Transcript Combination therapy

R
Diabetes Mellitus Type 2
Dr. Josephine Carlos-Raboca M.D.
Pharmaceuticals
Fixed Combination Therapy in
R
•
•
•
Pharmaceuticals
•
•
Outline
Diabetes – A Global Problem
Standards of Care – American Diabetes Association
2008
Combination therapy as a management strategy
Clinical Data on Metformin 400mg/Glibenclamide 2.5 mg
fixed combination (Eugloplus)
Conclusion
Diabetes Facts
Pharmaceuticals
• 2007 - 270 million diabetics worldwide
• Top 10 countries leading the diabetes
epidemic are all developing countries led
by India and China except for USA and
Japan
• Philippines - 4.6% prevalence
• Good news – not among top 10.
R
R
people with diabetes
2025 (64% increase)
Pharmaceuticals
333,000,000
R
Countries with the highest numbers of estimated cases of diabetes for
2030
Pharmaceuticals
Egypt
Philippines
Japan
Bangladesh
Brazil
Pakistan
Indonesia
USA
China
India
0
20
40
60
80
100
People with diabetes (millions)
Adapted from Wild SH et al. Diabetes Care 2004; 27: 2569–70.
R
Serious complications of type 2 diabetes
are present at diagnosis
Prevalence (%)*
Any complication
50
Retinopathy
21
Abnormal ECG
18
Absent foot pulses ( 2) and/or ischaemic feet
14
Impaired reflexes and/or decreased vibration sense
7
MI/angina/claudication
Pharmaceuticals
Complication
~ 2–3
Stroke/TIA
~1
* Some patients had more than one complication at time of diagnosis
Adapted from UKPDS Group. UKPDS 6. Diabetes Res 1990; 13: 1–11.
R
Decreased Quality
Type 2 Diabetes Mellitus
(Insulin Resistance and
Glucose Intolerance)
Pharmaceuticals
Therefore, the ultimate goal of therapy is to delay
and even prevent the development of
complications.
MICROVASCULAR COMPLICATIONS
MACROVASCULAR COMPLICATIONS
Of Life
SIGNIFICANT MORBIDITY &
MORTALITY
The Expert Committee on the
Diagnosis and Classification of
R
Diabetes Mellitus
R
Pharmaceuticals
Pathogenesis of Type 2 Diabetes: b-Cell Failure
Induced by Insulin Resistance
A Cartoonist’s View of the Pathogenesis of NIDDM
It’s
GLUT 2 !
It’s the
beta cell !
NIDDM
It’s the
insulin
receptor !
It’s
the
liver !
It’s
the
muscle !
It’s
GLUT 4 !
Pharmaceuticals
It’s
glucokinase !
R
KAHN
R
In the light of evidence, there is need for implementation
Pharmaceuticals
Evidence dies when not believed.
R
Pharmacologic Targets in Treating
Type 2 Diabetes Mellitus
Sulfas
Glinides
AGI
Sensitizers
Biguanides
Diones
Pharmaceuticals
Secretagogues
Sulfonylureas: Mechanism of Action
R
Pharmaceuticals
R
Glucose-Mediated Insulin Secretion
From the Beta Cell
GLUT-2
ATP
ADP
K+
CA++
Glucokinase
G-6-P
SIGNALS
Insulin
Secretory
Granules
Pharmaceuticals
Glucose
R
Glucose-Mediated Insulin Secretion
From the Beta Cell
Pharmaceuticals
Glucose
GLUT-2
ATP
ADP
K+
CA++
Glucokinase
G-6-P
SIGNALS
Insulin
Secretory
Granules
Insulin
Sulfonylureas: Efficacy
R
Pharmaceuticals
7
R
Dissociation
8
7
Glucose
6
Translocation
Transport
Insulin
sensitizer
Intracellular
Pool
Glucose
Transporters
5
1
Insulin
Fusion
3
Translocation
IRS1,IRS2,IRS3,IRS4
Binding
4
2 Signal
Plasma
Membrane
Association
Pharmaceuticals
Target Cell
Metformin: Mechanism of Action
R
Pharmaceuticals
Pharmaceuticals
Effect of Metformin on Insulin Resistance: R
HOMA-IR
R
Pharmaceuticals
Effect of Metformin in
Type 2 Diabetes: FPG
R
Pharmaceuticals
Effect of Metformin in
Type 2 Diabetes: HbA1c
Benefits of Metformin
R
Pharmaceuticals
• Decrease insulin resistance
• Decrease fatty acids and lipotoxicity
• Cardiovascular benefits
lowers CVD risk alone or with SU
Improves lipid profile- lower Tg and
LDL
antiatherogenic effect – antifibronolysis
and lowers inflammatory markers
R
Metformin and glibenclamide
Glibenclamide
O
CH3
S
O
N
NH
H C
3
NH
NH - HCl
2
Cl
O
N
O
N
N
H
H
OH
CH 3
NH
Sputnik
Apollo
1957
1968
Rich Efficacy and Safety Database
5 Million Patients Years of Experience Combined
Pharmaceuticals
Metformin
R
Why Combination
Therapy
Rationale
– Insulin resistance
– Insulin deficiency
Monotherapy
Effective but rarely able to restore to
near normal (HbA1c of < 6.5% )
especially if HbA1c is >7% with fasting
hyperglycemia
Pharmaceuticals
2 Defects are present
R
R
9
HbA1C
Median % HbA1C
Diet
Patients at HbA1C < 7.0%
Su
8
Metformin
7
Insulin
3 years
6 years
9 years
Pharmaceuticals
Long-term Efficacy
of Monotherapy
45%
30%
15%
6
0
2
4
6
8
Time from randomisation (years)
10
UKPDS 34, Lancet 1998; 352: 854-865
UKPDS 49. JAMA 1999; 281: 2005-12
R
Dose
Baseline mean
HbA1c (%)
Add’al decrease in
HbA1c (%)
Glibenclamide
20
8.8
1.3
Repaglinide
12
8.3
1.1
Acarbose
600
7.8
0.8
Rosiglitazone
8
8.9
1.2
Pioglitazone
30
9.9
0.8
Drug
Metformin>2000mg +
Rosiglitazone 8mg +
Sulfonylurea
1.4
Pioglitazone 30 mg +
Sulfonylurea
10
1.3
9.0
2.2
8.9
1.0
Insulin +
Metformin
2000
Sulfonylurea
Rosiglitazone
8
9.0
1.3
Pioglitazone
30
9.9
1.0
Lebovitz, HE Endocrinology and Metabolism Clinics 2001
Pharmaceuticals
Effect of Combination Therapy with oral
antihyperglycemic agents on glycemic control in
registration studies
R
Antidiabetic Oral Agent Combination Therapy:
Source
Randomization
Subject,
No.
Study
length
HbA1c
Reduction
Erle et al, 1999
Glyburide+metformin vs
glyburide+placebo
40
6 mo
1.0
UKPDS, 1998
SU+metformin vs
SU alone
591
3y
0.6
DeFronzo, and
Goodman, 1995
Glyburide+metformin vs
glyburide
632
29 wk
1.6
Rosenstock et al,
1998
Metformin+acarbose vs
SU+placebo
148
24 wk
0.7
Fonseca et al,
2000
Metfomin+rosiglitazone vs
metformin+placebo
348
26 wk
1.2
Wolffenbuttel et al,
2000
SU+rosiglitazone vs
SU+placebo
574
26 wk
1.0
Moses et al,
1999
Metformin+repaglinide vs
either drug alone
83
3 mo
1.1 vs met
1.0 vs rep.
JAMA, 2002
Pharmaceuticals
Randomized Controlled Trials
R
Pharmaceuticals
SU-Metformin Combination
Pharmaceuticals
• Uses two of the most widely used and
experienced medicines
• Targets dual defects effectively
• Cost effective
• Allows smaller effective doses for each
drug at less possible side effect
R
• Fixed Dose Combinations are single-pill agents
that combine therapies with complementary
therapeutic effects.
• Single-pill FDCs provide a convenient
alternative to taking two separate pills
Glibenclamide
Metformin
Pharmaceuticals
Combination Therapy
R
R
Pharmaceuticals
R
Combination Treatment With Metformin and Glibenclamide
Versus Single-Drug Therapies in Type 2 Diabetes Mellitus:
A Randomized, Double-Blind, Comparative Study
Tosi F et al.
Metabolism, Vol 52, No. 7, July 2003
Patients and Methods
– FPG >140mg%
– HbA1c >= 6.3%
• Dose titration: intervals of min. 20 days
glibenclamide 5mg
metformin 500mg
glibenclamide+metformin 2.5mg/400mg
• Treated to achieve target
FPG < 140mg%
HbA1c <= 6.0%
• 4 week run-in period
1st phase: 6 months
Crossover
2nd phase: 6 months
Pharmaceuticals
• Subjects: 88 Type 2DM
R
Study Design
R
Pharmaceuticals
R
Pharmaceuticals
R
Pharmaceuticals
Comparison of HbA1c and fasting plasma
glucose levels in patients treated with
metformin and metformin/glibenclamide
R
Pharmaceuticals
Comparison of HbA1c and fasting plasma
glucose levels in patients treated with
glibenclamide and glibenclamide/metformin
Comparison of percentages of success
(FPG < 140 mg/dL,HbA1c < 6%) with
monotherapy or combination in each treatment group
R
Plasma glucose on
monotheraphy
50
Plasma glucose on
combination
Hb1Ac on
monotheraphy
40
Hb1Ac on
combination
30
20
10
0
Metformin/ Combination
Glibenclamide/ Combination
Pharmaceuticals
% 60
R
Results
HbA1c(%)
Combination
147+/-32
6.5%+/-0.7%
Glibenclamide
188+/-49
7.6%+/-1.5%
Combination
139+/-35
6.1%+/-1.1%
Metformin
174+/-42
7.3%+/-1.4%
p < 0.0001 metformin vs combination
p <0.0001 metformin vs combination
Pharmaceuticals
FPG(mg%)
R
Efficacy of treatment
% reaching
HbA1c <=6%
Metformin
17.5%
9.8%
Combination
46.3%
51.2%
Glibenclamide
17.5%
17%
Combination
51.2%
24.4%
p <0.01 metformin vs combination
p<0.001 glibenclamide vs combination
Pharmaceuticals
% reaching
FPG <140mg%
Pancreatic B cell Function
B cell function
Metformin
39.9+/-23.1
Combination
69.5+/-64.9
Glibenclamide
52.3+/-45.6
Combination
70.5+/-63.8
p=0.004 metformin vs combination
p=0.042 glibenclamide vs combination
Pharmaceuticals
( estimated by HOMA method )
R
Conclusions
R
Pharmaceuticals
• 40% of patients treated with combination
of glibenclamide/metformin ( 2.5/400mg )
achieved good glycemic control
( HbA1c<=6%) compared with only 10%
to 17% of those treated with metformin or
glibenclamide alone.
Conclusions
R
– Less 40% for metformin
– Less 31% for glibenclamide
Pharmaceuticals
• Mean absolute decline of HbA1c was 2%
in combination versus 0.5% with each
single drug.
• Mean daily dose of each drug was lower
during the combined treatment than
monotherapy
R
Co-administered versus
Fixed dose
• Retrospective cohort study
• 72 patients
followed up after > 90 days from switch to fixed dose
• Mean reduction of HbA1c was 0.6%(p=0.002)
• Improvement was predominantly seen in HbA1c >=8%
baseline which eventually resulted in mean 1.3%
reduction of HbA1c
R
Pharmaceuticals
Improvements in glycemic control in Type 2 DM patients switched
from sulfonylurea coadministered with metformin to glyburidemetformin tablets
Duckworth W et al, J Manag Care Pharm 2003
R
• Objective: to examine adherence among Type 2 DM patients who
are receiving monotherapy ( metformin or glyburide), combination
( metformin and glyburide), and fixed dose combination
(metfotmin/glyburide)
• Results:
– Previous monotherapy who required combination vs previous
monotherapy shifted to fixed dose
• Adherence 54%, 95%CI, 0.52-0.55 vs 77%, 95%CI, 0.720.82
– Patients previously on combination then shifted to fixed dose
combination
• Significant improvement in adherence 71% vs 87% p < 0.001
Pharmaceuticals
Adherence to Oral Antidiabetic Therapy in a Managed Care
Organization: A Comparison of Monotherapy, Combination
Therapy, and Fixed-Dose Combination Therapy
Melikian C et al Clinical Therapeutics, vol,24, no.3, 2002
Adherence Rate (%)
100.0
77.0
80.0
60.0
54.0
40.0
20.0
0.0
Metformin and Glyburide
p < 0.001
Glyburide/ Metformin
R
Pharmaceuticals
Comparison of adjusted rates in patients receiving metformin and
Glyburide combination therapy and those receiving fixed-dose
Glyburide/metformin combination therapy
Adherence Rate (%)
100.0
80.0
87.0
71.0
60.0
40.0
20.0
0.0
Before Metformin and
Glyburide
p < 0.001
After Glyburide/ Metformin
R
Pharmaceuticals
Comparison of adjusted adherence rates before and after switch
from metformin and glyburide combination therapy to fixed-dose
glyburide/metformin combination therapy
Glyburide/Metformin Tablets: Indications
R
Pharmaceuticals
R
Glyburide/Metformin Tablets as Initial Therapy*
Pharmaceuticals
R
Glyburide/Metformin Tablets as Initial Therapy*
Pharmaceuticals
R
Pharmaceuticals
Glyburide/Metformin Tablets as SecondLine Therapy*
Effectiveness of Diabetes Therapy
R
Pharmaceuticals
Starting HbA1c
Diet &
Exercise
Metformin
1.5-2%
Insulin
Secretagogues
<7.5%
1%
TZD
Alpha-glucosidase 1-1.5%
Inhibitors
Combination
3-4%
Oral
Agents
Insulin 5% or more
<8.5%
<8.6-10.5%
>10.5%
How about issue of CV risk
R
• Ganji Diabetes Care 30 Feb 2007
• Conclusion: Glyburide was not associated
with increase risk of CV evnets, death or
weight gain
Pharmaceuticals
• A systemic review and metanalysis of
hypoglycemia and Cardiovascular events:
Do SUs produce B cell exhaustion?
R
Pharmaceuticals
• Progressive decline of B cell independent
of treatment
• Decline due to several factors glucosetoxicity, cytokines, stress,
mitochondrial dysfunction, genetic
predisposition, predetermined cell mass
• No in vivo evidence that it causes cell
exhaustion
R
Pharmaceuticals
Conclusions
R
Pharmaceuticals
• Metformin- Glibenclamide combination is a
good choice as initial and second line
therapy in diabetes mellitus type 2
• Choice should be individualized
R
R
AMERICAN DIABETES ASSOCIATION
DIABETES CARE, VOLUME 31, SUPPLEMENT 1, JANUARY 2008
Pharmaceuticals
STANDARDS OF MEDICAL
CARE IN DIABETES - 2008
- only 37% of adults achieved an A1C of <7%
- only 36% had a blood pressure <130/80 mmHg
Pharmaceuticals
BACKGROUND:
The implementation of the standards of care for diabetes
has been SUBOPTIMAL in most clinical settings.
R
- only 48% had a total cholesterol <200 mg/dl.
- only 7.3% of people with diabetes achieved all three
treatment goals
Shojania et. al. Effects of quality
improvement strategies for type 2
diabetes
on glycemic control: a meta-regression
STANDARDS OF MEDICAL CARE IN DIABETES - 2008
R
Pharmaceuticals
INTRODUCTION:
For clinicians, patients, researchers, payors, and other interested individuals
Components include diabetes care, treatment goals, and tools to evaluate
the quality of care.
Indicated are the desired targets for most patients with diabetes.
May need a more extensive evaluation and management by other
specialists.
A graded level of evidence after each recommendation using the letters A, B,
C, or E.
Diabetes Care, Jan 2008
R
CLINICAL CLASSIFICATION OF DIABETES
● Type 2 diabetes (results from a progressive insulin secretory defect on
the
background of insulin resistance)
Pharmaceuticals
● Type 1 diabetes (results from -cell destruction, usually leading to
absolute
insulin deficiency)
● Other specific types of diabetes due to other causes, e.g.,
genetic defects in cell function,
genetic defects in insulin action,
diseases of the exocrine pancreas (such as cystic fibrosis), and
drug or chemical-induced (such as in the treatment of AIDS or
after organ transplantation)
● Gestational diabetes mellitus (GDM) (diabetes diagnosed during
pregnancy)
Diabetes Care, Jan 2008
CRITERIA FOR THE DIAGNOSIS OF DIABETES
R
2. Symptoms of hyperglycemia and a casual plasma glucose ≥ 200
mg/dl
(11.1 mmol/l). Casual is defined as any time of day without regard to
time
since last meal. The classic symptoms of hyperglycemia include
polyuria,
polydipsia, and unexplained weight loss.
OR
Pharmaceuticals
1. FPG ≥126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake
for at
least 8 h.*
OR
3. 2-h plasma glucose ≥ 200 mg/dl (11.1 mmol/l) during an OGTT. The
test
should be performed as described by the World Health
Organization,
Diabetes Care, Jan 2008
using a glucose load containing the equivalent of 75 g anhydrous
ADA EVIDENCE-GRADING SYSTEM
R
Pharmaceuticals
Level A - Evidence from well-conducted, generalizable, RCTs that are adequately powered,
including:
● a well-conducted multi-center trial
● a meta-analysis that incorporated quality ratings in the analysis
- Compelling non-experimental evidence, i.e., “all or none” rule developed by the
Centre for Evidence-Based Medicine at Oxford
- Evidence from well-conducted RCTs that are adequately powered, including
● a well-conducted trial at one or more institutions
● a meta-analysis that incorporated quality ratings in the analysis
Level B - Evidence from well-conducted cohort studies, including:
● a well-conducted prospective cohort study or registry
● a well-conducted meta-analysis of cohort studies
- Evidence from a well-conducted case-control study
Level C - Evidence from poorly controlled or uncontrolled studies, including:
● RCTs with one or more major or three or more minor methodological flaws
that could invalidate the results
● observational studies with high potential for bias (such as case series with
comparison with historical controls)
● case series or case reports
- Conflicting evidence with the weight of evidence supporting the recommendation
Level E
- Expert consensus or clinical experience
Diabetes Care, Jan 2008
R
Pharmaceuticals
CRITERIA FOR TESTING FOR PRE-DIABETES AND DIABETES IN
ASYMPTOMATIC ADULT INDIVIDUALS
1. Testing should be considered in all adults who are overweight (≥ BMI 25
kg/m2*)
and have additional risk factors:
● physical inactivity
● first-degree relative with diabetes
● members of a high-risk ethnic population (e.g., African American,
Latino,
Native American, Asian American, and Pacific Islander)
● women who delivered a baby weighing 9 lb or were diagnosed with
GDM
● hypertension ( ≥140/90 mmHg or on therapy for hypertension)
● HDL-C level <35 mg/dl (0.90 mmol/l) &/or a TG level >250 mg/dl (2.82
mmol/l)
● women with polycystic ovarian syndrome (PCOS)
● IGT or IFG on previous testing
● other clinical conditions associated with insulin resistance (e.g., severe
obesity
and acanthosis nigricans)
● history of CVD
Diabetes Care, Jan 2008
2. In the absence of the above criteria, testing for pre-diabetes and
SUMMARY OF GLYCEMIC RECOMMENDATIONS FOR
ADULTS WITH DIABETES
< 7.0%*
70–130 mg/dl
(3.9–7.2 mmol/l)
< 180 mg/dl
Pharmaceuticals
A1C
Preprandial capillary plasma glucose
R
Peak postprandial capillary plasma glucose†
(10.0 mmol/l)
Key concepts in setting glycemic goals:
● A1C is the primary target for glycemic control
● Goals should be individualized based on:
● duration of diabetes
● pregnancy status
● age
● co-morbid conditions
● hypoglycemia unawareness
● individual patient considerations
● More stringent glycemic goals (i.e., a normal A1C, <6%) may further
reduce
complications at the cost of increased risk of
hypoglycemia
● Postprandial glucose may be targeted if A1C goals are not met
despite reaching preprandial glucose goals
Diabetes Care, Jan 2008
TESTING FOR PRE-DIABETES AND DIABETES
R
Pharmaceuticals
● Testing to detect pre-diabetes and type 2 diabetes in asymptomatic
people
should be considered in adults who are overweight or obese (BMI ≥25
kg/m2)
and who have one more additional risk factors for diabetes. In those
without these risk factors, testing should begin at age 45. (B)
● If tests are normal, repeat testing should be carried out at least at 3-year
intervals.(E)
● To test for pre-diabetes or diabetes, either an FPG test or 2-h oral
glucose tolerance test (OGTT; 75-g glucose load), or both, is appropriate.
(B)
● An OGTT may be considered in patients with impaired fasting glucose
(IFG) to better define the risk of diabetes. (E)
● In those identified with pre-diabetes, identify and, if appropriate, treat
Diabetes Care, Jan 2008
other
TESTING FOR TYPE 2 DIABETES IN CHILDREN
R
● Family history of type 2 diabetes in first- or second-degree
relative
● Race/ethnicity (Native American, African American, Latino, Asian
American, Pacific Islander)
Pharmaceuticals
Test children who are overweight (BMI >85th percentile for age and sex,
weight for height >85th percentile, or weight >120% of ideal for height) and
have two of the following risk factors:
● Signs of insulin resistance or conditions associated with insulin
resistance (acanthosis nigricans, hypertension,
dyslipidemia, or
polycystic ovary syndrome [PCOS])
● Maternal history of diabetes or gestational diabetes mellitus
(GDM) (E)
● Testing should begin at age 10 years or at onset of puberty, if
Diabetes Care, Jan 2008
puberty
occurs at a younger age, and
be repeated
SELF-MONITORING OF BLOOD GLUCOSE (SMBG)
R
● For patients using less frequent insulin injections, non-insulin therapies,
or
medical nutrition therapy (MNT) alone, SMBG may be useful in
achieving
glycemic goals. (E)
Pharmaceuticals
● SMBG should be carried out three or more times daily for patients using
multiple
insulin injections or insulin pump therapy. (A)
● To achieve postprandial glucose targets, postprandial SMBG may be
appropriate. (E)
● When prescribing SMBG, ensure that patients receive initial instruction
in, and routine follow-up evaluation of, SMBG technique and their ability to
use
data to adjust therapy. (E)
Care, Jan 2008
● Continuous glucose monitoring may be a supplemental toolDiabetes
to SMBG
for
R
A1C
● Perform the A1C test quarterly in patients whose therapy has changed
or
who are not meeting glycemic goals. (E)
Pharmaceuticals
● Perform the A1C test at least two times a year in patients who are
meeting
treatment goals (and who have stable glycemic control).
(E)
● Use of point-of-care testing for A1C allows for timely decisions on
therapy
changes, when needed. (E)
Diabetes Care, Jan 2008
GLYCEMIC GOALS
R
Pharmaceuticals
● Lowering A1C to an average of ~7% has clearly been shown to reduce
microvascular and neuropathic complications of diabetes and,
possibly,
macrovascular disease.
Therefore, the A1C goal for non-pregnant adults in general is <7%.
(A)
● Epidemiologic studies have suggested an incremental (albeit, in absolute
terms, a small) benefit to lowering A1C from 7% into the normal range.
Therefore, the A1C goal for selected individual patients is as close
to
normal (<6%) as possible without significant hypoglycemia. (B)
● Less stringent A1C goals may be appropriate for patients with a history
of severe
hypoglycemia, patients with limited life expectancies, children,
individuals
with co-morbid conditions, and those with longstanding diabetes
and
minimal or stable microvascular complications. (E)
Diabetes Care, Jan 2008
R
MEDICAL NUTRITION THERAPY (MNT)
● Individuals who have pre-diabetes or diabetes should receive
individualized
MNT as needed to achieve treatment goals, preferably provided
by a
registered dietitian familiar with the components of diabetes MNT.
(B)
Pharmaceuticals
GENERAL RECOMMENDATIONS:
● MNT should be covered by insurance and other payors. (E)
Diabetes Care, Jan 2008
MEDICAL NUTRITION THERAPY (MNT)
R
● In overweight and obese insulin resistant individuals, modest weight
loss has
been shown to reduce insulin resistance. Thus, weight
loss is recommended for all overweight or obese individuals who have
or are at risk for diabetes. (A)
Pharmaceuticals
ENERGY BALANCE, OVERWEIGHT, AND OBESITY
● For weight loss, either low-carbohydrate or low-fat calorie-restricted
diets
may be effective in the short term (up to 1 year). (A)
● For patients on low-carbohydrate diets, monitor lipid profiles, renal
function
and protein intake (in those with nephropathy), and adjust
hypoglycemic
therapy as needed. (E)
● Physical activity and behavior modification are important components
Diabetes Care, Jan 2008
of weight
MEDICAL NUTRITION THERAPY (MNT)
R
● Sugar alcohols and nonnutritive sweeteners are safe when consumed
within
the acceptable daily intake levels established by the FDA. (A)
● If adults with diabetes choose to use alcohol, daily intake should be
limited to a
moderate amount (one drink per day or less for adult women and
two
drinks per day or less for adult men). (E)
Pharmaceuticals
OTHER NUTRITION RECOMMENDATIONS
● Routine supplementation with anti-oxidants,such as vitamins E and C
and
carotene, is not advised because of lack of evidence of efficacy
and
concern related to long-term safety. (A)
● Benefit from chromium supplementation in people with diabetes or
obesity
Diabetes
Care, Jan 2008
has not been conclusively demonstrated and, therefore,
cannot
be
R
PHYSICAL ACTIVITY
● In the absence of contraindications, people with type 2 diabetes
should be
encouraged to perform resistance training three times per
week. (A)
Pharmaceuticals
● People with diabetes should be advised to perform at least 150
min/week of
moderate-intensity aerobic physical activity (50–70% of
maximum
heart rate). (A)
Diabetes Care, Jan 2008
IMMUNIZATION
R
● Provide at least one lifetime pneumococcal vaccine for adults with
diabetes.
A one-time revaccination is recommended for individuals ≥65 years
of
age previously immunized when they were <65 years of age if the
vaccine
was administered >5 years ago. Other indications for repeat
vaccination
include nephrotic syndrome, chronic renal disease, and
other immunocompromised states, such as after transplantation. (C)
Pharmaceuticals
● Annually provide an influenza vaccine to all diabetic patients ≥6 months
of age. (C)
Diabetes Care, Jan 2008
HYPERTENSION / BLOOD PRESSURE CONTROL
R
● Blood pressure should be measured at every routine diabetes visit.
Patients
found to have SBP of ≥130 mmHg or DBP ≥80 of mmHg
should have BP
confirmed on a separate day. Repeat SBP of
≥130mmHg or DBP of ≥80mmHg confirms a diagnosis of HPN. (C)
GOALS
Pharmaceuticals
SCREENING AND DIAGNOSIS
● Patients with diabetes should be treated to a SBP <130 mmHg. (C)
● Patients with diabetes should be treated to a DBP <80 mmHg. (B)
Diabetes Care, Jan 2008
HYPERTENSION / BLOOD PRESSURE CONTROL
Pharmaceuticals
TREATMENT
R
● Patients with a SBP of 130–139 mmHg or a DBP of 80–89mmHg may be
given
lifestyle therapy alone for a maximum of 3 months. If targets are not
achieved, add pharmacological agents. (E)
● Patients with more severe hypertension (SBP ≥140 or ≥DBP 90 mmHg) at
diagnosis
or follow-up should receive pharmacologic therapy in addition to
lifestyle
therapy. (A)
● For patients with DM & HPN start with either an ACEI or an ARB. If one
class is
not tolerated, the other should be substituted. If needed to
achieve BP, a thiazide diuretic should be added to those with an estimated
GFR of ≥ 50
ml/min per 1.73 m2 and a loop diuretic for those with an estimated
GFR of <50 ml/min per 1.73 m2. (E)
Diabetes Care, Jan 2008
HYPERTENSION / BLOOD PRESSURE CONTROL
R
● Multiple drug therapy (2 or more agents at maximal doses) is generally
required to
achieve BP targets. (B)
Pharmaceuticals
TREATMENT
● If ACEI, ARBs, or diuretics are used, kidney function and serum potassium
levels should be closely monitored. (E)
● In pregnant patients with DM & chronic HPN, BP target goals of 110–129 /
65–79 mmHg are suggested in the interest of long term maternal health
and
minimizing impaired fetal growth. ACEI and ARBs are
contraindicated during pregnancy. (E)
Diabetes Care, Jan 2008
DYSLIPIDEMIA / LIPID MANAGEMENT
R
● In most adult patients, measure fasting lipid profile at least annually.
In adults with low-risk lipid values (LDL-C cholesterol <100 mg/dl, HDLC > 50 mg/dl, and triglycerides < 150 mg/dl), lipid assessments may be
repeated
every 2 years. (E)
Pharmaceuticals
SCREENING
Diabetes Care, Jan 2008
DYSLIPIDEMIA / LIPID MANAGEMENT
R
Pharmaceuticals
TREATMENT RECOMMENDATIONS AND GOALS
● Lifestyle modification focusing on the reduction of saturated fat, trans fat,
and cholesterol intake; weight loss (if indicated); and increased
physical activity should be recommended to improve the lipid profile
in
patients with diabetes. (A)
● Statins should be added to lifestyle therapy, regardless of baseline lipid
levels,
for diabetic patients:
● with overt cardiovascular disease (CVD) (A)
● without CVD who are over the age of 40 and have one or more
other
CVD risk factors. (A)
● For patients at lower risk than those mentioned above (e.g., without overt
CVD and
under the age of 40), statins should be considered in
addition to lifestyle
therapy if LDL-C remains >100 mg/dl or in those with multiple CVD
risk
factors. (E)
Diabetes Care, Jan 2008
DYSLIPIDEMIA / LIPID MANAGEMENT
Pharmaceuticals
TREATMENT RECOMMENDATIONS AND GOALS
R
● In individuals without overt CVD, the primary goal is an LDL-C <100 mg/dl
(2.6 mmol/l). (A)
● In individuals with overt CVD, a lower LDL-C goal of <70 mg/dl (1.8 mmol/l),
using
a high dose of a statin, is an option. (E)
● If drug-treated patients do not reach the above targets on maximal tolerated
statin
therapy, a reduction in LDL-C of ~40% from baseline is an alternative
therapeutic goal. (A)
● Triglycerides levels <150 mg/dl (1.7 mmol/l) and HDL-C levels >40 mg/dl
(1.0
mmol/l) in men and >50 mg/dl (1.3 mmol/l) in women are desirable.
However, LDL-C -targeted statin therapy remains the preferred
strategy.
(C)
Diabetes Care, Jan 2008
ANTI-PLATELET AGENTS
R
Pharmaceuticals
● Use aspirin therapy (75–162 mg/day) as a secondary prevention strategy in
diabetic individuals with a history of CVD. (A)
● Use aspirin therapy (75–162 mg/day) as a primary prevention strategy in
those with
type 1 or type 2 diabetes at increased CV risk, including
those who are 40
years of age or who have additional risk factors
(family history of CVD,
HPN, smoking, dyslipidemia, or albuminuria).
(A)
● Aspirin therapy is not recommended in people under 30 years of age, due
to lack of
evidence of benefit, and is contraindicated in patients under
the age of
21 years because of the associated risk of Reye’s
syndrome. (E)
● Combination therapy using other antiplatelet agents such as clopidrogel in
addition
to aspirin should be used in patients with severe and
progressive CVD. (C)
Diabetes
Care, Jan 2008
● Other antiplatelet agents may be a reasonable alternative for
high-risk
CORONARY HEART DISEASE (CHD)
R
● In asymptomatic patients, evaluate risk factors to stratify patients by 10year risk,
and treat risk factors accordingly. (B)
TREATMENT
Pharmaceuticals
SCREENING
● In patients with known CVD, ACEI, aspirin, and statin therapy (if not
contraindicated) should be used to reduce the risk of CV events.
(A)
● In patients with a prior MI, add -blockers (if not contraindicated) to reduce
mortality. (A)
● In patients >40 years of age with another CV risk factor (HPN, family
history, dyslipidemia, microalbuminuria, cardiac autonomic neuropathy, or
smoking), ACEI, aspirin, and statin therapy (if not contraindicated)
Diabetes
Care, Jan 2008
should be used to reduce the risk of CV events.
(B)
NEPHROPATHY SCREENING AND TREATMENT
Pharmaceuticals
GENERAL RECOMMENDATIONS:
R
● To reduce the risk or slow the progression of nephropathy, optimize glucose
control. (A)
● To reduce the risk or slow the progression of nephropathy, optimize BP
control. (A)
SCREENING:
● Perform an annual test to assess urine albumin excretion in type 1 diabetic
patients
with diabetes duration of ≥ 5 years and in all type 2 diabetic patients,
starting at diagnosis. (E)
● Measure serum creatinine at least annually in all adults with diabetes
regardless
of the degree of urine albumin excretion. The serum
creatinine should
be used to estimate GFR and stage the level
of chronic kidney disease
(CKD), if present. (E)
Diabetes Care, Jan 2008
NEPHROPATHY SCREENING AND TREATMENT
● In the treatment of the non-pregnant patient with micro- or
macroalbuminuria,
either ACEI or ARBs should be used. (A)
Pharmaceuticals
TREATMENT
R
● While there are no adequate head-to-head comparisons of ACEI and ARBs,
there is clinical trial support for each of the following
statements:
● In patients with type 1 diabetes, with HPN and any degree of
albuminuria,
ACEI have been shown to delay the progression of
nephropathy. (A)
ARBs
● In patients with type 2 DM, HPN & microalbuminuria, both ACEI &
have been shown to delay the progression to macroalbuminuria. (A)
● In patients with type 2 DM, HPN, macroalbuminuria, and renal
insufficiency
(serum creatinine >1.5 mg/dl), ARBs have been
to
Diabetesshown
Care, Jan 2008
NEPHROPATHY SCREENING AND TREATMENT
R
Pharmaceuticals
TREATMENT
● Reduction of protein intake to 0.8 –1.0 g · KBW -1 · day-1 in individuals with
diabetes
and the earlier stages of CKD and to 0.8 g · KBW -1 · day -1 in
the later stages of CKD may improve measures of renal function (e.g., urine
albumin excretion
rate and GFR) and is recommended. (B)
● When ACEI, ARBs, or diuretics are used, monitor serum creatinine and
potassium
levels for the development of acute kidney disease and
hyperkalemia. (E)
● Continued monitoring of urine albumin excretion to assess both the
response
to therapy and the progression of disease is recommended. (E)
● Consider referral to a physician experienced in the care of kidney disease
when there is uncertainty about the etiology of kidney disease (active urine
sediment, absence of retinopathy, rapid decline in GFR),
Diabetes Care, Jan 2008
difficult management
RETINOPATHY SCREENING AND TREATMENT
R
● Adults and adolescents with type 1 diabetes should have an initial dilated
and
comprehensive eye examination by an ophthalmologist or
optometrist
within 5 years after the onset of diabetes. (B)
Pharmaceuticals
SCREENING:
● Patients with type 2 diabetes should have an initial dilated and
comprehensive
eye examination by an ophthalmologist or optometrist shortly after the
diagnosis of diabetes. (B)
● Subsequent examinations for type 1 and type 2 diabetic patients should be
repeated annually by an ophthalmologist or optometrist. Less frequent
exams
(every 2–3 years) may be considered following one or more normal
eye
exams. Examinations will be required more frequently if
retinopathy is progressing. (B)
● Women with preexisting diabetes who are planning pregnancy
or who have
Diabetes Care, Jan 2008