Relationship Between Insulin Resistance and Statin Induced Type 2 Diabetes, and Integrative Personal Omics Profiling

NCT02437084 | Completed Phase 4 Results

• 1 other identifier: STANFORD
• Study Type: interventional
• Target: 115
• Locations: 1 country
• Sites: 1

Brief Summary

Background: There is general agreement that statin-treatment of patients to lower plasma cholesterol levels can increase the incidence of type 2 diabetes mellitus (T2D) in some individuals1-5. The physiologic mechanism for the increased risk for T2D from statin treatment is unknown but could result from effects on insulin sensitivity or insulin secretion. This study will evaluate how the medication atorvastatin (trade name Lipitor) works in non-diabetic individuals in regards to its effect on insulin sensitivity and insulin secretion to help further understand the possible cause of the increased occurrence of T2D in people who are at risk for T2D. This research study will also examine what metabolic characteristics and variables (for example insulin resistance, high triglycerides, or both) will identify those people at highest risk of statin-induced T2D. The goals of this study are to:

1. 1.determine the effect of high-intensity atorvastatin (40 mg/day) for \~ 10 weeks on insulin sensitivity and insulin secretion (defined with gold standard methods) (PRIMARY OUTCOMES) as well as other glycemic traits (SECONDARY OUTCOMES);
2. 2.compare a number of cardio-metabolic characteristics (e.g. weight, lipids) before, during, and after administration of atorvastatin;
3. 3.determine if significant deterioration of insulin action and/or secretion following statin treatment will be confined to those with baseline insulin resistance (PRE-SPECIFIED SUBGROUP ANALYSES);
4. 4.perform Personal Omics Profiling (iPOP) 6,7 before and after taking atorvastatin to examine treatment-associated changes in all baseline variables and to analyze not only previously-known drug efficacy but also untargeted drug efficacy (EXPLORATORY ANALYSES).

Conditions

Hyperlipidemia; Insulin Resistance; Type 2 Diabetes

Keywords

statin; diabetes; insulin resistance; insulin secretion

Outcome Measures

Primary Outcomes (2)

• Steady-state Plasma Glucose (SSPG)

  Insulin sensitivity measured by SSPG concentration (mg/dL) during the insulin suppression test.

  baseline, week 9 or 10

• Insulin Secretion Rate Area Under the Curve (ISR-AUC)

  Insulin secretion measured by ISR-AUC (pmol/min x 4 h) during the graded glucose infusion test.

  baseline, week 9 or 10

Secondary Outcomes (4)

• Fasting Plasma Glucose

  10 weeks

• Fasting Plasma Insulin

  10 weeks

• OGTT Glucose AUC

  baseline, week 8

• OGTT Insulin AUC

  baseline, week 8

Study Arms (1)

Individuals without diabetes eligible to receive statin therapy

OTHER

Eligible participants will receive 40 mg of atorvastatin

Drug: Atorvastatin

Interventions

Atorvastatin DRUG

Study subjects will receive atorvastatin 40 mg for 10 weeks.

Also known as: Lipitor

Individuals without diabetes eligible to receive statin therapy

Eligibility Criteria

• Age: 30 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Healthy adults 30 - 70 years old
• BMI: 20 - 37 kg/m2
• Without diabetes as defined by fasting plasma glucose \<126 mg/dL and not taking glucose lowering medications
• Eligible for statin therapy for primary prevention of ASCVD based on LDL-C ≥ 130 mg/dL, \> 5% ASCVD risk over 10 years, or hs-CRP ≥ 2.0 mg/L

You may not qualify if:

• Younger than 30 or older than 70 years
• Persons with any significant co-morbidities, such as diabetes (fasting glucose ≥ 126 mg/dL or use of glucose lowering medications), active coronary artery disease, heart failure, accelerated or malignant hypertension, kidney disease (creatinine ≥ 1.5 mg/dL), liver disease (alanine aminotransferase \> 2 times upper limit of normal), or severe anemia (hematocrit \< 30%).
• Individuals taking any medications for weight loss or known to influence insulin sensitivity.
• Pregnant or lactating
• Women unwilling to use an effective birth control method
• History of statin intolerance

Sponsors & Collaborators

• Stanford University: lead
• Doris Duke Charitable Foundation: collaborator

Study Sites (1)

Stanford University School of Medicine

Stanford, California, 94305, United States

Location

Related Publications (20)

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• Kohli P, Waters DD, Nemr R, Arsenault BJ, Messig M, DeMicco DA, Laskey R, Kastelein JJP. Risk of new-onset diabetes and cardiovascular risk reduction from high-dose statin therapy in pre-diabetics and non-pre-diabetics: an analysis from TNT and IDEAL. J Am Coll Cardiol. 2015 Feb 3;65(4):402-404. doi: 10.1016/j.jacc.2014.10.053. No abstract available.

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• Waters DD, Ho JE, Boekholdt SM, DeMicco DA, Kastelein JJ, Messig M, Breazna A, Pedersen TR. Cardiovascular event reduction versus new-onset diabetes during atorvastatin therapy: effect of baseline risk factors for diabetes. J Am Coll Cardiol. 2013 Jan 15;61(2):148-52. doi: 10.1016/j.jacc.2012.09.042. Epub 2012 Dec 5.

  PMID: 23219296 BACKGROUND

• Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet. 2012 Aug 11;380(9841):565-71. doi: 10.1016/S0140-6736(12)61190-8.

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• Li-Pook-Than J, Snyder M. iPOP goes the world: integrated personalized Omics profiling and the road toward improved health care. Chem Biol. 2013 May 23;20(5):660-6. doi: 10.1016/j.chembiol.2013.05.001.

  PMID: 23706632 BACKGROUND

• Snyder M. iPOP and its role in participatory medicine. Genome Med. 2014 Jan 30;6(1):6. doi: 10.1186/gm512. eCollection 2014.

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• Chen R, Mias GI, Li-Pook-Than J, Jiang L, Lam HY, Chen R, Miriami E, Karczewski KJ, Hariharan M, Dewey FE, Cheng Y, Clark MJ, Im H, Habegger L, Balasubramanian S, O'Huallachain M, Dudley JT, Hillenmeyer S, Haraksingh R, Sharon D, Euskirchen G, Lacroute P, Bettinger K, Boyle AP, Kasowski M, Grubert F, Seki S, Garcia M, Whirl-Carrillo M, Gallardo M, Blasco MA, Greenberg PL, Snyder P, Klein TE, Altman RB, Butte AJ, Ashley EA, Gerstein M, Nadeau KC, Tang H, Snyder M. Personal omics profiling reveals dynamic molecular and medical phenotypes. Cell. 2012 Mar 16;148(6):1293-307. doi: 10.1016/j.cell.2012.02.009.

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• Abbasi F, Lamendola C, Harris CS, Harris V, Tsai MS, Tripathi P, Abbas F, Reaven GM, Reaven PD, Snyder MP, Kim SH, Knowles JW. Statins Are Associated With Increased Insulin Resistance and Secretion. Arterioscler Thromb Vasc Biol. 2021 Nov;41(11):2786-2797. doi: 10.1161/ATVBAHA.121.316159. Epub 2021 Aug 26.

  PMID: 34433298 DERIVED

MeSH Terms

Conditions

Hyperlipidemias; Insulin Resistance; Diabetes Mellitus, Type 2; Diabetes Mellitus

Interventions

Atorvastatin

Condition Hierarchy (Ancestors)

Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Hyperinsulinism; Glucose Metabolism Disorders; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heptanoic Acids; Fatty Acids; Lipids

Limitations and Caveats

Our study was a single-center trial with a single dose of atorvastatin without a placebo control group. The study was also short term and longer trials are needed to assess for potential decreases in insulin secretion or further increases in insulin resistance.

Results Point of Contact

• Title: Dr Joshua W. Knowles, MD, PhD; Assistant Professor, Cardiovascular Medicine
• Organization: Stanford University School of Medicine

knowlej@stanford.edu

650-723-1431

Study Officials

• Josh Knowles, M.D. Ph. D.

  Stanford University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: April 24, 2015
• First Posted: May 7, 2015
• Study Start: May 1, 2015
• Primary Completion: February 1, 2020
• Study Completion: April 1, 2020
• Last Updated: April 6, 2021
• Results First Posted: April 6, 2021

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)