Transcript Captopril in Patients with Type 1 DM and Nephropathy

What’s New in Type 2
Diabetes? Lots!
C. Wayne Weart, Pharm.D.
South Carolina College of Pharmacy
MUSC Campus
MUSC Department of Family Medicine
January 2012
Faculty Disclosure
• I am on the speakers bureau for Pfizer in the
area of lipids and pain
• I am a consultant for Merck in the area of
outcomes research
Diabetes and Obesity
• - Centers for Disease Control and
Prevention survey on the prevalence of
Type 2 diabetes from 1990 to 1998 in the
US (Diabetes Care 2000; 23: 1278-83).
• -prevalence of diagnosed diabetes increased
by 33% nationally, with a 70% increase in
individuals aged 30 to 39
• -primarily related to the upsurge in obesity
Diabetes Prevention Program: Study Design
• Entry Criteria
–
–
–
–
age 25 years
BMI 24 kg/m2 (22 kg/m2 in Asians)
fasting plasma glucose 95-125 mg/dL
postglucose challenge 140-199 mg/dL
• Intervention
– standard lifestyle recommendations + placebo twice daily
– standard lifestyle recommendations + metformin titrated to
850 mg twice daily
– intensive lifestyle modification (low-calorie/low-fat diet, moderate physical
activity 150 min/wk)
– troglitazone (later withdrawn)
• Outcome
– type 2 diabetes over average follow-up of 2.8 years
®
BMI=body mass index.
DPP Research Group. N Engl J Med. 2002;346:393-403.
© 2002 Thomson Professional Postgraduate Services ®
www.lipidhealth.org
Diabetes Prevention Program
• 3.2%ARR Placebo vs. Metformin NNT 32
• 6.2%ARR Placebo vs. Lifestyle NNT 16
• Recent analysis of DPP data found that the
lifestyle intervention group delayed the
development of Type 2 diabetes by about 11 years
with the metformin group delayed by about 3
years
• Cost per quality adjusted life year $1,100 and
$31,300 respectively
• Annals of Intern Med 2005;142:323-332
Walking and Mortality in US
Adults with DM
Arch Intern Med. 2003;163:1397-1398
• Editorial by Frank Hu from Harvard
• “So far, walking is probably the “best
medicine” for both the prevention and
treatment of diabetes mellitus.”
ADA: Physical Activity/Exercise
Recommendations for Patients With
Type 2 Diabetes
2010 ADA Update
• Revision of the section "Diagnosis of
Diabetes" now includes the use of the A1c
level for diabetes diagnosis, with a cutoff
point of 6.5%.
• The section formerly named "Diagnosis of
Pre-diabetes" is now named "Categories of
Increased Risk for Diabetes." Categories
suggesting an increased risk for future
diabetes now include an A1c range of 5.7% to
6.4%, as well as impaired fasting glucose and
impaired glucose tolerance levels.
Diabetes Care 2010;33 Suppl. 1
ADA and ACE Glycemic Goals
ADA 2012
AACE/ACE
Biochemical Index
Normal
Goal
Target
Fasting/preprandial
plasma glucose
(mg/dL)
<100
70–130
110
Postprandial plasma
glucose (mg/dL)
<140
<180
140
Hemoglobin A1c (%)
<6
<7
6.5
American Diabetes Association. Diabetes Care. 2012;35 Suppl 1
AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. Endocr Pract. 2007;13:(suppl 1)3–68.
Development and Progression of Type 2 Diabetes
(Conceptual Representation)
NGT  Insulin  IGT/ IFG  Type 2 Diabetes
Resistance
Postprandial glucose
Glucose
Fasting glucose
-10
Relative
Activity
-5
0
5
Insulin level
10
15
20
25
30
Insulin resistance —
hepatic and peripheral
Beta-cell function
–10
–5
0
5
10
15
20
Years from Diabetes Diagnosis
25
30
NGT=normal glucose tolerance; IGT=impaired glucose tolerance; IFG=impaired fasting glucose.
Kendall DM, Bergenstal RM. ©2005 International Diabetes Center, Minneapolis, MN. All rights reserved.
Adapted from Ferrannini E. Presentation at 65th ADA in Washington, DC, 2006.
ADA/EASD Consensus Algorithm for the Initiation
and Adjustment of Therapy
Diabetes Care 2009; 32:193–203
a - Sulfonylureas other than glybenclamide (glyburide) or chlorpropamide.
Avoid Use of Glyburide?
In-hospital mortality in patients on sulfonylureas before admission (n = 459) according to the type of sulfonylureas and stratified by
specific subgroups (J Clin Endocrinol Metab, November 2010, 95(11):4993–5002)
AACE/ACE Glycemic Control Algorithm
Consensus Panel
(Endocr Pract. 2009;15: 541-59)
• Management of Patients With A1C Levels of 6.5% to
7.5%
• Monotherapy
• For the patient with an A1C level within the range of
6.5% to 7.5%, it is possible that a single agent might
achieve the A1C goal of 6.5%. In this setting,
metformin, TZDs, DPP-4 inhibitors, and a-glucosidase
inhibitors (AGIs) are recommended. Because of its
safety and efficacy, metformin is the cornerstone of
monotherapy and is usually the most appropriate
initial choice for monotherapy unless there is a
contraindication, such as renal disease, hepatic disease,
gastrointestinal intolerance, or risk of lactic acidosis
AACE/ACE Glycemic Control Algorithm
Consensus Panel
(Endocr Pract. 2009;15: 541-59)
• Dual Therapy
• As a result of its safety and efficacy, metformin should
be the cornerstone of dual therapy for most patients.
When metformin is contraindicated, a TZD may be
used as the foundation for this group of options.
Because metformin or a TZD will serve as an insulin
sensitizer, the second component of the dual therapy is
usually an incretin mimetic, DPP-4 inhibitor, glinide, or
sulfonylurea. These agents are recommended in the
following order: incretin mimetic, DPP-4 inhibitor, or
an insulin secretagogue such as a glinide and
sulfonylurea
AACE/ACE Glycemic Control Algorithm
Consensus Panel
(Endocr Pract. 2009;15: 541-59)
• Insulin Therapy
• The considerations for insulin therapy for patients with a current
A1C of 7.6% to 9.0% are similar to those discussed previously for
patients with an A1C level of 6.5% to 7.5%. When transitioning to
insulin from a regimen involving triple therapy, it is customary to
discontinue one or more of the orally administered agents. Use of
TZDs or of sulfonylureas conjointly with insulin is associated with
a risk of weight gain and fluid retention. In patients at risk, TZDs
may cause or aggravate congestive heart failure, and they increase
the risk of bone fractures in both women and men. Neither GLP-1
agonists nor DPP-4 inhibitors have been approved by the FDA for
use with insulin. Thus, metformin is the only medication with a
relatively clear indication for use in conjunction with insulin in
patients with type 2 diabetes.
AACE/ACE Glycemic Control Algorithm
Consensus Panel
(Endocr Pract. 2009;15: 541-59)
• Not recommended
• Regular human insulin: Humulin R and Novolin R
– Onset of action is too slow and persistence of effect is too
long to mimic a normal prandial physiologic profile; the
result is impaired efficacy and increased risk of delayed
hypoglycemia
• NPH insulin: Humulin N and Novolin N
– Does not provide a sufficiently flat “peakless” basal
insulin; highly variable absorption even within
individuals; increased risk of hypoglycemia compared
with the long-acting insulin analogues glargine or detemir
AACE/ACE Glycemic Control Algorithm
Consensus Panel
(Endocr Pract. 2009;15: 541-59)
• “We believe that this algorithm represents the
treatment preferences of most clinical
endocrinologists, but in the absence of
meaningful comparative data, it is not
necessarily an official AACE position. Because
of the insufficient number or total absence of
RCTs for many combinations of therapies, the
participating clinical experts used their
judgment and experience.”
– GOBSAT? Dr Kelly Jones
UK Prospective Diabetes Study
Glucose Interventional Trial
Dietary
Run-in
Randomisation
1977-1991
Trial end
1997
744
Diet failure
2,729
Intensive
Intensive
FPG >15 mmol/l
with sulfonylurea/insulin
P
5,102
Newly-diagnosed
type 2 diabetes
4209
1,138 (411 overweight)
Conventional
Conventional
with diet
P
149
Diet satisfactory
342 (all overweight)
Intensive
FPG <6 mmol/l
with metformin
Mean age 54 years
(IQR 48–60)
UKPDS 80. N Eng J Med 2008; 359:
Intensive
Any Diabetes Related Endpoint (%)
at 10 years
• Diet + Metformin 28.7%
• Diet + Sulf/Insulin 36.8%
• Diet only 38.9%
– RRR 26.2% with diet + metformin vs. diet
alone
– ARR 10.2%
– NNT 10
Death Related to Diabetes (%)
at 10 years
• Diet + Metformin 8.2%
• Diet + Sulf/Insulin 10.8%
• Diet alone 13.4%
– RRR 38.8% with diet + metformin vs. diet
alone
– ARR 5.2%
– NNT 19
All Cause Mortality (%) at 10 years
• Diet + Metformin 14.6%
• Diet + Sulf/Insulin 20%
• Diet alone 21.7%
– RRR 32.7% with metformin + diet vs. diet
alone
– ARR 7.1%
– NNT 14
Myocardial Infarction (%)
at 10 years
• Diet + Metformin 11.4%
• Diet + Sulf/Insulin 14.6%
• Diet alone 17.8%
– RRR 36% with diet + metformin vs, diet alone
– ARR 6.4%
– NNT 16
Stroke (%) at 10 years
• Diet + Metformin 3.5%
• Diet + Sulf/Insulin 6.3%
• Diet alone 5.6%
– RRR 44.4% with diet + metformin vs, diet +
sulf/insulin
– ARR 2.8%
– NNT 36
Microvascular Disease (%)
at 10 years
•
•
•
•
Diet + Metformin 7.0%
Diet + Sulf/Insulin 7.8%
Diet alone 9.2%
Trend but not significant with diet +
metformin vs. diet alone
Long-term Effects of Metformin on Metabolism
and Microvascular and Macrovascular Disease
in Patients With Type 2 Diabetes Mellitus Treated with
Insulin Arch Intern Med. 2009;169(6):616-625
•390 patients treated with insulin in the
outpatient clinics of 3 hospitals in a
randomized, placebo-controlled trial with a
follow-up period of 4.3 years. Either
metformin hydrochloride, 850 mg, or placebo
(1-3 times daily) was added to insulin therapy.
•The primary end point was an aggregate of
microvascular and macrovascular morbidity
and mortality. The secondary end points were
microvascular and macrovascular morbidity
and mortality independently.
“Hyperinsulinemia the Outcome of its
Metabolic Effects (HOME)”
Long-term Effects of Metformin on Metabolism
and Microvascular and Macrovascular Disease
in Patients With Type 2 Diabetes Mellitus Treated with
Insulin Arch Intern Med. 2009;169(6):616-625
Results:
• Metformin treatment prevented weight gain (mean weight gain, −3.07 kg
[range, −3.85 to −2.28 kg]; P.001),
• Improved glycemic control (mean reduction in HbA1c level, 0.4%
percentage point [95% CI, 0.55-0.25]; P.001), despite the aim of similar
glycemic control in both groups,
• Reduced insulin requirements (mean reduction, 19.63 IU/d [95% CI,
24.91-14.36 IU/d]; P.001).
• Metformin was not associated with an improvement in the primary end
point.
• It was, however, associated with an improvement in the secondary,
macrovascular end point (hazard ratio, 0.61 (95% CI, 0.40-0.94; P=.02),
which was partly explained by the difference in weight.
• The number needed to treat to prevent 1 macrovascular end point was
16.1 (95% CI, 9.2-66.6).
• These sustained beneficial effects support the policy to continue
metformin treatment after the introduction of insulin in any patient with
DM2, unless contraindicated.
Metformin Use and Mortality Among Patients
With Diabetes and Atherothrombosis
Arch Intern Med. 2010;170(21):1892-1899
• 19,691 patients having diabetes with
established atherothrombosis participating in
the Reduction of Atherothrombosis for
Continued Health (REACH) Registry between
December 1, 2003, and December 31, 2004,
treated with or without metformin.
• Multivariable adjustment and propensity score
were used to account for baseline differences.
• The main outcome measure was 2-year
mortality
Metformin Use and Mortality Among Patients
With Diabetes and Atherothrombosis
Arch Intern Med. 2010;170(21):1892-1899
• Results: The mortality rates were 6.3% (95%
confidence interval [CI], 5.2%-7.4%) with metformin
and 9.8% (8.4%-11.2%) without metformin; the
adjusted hazard ratio (HR) was 0.76 (95%CI 0.65-0.89;
P.001). ARR 3.5%, NNT=29
• Association with lower mortality was consistent among
subgroups, noticeably in:
– patients with a history of congestive heart failure (HR 0.69;
95%CI, 0.54-0.90; P=.006),
– patients older than 65 years (0.77; 95%CI 0.62-0.95; P=.02),
– patients with an estimated creatinine clearance of 30 to
60mL/min/1.73m2 (0.64; 95%CI, 0.48-0.86; P=.003)
Metformin Use and Mortality Among Patients
With Diabetes and Atherothrombosis
Arch Intern Med. 2010;170(21):1892-1899
• Conclusions: “Metformin use may
decrease mortality among patients with
diabetes when used as a means of secondary
prevention, including subsets of patients in
whom metformin use is not now
recommended.”
Metformin
• Lactic acidosis is a rare but potentially fatal complication
– avoid in patients with renal dysfunction (IE males serum Cr
>1.5mg/dl and females serum Cr >1.4mg/dl)
– Heart failure?
• New data suggest reduced all cause mortality with
metformin vs. sulfonylurea (Diabetes Care 2005;28:2345-51)
– Adjusted HR 0.66 (0.44-0.97) metformin monotherapy @ 1 yr
– Adjusted HR 0.54 (0.42-0.70) combination therapy @ 1 yr
• Metformin may be used in patients with stable CHF if renal
function is normal. It should be avoided in unstable or
hospitalized patients with CHF. (C) ADA Standards Diabetes Care
2009; 32: suppl 1
–
–
–
–
–
Liver disease
Major surgery
Alcohol abuse
Pregnancy
Radio contrast media (hold dose for 48 hrs post test)
Risk of fatal and nonfatal lactic acidosis with
metformin use in type 2 diabetes mellitus
The Cochrane Library 2010, Issue 4
• Main results:
– Pooled data from 347 comparative trials and cohort studies
revealed no cases of fatal or nonfatal lactic acidosis in 70,490
patient years of metformin use or in 55,451 patients-years in
the non-metformin group. Using Poisson statistics the upper
limit for the true incidence of lactic acidosis per 100,000
patient-years was 4.3 cases in the metformin group and 5.4
cases in the non-metformin group.
– There was no difference in lactate levels, either as mean
treatment levels or as a net change from baseline, for
metformin compared to non-metformin therapies.
• Authors’ conclusions:
– “There is no evidence from prospective comparative trials or
from observational cohort studies that metformin is associated
with an increased risk of lactic acidosis, or with increased
levels of lactate, compared to other anti-hyperglycemic
treatments.”
Metformin in patients with type 2 diabetes
mellitus: reconsideration of traditional
contraindications.
• One trial by Rachmani and colleagues
questioned the standard contraindications by
studying 393 patients, all with at least one
contraindication to metformin use, and found
no cases of lactic acidosis over four years of the
trial duration. All of the patients in this trial
had renal insufficiency, with mean plasma
creatinine levels of 1.5 to 2.5 mg/dl (mean level
1.8 mg/dl).
– Eur J Int Med 2002;13:428–433.
Proposed Recommendations for Use of
Metformin Based on e-GFR
Diabetes Care 2011;34:1435
eGFR (ml/min per 1.73m2)
Action
>60
No renal contraindication to metformin
>45
Continue use
Increase monitoring of renal function (every 3–6
months)
<45 and >30
Prescribe metformin with caution
Use lower dose (e.g., 50%, or half-maximal dose)
Closely monitor renal function (every 3-6 months)
Do not start new patients on metformin
<30
Stop metformin
consistent with the National Institute for Health and Clinical Excellence guidelines in the U.K.
and those endorsed by the Canadian Diabetes Association and the Australian Diabetes Society
NOT FDA APPROVED!
Metformin-Induced Vitamin B12 Deficiency:
Can it Lead to Peripheral Neuropathy?
Studies note that vitamin B12 malabsorption may occur in up
to 30% of patients treated long-term with metformin
• Braza and colleagues presented information at the 2009
meeting of the American Diabetes Association of a review
of the prevalence of vitamin B12 deficiency in Hispanic
patients with type 2 diabetes (n=76) taking metformin. The
average duration of metformin therapy was 5 years. The
authors found no correlation between vitamin B12
deficiency and mean corpuscular volume. But peripheral
neuropathy was noted in 7%, 23% and 77% of those who
had normal, low-normal and deficient levels of vitamin
B12 deficiency, respectively.
– Presented at the American Diabetes Association meeting, New Orleans, LA. June
5-9, 2009. [Abstract 569-P].
B12-intrinsic factor complex uptake by the ileal cell surface receptor is known to be
calcium-dependent. and metformin may affect calcium dependent membrane action
resulting the deficiency
Metformin-Induced Vitamin B12 Deficiency:
Can it Lead to Peripheral Neuropathy?
Recommendations
• There are no formal clinical guidelines for the management of
patients with vitamin B12 deficiency associated with metformin
use.
• Management is geared towards identifying patients at high risk for
deficiency
– Risk factors for vitamin B12 deficiency (i.e., vegetarian diet,
chronic alcohol ingestion, prolonged use of a histamine-2receptor antagonists or proton pump inhibitor)
• The product information for Glucophage recommends monitoring
hematologic parameters (hemoglobin, hematocrit, and red blood
cell indices) annually. In addition, in patients at high-risk for
deficiency, routine serum vitamin B12 measurements at 2- to 3year intervals may be useful.
• In patients with vitamin B12 deficiency, treatment with oral
vitamin B12 1000 mcg daily should be initiated
• While neuropathy can be related to hyperglycemia, vitamin B12
deficiency should be ruled out as a cause, especially in those
patients with diabetes who are taking metformin
ACCORD Glucose Arm
Trial design: Type 2 diabetic patients were randomized to intensive therapy (glycated
hemoglobin <6%, n = 5,128) versus standard therapy (glycated hemoglobin 7%-7.9%, n =
5,123). Patients were followed for 3.5 years.
Results
(p = 0.16)
6.9
(p = 0.04)
• All-cause mortality: 5.0% vs. 4.0% (p = 0.04),
respectively
7.2
5.0
%
• CV death, MI, or stroke: 6.9% vs. 7.2% (p =
0.16), respectively
4.0
• CV mortality: 2.6% vs. 1.8% (p = 0.02),
respectively
Conclusions
Cardiovascular death,
MI, or stroke
Intensive
glucose
lowering
All-cause
mortality
Standard
therapy
• Intensive glucose lowering (mean glycated
hemoglobin 6.4%) increased all-cause and CV
mortality among type 2 diabetics
• National Heart, Lung, and Blood Institute
stopped the trial 17 months early
• Other studies testing intensive glycemic
control are ongoing
ACCORD Study Group. N Engl J Med 2008;358:2545-59
Epidemiologic Relationships Between A1C
and All-Cause Mortality During a Median
3.4-Year Follow-up of Glycemic Treatment
in the ACCORD Trial
• A higher average on-treatment A1C was a stronger
predictor of mortality than the A1C for the last interval
of follow-up or the decrease of A1C in the first year.
Higher average A1C was associated with greater risk of
death. The risk of death with the intensive strategy
increased approximately linearly from 6–9% A1C and
appeared to be greater with the intensive than with the
standard strategy only when average A1C was 7%.
• CONCLUSIONS— “These analyses implicate factors
associated with persisting higher A1C levels, rather
than low A1C per se, as likely contributors to the
increased mortality risk associated with the intensive
glycemic treatment strategy in ACCORD.”
– Diabetes Care 33:983–990, 2010
PROactive Trial
Lancet 2005;366:1279-89
• Pioglitazone up to 45mg or placebo added to
standard recommended therapy in 5238
patients with Type 2 DM not at goal on oral
agents except TZDs and +/- insulin and CV
disease
– Primary outcome was a composite of all cause
mortality, non-fatal MI, stroke, ACS,
revascularization
– Secondary outcomes all cause mortality and nonfatal MI
– Followed for an average of 2.8 years
PROactive Trial
Lancet 2005;366:1279-89
• Results:
– Primary composite endpoints
• 23.5% Placebo and 21% Pioglitazone
• HR 0.90 (0.80-1.02) p=0.095 NS
– Secondary endpoints (death, MI, except silent MI
and stroke) Not Pre-specified !!
• 14.4% Placebo and 12.3% Pioglitazone
• HR 0.84 (0.72-0.98) p=0.027
• RRR 16%, ARR 2.1%, NNT 48
– Heart failure (un-adjudicated)
• 8% Placebo and 11% Pioglitazone p<0.0001
• ARI 3%, NNH 34
• Edema was also significantly greater in the pioglitazone
group
MedWatch 2/20/2007
• Glaxo SmithKline (GSK) notified healthcare professionals of the
results of a randomized, double-blind parallel group study
[ADOPT] of 4,360 patients with recently diagnosed type 2 diabetes
mellitus followed for 4-6 years to compare glycemic control with
rosiglitazone relative to metformin and glyburide monotherapies.
– Significantly more female patients who received
rosiglitazone experienced fractures of the upper arm, hand,
or foot, than did female patients who received either
metformin or glyburide.
– At GSK's request, an independent safety committee reviewed
an interim analysis of fractures in another large; ongoing;
controlled clinical trial and preliminary analysis was reported
as being consistent with the observations from ADOPT.
• Takeda/Lilly have also gone back and the same association has
been seen with pioglitazone
• Healthcare professionals should consider the risk of fracture when
initiating or treating female patients with type 2 diabetes mellitus
with rosiglitazone and pioglitazone.
TZD’s and Fractures
• UK-based General Practice Research Database nested
case control analysis assessed the odds ratios (ORs) of
having a fracture associated with the use of
rosiglitazone, pioglitazone, other oral antidiabetic
agents, or insulin
• ORs for users of 8 or more thiazolidinedione
prescriptions (corresponding to approximately 12-18
months of therapy)
rosiglitazone (OR, 2.38; 95% CI,1.39-4.09) and
pioglitazone (OR 2.59; 95% CI, 0.96-7.01) were used
more frequently by case patients with fracture
(predominantly hip and wrist fractures) than by
controls.
– Arch Intern Med. 2008;168(8):820-825
TZD’s and Fractures
ADA Annual Meeting 6/25/2010
• A retrospective analysis conducted by the Scottish
Diabetes Research Network of more than 90% of all
patients with diabetes in Scotland. About 144,000
patients met the study criteria, taking at least 1 oral
antidiabetic agent but not insulin, during the 2000 to
2008 study period.
• Thiazolidinediones also elevate the risk of hip fracture
in women by 1.9 times (P<0.001) and in men by 2.23
times ( P=0.016) for a combined hazard ratio of 1.98
(P<0.0001).
– “We calculate that up to 17% of all hip fractures in the
diabetic population can be attributed to TZDs.”
TZD’s and Macular Edema
• About 170,000 persons with diabetes were identified
using the Diabetes Case Identification Database from
Kaiser Permanente Southern California
• Glitazone users were more likely to develop macular
edema (ME) in 2006 (odds ratio OR, 2.6; 95%
confidence interval , 2.4 to 3.0)
• After excluding patients who did not have the drug
benefit, did not have an eye exam, and had a HgA1c
<7.0, glitazone use was still associated with an
increased risk of developing ME (OR, 1.6; 95% CI, 1.4
to 1.8).
• The authors conclude: “When treating patients with
DME, ophthalmologists should consider the role of the
glitazones.”
– Am J Ophthalmol 2009;147:583–586
TZD’s and Diabetic Macular Edema (DME)
• Using electronic health records from a database comprised of 400
general practices in the United Kingdom, data from 109,295 patients
with type 2 diabetes were analyzed. Selected patients were older than
18 years of age and had been exposed to more than 6 months of TZD
therapy.
• The study was designed to determine the short-term (1 year) and longterm (10 years) risks of developing DME after TZD exposure, and
whether therapy with agents such as aspirin can modulate those risks.
• Results at the 1-year time point suggest a strong association between
TZD use and the incidence of DME. After adjustment for the covariates
of concomitant medications, weight, body mass index, blood pressure,
and lipid levels, the hazard ratio at 1 year was 3.29. Furthermore,
"concurrent use of TZDs and insulin was associated with a further
increase in DME incidence, with a hazard of 8.44.
– American Diabetes Association (ADA) 71st Scientific Sessions: Abstract 0135-OR.
Presented June 26, 2011
TZD’s and Diabetic Macular Edema
• Interestingly, at 10 years, the increased risk of DME is somewhat
lower than the initial risk (hazard ratio, 2.29 for TZD alone and
3.2 for TZD plus insulin).
• "In the 10-year model, HbA1c [glycosylated hemoglobin] appears
to be an important influence in modulating risk, with a reduction
in HbA1c being protective against developing DME." The use of
ACE inhibitors and aspirin also appears to be protective.
• Taken together, the results for the 2 time points indicate that TZD
exposure leads to a 3- to 6-fold increase in risk for DME. "If such
a relationship were to be firmly established, a balance of risk and
benefit needs to be made when prescribing TZDs in patients with
diabetes who are at high risk for DME.“
– American Diabetes Association (ADA) 71st Scientific Sessions: Abstract 0135OR. Presented June 26, 2011
FDA Ongoing Safety Review of Actos (pioglitazone) and
Potential Increased Risk of Bladder Cancer After Two
Years Exposure
• In preclinical carcinogenicity studies of pioglitazone, bladder
tumors were observed in male rats receiving doses of pioglitazone
that produced blood drug levels equivalent to those resulting from
a clinical dose. Additionally, results from two, three-year
controlled clinical studies of Actos (the PROactive study and a
liver safety study) demonstrated a higher percentage of bladder
cancer cases in patients receiving Actos versus comparators. These
findings are currently included in the label.
• To further address the long-term risk of bladder cancer associated
with Actos use the drug manufacturer, Takeda, is conducting a
ten-year, observational cohort study as well as a nested casecontrol study in patients with diabetes who are members of Kaiser
Permanente Northern California (KPNC) health plan.
– A planned five-year interim analysis was performed with data collected from
January 1, 1997 through April 30, 2008. The median duration of therapy
among Actos-treated patients was 2 years (range 0.2-8.5 years). The study
investigators did not observe a statistically significant association between any
Actos exposure and increased bladder cancer risk in the study (Hazard ratio =
1.2, 95% Confidence Interval: 0.9-1.5). However, the risk of bladder cancer
increased with increasing dose and duration of Actos use, reaching statistical
significance after 24 months of exposure.
•
FDA Drug Safety Communication 9-17-2010
Pioglitazone and Bladder
Cancer?
• Update 6-16-2011 The FDA warned that the diabetes drug
Actos, known generically as pioglitazone, increases the
risk of bladder cancer by at least 40% when used for more
than a year or in higher cumulative doses. The agency said
it will require changes in the label of the drug to reflect the
new findings.
• The FDA is not taking any further action against Actos
until it receives further results from an ongoing study of
the drug, but France has already suspended sales and
Germany has warned physicians not to prescribe the drug
to new patients.
DCCT/EDIC: Incidence of
Nonfatal MI, Stroke, or Death
European Assoc for the Study of
Diabetes (EASD) Consensus Report 9-06
• Calls for urgent action to drastically improve the
management of DM, particularly urging the increased
acceptance of insulin
• All patients with Type 2 DM, if they live long enough,
will need insulin
• Recent survey found that the major patient barrier to
achieving optimal blood sugar control was patient
resistance to insulin
• Clinical research shows that one half of patients who
are not at goal on oral medications are delaying at
least 4-6 years to add insulin
Glimepiride Combined with
Morning Insulin Glargine,
Bedtime Neutral Protamine
Hagedorn Insulin, or Bedtime
Insulin Glargine in Patients with
Type 2 Diabetes
Andreas Fritsche, Matthias Axel Schweitzer,
Hans-Ulrich Häring, and the 4001 Study Group
Ann Intern Med. 2003:138:952
Insulin Titration Schedule
• Initial dose calculation: (baseline FBG
[mg/dL] – 50)/10
• Insulin dose individually titrated using predefined
titration regimen with fasting blood glucose (FBG)
target 100 mg/dL (5.6 mmol/L)
–
–
–
–
>100
>120
>140
>160
 2 units
 4 units
 6 units
 8 units
Fritsche A et al, and the 4001 Study Group. Ann Intern Med. 2003:138:952
Mean A1C Levels During Study
9.5
Morning Glargine
Bedtime Glargine
Bedtime NPH
A1C (%)
9.0
8.5
8.3
8.1
8.0
7.8
*
7.5
0
4
8
12
16
20
24
Time (wk)
* Decrease in A1C from baseline for Morning Glargine: P<0.001 vs Bedtime NPH and P=0.008
vs Bedtime Glargine
Fritsche A et al, and the 4001 Study Group. Ann Intern Med. 2003:138:952
Nocturnal and Symptomatic
Hypoglycemia
Nocturnal
Symptomatic
P=0.001
P<0.001
P=0.004
60
60
50
50
38
40
30
20
23
17
10
Patients (%)
Patients (%)
P<0.001
58
56
43
40
30
20
10
0
Morning
Glargine
Bedtime
Glargine
Bedtime
NPH
0
Morning
Glargine
Bedtime
Glargine
Adapted from Fritsche A et al, and the 4001 Study Group. Ann Intern Med. 2003:138:952
Bedtime
NPH
Relative Contribution of FPG and PPG to Overall
Hyperglycemia Depending on A1C Quintiles
Postprandial glucose
Fasting glucose
Contribution, %
100
80
60
40
20
0
<7.3
n=58
7.3–8.4
n=58
8.5–9.2
9.3–10.2
>10.2
n=58
n=58
n=58
A1C
Monnier L et al. Diabetes Care. 2003;26:881–885.
57
When do we need to add prandial
insulin to basal insulin?
Zisman hypothesized that basal insulin therapy should parallel hepatic glucose production,
which would in turn maintain a narrow blood glucose range, specifically at night. Once the
difference in bedtime and morning values increases, this suggests maximum titration of
basal insulin has been reached and prandial doses may be needed to further improve
glycemic control. He termed this the BeAM (difference between Bedtime and AM glucose)
factor. A BeAM factor of 55 mg/dl or greater was established as the point at which patients
may benefit from the addition of prandial insulin to the regimen. (71st ADA Scientific
Sessions, San Diego, CA 6-27-2011)
The Incretin Effect in Subjects Without and
With Type 2 Diabetes
Control Subjects
(n=8)
0.6
Incretin
Effect
80
60
0.4
20
0.1
0
0
0
60
120
180
Time, min
60
0.5
0.4
0.3
40
nmol/L
0.2
nmol / L
0.3
40
0.6
The incretin effect
is diminished
in type 2 diabetes.
0.5
IR Insulin, mU/L
80
IR Insulin, mU/L
Patients With Type 2 Diabetes
(n=14)
0.2
20
0.1
0
0
0
60
120
180
Time, min
Oral glucose load
Intravenous (IV) glucose infusion
Adapted from Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag.
Permission pending.
59
Role of Incretins in Glucose Homeostasis
Ingestion of food
Pancreas2,3
GI tract
Glucose-dependent
 Insulin from beta cells
(GLP-1 and GIP)
Release of gut
hormones —
Incretins1,2
Active
GLP-1 & GIP
Glucose
uptake
by
muscles2,4
Blood
glucose
Beta cells
Alpha cells
DPP-4 Glucose dependent
enzyme  Glucagon from
Glucose
production
by liver
alpha cells
(GLP-1)
Inactive Inactive
GLP-1
GIP
DPP-4 = dipeptidyl-peptidase 4
1. Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913.
2. Ahrén B. Curr Diab Rep. 2003;2:365–372.
3. Drucker DJ. Diabetes Care. 2003;26:2929–2940.
4. Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441.
60
Exenatide - Byetta
• Synthetic injectable GLP-1 that binds to and
activates human GLP-1 receptors
• Increases glucose dependent insulin
synthesis and secretion in beta cells
• Inhibits glucagon secretion from the alpha
cells and thus hepatic glucose production
• Slows gastric motility
• Promotes early satiety and potential weight
loss
Exenatide – Byetta
November 2, 2009 FDA Alert – Renal Failure
• From April 2005 through October 2008, FDA received 78 cases of
altered kidney function (62 cases of acute renal failure and 16
cases of renal insufficiency), in patients using Byetta. Some cases
occurred in patients with pre-existing kidney disease or in patients
with one or more risk factors for developing kidney problems
including severe nausea and vomiting leading to dehydration.
Labeling changes include:
• Information regarding post-market reports of acute renal failure
and insufficiency, highlighting that Byetta should not be used in
patients with severe renal impairment (creatinine clearance <30
ml/min) or end-stage renal disease.
• Recommendations to healthcare professionals that caution should
be applied when initiating or increasing doses of Byetta from 5
mcg to 10 mcg in patients with moderate renal impairment
(creatinine clearance 30 to 50 ml/min).
• Recommendations that healthcare professionals monitor patients
carefully for the development of kidney dysfunction, and evaluate
the continued need for Byetta if kidney dysfunction is suspected
while using the product.
Liraglutide – Victoza by Novo-Nordisk
• A human analog of the glucagonlike peptide-1 (GLP-1) with 97%
amino acid sequence homology
to endogenous human GLP-1.
– T1/2 ~11-15 hrs
– 1.2 mg dose (2 pens/mo)
– $312.07 AWP
– 1.8 mg dose (3 pens/mo)
– $468.11 AWP
– Adjunct to diet and exercise for
Type 2 DM but not first line and no
data in combo with insulin
Liraglutide – Victoza by Novo-Nordisk
Liraglutide is contraindicated in patients with a personal or family
history of medullary thyroid carcinoma (MTC) or in patients with
Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
Risk of Thyroid C-cell Tumors BOX WARNING
• Liraglutide causes dose-dependent and treatment-duration-dependent
thyroid C-cell tumors (adenomas and/or carcinomas) at clinically
relevant exposures in both genders of rats and mice. Malignant thyroid
C-cell carcinomas were detected in rats and mice. A statistically
significant increase in cancer was observed in rats receiving
liraglutide at 8-times clinical exposure compared to controls. It is
unknown whether liraglutide will cause thyroid C-cell tumors,
including medullary thyroid carcinoma (MTC), in humans. It is
unknown whether monitoring with serum calcitonin or thyroid
ultrasound will mitigate human risk of thyroid C-cell tumors. Patients
should be counseled regarding the risk and symptoms of thyroid
tumors (e.g. a mass in the neck, dysphagia, dyspnea or persistent
hoarseness)
• In clinical trials of liraglutide, there were 6 reported cases of
papillary thyroid carcinoma in patients treated with liraglutide
and 1 case in a comparator-treated patient (1.9 vs. 0.6 cases per
1000 patient-years).
Liraglutide – Victoza by Novo-Nordisk
Pancreatitis
• In five clinical trials including more than 3,900 people,
there were seven cases of pancreatitis in patients using
liraglutide and one case in a patient using another
diabetes medicine. This constituted a 4:1 imbalance of
pancreatitis cases, when considering the number of
patient exposures (2.2 vs. 0.6 cases per 1000 patientyears). Five cases were reported as acute pancreatitis and
two cases with were reported as chronic pancreatitis.
• Patients taking liraglutide should be aware of the
symptoms of pancreatitis, such as severe abdominal
pain that may also radiate into the back, possibly with
nausea, and vomiting. If patients experience these
symptoms, they should immediately talk to their healthcare
professional.
June 13, 2011 FDA MedWatch Reminder Victoza
(liraglutide [rDNA origin]) Injection: REMS - Risk of
Thyroid C-cell Tumors, Acute Pancreatitis
Liraglutide with or without oral
antidiabetic drug therapy in type 2 diabetes: an
overview of the LEAD 1–5 studies
Diabetes, Obesity and Metabolism, 11 (Suppl. 3), 2009, 26–34
Liraglutide once a day versus exenatide twice a day for type 2
diabetes: a 26-week randomised, parallel-group,
multinational, open-label trial (LEAD-6)
• Mean baseline HbA1c for the study population was 8.2%.
Liraglutide reduced mean HbA1c significantly more than did
exenatide (–1.12%; estimated treatment difference –0.33;
p<0.0001) and more patients achieved a HbA1c value of less than
7% (54% vs 43%, respectively; odds ratio 2.02; p=0.0015).
Liraglutide reduced mean fasting plasma glucose more than did
exenatide (–24 mg/dl vs –9 mg/dl; estimated treatment difference –
16.5 mg/dl;p<0.0001) but postprandial glucose control was less
effective after breakfast (-20 mg/dl vs – 27.9 mg/dl; p<0.0001) and
dinner (-15 mg/dl vs -23.5 mg/dl; p<0.005).
• Both drugs promoted similar weight losses (liraglutide –3.24 kg vs
exenatide –2.87 kg). Both drugs were well tolerated, but nausea
was less persistent (estimated treatment rate ratio 0.448, p<0.0001)
and minor hypoglycemia less frequent with liraglutide than with
exenatide (1.93 vs 2.60 events per patient per year; rate ratio 0.55;
p=0.0131; 25.5% vs 33.6% had minor hypoglycemia).
Lancet 2009; 374: 39–47
Daily Liraglutide vs. Exenatide
Weekly
• 9-16-2011 from EASD Meeting
• In a "head-to-head study, the mean
reduction in HbA1c for patients on the more
convenient dosing schedule of exenatide
weekly was 1.26%, compared with a 1.48%
reduction with liraglutide (P<0.05)."
However, "patients taking liraglutide
experienced more gastrointestinal adverse
effects than those taking exenatide."
National Institute for Health and
Clinical Excellence (NICE) 10/2010 .
• Liraglutide 1.2 mg daily in dual therapy regimens (in
combination with metformin or a sulphonylurea) is
recommended as an option for the treatment of people with
type 2 diabetes, only if:
– The person is intolerant of either metformin or a sulphonylurea, or
treatment with metformin or a sulphonylurea is contraindicated,
and The person is intolerant of thiazolidinediones and dipeptidyl
peptidase-4 (DPP-4) inhibitors, or treatment with
thiazolidinediones and DPP-4 inhibitors is contraindicated.
– Treatment with liraglutide 1.2 mg daily in a dual therapy regimen
should only be continued if a beneficial metabolic response has
been shown (defined as a reduction of at least 1 percentage point in
HbA1c at 6 months).
• Liraglutide 1.8 mg daily is not recommended for the
treatment of people with type 2 diabetes.
Sitagliptin - Januvia & Saxagliptin Onglyza Indications and Usage
• Monotherapy
– Adjunct to diet and exercise to improve glycemic control in patients
with type 2 diabetes mellitus
• Combination therapy
– To improve glycemic control in combination with metformin or a
PPAR (peroxisome proliferator-activated receptor gamma) agonist
(eg, thiazolidinediones) when the single agent alone with diet and
exercise does not provide adequate glycemic control
– When used in combination with a sulfonylurea, a lower dose of
sulfonylurea may be required to reduce the risk of hypoglycemia
• Important limitations of use
– Should not be used in patients with type 1 diabetes or for the
treatment of diabetic ketoacidosis
Sitagliptin and Insulin Now FDA
Approved
• Add-on Combination Therapy with Insulin (with or
without Metformin)
– Sitagliptin provided significant improvements in A1C (-0.6%),
FPG (-15 mg/dl), and 2-hour PPG (-36 mg/dl) compared to
placebo. Both treatment groups had an adjusted mean increase
in body weight of 0.1 kg from baseline to Week 24.
– There was an increased rate of hypoglycemia in patients
treated with sitagliptin. (15.5% vs 7.8%)
• Sitagliptin was associated with an incremental costeffectiveness ratio of $169,572 per QALY saved
– Diabetes Care 33:695–700, 2010
Dosage and Administration
Saxagliptin - Onglyza
• Usual dose for Onglyza as monotherapy or in
combination with metformin or a TZD is 2.5 or 5 mg
once a day without regard to meals (a fixed dose combo
with QD metformin has been submitted to the FDA)
• The recommended dose for patients with moderate to
severe renal disease (IE CrCl<50 ml/min) is 2.5 mg
once daily
• Patients taking significant CYP 3A4 inhibitors
(ketoconazole, itraconazole, protease inhibitors,
clarithromycin, etc) should receive no more than 2.5
mg per day
• Saxagliptin 5-10 mg has produced a dose related
reduction in lymphocytes of about 100-120 cells/microl
but no clinically relevant adverse reactions have been
seen to date
Linagliptin - Tradjenta
• May 2, 2011 The FDA approved linagliptin
– Tradjenta the newest of the DPP-4
inhibitors by Boehringer Ingelheim and
Lilly for the treatment of Type 2 diabetes
– FDA approved either as monotherapy or in
combination with metformin, glimepiride or
pioglitazone
– Linagliptin is primary eliminated by non-renal
excretion and does not accumulate with mild to
moderate renal dysfunction
Linagliptin - Tradjenta
• Monotherapy - placebo-adjusted change in HbA1c
compared to placebo of - 0.69 % (p<0.0001).
• Metformin - placebo-adjusted change
in HbA1c compared to placebo of - 0.64 %
(p<0.0001).
• Metformin + Glimipiride - placebo-adjusted
change in HbA1c compared to placebo of
- 0.62 %
• Pioglitazone - placebo-adjusted change in a
HbA1c change compared to placebo of
- 0.51 (p<0.0001).
Linagliptin - Tradjenta
ADA Scientific Sessions Late Breaking
Abstract Sunday, June 26, 2011 Abstract
No: 0030-LB
ADA Scientific Sessions Late Breaking Abstract Sunday, June 26, 2011
Abstract No: 0030-LB
Linagliptin - Tradjenta
• One potential advantage of linagliptin over
sitagliptin and saxagliptin is that only a
small amount (less than 7%) is eliminated
by the kidneys.
– No dosage adjustment is needed for patients
with impaired renal or hepatic function
• The recommended dose of linagliptin is 5
mg once daily, without regards to meals.
Pancreatitis, Pancreatic, and Thyroid
Cancer With Glucagon-Like
Peptide-1–Based Therapies
GASTROENTEROLOGY 2011;141:150–156
• US Food and Drug Administration’s database of reported
adverse events for those associated with the dipeptidyl
peptidase4 inhibitor sitagliptin and the glucagon-like
peptide-1 mimetic exenatide, from 2004-2009; data on
adverse events associated with 4 other medications were
compared as controls.(rosiglitazone, nateglinide,
repaglinide and glipizide)
• The primary outcomes measures were rates of reported
pancreatitis, pancreatic and thyroid cancer, and all cancers
associated with sitagliptin or exenatide, compared with
other therapies.
Pancreatitis, Pancreatic, and Thyroid Cancer With GlucagonLike Peptide-1–Based Therapies
GASTROENTEROLOGY 2011;141:150–156
Pancreatitis, Pancreatic, and Thyroid Cancer With
Glucagon-Like Peptide-1–Based Therapies
GASTROENTEROLOGY 2011;141:150–156
• “For now this analysis of the FDA data base
does not establish that pancreatitis,
pancreatic and thyroid cancer are caused by
GLP-1based therapy. It simply raises the
level of concern that they may be and that
the appropriate prospective studies are
required to rule them out.”
ADA Clinical Practice
Recommendations - 2012
• Blood Pressure Treatment/Goals
A goal SBP < 130 mmHg is appropriate
for most patients with diabetes. (C)
Patients with diabetes should be treated
to a DBP < 80 mmHg. (B)
• Pharmacologic therapy for patients with diabetes
and hypertension should be with a regimen that
includes either an ACE inhibitor or an ARB. If
one class is not tolerated, the other should be
substituted.
Diabetes Care 2012;35 Suppl. 1
ADA 2012 Clinical Practice
Recommendations (Diabetes Care 2012;35: S11-S63)
• “Growing evidence suggests that there is an
association between increase in sleep-time blood
pressure and incidence of CVD events. A recent
RCT of 448 participants with type 2 diabetes and
hypertension demonstrated reduced cardiovascular
events and mortality with median follow-up of 5.4
years if at least one antihypertensive medication was
given at bedtime.”
• “Administer one or more antihypertensive
medications at bedtime. (A)”
Influence of Time of Day of Blood Pressure–Lowering Treatment on
Cardiovascular Risk in Hypertensive Patients with Type 2 Diabetes
Diabetes Care 2011; 34:1270-76
• A prospective, randomized, single study center in Spain,
open-label, blinded end point trial on 448 hypertensive
patients with type 2 diabetes, 255 men/193 women, mean
age 62.5 years, randomized to ingest all their prescribed
hypertension medications upon awakening or 1 or more of
them at bedtime.
• Ambulatory blood pressure was measured for 48 hrs at
baseline and again annually or even more frequently
(quarterly) after adjustments in treatment.
• The mean follow-up was 5.4 years.
• This was a subset of the original MAPEC Trial in 2156
hypertensive subjects from Spain (Chronobiology
International 2010; 27(8): 1629–1651)
Influence of Time of Day of Blood Pressure–Lowering Treatment on
Cardiovascular Risk in Hypertensive Patients with Type 2 Diabetes
(Diabetes Care 2011; 34:1270-76)
• Results: patients ingesting one or more
hypertension medications at bedtime showed a
significantly lower cardiovascular risk (adjusted by
age and sex) than subjects ingesting all medications
upon awakening (hazard ratio 0.33 [95% CI 0.21–
0.54]; P , 0.001).
• The difference between groups in the adjusted risk
of major events (cardiovascular death, myocardial
infarction, and stroke) was also statistically
significant (0.25 [0.10–0.61]; P = 0.003).
• There was a significant 12% cardiovascular risk
reduction per each 5 mmHg decrease in asleep
systolic blood pressure during follow-up (P , 0.001).
CV Risk Reduction Even Greater
in Patients With Diabetes
Effects Beyond Baseline Therapy
% Relative Risk Reduction
• Aspirin and other antiplatelets
• Beta-blockers
• Lipid-lowering agents
0
Nonfatal
MI
• Diuretics
• Calcium channel blockers
CV Death
Stroke
All-Cause
Mortality*
-5
-10
-15
-20
-25
16%
20%
P=0.0003
P=0.005
22%
P=0.01
-30
-35
-40
24%
26%
32%
P=0.0002
P=0.004
P=0.0002
33%
P=0.0074
37%
*Secondary end point
P=0.0001
The HOPE Study Investigators. N Engl J Med. 2000;342:145-153.
The HOPE Study Investigators. Lancet. 2000;355:253-259.
HOPE
MICRO-HOPE
ACCOMPLISH
Trial Design: ACCOMPLISH was a randomized, multinational double-blind trial (n=11,508). The aim was to
determine the most effective therapeutic pharmacotherapy for controlling systolic hypertension and preventing
CVD events in high risk patients. Participants were included if they were ≥ 60 Years with 1 risk factor and ≥ 55
years with 2 risk factors. One group received a single pill combination fixed dose of an ACE inhibitor (benzapril)
and a calcium channel blocker (CCB). The other group received a single pill fixed dose combination of an ACE
inhibitor and a diuretic (HCTZ). The primary endpoint was CV morbidity and mortality.
Results
80
80
60
60
40
37.2
37.9
% controlled
% controlled
%
Blood Pressure % control Rates
(SBP/DBP < 140/90 mmHg)
76.2
79.9
40
20
20
Conclusions
0
0
Baseline
HCTZ+ACEI
n=5723
Jamerson et al., Presented at ACC, 2008
• Primary endpoints of composite CV morbidity and
mortality were significantly reduced by 21% in the
CCB/ACEI group RR=1.21[CI 95%, (1.06-1.37)]
• Secondary endpoint of Systolic blood pressure was
reduced significantly over time (42 months) with both
treatments.
•BP control rates (SBP/DBP <140/90mm/Hg)
significantly increased for both groups between
baseline and 36 months (Figure).
36 months
CCB+ACEI
n=5700
• The study demonstrated the effectiveness of a single
pill fixed dose combination therapy of
amlodipine/benzapril compared to HCTZ/benzapril on
CV morbidity and mortlaity.
• Future initial hypertension pharmacotherapy could be
impacted by these findings.
© 2008, American Heart Association. All rights reserved.
ACCOMPLISH Results: ACEI/CCB
vs. ACEI/Diuretic
•
•
•
•
•
•
Men
Women
>/= 65y/o
>/= 70y/o
Diabetes
No Diabetes
RRR 20%
RRR 17%
RRR 19%
RRR 21%
RRR 21%
RRR 18%
NEJM 2008;359:2417-28
ARR 2.5%
ARR 1.6%
ARR 2.3%
ARR 2.8%
ARR 2.2%
ARR 2.1%
NNT 40
NNT 63
NNT 44
NNT 36
NNT 46
NNT 48
ADA Clinical Practice
Recommendations - 2012
Nephropathy – Treatment
• In the treatment of the nonpregnant patient
with micro- or macroalbuminuria, either
ACE inhibitors or ARBs should be used. (A)
• If one class is not tolerated, the other should
be substituted. (E)
Diabetes Care 2012;35 Suppl. 1
Captopril in Patients with Type 1
DM and Nephropathy
(NEJM 1993;329:1456-62)
Outcome
Placebo
Captopril
RRR
ARR
NNT
Death
6.93%
3.86%
44%
3.07%
32
Dialysis/
Transplant
15.34%
9.66%
37%
5.68%
18
Death/Dialysis/ 20.79%
Transplant
9.66%
47%
9.68%
10
Doubling
Serum
Creatinine
12.08%
43%
9.20%
11
21.28%
Angiotensin Receptor Blockers in
Patients with Type 2 DM and
Nephropathy
• RENAAL – losartan 50-100mg vs. placebo for
3.4yrs, 28% reduction in ESRD, 25% reduction
in doubling serum Cr, and no reduction in
death. (NEJM 2001;345:861-9)
• IDNT – irbesartan 300mg vs. amlodipine
10mg vs. placebo for 2.6 yrs, 33% reduction in
doubling serum Cr vs. placebo and 37%
reduction vs. amlodipine (NEJM 2001;345:851-60)
COOPERATE Trial
(Lancet 2003; 361:117-24)
• 263 patients with non-diabetic renal disease from
Japan randomized to losartan 100mg,
trandolapril 3mg or the combination 100mg plus
3mg daily
• Primary endpoint was doubling of serum Cr plus
ESRD at 3 years
• Results 23% of patients on losartan and 23% of
patients on trandolapril vs. 11% of patients on the
combination reached the primary endpoint and
BP control was similar in all groups NNT 9
• Dual Blockade of the RAS in Patients with Type 2
DM? Recent letter Lancet 2008 suggests data is
flawed
• CAUTION AVOID COMBO ACEI +ARB?
ONTARGET: Incidence of primary and
secondary renal outcomes
Outcome
R, n
(%)
T, n
(%)
R + T, T vs R p
n (%) HR
All dialysis,
doubling of
creatinine,
death
All dialysis and
doubling of
creatinine
1150 1147 1233 1.00
(13.4) (13.4) (14.5)
0.968 1.09
0.037
174
189
212
1.09
(2.03) (2.21) (2.49)
0.420 1.24
0.038
R=ramipril
T=telmisartan
Mann JFE et al. Lancet 2008; 372:547-553.
R + T vs R p
HR
ONTARGET Renal Outcomes
• “These findings of ONTARGET support previous
guidelines that propose use of drugs to block the
renin-angiotensin system as part of an
antihypertensive regimen to lower blood pressure
and urinary protein in chronic kidney disease.
These data should not lead to guideline
modifications. However, the admonishment
against use of combination therapy to block the
renin-angiotensin system in people at low risk of
chronic kidney disease is clear. Combined with
previous studies, ONTARGET supports the notion
that use of single agents to block the reninangiotensin system is well tolerated.”
Pantelis A Sarafidis, George L Bakris
– Lancet 2008;372:511-12
Aliskiren (Tekturna) Safety Update
• December 20, 2011 - Novartis announced that following
the seventh interim review of data from the ALTITUDE
study with Tekturna® (aliskiren), a decision to terminate
the trial has been taken on the recommendation of the
independent Data Monitoring Committee (DMC)
overseeing the trial. The trial involved 8606 patients with
type 2 diabetes and renal impairment who are at high risk
of cardiovascular and renal events
• The DMC concluded that patients were unlikely to benefit
from treatment added on top of standard anti-hypertensives
(ACEI or ARB), and identified higher adverse events in
patients receiving Tekturna in addition to standard of care
in the trial. Specifically, in the trial arm in which Tekturna
was added to the standard of care there was an increased
incidence after 18-24 months of non-fatal stroke, renal
complications, hyperkalemia and hypotension in this highrisk study population.
ADA Clinical Practice
Recommendations - 2012
Lipid Management
• Statin therapy should be added to lifestyle therapy, regardless of baseline
lipid levels, for diabetic patients:
– with overt CVD (A)
– without CVD who are over the age of 40 years and have one or more other
CVD risk factors (A)
•
•
•
•
For patients at lower risk than above (e.g. without overt CVD and under
the age of 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. (E)
In individuals without overt CVD, the primary goal is an LDL cholesterol
100 mg/dl (2.6 mmol/l). (A)
In individuals with overt CVD, a lower LDL cholesterol goal of 70 mg/dl
(1.8 mmol/l), using a high dose of a statin, is an option. (B)
If drug-treated patients do not reach the above targets on maximal
tolerated statin therapy, a reduction in LDL cholesterol of 30–40% from
baseline is an alternative therapeutic goal. (A)
Diabetes Care 2012;35 Suppl 1
Heart Protection Trial in
Patients with DM (Lancet 2003;361:2005-16)
• 5963 adults (age 40-80) with DM (90% Type
2) and TC of 135mg% or greater
randomized to simvastatin 40mg/d or
placebo for 5 yrs.
• Patients with LDL of 116mg% or more,
major vascular events 27.9% placebo vs.
23.3% simvastatin. (ARR 4.6%, NNT 22)
• Patients with LDL of less than 116mg%,
major vascular events 20.9% placebo vs,
15.7% simvastatin. (ARR 5.2%, NNT 20)
FDA Safety Update Simvastatin
6-8-2011 FDA Safety Update
• Based upon data from the SEARCH Trial the FDA is
recommending limiting the use of the highest approved
dose of the cholesterol-lowering medication, simvastatin
(80 mg) because of increased risk of muscle damage.
• Simvastatin 80 mg should be used only in patients who
have been taking this dose for 12 months or more without
evidence of muscle injury (myopathy).
• Simvastatin 80 mg should not be started in new
patients, including patients already taking lower doses
of the drug.
FDA Safety Update Simvastatin
• Fifty-two patients (0.9%) in the 80-mg group versus one
patient (0.02%) in the 20-mg group developed myopathy
(defined as unexplained muscle weakness or pain with a
serum CK >10 times the upper limit of normal [ULN]).
This was higher than the labeled risk (based on clinical
trial data) of 0.53%.
• Twenty-two patients (0.4%) in the 80-mg group versus no
patient in the 20-mg group developed rhabdomyolysis
(defined as unexplained muscle weakness or pain with
serum CK >40 times ULN).
• The risks for myopathy and rhabdomyolysis with
simvastatin 80 mg were highest in the first 12 months of
treatment, 5 per 1000 person-years and 2 per 1000 personyears, respectively, and decreased to 1 per 1000 personyears and 0.4 per 1000 person-years after that.
FDA Safety Update Simvastatin
FDA is requiring changes to the simvastatin label to add new
contraindications (should not be used with certain
medications) and dose limitations for using simvastatin with
certain medicines.
• Contraindicated with : Itraconazole, Ketoconazole,
Posaconazole (New), Erythromycin, Clarithromycin,
Telithromycin, HIV/HCV protease inhibitors, Nefazodone,
Gemfibrozil (old 10mg), Cyclosporine (old 10 mg), and
Danazol (old 10mg).
• Maximum 10 mg simvastatin dose with:, Verapamil (old
20mg) and Diltiazem (old 40 mg).
• Maximum 20 mg simvastatin dose with: Amiodarone
(old 10mg), Amlodipine (New) and Ranolazine (New)
CARDS
Lancet 2004,364:685-96
• 2838 patients (age 40-75) from the UK
and Ireland with Type 2 DM and no
history of CVD or PVD
• LDL < 160mg/dl but with a history of
HBP, smoking, retinopathy or
micro/macroalbuminuria randomized to
atorvastatin 10mg or placebo
• Trial stopped early after 3.9 years
CARDS
Lancet 2004,364:685-96
• Primary endpoint 9.0% vs 5.8%
– 37% RRR, 3.2% ARR%, NNT 32
• Acute coronary events 5.5% vs 3.6%
– 36% RRR, 1.9% ARR, NNT 53
• Stroke 2.8% vs 1.5%
– 48% RRR, 1.3% ARR, NNT 77
Benefits were similar regardless of baseline
lipids, age or gender
Henry C. Ginsberg, MD
College of Physicians & Surgeons , Columbia University, New York
For The ACCORD Study Group
N Engl J Med 2010; 362:1563-1574

All participants on open-labeled simvastatin, 20 to 40 mg/day
◦ Simvastatin dose complied with lipid guidelines

Patients randomized to double-blind placebo or fenofibrate, 54 to
160mg/day
◦ Dosing based upon eGFR level

Only blinded ACCORD trial

Observed Follow-up: 4 to 8 years (mean 4.7 years)
◦ N Engl J Med 2010; 362:1563-1574
Primary Outcome By Treatment Group and Baseline Subgroups
N Engl J Med 2010; 362:1563-1574
FDA Drug Safety
CommunicationTrilipix (fenofibric acid)
11/9/2011 Trilipix (fenofibric acid) may not lower a
patient's risk of having a heart attack or stroke.
• RECOMMENDATION: Fenofibrate at a dose
equivalent to 135 mg of Trilipix was not shown to
reduce coronary heart disease morbidity and
mortality in patients in two large randomized
controlled trials of patients with type 2 diabetes
mellitus (FIELD and ACCORD); healthcare
professionals should consider the benefits and
risks of Trilipix when deciding to prescribe the
drug to patients, and counsel patients about those
benefits and risks.
ADA Clinical Practice
Recommendations - 2012
Antiplatelet Therapy
● Consider aspirin therapy (75–162 mg/ 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 50 years of age or women 60 years of age who have at least
one additional major risk factor (family history of CVD,
hypertension, smoking, dyslipidemia, or albuminuria). (C)
● Aspirin should not be recommended for CVD prevention for adults
with diabetes at low CVD risk (10-year CVD risk <5%, such as in
men 50 years of age and women 60 years of age with no major
additional CVD risk factors), since the potential adverse effects from
bleeding likely offset the potential benefits. (C)
● Use aspirin therapy (75–162 mg/day) as a secondary prevention
strategy in those with diabetes with a history of CVD. (A)
● For patients with CVD and documented aspirin allergy,
clopidogrel (75 mg/day) should be used. (B)
● Combination therapy with ASA (75– 162 mg/day) and clopidogrel
(75 mg/day) is reasonable for up to a year after an acute coronary
syndrome. (B) AVOID using more than 81 mg ASA if on ticagrelor Brilinta
Diabetes Care 2012;35 Suppl. 1
Caution when using Aspirin!
• According to JNC-7 do not recommend
even low dose aspirin (IE 81mg) until
blood pressure is controlled first as the
risk of hemorrhagic stroke is increased.
• Data from the UK MRC Research Group
in 5499 men age 45-69 with CV risk
factors randomized to placebo or 75mg
aspirin/day
Caution when using Aspirin!
• The risk of CV events was reduced by
45% in those with SBP <130mmHg and
only 6% with SBP >145mmHg.
• The risk of stroke was reduced by 59% in
those with SBP <130mmHg but
hemorrhagic stroke increased by 42%
with SBP >145mmHg.
• (BMJ 2000;321:13-17)
STENO Type 2 DM Trial
(Lancet 1999;353:617-22/NEJM 2003;348;383-93)
• 160 patients (mean age 55, 74% men) with
type 2 DM and urinary albumin excretion
rate between 30 and 300mg/24hrs.
• Intensive treatment to control BP, glucose,
& lipids, in addition to diet, exercise, and
aspirin vs. standard care.
• All diabetic outcomes at 4 and 8 years
(death, CV events, nephropathy,
neuropathy and retinopathy).
STENO Type 2 DM Trial
(Lancet 1999;353:617-22/NEJM 2003;348;383-93)
Outcomes
Intensive Standard RRR
NNT
Nephropathy
11%
25%
56%
7
Retinopathy progression
26%
43%
49%
6
Blindness in 1 eye
1%
9%
85%
13
Progression of autonomic
neuropathy
11%
29%
62%
6
Combined death and
macrovascular events
34%
54%
37%
5