Johanna H. M. Driessen

Use of dipeptidyl peptidase-4 inhibitors for type 2 diabetes mellitus and risk of fracture

INTRODUCTION Although patients with type 2 diabetes mellitus have an increased bone mineral density as compared to healthy patients, their risk of fracture is elevated. Incretins, new anti-diabetic drugs, may have a protective effect on bone mineral density. However, data on the effect of incretins on fracture risk are limited. Therefore the aim of this study was to investigate the association between the use of DPP4-I and the risk of fracture. METHODS A retrospective population based cohort study, using data from the Clinical Practice Research Datalink (CPRD) database (2007-2012), was conducted. Patients (N=216,816) with at least one prescription for a non-insulin anti-diabetic drug (NIAD), aged 18+ during data collection, were matched to one control patient. Cox proportional hazards models were used to estimate the hazard ratio of any fracture in DPP4 inhibitor (DPP4-I) users versus controls and versus other NIAD patients. Time-dependent adjustments were made for age, sex, life style, comorbidity and drug use. RESULTS The actual duration of DPP4-I use was 1.3years. There was no different risk of fracture comparing current DPP4-I users to controls (adjusted hazard ratio (adj. HR) 0.89, 95% confidence interval (CI) 0.71-1.13). There was also no increased risk comparing current DPP4-I users to other NIAD users, adj. HR 1.03 (95% CI 0.92-1.15). CONCLUSIONS DPP4-I use was not associated with fracture risk compared to controls and to other NIAD users. However, the duration of DPP4-I use in our database might have been too short to show an association with fracture risk.

Risk of hypoglycaemia in users of sulphonylureas compared with metformin in relation to renal function and sulphonylurea metabolite group: population based cohort study

Objective To determine the association between use of sulphonylureas and risk of hypoglycaemia in relation to renal function and sulphonylurea metabolic group compared with use of metformin. Design Population based cohort study using routinely collected data from general practices in England. Setting Clinical Practice Research Datalink (CPRD) database, 2004-12. Participants 120 803 new users of a non-insulin antidiabetic agent with at least one prescription and aged 18 years or more. The first prescription defined start of follow-up. Patients were followed until the end of data collection, a record for hypoglycaemia, or a blood glucose level of less than 3.0 mmol/L. Main outcome measures Associations between sulphonylurea dose, renal impairment, type of sulphonylurea used, and risk of hypoglycaemia, were determined using Cox proportional hazard models. Adjustments were made for age, sex, lifestyle, comorbidity, and drug use. Results The risk of hypoglycaemia in current users of sulphonylureas only was significantly increased compared with current users of metformin only (adjusted hazard ratio 2.50, 95% confidence interval 2.23 to 2.82). The higher risk in current users of sulphonylureas only was further increased in patients with an estimated glomerular filtration rate of less than 30 mL/min/1.73 m2 (4.96, 3.76 to 6.55). The risk of hypoglycaemia was also significantly higher in patients with a high sulphonylurea dose (3.12, 2.68 to 3.62) and in current users of glibenclamide (7.48, 4.89 to 11.44). Gliclazide, the sulphonylurea of first choice, showed a similar risk of hypoglycaemia compared with other sulphonylureas. Conclusions Sulphonylurea treatment in patients with a renal function of less than 30 mL/min/1.73 m2 should be considered with caution. Moreover, an increased risk of hypoglycaemic events was observed among all users of sulphonylureas. This contrasts with several guidelines that recommend gliclazide as first choice sulphonylurea, and therefore requires further investigation.

Use of dipeptidyl peptidase 4 inhibitors and fracture risk compared to use of other anti-hyperglycemic drugs

Dipeptidyl peptidase‐4 inhibitors (DPP4‐Is) are a new class of anti‐hyperglycemic drugs which might have a potential beneficial effect on bone metabolism. Data on the effect of DPP4‐I use and fracture risk is limited and conflicting. The aim of the present study was to investigate the association between use of DPP4‐Is and fracture risk.

Long-term use of dipeptidyl peptidase-4 inhibitors and risk of fracture : A retrospective population-based cohort study

To investigate the association between long‐term dipeptidyl peptidase‐4 (DPP‐4) inhibitor use and risk of fracture among people with type 2 diabetes mellitus (T2DM).

The use of incretins and fractures - a meta-analysis on population-based real life data

&NA; The aim of the present study was to estimate the effect of incretins on fracture risk in the real‐world situation by meta‐analysis of the available population‐based cohort data. Pubmed and Embase were searched for original articles investigating use of incretin agents, and fracture risk up to December 2015. Adjusted results were extracted and pooled by use of generic inverse variance methods, assuming a random‐effects model. Neither current dipeptidyl peptidase 4‐inhibitor use nor current glucagon‐like peptide 1 receptor agonist use was associated with a decreased risk of fracture: pooled relative risk (pooled RR [95% confidence interval]: 1.02 [0.91–1.13] and 1.03 [0.87–1.22]), respectively. This meta‐analysis demonstrated that current use of incretin agents, was not associated with decreased fracture risk. Our findings show the value of representative real‐world populations, and the risks associated with suggesting benefits for medications on the basis of safety reporting in randomized controlled trials.

Use of incretin agents and risk of pancreatic cancer: a population‐based cohort study

To investigate the association between the use of incretin agents and the risk of pancreatic cancer.

Use of incretin agents and risk of acute and chronic pancreatitis: A population-based cohort study

To determine the association between the use of incretin agents (dipeptidyl peptidase‐4 inhibitors and glucagon‐like peptide‐1 receptor agonists) for the treatment of type 2 diabetes mellitus (T2DM) and the risk of any, acute and chronic pancreatitis.

Individuals With Type 2 Diabetes Mellitus Are at an Increased Risk of Gout But This Is Not Due to Diabetes: A Population-Based Cohort Study.

AbstractThe relationship between type 2 diabetes and gout is complex. The objective of this study was to understand the role of diabetes itself and its comorbidities within the association between type 2 diabetes and gout.We conducted a retrospective cohort study using the UK Clinical Practice Research Datalink (CPRD) GOLD. Persons with type 2 diabetes were identified as persons on a noninsulin antidiabetic drug (NIAD) between 2004 and 2012, and were matched to 1 control based on age, sex, and general practice. We estimated gout risk in NIAD users using Cox regression analysis. All analyses were stratified for sex.In total, 221,117 NIAD users were identified. NIAD users had an increased risk of gout (hazard ratio (HR) 1.48; 95% CI 1.41–1.54). This association was stronger in women (HR 2.23; 95% CI 2.07–2.41) compared with men (HR 1.19; 95% CI 1.13–1.26). After adjustments for BMI, eGFR, hypertension, renal transplantation, diuretics, statins, low-dose aspirin, ciclosporin, and tacrolimus, the risk disappeared in women (HR 1.01; 95% CI 0.92–1.11) and reversed in men (HR 0.61; 95% CI 0.58–0.66) (P for interaction <0.001). When stratifying gout risk according to HbA1c in male and female NIAD users, we found an inverse association between raising HbA1c and incident gout in men only. Further adjustment gave similar results.Individuals with type 2 diabetes are at increased risk of gout. This is not due to diabetes itself, but to the comorbid conditions. Diabetes itself is apparently associated with a decreased risk of gout, especially in men.

The association between insulin use and volumetric bone mineral density, bone micro-architecture and bone strength of the distal radius in patients with type 2 diabetes - The Maastricht study

Type 2 diabetes mellitus (T2DM) has been associated with an increased risk of fractures, despite normal to increased bone mineral density (BMD). Insulin use is one of the factors linked to this increased fracture risk. However, direct negative effects of insulin on bone quality are not expected since insulin is thought to be anabolic to bone. In this cross-sectional study the association between insulin use and volumetric BMD (vBMD), bone micro-architecture and bone strength of the distal radius, as measured with HR-pQCT, was examined. Data from 50 participants with T2DM of The Maastricht Study (mean age 62±7.5years, 44% women) was used. Participants were classified as insulin user (n=13) or non-insulin user (n=37) based on prescription data. Linear regression analysis was used to estimate the association between current insulin use and HR-pQCT derived parameters. After adjustment for age, sex, body mass index, glycated hemoglobin A1c and T2DM duration, insulin use was associated with lower total vBMD (standardized beta (β):-0.56 (95% CI:-0.89 to -0.24)), trabecular vBMD (β:-0.58 (95% CI:-0.87 to -0.30)), trabecular thickness (β:-0.55 (95% CI:-0.87 to -0.23)), cortical thickness (β:-0.41 (95% CI:-0.74 to -0.08)), log cortical pore volume (β:-0.43 (95% CI:-0.73 to -0.13)), bone stiffness (β:-0.39 (95% CI:-0.62 to -0.17)) and failure load (β:-0.39 (95% CI:-0.60 to -0.17)) when compared to the non-insulin users. Insulin use was not associated with cortical vBMD, trabecular number, trabecular separation, cortical porosity and cortical pore diameter. This study indicates that insulin use is negatively associated with bone density, bone micro-architectural and bone strength parameters. These findings may partly explain the previously observed increased fracture risk in insulin users, although there may be residual confounding by other factors related to disease severity in insulin users.

Use of Dipeptidyl-Peptidase-4 Inhibitors and the Risk of Pneumonia: A Population-Based Cohort Study

Background Dipeptidyl-peptidase-4 inhibitors (DPP4Is) are drugs for the treatment of type 2 diabetes mellitus (T2DM). There is increasing evidence that DPP4Is may result in suppression of the immune system and may increase the risk of infections such as pneumonia. Aim of this study was to evaluate the association between the use of DPP4Is and the risk of pneumonia in a population-based study. Methods We conducted a population-based cohort study using data from the world’s largest primary care database, the UK Clinical Practice Research Datalink (CPRD). We selected all users of non-insulin antidiabetic drugs (NIADs), including DPP4Is, between 2007 and 2012. To each NIAD user, we matched randomly selected non-users. The NIAD user’s first prescription defined the index date, which was then assigned to the matched non-users. Patients were followed from their first prescription until end of data collection or the first event of pneumonia, whichever came first. Cox regression analysis estimated the association between pneumonia and current use of DPP4Is versus 1) current use of other NIADs and 2) non-users. DPP4I use was then stratified to daily and cumulative dose. Analyses were statistically adjusted for age, sex, lifestyle factors and comorbidities and concomitant use of various other drugs. Results Risk of pneumonia was not increased with current DPP4I use versus use of other NIADs, adjusted Hazard Ratio (HR) 0.70; 95% Confidence Interval (CI) 0.55–0.91. Also higher cumulative doses or daily doses did not further increase risk of pneumonia. Conclusion We found no increased risk of pneumonia in T2DM patients using DPP4Is compared to T2DM patients using other NIADs. Our finding is in line with direct and indirect evidence from observational studies and RCTs. There is probably no need to avoid prescribing of DPP4Is to elderly patients who are at risk of pneumonia.