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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2866_Библиотеки_им_академика_М_И_Перельмана.pdf
Chapter 7. Diabetes
Initial Assessment
167
A1C < 7.5%
Monotherapy
Metformin
(preferred) or
other
DM med
A1C > 7.5% - 9%
Dual Therapy
Metformin
(preferred) +
additional DM
medication
Asymptomatic
Dual or triple
therapy
A1C > 9%
Symptomatic
Basal insulin +/-
other DM med
F . Initial glycemic management (adapted from the AACE
Comprehensive Type 2 Diabetes Management Algorithm, 2020)
Choice ofTherapy
Both the American Diabetes Association and the American
Association of Clinical Endocrinologists have created comprehensive algorithms for pharmacotherapy in T2D [13, 16].
Below is a summary of commonly available diabetic medications, and is also available in Table7. 1.
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 prescribed
for patients with T2D and remains the backbone of therapy.
168
A. Geliebter
GI upset, B12 deficiency,
IR: 2–3×/day
renal dosing, lactic acidosis
(rare)
XR: 1–2×/day
IR: 1–2×/day
XR: 1×/day
XR: 500–2000mg
Oral IR: 500–2550mg
T . Commonly used non-insulin diabetic medications
Drug name Route Dosage Timing Notable side effects
Biguanides
(MOA: Decreased hepatic glucose output)
Metformin IR/metformin
XR
Sulfonylureas/meglitinides
(MOA: Increased insulin secretion)
Glimepiride Oral 1–8mg 1–2×/day Hypoglycemia, weight gain
XR: 5–20mg
Glyburide 2.5–20mg 1–2×/day
Glipizide IR/glipizide XR IR: 2.5–20mg
Repaglinide 0.5–4mg With meals
Nateglinide 60–120mg
GI upset
IR: 2×/day
XR: Weekly
Chapter 7. Diabetes
169
(continued)
XR: 2mg
SQ IR: 5–10 mcg
GLP-1 receptor agonists
(MOA: Glucose-dependent insulin release via GLP-1)
Exenatide IR
Exenatide XR
Liraglutide 0.6–1.8mg Daily
Lixisenatide 10–20mg Daily
Dulaglutide 0.75–4.5mg Daily
Semaglutide 0.25–1mg Weekly
Semaglutide Oral 3–14mg Daily
Dipeptidyl peptidase 4 (DPP-4) inhibitors
(MOA: Inhibiting DPP-4, thereby increasing GLP-1)
Sitagliptin Oral 25–100mg Daily Well tolerated
Saxagliptin 2.5–5mg
Linagliptin 5mg
Alogliptin 6.25–25mg
170
A. Geliebter
possible increase in
fractures
urinary tract infections,
hypotension
With meals GI upset
Thiazolidinediones (TZDs)
(MOA: Increases insulin sensitivity through binding of PPAR)
Drug name Route Dosage Timing Notable side effects
T . (continued)
Pioglitazone Oral 15–45mg Daily Weight gain, edema,
Sodium-glucose co-transporter 2 (SGLT-2) inhibitors
(MOA: Inhibition of urinary glucose reabsorption)
Canagliflozin Oral 100–300mg Daily Vulvovaginal candidiasis,
Ertugliflozin 5–15mg
Empagliflozin 10–25mg
Dapagliflozin 5–10mg
Alpha-glucosidase inhibitors (AGIs)
25–100mg
Oral
(MOA: Inhibition of carbohydrate absorption)
Acarbose
Miglitol 25–100mg
Chapter 7. Diabetes
Adverse effects include gastrointestinal effects, B12 deficiency, 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/minute/1.73 m2, should be reconsidered in
patients already on metformin when eGFR drops below
45 mL/minute/1.73 m2, and should be stopped completely
when eGFR drops below 30mL/minute/1.73m2. Metformin
should also be stopped prior to imaging studies with iodinated contrast [17].
171
Sulfonylureas (Glimepiride, Glyburide, Glipizide)
andMeglitinides (Repaglinide, Nateglinide)
Sulfonylureas act by binding to potassium channels on pancreatic 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
sulfonylureas. Sulfonylurea doses need to be adjusted in
patients with underlying kidney disease given the overall long
duration of action. Glipizide is the preferred sulfonylurea in
patients with chronic kidney disease. The meglitinides have a
shorter half-life as compared with sulfonylureas, are taken
with meals, and may carry a lower risk of hypoglycemia.
Adverse effects include hypoglycemia, lack of durability,
and weight gain. Sulfonylureas have a high incidence of hypoglycemia as compared with other non-insulin therapies, and
patients should be advised to monitor their glucose while on
therapy.
172
A. Geliebter
GLP-1 Receptor Agonists (Exenatide, Liraglutide, Dulaglutide, Lixisenatide)
GLP-1 receptor agonists act by binding to glucagon-like
peptide- 1 receptors and inducing glucose-dependent insulin
release from the beta cells. GLP-1 receptor agonists have a
strong glycemic effect and are associated with weight loss and
blood pressure reductions. Importantly, they have demonstrated significant cardiovascular and renal benefits and are
recommended for use in patients with high risk for
cardiovascular disease (established atherosclerotic disease,
heart failure, established kidney disease). They may be used
as add-on therapy to metformin and can often be used as an
alternative to basal insulin therapy in selected patients.
GLP-1 receptor agonists are available as daily or weekly
injectables, and in a daily oral formulation. Exenatide should
not be used with eGFR<30ml/min.
Adverse Effects Gastrointestinal side effects include nausea,
vomiting, and diarrhea and may be improve over time and
with slow dose titration. GLP-1 receptor agonists should be
used with caution in patients with gastroparesis. GLP-1
agonists have also been associated with pancreatitis in some
studies and should be used cautiously in patients with a
personal history of pancreatitis.
GLP-1 agonists should not be given to patients with a personal or family history of MEN type 2 (multiple endocrine
neoplasia) or medullary thyroid cancer.
DPP-4 Inhibitors (Sitagliptin, Saxagliptin, Linagliptin, Alogliptin)
DPP-4 inhibitors act by inhibiting dipeptidyl peptidase 4
(DPP-4), leading to increased levels of GLP-1. DPP-4 inhibitors have modest glycemic effect but are commonly prescribed as they have few adverse effects, are weight neutral,
dosed once daily, and are available in combination with met-
Chapter 7. Diabetes
formin. DPP-4 inhibitor dosages need to be adjusted in
patients with underlying kidney disease except for
linagliptin.
Adverse Effects DPP-4 inhibitors have also been associated
with pancreatitis in some studies and should be used cautiously
in patients with a history of pancreatitis.
173
SGLT-2 Inhibitors (Canagliflozin, Dapagliflozin, Empagliflozin, Ertugliflozin)
Sodium-glucose co-transporter 2 (SGLT-2) inhibitors block the
reabsorption of glucose in the nephron, resulting in an osmotic
diuresis. SGLT-2 inhibitors have modest glycemic effects and
can decrease weight and systolic blood pressure. SGLT-2 inhibitors as a class have generally been associated with decreased
all-cause and CV death, heart failure hospitalizations, and progression of chronic kidney disease. SGLT-2 inhibitor dosages
need to be adjusted in patients with underlying kidney disease.
Adverse Effects SGLT-2 inhibitors can lead to dehydration
and hypotension. They have been associated with an increased
incidence of genital mycotic infections, necrotizing fasciitis of
the perineum, bone fractures, and the development of
euglycemic ketoacidosis with SGLT-2 inhibitor use.
Thiazolidinediones (Pioglitazone)
TZDs are the only diabetes medication class that directly
reduces insulin resistance by binding to peroxisome
proliferator- activated receptors, although the exact mechanisms are unknown. Patients with severe insulin resistance
may benefit from TZD therapy. TZDs have modest glycemic
efficacy, have a durable effect, and have a low risk of hypoglycemia. Pioglitazone may also have a beneficial impact on
lipids, as well as on hepatic steatosis.
174
A. Geliebter
Adverse Effects TZDs are associated with significant dosedependent weight gain and edema and should not be used in
patients at increased risk for heart failure. TZDs have also
been linked to an increased rate of bone fractures as well as a
possible association with bladder cancer.
Alpha-Glucosidase Inhibitors (AGIs) (Acarbose, Miglitol)
AGIs act by inhibiting carbohydrate absorption in the small
intestine and have a significant dose-dependent impact on
post-prandial glucose levels. Acarbose has also been associated with improved CV outcomes in patients with impaired
glucose tolerance. AGI doses need to be adjusted in patients
with underlying kidney disease.
Adverse Effects AGIs often cause flatulence and diarrhea,
which can often be improved with lower doses.
Insulin
Insulin remains a potent and effective treatment to lower
blood glucose in the majority of patients and may be the
appropriate choice of therapy for selected patients. Longstanding patient with diabetes patients with diabetes already
on two non-insulin agents with an A1C > 8% will likely
require the addition of insulin to achieve glycemic targets.
Additionally, if the A1C is significantly elevated on initial
diagnosis (>9–9.5%) and the patient is significantly symptomatic from the hyperglycemia, insulin can be useful to help
rapidly lower the A1C and improve symptoms.
Insulin can be given as either a basal dose to help suppress
hepatic glucose production, or as a prandial dose to help
improve post-prandial spikes in glucose. See Table7. 2 for the
time profiles of the commonly prescribed insulin formulations. Generally, basal insulin is initially prescribed and slowly
up titrated to achieve normal fasting glycemic levels. Basal
insulin can be initiated at a dose of 0.1–0.2U/kg and should
be slowly titrated every 2–3days in order to achieve a fasting
Chapter 7. Diabetes
T . Common insulin formulations [18]
Long-acting Onset Peak effect Duration (h)
Degludec U-100/U-200 1–2h None >40
Detemir 1–2h None 14–24
Glargine U-100/U-300 3–6h None 24
Intermediate-acting
NPH 1–2h 4–12h 18–26
Rapid-acting
Regular U-100 30–60min 2–4h 6–8
Lispro/aspart/glulisine 5–15min 40–75min 3–5
Lispro-aabc <10min 1–2hours 4–6
175
blood glucose of <130mg/dL.Some patients with significant
insulin resistance may require very high doses of insulin in
order to achieve their glycemic targets. Prandial insulin
should be considered once the basal insulin dose is greater
than 0.5 U/kg, with the goal of lowering a 2-hour postprandial glucose of <180mg/dL.Of note, multiple injections
of insulin daily may impose a significant burden on patients
and should be carefully considered before initiation.
When insulin is prescribed, patients should be educated
carefully about administration techniques, timing, and consistency of dosing and the proper use of blood glucose monitoring with a glucometer. Hypoglycemia remains a primary
concern with insulin use given its association with significant
comorbidity, and patients should be educated about the
symptoms and management of hypoglycemia.
Clinical Pearls
• Diabetes mellitus is an increasingly common diagnosis in
the USA and should be considered in patients with poly-
uria, polydipsia, and fatigue.
• Diagnosis of DM can be made in the office if fasting
plasma glucose is >126 mg/dl or if plasma glucose is
>200mg/dl with hyperglycemic symptoms.
176
A. Geliebter
• Screening for diabetes is indicated for individuals at high
risk for diabetes including patients who are 35–70 years
old and overweight or obese.
• Given the many treatment options available in T2D,
patients and providers should be in agreement about gly-
cemic aims before a new regimen is initiated.
• SGLT2 inhibitors and GLP1 agonists have been demon-
strated to improve cardiovascular and renal outcomes in
selected patients.
• Insulin therapy is ultimately required in many patients
with T2D.
Don’t Miss This!
• Diabetes mellitus is a chronic and complicated disease,
and successful management can often be overwhelming
for patients and lead to poor medication adherence. When
assessing a potential treatment failure, don’t forget to care-
fully assess for adherence before changing the DM
regimen!
References
1. American Diabetes Association. 1. Strategies for improving care.
Diabetes Care. 2016;39(Supplement 1):S6–12.
2. UK prospective diabetes study (UKPDS) group. Intensive
blood- glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet.
1998;352(9131):837–53.
3. 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;1993(329):977–86.
4. Ismail-Beigi F, Craven T, Banerji MA, Basile J, Calles J, Cohen
RM, Cuddihy R, Cushman WC, Genuth S, Grimm RH, Hamilton
BP.Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD
randomised trial. Lancet. 2010;376(9739):419–30.