Metformin and the Progression of Abdominal Aortic Aneurysms

Nathan K Itoga1; Kara Rothenberg1; Vivian Ho1; Lauren Aalami1; Matthew W Mell1; Baohui Xu1; Paola Suarez2; Catherin Curtin2; Ronald L Dalman1

1Division of Vascular Surgery

2Division of Plastic Surgery

Outline

• Background• Methods• Results• Discussion

• Questions for group– Discuss methods: mixed linear regression– Discuss limitations of study – how to handle

outliers, differences in regression. – Discuss future work

Abdominal Aortic Aneurysm (AAA)

• 200,000 patients / year in the US• 15th leading cause of death in the US

• Risk factors: age, smoking, family history of AAA• Protective factors: Diabetes

Surveillance for AAA

Ultrasound CT angiogram

• Antibiotics may slight protective effect in retarding the expansion rates of small AAAs.

• “In general, there is surprisingly little high quality evidence on medical treatment for small AAAs, especially in relation to the use of newer beta-blockers, ACE inhibitors, and statins”

Difficulties in evaluating pharmacotherapy

Metformin and AAA

2010

2016

2017

2017

Metformin associated with decrease odds in AAA enlargement over median rate

• 58 patients

• Cohort 1 – 1357 patients -Ultrasound

• Cohort 2 – 287 patients –Repeated CT

• Cohort 3 – 53 patients –detailed repeat CT

VA Metformin Project

• VA database 2003-13– Diagnosis of AAA and Diabetes

– Inclusion criteria• ≥ 2 imaging procedures (Ultrasound, CT, MRI)• > 6 months apart

• Measure rate of change of aneurysm size (mm/year)– Compare patients on metformin vs. without metformin (at

time of AAA diagnosis)– Linear regression of rate of change– Regression of rate of change with other variables

Methods

• VA database 2003-13– Diagnosis of AAA and Diabetes

– Inclusion criteria• ≥ 2 imaging procedures (Ultrasound, CT, MRI)• > 6 months apart

– Evaluate patient co-morbidities, demographics, medications

Diabetic MedicationInsulin - Regular insulin (Humulin R, Novolin R), insulin lispro (Humalog), insulin aspart (Novolog), insulin glulisine (Apidra), prompt insulin zinc (Semilente)Metformin - GlucophageThiazolidinediones - Rosiglitazone (Avandia), pioglitazone (Actos)Sulfonylureas -Tolbutamide (Orinase), acetohexamide (Dymelor), tolazamide (Tolinase), chlorpropamide(Diabinese), glipizide (Glucotrol), glyburide/glibenclamide (Diabeta, Micronase, Glynase), glimepiride (Amaryl), gliclazide (Diamicron)DPP4 inhibitors - Vildagliptin (Galvus), sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta)

Other Cardiovascular MedicationStatins - Simvastatin (Zocor), atorvastatin (Lipitor), pravastatin (Pravachol), ezetimibe (Vytorin)ACE inhibitors - Captopril (Capoten), enalapril (Vasotec), fosinopril, lisinopril (Zestril, Prinivil), ramipril(Altace), moexipril (Univasc), quinapril, trandolapril (Mavik)ARBs - Candesartan (Atacand), irbesartan, losartan (Cozaar), telmisartan (Micardis), valsartan (Diovan), olmesartan (Benicar)Calcium channel blockers - Nifedipine (Adalat, Procardia), felodipine (Plendil), lacidipine (Caldine, Aponil, Lacicard), amlodipine (Norvasc), cilnidipine (Atelec, Ajinomoto), verapamil (Isoptin, Verelan), diltiazem (Cardizem)Beta-blockers - Atenolol (Tenormin), metoprolol (Lopressor, Toprol), propranolol (Inderal, InnoPran), terazosin (Hytrin), carvedilol (Coreg)

Medication list

Methods

• Extract AAA size from radiology text – CPT codes for radiology scans– Infra-renal AAA diameter recorded in cm. – If 2 measurements - largest

• e.g. "4.5 x 4.8 cm AAA"

– If three measurements – largest of first two• e.g. "4.5 x 4.8 x 6.5 cm AAA"

CPT code Radiographic Study74150 CT Abdomen, without contrast74160 CT Abdomen, with contrast74170 CT abdomen, without contrast followed by contrast74174 CT Angiogram of the Abdomen and Pelvis74175 CT Angiogram of the Abdomen74176 CT Abdomen and pelvis, without contrast74177 CT Abdomen and pelvis, with contrast74178 CT abdomen and pelvis, without contrast followed by contrast74181 MRI Abdomen, without contrast74182 MRI Abdomen, with contrast74183 MRI abdomen, without contrast followed by contrast74185 MRA abdomen, without contrast followed by contrast75635 CT Angiogram of the Abdomen with runoff76700 Ultrasound – abdomen complete76705 Ultrasound – abdomen limited76706 Ultrasound – abdominal aorta screen76770 Ultrasound – retroperitoneal complete76775 Ultrasound – retroperitoneal limited93975 Ultrasound – Duplex scan abdomen complete93976 Ultrasound – Duplex scan abdomen limited

Radiology CPT codes

Example of radiology text3.5 cm AP diameter distal abdominal aortic aneurysm

IMPRESSION: DISTAL ABDOMINAL AORTIC ANEURYSM MEASURING 3.3 X 3.1 X 3.1 CM.

Administratively verified.

Impression: Stable infra-renal distal abdominal aortic aneurysm measuring 3.25 by 3.36 cms.

1) Focal fusiform abdominal aortic aneurysm measuring 5.3 cm -- previouslymeasured 5.0 cm (4/24/06).

2) Bilateral renal parenchymal thinning consistent with atrophy -- stable.

3) Two left renal cysts -- largest measuring 1.0 cm.

1. Essentially normal kidneys -- mild age related atrophy. Nohydronephrosis.

2. 1.9 cm right renal cyst.

3. Enlarged spleen -- 13.7 cm.

Methods

• Analysis– Rate of AAA growth

• Least squares regression (size of AAA vs. time)

– Compare rate of AAA growth - metformin vs. without metformin (at time of AAA diagnosis)

• ttest

– Regression of rate of change with other variables• Linear regression vs. mixed methods

Example of growth

Year

Results• 13,828 9065 (66%) patients with ≥ 2 scans

– Average Follow-up – 3.7 years (range 0.5-14.4)– Average number of scans – 3.93 (range 2-21)

No Metformin(n=5,145)

Metformin (n=3,920)

Mean AAA growth rate (mm/year)

1.43 (SD 3.20)

1.18(SD 2.87)

17% decrease in AAA growth rate

Stata output – ttest

Distribution of yearly growth rate

0 = no metformin1= metformin

0.1

.2.3

-20 -10 0 10 20 -20 -10 0 10 20

0 1D

ensi

ty

yrateGraphs by MetforminRX

Multivariate regression Adjusted Difference

(mm/yr)95% CI P-value

Starting AAA Size (mm) -0.003 -0.005, 0.012 0.43

Ace-inhibitor -0.04 -0.198, 0.122 0.59

Alpha-blocker -0.18 -0.324, 0.085 0.06

ARB -0.24 -0.498, -0.048 0.023

β-blocker 0.10 -0.052, 0.252 0.15

Calcium channel blocker 0.03 -0.219, 0.081 0.45

Diuretic -0.02 -0.115, 0.175 0.82

Statin -0.06 -0.246, 0.060 0.38

Metformin -0.24 -0.374, -0.085 <0.001

Oral anti-hyperglycemic agent* -0.07 -0.260, -0.027 0.025

Age (year) -0.01 -0.015, 0.003 0.225

Female Gender -0.12 -0.852, 1.028 0.855

American Indian -0.34 -1.241, 0.545 0.45

Asian 0.33 -0.830, 1.300 0.67

Black -0.11 -0.751, 0.028 0.07

White -0.05 -0.579, 0.034 0.08

Native Hawaiian -0.03 -0.811, 0.552 0.71

Hispanic -0.02 -0.157, 0.561 0.27* Excluding metformin

Stata output – regression

Mixed linear regression

Logistic regression to median growth rate

Code

Future Work• Specific Aims:• Aim 1: Describe the effects of metformin on abdominal aortic aneurysm (AAA)

growth in the diabetic population. Patients with a diagnosis of diabetes, AAA, and appropriate radiographic follow-up will be included. AAA diameter growth rates will be compared between patients on metformin and patients not on metformin. The effects of metformin on AAA growth will be calculated using mixed linear regression.

• Aim 2: Describe the effects of metformin on AAA growth in patients with a diagnosis of hyperglycemia/ pre-diabetes without a diagnosis of diabetes. As diabetes is known to be protective of AAA growth, the effects of metformin will be attempted to be studied in the non-diabetic population as physicians may prescribe metformin in the pre-diabetes stage. Similar methods will be used to understand the effects of metformin on AAA growth rates in this population.

• Aim 3: Describe the effects of metformin on overall mortality and AAA related mortality. Patient mortality will be evaluated in the two cohort groups above. Kaplan-Meier survival analysis will be used to calculate the effects of metformin on overall mortality and AAA related mortality.

Patients with AAA diagnosis (ICD-9 441.4)

Patients with diabetes diagnosis (ICD9-250.x)

Patients without diabetes diagnosis

Patients without hyperglycemia diagnosis

Patients with hyperglycemia diagnosis

(ICD-9 790.29)

Patients on metformin

Patients not on metformin

VA database from 2003-2013

Include patients with ≥ 2 radiographic imaging (ultrasound, CT, MRI of aorta) ≥ 6 months apart

Group A

Patients on metformin

Patients not on metformin

Group B

Future Work

• Clinical Trial