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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3055_Библиотеки_им_академика_М_И_Перельмана.pdf
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their ability to achieve treatment aims and to impact quality
of life. A patient-centered approach remains the foundation
for successful management of DM and the prevention of
DM-related complications [1].
Much has been written about the large increase in the
global incidence of DM. According to the CDC, the number
of Americans diagnosed with DM has increased fourfold
between 1980 and 2014 [5]. As many as 29.1 million people, or
9.3% of the US population, have diabetes as of 2012, and
nearly a third of those patients are unaware of their diagnosis
[6]. Given the great benefit of tight glycemic control early on
in the disease process, identification and screening high-risk
individuals remains a priority.
The majority of patients fall into one of two categories:
type 1 diabetes or type 2 diabetes.
• Type 1 diabetes (T1D): an autoimmune disease in which
the insulin-producing beta cells are destroyed, leading to
an insulin-deficient state. Overall, 5–10% of all diabetics
have T1D [7]. While the majority of T1D patients are diag-
nosed at a relatively young age, a new diagnosis of T1D
can occur later in life. The rate of beta cell destruction is
variable, and patients with T1D may still produce varying
amounts of insulin for some time. T1D patients eventually
become dependent on exogenous insulin administration to
maintain glycemic control.
• Type 2 diabetes (T2D): a disease state in which glycemic
control is lost due to a combination of factors, including
insulin resistance and relative insulin insufficiency.
Approximately 90–95% of all diabetics have T2D [7]. The
average age at diagnosis of T2D is older than of T1D; how-
ever T2D has also been increasingly diagnosed in younger
ages.
• Other DM types: gestational DM, maturity-onset diabetes
of the young (MODY), and drug-induced DM.
• Pre-DM: a state in which patients do not meet criteria for
DM, but glucose levels are abnormal. Studies have demon-
strated that pre-DM often progresses to overt DM, and
thus early intervention is considered important.
A. Geliebter
121
Diagnosis of DM
DM is commonly diagnosed based on the following ADA
criteria [7]:
1. Fasting plasma glucose of ≥126 mg/dL (fasting for 8 h)
2. Hemoglobin A1c ≥ 6.5%
3. Classic symptoms of hyperglycemia + plasma glucose of
≥200 mg/dL
4. 2-h plasma glucose of ≥200 mg/dL after a 75-gram oral glu-
cose load
Pre-DM is diagnosed with the following ADA criteria [7]:
1. Fasting plasma glucose of 100–125 mg/dL
2. Hemoglobin A1c 5.7–6.4%
3. 2-h plasma glucose of 140–199 g/dL after a 75-gram oral
glucose load
A single abnormal test is typically insufficient for the diag-
nosis of DM and should be repeated to confirm the diagnosis.
Distinguishing between T1D and T2D may initially be
difficult. A careful history and physical examination may
suggest a specific diagnosis, but final confirmation usually
occurs over time. While diabetic ketoacidosis (DKA) is
often the hallmark of T1D, it can also occur on occasion in
T2D. Similarly, while certain characteristics such as obesity
and dyslipidemia are more common in T2D, they can be
encountered in T1D and thus cannot be used to definitively
classify a disease type. When T1D is suspected, autoim-
mune markers such as antibodies to islet cells and insulin,
GAD-65, IA-2 and IA-2B, and ZnT8 can be used to help
aid in the diagnosis [7]. Insulin secretion can also be
assessed in the ambulatory setting by measuring a c-pep-
tide level in the setting of hyperglycemia, with a low value
being more consistent with insulin deficiency and T1D.
6. Diabetes
122
Screening for DM
Given the large number of patients with undiagnosed diabe-
tes, an evidence-based screening program is important.
According to the US Preventive Services Task Force, the
following patient populations without obvious diabetes
symptoms should be screened in the ambulatory setting [8]:
• Adults aged 40–70 who are overweight or obese
• Non-overweight patients younger than 40 with a family
history of DM, personal history of gestational DM or poly-
cystic ovarian syndrome, and certain racial/ethnic groups
such as African-Americans, American Indians or Alaskan
Natives, Asian-Americans, Hispanics or Latinos, or Native
Hawaiians or Pacific Islanders
The ADA recommends repeat testing of high-risk patients
every 3 years or more frequently in patients with higher-risk
features such as pre-DM [7].
Key H&P
The symptoms and signs of DM are often due to the presence
of hyperglycemia. The early stages of DM may often be asymp-
tomatic when the hyperglycemia is mild, but a comprehensive
history and physical exam might suggest the diagnosis.
History
The classic symptoms of polyuria, polydipsia, and weight loss
are consistent with the osmotic diuresis that can accompany
hyperglycemia. Additionally, symptoms such as fatigue, mal-
aise, and blurry vision may be present as well. When T1D is
suspected, patients should be asked about the presence of
any coexisting autoimmune diseases such as vitiligo and pri-
mary hypothyroidism.
A. Geliebter
123
Physical Exam
There are few exam findings specific to DM. Cutaneous find-
ings such as acanthosis nigricans and skin tags may suggest
the presence of insulin resistance.
Healthcare Maintenance in the Diabetic Patient
• Annual eye exam
• Annual monofilament test or other test for detecting
neuropathy
• Hemoglobin a1c every 3–6 months depending on control
• Annual fasting lipid panel
• Annual urine albumin-to-creatinine ratio
• Blood pressure at every visit
• Annual influenza vaccine and pneumococcal vaccine at
appropriate intervals
Treatment
Effectively treating DM requires a patient-centered approach
that includes lifestyle modification, glycemic control, and
management of comorbid conditions such as obesity, hyper-
tension, and dyslipidemia. Patients with DM are at signifi-
cantly increased risk for cardiovascular disease including
myocardial infarction and stroke, as well as retinopathy and
nephropathy, and mitigating these risks remains a primary
goal of DM management and treatment [1].
DM complications can be divided into microvascular (reti-
nopathy, nephropathy, neuropathy) and macrovascular (CV
disease) categories. Intensive glycemic control has been associ-
ated with significant reductions in microvascular complications
in both T1D and T2D and in macrovascular complications in
T1D [2–4]. Importantly, intensive glycemic control has not been
consistently found to reduce macrovascular complications in
T2D, and therefore a more comprehensive cardiovascular risk
6. Diabetes
124
reduction strategy should be implemented addressing the tradi-
tional risk factors of hypertension, hyperlipidemia, smoking
cessation, and weight loss.
Treatment Goals in DM [9]
6.0–6.5%: patients with new DM diagnosis lack of comor-
bidities, and if able to avoid adverse outcomes with
therapy
7.0–8.0%: patients with long-standing DM, high risk for
hypoglycemia, multiple comorbidities
Type 1 Diabetes
Insulin therapy is required in the management of T1D, and a
comprehensive guide to T1D management is beyond the
scope of this resource.
Patients with T1D require both basal and prandial insulin
administration. Insulin can be administered with multiple
daily injections or using a continuous subcutaneous insulin
infusion (“insulin pump”). Prandial insulin should account
for the anticipated carbohydrate intake and pre-meal sugars,
and a personalized assessment for prandial insulin require-
ments is a essential part in the successful glycemic manage-
ment in T1D. Self-monitoring of glucose should be performed
both pre-meal and post-meal to assess adequacy of the insu-
lin regimen. A continuous glucose monitoring (CGM) may be
used to further assess glycemic management and has been
associated with hemoglobin A1c reductions.
Type 2 Diabetes
The American Diabetes Association (ADA) and the
American Association of Clinical Endocrinologists (AACE)
have published comprehensive treatment guidelines for T2D
[1, 9]. While there are many different treatment approaches
for patients with T2D, it is important that the chosen
approach be mutually understood and agreed upon by both
patient and provider for the highest chances of success.
A. Geliebter
125
Lifestyle Changes
Lifestyle changes remain a backbone of treatment for most
patients with T2D as they may partially correct the insulin
resistance and impaired insulin secretion associated with the
disease. These changes include weight loss, increased physical
activity, and smoking cessation. Caloric restriction is a critical
aspect of successful weight loss, and nutritional counseling
and support with realistic goals can help patients make the
appropriate changes to their diet necessary for weight loss
[9]. Meal planning for the diabetic patient requires an under-
standing of the glycemic index of carbohydrate-containing
foods. Educating patients regarding meal composition and
portion size is also essential. Patients should be given a pre-
scription for increased physical activity advising 30–45 min
4–5 times/week of aerobic exercise.
Motivated patients with newly diagnosed DM with an A1c
≤7.5% may be tried on a 3–6-month trial of lifestyle changes
alone but should be started on pharmacotherapy if glycemic
targets are not reached. In the majority of patients, lifestyle
changes alone are insufficient to achieve sustained adequate
glycemic management, and pharmacotherapy will be
necessary.
Pharmacological Therapy in T2D
Pharmacological therapy is eventually needed in the majority
of patients with T2D. Since early achievement of tight glyce-
mic control has been associated with overall improved out-
comes, it is imperative that pharmacological therapy adequate
to achieve glycemic goals be initiated early in the disease
course. There are a number of pathophysiological defects in
T2D, and combination therapies that address several of these
defects should be considered in all patients [10].
The choice of therapy should be tailored to fit each
patient’s individual glycemic goals while balancing the
potential adverse effects of therapy including hypoglycemia.
6. Diabetes
126
In adults with recently diagnosed T2D and without signifi-
cant comorbidities such as established cardiovascular dis-
ease, intensive therapy sufficient to achieve an A1c of
6.0–6.5% (AACE guidelines) should be considered to
reduce microvascular and macrovascular disease [9]. In
adults with a longer diabetes course, established cardiovas-
cular disease, or other significant comorbidities, the risk of
hypoglycemia and other adverse events associated with the
intensive therapy begins to outweigh the potential benefits,
and a more lenient A1c target of 7.0–8.0% is appropriate.
See Fig. 6.1 for a suggested pharmacological approach to
glycemic management.
Choice of Therapy
Both the American Diabetes Association and the American
Association of Clinical Endocrinologists have created com-
prehensive algorithms for pharmacotherapy in T2D [1, 9].
Below is a summary of commonly available diabetic medica-
tions, also summarized in Table 6.1.
Initial
Assessment
A1c < 7.5% A1c > 9%
Monotherapy
Metformin
(preferred) or
other DM med
Metformin
(preferred) +
additional DM
medication
Dual or triple
therapy
Asymptomatic Symptomatic
Basal insulin
+/- other DM
med
Dual Therapy
A1c ≥ 7.5%
Fig. 6.1 Initial glycemic management (Adapted from the AACE
Glycemic Control Algorithm, 2016)
A. Geliebter
127
Table 6.1 Commonly used non-insulin diabetic medications
Drug name Route Dosage Timing Notable side effects
Biguanides [MOA: Decreased hepatic glucose output]
Metformin IR/
metformin XR
Oral IR: 500–2550 mg
XR: 500–2000 mg
IR: 2–3×/day
XR: 1–2×/day
GI upset, B12 deficiency, lactic
acidosis (rare)
Sulfonylureas/meglitinides [MOA: Increased insulin secretion]
Glimepiride Oral 1–8 mg 1–2×/day Hypoglycemia, weight gain
Glyburide 2.5–20 mg 1–2×/day
Glipizide IR/
glipizide XR
IR: 2.5–20 mg
XR: 5–20 mg
IR: 1–2×/day
XR: 1×/day
Repaglinide 0.5–2 mg With meals
Nateglinide 60–120 mg
GLP-1 receptor agonists [MOA: Glucose-dependent insulin release via GLP-1]
Exenatide IR/
exenatide XR
SQ IR: 5–10 mcg
XR: 2 mg
IR: 2×/day
XR: weekly
GI upset, pancreatitis
Liraglutide 0.6–1.8 mg Daily
Dulaglutide 0.75–1.5 mg
6. Diabetes
128
Drug name Route Dosage Timing Notable side effects
Dipeptidyl peptidase 4 (DPP-4) inhibitors [MOA: Inhibiting DPP-4, thereby increasing GLP-1]
Sitagliptin Oral 25–100 mg Daily Pancreatitis, rare hypersensitivity
reactions
Saxagliptin 2.5–5 mg
Linagliptin 5 mg
Alogliptin 6.25–25 mg
Thiazolidinediones (TZDs) [MOA: Increases insulin sensitivity through binding of PPAR]
Pioglitazone Oral 15–45 mg Daily Weight gain, edema, possible
increase in fractures
Sodium-glucose co-transporter 2 (SGLT-2) inhibitors [MOA: Inhibition of urinary glucose reabsorption]
Canagliflozin Oral 100–300 mg Daily Vulvovaginal candidiasis, urinary
tract infections, hypotension,
lower extremity amputations
Empagliflozin 10–25 mg
Dapagliflozin 5–10 mg
Alpha-glucosidase inhibitors (AGIs) [MOA: Inhibition of carbohydrate absorption]
Acarbose
Oral
25–100 mg
With meals GI upset
Miglitol 25–100 mg
Table 6.1
(continued)
A. Geliebter
129
Metformin
The exact mechanism of action of metformin remains unclear,
but it appears to primarily decrease hepatic glucose
production. Metformin has a long-established cardiovascular
safety profile, can promote weight loss, and has a low risk of
hypoglycemia. Metformin can have a substantial positive
impact on glycemic control with doses of 2000–2500 mg daily.
For these reasons, metformin is often the initial agent pre-
scribed for patients with T2D and remains the backbone of
therapy.
Adverse effects include gastrointestinal effects, B12 defi-
ciency, and the potential for lactic acidosis. GI effects can be
minimized with slow dose titration, administration with
foods, and the use of extended-release formulations. B12
deficiency has been associated with metformin use, and B12
levels should be measured in all patients on metformin.
Of note, lactic acidosis is an extremely rare consequence of
metformin therapy and is associated with pre-existing renal
insufficiency. The new FDA guidelines (2016) recommend
that metformin should not be initiated when eGFR drops
below 45 mL/min/1.73 m
2
, should be reconsidered in patients
already on metformin when eGFR drops below 45 mL/
min/1.73 m
2
, and should be stopped completely when eGFR
drops below 30 mL/min/1.73 m
2
. Metformin should also be
stopped prior to imaging studies with iodinated contrast [11].
Sulfonylureas (Glimepiride, Glyburide, Glipizide)
and Meglitinides (Repaglinide, Nateglinide)
Sulfonylureas act by binding to potassium channels on pancre-
atic beta cells, inducing insulin secretion. Sulfonylureas can
significantly improve glycemic control, are available in once-
daily formulations, and are often prescribed as add-on therapy
to metformin. Dosing should be increased slowly as some
patients are prone to becoming hypoglycemic while on sulfo-
nylureas. Sulfonylurea doses need to be adjusted in patients
with underlying kidney disease given the overall long duration
6. Diabetes