Capturing Adult Patient Preferences Toward Benefits and Risks of Second-Line Antihyperglycemic Medications Used in Type 2 Diabetes: A Discrete Choice Experiment.

OBJECTIVES: To estimate the strength of preferences, relative importance and trade-offs that patients with type 2 diabetes make between characteristics of antihyperglycemic medications. METHODS: We conducted a discrete choice experiment with a sample of Canadians with type 2 diabetes. Respondents completed 14 choice tasks and choose between 2 hypothetical drug alternatives, described by 8 characteristics (cost, efficacy, life expectancy, risk of macrovascular event, risk of microvascular event, risk of severe hypoglycemia, risk of minor side effects and risk of rare but serious side effects). An opt-out option was also provided. Characteristics used to describe the 2 drugs were identified using a literature review, focus groups and interviews. A multinomial mixed logit model was used to estimate choice probabilities. Willingness to pay (WTP) was used to assess trade-offs between characteristics. RESULTS: A total of 502 survey responses were included. The average age of participants was 59±12 years. Participants were 59% men, and 62% had diabetes for at least 6 years. All characteristics were found to significantly influence choice. On average, patients were willing to pay a monthly cost for their therapy of $134 to achieve 3 additional years of life; $49 and $36 for a 20% reduction in their risk of macrovascular and microvascular events, respectively; $34 for a 1% drop in glycated hemoglobin; $29 for a 50% less risk of severe hypoglycemia over 10 years; $29 for a 50% less risk of a minor side effect and $17 for a 50% less risk of a rare but serious side effect over 10 years. CONCLUSIONS: All 8 characteristics were shown to significantly influence choice, with cost and life expectancy carrying the most weight and serious and minor side effects carrying the least weight.

Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: a systematic review and meta-analysis.

OBJECTIVE: To estimate the association between the use of sodium glucose co-transporter-2 (SGLT2) inhibitors and postmarket harms as identified by drug regulatory agencies. DESIGN: We conducted a systematic review and meta-analysis of randomised controlled trials (RCT). Six large databases were searched from inception to May 2018. Random effects models were used to estimate pooled relative risks (RRs). INTERVENTION: SGLT2 inhibitors, compared with placebo or active comparators. PRIMARY OUTCOMES: Acute kidney injury (AKI), diabetic ketoacidosis (DKA), urinary tract infections (UTI), bone fractures and lower limb amputations. RESULTS: We screened 2418 citations of which 109 were included. Most studies included one of four SGLT2 inhibitors, dapagliflozin, canagliflozin, empagliflozin and ipragliflozin. When compared with placebo, SGLT2 inhibitors were found to be significantly protective against AKI (RR=0.59; 95% CI 0.39 to 0.89; I2=0.0%), while no difference was found for DKA (RR 0.66; 95% CI 0.30 to 1.45, I2=0.0%), UTI (RR 1.02; 95% CI 0.95 to 1.09, I2=0.0%) or bone fracture (RR 0.87; 95% CI 0.69 to 1.09, I2=1.3%). Three studies reported on amputation, with one finding a significant increase risk. No increased risk for either outcome was found when compared with active controls. Subgroup analysis did show an increased risk of UTI with dapagliflozin only (RR 1.21; 95% CI 1.02 to 1.43, I2=0.0%), but no other analysis supported an increased risk of AKI, DKA, UTI or fracture. CONCLUSIONS: Current evidence from RCTs does not suggest an increased risk of harm with SGLT2 inhibitors as a class over placebo or active comparators with respect to AKI, DKA, UTI or fracture. However, wide CIs for many comparisons suggest limited precision, and therefore clinically important adverse events cannot be ruled out. Dapagliflozin, appears to independently increase the risk of UTI, although the mechanism for this intraclass variation in risk is unclear. PROSPERO REGISTRATION NUMBER: CRD42016038715.

Dose response of sodium glucose cotransporter-2 inhibitors in relation to urinary tract infections: a systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: The sodium glucose cotransporter-2 (SGLT2) inhibitors are a novel group of drugs for treatment of type 2 diabetes mellitus. We investigated whether there is a dose-response relation between SGLT2 inhibitors and urinary tract infections (UTIs) in patients with type 2 diabetes, relative to other diabetes therapies or placebo. METHODS: We conducted a systematic review and network meta-analysis of randomized controlled trials (RCTs) of SGLT2 inhibitors in patients with type 2 diabetes. We searched 6 databases and the reference lists of key papers. We included studies with placebo or active antidiabetic comparators that reported the outcome of UTI, and established thresholds for high and low doses of SGLT2 inhibitors. We used a random-effects model to estimate the pooled effect estimates and 95% credible intervals. RESULTS: We screened 2418 citations and included 105 references for studies of 8 unique SGLT2 inhibitors, representing 60 082 individuals (with a total of 4348 UTIs). Most mixed-treatment comparisons showed no significant difference in risk of UTI, with the exception of high-dose dapagliflozin (≥ 10 mg) compared with placebo (odds ratio [OR] 1.30, 95% credible interval 1.09-1.57), with active comparators (OR 1.44, 95% credible interval 1.15-1.79), with empagliflozin at both low (OR 1.30, 95% credible interval 1.04-1.60) and high (OR 1.39, 95% credible interval 1.12-1.72) doses, and with low-dose ertugliflozin (OR 1.43, 95% credible interval 1.01-2.01). When the analysis was restricted to RCTs with a low risk of bias, the results were nonsignificant. INTERPRETATION: Current RCT evidence does not suggest a dose-response relation between most SGLT2 inhibitors and UTIs, with the exception of dapagliflozin. Further research is needed to quantify the relation between SGLT2 inhibitors and more serious infections. TRIAL REGISTRATION: PROSPERO registration no. CRD42016038715.

Comparative Safety of Dipeptidyl Peptidase-4 Inhibitors Versus Sulfonylureas and Other Glucose-lowering Therapies for Three Acute Outcomes.

Although the glucose lowering effect of dipeptidyl peptidase-4 (DPP4) inhibitors is well established, several potential serious acute safety concerns have been raised including acute kidney injury, respiratory tract infections, and acute pancreatitis. Using the UK-based Clinical Practice Research Datalink (CPRD), we identified initiators (365-day washout period) of DPP4 inhibitors and relevant comparators including initiators of sulfonylureas, metformin, thiazolidinediones, and insulin between January 2007 and January 2016 to quantify the association between DPP4 inhibitors and three acute health events - acute kidney injury, respiratory tract infections, and acute pancreatitis. The associations between drug and study outcomes were estimated using Cox proportional hazard models adjusted for deciles of high-dimensional propensity scores and number of additional glucose lowering agents. After controlling for potential confounders, the risk was not significantly increased or decreased for initiators of DPP4 inhibitors compared to sulfonylureas (hazard ratio (HR) [95% confidence interval (CI)] for acute kidney injury: 0.81 [0.56-1.18]; HR for respiratory tract infections: 0.93 [0.84-1.04]; HR for acute pancreatitis 1.03 [0.42-2.52], metformin (HR for respiratory tract infection 0.91 [0.65-1.27]), thiazolidinediones (HR for acute kidney injury: 1.12 [0.60-2.10]; HR for respiratory tract infections: 1.02 [0.86-1.21]; HR for acute pancreatitis: 1.21 [0.25-5.72]), or insulin (HR for acute kidney injury: 1.40 [0.77-2.55]; HR for respiratory tract infections: 0.74 [0.60-0.92]; HR for acute pancreatitis: 1.01 [0.24-4.19]). Initiators of DPP4 inhibitors were associated with an increased risk of acute kidney injury when compared to metformin initiators (HR [95% CI] for acute kidney injury: 1.85 [1.10-3.12], although this association was attenuated when DPP4 inhibitor monotherapy was compared to metformin monotherapy exposure as a time-dependent variable (HR 1.39 [0.91-2.11]). Initiation of a DPP4 inhibitor was not associated with an increased risk of acute kidney injury, respiratory tract infections, or acute pancreatitis compared to sulfonylureas or other glucose-lowering therapies.

Examining the risk of depression or self-harm associated with incretin-based therapies used to manage hyperglycaemia in patients with type 2 diabetes: a cohort study using the UK Clinical Practice Research Datalink.

OBJECTIVES: To compare population-based incidence rates of new-onset depression or self-harm in patients initiating incretin-based therapies with that of sulfonylureas (SU) and other glucose-lowering agents. DESIGN: Population-based cohort study. SETTING: Patients attending primary care practices registered with the UK-based Clinical Practice Research Datalink (CPRD). PARTICIPANTS: Using the UK-based CPRD, we identified two incretin-based therapies cohorts: (1) dipeptidyl peptidase-4 inhibitor (DPP-4i)-cohort, consisting of new users of DPP-4i and SU and (2) glucagon-like peptide-1 receptor agonists (GLP-1RA)-cohort, consisting of new users of GLP-1RA and SU, between January 2007 and January 2016. Patients with a prior history of depression, self-harm and other serious psychiatric conditions were excluded. MAIN OUTCOME MEASURES: The primary study outcome comprised a composite of new-onset depression or self-harm. Unadjusted and adjusted Cox proportional hazards regression was used to quantify the association between incretin-based therapies and depression or self-harm. Deciles of High-Dimensional Propensity Scores and concurrent number of glucose-lowering agents were used to adjust for potential confounding. RESULTS: We identified new users of 6206 DPP-4i and 22 128 SU in the DPP-4i-cohort, and 501 GLP-1RA and 16 409 SU new users in the GLP-1RA-cohort. The incidence of depression or self-harm was 8.2 vs 11.7 events/1000 person-years in the DPP-4i-cohort and 18.2 vs 13.6 events/1000 person-years in the GLP-1RA-cohort for incretin-based therapies versus SU, respectively. Incretin-based therapies were not associated with an increased or decreased incidence of depression or self-harm compared with SU (DPP-4i-cohort: unadjusted HR 0.70, 95% CI 0.51 to 0.96; adjusted HR 0.80, 95% CI 0.57 to 1.13; GLP-1RA-cohort: unadjusted HR 1.36, 95% CI 0.72 to 2.58; adjusted HR 1.25, 95% CI 0.63 to 2.50). Consistent results were observed for other glucose-lowering comparators including insulin and thiazolidinediones. CONCLUSIONS: Our findings suggest that the two incretin-based therapies are not associated with an increased or decreased risk of depression or self-harm.

The risk of fragility fractures in new users of dipeptidyl peptidase-4 inhibitors compared to sulfonylureas and other anti-diabetic drugs: A cohort study.

AIMS: Mixed evidence exists for the effect of incretin-based therapies on osteoporosis in type-2 diabetes. Therefore, we conducted a cohort study to determine the association between dipeptidyl peptidase-4 (DPP-4) inhibitors and common osteoporotic "fragility fractures" (upper extremity, hip, spine). METHODS: The UK-based Clinical Practice Research Datalink was used to identify adults without prior fractures receiving a new anti-diabetic drug or a new type-2 diabetes diagnosis between 2007 and 2016. The primary aim was to compare new-users of DPP-4 inhibitors versus new-users of sulfonylureas (SU). The association between DPP-4 inhibitors and incident fractures was estimated using Cox proportional hazards models. Deciles of high-dimensional propensity scores and other anti-diabetic drugs were used as covariates. RESULTS: We identified 7993 and 26,636 new-users of DPP-4 inhibitors and SUs, respectively. At cohort entry, the mean age was 58.8, 40% were female, mean diabetes duration was 1.3 years, and 42% had A1c > 9%. Over 9 years (mean follow-up = 1.2 years), the incident rate of fragility fractures was lower among DPP-4 versus SU users (3.0/1000 vs. 5.2/1000 person-years; P-value = 0.007). After adjustment, there was no statistically significant difference in fracture risk (hazard ratio adjusted, aHR = 0.80, 95%CI 0.51-1.24; P-value = 0.3125). In a secondary analysis, DPP-4 inhibitors were not associated with a difference in fracture risk compared to insulin (aHR = 0.91, 95%CI 0.40-2.09); however were associated with a lower fracture risk versus thiazolidinediones (aHR = 0.47, 95%CI 0.26-0.83). Sensitivity analyses supported findings. CONCLUSIONS: DPP-4 inhibitors are not associated with an increased risk of fragility fractures compared with SUs or insulin; however, are associated with a lower risk versus thiazolidinediones.

Association of insulin dosage with mortality or major adverse cardiovascular events: a retrospective cohort study.

BACKGROUND: Existing studies have shown conflicting evidence regarding the safety of exogenous insulin therapy in patients with type 2 diabetes. In particular, observational studies have reported an increased risk of death and cardiovascular disease among users of higher versus lower doses of insulin. We aimed to quantify the association between increasing dosage of insulin exposure and death and cardiovascular events, while taking into account time-dependent confounding and mediation that might have biased previous studies. METHODS: We did a cohort study using primary care records from the UK-based Clinical Practice Research Datalink (CPRD). New users of metformin monotherapy were identified in the period between Jan 1, 2001, and Dec 31, 2012. We then identified those in this group with a new prescription for insulin. Insulin exposure was categorised into groups according to the mean dose (units) per day within 180-day time segments throughout each patient's follow-up. Relative differences in mortality and major adverse cardiovascular events (non-fatal myocardial infarction, non-fatal stroke, cardiovascular-related mortality) were assessed using conventional multivariable Cox proportional hazards models. Marginal structural models were then applied to reduce bias introduced by the time-dependent confounders affected by previous treatment. FINDINGS: We identified 165 308 adults with type 2 diabetes in the CPRD database. After applying our exclusion criteria, 6072 (mean age 60 years [SD 12·5], 3281 [54%] men, mean HbA1c 8·5% [SD 1·75], and median follow-up 3·1 years [IQR 1·7-5·3) were new add-on insulin users and were included in the study cohort; 3599 were new add-on insulin users and were included in the subcohort linked to hospital records and death certificate information. Crude mortality rates were comparable between insulin dose groups; <25 units per day (46 per 1000 person-years), 25 to <50 units per day (39 per 1000 person-years), 50 to <75 units per day (27 per 1000 person-years), 75 to <100 units per day (34 per 1000 person-years), and at least 100 units per day (32 per 1000 person-years; p>0·05 for all; mean rate of 31 deaths per 1000 person-years [95% CI 29-33]). With adjustment for baseline covariates, mortality rates were higher for increasing insulin doses: less than 25 units per day [reference group]; 25 to <50 units per day, hazard ratio (HR) 1·41 [95% CI 1·12-1·78]; 50 to <75 units per day, 1·37 [1·04-1·80]; 75 to <100 units per day, 1·85 [1·35-2·53]; and at least 100 units per day, 2·16 [1·58-2·93]. After applying marginal structural models, insulin dose was not associated with mortality in any group (p>0·1 for all). INTERPRETATION: In conventional multivariable regression analysis, higher insulin doses are associated with increased mortality after adjustment for baseline covariates. However, this effect seems to be confounded by time-dependent factors such as insulin exposure, glycaemic control, bodyweight gain, and the occurrence of cardiovascular and hypoglycaemic events. This study provides reassurance of the overall safety of insulin use in the treatment of type 2 diabetes and contributes to our understanding of the contrasting conclusions from non-randomised and randomised studies regarding dose-dependent effects of insulin on cardiovascular events and mortality. FUNDING: Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, and the Newfoundland and Labrador Research and Development Corporation.