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Background: Type 2 diabetes (T2D) patients are at increased risk for cardiovascular (CV) events. Most guidelines recommend treating low-density lipoprotein cholesterol (LDL-C) levels to ≤70 mg/dL (1.8 mM) for patients with T2D and established atherosclerotic CV disease, and some a more aggressive target of ≤55 mg/dL (1.4 mM). Our objective was to assess the degree to which these LDL-C targets are achieved in routine practice.Methods: Using data from TECOS, an international pragmatic CV outcomes trial of sitagliptin vs placebo, we assessed lipid-lowering treatment among patients with T2D and CV disease, baseline lipid values, and the association between baseline LDL-C and 5-year risk for major adverse cardiac events (MACE; ie, CV death, nonfatal myocardial infarction, or nonfatal stroke).Results: Overall, 11,066 of 14,671 TECOS participants (75.4%) had LDL-C measured at baseline. Median age was 65 years, 72% were male, and median T2D duration was 10 years. Overall, 82.5% of patients were on statins; only 5.8% were on ezetimibe. At baseline, 14.3% had LDL-C ≤55 mg/dL, 18.4% between 55.1 and 70 mg/dL, 35% between 70.1 and 100 mg/dL, and 32.3% >100 mg/dL. Each 10 mg/dL higher LDL-C value was associated with a higher risk of MACE (HR 1.05, 95% CI 1.03-1.07) or CV death (HR 1.06, 95% CI 1.04-1.09).Conclusions: Although most high-risk patients with T2D and CV disease were on lipid-lowering therapy, only 1:3 had LDL-C <70 mg/dL and 1:6 had LDL-C <55 mg/dL. Each 10 mg/dL higher LDL-C value was associated with a 5% and 6% higher 5-year incidence of MACE and CV death, respectively. (TECOS, NCT00790205). [ABSTRACT FROM AUTHOR]

Background: Obesity is a risk factor for type 2 diabetes (T2D) and cardiovascular disease (CVD). Whether obesity affects outcomes among those with T2D and atherosclerotic CVD (ASCVD) remains uncertain. Our objective was to investigate the relationship between body mass index (BMI) and ASCVD outcomes among TECOS participants with T2D and ASCVD.Methods: BMI categories were defined as underweight/normal weight (BMI <25 kg/m2), overweight (25-29.9 kg/m2), obese class I (30-34.9 kg/m2), obese class II (35-39.9 kg/m2), and obese class III (≥ 40 kg/m2). Asian-specific BMI categories were applied to Asian participants. Kaplan-Meier survival analysis and Cox proportional hazards models were used to examine associations between baseline BMI and a composite CV outcome (CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina).Results: For 14,534 TECOS patients with available BMI, mean age was 65.5 years; 29.3% were female, 32.0% non-White, and 23.1% insulin-treated, with median 3 years' follow-up. At baseline, 11.6% (n = 1686) were underweight/normal weight, 38.1% (n = 5532) overweight, 32.2% (n = 4683) obese class I, 12.4% (n = 1806) obese class II, and 5.7% (n = 827) obese class III. The composite CV outcome occurred in 11.4% (n = 1663) of participants; the outcome risk was lower, compared with under/normal weight, in overweight (HR 0.83, 95% CI 0.71-0.98) and obese class I (HR 0.79, 95% CI 0.67-0.93) individuals. Obesity was not associated with worse glycemic control.Conclusions: The majority of TECOS participants with ASCVD and T2D were overweight or obese, yet overweight or obese class I individuals had lower CV risk than those who were under/normal weight. These results suggest the presence of an obesity paradox, but this paradox may reflect an epidemiological artifact rather than a true negative association between normal weight and clinical outcomes. [ABSTRACT FROM AUTHOR]

International differences in management/outcomes among patients with type 2 diabetes and heart failure (HF) are not well characterized. We sought to evaluate geographic variation in treatment and outcomes among these patients. METHODS AND RESULTS: Among 14,671 participants in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), those with HF at baseline and a documented ejection fraction (EF) (N = 1591; 10.8%) were categorized by enrollment region (North America, Latin America, Western Europe, Eastern Europe, and Asia Pacific). Cox models were used to examine the association between geographic region and the primary outcome of all-cause mortality (ACM) or hospitalization for HF (hHF) in addition to ACM alone. Analyses were stratified by those with EF <40% or EF ≥40%. The majority of participants with HF were enrolled in Eastern Europe (53%). Overall, 1,267 (79.6%) had EF ≥40%. β-Blocker (83%) and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (86%) use was high across all regions in patients with EF <40%. During a median follow-up of 2.9 years, Eastern European participants had lower rates of ACM/hHF compared with North Americans (adjusted hazard ratio: 0.45; 95% CI: 0.32-0.64). These differences were seen only in the EF ≥40% subgroup and not the EF <40% subgroup. ACM was similar among Eastern European and North American participants (adjusted hazard ratio: 0.79; 95% CI: 0.44-1.45). CONCLUSIONS: Significant variation exists in the clinical features and outcomes of HF patients across regions in TECOS. Patients from Eastern Europe had lower risk-adjusted ACM/hHF than those in North America, driven by those with EF ≥40%. These data may inform the design of future international trials. [ABSTRACT FROM AUTHOR]

Aim: To examine sex differences in baseline characteristics and outcomes in patients with type 2 diabetes and atherosclerotic vascular disease. Materials and methods: Cox models were used to analyse the association between sex and outcomes in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), a randomized, placebo‐controlled trial assessing the impact of sitagliptin on cardiovascular (CV) outcomes in patients with type 2 diabetes and atherosclerotic vascular disease. Results: A total of 4297 women and 10 374 men were followed for a median of 3.0 years. Women were slightly older and more often had cerebrovascular disease and peripheral arterial disease but less often coronary heart disease than men. At baseline, women were less likely to use aspirin or statins. The primary composite outcome of CV death, myocardial infarction, stroke, or hospitalization for unstable angina occurred in 418 women (9.7%) and 1272 men (12.3%; 3.48 vs 4.38 events/100 participant‐years, crude hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.71‐0.89, adjusted HR 0.64, 95% CI 0.55‐0.74; P < .0001). Women also had a significantly lower risk of secondary CV outcomes and all‐cause death. Conclusions: In this large prospective study of people with type 2 diabetes and CV disease, women had different CV disease burden, worse CV risk factor profiles, and less use of indicated medications than men. Despite this, women had significantly lower risk of CV events, suggesting that the cardioprotective effects of female sex extend to populations with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aims: TECOS, a cardiovascular safety trial ( ClinicalTrials.gov identifier: NCT00790205) involving 14 671 patients with type 2 diabetes and cardiovascular disease, demonstrated that sitagliptin was non‐inferior to placebo for the primary composite cardiovascular outcome when added to best usual care. This study tested hypotheses that medical resource use and costs differed between these 2 treatment strategies. Materials and methods: Information concerning medical resource use was collected on case report forms throughout the trial and was valued using US costs for: Medicare payments for hospitalizations, medical procedures and outpatient visits, and wholesale acquisition costs (WAC) for diabetes‐related medications. Hierarchical generalized linear models were used to compare resource use and US costs, accounting for variable intercountry practice patterns. Sensitivity analyses included resource valuation using English costs for a UK perspective. Results: There were no significant differences in hospitalizations, inpatient days, medical procedures, or outpatient visits during follow‐up (mean and median 3.0 years in both groups). Hospitalization rates appeared to diverge after 2 years, with lower rates among sitagliptin‐treated vs placebo patients after 2.5 years (relative rate, 0.90 [95% CI, 0.83‐0.97]; P = .01). Mean medical costs, exclusive of study medication, were 11 937 USD in the sitagliptin arm and 12 409 USD in the placebo arm (P = .06). Mean sitagliptin costs based on undiscounted WAC were 9978 USD per patient. Differential UK total costs including study drug costs were smaller (911 GBP), primarily because of lower mean costs for sitagliptin (1072 GBP). Conclusions: Lower hospitalization rates across time with sitagliptin slightly offset sitagliptin treatment costs over 3 years in type 2 diabetes patients at high risk for cardiovascular events. [ABSTRACT FROM AUTHOR]

Aim: Pooled efficacy studies suggest that glycaemic responses to dipeptidyl‐peptidase 4 inhibitors in type 2 diabetes are greatest in Asians, who may also respond better to alpha‐glucosidase inhibitors. We assessed the glycaemic impact of sitagliptin by race in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), and whether this was enhanced in Asians with concomitant acarbose therapy. Materials and methods: TECOS enrolled 14 671 patients with type 2 diabetes, cardiovascular disease and HbA1c of 48–64 mmol/mol (6.5%‐8.0%), and randomized them, double‐blind, to sitagliptin or placebo. There were 3265 patients (22.3%) from Asian countries. Background glucose‐lowering therapies were unaltered for the first 4 months post randomization unless clinically essential, facilitating comparison of sitagliptin‐associated effects in self‐identified East Asian, Other (South) Asian, White Caucasian, Hispanic, Black and Indigenous groups. Results: Median baseline HbA1c by race was 54 to 57 mmol/mol (7.1%‐7.4%). Mean 4‐month reduction in placebo‐adjusted HbA1c was greatest in East Asians (−6.6 mmol/mol [−0.60%] vs ≤6.0 mmol/mol [≤0.55%] in other groups), with significantly greater reduction vs the 2 largest groups (White Caucasians, Other Asians; P < .0001) after adjustment for covariates. After the first 4 months, East and Other Asians were more likely to initiate additional oral therapy (metformin and/or sulfonylureas) than insulin vs White Caucasians (P < .0001). Acarbose use increased in the Asian patients, but no glycaemic interaction with allocated study medication was observed (adjusted P = .12). Conclusions: The greatest initial reduction in HbA1c with sitagliptin in the TECOS population was in East Asians. No enhanced glycaemic effect was seen when sitagliptin was given with acarbose. [ABSTRACT FROM AUTHOR]

Objective: Severe hypoglycemic events (SHEs) in type 2 diabetes are associated with subsequent cardiovascular (CV) event risk. We examined whether CV events were associated with subsequent SHE risk.Research Design and Methods: Time-dependent associations between SHEs and a composite CV end point (fatal/nonfatal myocardial infarction or stroke, hospitalization for unstable angina, hospitalization for heart failure [hHF]) were examined post hoc in 14,671 TECOS (Trial Evaluating Cardiovascular Outcomes With Sitagliptin) participants with type 2 diabetes and CV disease followed for a median of 3.0 years.Results: SHEs were uncommon and unassociated with sitagliptin therapy (N = 160 [2.2%], 0.78/100 patient-years vs. N = 143 [1.9%], 0.70/100 patient-years for placebo; hazard ratio [HR] 1.12 [95% CI 0.89, 1.40], P = 0.33). Patients with (versus without) SHEs were older with longer diabetes duration, lower body weight, and lower estimated glomerular filtration rate; were more frequently women, nonwhite, and insulin treated; and more often had microalbuminuria or macroalbuminuria. Analyses adjusted for clinical factors showed SHEs were associated with increased risk of the primary composite CV end point (1.55 [1.06, 2.28], P = 0.025), all-cause death (1.83 [1.22, 2.75], P = 0.004), and CV death (1.72 [1.02, 2.87], P = 0.040). Conversely, nonfatal myocardial infarction (3.02 [1.83, 4.96], P < 0.001), nonfatal stroke (2.77 [1.36, 5.63], P = 0.005), and hHF (3.68 [2.13, 6.36], P < 0.001) were associated with increased risk of SHEs. Fully adjusted models showed no association between SHEs and subsequent CV or hHF events, but the association between CV events and subsequent SHEs remained robust.Conclusions: These findings, showing greater risk of SHEs after CV events and greater risk of CV events after SHEs, suggest a common at-risk type 2 diabetes frail patient phenotype. [ABSTRACT FROM AUTHOR]

Objective: We evaluated the specific causes of death and their associated risk factors in a contemporary cohort of patients with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD).Research Design and Methods: We used data from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) study (n = 14,671), a cardiovascular (CV) safety trial adding sitagliptin versus placebo to usual care in patients with type 2 diabetes and ASCVD (median follow-up 3 years). An independent committee blinded to treatment assignment adjudicated each cause of death. Cox proportional hazards models were used to identify risk factors associated with each outcome.Results: A total of 1,084 deaths were adjudicated as the following: 530 CV (1.2/100 patient-years [PY], 49% of deaths), 338 non-CV (0.77/100 PY, 31% of deaths), and 216 unknown (0.49/100 PY, 20% of deaths). The most common CV death was sudden death (n = 145, 27% of CV death) followed by acute myocardial infarction (MI)/stroke (n = 113 [MI n = 48, stroke n = 65], 21% of CV death) and heart failure (HF) (n = 63, 12% of CV death). The most common non-CV death was malignancy (n = 154, 46% of non-CV death). The risk of specific CV death subcategories was lower among patients with no baseline history of HF, including sudden death (hazard ratio [HR] 0.4; P = 0.0036), MI/stroke death (HR 0.47; P = 0.049), and HF death (HR 0.29; P = 0.0057).Conclusions: In this analysis of a contemporary cohort of patients with diabetes and ASCVD, sudden death was the most common subcategory of CV death. HF prevention may represent an avenue to reduce the risk of specific CV death subcategories. [ABSTRACT FROM AUTHOR]

Systolic blood pressure (SBP) treatment targets for adults with diabetes mellitus remain unclear. SBP levels among 12 275 adults with diabetes mellitus, prior cardiovascular disease, and treated hypertension were evaluated in the TECOS (Trial Evaluating Cardiovascular Outcomes With Sitagliptin) randomized trial of sitagliptin versus placebo. The association between baseline SBP and recurrent cardiovascular disease was evaluated using multivariable Cox proportional hazards modeling with restricted cubic splines, adjusting for clinical characteristics. Kaplan-Meier curves by baseline SBP were created to assess time to cardiovascular disease and 2 potential hypotension-related adverse events: worsening kidney function and fractures. The association between time-updated SBP and outcomes was examined using multivariable Cox proportional hazards models. Overall, 42.2% of adults with diabetes mellitus, cardiovascular disease, and hypertension had an SBP ≥140 mm Hg. The association between SBP and cardiovascular disease risk was U shaped, with a nadir ≈130 mm Hg. When the analysis was restricted to those with baseline SBP of 110 to 150 mm Hg, the adjusted association between SBP and cardiovascular disease risk was flat (hazard ratio per 10-mm Hg increase, 0.96; 95% confidence interval, 0.91-1.02). There was no association between SBP and risk of fracture. Above 150 mm Hg, higher SBP was associated with increasing risk of worsening kidney function (hazard ratio per 10-mm Hg increase, 1.10; 95% confidence interval, 1.02-1.18). Many patients with diabetes mellitus have uncontrolled hypertension. The U-shaped association between SBP and cardiovascular disease events was largely driven by those with very high or low SBP, with no difference in cardiovascular disease risk between 110 and 150 mm Hg. Lower SBP was not associated with higher risks of fractures or worsening kidney function. [ABSTRACT FROM AUTHOR]

Objective: Limited data exist regarding safety and efficacy of antihyperglycemic drugs in older patients with type 2 diabetes. The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) was a randomized, double-blind, placebo-controlled trial assessing the impact of sitagliptin on a primary composite outcome of cardiovascular death, nonfatal stroke, nonfatal myocardial infarction, or unstable angina hospitalizations in patients with type 2 diabetes (HbA1c ≥6.5% [48 mmol/mol] and ≤8.0% [64 mmol/mol]) and cardiovascular disease. We analyzed baseline characteristics and clinical outcomes for TECOS participants aged ≥75 years.Research Design and Methods: Clinical and safety event summaries are presented for older versus younger participants and for the treatment groups within the older cohort.Results: Of 14,351 participants with age recorded, 2,004 (14%) were ≥75 years old (mean age 78.3 years [SD 3.1]), with 68% men and type 2 diabetes duration median 12.0 years (IQR 7, 21). During 2.9 years median follow-up, older participants had higher rates of the primary outcome (6.46 vs. 3.67 events per 100 person-years; hazard ratio 1.72 [95% CI 1.52-1.94]), death (2.52 [2.20-2.89]), severe hypoglycemia (1.53 [1.15-2.03]), and fractures (1.84 [1.44-2.35]). In the older cohort, sitagliptin did not significantly impact the primary composite (1.10 [0.89-1.36]), death (1.05 [0.83-1.32]), heart failure hospitalization (0.99 [0.65-1.49]), severe hypoglycemia (1.03 [0.62-1.71]), rates of acute pancreatitis and pancreatic cancer, or serious adverse events.Conclusions: Among older patients with well-controlled type 2 diabetes and cardiovascular disease, sitagliptin had neutral effects on cardiovascular risk and raised no significant safety concerns. [ABSTRACT FROM AUTHOR]

Objective: We evaluated the incidence of acute pancreatitis and pancreatic cancer in patients with type 2 diabetes and cardiovascular disease who were treated with sitagliptin, a dipeptidyl peptidase-4 inhibitor (DPP-4i).Research Design and Methods: In the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) study, a cardiovascular safety study of sitagliptin, all suspected cases of acute pancreatitis and pancreatic cancer were collected prospectively for 14,671 participants during a median follow-up time of 3 years, and were adjudicated blindly.Results: Baseline differences were minimal between participants confirmed to have no pancreatic events, acute pancreatitis, or pancreatic cancer. Among those participants randomized to receive sitagliptin, 23 (0.3%) (vs. 12 randomized to receive placebo [0.2%]) had pancreatitis (hazard ratio 1.93 [95% CI 0.96-3.88], P = 0.065; 0.107 vs. 0.056/100 patient-years), with 25 versus 17 events, respectively. Severe pancreatitis (two fatal) occurred in four individuals allocated to receive sitagliptin. Cases of pancreatic cancer were numerically fewer with sitagliptin (9 [0.1%]) versus placebo (14 [0.2%]) (hazard ratio 0.66 [95% CI 0.28-1.51], P = 0.32; 0.042 vs. 0.066 events/100 patient-years). Meta-analysis with two other DPP-4i cardiovascular outcome studies showed an increased risk for acute pancreatitis (risk ratio 1.78 [95% CI 1.13-2.81], P = 0.01) and no significant effect for pancreatic cancer (risk ratio 0.54 [95% CI 0.28-1.04], P = 0.07).Conclusions: Pancreatitis and pancreatic cancer were uncommon events with rates that were not statistically significantly different between the sitagliptin and placebo groups, although numerically more sitagliptin participants developed pancreatitis and fewer developed pancreatic cancer. Meta-analysis suggests a small absolute increased risk for pancreatitis with DPP-4i therapy. [ABSTRACT FROM AUTHOR]

Objective: To evaluate chronic kidney disease (CKD) and cardiovascular outcomes in TECOS (Clinical trial reg. no. NCT00790205, clinicaltrials.gov) participants with type 2 diabetes and cardiovascular disease treated with sitagliptin, a dipeptidyl peptidase 4 inhibitor, according to baseline estimated glomerular filtration rate (eGFR).Research Design and Methods: We used data from 14,671 TECOS participants assigned in a double-blind design to receive sitagliptin or placebo added to existing therapy, while aiming for glycemic equipoise between groups. Cardiovascular and CKD outcomes were evaluated over a median period of 3 years, with participants categorized at baseline into eGFR stages 1, 2, 3a, and 3b (≥90, 60-89, 45-59, or 30-44 mL/min/1.73 m2, respectively).Results: Participants with eGFR stage 3b were older, were more often female, and had a longer duration of diabetes. Four-point major adverse cardiovascular event rates increased with lower baseline eGFR (3.52, 3.55, 5.74, and 7.34 events/100 patient-years for stages 1-3b, respectively). Corresponding adjusted hazard ratios for stages 2, 3a, and 3b versus stage 1 were 0.93 (95% CI 0.82-1.06), 1.28 (1.10-1.49), and 1.39 (1.13-1.72), respectively. Sitagliptin therapy was not associated with cardiovascular outcomes for any eGFR stage (interaction P values were all >0.44). Kidney function declined at the same rate in both treatment groups, with a marginally lower but constant eGFR difference (-1.3 mL/min/1.73 m2) in those participants who were assigned to sitagliptin. Treatment differences in these eGFR values remained after adjustment for region, baseline eGFR, baseline HbA1c, time of assessment, and within-study HbA1c levels.Conclusions: Impaired kidney function is associated with worse cardiovascular outcomes. Sitagliptin has no clinically significant impact on cardiovascular or CKD outcomes, irrespective of baseline eGFR. [ABSTRACT FROM AUTHOR]

The authors reviews the study by Davis et al that investigated the relationship between severe hypoglycemic events (SHE) and subsequent risk of cardiovascular (CV) events or deaths observed in the Veterans Affairs Diabetes Trial (VADT). They claim that by not acknowledging an earlier study that investigated SHE before and after cardiovascular outcome, the present study missed the opportunity to potentially confirm the intriguing reverse scenario between non-fatal CV and subsequent risk of SHE.

Background: Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease.Methods: In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina.Results: During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P=0.98). There were no significant between-group differences in rates of acute pancreatitis (P=0.07) or pancreatic cancer (P=0.32).Conclusions: Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events. (Funded by Merck Sharp & Dohme; TECOS ClinicalTrials.gov number, NCT00790205.). [ABSTRACT FROM AUTHOR]