Antidiabetic Medication Use and Fracture Risk in T2DM Patients:

a nested case-control study

M Sanni Ali, Eladio L, Berta S, Dídac M, and Daniel Prieto-Alhambra

National Osteoporosis Conference 2016

Introduction

Type 2 diabetes (T2DM) is associated with increased bone mineral density (BMD) and higher risk of fracture.

Existing prediction tools such as FRAX underestimate fracture risk.

Hypoglycaemic treatment could modulate the risk of fractures in many ways.

Observational studies on the effect of antidiabetic medications have conflicting findings.

Some studies reported higher risk of fractures in insulin-treated patients:

- Higher prevalence of diabetic complications/comorbidities.

- Higher risk of hypoglycaemic episodes and falls.

Introduction

Only few studies have looked at the comparative safety of different antidiabetic medications.

Palermo A et al. Osteoporos Intl 2015

Introduction

Aim: To investigate the comparative fracture risk associated with the different antidiabetic medications in primary care practice.

Methods

Data source: SIDIAP database- One primary care health provider using one same e-records

software.- 274 Primary Care Centres in Catalonia - > 3,400 GPs.- > 5 million patients (>80% population).- > 55 million person-years of research-usable data (2005 onwards).

Study participants:

- Incident T2DM patients registered in SIDIAP, aged 40 years or older, with an eGFR >15 at T2DM diagnosis.

Methods

Methods

Study period: 1st January 2006 - 31st December 2013

Design: Nested case-control study.

Exposure: Antidiabetic medications (Reference = Metformin)

Outcome: Osteoporotic fracture (cases)

Exclusion Criteria:

- Patients having fractures before entry date. - T2DM diagnosis date before 1st January 2006 or practice

registration date or within the last year of the study period.- Patients with chronic kidney failure (eGFR <15).- Patients < 40 years of age on the date of T2DM diagnosis.

Methods

Cases were (risk set) matched with up to 5 controls on (“epi” package)• 10-year bands on calendar year of birth • Calendar year of cohort entry (T2DM cohort)• Gender

Multiple imputation with chained equation was used to impute missing data (“mice” in R).

Conditional logistic regression was used to estimate OR and 95%CI adjusting for the confounders listed in the baseline table (ccwc, R).

Potential confounders: demographic variables, comorbidities (eGFR and HBA1c), comedication, life style factors (Smoking, Alcohol use, socioeconomic status)

Results

166,106 Patients

102,564 patients :T2DX (< 2006) = 90,183 T2DM (in 2013) = 8,490 T2DM<practice reg. = 17,759eGFR (≤15) = 166Date entry<= Date exit = 328Age at Index < 40 = 319Fracture before cohort entry = 1,455 *Not mutually exclusive

62,087 PatientsCases = 2,049Controls = 60,038

12,277 Case-controlsCases = 2,049Controls = 10,228

49,810 Unmatched PatientsCases = 0

Controls = 49,810

Flow chart of data extraction for T2DM cohort and case-control

Results

Table: Baseline Characteristics of Cases and Controls

ResultsTable: Association Between Different Antidiabetic Medications and Risk of

Fracture

Total

(N= 12,277)Cases

(N=2,049)

Adjusted

Odds Ratio 95% CI

Metformin 4079 625 REFERENCE

Insulin 546 126 1.63 1.30 2.04

Sulfonylurea 697 119 1.13 0.91 1.41

Gliptins:DPP4 77 14 1.21 0.67 2.19Insulin +

Metformin 329 58 1.22 0.89 1.65

Metformin and Sulfonylurea 946 177 1.29 1.07 1.56

Metformin and DPP4 218 36 1.12 0.77 1.62Adjusted for age/sex, comedications, comorbidities, BMI, eGFR, HBA1c, smoking,

alcohol use and socioeconomic Status.

Results

Table: Timing of Insulin Use and Fracture Risk

Total Cases Odds Ratio 95% CI

Never Users Past 2 Years 3933 666 1.00 Current Users- Previous 6 Months 470 116 1.52 1.19 1.93Recent Users- Between Previous 6 and 12 Months 78 14 1.02 0.57 1.85Past Users- Between 12 and 18 Months 37 7 1.19 0.51 2.74Previous Past Users- Between 18 and 24 Months 22 2 0.46 0.10 2.00

Discussion

Insulin treatment is associated with increased risk of fractures compared to metformin.

Fracture risk appears to increase during insulin use (6-months) and disappear with insulin discontinuation.

Strengths: adjustment was possible for several confounders including HBA1c, eGFR, among others.

Limitations: Power and unmeasured confounding could still explain the observed association.