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130
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 hypo-
glycemia as compared with other non-insulin therapies, and
patients should be advised to monitor their glucose while on
therapy.
GLP-1 Receptor Agonists (Exenatide, Liraglutide,
Albiglutide, Dulaglutide)
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. They may be used as add-on
therapy to metformin and potentially as an alternative to
basal insulin therapy in selected patients. GLP-1 receptor
agonists are injectables and are available in twice-daily, daily,
and weekly formulations. Liraglutide has demonstrated car-
diovascular safety in high CV risk patients [12]. Exenatide
should not be used with eGFR <30 mL/min.
Adverse Effects
Gastrointestinal side effects include nausea, vomiting, and
diarrhea and may be improved over time and with slow dose
titration. GLP-1 receptor agonists should be used with cau-
tion 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 per-
sonal or family history of MEN type 2 (multiple endocrine
neoplasia) or medullary thyroid cancer.
A. Geliebter
131
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 inhibi-
tors have modest glycemic effect but are commonly prescribed
as they have few adverse effects, are weight neutral, are dosed
once daily, and are available in combination with metformin.
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. There have also been rare reports of
hypersensitivity reactions.
SGLT-2 Inhibitors (Canagliflozin, Dapagliflozin,
Empagliflozin)
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 also result in decreased blood pressure.
Empagliflozin has been found to lower all-cause and cardio-
vascular death and to lower the risk of heart failure hospital-
izations [13]. 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, as well as an association with bone
fractures. Some reports have described the development of
euglycemic ketoacidosis with SGLT-2 inhibitor use. There has
been an increased incidence of leg and foot amputation with
canagliflozin.
6. Diabetes
132
Thiazolidinediones (Pioglitazone)
TZDs are the only diabetes medication class that directly
reduces insulin resistance by binding to peroxisome
proliferator- activated receptors, although the exact mecha-
nisms 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 hypogly-
cemia. Pioglitazone may also have a beneficial impact on
lipids, as well as on hepatic steatosis.
Adverse Effects
TZDs are associated with significant dose-dependent 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
postprandial glucose levels. Acarbose has also been associ-
ated 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 is an effective treatment to lower blood glucose and
may be the appropriate initial choice of therapy in certain
clinical situations. Long-standing diabetics already on two
A. Geliebter
133
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 may be useful to help rapidly lower
the A1c and improve symptoms [9].
Insulin can be given as either a basal dose to help sup-
press hepatic glucose production or as a prandial dose to
help improve postprandial spikes in glucose. See Table 6.2
for a listing of commonly used insulin formulation and peaks
of onset. 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 0.1–0.2 U/kg and
should be slowly titrated every 2–3 days in order to achieve
a fasting blood glucose of <110 mg/dL. Some patients with
significant insulin resistance may require very high doses of
insulin in order to achieve their glycemic targets. If patients
are unable to reach their target hemoglobin A1c with basal
insulin, the addition of prandial insulin can be considered
with the goal of a 2-h postprandial glucose of <140 mg/dL.
Of note, multiple injections of insulin daily may impose a
Table 6.2 Insulin formulations
Onset
Peak
effect
Duration
Insulin: long acting
Degludec U-100/U-200 30–90 min None 42 h
Detemir 1 h None 12–24 h
Glargine U-100/U-300 1.5 h 5 h 24 h
Insulin: intermediate acting
NPH 1–2 h 5 h 12–24 h
Insulin: rapid acting
Regular U-100/U-500 ½–1 h 2–4 h 6–8 h
Lispro/aspart/glulisine
U-100/U-200
<15 min 1–2 h 4–6 h
6. Diabetes
134
significant burden on patients and should be carefully con-
sidered before initiation.
When insulin is prescribed, patients should be educated
carefully about administration techniques, timing and consis-
tency of dosing, and the proper use of blood glucose monitor-
ing 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 US and should be considered in patients with polyuria,
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
>200 mg/dL with hyperglycemic symptoms.
• Screening for diabetes is indicated for individuals at high
risk for diabetes including patients who are 40–70 years
old and overweight.
• A target hemoglobin A1c of 6.0–6.5% should be consid-
ered in newly diagnosed diabetics without significant
comorbidities.
• 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.
• Insulin therapy is eventually required in many patients
with diabetes.
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 for-
get to carefully assess for adherence before changing the
DM regimen!
A. Geliebter
135
References
1. American Diabetes Association. 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 com-
pared with conventional treatment and risk of complica-
tions 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 microvas-
cular outcomes in type 2 diabetes: an analysis of the ACCORD
randomised trial. Lancet. 2010;376(9739):419–30.
5. Statistics Report | Data & Statistics | Diabetes | CDC [Internet].
Cdc.gov. 2016 [cited 19 December 2016]. https://www.cdc.gov/
diabetes/data/statistics/2014statisticsreport.html.
6. CDC - Number of Persons - Diagnosed Diabetes - Data &
Trends - Diabetes DDT [Internet]. Cdc.gov. 2016 [cited 19
December 2016]. https://www.cdc.gov/diabetes/statistics/prev/
national/figpersons.htm.
7. American Diabetes Association. Classification and diagnosis of
diabetes. Diabetes Care. 2016;39(Supplement 1):S13–22.
8. Siu AL. Screening for abnormal blood glucose and type 2 diabe-
tes mellitus: US preventive services task force recommendation
statement. Ann Intern Med. 2015;163(11):861–8.
9. Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden
ZT, Bush MA, Dagogo-Jack S, Davidson MB, Einhorn D, Garber
JR, Garvey WT. AACE/ACE comprehensive diabetes manage-
ment algorithm 2015. Endocr Pract. 2015;21(4):438–47.
10. DeFronzo RA. From the triumvirate to the ominous octet: a new
paradigm for the treatment of type 2 diabetes mellitus. Diabetes.
2009;58(4):773–95.
11. FDA Drug Safety Communication: FDA revises warnings
regarding use of the diabetes medicine metformin in cer-
tain patients with reduced kidney function [Internet]. Fda.
gov. 2016 [cited 19 December 2016]. http://www.fda.gov/Drugs/
DrugSafety/ucm493244.htm.
6. Diabetes
136
12. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann
JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS,
Steinberg WM. Liraglutide and cardiovascular outcomes in type
2 diabetes. N Engl J Med. 2016;375(4):311–22.
13. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel
S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl
UC. Empagliflozin, cardiovascular outcomes, and mortality in
type 2 diabetes. N Engl J Med. 2015;373(22):2117–28.
A. Geliebter
137© Springer International Publishing AG 2018
E. Sydney et al. (eds.), Handbook of Outpatient Medicine,
https://doi.org/10.1007/978-3-319-68379-9_7
Introduction
Hyperlipidemia, also called dyslipidemia, is defined as
increased serum levels of lipids, including cholesterol and
triglycerides. It might be secondary to other diseases, such as
diabetes mellitus, HIV, nephrotic syndrome, hypothyroidism,
and other metabolic disorders, or due to genetic causes in the
case of familial hyperlipidemia, which is termed as primary
hyperlipidemia [1].
Hyperlipidemia is a well-studied and important risk fac-
tor for atherosclerotic cardiovascular disease (ASCVD)
[2], which is the leading cause of death not only in the
United States but also worldwide [3]. Screening and treat-
ing hyperlipidemia for primary and secondary prevention
of cardiovascular disease are an important task in primary
care practice.
Chapter 7
Lipids
Dan L. Li
D.L. Li, MD, PhD (*)
Department of Internal Medicine, Jacobi Medical Center,
1400 Pelham Pkway S, Bronx, NY 10461, USA
e-mail: Dan.Li@nbhn.net; lidanleslie@gmail.com
138
Key H&P
History
Lipid disorders usually are asymptomatic. The history is
focused on the patient’s other medical conditions, family his-
tory, lifestyle, and risks of cardiovascular disease.
Medical History
A review of the patient’s medical history is critical to identify
possible medical conditions that could potentially lead to
hyperlipidemia and to evaluate the risk for ASCVD. Personal
histories of hypertension, diabetes, obesity, cardiovascular
disease (CVD), or peripheral vascular disease (PVD) are risk
factors that warrant further screening for lipid disorders,
according to the USPSTF guidelines (see Decision-Making
session for further details).
Family History
A complete family history of chronic metabolic diseases
including diabetes, lipid disorders, and cardiovascular disease
should be obtained. Specifically, early-onset cardiovascular
disease in first-degree family members is an important risk
factor for ASCVD and should also be ascertained.
Social History
The patient’s dietary patterns, physical activities, and tobacco
use should be evaluated. They are parameters to evaluate a
patient’s risk of lipid disorders, metabolic syndrome, and car-
diovascular events. In addition, these factors are also signifi-
cant points of possible intervention after establishing the
clinical diagnosis of hyperlipidemia (see Treatment Strategies
session for details).
D.L. Li
139
Physical Exam
In most patients there is no specific physical exam for lipid
disorder. Xanthomas are circumscribed plaque or nodule-
like lesions in the skin, tendons, or fasciae and could be seen
occasionally in patients with primary or secondary hyperlip-
idemia. They are derived from macrophages containing a
high amount of LDL particles [4]. On the other hand, physi-
cal exam might reveal signs of atherosclerotic vascular dis-
eases, such as carotid bruits, cardiac murmurs due to aortic
valve atherosclerosis, renal artery bruits due to atheroscle-
rotic stenosis, and signs of peripheral vascular disease (e.g.,
diminished pulses; cold, dry, and shiny skin; ulceration or
gangrene; etc.)
Decision-Making/Differential Diagnosis
Screening Population
The US Preventive Services Task Force (USPSTF) strongly
recommends screening for lipid disorders in men ≥35 years
of age and women ≥45 years of age (Grade A recommenda-
tion). The screening is also recommended in men of age
20–35 and women of age 20–45, with increased risks for car-
diovascular disease (Grade B recommendation). The risk
factors for CVD include hypertension, diabetes, obesity
(BMI ≥ 30), tobacco use, family history of early-onset CVD
(onset before age 55 in male or age 65 in female first-degree
relatives), and personal history of CVD or non-coronary ath-
erosclerosis (e.g., abdominal aortic aneurysm, peripheral
artery disease, carotid artery stenosis, etc.).
USPSTF recommends screening for lipid disorders every
5 years and with shorter intervals for patients with lipid val-
ues that are close to warranting therapy.
7. L ipids