levels but
require lifelong immunosuppression to prevent graft rejection and
recurrence of autoimmune islet destruction. Given the potential
adverse effects of immunosuppressive therapy, pancreas
transplantation should be reserved for patients with type 1 diabetes
undergoing simultaneous renal transplantation, following renal
transplantation, or for those with recurrent ketoacidosis or severe
hypoglycemia despite aggressive glycemic management. Islet cell
transplantation remains investigational. Auto-islet transplantation
may be considered for patients requiring total pancreatectomy who
meet eligibility criteria.
Investigational
Agents
Metformin
Adding metformin to
insulin therapy may reduce insulin requirements and improve
metabolic control in overweight/obese patients with poorly
controlled type 1 diabetes. In a meta-analysis, metformin in type 1
diabetes was found to reduce insulin requirements (6.6 units/day, P
, 0.001) and led to small reductions in weight and total and LDL
cholesterol but not to improved glycemic control (absolute A1C
reduction 0.11%, P 5 0.42).
Incretin-Based
Therapies
Therapies approved
for the treatment of type 2 diabetes are currently being evaluated
in type 1 diabetes. Glucagon-like peptide 1 (GLP-1) agonists and
dipeptidyl peptidase 4 (DPP-4) inhibitors are not currently FDA
approved for those with type 1 diabetes but are being studied in
this population.
Sodium–Glucose
Cotransporter 2 Inhibitors
Sodium–glucose
cotransporter 2 (SGLT2) inhibitors provide insulin-independent
glucose lowering by blocking glucose re-absorption in the proximal
renal tubule by inhibiting SGLT2. These agents provide modest weight
loss and blood pressure reduction. There are three FDA-approved
agents for use in patients with type 2 diabetes, but there are
insufficient data to recommend treatment in type 1 diabetes. The FDA
recently issued a warning about the risk of ketoacidosis with SGLT2
inhibitors in individuals with type 1 or type 2 diabetes. Symptoms
of ketoacidosis include nausea, vomiting, abdominal pain, tiredness,
and dyspnea. Urinary tract infections leading to urosepsis and
pyelonephritis may also occur with SGLT2 inhibitors. Patients should
stop taking their SGLT2 inhibitor and seek medical attention
immediately if they have symptoms of ketoacidosis.
PHARMACOLOGICAL
THERAPY FOR TYPE 2 DIABETES
Recommendations
Metformin, if not
contraindicated and if tolerated, is the preferred initial
pharmacological agent for type 2 diabetes. A
Consider
initiating insulin therapy (with or without additional agents) in
patients with newly diagnosed type 2 diabetes and markedly
symptomatic and/or elevated blood glucose levels or A1C. E
If noninsulin
monotherapy at maximum tolerated dose does not achieve or maintain
the A1C target over 3 months, then add a second oral agent, a
glucagon-like peptide 1 receptor agonist, or basal insulin. A
A
patient-centered approach should be used to guide the choice of
pharmacological agents. Considerations include efficacy, cost,
potential side effects, weight, comorbidities, hypoglycemia risk,
and patient preferences. E
For patients with
type 2 diabetes who are not achieving glycemic goals, insulin
therapy should not be delayed. B
An American Diabetes
Association/ European Association for the Study of Diabetes position
statement evaluated the data and developed recommendations, including
advantages and disadvantages, for antihyperglycemic agents for
patients with type 2 diabetes. A patient-centered approach is
stressed, including patient preferences, cost, and potential side
effects of each class, effects on body weight, and hypoglycemia risk.
Lifestyle modifications that improve health (see Section 3
“Foundations of Care and Comprehensive Medical Evaluation”)
should be emphasized along with any pharmacological therapy.
Initial Therapy
Most patients should
begin with lifestyle changes, which may include lifestyle counseling,
setting a physical activity goal of 150 min/week minimum, and weight
loss counseling to lose a minimum of 7% of body weight (for details
on lifestyle therapy, see Section 6 “Obesity Management for the
Treatment of Type 2 Diabetes”). When lifestyle efforts alone do not
achieve or maintain glycemic goals, metformin monotherapy should be
added at, or soon after, diagnosis, unless there are
contraindications or intolerance. Metformin has a longstanding
evidence base for efficacy and safety, is inexpensive, and may reduce
risk of cardiovascular events and death. Accumulating observational
data suggest that metformin may be safely continued down to
glomerular filtration rate (GFR) of 45 mL/min/1.73 m2 or even 30
mL/min/1.73 m2. If metformin is used in the lower GFR range, the dose
should be reduced and patients should be advised to stop the
medication for nausea, vomiting, and dehydration. In patients with
metformin intolerance or contraindications, consider an initial drug
from other classes depicted under “Dual therapy” and proceed
accordingly
Figure
7.1—Antihyperglycemic therapy in type 2 diabetes: general
recommendations. The order in the chart was determined by
historical availability and the route of administration, with
injectables to the right; it is not meant to denote any specific
preference. Potential sequences of antihyperglycemic therapy for
patients with type 2 diabetes are displayed, with the usual
transition moving vertically from top to bottom (although horizontal
movement within therapy stages is also possible, depending on the
circumstances). DPP-4-i, DPP-4 inhibitor; fxs, fractures; GI,
gastrointestinal; GLP-1-RA, GLP-1 receptor agonist; GU,
genitourinary; HF, heart failure; Hypo, hypoglycemia; SGLT2-i, SGLT2
inhibitor; SU, sulfonylurea; TZD, thiazolidinedione. †Consider starting at this
stage when A1C is $9% (75 mmol/mol). ‡Consider starting at this
stage when blood glucose is $300–350 mg/dL (16.7–19.4 mmol/L)
and/or A1C is $10–12% (86–108 mmol/mol), especially if
symptomatic or catabolic features are present, in which case basal
insulin 1 mealtime insulin is the preferred initial regimen. §Usually
a basal insulin (NPH, glargine, detemir, degludec). Adapted with
permission from Inzucchi et al.
Combination Therapy
Although there are
numerous trials comparing dual therapy with metformin alone, few
directly compare drugs as add-on therapy. A comparative effectiveness
meta-analysis suggests that overall each new class of non insulin
agents added to initial therapy lowers A1C around 0.9–1.1%. A
comprehensive listing, including the cost, is available. The ongoing
Glycemia Reduction Approaches in Diabetes: A Comparative
Effectiveness Study (GRADE) will compare the effect of four major
drug classes (sulfonylurea, DPP-4 inhibitor, GLP-1 analog, and basal
insulin) over 4 years on glycemic control and other medical,
psychosocial, and health economic outcomes.
If the A1C target is
not achieved after approximately 3 months, consider a combination of
metformin and one of these six treatment options: sulfonylurea,
thiazolidinedione, DPP-4 inhibitors, SGLT2 inhibitors, GLP-1 receptor
agonists, or basal insulin. Drug choice is based on patient
preferences, as well as various patient, disease, and drug
characteristics, with the goal of reducing blood glucose levels while
minimizing side effects, especially hypoglycemia. emphasizes drugs
commonly used in the U.S. and/or Europe. Cost-effectiveness models
have suggested that some of the newer agents may be low-value based
on high cost and moderate glycemic effect.
Rapid-acting
secretagogues (meglitinides) may be used instead of sulfonylureas in
patients with irregular meal schedules or those who develop late
postprandial hypoglycemia on a sulfonylurea. Other drugs not shown in
the figure (e.g., a-glucosidase inhibitors, colesevelam,
bromocriptine, pramlintide) may be tried in specific situations, but
are generally not favored due to modest efficacy, the frequency of
administration, and/or side effects.
For all patients,
consider initiating therapy with a dual combination when A1C is $9%
(75 mmol/mol) to more
Figure
7.2—Approach to starting and adjusting insulin in type 2 diabetes
(17). FBG, fasting blood glucose; GLP-1-RA, GLP-1 receptor agonist;
hypo, hypoglycemia; mod., moderate; PPG, postprandial glucose; #,
number. Adapted with permission from Inzucchi et al. (17).
expeditiously achieve
the target A1C level. Insulin has the advantage of being effective
where other agents may not be and should be considered as part of any
combination regimen when hyperglycemia is severe, especially if
symptoms are present or any catabolic features (weight loss, ketosis)
are present. Consider initiating combination insulin injectable
therapy when blood glucose is $300– 350 mg/dL (16.7–19.4 mmol/L)
and/or A1C is $10–12% (86–108 mmol/mol). As the patient’s
glucose toxicity resolves, the regimen may, potentially, be
simplified.
Insulin Therapy
Consider initiating
insulin therapy (with or without additional agents) in patients with
newly diagnosed type 2 diabetes and markedly symptomatic and/or
elevated blood glucose levels or A1C. Many patients with type 2
diabetes eventually require and benefit from insulin therapy.
Providers may wish to consider regimen flexibility when de vising a
plan for the initiation and adjustment of insulin therapy in people
with type 2 diabetes. The progressive nature of type 2 diabetes and
its therapies should be regularly and objectively explained to
patients. For patients with type 2 diabetes who are not achieving
glycemic goals, providers should promptly initiate insulin therapy.
Providers should
avoid using insulin as a threat or describing it as a failure or
punishment. Equipping patients with an algorithm for self-titration
of insulin doses based on self-monitoring of blood glucose (SMBG)
improves glycemic control in patients with type 2 diabetes initiating
insulin.
Basal Insulin
Basal insulin alone is
the most convenient initial insulin regimen, beginning at 10 units or
0.1–0.2 units/kg, depending on the degree of hyperglycemia. Basal
insulin is usually prescribed in conjunction with metformin and
possibly one additional noninsulin agent. While there is evidence for
reduced risk of hypoglycemia with newer, longer-acting, basal insulin
analogs, people with type 2 diabetes without history of hypoglycemia
or severe hypoglycemia may use NPH safely at much lower cost.
Concentrated preparation of basal insulin such as U-500 regular is
five times as potent per volume of insulin (i.e., 0.01 mL ;5 units of
U-100 regular) and has a delayed onset and longer duration of action
than U-100 regular. U-300 glargine and U-200 degludec are three and
two times, respectively, as potent per volume, have a longer duration
of action, and may allow higher doses of insulin administration in
smaller volumes. These concentrated preparations may be more
comfortable for the patient and allow better absorption. However,
they are more expensive, and accurate dosing may be more complicated.
If basal insulin has
been titrated to an acceptable fasting blood glucose level, but A1C
remains above target, consider advancing to combination injectable
therapy to cover postprandial glucose excursions. Options include
adding a GLP-1 receptor agonist or mealtime insulin, consisting of
one to three injections of rapid-acting insulin analog (lispro,
aspart, or glulisine) administered just before eating. A less studied
alternative, transitioning from basal insulin to twice-daily premixed
(or biphasic) insulin analogs (70/30 aspart mix, 75/25 or 50/50
lispro mix), could also be considered; pharmacodynamic profiles make
them suboptimal to cover postprandial glucose excursions.
Bolus Insulin
Some individuals with
type 2 diabetes may require bolus insulin dosing in addition to basal
insulin. Rapid-acting analogs are preferred due to their prompt onset
of action after dosing. The FDA recently approved a more concentrated
formulation of rapid-acting insulin analog, U-200 (200 units/mL),
dosed 15 min or immediately prior to a meal.
Regular human insulin
and human NPH-Regular premixed formulations (70/30) are less costly
alternatives to rapid-acting insulin analogs and premixed insulin
analogs, respectively, but their pharmacodynamic profiles make them
suboptimal to cover postprandial glucose excursions.
Continuous
Subcutaneous Insulin Infusion
A less commonly used
and more costly alternative to “basal–bolus” therapy with
multiple daily injections is CSII (insulin pump). In addition to the
suggestions provided for determining the starting dose of mealtime
insulin under a basal–bolus regimen, another method consists of
adding up the total current insulin dose and then providing one-half
of this amount as basal and one-half as mealtime insulin, the latter
split evenly between three meals. It is critical that individuals who
have been successfully using CSII should have continued access after
they turn 65 years of age.
Inhaled Insulin
Inhaled insulin is now
available for prandial use with a more limited dosing range and may
require serial lung function testing prior to and after starting
therapy.
Treatment
Strategies
focuses solely on
sequential insulin strategies, describing the number of injections
and the relative complexity and flexibility of each stage. Once an
insulin regimen is initiated, dose titration is important, with
adjustments made in both mealtime and basal insulins based on the
prevailing blood glucose levels and an understanding of the
pharmacodynamic profile of each formulation (pattern control).
Noninsulin agents may
be continued, although sulfonylureas, DPP-4 inhibitors, and GLP-1
receptor agonists are typically stopped once more complex insulin
regimens beyond basal are used. In patients with suboptimal blood
glucose control, especially those requiring increasing insulin doses,
adjunctive use of thiazolidinediones (usually pioglitazone) or SGLT2
inhibitors may be helpful in improving control and reducing the
amount of insulin needed. Comprehensive education regarding SMBG,
diet, exercise, and the avoidance of and response to hypoglycemia are
critically important in any patient using insulin.
BARIATRIC SURGERY
Bariatric surgery also
improves glycemic control in type 2 diabetes. Its effects are
discussed in Section 6 “Obesity Management for the Treatment of
Type 2 Diabetes.
