Shona Livingstone

Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial

BACKGROUND Type 2 diabetes is associated with a substantially increased risk of cardiovascular disease, but the role of lipid-lowering therapy with statins for the primary prevention of cardiovascular disease in diabetes is inadequately defined. We aimed to assess the effectiveness of atorvastatin 10 mg daily for primary prevention of major cardiovascular events in patients with type 2 diabetes without high concentrations of LDL-cholesterol. METHODS 2838 patients aged 40-75 years in 132 centres in the UK and Ireland were randomised to placebo (n=1410) or atorvastatin 10 mg daily (n=1428). Study entrants had no documented previous history of cardiovascular disease, an LDL-cholesterol concentration of 4.14 mmol/L or lower, a fasting triglyceride amount of 6.78 mmol/L or less, and at least one of the following: retinopathy, albuminuria, current smoking, or hypertension. The primary endpoint was time to first occurrence of the following: acute coronary heart disease events, coronary revascularisation, or stroke. Analysis was by intention to treat. FINDINGS The trial was terminated 2 years earlier than expected because the prespecified early stopping rule for efficacy had been met. Median duration of follow-up was 3.9 years (IQR 3.0-4.7). 127 patients allocated placebo (2.46 per 100 person-years at risk) and 83 allocated atorvastatin (1.54 per 100 person-years at risk) had at least one major cardiovascular event (rate reduction 37% [95% CI -52 to -17], p=0.001). Treatment would be expected to prevent at least 37 major vascular events per 1000 such people treated for 4 years. Assessed separately, acute coronary heart disease events were reduced by 36% (-55 to -9), coronary revascularisations by 31% (-59 to 16), and rate of stroke by 48% (-69 to -11). Atorvastatin reduced the death rate by 27% (-48 to 1, p=0.059). No excess of adverse events was noted in the atorvastatin group. INTERPRETATION Atorvastatin 10 mg daily is safe and efficacious in reducing the risk of first cardiovascular disease events, including stroke, in patients with type 2 diabetes without high LDL-cholesterol. No justification is available for having a particular threshold level of LDL-cholesterol as the sole arbiter of which patients with type 2 diabetes should receive statins. The debate about whether all people with this disorder warrant statin treatment should now focus on whether any patients are at sufficiently low risk for this treatment to be withheld.

Effects of atorvastatin on kidney outcomes and cardiovascular disease in patients with diabetes: an analysis from the Collaborative Atorvastatin Diabetes Study (CARDS).

BACKGROUND We examined whether atorvastatin affects diabetic kidney disease and whether the effect of atorvastatin on cardiovascular disease (CVD) varies by kidney status in patients with diabetes. STUDY DESIGN The Collaborative Atorvastatin Diabetes Study (CARDS) randomized placebo-controlled trial. SETTING & PARTICIPANTS Patients with type 2 diabetes and no prior CVD (n = 2,838). INTERVENTION Random allocation to atorvastatin, 10 mg/d, or placebo, with a median follow-up of 3.9 years. OUTCOMES Estimated glomerular filtration rate (eGFR), albuminuria, CVD. MEASUREMENTS Baseline and follow-up GFRs were estimated by using the Modification of Diet in Renal Disease Study equation. Urinary albumin-creatinine ratio was measured on spot urine samples. RESULTS At baseline, 34% of patients had an eGFR of 30 to 60 mL/min/1.73 m(2). Atorvastatin treatment was associated with a modest improvement in annual change in eGFR (net, 0.18 mL/min/1.73 m(2)/y; 95% confidence interval [CI], 0.04 to 0.32; P = 0.01) that was most apparent in those with albuminuria (net improvement, 0.38 mL/min/1.73 m(2)/y; P = 0.03). At baseline, 21.5% of patients had albuminuria and an additional 6.8% developed albuminuria during follow-up. Atorvastatin did not influence the incidence of albuminuria (hazard ratio, 1.49; 95% CI, 0.73 to 3.04; P = 0.3) or regression to normoalbuminuria (hazard ratio, 1.19; 95% CI, 0.57 to 2.49; P = 0.6). In 970 patients with a moderately decreased eGFR of 30 to 60 mL/min/1.73 m(2), there was a 42% reduction in major CVD events with treatment, including a 61% reduction in stroke. This treatment effect was similar to the 37% (95% CI, 17 to 52; P < 0.001) reduction in CVD observed in the study overall (P = 0.4 for the eGFR-treatment interaction). LIMITATIONS Low incidence rates of albuminuria and transition to more severe kidney status limit power to detect treatment effects. CONCLUSIONS A modest beneficial effect of atorvastatin on eGFR, particularly in those with albuminuria, was observed. Atorvastatin did not influence albuminuria incidence. Atorvastatin was effective at decreasing CVD in those with and without a moderately decreased eGFR and achieved a high absolute benefit.

Estimated Life Expectancy in a Scottish Cohort With Type 1 Diabetes, 2008-2010

IMPORTANCE Type 1 diabetes has historically been associated with a significant reduction in life expectancy. Major advances in treatment of type 1 diabetes have occurred in the past 3 decades. Contemporary estimates of the effect of type 1 diabetes on life expectancy are needed. OBJECTIVE To examine current life expectancy in people with and without type 1 diabetes in Scotland. We also examined whether any loss of life expectancy in patients with type 1 diabetes is confined to those who develop kidney disease. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort of all individuals alive in Scotland with type 1 diabetes who were aged 20 years or older from 2008 through 2010 and were in a nationwide register (n=24,691 contributing 67,712 person-years and 1043 deaths). MAIN OUTCOMES AND MEASURES Differences in life expectancy between those with and those without type 1 diabetes and the percentage of the difference due to various causes. RESULTS Life expectancy at an attained age of 20 years was an additional 46.2 years among men with type 1 diabetes and 57.3 years among men without it, an estimated loss in life expectancy with diabetes of 11.1 years (95% CI, 10.1-12.1). Life expectancy from age 20 years was an additional 48.1 years among women with type 1 diabetes and 61.0 years among women without it, an estimated loss with diabetes of 12.9 years (95% CI, 11.7-14.1). Even among those with type 1 diabetes with an estimated glomerular filtration rate of 90 mL/min/1.73 m2 or higher, life expectancy was reduced (49.0 years in men, 53.1 years in women) giving an estimated loss from age 20 years of 8.3 years (95% CI, 6.5-10.1) for men and 7.9 years (95% CI, 5.5-10.3) for women. Overall, the largest percentage of the estimated loss in life expectancy was related to ischemic heart disease (36% in men, 31% in women) but death from diabetic coma or ketoacidosis was associated with the largest percentage of the estimated loss occurring before age 50 years (29.4% in men, 21.7% in women). CONCLUSIONS AND RELEVANCE Estimated life expectancy for patients with type 1 diabetes in Scotland based on data from 2008 through 2010 indicated an estimated loss of life expectancy at age 20 years of approximately 11 years for men and 13 years for women compared with the general population without type 1 diabetes.

Risk of cardiovascular disease and total mortality in adults with type 1 diabetes: Scottish registry linkage study

Helen Colhoun and colleagues report findings from a Scottish registry linkage study regarding contemporary risks for cardiovascular events and all-cause mortality among individuals diagnosed with type 1 diabetes.

Total Soluble and Endogenous Secretory Receptor for Advanced Glycation End Products as Predictive Biomarkers of Coronary Heart Disease Risk in Patients With Type 2 Diabetes An Analysis From the CARDS Trial

OBJECTIVE Circulating levels of soluble receptor for advanced glycation end products (sRAGE) likely comprise both a secreted isoform (esRAGE) and wild-type RAGE cleaved from the cell membrane. Both sRAGE and esRAGE have been proposed as biomarkers of cardiovascular disease (CVD), but prospective data are limited. We examined the relationship of sRAGE and esRAGE to incident coronary heart disease (CHD) and stroke in type 2 diabetic patients followed for 3.9 years in a trial of atorvastatin: the Collaborative Atorvastatin Diabetes Study (CARDS). RESEARCH DESIGN AND METHODS We used a nested case-control design sampling all incident cases of CVD with available plasma and randomly selecting three control subjects, who were free of CVD throughout follow-up, per case. Analysis was by Cox regression with adjustment for treatment allocation and relevant covariates. RESULTS sRAGE and esRAGE were strongly correlated (ρ = 0.88) and were both higher in those with lower BMI (P < 0.001), higher adiponectin (P < 0.001), lower estimated glomerular filtration rate (P = 0.009), and white ethnicity (P < 0.001). Both sRAGE and esRAGE were associated with incident CHD events, independently of treatment allocation and the above factors; hazard ratio (HR) = 1.74 (95% CI 1.25–2.41; P = 0.002) for a doubling of the sRAGE level; HR = 1.45 (1.11–1.89; P = 0.006) for a doubling of the esRAGE level. There was no significant association with stroke; HR for sRAGE = 0.66 (0.38–1.14). Atorvastatin, 10 mg daily, did not alter sRAGE. CONCLUSIONS Higher levels of sRAGE and esRAGE are associated with incident CHD but not stroke in type 2 diabetes.

Hospitalised hip fracture risk with rosiglitazone and pioglitazone use compared with other glucose-lowering drugs

Aims/hypothesisCurrent drug labels for thiazolidinediones (TZDs) warn of increased fractures, predominantly for distal fractures in women. We examined whether exposure to TZDs affects hip fracture in women and men and compared the risk to that found with other drugs used in diabetes.MethodsUsing a nationwide database of prescriptions, hospital admissions and deaths in those with type 2 diabetes in Scotland we calculated TZD exposure among 206,672 individuals. Discrete-time failure analysis was used to model the effect of cumulative drug exposure on hip fracture during 1999–2008.ResultsThere were 176 hip fractures among 37,479 exposed individuals. Hip fracture risk increased with cumulative exposure to TZD: OR per year of exposure 1.18 (95% CI 1.09, 1.28; p = 3 × 10−5), adjusted for age, sex and calendar month. Hip fracture increased with cumulative exposure in both men (OR 1.20; 95% CI 1.03, 1.41) and women (OR 1.18; 95% CI 1.07, 1.29) and risks were similar for pioglitazone (OR 1.18) and rosiglitazone (OR 1.16). The association was similar when adjusted for exposure to other drugs for diabetes and for other potential confounders. There was no association of hip fracture with cumulative exposure to sulfonylureas, metformin or insulin in this analysis. The 90-day mortality associated with hip fractures was similar in ever-users of TZD (15%) and in never-users (13%).Conclusions/interpretationHip fracture is a severe adverse effect with TZDs, affecting both sexes; labels should be changed to warn of this. The excess mortality is at least as much as expected from the reported association of pioglitazone with bladder cancer.

Genome-wide association study of genetic determinants of LDL-c response to atorvastatin therapy: importance of Lp(a).

We carried out a genome-wide association study (GWAS) of LDL-c response to statin using data from participants in the Collaborative Atorvastatin Diabetes Study (CARDS; n = 1,156), the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT; n = 895), and the observational phase of ASCOT (n = 651), all of whom were prescribed atorvastatin 10 mg. Following genome-wide imputation, we combined data from the three studies in a meta-analysis. We found associations of LDL-c response to atorvastatin that reached genome-wide significance at rs10455872 (P = 6.13 × 10−9) within the LPA gene and at two single nucleotide polymorphisms (SNP) within the APOE region (rs445925; P = 2.22 × 10−16 and rs4420638; P = 1.01 × 10−11) that are proxies for the ε2 and ε4 variants, respectively, in APOE. The novel association with the LPA SNP was replicated in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial (P = 0.009). Using CARDS data, we further showed that atorvastatin therapy did not alter lipoprotein(a) [Lp(a)] and that Lp(a) levels accounted for all of the associations of SNPs in the LPA gene and the apparent LDL-c response levels. However, statin therapy had a similar effect in reducing cardiovascular disease (CVD) in patients in the top quartile for serum Lp(a) levels (HR = 0.60) compared with those in the lower three quartiles (HR = 0.66; P = 0.8 for interaction). The data emphasize that high Lp(a) levels affect the measurement of LDL-c and the clinical estimation of LDL-c response. Therefore, an apparently lower LDL-c response to statin therapy may indicate a need for measurement of Lp(a). However, statin therapy seems beneficial even in those with high Lp(a).

Analysis of Efficacy and Safety in Patients Aged 65-75 Years at Randomization Collaborative Atorvastatin Diabetes Study (CARDS)

OBJECTIVE—Rates of cardiovascular disease are highest in the elderly. Lipid-lowering statin therapy reduces the proportional risk as effectively in older patients as in younger individuals; however, limited data are available for elderly patients with type 2 diabetes. We conducted a post hoc analysis to compare the efficacy and safety of atorvastatin among 1,129 patients aged 65–75 years at randomization with 1,709 younger patients in the Collaborative Atorvastatin Diabetes Study (CARDS). RESEARCH DESIGN AND METHODS—CARDS was a randomized placebo-controlled trial of 10 mg/day atorvastatin for primary prevention of cardiovascular disease in patients aged 40–75 years with LDL cholesterol concentrations ≤4.14 mmol/l followed for a median of 3.9 years. The primary end point was time to first occurrence of acute coronary heart disease events, coronary revascularizations, or stroke. RESULTS—Atorvastatin treatment resulted in a 38% reduction in relative risk ([95% CI −58 to −8], P = 0.017) of first major cardiovascular events in older patients and a 37% reduction ([−57 to −7], P = 0.019) in younger patients. Corresponding absolute risk reductions were 3.9 and 2.7%, respectively (difference 1.2% [95% CI −2.8 to 5.3], P = 0.546); numbers needed to treat for 4 years to avoid one event were 21 and 33, respectively. All-cause mortality was reduced nonsignificantly by 22% ([−49 to 18], P = 0.245) and 37% ([−64 to 9], P = 0.98), respectively. The overall safety profile of atorvastatin was similar between age-groups. CONCLUSIONS—Absolute and relative benefits of statin therapy in older patients with type 2 diabetes are substantial, and all patients warrant treatment unless specifically contraindicated.

Contemporary Risk of Hip Fracture in Type 1 and Type 2 Diabetes: A National Registry Study From Scotland

The purpose of this study was to compare contemporary risk of hip fracture in type 1 and type 2 diabetes with the nondiabetic population. Using a national diabetes database, we identified those with type 1 and type 2 diabetes who were aged 20 to 84 years and alive anytime from January 1, 2005 to December 31, 2007. All hospitalized events for hip fracture in 2005 to 2007 for diabetes patients were linked and compared with general population counts. Age‐ and calendar‐year‐adjusted incidence rate ratios were calculated by diabetes type and sex. One hundred five hip fractures occurred in 21,033 people (59,585 person‐years) with type 1 diabetes; 1421 in 180,841 people (462,120 person‐years) with type 2 diabetes; and 11,733 hip fractures over 10,980,599 person‐years in the nondiabetic population (3.66 million people). Those with type 1 diabetes had substantially elevated risks of hip fracture compared with the general population incidence risk ratio (IRR) of 3.28 (95% confidence interval [CI] 2.52–4.26) in men and 3.54 (CI 2.75–4.57) in women. The IRR was greater at younger ages, but absolute risk difference was greatest at older ages. In type 2 diabetes, there was no elevation in risk among men (IRR 0.97 [CI 0.92–1.02]) and the increase in risk in women was small (IRR 1.05 [CI 1.01–1.10]). There remains a substantial elevation relative risk of hip fracture in people with type 1 diabetes, but the relative risk is much lower than in earlier studies. In contrast, there is currently little elevation in overall hip fracture risk with type 2 diabetes, but this may mask elevations in risk in particular subgroups of type 2 diabetes patients with different body mass indexes, diabetes duration, or drug exposure.

Targets of Statin Therapy : LDL Cholesterol, Non-HDL Cholesterol, and Apolipoprotein B in Type 2 Diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS)

BACKGROUND LDL can vary considerably in its cholesterol content; thus, lowering LDL cholesterol (LDLC) as a goal of statin treatment implies the existence of considerable variation in the extent to which statin treatment removes circulating LDL particles. This consideration is particularly applicable in diabetes mellitus, in which LDL is frequently depleted of cholesterol. METHODS Type 2 diabetes patients randomly allocated to 10 mg/day atorvastatin (n = 1154) or to placebo (n = 1196) for 1 year were studied to compare spontaneous and statin-induced apolipoprotein B (apo B) concentrations (a measure of LDL particle concentration) at LDLC and non-HDL cholesterol (non-HDLC) concentrations proposed as statin targets in type 2 diabetes. RESULTS Patients treated with atorvastatin produced lower serum apo B concentrations at any given LDLC concentration than patients on placebo. An LDLC concentration of 1.8 mmol/L (70 mg/dL) during atorvastatin treatment was equivalent to a non-HDLC concentration of 2.59 mmol/L (100 mg/dL) or an apo B concentration of 0.8 g/L. At the more conservative LDLC targets of 2.59 mmol/L (100 mg/dL) and 3.37 mmol/L (130 mg/dL) for non-HDLC, however, the apo B concentration exceeded the 0.9-g/L value anticipated in the recent Consensus Statement from the American Diabetes Association and the American College of Cardiology. CONCLUSIONS The apo B concentration provides a more consistent goal for statin treatment than the LDLC or non-HDLC concentration.