Presentation

1. LINH HUYNH
MCPHS UNIVERSITY, PHARMD CANDIDATE
FEB 11, 2016

2. 
Understand The Pathological Pathway Of
Statin-induced Diabetogenic Effects
Evaluate Study Reports On Incidence Of
Diabetes With Statin Use
Discuss The Implications of Statin Use with
The Risk of Developing Diabetes In Clinical
Practice
OBJECTIVES

4. 
EFFECTS OF STATIN ON
GLUCOSE HOMEOSTASIS
Sattar N, Taskinen. Statins are diabetogenic – Myth or reality? Atherosclerosis Supplements. 2012;13:1-10.

5. 
Type 2
Diabetes
Insulin
Secretion
Insulin
Sensitivity
Statins
L-type Ca
channel
blockage
ATP
synthesis
Alteration of
LDL
concentration
Adiponectin GLUT-4

7. 
 17,802 healthy men and women with LDL < 130mg/dL and
high-sensitivity C-reactive protein levels ≥ 2md/L were
assigned to rosuvastatin 20mg QD or placebo (1:1) and were
followed for occurrence of cardiovascular events
 An unexpected finding through physician reports regarding
newly diagnosed cases of diabetes during the follow-up
period:
 Rosuvastatin-treated group: 270 in 8901 individuals (3%)
 Placebo-treated group: 214 in 8901 individuals (2.4%)
 P value: 0.01
JUPITER TRIAL
Ridker P, Danielson E, Fonseca F. Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein. Journal of
Vascular Surgery 2009;49(2):534.

8. 
 A clinical review (meta-analysis) of experimental
studies has shown relevant findings regarding the
association of statin use with diabetes incidence
 Statins, as a class, increase the risk of incident diabetes
 However, individual statin data showed that statins
have a variable effect.
FURTHER ANALYSES
Park ZH, Juska A, Dyakov D, Patel RV. Statin-Associated Incident Diabetes: A Literature Review. The Consultant Pharmacist 2014;29(5):317–334.

9. 
ATORVASTATIN PRAVASTATIN ROSUVASTATIN SIMVASTATIN
SUMMARY OF
FINDINGS
-1 study showed
improvement of insulin
sensitivity1
-2 studies showed some
degree of insulin
resistance2,3
- An analysis of three large
RCT suggested higher
doses of atorvastatin may
increase risk of incident
diabetes in patients with
more than two risk factors4
- Analysis of clinical
trials (meta-analysis)
showed conflicting
results (might be due
to difference in study
population)5
- A RCT suggested that
rosuvastatin may not
increase the risk of
newly diagnosed
diabetes6
- A study in patients
with familial combined
hyperlipidemia found
rosuvastatin did not
significantly change
insulin sensitivity
compared to placebo8
- JUPITER trial showed
increase in physician-
reported diabetes
- 1 study evaluating
blood samples from
subjects taking
atorvastatin and
rosuvastatin showed a
significant increase in
insulin level from
baseline7
- Two studies found
conflicting results9,10
INDIVIDUAL STATINS

10. 
 Evaluation of observational studies indicated a
strong association of atorvastatin and simvastatin
with incidence of diabetes.1,2,3,4,5
 Two meta-analyses strongly implicated rosuvastatin
association with incidence of diabetes.6,7
STATINS AS A CLASS
1. Ma T, Tien L, Fang CL et al. Statins and new-onset diabetes: a retrospective longitudinal cohort study. ClinTher 2012;34:1977-83.
2. Culver AL, Ockene IS, Balasubramanian R et al. Statin use and risk of diabetes mellitus in postmenopausal women in the Women’s Health Initiative. Arch
Intern Med 2012;172:144-52.
3. Zaharan NL, Williams D, Bennett K. Statins and risk of treated incident diabetes in a primary care population. Br J Clin Pharmacol 2013;75: 1118-24.
4. Danaei G, Cantero OF, Rodríguez LAG et al. Statins and risk of diabetes: an analysis of electronic medical records to evaluate possible bias due to differential
survival. Diabetes Care 2013;36:1236-40.
5. Carter AA, Gomes T, Camacho X et al. Risk of incident diabetes among patients treated with statins: population based study. BMJ 2013;346:f2610.
6. Alberton M, Wu P, Druyts E et al. Adverse events associated with individual statin treatments for cardiovascular disease: an indirect comparison meta-
analysis. Q J Med 2012;105:145-57.
7. Naci H, Brugts J, Ades T. Comparative tolerability and harms of individual statins: a study-level network meta-analysis of 246955 participants from 135
randomized controlled trials. Circ Cardiovasc Qual Outcomes 2013;6:390-9

11. 
 A meta-analysis with 5 statin trials (total of 32 752
participants without diabetes at baseline):
 Of 2749 developed diabetes, 1449 were assigned
intensive-dose therapy and 1300 were assigned
moderate-dose therapy
 Of 6684 experienced cardiovascular events, 3134 were
assigned intensive-dose therapy and 3550 were
assigned moderate-dose therapy
 Higher intensity statins were associated with an increased
risk of new-onset diabetes, yet a reduction in CV events
compared to lower intensity statins
DOSE-RELATED
EFFECTS
Preiss D. Risk of Incident Diabetes With Intensive-Dose Compared With Moderate-Dose Statin Therapy. Jama 2011;305(24):2556.

13. 
 An analysis of participants from JUPITER trial to
address the balance of vascular benefits versus diabetes
risk of statin use:
 Of 17,802 subjects, 0.4% were found at randomization to
have FBG ≥ 126mg/dL or clinical diabetes and 0.7% were
missing data on at least one risk factor for DM. 98.9%
(N=17,603) had complete data and were included in the
analysis
 Those with at least one major diabetes risk factor (N=11,508)
were more likely to be female, have lower baseline levels of
HDL, and higher baseline of BP, A1C, glucose, and TG.
 Those with at least one major diabetes risk factor had higher
risk of developing diabetes during trial follow-up
Cardiovascular Protection versus
Diabetes Risk
Ridker P, Pradhan A, Macfadyen J. Cardiovascular Benefits and Diabetes Risks of Statin Therapy in Primary Prevention: An Analysis From the JUPITER Trial.
Journal of Vascular Surgery 2012;56(6):1809.

14. 
Cardiovascular Protection versus
Diabetes Risk (cont.)
Ridker P, Pradhan A, Macfadyen J. Cardiovascular Benefits and Diabetes Risks of Statin Therapy in Primary Prevention: An Analysis From the JUPITER Trial.
Journal of Vascular Surgery 2012;56(6):1809.
CARDIOVASCULAR
BENEFITS
RISK OF DEVELOPING
DIABETES
INTERPRETATION
Participants with at least
one major diabetes risk
factor, random allocation
to rosuvastatin was
associated with:
 39% reduction in primary
endpoints (MI, stroke,
hospitalization for unstable
angina, arterial
revascularization or
cardiovascular death),
P=0.0001
 36% reduction in VTE,
P=0.08
 17% reduction in total
mortality, P=0.15
 28% increase in diabetes,
P=0.01
134 total CV events or deaths
were avoided for every 54
new cases of diabetes
diagnosed
Risks of diabetes associated
with rosuvastatin did not
change substantially as
number of major diabetes
risk factors increased.
Participants with no
major diabetes risk
factor, random allocation
to rosuvastatin was
associated with:
• 52% reduction in primary
endpoint, P=0.0001
• 53% reduction in VTE, P=0.05
• 22% reduction in total
mortality, P=0.08
• No increase in diabetes,
P=0.99
86 total CV events or death
were avoided with no new
cases of diabetes diagnosed
Participants who
developed diabetes
during the JUPITER trial
(N=270 on rosuvastatin,
N=216 on placebo)
• Of 18 primary cardiovascular
enpoints occurred, 8 were on
rosuvastatin and 10 were on
placebo

15. 
 T2DM is a CHD risk equivalent
 Dyslipidemia is a characteristic feature of diabetes
 Person at risk for CVD may be prediabetic
 Risk factors for diabetes and CVD are overlapping
DILEMMA FOR PHYSICIANS

16. 
 Womens’ Health Initiative data demonstrated that
hypercholesterolemic, postmenopausal women without CVD and
with a BMI <25 may be at higher risk for statin-associated incident
diabetes1. The data also showed a trend for greater risk in Asian
women
 Patients with higher BMI (>30), history of HTN, elevated FBG >100
or TG > 150 at baseline are more prone to develop incident
diabetes2,3
 Age of 65 or above was also suggested as a risk factor4,5
 An atorvastatin 80mg dose, in patients with more than two risk
factors at baseline, was associated with higher rates of incident
diabetes6
 Patients with more pronounced dyslipidemia (such as Familial
Combined Hyperlipidemia), are at lower risk of for statin-induced
siabetes7
Patient-specific Consideration

17.  Can Statins Cause Diabetes?
 Careful review of findings from many studies does show that statins may be
associated with risk for developing diabetes
 Should statin-eligible candidates without diabetes be on statins?
 No major diabetes risk factors, benefits of statins seem to outweigh the risk of
developing diabetes
 With at least one major diabetes risk factors, benefits are still more likely than
the risk. However, close monitor (such as signs and symptoms of diabetes, more
frequent screening of blood glucose, A1C, etc). Further studies are necessary for
definite suggestion.
 Patient-specific consideration
 What if they have diabetes? Will statins make it worse?
 No data supports the discontinuation of statins if patients have diabetes
 Statins used in patients with lower risk for CVD is less certain than in patients
with higher risk or with established cardiac disease, thus the risk of statin-
induced diabetes may be important to consider
 However, lifestyle modification and antidiabetic medications are still the keys in
diabetes management
 Patient-specific consideration
CLINICAL JUGDEMENTS

18. 
What Do You Think?

19. 