Comorbidities in type 2 diabetes patients with and without atherosclerotic cardiovascular disease: a retrospective database analysis.

Objective: The objective of this study was to describe the pattern of comorbidities in patients with type 2 diabetes mellitus with and without atherosclerotic cardiovascular disease.Methods: This was a retrospective, cross-sectional analysis of the IQVIA Commercial Data Delivery database. Patients were ≥18 years on their last encounter between 1 October 2014 and 30 September 2015 and had either a type 2 diabetes mellitus diagnosis or a prescription for an oral diabetes medication. Atherosclerotic cardiovascular disease was confirmed by diagnosis codes. Comorbidities were identified using diagnosis codes, clinical measurements, and/or medication use.Results: A total of 1,522,526 type 2 diabetes mellitus patients were included in the analysis, 25% of whom had atherosclerotic cardiovascular disease. The most common comorbidities were hypertension, hyperlipidemia, overweight/obesity, chronic kidney disease, congestive heart failure, and neuropathy. These were present, respectively, in the following percentages of patients with and without cardiovascular disease: 98.3 and 91.0%, 94.8 and 78.5%, 80.5 and 80.6%, 38.5 and 18.9, 20.2, and 4.3%, and 13.7 and 8.6%. Thus, the frequencies of hyperlipidemia, chronic kidney disease, and congestive heart failure were notably higher in patients with cardiovascular disease. This trend held true for patients grouped by sex, age, and race.Conclusions: Patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease have different rates of certain comorbidities compared to those without atherosclerotic cardiovascular disease.

Efficacy and Safety of Ertugliflozin in Patients with Overweight and Obesity with Type 2 Diabetes Mellitus.

OBJECTIVE: This study aimed to evaluate ertugliflozin in patients with overweight and obesity with type 2 diabetes mellitus. METHODS: Data from three placebo-controlled, randomized, Phase 3 studies were pooled. Patients with baseline BMI ≥ 25 (1,377/1,544; 89%) were assessed with a stratification by BMI subgroup. RESULTS: At week 26, reductions from baseline in glycated hemoglobin A1c (HbA1c), fasting plasma glucose, body weight (BW), and systolic blood pressure (SBP) were greater with ertugliflozin versus placebo. For placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively, least squares mean change was 0.1%, -0.8%, and -0.9% for HbA1c and -1.2 kg, -3.1 kg, and -3.2 kg for BW. HbA1c reductions were consistent across BMI subgroups. For ertugliflozin 5 mg and 15 mg, least squares mean change (placebo adjusted) in absolute BW was -1.4 kg and -1.2 kg for BMI 25 to < 30, -1.8 kg and -1.9 kg for BMI 30 to < 35, and -2.5 kg and -2.9 kg for BMI ≥ 35. Percent BW changes were similar across BMI subgroups. Incidence of adverse events was 52.5%, 44.6%, and 50.1% with placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively. CONCLUSIONS: Meaningful reductions in HbA1c, fasting plasma glucose, BW, and SBP were observed with ertugliflozin in patients with overweight and obesity with type 2 diabetes mellitus. Ertugliflozin improved HbA1c and SBP and reduced BW across BMI subgroups. Ertugliflozin was generally well tolerated.

Distance to glycemic goal at the time of treatment intensification in patients with type 2 diabetes mellitus failing metformin monotherapy in the United States.

Background: A substantial proportion of patients with type 2 diabetes mellitus (T2DM) do not reach their target HbA1c level on metformin. The objective of this retrospective observational cohort study is to better characterize the distance between HbA1c target and patient's actual HbA1c level (the distance to goal), using a target HbA1c of 7.0% (53 mmol/mol), in patients with T2DM who have started metformin monotherapy.Methods: We used data from the GE Centricity Electronic Medical Record database by IQVIA in 2016 in the United States (US) to identify adults with T2DM who started metformin monotherapy (MM) and received at least 90 days of treatment. Patients were categorized into three groups: those who achieved the goal of HbA1c <7.0%, those who did not achieve the goal of HbA1c <7.0% (i.e. failed MM) and received intensified treatment, and those who failed MM and did not receive intensified treatment. Distance to goal was computed for patients in each group.Results: We identified 20,704 patients in the US database who started MM; 1741 (8.4%) failed MM and received intensified treatment, while 4977 (24.0%) failed MM and did not receive intensified treatment. The mean post-MM HbA1c for those who failed MM and received intensified treatment was 8.7% (72 mmol/mol) (median 8.2%, 66 mmol/mol) and the mean distance to goal was 1.7% (median 1.2%). The mean post-MM HbA1c for those who failed MM and did not receive intensified treatment was 8.0% (64 mmol/mol) (median 7.5%, 58 mmol/mol) and the mean distance to goal was 1.0% (median 0.5%).Conclusion: A proportion of US T2DM patients do not achieve glycemic control (target HbA1c < 7.0%) despite 90 days of MM. Patients who failed MM and eventually received intensified treatment did so when their HbA1c distance to goal exceeded the level at which one add-on therapy alone might be sufficient to bring them to goal.

Ertugliflozin Compared to Other Anti-hyperglycemic Agents as Monotherapy and Add-on Therapy in Type 2 Diabetes: A Systematic Literature Review and Network Meta-Analysis.

INTRODUCTION: Ertugliflozin is a new sodium-glucose co-transporter-2 inhibitor (SGLT2i) for the treatment of type 2 diabetes mellitus. As there are no head-to-head trials comparing the efficacy of SGLT2is, the primary objective of this analysis was to indirectly compare ertugliflozin to other SGLT2i in patient populations with inadequately controlled glycated hemoglobin (HbA1c > 7.0%) and previously treated with either diet/exercise, metformin alone or metformin plus a dipeptidyl peptidase-4 inhibitor (DPP4i). METHODS: A systematic literature review (SLR) identified randomized controlled trials (RCTs) reporting outcomes at 24-26 weeks of treatment. Comparators to ertugliflozin were the SGLT2is canagliflozin, dapagliflozin and empagliflozin, with non-SGLT2i comparators also evaluated third-line [insulin and glucagon-like peptide-1 receptor agonists (GLP-1 RAs)]. Outcomes were change from baseline in HbA1c, weight and systolic blood pressure (SBP) as well as HbA1c < 7% and key safety events. Bayesian network meta-analysis was used to synthesize evidence. Results are presented as the median of the mean difference (MD) or as odds ratios with 95% credible intervals (CrI). RESULTS: In patients uncontrolled on diet/exercise, the efficacy of ertugliflozin 5 mg monotherapy was not significantly different from that of other low-dose SGLT2is in terms of HbA1c reduction, while ertugliflozin 15 mg was more effective than dapagliflozin 10 mg (MD - 0.36%, CrI - 0.65, - 0.08) and empagliflozin 25 mg (MD - 0.31%, CrI - 0.58, - 0.04). As add-on therapy to metformin, ertugliflozin 5 mg was more effective in lowering HbA1c than dapagliflozin 5 mg (MD - 0.22%, CrI - 0.42, - 0.02), and ertugliflozin 15 mg was more effective than dapagliflozin 10 mg (MD - 0.26%, CrI - 0.46, - 0.06) and empagliflozin 25 mg (MD - 0.23%, CrI - 0.44, - 0.03). Among patients uncontrolled on combination therapy metformin plus a DPP4i, no relevant RCTs with insulin were identified from the SLR. One study with a GLP-1 RA was included in a sensitivity analysis due to limited data. There were no differences between ertugliflozin 5 or 15 mg and other SGLT2is, with the exception of dapagliflozin 10 mg, which was significantly less effective when added to sitagliptin and metformin. Overall, there were no other significant differences for remaining efficacy and safety outcomes except for a lower SBP for canagliflozin 300 mg compared to ertugliflozin 15 mg in the diet/exercise population. CONCLUSIONS: Indirect comparisons for HbA1c reduction found that ertugliflozin 5 mg was more effective than dapagliflozin 5 mg when added to metformin monotherapy, whereas ertugliflozin 15 mg was more effective than dapagliflozin 10 mg and empagliflozin 25 mg when added to diet/exercise and to metformin monotherapy. The HbA1c reduction associated with ertugliflozin was no different than that associated with canagliflozin across all populations. FUNDING: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Pfizer Inc., New York, NY, USA.

Retrospective Cohort Analysis of the Reduced Burden of Hypoglycemia Associated with Dipeptidyl Peptidase-4 Inhibitor Use in Patients with Type 2 Diabetes Mellitus.

INTRODUCTION: The use of antihyperglycemic agents (AHA), especially insulin and sulfonylureas (SU), is a risk factor for hypoglycemia. Despite the significant clinical and economic burdens associated with hypoglycemia and the decreasing use of SU in favor of other oral AHA, relatively little is known about hypoglycemia trends specific to the use of non-insulin AHA. We sought to estimate annual hypoglycemia event rates and costs among patients with type 2 diabetes mellitus (T2DM) who started either SU or dipeptidyl peptidase-4 inhibitors (DPP-4i) and to predict rates and costs in the absence of DPP-4i. METHODS: Truven's MarketScan Commercial Claims database was used to estimate hypoglycemia event rates and costs from 2007 to 2013. Hypoglycemia, defined using diagnosis codes, was assessed during the 12 months following SU (n = 245,201) or DPP-4i (n = 176,786) initiation by adults with T2DM. Coefficients from a Poisson regression model used to estimate the impact of patient characteristics on hypoglycemia rates for patients who started SU were used to predict rates for patients who started DPP-4i had they started SU instead. RESULTS: Hypoglycemia events per 100 patient-years (costs per event) ranged from 5.4 ($565) in 2007 to 10.4 ($1154) in 2013 for patients starting SU; rates (costs) for patients starting DPP-4i ranged from 3.2 ($308) in 2007 to 6.4 ($482) in 2013. Predicted hypoglycemia rates would have been 5.3-9.9 per 100 person-years for patients who started DPP-4i had they started SU instead. Starting DPP-4i, rather than SU, would have resulted in national savings of $750.3 million in healthcare costs due to avoided hypoglycemia events during this period. CONCLUSIONS: Hypoglycemia rates and costs were consistently higher for patients who started SU rather than DPP-4i. The overall burden of hypoglycemia could be lowered substantially in the USA if, when feasible, patients with T2DM initiate DPP-4i instead of SU. FUNDING: Merck & Co., Inc., Kenilworth, NJ USA.

Geographic variation and risk factors for systemic and limb ischemic events in patients with symptomatic peripheral artery disease: Insights from the REACH Registry.

BACKGROUND: Patients with symptomatic peripheral artery disease (PAD) are at high risk of ischemic events. However, data about predictors of this risk are limited. HYPOTHESIS: We analyzed baseline characteristics and 4-year follow-up of patients enrolled in the international REduction of Atherothrombosis for Continued Health (REACH) Registry with symptomatic PAD and no history of stroke/transient ischemic attack to describe annual rates of recurrent ischemic events globally and geographically. METHODS: The primary outcome was systemic ischemic events (composite of cardiovascular death, myocardial infarction, or stroke) at 4 years. The secondary outcome was limb ischemic events (composite of lower limb amputation, peripheral bypass graft, and percutaneous intervention for PAD) at 2 years. Multivariate analysis identified risk factors associated with recurrent ischemic events. RESULTS: The primary endpoint rate reached 4.7% during the first year and increased continuously (by 4%-5% each year) to 17.6% by year 4, driven mainly by cardiovascular mortality (11.1% at year 4). Japan experienced lower adjusted ischemic rates (P < 0.01) vs North America. Renal impairment (P < 0.01), congestive heart failure (P < 0.01), history of diabetes (P < 0.01), history of myocardial infarction (P = 0.01), vascular disease (single or poly, P < 0.01), and older age (P < 0.01) were associated with increased risk of systemic ischemic events, whereas statin use was associated with lower risk (P = 0.03). The limb ischemic event rate was 5.7% at 2 years. CONCLUSIONS: Four-year systemic ischemic risk in patients with PAD and no history of stroke or transient ischemic attack remains high, and was mainly driven by cardiovascular mortality.

Demographic and clinical profiles of type 2 diabetes mellitus patients initiating sitagliptin in the real-world setting.

OBJECTIVE: Dipeptidyl peptidase-4 (DPP-4) inhibitors have been used for the management of type 2 diabetes (T2D) for over a decade; however, there is a limited understanding of the evolution of their use in the real-world setting over this time period. This study evaluated the demographics and clinical characteristics of patients initiating sitagliptin over a 10 year period in the United States. RESEARCH DESIGN AND METHODS: Quintiles electronic medical records database was used to identify adults with a new prescription of sitagliptin over two 5 year time periods: 2006-2010 (n = 57,604), and 2011-2015 (n = 147,326). In addition, we also evaluated how the most recent (year 2015) profile of sitagliptin initiators (n = 29,295) compares to the treated T2D patients (N = 474,877) in 2015. MAIN OUTCOME MEASURES: No outcomes were assessed. Descriptive statistics were used to summarize baseline patient characteristics. RESULTS: The overall demographics and clinical characteristics of patients initiating sitagliptin were generally similar over the two time periods; however, baseline HbA1c (median) was higher in the later time period: 7.6% vs. 7.9% respectively. Sitagliptin was initiated in patients across a broad range of age (18-79) years, body mass index (BMI) (10-70) kg/m2 and HbA1c (3-20) %. The most prevalent comorbidities observed in these patients were hypertension (93%), hyperlipidemia (81%), obesity (55%), chronic kidney disease (22%) and cardiovascular disease (21%). Additionally, when we assessed the treated T2D patients and patients initiating sitagliptin in 2015, several characteristics were comparable such as age (median) (64 vs. 63) years and BMI (33 vs. 33) kg/m2, and the most prevalent comorbidities were hypertension (97 vs. 95) %, and hyperlipidemia (86 vs. 81) % respectively. CONCLUSION: The overall demographic and comorbidity profile of patients initiating sitagliptin did not substantially change over the last decade and is similar to the treated T2D population.

Residual Ischemic Risk and Its Determinants in Patients With Previous Myocardial Infarction and Without Prior Stroke or TIA: Insights From the REACH Registry.

BACKGROUND: Although the rate of in-hospital ischemic events after myocardial infarction (MI) has dramatically decreased, long-term residual risk may remain substantial. However, most of the information on current residual risk is derived from highly selected randomized trials. HYPOTHESIS: In patients with previous MI and no prior ischemic stroke/transient ischemic attack (TIA), residual ischemic risk increases over time. METHODS: Using the international Reduction of Atherothrombosis for Continued Health (REACH) registry, we analyzed baseline characteristics and 4-year follow-up of patients with previous MI and no history of stroke/TIA to describe annual rates of recurrent ischemic events globally and by geography. The primary outcome was the composite of cardiovascular death, MI, or stroke. Multivariate analysis identified risk factors associated with recurrent ischemic events. RESULTS: Data from 16 770 patients enrolled at 5587 sites in 44 countries were analyzed. The rate of the primary outcome increased annually from 4.7% during year 1 to reach a 4-year rate of 15.1%. Compared with North America, Japan experienced lower ischemic event rates (P < 0.01), whereas Eastern Europe (P < 0.01) and the Middle East (P = 0.01) experienced higher ischemic event rates. The presence of congestive heart failure, polyvascular disease, diabetes, atrial fibrillation or flutter, and older age were associated with increased residual risk (all P < 0.01). Statin use was associated with lower ischemic risk (P < 0.01). CONCLUSIONS: In this study, residual ischemic risk after MI accrued progressively up to 4 years of follow-up, emphasizing the value of intensive secondary prevention strategies to minimize residual risk.

Prevalence and co-prevalence of comorbidities among patients with type 2 diabetes mellitus.

OBJECTIVE: Patients with type 2 diabetes (T2DM) often have multiple comorbidities which may impact the selection of antihyperglycemic therapies. The purpose of this study was to quantify the prevalence and co-prevalence of common comorbidities. RESEARCH DESIGN AND METHODS: A retrospective study was conducted using the Quintiles Electronic Medical Record database. Adult patients with T2DM who had ≥1 encounter from July 2014 to June 2015 (index period) with ≥1 year medical history available were included. The index date was defined as the most recent encounter date during the 1 year index period. MAIN OUTCOME MEASURES: Comorbid conditions were assessed using all data available prior to and including the index date. Patient characteristics, laboratory measures, and comorbidities were summarized via descriptive analyses, overall and by subgroups of age (<65, 65-74, 75+ years) and gender. RESULTS: Of the 1,389,016 eligible patients, 53% were female and the median age was 65 years. 97.5% of patients had at least one comorbid condition in addition to T2DM and 88.5% had at least two. The comorbidity burden tended to increase in older age groups and was higher in men than women. The most common conditions in patients with T2DM included hypertension (HTN) in 82.1%; overweight/obesity in 78.2%; hyperlipidemia in 77.2%; chronic kidney disease (CKD) in 24.1%; and cardiovascular disease (CVD) in 21.6%. The highest co-prevalence was demonstrated for the combination of HTN and hyperlipidemia (67.5%), followed by overweight/obesity and HTN (66.0%), overweight/obesity and hyperlipidemia (62.5%), HTN and CKD (22.4%), hyperlipidemia and CKD (21.1%), HTN and CVD (20.2%), hyperlipidemia and CVD (20.1%), overweight/obesity and CKD (19.1%) and overweight/obesity and CVD (17.0%). LIMITATIONS: Limitations include the potential for misclassification/underreporting due to the use of diagnostic codes, drug codes, or laboratory measures for identification of medical conditions. CONCLUSIONS: The vast majority of patients with T2DM have multiple comorbidities. To ensure a comprehensive approach to patient management, the presence of multimorbidity should be considered in the context of clinical decision making.

Improving clinical trials for cardiovascular diseases: a position paper from the Cardiovascular Round Table of the European Society of Cardiology.

AIMS: Cardiovascular disease is the most common cause of mortality and morbidity in the world, but the pharmaceutical industry's willingness to invest in this field has declined because of the many challenges involved with bringing new cardiovascular drugs to market, including late-stage failures, escalating regulatory requirements, bureaucracy of the clinical trial business enterprise, and limited patient access after approval. This contrasts with the remaining burden of cardiovascular disease in Europe and in the world. Thus, clinical cardiovascular research needs to adapt to address the impact of these challenges in order to ensure development of new cardiovascular medicines. METHODS AND RESULTS: The present paper is the outcome of a two-day workshop held by the Cardiovascular Round Table of the European Society of Cardiology. We propose strategies to improve development of effective new cardiovascular therapies. These can include (i) the use of biomarkers to describe patients who will benefit from new therapies more precisely, achieving better human target validation; (ii) targeted, mechanism-based approaches to drug development for defined populations; (iii) the use of information technology to simplify data collection and follow-up in clinical trials; (iv) streamlining adverse event collection and reducing monitoring; (v) extended patent protection or limited rapid approval of new agents to motivate investment in early phase development; and (vi) collecting data needed for health technology assessment continuously throughout the drug development process (before and after approval) to minimize delays in patient access. Collaboration across industry, academia, regulators, and payers will be necessary to enact change and to unlock the existing potential for cardiovascular clinical drug development. CONCLUSIONS: A coordinated effort involving academia, regulators, industry, and payors will help to foster better and more effective conduct of clinical cardiovascular trials, supporting earlier availability of innovative therapies and better management of cardiovascular diseases.

How can the quality of medical data in pharmacovigilance, pharmacoepidemiology and clinical studies be guaranteed?

The development of medicinal products is subject to quality standards aimed at guaranteeing that database contents accurately reflect the source documents. Paradoxically, these standards hardly address the quality of the source data itself. The objective of this work was to propose recommendations to improve data quality in three fields (pharmacovigilance, pharmacoepidemiology and clinical studies). The analysis was focused on the data and on the critical stages presenting critical quality problems, for which the current guidelines are insufficiently detailed, unsuitable and/or poorly applied. Finally, recommendations have been proposed, mainly focused on the origin of the data and its transcription.