STATIN USE AND DIABETES RISK

LINH HUYNHMCPHS UNIVERSITY, PHARMD CANDIDATE

FEB 11, 2016

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

ETIOLOGY

EFFECTS OF STATIN ON GLUCOSE HOMEOSTASIS

Sattar N, Taskinen. Statins are diabetogenic – Myth or reality? Atherosclerosis Supplements. 2012;13:1-10.

Type 2 Diabet

es

Insulin Secretio

n

Insulin Sensitivit

y

Statins

L-type Ca channel blockage

ATP synthesis

Alteration of LDL

concentration

Adiponectin GLUT-4

STUDY REPORTS

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.

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.

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

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

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.

CLINICAL IMPLICATIONS

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.

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

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

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

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

What Do You Think?