Alan J.
Garber, MD, PhD, FACE1; Martin J. Abrahamson, MD2;
Joshua I.
Barzilay, MD, FACE3; Lawrence Blonde, MD, FACP, FACE4;
Zachary T.
Bloomgarden, MD, MACE5; Michael A. Bush, MD6;
Samuel
Dagogo-Jack, MD, DM, FRCP, FACE7;
Ralph A. DeFronzo, MD, BMS, MS,
BS8;
Daniel
Einhorn, MD, FACP, FACE9; Vivian A. Fonseca, MD, FACE10;
Jeffrey R.
Garber, MD, FACP, FACE11; W. Timothy Garvey, MD, FACE12;
George
Grunberger, MD, FACP, FACE13;
Yehuda Handelsman, MD, FACP, FNLA,
FACE14;
Robert R.
Henry, MD, FACE15; Irl B. Hirsch, MD16;
Paul S.
Jellinger, MD, MACE17; Janet B. McGill, MD, FACE18;
Jeffrey I.
Mechanick, MD, FACN, FACP, FACE, ECNU19;
Paul D.
Rosenblit, MD, PhD, FNLA, FACE20;
Guillermo E. Umpierrez, MD, FACP,
FACE21
This
document represents the official position of the American Association
of Clinical Endocrinologists and American College of Endocrinology.
Where there were no randomized controlled trials or specific U.S. FDA
labeling for issues in clinical practice, the participating clinical
experts utilized their judgment and experience. Every effort was made
to achieve consensus among the committee members. Position statements
are meant to provide guidance, but they are not to be considered
prescriptive for any individual patient and cannot replace the
judgment of a clinician.
Principles
The
founding principles of the Comprehensive Type 2 Diabetes Management
are as follows
1.
Lifestyle optimization is essential for all patients with diabetes.
Lifestyle optimization is multifaceted, ongoing, and should engage
the entire diabetes team. However, such efforts should not delay
needed pharmacotherapy, which can be initiated simultaneously and
adjusted based on patient response to lifestyle efforts. The need for
medical therapy should not be interpreted as a failure of lifestyle
management, but as an adjunct to it.
2. The
hemoglobin A1C (A1C) target should be individualized based on
numerous factors, such as age, life expectancy, comorbid conditions,
duration of diabetes, risk of hypoglycemia or adverse consequences
from hypoglycemia, patient motivation, and adherence. An A1C level of
≤6.5% is considered optimal if it can be achieved in a safe and
affordable manner, but higher targets may be appropriate for certain
individuals and may change for a given individual over time.
3.
Glycemic control targets include fasting and post-prandial glucose as
determined by self-monitoring of blood glucose (SMBG).
4. The
choice of diabetes therapies must be individualized based on
attributes specific to both patients and the medications themselves.
Medication attributes that affect this choice include
antihyperglycemic efficacy, mechanism of action, risk of inducing
hypoglycemia, risk of weight gain, other adverse effects,
tolerability, ease of use, likely adherence, cost, and safety in
heart, kidney, or liver disease.
5.
Minimizing risk of both severe and nonsevere hypoglycemia is a
priority. It is a matter of safety, adherence, and cost.
6.
Minimizing risk of weight gain is also a priority. It too is a matter
of safety, adherence, and cost.
7. The
initial acquisition cost of medications is only a part of the total
cost of care, which includes monitoring requirements and risks of
hypoglycemia and weight gain. Safety and efficacy should be given
higher priority than medication cost.
8. This
stratifies choice of therapies based on initial A1C level. It
provides guidance as to what therapies to initiate and add but
respects individual circumstances that could lead to different
choices.
9. Combination
therapy is usually required and should involve agents with
complementary mechanisms of action.
10. Comprehensive
management includes lipid and BP therapies and treatment of related co-morbidities.
11. Therapy
must be evaluated frequently (e.g., every 3 months) until stable
using multiple criteria, including A1C, SMBG records (fasting and
post-prandial), documented and suspected hypoglycemia events, lipid
and BP values, adverse events (weight gain, fluid retention, hepatic
or renal impairment, or CVD), co-morbidities, other relevant
laboratory data, concomitant drug administration, diabetic
complications, and psychosocial factors affecting patient care. Less
frequent monitoring is acceptable once targets are achieved.
12. The therapeutic regimen should be as simple as possible to
optimize adherence.
13. This algorithm includes every FDA-approved class of medications
for T2D (as of December 2015).
Lifestyle
Therapy
The key
components of lifestyle therapy include medical nutrition therapy,
regular physical activity, sufficient amounts of sleep, behavioral
support, and smoking cessation and avoidance of all tobacco products.
In the algorithm, recommendations appearing on the left apply to all
patients. Patients with increasing burden of obesity or related
comorbidities may also require the additional interventions listed in
the middle and right side of the figure.
Lifestyle
therapy begins with nutrition counseling and education. All patients
should strive to attain and maintain an optimal weight through a
primarily plant-based diet high in polyunsaturated and
monounsaturated fatty acids, with limited intake of saturated fatty
acids and avoidance of trans fats. Patients who are overweight (body
mass index [BMI] of 25 to 29.9 kg/m2) or obese (BMI ≥30 kg/m2)
should also restrict their caloric intake with the goal of reducing
body weight by at least 5 to 10%. As shown in the Look AHEAD (Action
for Health in Diabetes) and Diabetes Prevention Program studies,
lowering caloric intake is the main driver for weight loss. The
clinician or a registered dietitian (or nutritionist) should discuss
recommendations in plain language at the initial visit and
periodically during follow-up office visits. Discussion should focus
on foods that promote health versus those that promote metabolic
disease or complications and should include information on specific
foods, meal planning, grocery shopping, and dining-out strategies. In
addition, education on medical nutrition therapy for patients with
diabetes should also address the need for consistency in day-to-day
carbohydrate intake, limiting sucrose containing or
high-glycemic-index foods, and adjusting insulin doses to match
carbohydrate intake (e.g., use of carbohydrate counting with glucose
monitoring). Structured counseling (e.g., weekly or monthly sessions
with a specific weight-loss curriculum) and meal replacement programs
have been shown to be more effective than standard in-office
counseling. Additional nutrition recommendations can be found in the
2013 Clinical Practice Guidelines for Healthy Eating for the
Prevention and Treatment of Metabolic and Endocrine Diseases in
Adults from AACE/ACE and The Obesity Society.
After
nutrition, physical activity is the main component in weight loss and
maintenance programs. Regular physical exercise—both aerobic
exercise and strength training—improves glucose control, lipid
levels, and BP; decreases the risk of falls and fractures; and
improves functional capacity and sense of well-being. In Look AHEAD,
which had a weekly goal of ≥175 minutes per week of moderately
intense activity, minutes of physical activity were significantly
associated with weight loss, suggesting that those who were more
active lost more weight. The physical activity regimen should involve
at least 150 minutes per week of moderate-intensity exercise such as
brisk walking (e.g., 15- to 20-minute mile) and strength training;
patients should start any new activity slowly and increase intensity
and duration gradually as they become accustomed to the exercise.
Structured programs can help patients learn proper technique,
establish goals, and stay motivated. Patients with diabetes and/or
severe obesity or complications should be evaluated for
contraindications and/or limitations to increased physical activity,
and an exercise prescription should be developed for each patient
according to both goals and limitations. More detail on the benefits
and risks of physical activity and the practical aspects of
implementing a training program in people with T2D can be found in a
joint position statement from the American College of Sports Medicine
and American Diabetes Association.
Adequate
rest is important for maintaining energy levels and well-being, and
all patients should be advised to sleep approximately 7 hours per
night. Evidence supports an association of 6 to 9 hours of sleep per
night with a reduction in cardiometabolic risk factors, whereas sleep
deprivation aggravates insulin resistance, hypertension,
hyperglycemia, and dyslipidemia and increases inflammatory cytokines.
Daytime drowsiness—a frequent symptom of sleep disorders such as
sleep apnea—is associated with increased risk of accidents, errors
in judgment, and diminished performance. The most common type of
sleep apnea, obstructive sleep apnea (OSA), is caused by physical
obstruction of the airway during sleep. The resulting lack of oxygen
causes the patient to awaken and snore, snort, and grunt throughout
the night. The awakenings may happen hundreds of times per night,
often without the patient’s awareness. OSA is more common in men,
the elderly, and persons with obesity. Individuals with suspected OSA
should be referred to a sleep specialist for evaluation and
treatment.
Behavioral
support for lifestyle therapy includes the structured weight loss and
physical activity programs mentioned above as well as support from
family and friends. Patients should be encouraged to join community
groups dedicated to a healthy lifestyle for emotional support and
motivation. In addition, obesity and diabetes are associated with
high rates of anxiety and depression, which can adversely affect
outcomes. Healthcare professionals should assess patients’ mood and
psychological well-being and refer patients with mood disorders to
mental healthcare professionals. Cognitive behavioral therapy may be
beneficial. A recent meta-analysis of psychosocial interventions
provides insight into successful approaches.
Smoking
cessation is the final component of lifestyle therapy and involves
avoidance of all tobacco products. Structured programs should be
recommended for patients unable to stop smoking on their own.
Obesity
Obesity
is a disease with genetic, environmental, and behavioral determinants
that confers increased morbidity and mortality. An evidence-based
approach to the treatment of obesity incorporates lifestyle, medical,
and surgical options, balances risks and benefits, and emphasizes
medical outcomes that address the complications of obesity rather
than cosmetic goals. Weight loss should be considered in all
overweight and obese patients with prediabetes or T2D, given the
known therapeutic effects of weight loss to lower glycemia, improve
the lipid profile, reduce BP, and decrease mechanical strain on the
lower extremities (hips and knees).
The AACE
Obesity Treatment Algorithm emphasizes a complications-centric model
as opposed to a BMI-centric approach for the treatment of patients
who have obesity or are overweight. The patients who will benefit
most from medical and surgical intervention have obesity-related
comorbidities that can be classified into 2 general categories:
insulin resistance/cardio-metabolic disease and biomechanical
consequences of excess body weight. Clinicians should evaluate and
stage patients for each category. The presence and severity of
complications, regardless of patient BMI, should guide treatment
planning and evaluation. Once these factors are assessed, clinicians
can set therapeutic goals and select appropriate types and
intensities of treatment that will help patients achieve their
weight-loss goals. Patients should be periodically reassessed
(ideally every 3 months) to determine if targets for improvement have
been reached; if not, weight loss therapy should be changed or
intensified. Lifestyle therapy can be recommended for all patients
with overweight or obesity, and more intensive options can be
prescribed for patients with comorbidities. For example, weight-loss
medications can be used in combination with lifestyle therapy for all
patients with a BMI ≥27 kg/m2 and comorbidities. As of 2015, the
FDA has approved 8 drugs as adjuncts to lifestyle therapy in patients
with overweight or obesity. Diethylproprion, phendimetrazine, and
phentermine are approved for short-term (a few weeks) use, whereas
orlistat, phentermine/topiramate extended release (ER), lorcaserin,
naltrexone/bupropion, and liraglutide 3 mg may be used for long-term
weight-reduction therapy. In clinical trials, the 5 drugs approved
for long-term use were associated with statistically significant
weight loss (placebo-adjusted decreases ranged from 2.9% with
orlistat to 9.7% with phentermine/topiramate ER) after 1 year of
treatment. These agents improve BP and lipids, prevent progression to
diabetes during trial periods, and improve glycemic control and
lipids in patients with T2D. Bariatric surgery should be considered
for adult patients with a BMI ≥35 kg/m2 and comorbidities,
especially if therapeutic goals have not been reached using other
modalities.
Prediabetes
Prediabetes
reflects failing pancreatic islet beta-cell compensation for an
underlying state of insulin resistance, most commonly caused by
excess body weight or obesity. Current criteria for the diagnosis of
prediabetes include impaired glucose tolerance, impaired fasting
glucose, or metabolic syndrome (see Comprehensive Type 2 Diabetes
Management Algorithm—Prediabetes Algorithm).
Any one
of these factors is associated with a 5-fold increase in future T2D
risk.
The
primary goal of prediabetes management is weight loss. Whether
achieved through lifestyle therapy, pharmacotherapy, surgery, or some
combination thereof, weight loss reduces insulin resistance and can
effectively prevent progression to diabetes as well as improve plasma
lipid profile and BP. However, weight loss may not directly address
the pathogenesis of declining beta-cell function. When indicated,
bariatric surgery can be highly effective in preventing progression
from prediabetes to T2D.
No
medications (either weight loss drugs or antihyperglycemic agents)
are approved by the FDA solely for the management of prediabetes
and/or the prevention of T2D. However antihyperglycemic medications
such as metformin and acarbose reduce the risk of future diabetes in
prediabetic patients by 25 to 30%. Both medications are relatively
well-tolerated and safe, and they may confer a cardiovascular risk
benefit. In clinical trials, thiazolidinediones (TZDs) prevented
future development of diabetes in 60 to 75% of subjects with
prediabetes, but this class of drugs has been associated with a
number of adverse outcomes. Glucagon-like peptide 1 (GLP-1) receptor
agonists may be equally effective, as demonstrated by the profound
effect of liraglutide 3 mg in safely preventing diabetes and
restoring normoglycemia in the vast majority of subjects with
prediabetes. However, owing to the lack of long-term safety data on
the GLP-1 receptor agonists and the known adverse effects of the
TZDs, these agents should be considered only for patients at the
greatest risk of developing future diabetes and those failing more
conventional therapies.
As with
diabetes, prediabetes increases the risk for atherosclerotic
cardiovascular disease (ASCVD). Patients with prediabetes should be
offered lifestyle therapy and pharmacotherapy to achieve lipid and BP
targets that will reduce ASCVD risk.
T2D
Pharmacotherapy
In
patients with T2D, achieving the glucose target and A1C goal requires
a nuanced approach that balances age, comorbidities, and hypoglycemia
risk. The AACE supports an A1C goal of ≤6.5% for most patients and
a goal of >6.5% (up to 8%; see below) if the lower target cannot
be achieved without adverse outcomes (see Comprehensive Type 2
Diabetes Management Algorithm—Goals for Glycemic Control).
Significant reductions in the risk or progression of nephropathy were
seen in the Action in Diabetes and Vascular Disease: Preterax and
Diamicron MR Controlled Evaluation (ADVANCE) study, which targeted an
A1C <6.5% in the intensive therapy group versus standard
approaches. In the Action to Control Cardiovascular Risk in Diabetes
(ACCORD) trial, intensive glycemic control significantly reduced the
risk and/or progression of retinopathy, nephropathy, and neuropathy.
However, in ACCORD, which involved older and middle-aged patients
with longstanding T2D who were at high risk for or had established
CVD and a baseline A1C>8.5%, patients randomized to intensive
glucose-lowering therapy (A1C target of <6.0%) had increased
mortality. The excess mortality occurred only in patients whose A1C
remained >7% despite intensive therapy, whereas in the standard
therapy group (A1C target 7 to 8%), mortality followed a U-shaped
curve with increasing death rates at both low (<7%) and high (>8%)
A1C levels. In contrast, in the Veterans Affairs Diabetes Trial
(VADT), which had a higher A1C target for intensively treated
patients (1.5% lower than the standard treatment group), there were
no between-group differences in CVD endpoints, cardiovascular death,
or overall death during the 5.6-year study period. After
approximately 10 years, however, VADT patients participating in an
observational follow-up study were 17% less likely to have a major
cardiovascular event if they received intensive therapy during the
trial (P<.04; 8.6 fewer cardiovascular events per 1,000
person-years), whereas mortality risk remained the same between
treatment groups. Severe hypoglycemia occurs more frequently with
intensive glycemic control. In ACCORD, severe hypoglycemia may have
accounted for a substantial portion of excess mortality among
patients receiving intensive therapy, although the hazard ratio for
hypoglycemia-associated deaths was higher in the standard treatment
group. Cardiovascular autonomic neuropathy may be another useful
predictor of cardiovascular risk, and a combination of cardiovascular
autonomic neuropathy and symptoms of peripheral neuropathy increase
the odds ratio to 4.55 for CVD and mortality.
Taken
together, this evidence supports individualization of glycemic goals.
In adults with recent onset of T2D and no clinically significant CVD,
an A1C between 6.0 and 6.5%, if achieved without substantial
hypoglycemia or other unacceptable consequences, may reduce lifetime
risk of
microvascular
and macrovascular complications. A broader A1C range may be suitable
for older patients and those at risk for hypoglycemia. A less
stringent A1C of 7.0 to 8.0% is appropriate for patients with history
of severe hypoglycemia, limited life expectancy, advanced renal
disease or macrovascular complications, extensive comorbid
conditions, or long-standing T2D in which the A1C goal has been
difficult to attain despite intensive efforts, so long as the patient
remains free of polydipsia, polyuria, polyphagia, or other
hyperglycemia-associated symptoms. Therefore, selection of
glucose-lowering agents should consider a patient’s therapeutic
goal, age, and other factors that impose limitations on treatment, as
well as the attributes and adverse effects of each regimen.
Regardless of the treatment selected, patients must be followed
regularly and closely to ensure that glycemic goals are met and
maintained.
The
order of agents in each column of the Glucose Control Algorithm
suggests a hierarchy of recommended usage, and the length of each
line reflects the strength of the expert consensus recommendation.
Each medication’s properties should be considered when selecting a
therapy for individual patients, and healthcare professionals should
consult the FDA prescribing information for each agent.
•
Metformin has a low risk of hypoglycemia, can promote modest weight
loss, and has good antihyperglycemic efficacy at doses of 2,000 to
2,500 mg/day. Its effects are quite durable compared to sulfonylureas
(SFUs), and it also has robust cardiovascular safety relative to
SFUs. Owing to risk of lactic acidosis, the U.S. prescribing
information states that metformin is contraindicated if serum
creatinine is >1.5 mg/dL in men or >1.4 mg/dL in women, or if
creatinine clearance is “abnormal” . However, the risk for lactic
acidosis in patients on metformin is extremely low, and the FDA
guidelines prevent many individuals from benefiting from metformin.
Newer chronic kidney disease (CKD) guidelines reflect this concern,
and some authorities recommend stopping metformin at an estimated
glomerular filtration rate (eGFR) <30 mL/min/1.73 m2. AACE
recommends metformin not be used in patients with stage 3B, 4, or 5
CKD. In up to 16% of users, metformin is responsible for vitamin B12
malabsorption and/or deficiency, a causal factor in the development
of anemia and peripheral neuropathy. Vitamin B12 levels should be
monitored in all patients taking metformin, and vitamin B12
supplements should be given to affected patients.
• GLP-1
receptor agonists have robust A1C-lowering properties, are usually
associated with weight loss and BP reductions, and are available in
several formulations. The risk of hypoglycemia with GLP-1 receptor
agonists is low, and they reduce fluctuations in both fasting and
postprandial glucose levels. GLP-1 receptor agonists should not be
used in patients with personal or family history of medullary thyroid
carcinoma or those with multiple endocrine neoplasia syndrome type 2.
Exenatide should not be used if creatinine clearance is <30
mL/min. No studies have confirmed that incretin agents cause
pancreatitis; however, GLP-1 receptor agonists should be used
cautiously—if at all—in patients with a history of pancreatitis
and discontinued if acute pancreatitis develops. Some GLP-1 receptor
agonists may retard gastric emptying, especially with initial use.
Therefore, use in patients with gastroparesis or severe
gastroesophageal reflux disease requires careful monitoring and dose
adjustment.
• Sodium
glucose cotransporter 2 (SGLT-2) inhibitors have a glucosuric effect
that results in decreased A1C, weight, and systolic BP. In the only
SGLT-2 inhibitor cardiovascular outcomes trial reported to date,
empagliflozin was associated with significantly lower rates of
all-cause and cardiovascular death and lower risk of hospitalization
for heart failure. Heart failure–related endpoints appeared to
account for most of the observed benefits in this study. SGLT-2
inhibitors are associated with increased risk of mycotic genital
infections and slightly increased low-density-lipoprotein cholesterol
(LDL-C) levels, and because of their mechanism of action, they have
limited efficacy in patients with an eGFR <45 mL/min/1.73 m2.
Dehydration due to increased diuresis may lead to hypotension. The
incidence of bone fractures in patients taking canagliflozin and
dapagliflozin was increased in clinical trials. Investigations into
postmarketing reports of SGLT-2 inhibitor–associated diabetic
ketoacidosis (DKA), which has been reported to occur in type 1
diabetes and T2D patients with less than expected hyperglycemia
(euglycemic DKA), are ongoing. After a thorough review of the
evidence during an October 2015 meeting, an AACE/ACE Scientific and
Clinical Review expert consensus group found that the incidence of
DKA is infrequent and recommended no changes in SGLT-2 inhibitor
labeling.
• Dipeptidyl
peptidase 4 (DPP-4) inhibitors exert antihyperglycemic effects by
inhibiting DPP-4 and thereby enhancing levels of GLP-1 and other
incretin hormones. This action stimulate glucose-dependent insulin
synthesis and secretion and suppresses glucagon secretion. DPP-4
inhibitors have modest A1C-lowering properties, are weight neutral,
and are available in combination tablets with metformin, an SGLT-2
inhibitor, and a TZD. The risk of hypoglycemia with DPP-4 inhibitors
is low. The DPP-4 inhibitors, except linagliptin, are excreted by the
kidneys; therefore, dose adjustments are advisable for patients with
renal dysfunction. These agents should be used with caution in
patients with a history of pancreatitis, although a causative
association has not been established.
• The
TZDs, the only antihyperglycemic agents to directly reduce insulin
resistance, have relatively potent A1C-lowering properties, a low
risk of hypoglycemia, and durable glycemic effects. Pioglitazone may
confer CVD benefits, whereas rosiglitazone has a neutral effect on
CVD risk. Side effects that have limited TZD use include weight gain,
increased bone fracture risk in postmenopausal women and elderly men,
and elevated risk for chronic edema or heart failure. A possible
association with bladder cancer has largely been refuted. Side
effects may be mitigated by using a moderate dose (e.g., ≤30 mg) of
pioglitazone.
• In
general, alpha-glucosidase inhibitors (AGIs) have modest A1C-lowering
effects and low risk for hypoglycemia. Clinical trials have shown CVD
benefit in patients with impaired glucose tolerance and diabetes.
Side effects (e.g., bloating, flatulence, diarrhea) have limited
their use in the United States. These agents should be used with
caution in patients with CKD.
• The
insulin-secretagogue SFUs have relatively potent A1C-lowering effects
but lack durability and are associated with weight gain and
hypoglycemia. SFUs have the highest risk of serious hypoglycemia of
any noninsulin therapy, and analyses of large datasets have raised
concerns regarding the cardiovascular safety of this class when the
comparator is metformin, which may itself have cardioprotective
properties. The secretagogue glinides have somewhat lower
A1C-lowering effects, have a shorter half-life, and carry a lower
risk of hypoglycemia risk than SFUs.
• Colesevelam,
which is a bile acid sequestrant (BAS), lowers glucose modestly, does
not cause hypoglycemia, and decreases LDL-C. A perceived modest
efficacy for both A1C and LDL-C lowering as well as gastrointestinal
intolerance (constipation and dyspepsia), which occurs in 10% of
users, may contribute to limited use. In addition, colesevelam can
increase triglyceride levels in individuals with pre-existing
triglyceride elevations.
• The
quick-release dopamine receptor agonist bromocriptine mesylate has
slight glucose-lowering properties and does not cause hypoglycemia.
It can cause nausea and orthostasis and should not be used in
patients taking antipsychotic drugs. Bromocriptine mesylate may be
associated with reduced cardiovascular event rates.
For
patients with recent-onset T2D or mild hyperglycemia (A1C <7.5%),
lifestyle therapy plus antihyperglycemic monotherapy (preferably with
metformin) is recommended. Acceptable alternatives to metformin as
initial therapy include GLP-1 receptor agonists, SGLT-2 inhibitors,
DPP-4 inhibitors, and TZDs. AGIs, SFUs, and glinides may also be
appropriate as monotherapy for select patients.
Metformin
should be continued as background therapy and used in combination
with other agents, including insulin, in patients who do not reach
their glycemic target on monotherapy Patients who present with an A1C
>7.5% should be started on metformin plus another agent in
addition to lifestyle therapy. In metformin-intolerant patients, 2
drugs with complementary mechanisms of action from other classes
should be considered.
The
addition of a third agent may safely enhance treatment efficacy,
although any given third-line agent is likely to have somewhat less
efficacy than when the same medication is used as first- or
second-line therapy. Patients with A1C >9.0% who are symptomatic
would derive greater benefit from the addition of insulin, but if
presenting without significant symptoms, these patients may initiate
therapy with maximum doses of 2 other medications. Doses may then be
decreased to maintain control as the glucose falls. Therapy
intensification should include intensified lifestyle therapy and
anti-obesity treatment (where indicated).
Certain
patient populations are at higher risk for adverse treatment-related
outcomes, underscoring the need for individualized therapy. Although
several antihyperglycemic classes carry a low risk of hypoglycemia
(e.g., metformin, GLP-1 receptor agonists, SGLT-2 inhibitors, DPP-4
inhibitors, and TZDs), significant hypoglycemia can occur when these
agents are used in combination with a insulin secretagogue or
exogenous insulin. When such combinations are used, one should
consider lowering the dose of the insulin secretagogue or insulin to
reduce the risk of hypoglycemia. Many antihyperglycemic agents (e.g.,
metformin, GLP-1 receptor agonists, SGLT-2 inhibitors, some DPP-4
inhibitors, AGIs, SFUs) have limitations in patients with impaired
renal function and may require dose adjustments or special
precautions. In general, diabetes therapy does not require
modification for mild to moderate liver disease, but the risk of
hypoglycemia increases in severe cases.
Insulin
Insulin
is the most potent glucose-lowering agent. However, many factors come
into play when deciding to start insulin therapy and choosing the
initial insulin formulation. These decisions, made in collaboration
with the patient, depend greatly on each patient’s motivation,
cardiovascular and end-organ complications, age, general well-being,
risk of hypoglycemia, and overall health status, as well as cost
considerations. Patients taking 2 oral antihyperglycemic agents who
have an A1C >8.0% and/or long-standing T2D are unlikely to reach
their target A1C with a third oral antihyperglycemic agent. Although
adding a GLP-1 receptor agonist as the third agent may successfully
lower glycemia, eventually many patients will still require insulin.
In such cases, single daily dose of basal insulin should be added to
the regimen. The dosage should be adjusted at regular and fairly
short intervals to achieve the glucose target while avoiding
hypoglycemia. Recent studies have shown that titration is equally
effective whether it is guided by the healthcare professional or a
patient who has been instructed in SMBG.
Basal
insulin analogs are preferred over neutral protamine Hagedorn (NPH)
insulin because a single basal dose provides a relatively flat serum
insulin concentration for up to 24 hours. Although insulin analogs
and NPH have been shown to be equally effective in reducing A1C in
clinical trials, insulin analogs caused significantly less
hypoglycemia.
Premixed
insulins provide less dosing flexibility and have been associated
with a higher frequency of hypoglycemic events compared to basal and
basal-bolus regimens. Nevertheless, there are some patients for whom
a simpler regimen using these agents is a reasonable compromise.
Patients
whose basal insulin regimens fail to provide glucose control may
benefit from the addition of a GLP-1 receptor agonist, SGLT-2
inhibitor, or DPP-4 inhibitor. When added to insulin therapy, the
incretins and SGLT-2 inhibitors enhance glucose reductions and may
minimize weight gain without increasing the risk of hypoglycemia, and
the incretins also increase endogenous insulin secretion in response
to meals, reducing postprandial hyperglycemia. Depending on patient
response, basal insulin dose may need to be reduced to avoid
hypoglycemia.
Patients
whose glycemia remains uncontrolled while receiving basal insulin and
those with symptomatic hyperglycemia may require combined basal and
mealtime bolus insulin. Rapid-acting analogs (lispro, aspart, or
glulisine) or inhaled insulin are preferred over regular human
insulin because the former have a more rapid onset and offset of
action and are associated with less hypoglycemia. The simplest
approach is to cover the largest meal with a prandial injection of a
rapid-acting insulin analog or inhaled insulin and then add
additional mealtime insulin later, if needed. Several randomized
controlled trials have shown that the stepwise addition of prandial
insulin to basal insulin is safe and effective in achieving target
A1C with a low rate of hypoglycemia. A full basal-bolus program is
the most effective insulin regimen and provides greater flexibility
for patients with variable mealtimes and meal carbohydrate content.
Pramlintide
is indicated for use with basal-bolus insulin regimens. Pioglitazone
is indicated for use with insulin at doses of 15 and 30 mg, but this
approach may aggravate weight gain. There are no specific approvals
for the use of SFUs with insulin, but when they are used together the
risks of both weight gain and hypoglycemia increase.
It is
important to avoid hypoglycemia. Approximately 7 to 15% of
insulin-treated patients experience at least one annual episode of
hypoglycemia, and 1 to 2% have severe hypoglycemia. Several large
randomized trials found that T2D patients with a history of one or
more severe hypoglycemic events have an approximately 2- to 4-fold
higher death rate (82,146). It has been proposed that hypoglycemia
may be a marker for persons at higher risk of death, rather than the
proximate cause of death. Patients receiving insulin also gain about
1 to 3 kg more weight than those receiving other agents.
BP
Elevated
BP in patients with T2D is associated with an increased risk of
cardiovascular events. AACE recommends that BP control be
individualized, but that a target of <130/80mm Hg is appropriate
for most patients. Less stringent goals may be considered for frail
patients with complicated comorbidities or those who have adverse
medication effects, whereas a more intensive goal (e.g., <120/80
mmHg) should be considered for some patients if this target can be
reached safely without adverse effects from medication. Lower BP
targets have been shown to be beneficial for patients at high risk
for stroke. Among participants in the Action to Control
Cardiovascular Risk in Diabetes Blood Pressure (ACCORD BP) trial,
there were no significant differences in primary cardiovascular
outcomes or all-cause mortality between standard therapy (which
achieved a mean BP of 133/71 mm Hg) and intensive therapy (mean BP of
119/64 mm Hg). Intensive therapy did produce a comparatively
significant reduction in stroke and microalbuminuria, but these
reductions came at the cost of requiring more antihypertensive
medications and produced a significantly higher number of serious
adverse events (SAEs). A meta-analysis of antihypertensive therapy in
patients with T2D or impaired fasting glucose demonstrated similar
findings. Systolic BP ≤135 mm Hg was associated with decreased
nephropathy and a significant reduction in all-cause mortality
compared with systolic BP ≤140 mm Hg. Below 130 mm Hg, stroke and
nephropathy, but not cardiac events, declined further, but SAEs
increased by 40%.
Lifestyle
therapy can help T2D patients reach their BP goal:
•
Weight loss can improve BP in patients with T2D. Compared with
standard intervention, the results of the Look AHEAD trial found that
significant weight loss is associated with significant reduction in
BP, without the need for increased use of antihypertensive
medications.
•
Sodium restriction is recommended for all patients with hypertension.
Clinical trials indicate that potassium chloride supplementation is
associated with BP reduction in people without diabetes. The Dietary
Approaches to Stop Hypertension (DASH) diet, which is low in sodium
and high in dietary potassium, can be recommended for all patients
with T2D without renal insufficiency.
•
Numerous studies have shown that moderate alcohol intake is
associated with a lower incidence of heart disease and cardiovascular
mortality.
• The
effect of exercise in lowering BP in people without diabetes has been
well-established. In hypertensive patients with T2D, however,
exercise appears to have a more modest effect; still, it is
reasonable to recommend a regimen of moderately intense physical
activity in this population.
Most
patients with T2D and hypertension will require medications to
achieve their BP goal. Angiotensin converting enzyme inhibitors
(ACEIs), angiotensin II receptor blockers (ARBs), beta blockers,
calcium-channel blockers (CCBs), and thiazide diuretics are favored
choices for first-line treatment. The selection of medications should
be based on factors such as the presence of albuminuria, CVD, heart
failure, or post–myocardial infarction status as well as patient
race/ethnicity, possible metabolic side effects, pill burden, and
cost. Because ACEIs and ARBs can slow progression of nephropathy and
retinopathy, they are preferred for patients with T2D. Patients with
heart failure could benefit from beta blockers, those with prostatism
from alpha blockers, and those with coronary artery disease (CAD)
from beta blockers or CCBs. In patients with BP >150/100 mm Hg, 2
agents should be given initially because it is unlikely any single
agent would be sufficient to achieve the BP target. An ARB/ACEI
combination more than doubles the risk of renal failure and
hyperkalemia and is therefore not recommended.
Lipids
Compared
to those without diabetes, patients with T2D have a significantly
increased risk of ASCVD. Whereas blood glucose control is fundamental
to prevention of microvascular complications, controlling atherogenic
cholesterol particle concentrations is fundamental to prevention of
macrovascular disease (i.e., ASCVD). To reduce the significant risk
of ASCVD, including coronary heart disease (CHD), in T2D patients,
early intensive management of dyslipidemia is warranted.
The
classic major risk factors that modify the LDL-C goal for all
individuals include cigarette smoking, hypertension (BP ≥140/90 mm
Hg or use of antihypertensive medications), high density-lipoprotein
cholesterol (HDLC) <40 mg/dL, family history of CHD, and age ≥45
years for men or ≥55 years for women. Recognizing that T2D carries
a high lifetime risk for developing ASCVD, risk should be stratified
for primary prevention as “high” (patients <40 years of age;
≤1 major risk factor) or “very high” (≥2 major risk factors).
Patients with T2D and a prior ASCVD event (i.e., recognized “clinical
ASCVD”) are also stratified as “very high” or “extreme”
risk in this setting for secondary or recurrent events prevention.
Risk stratification in this manner can guide management strategies.
In
addition to hyperglycemia, the majority of T2D patients have a
syndrome of insulin resistance, which is characterized by a number of
ASCVD risk factors, including hypertension; hypertriglyceridemia; low
HDL-C; elevated apolipoprotein (apo) B and small, dense LDL; and a
procoagulant and proinflammatory milieu. The presence of these
factors justifies classifying these patients as being at either high
or very high risk; as such, AACE recommends LDL-C targets of <100
mg/dL or <70 mg/dL and non-HDL-C targets of <130 mg/dL or <100
mg/dL, respectively, with additional lipid targets shown in Table
The
atherogenic cholesterol goals appear identical for very high risk
primary prevention and for very high risk secondary (or recurrent
events) prevention. However, AACE does not define how low the goal
should be and recognizes that even more intensive therapy, aimed at
lipid levels far lower than an LDL-C <70 mg/dL or non HDL-C <100
mg/dL, might be warranted for the secondary prevention group. A
meta-analysis of 8 major statin trials demonstrated that those
individuals achieving an LDL-C<50 mg/dL, a non-HDL-C <75 mg/dL,
and apo B <50 mg/dL have the lowest ASCVD events. Furthermore, the
primary outcome and subanalyses of the Improved Reduction of
Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), a study
involving 18,144 patients, provided evidence that lower LDL-C is
better in patients after acute coronary syndromes.
Many
patients with T2D can achieve lipid profile improvements using
lifestyle therapy (smoking cessation, physical activity, weight
management, and healthy eating). However, most patients will require
pharmacotherapy to reach their target lipid levels and reduce their
cardiovascular risk.
A statin
should be used as first-line cholesterol-lowering drug therapy,
unless contraindicated; current evidence supports a moderate- to
high-intensity statin. Numerous randomized clinical trials and
meta-analyses conducted in primary and secondary prevention
populations have demonstrated that statins significantly reduce the
risk of cardiovascular events and death in patients with T2D .
However, considerable residual risk persists even after aggressive
statin monotherapy in primary prevention patients with multiple
cardiovascular risk factors and in secondary prevention patients with
stable clinical ASCVD or acute coronary syndrome
(ACS).
Although intensification of statin therapy (e.g., through use of
higher dose or higher potency agents) can further reduce atherogenic
cholesterol particles (primarily LDL-C) and the risk of ASCVD events,
some residual risk will remain. Data from several studies have shown
that even when LDL-C reaches an optimal level (20th percentile),
non-HDL-C, apo B, and low-density-lipoprotein particle (LDL-P) number
can remain suboptimal. Furthermore, statin intolerance (usually
muscle-related adverse effects) can limit the use of intensive statin
therapy in some patients.
Other
lipid-modifying agents should be utilized in combination with
maximally tolerated statins when therapeutic levels of LDL-C,
non-HDL-C, apo B, or LDL-P have not been reached:
•
Ezetimibe inhibits intestinal absorption of cholesterol, reduces
chylomicron production, decreases hepatic cholesterol stores,
upregulates LDL receptors, and lowers apo B, non-HDL-C, LDL-C, and
triglycerides. In IMPROVE-IT, the relative risk of ASCVD was reduced
by 6.4% (P = .016) in patients taking simvastatin plus ezetimibe for
7 years (mean LDL-C, 54 mg/dL) compared to simvastatin alone (LDL-C,
70 mg/dL). The ezetimibe benefit was almost exclusively noted in the
prespecified diabetes subgroup, which comprised 27% of the study
population and in which
the
relative risk of ASCVD was reduced by 14.4% (P = .023).
• Monoclonal
antibody inhibitors of proprotein convertase subtilisin–kexin type
9 (PCSK9) serine protease, a protein that regulates the recycling of
LDL receptors, have recently been approved by the FDA for primary
prevention in patients with hetero- and homozygous familial
hypercholesterolemia or as secondary prevention in patients with
clinical ASCVD who require additional LDL-C–lowering therapy. This
class of drugs meets a large unmet need for more aggressive
lipid-lowering therapy beyond statins in an attempt to further reduce
residual ASCVD risk in many persons with clinical ASCVD and diabetes.
When added to maximal statin therapy, these once- or twice-monthly
injectable agents reduce LDL-C by approximately 50%, raise HDL-C, and
have favorable effects on other lipids. In post hoc cardiovascular
safety analyses of alirocumab and evolocumab added to statins with or
without other lipid-lowering therapies, mean LDL-C levels of 48 mg/dL
were associated with statistically significant relative risk
reductions of 48 to 53% in major ASCVD events. Furthermore, a
subgroup analysis of patients with diabetes taking alirocumab
demonstrated that a 59% LDL-C reduction was associated with an ASCVD
event relative risk reduction trend of 42%.
• The
highly selective BAS colesevelam, by increasing elimination of bile
acids, increases hepatic bile acid production, thereby decreasing
hepatic cholesterol stores. This leads to an upregulation of LDL
receptors and reduces LDL-C, non-HDL-C, apo B, and LDL-P and improves
glycemic status. There is a small compensatory increase in de novo
cholesterol biosynthesis, which can be suppressed by the addition of
statin therapies.
• Fibrates
have only small effects on lowering atherogenic cholesterol (5%) and
are used mainly for lowering triglycerides. By lowering
triglycerides, fibrates unmask residual atherogenic cholesterol in
triglyceride-rich remnants (i.e., very-low-density-lipoprotein
cholesterol). In progressively higher triglyceride settings, as
triglycerides decrease, LDL-C increases, thus exposing the need for
additional lipid therapies. As monotherapy, fibrates have
demonstrated significantly favorable outcomes in populations with
high non-HDL-C and low HDL-C. The addition of fenofibrate to statins
in the ACCORD study showed no benefit in the overall cohort in which
mean baseline triglycerides and HDL-C were within normal limits.
Subgroup analyses and metaanalyses, however, have shown a relative
risk reduction for CVD events of 26 to 35% among patients with
moderate dyslipidemia (triglycerides >200 mg/dL and HDL-C <40
mg/dL).
• Niacin
lowers apo B, LDL-C, and triglycerides in a dose-dependent fashion
and is the most powerful lipid modifying agent for raising HDL-C on
the marke. It may reduce cardiovascular events through a mechanism
other than an increase in HDL-C. Two trials designed to test the HDL
C–raising hypothesis (Atherothrombosis Intervention in Metabolic
Syndrome with Low HDL/High Triglycerides: Impact on Global Health
Outcomes [AIM-HIGH] and Heart Protection Study 2—Treatment of HDL
to Reduce the Incidence of Vascular Events [HPS2-THRIVE]) failed to
show CVD protection during the 3- and 4-year trial periods,
respectively; by design, between group differences in LDL-C were
nominal at 5 mg/dL and 10 mg/dL, respectively. Previous trials with
niacin that showed CVD benefits utilized higher doses of niacin,
which were associated with much greater between-group differences in
LDL-C, suggesting niacin benefits may result solely from its
LDL-C–lowering properties. Although niacin may increase blood
glucose, its beneficial effects appear to be greatest among patients
with the highest baseline glucose levels and those with metabolic
syndrome.
• Dietary
intake of fish and omega-3 fish oil is associated with reductions in
the risks of total mortality, sudden death, and CAD through various
mechanisms of action other than lowering of LDL-C. In a large
clinical trial, highly purified, prescription-grade, moderate-dose
(1.8 grams) eicosapentaenoic acid (EPA) added to a statin regimen was
associated with a significant 19% reduction in risk of any major
coronary event among Japanese patients with elevated total
cholesterol and a 22% reduction in CHD in patients with impaired
fasting glucose or T2D. Among those with triglycerides >150 mg/dL
and HDL-C <40 mg/dL, EPA treatment reduced the risk of coronary
events by 53%. Other studies of lower doses (1 gram) of omega-3 fatty
acids (combined EPA and docosahexaenoic acid) in patients with
baseline triglycerides <200 mg/dL have not demonstrated
cardiovascular benefits. Studies evaluating high-dose (4 grams)
prescription-grade omega-3 fatty acids in the setting of triglyceride
levels >200 mg/dL are ongoing.
Relative
to statin efficacy (30 to >50% LDL-C lowering), drugs such as
ezetimibe, BASs, fibrates, and niacin have lesser LDL-C–lowering
effects (7 to 20%) and ASCVD reduction. However, these agents can
significantly lower LDL-C when utilized in various combinations,
either in statin-intolerant patients or as add-on to maximally
tolerated statins. Triglyceride-lowering agents such as
prescription-grade omega-3 fatty acids, fibrates, and niacin are
important agents that expose the atherogenic cholesterol within
triglyceride-rich remnants that require additional cholesterol
lowering.
If
triglyceride levels are severely elevated (>500 mg/dL), begin
treatment with a very-low fat diet and reduced intake of simple
carbohydrates and initiate combinations of a fibrate,
prescription-grade omega-3-fatty acid, and/or niacin to reduce
triglyceride levels and to prevent pancreatitis. Although no large
clinical trials have been designed to test this objective,
observational data and retrospective analyses support long-term
dietary and lipid management of hypertriglyceridemia for prophylaxis
against or treatment of acute pancreatitis.
