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Fixed Combination Therapy in Diabetes Mellitus Type 2 Dr. Josephine Carlos-Raboca M.D.

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Title: Fixed Combination Therapy in Diabetes Mellitus Type 2 Dr. Josephine Carlos-Raboca M.D.


1
Fixed Combination
Therapy in Diabetes Mellitus
Type 2 Dr. Josephine
Carlos-Raboca M.D.
2
  • 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

3
Diabetes Facts
  • 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.

4
333,000,000 people with diabetes 2025 (64
increase)
5
Countries with the highest numbers of estimated
cases of diabetes for 2030
Adapted from Wild SH et al. Diabetes Care 2004
27 256970.
6
Serious complications of type 2 diabetes are
present at diagnosis
Complication 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
23 Stroke/TIA 1
Some patients had more than one complication at
time of diagnosis
Adapted from UKPDS Group. UKPDS 6. Diabetes Res
1990 13 111.
7
Therefore, the ultimate goal of therapy is to
delay and even prevent the development of
complications.
Decreased Quality Of Life
SIGNIFICANT MORBIDITY MORTALITY
8
Diabetes Mellitus
9
Pathogenesis of Type 2 Diabetes b-Cell Failure
Induced by Insulin Resistance
10
A Cartoonists View of the Pathogenesis of NIDDM
KAHN
Its glucokinase !
Its GLUT 2 !
Its the beta cell !
Its the muscle !
NIDDM
Its GLUT 4 !
Its the insulin receptor !
Its the liver !
11
DCCT
Evidence dies when not believed.
In the light of evidence, there is need for
implementation
UKPDS
12
Pharmacologic Targets in Treating Type 2
Diabetes Mellitus
Secretagogues Sulfas Glinides
AGI
Sensitizers
Biguanides
Diones
13
Sulfonylureas Mechanism of Action
14
Glucose-Mediated Insulin Secretion From the Beta
Cell
Glucose
GLUT-2
SIGNALS
Insulin Secretory Granules
K
CA
15
Glucose-Mediated Insulin Secretion From the Beta
Cell
Glucose
GLUT-2
SIGNALS
Insulin Secretory Granules
K
CA
Insulin
16
Sulfonylureas Efficacy
17
Dissociation
7

Target Cell
Translocation
Insulin sensitizer
7
8
Glucose
Transport
6
Glucose Transporters
Fusion
5
Translocation
3
IRS1,IRS2,IRS3,IRS4
Binding
4
Signal
2
Plasma Membrane
Association
1
Insulin
18
Metformin Mechanism of Action
19
Effect of Metformin on Insulin Resistance HOMA-IR
20
Effect of Metformin in Type 2 Diabetes FPG
21
Effect of Metformin in Type 2 Diabetes HbA1c
22
Benefits of Metformin
  • 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

23
Metformin and glibenclamide
Metformin
Glibenclamide
O
O
O
CH3
S
O
N
N
N
H
N
N
H
-

H
C
l
Cl
H
H
2
N
C
H
3
H
O
N
H
N
H
C
H
3
Sputnik
Apollo
1957
1968
Rich Efficacy and Safety Database
5 Million Patients Years of Experience Combined
24
  • Why Combination
  • Therapy

25
Rationale
  • 2 Defects are present
  • Insulin resistance
  • Insulin deficiency

Monotherapy Effective but rarely able to restore
to near normal (HbA1c of lt 6.5 ) especially if
HbA1c is gt7 with fasting hyperglycemia
26
Long-term Efficacy of Monotherapy
9
8
1C
Median HbA
7
6
0
2
4
6
8
10
UKPDS 34, Lancet 1998 352 854-865
Time from randomisation (years)
UKPDS 49. JAMA 1999 281 2005-12
27
Class Target Advantage Drawback
Sulfonylureas (Glibenclamide) Loss of first-phase insulin secretion Generally well-tolerated other than transient mild side effects (e.g., nausea, vomiting, headache). Associated with weight gain hypoglycemia efficacy depends upon presence of functioning pancreatic beta cells.
Biguanides (Metformin) Hepatic glucose overproduction Insulin resistance Reduce HbA1c levels more rapidly than other ADA Unlike sulfonylureas biguanides do not cause hypoglycemia or weight gain. Gastrointestinal irritation (i.e., nausea and diarrhea) occurs in about one-third of patients during the first few weeks of therapy risk of lactic acidosis in some patients.
28
Effect of Combination Therapy with oral
antihyperglycemic agents on glycemic control in
registration studies
Drug Dose Baseline mean HbA1c () Addal decrease in HbA1c ()
Metformingt2000mg
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
Rosiglitazone 8mg
Sulfonylurea 1.4
Pioglitazone 30 mg
Sulfonylurea 10 1.3
Insulin
Metformin 2000 9.0 2.2
Sulfonylurea 8.9 1.0
Rosiglitazone 8 9.0 1.3
Pioglitazone 30 9.9 1.0
Lebovitz, HE Endocrinology and Metabolism Clinics
2001
29
Antidiabetic Oral Agent Combination
TherapyRandomized Controlled Trials
Source Randomization Subject, No. Study length HbA1c Reduction
Erle et al, 1999 Glyburidemetformin vs glyburideplacebo 40 6 mo 1.0
UKPDS, 1998 SUmetformin vs SU alone 591 3 y 0.6
DeFronzo, and Goodman, 1995 Glyburidemetformin vs glyburide 632 29 wk 1.6
Rosenstock et al, 1998 Metforminacarbose vs SUplacebo 148 24 wk 0.7
Fonseca et al, 2000 Metfominrosiglitazone vs metforminplacebo 348 26 wk 1.2
Wolffenbuttel et al, 2000 SUrosiglitazone vs SUplacebo 574 26 wk 1.0
Moses et al, 1999 Metforminrepaglinide vs either drug alone 83 3 mo 1.1 vs met 1.0 vs rep.
JAMA, 2002
30
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31
SU-Metformin Combination
  • 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

32
Combination Therapy
  • 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

33
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34
Combination Treatment With Metformin and
Glibenclamide Versus Single-Drug Therapies in
Type 2 Diabetes MellitusA Randomized,
Double-Blind, Comparative Study
  • Tosi F et al.
  • Metabolism, Vol 52, No. 7, July 2003

35
Patients and Methods
  • Subjects 88 Type 2DM
  • FPG gt140mg
  • HbA1c gt 6.3
  • Dose titration intervals of min. 20 days
  • glibenclamide 5mg
  • metformin 500mg
  • glibenclamidemetformin 2.5mg/400mg
  • Treated to achieve target
  • FPG lt 140mg
  • HbA1c lt 6.0
  • 4 week run-in period
  • 1st phase 6 months
  • 2nd phase 6 months

Crossover
36
Study Design
37
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38
Comparison of HbA1c and fasting plasma glucose
levels in patients treated with metformin and
metformin/glibenclamide
39
Comparison of HbA1c and fasting plasma glucose
levels in patients treated with glibenclamide
and glibenclamide/metformin
40
Comparison of percentages of success (FPG lt 140
mg/dL,HbA1c lt 6) with monotherapy or
combination in each treatment group

Plasma glucose on monotheraphy
Plasma glucose on combination
Hb1Ac on monotheraphy
Hb1Ac on combination
Metformin/ Combination
Glibenclamide/ Combination
41
Results
FPG(mg) 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 lt 0.0001 metformin vs combination p lt0.0001
metformin vs combination
42
Efficacy of treatment
reaching FPG lt140mg reaching HbA1c lt6
Metformin 17.5 9.8
Combination 46.3 51.2
Glibenclamide 17.5 17
Combination 51.2 24.4
p lt0.01 metformin vs combination plt0.001
glibenclamide vs combination
43
Pancreatic B cell Function( estimated by HOMA
method )
B cell function
Metformin 39.9/-23.1
Combination 69.5/-64.9
Glibenclamide 52.3/-45.6
Combination 70.5/-63.8
p0.004 metformin vs combination p0.042
glibenclamide vs combination
44
Conclusions
  • 40 of patients treated with combination of
    glibenclamide/metformin ( 2.5/400mg ) achieved
    good glycemic control
  • ( HbA1clt6) compared with only 10
  • to 17 of those treated with metformin or
    glibenclamide alone.

45
Conclusions
  • 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
  • Less 40 for metformin
  • Less 31 for glibenclamide

46
  • Co-administered versus
  • Fixed dose

47
Improvements in glycemic control in Type 2 DM
patients switched from sulfonylurea
coadministered with metformin to
glyburide-metformin tabletsDuckworth W et al, J
Manag Care Pharm 2003
  • Retrospective cohort study
  • 72 patients
  • followed up after gt 90 days from switch to fixed
    dose
  • Mean reduction of HbA1c was 0.6(p0.002)
  • Improvement was predominantly seen in HbA1c gt8
    baseline which eventually resulted in mean 1.3
    reduction of HbA1c

48
Adherence to Oral Antidiabetic Therapy in a
Managed Care Organization A Comparison of
Monotherapy, Combination Therapy, and Fixed-Dose
Combination TherapyMelikian C et al Clinical
Therapeutics, vol,24, no.3, 2002
  • 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, 95CI, 0.52-0.55 vs 77, 95CI,
    0.72-0.82
  • Patients previously on combination then shifted
    to fixed dose combination
  • Significant improvement in adherence 71 vs 87 p
    lt 0.001

49
Comparison of adjusted rates in patients
receiving metformin and Glyburide combination
therapy and those receiving fixed-dose Glyburide/m
etformin combination therapy
77.0
54.0
Adherence Rate ()
p lt 0.001
50
Comparison of adjusted adherence rates before and
after switch from metformin and glyburide
combination therapy to fixed-dose glyburide/metfor
min combination therapy
87.0
71.0
Adherence Rate ()
p lt 0.001
51
Glyburide/Metformin Tablets Indications
52
Glyburide/Metformin Tablets as Initial Therapy
53
Glyburide/Metformin Tablets as Initial Therapy
54
Glyburide/Metformin Tablets as Second-Line
Therapy
55
Effectiveness of Diabetes Therapy
56
How about issue of CV risk
  • A systemic review and metanalysis of hypoglycemia
    and Cardiovascular events
  • Ganji Diabetes Care 30 Feb 2007
  • Conclusion Glyburide was not associated with
    increase risk of CV evnets, death or weight gain

57
Do SUs produce B cell exhaustion?
  • 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

58
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59
Conclusions
  • Metformin- Glibenclamide combination is a good
    choice as initial and second line therapy in
    diabetes mellitus type 2
  • Choice should be individualized

60
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61
STANDARDS OF MEDICAL CARE IN DIABETES - 2008
AMERICAN DIABETES ASSOCIATION
DIABETES CARE, VOLUME 31, SUPPLEMENT 1, JANUARY
2008
62
  • BACKGROUND
  • The implementation of the standards of care for
    diabetes has been SUBOPTIMAL in most clinical
    settings.
  • - only 37 of adults achieved an A1C of lt7
  • only 36 had a blood pressure lt130/80 mmHg
  • - only 48 had a total cholesterol lt200 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 analysis. JAMA
296427440, 2006
63
STANDARDS OF MEDICAL CARE IN DIABETES - 2008
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
64
CLINICAL CLASSIFICATION OF DIABETES ? Type 1
diabetes (results from -cell destruction, usually
leading to absolute insulin deficiency) ?
Type 2 diabetes (results from a progressive
insulin secretory defect on the background of
insulin resistance) ? 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
65
CRITERIA FOR THE DIAGNOSIS OF DIABETES 1.
FPG 126 mg/dl (7.0 mmol/l). Fasting is defined
as no caloric intake for at least 8
h. OR 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 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, using
a glucose load containing the equivalent of 75 g
anhydrous glucose dissolved in water.
In the absence of unequivocal
hyperglycemia, these criteria should be confirmed
by repeat testing on a different day.
Diabetes Care, Jan 2008
66
ADA EVIDENCE-GRADING SYSTEM 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
67
  • CRITERIA FOR TESTING FOR PRE-DIABETES AND
    DIABETES IN ASYMPTOMATIC ADULT INDIVIDUALS
  • 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 lt35 mg/dl (0.90 mmol/l) /or a TG
    level gt250 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
  • 2. In the absence of the above criteria, testing
    for pre-diabetes and diabetes should begin at age
    45 years
  • 3. If results are normal, testing should be
    repeated at least at 3-year intervals, with
  • consideration of more frequent testing depending
    on initial results and risk status.

Diabetes Care, Jan 2008
68
SUMMARY OF GLYCEMIC RECOMMENDATIONS FOR ADULTS
WITH DIABETES A1C lt 7.0 Preprandial
capillary plasma glucose 70130 mg/dl
(3.97.2 mmol/l) Peak postprandial capillary
plasma glucose lt 180 mg/dl (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, lt6) 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
Referenced to a nondiabetic range of 4.06.0
using a DCCT-based assay. Postprandial
glucose measurements should be made 12 h after
the beginning of the meal, generally peak
levels in patients with diabetes.
Diabetes Care, Jan 2008
69
TESTING FOR PRE-DIABETES AND DIABETES ? 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 other CVD risk factors. (B)
Diabetes Care, Jan 2008
70
TESTING FOR TYPE 2 DIABETES IN CHILDREN Test
children who are overweight (BMI gt85th percentile
for age and sex, weight for height gt85th
percentile, or weight gt120 of ideal for height)
and have two of the following risk factors ?
Family history of type 2 diabetes in first- or
second-degree relative ? Race/ethnicity (Native
American, African American, Latino, Asian
American, Pacific Islander) ? 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 puberty occurs at a younger
age, and be repeated every 2 years. (E) ? The
FPG is the preferred test. (E)
Diabetes Care, Jan 2008
71
SELF-MONITORING OF BLOOD GLUCOSE (SMBG) ? SMBG
should be carried out three or more times daily
for patients using multiple insulin injections
or insulin pump therapy. (A) ? 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) ? 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) ? Continuous glucose
monitoring may be a supplemental tool to SMBG for
selected patients with type 1 diabetes,
especially those with hypoglycemia unawareness.
(E)
Diabetes Care, Jan 2008
72
A1C ? Perform the A1C test at least two times a
year in patients who are meeting treatment goals
(and who have stable glycemic control). (E) ?
Perform the A1C test quarterly in patients whose
therapy has changed or who are not meeting
glycemic goals. (E) ? Use of point-of-care
testing for A1C allows for timely decisions on
therapy changes, when needed. (E)
Diabetes Care, Jan 2008
73
GLYCEMIC GOALS ? 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 lt7. (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 (lt6) 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
74
MEDICAL NUTRITION THERAPY (MNT) GENERAL
RECOMMENDATIONS ? 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) ? MNT should be
covered by insurance and other payors. (E)
Diabetes Care, Jan 2008
75
MEDICAL NUTRITION THERAPY (MNT) ENERGY BALANCE,
OVERWEIGHT, AND OBESITY ? 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) ? 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 of
weight loss programs and are most helpful in
maintenance of weight loss. (B)
Diabetes Care, Jan 2008
76
MEDICAL NUTRITION THERAPY (MNT) OTHER NUTRITION
RECOMMENDATIONS ? 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) ?
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 has not been
conclusively demonstrated and, therefore, cannot
be recommended. (E)
Diabetes Care, Jan 2008
77
PHYSICAL ACTIVITY ? People with diabetes should
be advised to perform at least 150 min/week
of moderate-intensity aerobic physical activity
(5070 of maximum heart rate). (A) ? In the
absence of contraindications, people with type 2
diabetes should be encouraged to perform
resistance training three times per week. (A)
Diabetes Care, Jan 2008
78
IMMUNIZATION ? Annually provide an influenza
vaccine to all diabetic patients 6 months of
age. (C) ? 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 lt65 years of age if the
vaccine was administered gt5 years ago. Other
indications for repeat vaccination include
nephrotic syndrome, chronic renal disease, and
other immunocompromised states, such as after
transplantation. (C)
Diabetes Care, Jan 2008
79
HYPERTENSION / BLOOD PRESSURE CONTROL SCREENING
AND DIAGNOSIS ? 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 ? Patients with diabetes should be
treated to a SBP lt130 mmHg. (C) ? Patients with
diabetes should be treated to a DBP lt80 mmHg. (B)
Diabetes Care, Jan 2008
80
HYPERTENSION / BLOOD PRESSURE CONTROL TREATMENT
? Patients with a SBP of 130139 mmHg or a DBP of
8089mmHg 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
lt50 ml/min per 1.73 m2. (E)
Diabetes Care, Jan 2008
81
HYPERTENSION / BLOOD PRESSURE CONTROL TREATMENT
? Multiple drug therapy (2 or more agents at
maximal doses) is generally required to achieve
BP targets. (B) ? 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 110129 / 6579 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
82
DYSLIPIDEMIA / LIPID MANAGEMENT SCREENING ? In
most adult patients, measure fasting lipid
profile at least annually. In adults with
low-risk lipid values (LDL-C cholesterol lt100
mg/dl, HDL-C gt 50 mg/dl, and triglycerides lt 150
mg/dl), lipid assessments may be repeated every 2
years. (E)
Diabetes Care, Jan 2008
83
DYSLIPIDEMIA / LIPID MANAGEMENT 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 gt100 mg/dl or
in those with multiple CVD risk factors. (E)
Diabetes Care, Jan 2008
84
DYSLIPIDEMIA / LIPID MANAGEMENT TREATMENT
RECOMMENDATIONS AND GOALS ? In individuals
without overt CVD, the primary goal is an LDL-C
lt100 mg/dl (2.6 mmol/l). (A) ? In individuals
with overt CVD, a lower LDL-C goal of lt70 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 lt150 mg/dl (1.7
mmol/l) and HDL-C levels gt40 mg/dl (1.0 mmol/l)
in men and gt50 mg/dl (1.3 mmol/l) in women are
desirable. However, LDL-C -targeted statin
therapy remains the preferred strategy. (C) ?
Combination therapy using statins and other
lipid-lowering agents may be considered to
achieve lipid targets but has not been evaluated
in outcome studies for either CVD outcomes or
safety. (E) ? Statin therapy is contraindicated
in pregnancy. (E)
Diabetes Care, Jan 2008
85
ANTI-PLATELET AGENTS ? Use aspirin therapy
(75162 mg/day) as a secondary prevention
strategy in diabetic individuals with a history
of CVD. (A) ? Use aspirin therapy (75162
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 Reyes
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) ? Other
antiplatelet agents may be a reasonable
alternative for high-risk patients with aspirin
allergy, with bleeding tendency, who are
receiving anticoagulant therapy, with recent GI
bleeding, and with clinically active hepatic
disease who are not candidates for aspirin
therapy. (E)
Diabetes Care, Jan 2008
86
CORONARY HEART DISEASE (CHD) SCREENING ? In
asymptomatic patients, evaluate risk factors to
stratify patients by 10-year risk, and treat
risk factors accordingly. (B) TREATMENT ? 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 gt40 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) should be used to
reduce the risk of CV events. (B) ? In patients
with treated CHF, metformin and thiazolidinedione
(TZD) use are contraindicated. (C)
Diabetes Care, Jan 2008
87
NEPHROPATHY SCREENING AND TREATMENT GENERAL
RECOMMENDATIONS ? 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
88
NEPHROPATHY SCREENING AND TREATMENT TREATMENT ?
In the treatment of the non-pregnant patient with
micro- or macroalbuminuria, either ACEI or ARBs
should be used. (A) ? 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) ? In
patients with type 2 DM, HPN microalbuminuria,
both ACEI ARBs have been shown to delay the
progression to macroalbuminuria. (A) ? In
patients with type 2 DM, HPN, macroalbuminuria,
and renal insufficiency (serum creatinine
gt1.5 mg/dl), ARBs have been shown to delay the
progression of nephropathy. (A) ? If one
class is not tolerated, the other should be
substituted. (E)
Diabetes Care, Jan 2008
89
NEPHROPATHY SCREENING AND TREATMENT 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), difficult management issues, or
advanced kidney disease. (B)
Diabetes Care, Jan 2008
90
RETINOPATHY SCREENING AND TREATMENT SCREENING ?
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) ? 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 23 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 become pregnant should have a
comprehensive eye examination and be counseled on
the risk of development and/or progression of
diabetic retinopathy. Eye examination should
occur in the first trimester with close
follow-up throughout pregnancy and for 1 year
postpartum. (B)
Diabetes Care, Jan 2008
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