IN THE NAME OF GOD
Hypoglycemic Agents
Recommendations:
Glycemic Goals in Adults
• Hb A1C < 7%
• Hb A1C < 6.5%
• Hb A1C < 8%
Recommendations:
Glycemic Goals in Adults (1)
• Lowering A1C to below or around 7% has
been shown to reduce microvascular
complications and, if implemented soon after
the diagnosis of diabetes, is associated with
long-term reduction in macrovascular disease.
Therefore, a reasonable A1C goal for many
nonpregnant adults is <7% . B
Recommendations:
Glycemic Goals in Adults (2)
• Providers might reasonably suggest more
stringent A1C goals (such as <6.5%) for
selected individual patients, if this can be
achieved:
• without significant hypoglycemia
• or other adverse effects of treatment.
Appropriate patients might include those
• with short duration of diabetes,
• long life expectancy,
• and no significant CVD. C
Recommendations:
Glycemic Goals in Adults (3)
• Less stringent A1C goals (such as <8%) may be
appropriate for patients with (B):
• History of severe hypoglycemia, limited life
expectancy, advanced microvascular or
macrovascular complications, extensive
comorbid conditions.
• Those with longstanding diabetes in whom the
general goal is difficult to attain despite DSME,
appropriate glucose monitoring, and effective
doses of multiple glucose lowering agents
including insulin
Oral Hypoglycemic Agents
• 1-Insulin Sensitizers with Predominant Action in
the Liver
• 2- Insulin Sensitizers with Predominant Action in
Peripheral Insulin-Sensitive Tissues
• 3-Insulin Secretagogues
• 4-Incretin-Related Therapies(DPP4 Inhibitors)
• 5-Sodium-glucose cotransporters type 2 inhibitors
• 6-Alpha-glucosidase inhibitors
• 7-Colesevelam
• 8-Bromocriptine
PHARMACOLOGICAL THERAPY
FOR TYPE 1 DIABETES(Slide1)
• Most people with type 1 diabetes should be
treated with multiple-dose insulin (MDI)
injections (three to four injections per day of
basal and prandial insulin)
• or continuous subcutaneous insulin infusion
(CSII). A (Diabetes Care)
ORAL HYPOGLYCEMIC AGENT
THERAPY FOR TYPE 1
DIABETES(Slide2)
• 1- Metformin
• 2- ALPHA-GLUCOSIDASE INHIBITORS
PHARMACOLOGICAL THERAPY
FOR TYPE 1 DIABETES(Slide3)
• Adding metformin to insulin therapy:
• 1- may reduce insulin requirements
• 2- 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 U/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 = 0.42)
(Diabetes Care).
PHARMACOLOGICAL THERAPY
FOR TYPE 1 DIABETES(4)
• 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.
PHARMACOLOGICAL THERAPY
FOR TYPE 1 DIABETES(4)
• Sodium–Glucose Cotransporter 2 Inhibitors
• Sodium–glucose cotransporter 2 (SGLT2)
inhibitors provide insulin-independent glucose
lowering by blocking glucose reabsorption in the
proximal renal tubule by inhibiting SGLT2. These
agents provide modest weight loss and blood
pressure reduction. Although there are two
FDAapproved agents for use in patients with type
2 diabetes, there are insufficient data to
recommend clinical use in type 1 diabetes at this
time (Diabetes Care).
PHARMACOLOGICAL
THERAPY FOR
TYPE 2 DIABETES
ADA. 7. Approaches to Glycemic Treatment. Diabetes Care 2015;38(suppl 1):S43. Figure 7.1;
adapted with permission from Inzucchi SE, et al. Diabetes Care, 2015;38:140-149
Choice
of Pharmacological Agents
•
•
•
•
•
•
•
•
•
Considerations include:
efficacy
cost
potential side effects
weight
comorbidities
hypoglycemia risk
and patient preferences. E
Due to the progressive nature of type 2 diabetes,
insulin therapy is eventually indicated for many
patients with type 2 diabetes. B (Diabetes Care).
Dual Therapy
• For all patients, consider initiating therapy
with a dual combination when A1C is 9% to
more expeditiously achieve the target A1C
level. (Diabetes Care).
Insulin
• When hyperglycemia is severe, especially if
symptoms are present or any catabolic features
(weight loss, ketosis) are in evidence.
• Consider initiating combination insulin
injectable therapy when blood glucose is 300–
350 mg/dL and/or A1C is 10–12%.
• As the patient’s glucose toxicity resolves, the
regimen can, potentially, be subsequently
simplified. (Diabetes Care)
Metformin
(MECHANISM OF ACTION(1))
• Is effective only in the presence of insulin
• its major effect is to decrease hepatic glucose output
• In addition, metformin increases insulin-mediated
glucose utilization in peripheral tissues (such as
muscle and liver), particularly after meals, and has
an antilipolytic effect that lowers serum free fatty
acid concentrations, thereby reducing substrate
availability for gluconeogenesis.
• As a result of the improvement in glycemic control,
serum insulin concentrations decline slightly.
Metformin
(MECHANISM OF ACTION(2))
• The molecular mechanisms of metformin action are not
fully known.
• Activation of the enzyme AMP-activated protein kinase
(AMK) appears to be the mechanism by which
metformin lowers serum lipid and blood glucose
concentrations.
• Metformin works through the Peutz-Jeghers protein,
LKB1, to regulate AMPK. LKB1 is a tumor suppressor
and activation of AMPK through LKB1 may play a role
in inhibiting cell growth. In case-control and cohort
studies in patients with type 2 diabetes, metformin use
has been associated with a reduced risk of cancer and
lower cancer mortality?
Metformin
•
•
•
•
HbA1c Lowering >1 (%)
Fasting & Postprandial effect
Usual Dosing Frequency (1-3 Doses/Day)
Maximum effective dose (1000 mg bid)
Agent -Specific Advantages
Metformin
• 1- May be less likely to cause
hypoglycemia.(Careful blood glucose monitoring is still
needed during the first weeks or months of treatment with
metformin to avoid this problem.)
•
•
•
•
2- Weight neutral
3- (LDL &TG), HDL
4-Inexpensive
5-Decreased all-cause mortality and decreased rate
of myocardial infarction .
SIDE EFFECTS
•
The most common side effects of metformin are gastrointestinal,
including a metallic taste in the mouth, mild anorexia, nausea,
abdominal discomfort, and soft bowel movements or diarrhea. These
symptoms are usually mild, transient, and reversible after dose
reduction or discontinuation of the drug. In clinical trials, only 5
percent of study subjects discontinue metformin because of the
gastrointestinal side effects.
• Metformin reduces intestinal absorption of vitamin B12 in up to 30
percent of patients, and lowers serum vitamin B12 concentrations in
5 to 10 percent, but only rarely causes megaloblastic anemia. The
dose and duration of use of metformin correlates with the risk of
vitamin B12 deficiency . This reduction appears to be due to
absorption in the ileum and can be corrected by administration of
oral calcium.
Agent -Specific Disadvantages
• The most common side effects:
– Metallic taste in the mouth,
– mild anorexia
– nausea
– abdominal discomfort
– soft bowel movements or diarrhea
• Reduces intestinal absorption of vitamin B12
• lactic acidosis (Rare problem){anorexia,
nausea, vomiting, abdominal pain, lethargy,
hyperventilation, and hypotension}
Contraindications
•
•
•
•
•
•
•
1-Serum Cr >1.5 mg/dL (men) >1.4 mg/dL (women)
2- CHF
3-radiographic contrast studies
4-seriously ill patients
5-acidosis
6-Concurrent liver disease or alcohol abuse
7-Past history of lactic acidosis
parenteral administration of iodinated
contrast
• should be discontinued immediately prior to and
for 48 hours after any radiologic procedure
involving parenteral administration of iodinated
contrast material. The rationale for this
recommendation is to avoid the potential for high
plasma metformin concentrations (and lactic
acidosis) if the patient develops contrast-induced
acute renal failure.
DOSING
• Tab 500, 850, 1000 mg
• Metformin is absorbed rapidly from the small intestine,
with peak plasma concentrations attained in two hours.
It is not bound to plasma proteins, is not metabolized,
and is rapidly excreted in the urine .
• and should be taken with meals
• We begin with 500 mg once daily with the evening
meal and, if tolerated, add a second 500 mg dose with
breakfast.
• The dose can be increased slowly (one tablet every one
to two weeks) as necessary .
• The usual effective dose is 1500 to 2000 mg/day per
day; the maximum dose of 2550 mg/day
combination of metformin and one
of these …
• 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.
Sulfonylureas
Drug
Duration of
Biologic
Effect,h
Usual Daily
Dose,mg
Dosing Per Day
12-18
500-750
Once or Divided
Chlorpropamide 24-72
250-500
Once
Tulbotamide
1000-2000
Once or Divided
First-generation
sulfonylureas
Acetohexamide
14-16
Second-generation sulfonylureas
Drug
Duration of
biologic effect, h
Usual daily dose,
mg
Dosing per day
Glipizide
14 to 16
2.5 to 10
Once or divided
5 to 10
Once
40 to 240
Once
(Glucotrol)
(Glucotrol XL)
Gliclazide
24
(Diamicron R)
Once
(Diamicron MR)
Once
Glyburide
(Glibenclamide)
20 to 24+
2.5 to 10
Once
Glimepiride
(Amaryl)
24+
2 to 4
Once
Gliclazide
•
•
•
•
Tablet, oral:Immediate release tablet
Diamicron®: 80 mg
Tablet, modified release, oral:
Diamicron® MR: 30 mg, 60 mg
Gliclazide:
Administration
• Administration Patients that are
• NPO or
• require decreased caloric intake may need doses held
to avoid hypoglycemia.
• Administer with meals (modified release tablet should
be administered with breakfast). May split the 60 mg
modified release tablets in half; however, the 30 mg
modified release tablets must be swallowed whole.
Modified release tablets should not be crushed or
chewed.
• Administer with meals (modified release tablet should
be administered with breakfast).
Gliclazide:
Dosing:
• Immediate release tablet:
• Recommended initial:
• 80 mg twice daily; titrate based on blood glucose
levels. Usual dosage range 80-320 mg/day (maximum
dose: 320 mg/day); dosage of ≥160 mg should be
divided into 2 equal parts for twice-daily administration
• Modified release tablet:
• Initial:
• 30 mg once daily; titrate in 30 mg increments every 2
weeks based on blood glucose levels. Maximum dose:
120 mg once daily
Conversion from Insulin to Gliclazide
• Maturity-onset diabetes: Oral: May consider
conversion from insulin to gliclazide therapy
in patients receiving <40 units/day insulin.
Prior to conversion, discontinue insulin for 4872 hours with close monitoring (≥3 times/day)
of urine for glucose and ketones. Patients with
ketonuria and glycosuria 12-24 hours after
discontinuing insulin should not be converted
to gliclazide therapy and should remain on
insulin therapy.
gliclazide
Dosing: Renal Impairment
• Mild-moderate impairment (Clcr ≥15
mL/minute): Dose reductions may be
necessary. There are no dosage adjustments
provided in manufacturer's labeling.
• Severe impairment: Use is contraindicated.
Gliclazide
Dosing: Hepatic Impairment
• Mild-moderate impairment: Dose reductions
may be necessary. There are no dosage
adjustments provided in manufacturer's
labeling.
• Severe impairment: Use is contraindicated.
Drug Interactions of Gliclazide
•
•
•
•
•
•
•
•
•
•
Alcohol (Ethyl)
Beta-Blockers
Chloramphenicol
Cimetidine
Corticosteroids (Orally Inhaled), (Systemic)
Cyclic Antidepressants
Fibric Acid Derivatives
Fluconazole
GLP-1 Agonists
Miconazole (Oral )
Contraindications
• 1-Hypersensitivity to gliclazide, other sulfonylureas or
sulfonamides, or any component of the formulation;
• 2-Type 1 diabetes mellitus (insulin dependent, IDDM);
• 3-Diabetic ketoacidosis with or without coma;
• 4-Severe renal impairment;
• 5-Severe hepatic impairment
• 6-stress conditions (eg, serious infection, trauma,
surgery);
• 7- concurrent use with miconazole (systemic or
oromucosal gel);
Disease-related concerns:
• Glucose-6-phosphate dehydrogenase (G6PD)
deficiency: Patients with G6PD deficiency
may be at an increased risk of sulfonylureainduced hemolytic anemia; however, cases
have also been described in patients without
G6PD deficiency during postmarketing
surveillance. Use with caution and consider a
nonsulfonylurea alternative in patients with
G6PD deficiency.
DPP-4 inhibitors
Discovery of DPP-4 Inhibitors as Antidiabetic Agents
Tesfaye Biftu
Merck & Co., Inc.
Incretin-Related Therapies(SLIDE 1)
• The incretin effect describes the observation that
oral glucose has a greater stimulatory effect on
insulin secretion than does intravenous glucose at
the same circulating glucose concentration. In
humans, this effect seems to be primarily mediated
by GLP1 and GIP(Glucose-dependent
insulinotropic polypeptide) . GLP1 is produced
from the proglucagon gene in intestinal L cells
and is secreted in response to nutrients. (Williams)
Incretin-Related Therapies(SLIDE 2)
• GLP1:
• 1-Stimulates insulin secretion in a glucosedependent fashion
• 2-Inhibits inappropriate hyperglucagonemia
• 3-Slows gastric emptying
• 4-Reduces appetite and improves satiety
• 5-Beta-cell proliferative, antiapoptotic, and
differentiation effects at least in vitro and in
preclinical models. (Williams)
Incretin-Related Therapies(SLIDE 3)
• GLP1 has a very short half-life in plasma (1 to
2 minutes) due to aminoterminal degradation
by the enzyme dipeptidyl peptidase IV
(DPP4). (Williams)
Incretin-Related Therapies(SLIDE 4)
• GLP1 receptor agonists, which are peptides
that produce increases of 10-fold or higher in
GLP1 activity
• DPP4 inhibitors, which are small molecule
inhibitors of the degradation of GLP1 and GIP
as well as other hormones.
• DPP-4 inhibitors may be used in the:
• full spectrum of type 2 diabetes (T2DM):
– monotherapy in drug-naive patients,
– dual or triple oral therapies
– or even as add-onto insulin. (Andre J Scheen)
special populations
• Because of their favourable efficacy/safety
profile, DPP-4 inhibitors are best suited for
special populations of T2DM patients such as
• elderly people,
• patients with renal impairment
• or patients at risk of hypoglycaemia
(‘personalized medicine’). (Andre J Scheen)
• The pancreatic safety remains a matter of
debate and requires careful post-marketing
surveillance,
whereas the
• cardiovascular safety of DPP-4 inhibitors is
already better known and will be even more
extensively demonstrated in further ongoing
trials.
Role of Incretins in Glucose Homeostatis
Ingestion of food
Pancreas
Glucose-dependent
insulin from beta
cells
(GLP-1, GIP)
Release of gut
hormones –
Incretins
Beta cells
Alpha cells
Active
GLP-1 & GIP
GI tract
Inactive
GLP-1
Glucose
uptake by
muscles
DPP-4
enzyme
Inactive
GIP
DPP-4=dipeptidyl peptidase–4
GIP=glucose-dependent insulinotropic peptide
GLP-1=glucagon-like peptide–1
Glucose dependent
glucagon from alpha
cells
(GLP-1)
Blood
Glucose
Glucose
production
by liver
DPP-4 Inhibitors MOA
Meal
Intestinal
GLP-1
release
Intestinal
GIP
release
Active
GIP
Active
GLP-1
DPP-4
inhibitor
DPP-4
Inactive
GLP-1
Incretin effects
DPP-4
inhibitor
DPP-4
– Augments glucose-dependent
insulin secretion
– Inhibits glucagon secretion
and hepatic glucose production
– Improves hyperglycemia
Inactive
GIP
Selective inhibition of DPP-4 increases plasma GLP-1
levels, resulting in reduction in glycemia
55
Plasma glucose multihormonal regulation of glucose
Native GLP-1 is rapidly degraded by DPP-IV
Human ileum,
GLP-1 producing
L-cells
Capillaries,
DPP-IV (Di-Peptidyl
Peptidase-IV)
Double immunohistochemical staining for DPP-IV (red) and GLP-1 (green) in
the human ileum
Adapted from: Hansen et al. Endocrinology 1999;140:5356–5363.
Table 1. The family of commercialized dipeptidyl
peptidase-4 inhibitors.
Generic name
Country
Brand name
Fixed-dose
combination
Brand name
Sitagliptin
Europe, US, Japan
Januvia
Sitagli+Met
Sitagli+ simva
Janumet
Juvisync
Vildagliptin
Europe, Japan
Galvus, Equa
Vildagli+Met
Eucreas,
Galvusmet
Saxagliptin
Europe, US
Onglyza
Saxagli+Met
Komboglyze,
Kombiglyze
Linagliptin
Europe, US, Japan
Trajenta, Tradjenta,
Trazenta
Linagli+Met
Jentadueto
Alogliptin
Europe, US, Japan
Vipidia, Nesina
Alogli+Met
Alogli+ piogli
Vipdomet,Kazano
Oseni
Anagliptin
Japan
Suiny
Teneligliptin
Japan
Tenelia
Gemigliptin
Korea
Zemiglo
Clinical indications of DDP4
inhibitors for the management of
hyperglycaemia in type 2 diabetes.
Positioning
Comment
Monotherapy (add-on to diet and exercise) Mainly when metformin contra-indicated
or not tolerated
Dual therapy as add-on to metformin
Less hypoglycaemia and weight gain
compared to sulphonylureas
Less weight gain and better tolerance
compared to pioglitazone
Dual therapy as add-on to a sulphonylurea
Mainly when metformin contra-indicated
or not tolerated
Dual therapy as add-on to a
thiazolidinedione
Mainly tested with the combination
alogliptin-pioglitazone
Dual therapy as add-on to α-glucosidase
inhibitors
Mainly studied in Asian patients
Triple therapy as add-on to metformin plus
sulphonylurea
Before considering shift to injectable drugs
(insulin or glucagon-like peptide-1 receptor
agonists)
Triple therapy as add-on to metformin plus
pioglitazone
Less hypoglycaemia and weight gain
compared to sulphonylureas
As add-on to insulin therapy
Better glucose control with less insulin and
no increase of hypoglycaemia
DDP4 inhibitors
• These agents produce approximately twofold
increases in fasting and postprandial GLP1 and
GIP levels, with subsequent HbA1c reductions of
approximately 0.7%.
• well tolerated
• Specifically, they are not associated with nausea.
• because of the lesser increase in GLP1 activity
than with the GLP1 receptor agonists, there is no
weight loss with DPP4 inhibitors; they tend to be
weight neutral
Sitagliptin
• Dosing: Adult Type 2 diabetes: Oral: 100 mg once
daily
• Concomitant use with insulin and/or insulin
secretagogues (eg, sulfonylureas): Reduced dose of
insulin and/or insulin secretagogues may be needed
• Tablet, oral:
• Januvia®: 25 mg, 50 mg, 100 mg
Sitagliptin
Dosing: Renal Impairment
• Clcr ≥50 mL/minute: No adjustment required
• Clcr ≥30 to <50 mL/minute: 50 mg once daily
• Scr: Males: >1.7 to ≤3.0 mg/dL; Females: >1.5 to
≤2.5 mg/dL: 50 mg once daily
• Clcr<30 mL/minute: 25 mg once daily
• Scr: Males: >3.0 mg/dL; Females: >2.5 mg/dL: 25
mg once daily
• ESRD requiring hemodialysis or peritoneal
dialysis: 25 mg once daily; administered without
regard to timing of hemodialysis
Dosing: Hepatic Impairment
• Mild-to-moderate impairment (Child-Pugh
score 7-9): No dosage adjustment required
• Severe impairment (Child-Pugh score >9): Not
studied
• Pregnancy Risk Factor B
• Breast-Feeding Considerations It is not known
if sitagliptin is excreted in breast milk. The
manufacturer recommends that caution be used
if administered to breast-feeding women.
• Dietary Considerations May be taken with or
without food.
• Monitoring Parameters Hb A1c, serum glucose;
renal function prior to initiation and
periodically during treatment
Contraindication
• Postmarketing cases of pancreatitis have been
reported for the DPP4 inhibitors, and they are
contraindicated for use in those with a prior
history.
• Specificity for DPP4 appears to be crucial,
because less specific inhibitors have
demonstrated adverse effects on immune
function and cancer growth in animal studies.
• The usual dose is the maximum marketed
dose; because these drugs are cleared renally,
smaller doses are recommended in the setting
of stage 3 or greater chronic kidney disease.
hypersensitivity reactions
• Serious hypersensitivity reactions have been
reported, including:
• anaphylaxis,
• angioedema,
• and exfoliative skin conditions with sitagliptin,
but causality has not been substantiated due to
the rarity of events.
sodium glucose cotransporter
• SGLT2 is a member of the sodium glucose
cotransporter family which are sodiumdependent glucose transport proteins. SGLT2
is the major cotransporter involved in glucose
reabsorption in the kidney.
•
•
•
•
•
Dapagliflozin, approved in the United States.
Canagliflozin, approved in the United States
Ipragliflozin (ASP-1941), in Phase III clinical trials
Tofogliflozin, in Phase III clinical trials
Empagliflozin (BI-10773), approved in the United
States.
• Sergliflozin etabonate, discontinued after Phase II trials
• Remogliflozin etabonate, in phase IIb trials
• Ertugliflozin (PF-04971729 / MK-8835), in phase III
trials
Clinical significance
• Mutations in this gene are also associated with
renal glucosuria
Dapagliflozin
• Mechanism of action
• Dapagliflozin inhibits subtype 2 of the sodiumglucose transport proteins (SGLT2) which are
responsible for at least 90% of the glucose
reabsorption in the kidney. Blocking this
transporter mechanism causes blood glucose to
be eliminated through the urine. In clinical
trials, dapagliflozin lowered HbA1c by 0.90
percentage points when added to metformin.
Dapagliflozin
Side effects
• Since dapagliflozin leads to heavy glycosuria
(sometimes up to about 70 grams per day) it can
lead to rapid weight loss and tiredness. The
glucose acts as an osmotic diuretic (this effect is
the cause of polyuria in diabetes) which can lead
to dehydration. The increased amount of glucose
in the urine can also worsen the infections already
associated with diabetes, particularly urinary tract
infections and thrush (candidiasis). Dapagliflozin
is also associated with hypotensive reactions.
DYSLIPIDEMIA/LIPID
MANAGEMENT
•
•
•
•
•
•
Screening
In adults, a screening lipid profile is
reasonable at the time of first diagnosis,
at the initial medical evaluation,
and/or at age 40 years and
periodically (e.g., every 1–2 years) thereafter. E
Dyslipidemia/Lipid Management
• – Screening
• In most adult patients with diabetes, measure
fasting lipid profile at least annually (B)
• In adults with low-risk lipid values
– (LDL cholesterol <100 mg/dL,
– HDL cholesterol >50 mg/dL, and
– triglycerides <150 mg/dL),
– lipid assessments may be repeated every 2 years
(E)
Dyslipidemia/Lipid Management
Treatment Recommendations and Goals
• To improve the lipid profile in patients with diabetes,
recommended Lifestyle modification (A) focusing on
– Reduction of saturated fat, trans fat, and cholesterol intake
• Increase of omega-3 fatty acids, viscous fiber (such
as in oats, legumes, and citrus), and plant
stanols/sterols
• Weight loss (if indicated)
• Increased physical activity should be recommended
to improve the lipid profile in patients with diabetes
(A)
• Glycemic control can also beneficially modify
plasmalipid levels, particularly in patients with very
high triglycerides and poor glycemic control.
• Intensify lifestyle therapy and optimize
glycemic control for patients with elevated
triglyceride levels (≥150 mg/dL) and/or low
HDL cholesterol (<40 mg/dLfor men, <50
mg/dL for women). C
• For patients with fasting triglyceride levels
≥500 mg/dL,evaluate for secondary causes and
consider medical therapy to reduce risk of
pancreatitis. C
• For patients of all ages with diabetes and overt
CVD:
• high-intensity statin therapy should be added to
lifestyle therapy. A
• For patients with diabetes aged,40 years with
additional CVD risk factors, consider using
moderateor high-intensity statin and lifestyle
therapy. C
Statin therapy should be added to
lifestyle therapy
• 1-regardless of baseline lipid levels, for diabetic
patients
a
-With overt CVD (A)
b- Without CVD who are over the age of 40 years and
have one or more other CVD risk factors (A)
2-For patients at lower risk (e.g., without overt CVD
and younger than age 40 years)
a-LDL cholesterol remains >100 mg/dL
b-In those with multiple CVD risk factors (C)
•
•
•
•
•
For patients with diabetes aged
40–75 years without additional
CVD risk factors, consider using
moderate-intensity statin and lifestyle
therapy. A
•
•
•
•
•
•
Therefore, in
patients with increased cardiovascular
risk (e.g., LDL cholesterol $100 mg/dL
[2.6 mmol/L], high blood pressure, smoking,
and overweight/obesity) or with overt
CVD, high-dose statins are recommended
•
•
•
•
•
•
Combination therapy (statin/
fibrate and statin/niacin) has not
been shown to provide additional
cardiovascular benefit above statin
therapy alone and is not generally
recommended. A
• Statin therapy is contraindicated
• in pregnancy. B
Treatment Recommendations and
Goals
• In individuals without overt CVD, the goal is:
LDL cholesterol <100 mg/dL (B)
• In individuals with overt CVD,
– a lower LDL cholesterol goal of <70 mg/dL , with
a high dose of a statin, is an option (B)
Treatment Recommendations and
Goals
• If targets not reached on maximal tolerated
statin therapy
• Alternative therapiotic goal: reduce in LDL cholesterol
~30-40% from baseline (B)
• Triglyceride levels <150 mg/dl, HDL
cholesterol >40 mg/dL in men and >50 mg/dL
in women, are desirable (C).
However, LDL cholesterol-targeting statin
therapy remains the preferred strategy (A)
Treatment Recommendations and
Goals
• Combination therapy has been shown not to
provide additional cardiovascular benefit
above statin therapy alone and is not generally
recommended (A)
• Statin therapy is contraindicated in pregnancy
(B)
• If severe hypertriglyceridemia is absent, then
therapy targeting HDL cholesterol or triglycerides
lacks the strong evidence base of statin therapy.
• If HDL cholesterol is ,40 mg/dL and LDL
cholesterolis between100 and 129 mg/dL, a
fibrate or niacin might be used, especially if a
patient is intolerant to statins.
Combination Therapy
• Statin and Fibrate
• may be efficacious for treatment for LDLcholesterol, HDL
cholesterol, and triglycerides,
• but this combination is associated with an increased risk for
abnormal transaminase levels, myositis, or rhabdomyolysis.
• The risk of rhabdomyolysis is more common with
• 1-higher doses of statins and
2-with renal insufficiency and
3-seems seems to belower when statins are combined with
fenofibrate than gemfibrozil.
In the ACCORD study
• in patients with type 2 diabetes who were at
high risk for CVD, the combination of
fenofibrate and simvastatin did not reduce the
rate of
• fatalcardiovascular events,
• nonfatalMI,
• or nonfatal stroke,
• as compared with simvastatin alone.
Benefit of Combination
Therapy
• for men
• and possible harm for women,
• and a possible benefit for patients with
both triglyceride level ≥204mg/dL
• and HDL cholesterol level ≤34 mg/dL
Statin and Niacin
• Combination therapy with niacin is not
recommended given the lack of efficacy on
• major CVD outcomes, possible increase in
• risk of ischemic stroke, and side effects.
Diabetes With Statin Use
• There is an increased risk of incident diabetes
with statin use , which may be limited to those
with diabetes risk factors.
• These patients may benefit from diabetes
screening when on statin therapy.
• The absolute risk increase was small (over 5 years
of follow-up, 1.2%of participants on placebo
developed diabetes and 1.5% on rosuvastatin).
• while simultaneously preventing 5.4 vascular
events
Recommendations:Glycemic,Blood
Pressure, Lipid Control in Adults
•
•
•
•
•
A1C
<7.0%
Blood Preshure
<140/90 mmHg
Lipids: LDL
<100 mg/dl
cholestrol
Statin therapy for those with history of MI or
age < 40 + other risk factors, or age > 40
ANTIPLATELET AGENTS
• Consider aspirin therapy (75–162mg/day) as a
primary prevention strategy in those with type 1
or type 2 diabetes at increased cardiovascular risk
(10-year risk>10%). This includes most men aged
>50 years or women aged>60 years who have at
least one additional major risk factor (family
history of CVD, hypertension, smoking,
dyslipidemia, or albuminuria). C
• Aspirin should not be recommendedfor CVD
prevention for adults with diabetes at low CVD
risk (10-year CVD risk ,5%, such as in men aged
,50 years and women aged ,60 years with no
major additional CVD risk factors),
• since the potential adverse effects from bleeding
likely offset the potential benefits. C
• In patients in these age-groups with multiple
other risk factors (e.g., 10-year risk 5–10%),
clinical judgment is required. E
• Use aspirin therapy (75–162mg/day) as a
secondary prevention strategy in those with
diabetes and a history of CVD. A
Revised CKD classification based upon
GFR and albuminuria
GFR stages
GFR (mL/min/1.73 m2)
Terms
G1
>90
Normal or high
G2
60-89
Mildly decreased
G3a
45-59
Mildly to moderately decreased
G3b
30-44
Moderately to severely decreased
G4
15-29
Severely decreased
G5
<15
Kidney failure (add D if treated by dialysis)
CVD risk factors
•
•
•
•
•
family history of CVD
hypertension
Smoking
Dyslipidemia
albuminuria
Low Risk For CVD
• without overt CVD and younger than age 40
years), statin therapy should be considered in
addition to lifestyle therapy if LDL cholesterol
remains >100 mg/dL or in those with multiple
CVD risk factors (C)