Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial.
Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, Forder P, Pillai A, Davis T, Glasziou P, Drury P, Kesaniemi YA, Sullivan D, Hunt D, Colman P, d'Emden M, Whiting M, Ehnholm C, Laakso M; FIELD study investigators.
Lancet 2005 Nov 26;366(9500):1849-61.
BACKGROUND: Patients with type 2 diabetes mellitus are at increased risk of cardiovascular disease, partly owing to dyslipidaemia, which can be amenable to fibrate therapy. We designed the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study to assess the effect of fenofibrate on cardiovascular disease events in these patients. METHODS: We did a multinational, randomised controlled trial with 9795 participants aged 50-75 years, with type 2 diabetes mellitus, and not taking statin therapy at study entry. After a placebo and a fenofibrate run-in phase, we randomly assigned patients (2131 with previous cardiovascular disease and 7664 without) with a total-cholesterol concentration of 3.0-6.5 mmol/L and a total-cholesterol/HDL-cholesterol ratio of 4.0 or more or plasma triglyceride of 1.0-5.0 mmol/L to micronised fenofibrate 200 mg daily (n=4895) or matching placebo (n=4900). Our primary outcome was coronary events (coronary heart disease death or non-fatal myocardial infarction); the outcome for prespecified subgroup analyses was total cardiovascular events (the composite of cardiovascular death, myocardial infarction, stroke, and coronary and carotid revascularisation). Analysis was by intention to treat. The study was prospectively registered (number ISRCTN 64783481). FINDINGS: Vital status was confirmed on all but 22 patients. Averaged over the 5 years' study duration, similar proportions in each group discontinued study medication (10% placebo vs 11% fenofibrate) and more patients allocated placebo (17%) than fenofibrate (8%; p<0.0001) commenced other lipid treatments, predominantly statins. 5.9% (n=288) of patients on placebo and 5.2% (n=256) of those on fenofibrate had a coronary event (relative reduction of 11%; hazard ratio [HR] 0.89, 95% CI 0.75-1.05; p=0.16). This finding corresponds to a significant 24% reduction in non-fatal myocardial infarction (0.76, 0.62-0.94; p=0.010) and a non-significant increase in coronary heart disease mortality (1.19, 0.90-1.57; p=0.22). Total cardiovascular disease events were significantly reduced from 13.9% to 12.5% (0.89, 0.80-0.99; p=0.035). This finding included a 21% reduction in coronary revascularisation (0.79, 0.68-0.93; p=0.003). Total mortality was 6.6% in the placebo group and 7.3% in the fenofibrate group (p=0.18). Fenofibrate was associated with less albuminuria progression (p=0.002), and less retinopathy needing laser treatment (5.2%vs 3.6%, p=0.0003). There was a slight increase in pancreatitis (0.5%vs 0.8%, p=0.031) and pulmonary embolism (0.7%vs 1.1%, p=0.022), but no other significant adverse effects. INTERPRETATION: Fenofibrate did not significantly reduce the risk of the primary outcome of coronary events. It did reduce total cardiovascular events, mainly due to fewer non-fatal myocardial infarctions and revascularisations. The higher rate of starting statin therapy in patients allocated placebo might have masked a moderately larger treatment benefit.
Diagnosis and Management of the Metabolic Syndrome: An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement
Scott M. Grundy, James I. Cleeman, Stephen R. Daniels, Karen A. Donato, Robert H. Eckel, Barry A. Franklin, David J. Gordon, Ronald M. Krauss, Peter J. Savage, Sidney C. Smith, Jr, John A. Spertus, Fernando Costa
In recent years, the metabolic syndrome (MetS) has received increased attention. The statement issued jointly by the American Heart Association and the National Heart, Lung, and Blood Institute provides up-to-date guidance for healthcare professionals on the diagnosis and management of MetS in adults. It is often discussed as if it were a discrete entity with a single cause.
The following emphasizes the Guidelines’ critical points:
- MetS is a term for a “constellation of risk factors” that increases the risk of developing both atherosclerotic cardiovascular disease and type 2 diabetes.
- MetS is not caused by a single factor. In addition, it shows substantial variation in the components among different individuals, with an even greater variation among different racial/ethnic groups.
- In the United States, MetS strongly correlates with the presence of abdominal obesity.
- MetS is a secondary target for reducing cardiovascular events. Smoking cessation, lowering LDL levels, as well as controlling blood pressure are the primary targets for risk reduction.
- Lifestyle interventions are the primary therapies recommended for MetS treatment. If lifestyle change is not sufficient, then drug therapies for abnormalities in the individual risk factors may be indicated.
- At this time, there is not enough evidence for primary use of drugs that target the underlying causes of MetS.
- Additional research is necessary to help clarify the most appropriate suitable therapies for persons with MetS.
Treatment of Lipids to Reduce Cardiovascular Risk Among People With the Metabolic Syndrome or Type 2 Diabetes
Sarah H Wild; Christopher D Byrne
Br J Diabetes Vasc Dis. 2006;5(6):315-319
The metabolic syndrome is present in approximately 20% of general populations in developed countries and in approximately 80% of people with type 2 diabetes. High triglyceride levels, low high-density cholesterol levels and central obesity are three of the five features of the metabolic syndrome and contribute to the increased risk of cardiovascular disease (CVD) among people with the metabolic syndrome. Lifestyle interventions and treatment with statins reduce risk of CVD but absolute risk of cardiovascular events among high-risk populations remains high. This article reviews the options for treating the atherogenic dyslipidaemia associated with the metabolic syndrome.
Contraindications can damage your health. Is metformin a case in point?
Diabetologia. 2005 Dec;48(12):2454-9.
Holstein A, Stumvoll M.
Clinic Lippe, First Department of Medicine, Detmold, Germany.
Metformin is an effective anti-hyperglycaemic and cardioprotective agent, but a long list of contraindications precludes millions of patients with type 2 diabetes from using it. This is largely due to the historical experience of lactic acidosis with phenformin, despite the fact that metformin does not predispose to this when compared with other therapies. Contraindications such as old age, renal impairment and cardiac insufficiency are increasingly disregarded in clinical practice, yet there is no evidence that the incidence of lactic acidosis has changed. Metformin has been shown to improve metabolic control without causing lactic acidosis in elderly patients with multiple comorbidities, including explicit contraindications, and its use in patients with type 2 diabetes over the age of 70 with mild renal impairment did not produce a clinically relevant increase in plasma lactate. There is no correlation between levels of metformin and lactate in patients with lactic acidosis, and its prognosis is mainly related to the causal hypoxic underlying disease and comorbidities. These findings raise doubts about the pathogenetic significance of metformin in lactic acidosis. We propose that advanced age per se, mild renal impairment and compensated heart failure can no longer be upheld as contraindications for metformin. A clear re-definition of contraindications to metformin will enable more physicians to prescribe within guidelines.
Intensive Diabetes Treatment and Cardiovascular Disease in Patients with Type 1 Diabetes
N Engl J Med 2005;353:2643-53.
The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC)Study Research Group*
Intensive diabetes therapy aimed at achieving near normoglycemia reduces the riskof microvascular and neurologic complications of type 1 diabetes.We studied whether the use of intensive therapy as compared with conventional therapy during the Diabetes Control and Complications Trial (DCCT)affected the long-term incidence of cardiovascular disease. methods. The DCCT randomly assigned 1441 patients with type 1 diabetes to intensive or conventional therapy,treating them for a mean of 6.5 years between 1983 and 1993. Ninety-three percent were subsequently followed until February 1,2005,during the observational Epidemiology of Diabetes Interventions and Complications study. Cardiovascular disease (defined as nonfatal myocardial infarction, stroke, death from cardiovascular disease,confirmed angina,or the need for coronary-artery revascularization)was assessed with standardized measures and classified by an independent committee.
During the mean 17 years of follow-up,46 cardiovascular disease events occurred in 31 patients who had received intensive treatment in the DCCT,as compared with 98 events in 52 patients who had received conventional treatment.Intensive treatment reduced the risk of any cardiovascular disease event by 42 percent (95 percent confidence interval,9 to 63 percent;P =0.02)and the risk of nonfatal myocardial infarction,stroke,or death from cardiovascular disease by 57 percent (95 percent confidence interval,12 to 79 percent;P =0.02).The decrease in glycosylated hemoglobin values during the DCCT was signif icantly associated with most of the positive effects of intensive treatment on the risk of cardiovascular disease. Microalbuminuria and albuminuria were associated with a significant increase in the risk of cardiovascular disease,but differences between treatment groups remained significant (P = 0.05)after adjusting for these factors.
Intensive diabetes therapy has long-term beneficial effects on the risk of cardiovascular disease in patients with type 1 diabetes
Obstructive Sleep Apnoea Syndrome, Plasma Adiponectin Levels, and Insulin Resistance
Shinya Makino; Hiroshi Handa; Koji Suzukawa; Masayoshi Fujiwara; Masaharu Nakamura; Shogo Muraoka; Ikumi Takasago; Yasushi Tanaka; Kozo Hashimoto; Tamotsu Sugimoto
Clin Endocrinol. 2006;64(1):12-19
Objective: To investigate whether sleep-disordered breathing and/ or plasma adiponectin levels are associated with insulin resistance independent of obesity or fat distribution in obstructive sleep apnoea syndrome (OSAS).
Design: Cross-sectional clinical study.
Patients: Two-hundred and thirteen Japanese patients with OSAS aged 27-80 years were divided into three groups: 30 with mild OSAS [apnoea-hypopnoea index (AHI) = 10•3 ± 0•9 episodes/h, minimum oxygen saturation (min SpO2) = 87•3 ± 0•9%], 98 with moderate OSAS (AHI = 28•9 ± 0•6 episodes/h, min SpO2 = 82•1 ± 0•7%), and 85 with severe OSAS (AHI = 68•1 ± 2•8 episodes/h, min SpO2 = 72•3 ± 1•6%). Twenty-one patients undergoing diabetic treatments (two mild, nine moderate and 10 severe) were excluded from the assessment of insulin resistance and plasma adiponectin measurements.
Measurements: Fat distribution [evaluated according to visceral (V) and subcutaneous (S) fat areas using computed tomography scanning at the umbilical level], blood pressure, metabolic parameters and hormones including insulin and adiponectin were measured. After full polysomnography, venous blood was collected between 0600 and 0700 h.
Results: Severe OSAS patients were more hypertensive than mild and moderate OSAS. Fasting plasma glucose (FPG) and fasting plasma insulin and homeostasis model assessment of insulin resistance (HOMA-IR) levels were all higher in severe OSAS than mild and moderate OSAS patients. HOMA-IR was correlated not only with obesity [body mass index (BMI),V and S areas] but also with apnoea (AHI, min SpO2 and desaturation time). Additionally, HOMA-IR was correlated positively with haemoglobin (Hb)A1c, systolic (SBP) and diastolic blood pressure (DBP), triglycerides and free fatty acids (FFA), and negatively with high density lipoprotein (HDL)-cholesterol, suggesting that insulin resistance is a key component of the metabolic syndrome in OSAS. Plasma adiponectin levels were not different between mild, moderate and severe OSAS groups. Plasma adiponectin levels were correlated with HOMA-IR and V area, but not AHI or min SpO2. Stepwise multiple regression analysis, however, revealed that BMI, AHI and plasma adiponectin were independently associated with HOMA-IR.
Conclusion: Sleep-disordered breathing was associated with insulin resistance independent of obesity. Although plasma adiponectin was also an independent determinant of HOMA-IR in OSAS patients, plasma adiponectin was more closely related to obesity than to sleep apnoea. Although treatment of sleep-disordered breathing with nasal continuous positive airway pressure reportedly improves insulin sensitivity, our findings suggest that treatment of obesity is also essential in ameliorating insulin resistance at least through increased plasma adiponectin levels in OSAS.
Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial.
DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators;
Lancet. 2006 Sep 23;368(9541):1096-105
BACKGROUND: Rosiglitazone is a thiazolidinedione that reduces insulin resistance and might preserve insulin secretion. The aim of this study was to assess prospectively the drug's ability to prevent type 2 diabetes in individuals at high risk of developing the condition.
METHODS: 5269 adults aged 30 years or more with impaired fasting glucose or impaired glucose tolerance, or both, and no previous cardiovascular disease were recruited from 191 sites in 21 countries and randomly assigned to receive rosiglitazone (8 mg daily; n=2365) or placebo (2634) and followed for a median of 3 years. The primary outcome was a composite of incident diabetes or death. Analyses were done by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT00095654.
FINDINGS: At the end of study, 59 individuals had dropped out from the rosiglitazone group and 46 from the placebo group. 306 (11.6%) individuals given rosiglitazone and 686 (26.0%) given placebo developed the composite primary outcome (hazard ratio 0.40, 95% CI 0.35-0.46; p<0.0001); 1330 (50.5%) individuals in the rosiglitazone group and 798 (30.3%) in the placebo group became normoglycaemic (1.71, 1.57-1.87; p<0.0001). Cardiovascular event rates were much the same in both groups, although 14 (0.5%) participants in the rosiglitazone group and two (0.1%) in the placebo group developed heart failure (p=0.01).
INTERPRETATION: Rosiglitazone at 8 mg daily for 3 years substantially reduces incident type 2 diabetes and increases the likelihood of regression to normoglycaemia in adults with impaired fasting glucose or impaired glucose tolerance, or both.
Effect of Ramipril on the Incidence of Diabetes.
DREAM Trial Investigators
N Engl J Med. 12 Oct 2006
Background: Previous studies have suggested that blockade of the renin-angiotensin system may prevent diabetes in people with cardiovascular disease or hypertension.
Methods: In a double-blind, randomized clinical trial with a 2-by-2 factorial design, we randomly assigned 5269 participants without cardiovascular disease but with impaired fasting glucose levels (after an 8-hour fast) or impaired glucose tolerance to receive ramipril (up to 15 mg per day) or placebo (and rosiglitazone or placebo) and followed them for a median of 3 years. We studied the effects of ramipril on the development of diabetes or death, whichever came first (the primary outcome), and on secondary outcomes, including regression to normoglycemia.
Results: The incidence of the primary outcome did not differ significantly between the ramipril group (18.1%) and the placebo group (19.5%; hazard ratio for the ramipril group, 0.91; 95% confidence interval [CI], 0.81 to 1.03; P=0.15). Participants receiving ramipril were more likely to have regression to normoglycemia than those receiving placebo (hazard ratio, 1.16; 95% CI, 1.07 to 1.27; P=0.001). At the end of the study, the median fasting plasma glucose level was not significantly lower in the ramipril group (102.7 mg per deciliter [5.70 mmol per liter]) than in the placebo group (103.4 mg per deciliter [5.74 mmol per liter], P=0.07), though plasma glucose levels 2 hours after an oral glucose load were significantly lower in the ramipril group (135.1 mg per deciliter [7.50 mmol per liter] vs. 140.5 mg per deciliter [7.80 mmol per liter], P=0.01).
Conclusions: Among persons with impaired fasting glucose levels or impaired glucose tolerance, the use of ramipril for 3 years does not significantly reduce the incidence of diabetes or death but does significantly increase regression to normoglycemia. (ClinicalTrials.gov number, NCT00095654.)
Effects of low dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin: randomised, double blind, placebo controlled trial (the DIABHYCAR study).
• DIABHYCAR Study Investigators.
• BMJ. 2004 Feb 28;328(7438):495.
Endocrinologie-Diabetologie-Nutrition, Groupe Hospitalier Bichat-Claude Bernard, Assistance Publique des Hopitaux de Paris, 46 rue Henri Huchard, 75877 Paris Cedex 18, France. email@example.com
OBJECTIVE: To investigate whether a low dose of the angiotensin converting enzyme (ACE) inhibitor ramipril lowers cardiovascular and renal events in patients with type 2 diabetes who have microalbuminuria or proteinuria.
DESIGN: Randomised, double blind, parallel group trial comparing ramipril (1.25 mg/day) with placebo (on top of usual treatment) for cardiovascular and renal outcomes for at least three years. SETTING: Multicentre, primary care study conducted mostly by general practitioners in 16 European and north African countries.
PARTICIPANTS: 4912 patients with type 2 diabetes aged >50 years who use oral antidiabetic drugs and have persistent microalbuminuria or proteinuria (urinary albumin excretion > or = 20 mg/l in two consecutive samples), and serum creatinine < or = 150 micromol/l.
MAIN OUTCOME MEASURES: The primary outcome measure was the combined incidence of cardiovascular death, non-fatal myocardial infarction, stroke, heart failure leading to hospital admission, and end stage renal failure.
RESULTS: Participants were followed for 3 to 6 (median 4) years. There were 362 primary events among the 2443 participants taking ramipril (37.8 per 1000 patient years) and 377 events among the 2469 participants taking placebo (38.8 per 1000 patient years; hazard ratio 1.03 (95% confidence interval 0.89 to 1.20, P = 0.65)). None of the components of the primary outcome was reduced. Ramipril lowered systolic and diastolic blood pressures (by 2.43 and 1.06 mm Hg respectively after two years) and favoured regression from microalbuminuria (20-200 mg/l) or proteinuria (> 200mg/l) to normal level (< 20 mg/l) or microalbuminuria (P < 0.07) in 1868 participants who completed the study.
CONCLUSIONS: Low dose (1.25 mg) ramipril once daily has no effect on cardiovascular and renal outcomes of patients with type 2 diabetes and albuminuria, despite a slight decrease in blood pressure and urinary albumin. The cardiovascular benefits of a daily higher dose (10 mg) ramipril observed elsewhere are not found with an eightfold lower daily dose.
Cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial of patients with type 2 diabetes and overt nephropathy.
• Irbesartan Diabetic Nephropathy Trial. Collaborative Study Group.
Ann Intern Med. 2003 Apr 1;138(7):542-9.
BACKGROUND: Patients with diabetes have increased risk for adverse cardiovascular events. Angiotensin-converting enzyme inhibitors are protective in type 1 diabetes. However, no definitive studies have examined the use of angiotensin-receptor blockers in patients with type 2 diabetes and overt nephropathy. The primary outcomes of the Irbesartan Diabetic Nephropathy Trial were doubling of serum creatinine levels, end-stage renal disease, and death from any cause. OBJECTIVE: To compare rates of cardiovascular events among patients with type 2 diabetic nephropathy who received conventional antihypertensive therapy with an angiotensin-receptor blocker (irbesartan) or a calcium-channel blocker (amlodipine), or placebo. DESIGN: Randomized double-blind, placebo-controlled trial with a median follow-up of 2.6 years. A time event analysis was used. SETTING: 209 centers in the Americas, Europe, Israel, and Australasia. PARTICIPANTS: 1715 adults with type 2 diabetic nephropathy and hypertension; serum creatinine levels of 89 micromol/L (1.0 mg/dL) to 266 micromol/L (3.0 mg/dL) in women and 106 micromol/L (1.2 mg/dL) to 266 micromol/L (3.0 mg/dL) in men; and urinary protein excretion rates of at least 900 mg/d. INTERVENTION: Treatment with irbesartan, amlodipine, or placebo. MEASUREMENTS: Time to cardiovascular death, myocardial infarction, congestive heart failure, strokes, and coronary revascularization. RESULTS: The three groups were not statistically different in the composite of cardiovascular events. Among the components of the composite, there was a trend toward a decrease in strokes in patients receiving amlodipine versus those receiving placebo (hazard ratio, 0.65 [95% CI, 0.35 to 1.22]; P = 0.18). Likewise, patients receiving amlodipine had a significantly lower rate of myocardial infarction when compared with placebo recipients (hazard ratio, 0.58 [CI, 0.37 to 0.92]; P = 0.02). In contrast, patients receiving irbesartan had a significantly lower incidence of congestive heart failure when compared with placebo recipients (hazard ratio, 0.72 [CI, 0.52 to 1.00]; P = 0.048) or amlodipine recipients (hazard ratio, 0.65 [CI, 0.48 to 0.87]; P = 0.004). CONCLUSION: The composite cardiovascular event rate did not differ in patients with type 2 diabetes and overt nephropathy treated with irbesartan, amlodipine, or placebo in addition to conventional antihypertensive therapy.