English: Cartoon representation of the molecular structure of protein registered with 1lj7 code. Deutsch: Grafik des Molekularstruktur von jenem Protein, das mit 1lj7 code registriert ist. Plattdüütsch: Grafik, de de Molekularstruktur von dat Protein wiest, dat mit’n Kood 1lj7 registreert is. (Photo credit: Wikipedia)
- Influenza vaccine is now recommended in healthy children 2 to 4 years of age"
- Herpes zoster vaccine is recommended in people over 60 years old.
- CRP is now used to make treatment decisions in patients with lipid disorders: "use of high-sensitivity C-reactive protein testing in men older than 50 years and women older than 60 years who are at moderate risk of cardiovascular disease (using the Framingham risk score) and whose level of low-density lipoprotein cholesterol is less than 3.5 mmol/L. Two high-sensitivity C-reactive protein samples should be taken at least 2 weeks apart in a patient not suffering from any acute illness. If the lower of the 2 values is greater than 2.0 mg/L, individuals might benefit from pharmacotherapy."
The blue circle is the global symbol for diabetes, introduced by the International Diabetes Federation with the aim of giving diabetes a common identity, supporting existing efforts to raise awareness of diabetes and placing the diabetes epidemic firmly in the public spotlight. (Photo credit: Wikipedia)
This Journal feature begins with a
case vignette highlighting a common clinical problem. Evidence
supporting various strategies is then presented, followed by a review of
formal guidelines, when they exist. The article ends with the author's
clinical recommendations.
A
39-year-old man with a 2-year history of type 2 diabetes mellitus
presents for care. He has no microvascular or macrovascular
complications. His family history is positive for type 2 diabetes and
cardiovascular disease in his mother and older brother. On examination,
his weight is 99.8 kg (220 lb), with a body-mass index (BMI; the weight
in kilograms divided by the square of the height in meters) of 37, and
his blood pressure is 125/85 mm Hg. His glycated hemoglobin level is
8.9%, serum creatinine level 1.0 mg per deciliter (88.4 μmol per liter),
low-density lipoprotein (LDL) cholesterol 88 mg per deciliter (2.3 mmol
per liter), high-density lipoprotein (HDL) cholesterol 45 mg per
deciliter (1.2 mmol per liter), and triglyceride level 130 mg per
deciliter (1.5 mmol per liter); he does not have microalbuminuria. His
medications include metformin (500 mg twice daily), glipizide (5 mg
twice daily), simvastatin (20 mg daily), and lisinopril (10 mg daily).
What would you recommend to improve his glycemic control?
The Clinical Problem
Type
2 diabetes is the leading cause of blindness, nontraumatic lower-limb
amputation, and chronic kidney disease in the United States. It is a
major cause of cardiovascular disease, leading to early death.1
According to the Centers for Disease Control and Prevention, the number
of persons with type 2 diabetes in the United States will more than
triple by 2050 from the current estimate of 26 million.2
The increasing incidence of type 2 diabetes is largely attributable to
changes in lifestyle (diet and activity levels) and obesity.1,2 The problem is global, affects affluent and lower-income societies,3
has substantial adverse effects on health status and life span, and
carries high societal costs. Commonly associated metabolic abnormalities
include hypertension, dyslipidemia, inflammation, hypercoagulation, and
endothelial-cell dysfunction.4,5 Type
2 diabetes is a chronic, progressive, and incompletely understood
metabolic disease defined by the presence of chronic hyperglycemia.6
Although resistance to some actions of insulin and inadequate secretion
of insulin for the given metabolic state are the critical abnormalities
in type 2 diabetes, several other factors contribute to the
hyperglycemic state (Figure 1Figure 1Pathophysiological Alterations Leading to Hyperglycemia in Type 2 Diabetes and Specific Types of Treatment.).
Insulin resistance is typically present for some years before
diagnosis, manifested as diminished stimulation of glucose transport in
muscle and adipose tissue and inadequate suppression of glucose
production in the liver in response to insulin. However, euglycemia is
maintained as long as beta cells secrete higher amounts of insulin.5 Over time, insulin levels decline because of the decreased number of beta cells and their diminished secretory capacity.5,7,8 Longitudinal studies involving Pima Indians9 and other populations10 have shown a 50% or greater decrease in maximal beta-cell function at diagnosis.5
Abnormal postprandial suppression of glucagon secretion also occurs.
Beta-cell failure is mediated by genetic factors and exposure to
chronically elevated levels of blood glucose (glucotoxicity) and free
fatty acids (lipotoxicity). Older age, amyloid fibrils in islets, and
chronically high rates of insulin secretion also play mechanistic roles.
The majority of genetic abnormalities that have been identified in
patients with type 2 diabetes are related to beta-cell function.11 According
to the American Diabetes Association, the diagnosis of type 2 diabetes
is based on a glycated hemoglobin level of 6.5% or more, a fasting
plasma glucose level of 126 mg per deciliter (7.0 mmol per liter) or
more, or a 2-hour plasma glucose level of 200 mg per deciliter (11.1
mmol per liter) or more during an oral glucose-tolerance test.6
The diagnosis can also be established by classic symptoms of
hyperglycemia and a random plasma glucose level of 200 mg per deciliter
or more. Test results require confirmation with the use of the above
criteria, unless the diagnosis is obvious on the basis of the symptoms.6
Strategies and Evidence
This
article focuses on glycemic management in type 2 diabetes. However,
glycemic control is only one facet of the multifactorial approach
required for attempted control of all known risk factors for the
development of cardiovascular and microvascular disease.12
The
overall aim of glycemic management is to minimize long-term
complications while avoiding severe hypoglycemic events. Results of
large randomized trials involving patients with type 1 diabetes or newly
recognized or established type 2 diabetes show that control of glycemia
delays the onset and slows the progression of microvascular
complications, including nephropathy, retinopathy, and neuropathy.13-18
Long-term follow-up of patients with newly diagnosed type 2 diabetes
enrolled in the U.K. Prospective Diabetes Study (Current Controlled
Trials number, ISRCTN75451837) showed a reduced risk of cardiovascular
disease events 10 years after the end of the trial among patients who
were initially randomly assigned to intensive glycemic management, as
compared with conventional therapy (average glycated hemoglobin level,
7.0% vs. 7.9%).19
Results of three trials involving older patients with established type 2
diabetes and a history of or risk factors for cardiovascular disease
showed no reduction in total mortality or cardiovascular disease–related
mortality associated with intensive lowering of glucose levels to
near-normal levels with the use of multiple agents, as compared with
standard glycemic control15,16,20; one of the studies showed increased mortality.20
Moreover, intensive glycemic control was associated with higher rates
of hypoglycemia and weight gain. Thus, the microvascular benefits that
are derived from intensive glycemic control must be balanced against the
risks. The first step in glycemic management is setting an
appropriate glycemic target in each individual patient. Current
guidelines specify glycated hemoglobin targets of less than 7.0% or less
than 6.5%.21,22
However, the appropriateness of these goals varies according to
clinical characteristics and psychosocial factors, including the
patient's capacity for self-care and home support systems. Intensive
glycemic control often requires a greater number and larger dosages of
medications, resulting in an increase in adverse events and costs. Figure 2Figure 2Suggested Goals for Glycemic Treatment in Patients with Type 2 Diabetes. shows the influence of various patient-specific features on the selection of glycated hemoglobin targets.28In
general, in patients with recently recognized type 2 diabetes and few
or no complications (especially younger patients), a near-normal
glycemic target aimed at prevention of complications over many years of
life can be suggested. In contrast, in older persons with cardiovascular
disease or multiple risk factors for cardiovascular diseases, higher
targets are often appropriate.15,16,28
General Treatment Considerations
Whenever possible, patients should be involved in decision making regarding glycemic targets29,30
and should be informed that the targets may require adjustment over
time with changes in clinical or personal factors, such as the patient's
experience with and acceptance of frequent self-monitoring of blood
glucose levels and his or her ability to identify and prevent
hypoglycemic events. In general, the glycated hemoglobin level should be
checked at least twice yearly. Long-term maintenance of glycemic
control ideally should involve a multidisciplinary approach, including
nutrition counseling and visits with a diabetes nurse, certified
diabetes educator, or both.6
Educational programs that empower patients to become involved in their
day-to-day glycemic management and education of health care providers
are helpful.6
Successful glycemic control at a reasonable cost has been reported with
the use of telecommunication and computer-based information-transfer
systems.31,32
Lifestyle Approaches
Weight loss and exercise are important nonpharmacologic approaches to improving glycemic control (Figure 1).
The American Diabetes Association recommends a balanced diet that is
rich in fiber, whole grains, and legumes; contains less than 7%
saturated fat and reduced trans fats; and is limited in calories and
foods with a high glycemic index.6,33, Exercise has an additive effect when combined with caloric restriction for glycemic control.6 Patients should be encouraged to engage in at least 150 minutes of moderate-intensity aerobic exercise per week.6
Pharmacotherapy
Medications that are available for glycemic management of type 2 diabetes,4,5,21,34-46 their usual effects on the glycated hemoglobin level, and their major advantages and disadvantages are summarized in Table 1Table 1Pharmacologic Agents for Glycemic Control in Patients with Type 2 Diabetes..
Treatment options have greatly expanded in the past two decades.
Available agents reduce glucose levels, often through a variety of
mechanisms (Figure 1).
Agents That Improve Insulin Sensitivity
Metformin is the cornerstone of type 2 diabetes treatment.4,21,34,40
By stimulating AMP-activated protein kinase, metformin reduces hepatic
glucose production. It does not cause weight gain and may result in a
slight weight loss, and it rarely causes hypoglycemia; gastrointestinal
side effects may occur, especially if therapy is initiated at higher
doses. Thiazolidinediones (pioglitazone and rosiglitazone) are
peroxisome proliferator–activated receptor γ activators that enhance
insulin sensitivity in peripheral tissues and reduce hepatic glucose
production.5,21
Although a randomized trial showed that rosiglitazone, as compared with
metformin or a sulfonylurea as the only initial therapy, maintained
glycemic control for a longer period,35
the use of rosiglitazone is highly restricted in the United States (and
was discontinued in Europe) owing to concern about an increased risk of
myocardial infarction. This concern was based mostly on a meta-analysis
of observational studies.44
In a randomized study, pioglitazone was associated with a reduction in
the secondary composite cardiovascular disease outcome but also with
increased risks of edema and heart failure.43
Agents That Increase Circulating Insulin Levels
Insulin
is the most potent agent for reducing glycemia. By activating
plasma-membrane receptors, it stimulates glucose uptake by responsive
tissues and decreases hepatic glucose production. The use of insulin
causes weight gain and may cause severe hypoglycemia.21 Long-acting (basal) and short- and rapid-acting insulin formulations and combined formulations are available. Sulfonylureas
(e.g., glipizide) stimulate insulin release by closure of specific
potassium channels on beta cells. Their use is associated with modest
weight gain and hypoglycemia. Meglitinides (e.g., repaglinide) have
actions similar to those of sulfonylureas but have a short duration of
action (hours) and are most effective preprandially. The
Food and Drug Administration (FDA) has approved agents that increase
blood glucagon-like peptide 1 (GLP-1) activity or levels and stimulate
insulin secretion (in a glucose-dependent manner) while inhibiting
glucagon secretion. GLP-1–receptor agonists (e.g., exenatide and
liraglutide) are injectable agents that are structurally similar to
endogenous GLP-1 and activate GLP-1 receptors in many tissues. Other
effects include delayed gastric emptying and appetite suppression,
typically resulting in a weight loss of approximately 2 to 4 kg (4.4 to
8.8 lb).21
Dipeptidyl peptidase IV (DPP-IV) inhibitors (e.g., sitagliptin) are
oral agents that inhibit the degradation of GLP-1 and result in modest
elevations of circulating GLP-1 levels; they do not affect weight.
Either class of agent may cause hypoglycemia if used with insulin or
sulfonylureas. The long-term safety of these agents (including their
potential for causing pancreatitis), as well as their effects on the
risk of cardiovascular disease, are unknown.
Other Agents
Other
FDA-approved agents are used less frequently because of the smaller
reductions in glycated hemoglobin levels (typically, approximately 0.6%)
and, in some cases, side effects (Table 1).21
Alpha-glucosidase inhibitors (e.g., acarbose) interfere with the
digestion of glucose polymers, thereby decreasing carbohydrate
absorption; a high frequency of gastrointestinal side effects limits
their use. The bile acid sequestrant colesevelam reduces hepatic glucose
production and increases incretin levels by unknown mechanisms; it also
reduces LDL cholesterol levels. The dopamine agonist bromocriptine
activates D2 dopamine receptors and increases insulin sensitivity by
unknown mechanisms; a rapid-release form was approved by the FDA for
this indication. Pramlintide, an amylin mimetic, is an injectable agent
that stimulates receptors for amylin. It suppresses glucagon secretion,
delays gastric emptying, and decreases appetite.
Strategies for Implementation
Of the various strategies for glycemic control, lifestyle modification and metformin are preferred and are cost-effective.21,34,38,40,,,
Patients with chronically high levels of glycated hemoglobin
(approximately 9.0%) are unlikely to have adequate glycemic control with
metformin alone, and in patients with clinically significant
hyperglycemia (blood glucose level, >300 mg per deciliter [>16.7
mmol per liter]; glycated hemoglobin level, >10%), initial insulin
therapy should be considered. If metformin monotherapy cannot be
used, other oral agents (e.g., a sulfonylurea, a DPP-IV inhibitor, or
pioglitazone) or a GLP-1–receptor agonist can be administered. Over
time, additional medications become necessary for glycemic control. A
logical strategy is to consider agents with complementary mechanisms of
action (Figure 1).5,21
Combinations that are effective in reducing glycemia include metformin
plus another oral agent, a GLP-1–receptor agonist, or long-acting
insulin.21,34,38,46 However, strong evidence is lacking to support any one particular second agent over another. Perhaps because of the reluctance of patients and providers, insulin is generally added much later than medically indicated.21 The recent introduction of disposable pen devices may make insulin therapy more acceptable to patients.42
Initiation of insulin therapy with the use of a single dose of basal
(long-acting) insulin, preferably at bedtime (starting with
approximately 10 units and increasing by 2 to 3 units every several
days) can reduce the glycated hemoglobin level by 1.5 to 2.0% or more.21,36
If glycemia is not controlled, a dose of rapid-acting insulin can be
added at the largest meal. Premixed “biphasic insulin” preparations,
typically administered before breakfast and dinner, or basal insulin
plus rapid-acting insulin (“basal-bolus”) therapy before a meal can also
be considered. Lower glycated hemoglobin levels are obtained with the
use of biphasic or basal-bolus regimens but at the expense of a greater
likelihood of hypoglycemia and weight gain.36,39
Surgical Approaches to Glycemic Control
Long-term
observational studies have shown considerable improvements in glycemic
control, as well as improvements in associated cardiovascular risk
factors and a reduced risk of cardiovascular disease,47
among patients who have undergone bariatric surgery (laparoscopic
adjustable gastric banding or Roux-en-Y gastric bypass), as compared
with obese patients who have not undergone surgery. Benefits have been
noted particularly among very obese persons with a shorter duration of
type 2 diabetes and in association with procedures that limit the
absorptive surface (bypass surgery).48
Bariatric surgery is increasingly used in patients with type 2 diabetes
who are obese but not morbidly obese. The results of two recently
published randomized trials of bariatric surgery involving patients with
type 2 diabetes (one of which included patients with a BMI of <35)
showed significant improvement in glycemia at follow-up 1 to 2 years
postoperatively.49,50
Weight loss in some patients is minimal and may not be sustained; data
on the long-term effects of these procedures are lacking.
Areas of Uncertainty
The
underlying cause or causes of accelerated cardiovascular disease in
type 2 diabetes and the effects of glycemic control on this process
remain incompletely understood. Whereas intensive glycemic control
clearly reduces the risk of microvascular complications, its effect
(measured as the glycated hemoglobin level, a surrogate marker) on
outcomes of cardiovascular disease is less certain. A better
understanding of the factors underlying the large variations in insulin
resistance and beta-cell number and function in healthy persons is
needed for the development of strategies to prevent and treat type 2
diabetes; data are lacking on treatments that preserve beta-cell
function.51,52
Although there is general agreement on the first-line use of metformin
in most patients with type 2 diabetes, evidence is lacking to inform the
most appropriate choice of second-line agents. Devices such as
continuous glucose-monitoring systems (to ascertain glycemic patterns
over a period of a few days) and insulin pumps are increasingly used in
patients with type 2 diabetes who require insulin, but data on the
benefits and risks of these devices are lacking. Mechanisms underlying
the impressive effects of bariatric surgery on glycemic control warrant
further exploration. Finally, the long-term safety of GLP-1–receptor
agonists, DPP-IV inhibitors, and other newer agents and their effects on
diabetic complications, including cardiovascular disease, need to be
determined.
Guidelines
The
American Diabetes Association, the European Association for the Study
of Diabetes, and other organizations have published guidelines for
glycemic control in patients with type 2 diabetes.6,21,29,30,53,54
All these guidelines specify that glycemic goals should be
individualized (with some placing particular emphasis on psychosocial
factors in setting goals),29,30 and all advocate lifestyle modifications and metformin as first-line therapy,
though they differ in their subsequent recommendations. A joint
statement by the American Diabetes Association and the European
Association for the Study of Diabetes recommends that for patients with
glycemia that is not adequately controlled with lifestyle changes and
metformin, “well-validated” therapies, including sulfonylureas or basal
insulin, should be used, followed by more intensive insulin therapy, as
needed21;
pioglitazone, GLP-1 agonists, and other medications discussed above are
considered “less-well-validated” options. The recommendations in this
article are generally concordant with these guidelines.
Conclusions and Recommendations
The
patient in the vignette is relatively young and has a recent diagnosis
of type 2 diabetes with inadequately controlled glycemia and a family
history of type 2 diabetes and cardiovascular disease. The major goals
of treatment should be to prevent microvascular and macrovascular
complications over a period of many years, given his long life
expectancy. His blood pressure and lipid levels are well controlled. I
would discuss with him the risks associated with hyperglycemia and the
benefits of glycemic control, and I would assess his capacity and
willingness to self-monitor his blood glucose levels. In the absence of
any apparent contraindications to targeting a normal or near-normal
glycemic range, I would recommend a target glycated hemoglobin level of
6.0 to 6.5% (if it can be implemented safely). I would also recommend an
exercise program (preferably at least 150 minutes per week) and
encourage him to follow a diet that is low in fat, carbohydrates, and
salt and high in grains and fiber, with the aim of gradual weight loss
(perhaps 4.5 to 6.8 kg [10 to 15 lb] over the next year). I would
increase the dose of metformin to 2000 mg daily while diet and exercise
are actively pursued. If these approaches are effective, it may
be possible to decrease or discontinue glipizide. If the glycated
hemoglobin level remains high, it is unlikely that the addition of
another oral agent would reduce the glycated hemoglobin level from
approximately 9% to near-normal levels. Although data are currently
insufficient to guide the most appropriate choice among additional
therapies, I would recommend adding long-acting insulin at bedtime or a
GLP-1–receptor agonist to his regimen. Although some clinicians would
consider the discontinuation of glipizide, I favor its continuation, at
least initially. Basal insulin is effective and less expensive, but it
is associated with hypoglycemia and weight gain. GLP-1–receptor agonists
have the advantage of causing weight loss in most patients. They rarely
cause hypoglycemia but are more costly than basal insulin, and data are
lacking on their long-term safety.
Dr.
Ismail-Beigi reports receiving consulting fees from Eli Lilly and
owning stock in Thermalin Diabetes. No other potential conflict of
interest relevant to this article was reported.
Disclosure forms provided by the author are available with the full text of this article at NEJM.org.
Source Information
From
the Department of Medicine, University Hospitals and Veterans Affairs
Medical Center, Case Western Reserve University, Cleveland. Address
reprint requests to Dr. Ismail-Beigi at the Department of Medicine,
Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH
44106-4951, or at fxi2@case.edu.
Key Clinical Points
GLYCEMIC CONTROL IN TYPE 2 DIABETES MELLITUS
•
Intensive glycemic control reduces the risk of microvascular
complications of type 2 diabetes, but the effect of strict glycemic
control on the risk of macrovascular disease (especially in
well-established type 2 diabetes) is less certain.
• Psychosocial
factors (e.g., motivation and capacity for self-care) and clinical
factors (e.g., age, presence or absence of coexisting conditions, and
presence or absence of a tendency toward hypoglycemia) should be
considered in setting a target range of glycated hemoglobin for an
individual patient.
• A near-normal glycemic target range (6.0 to
6.5%), if implemented safely, could be considered for otherwise healthy
patients with recently diagnosed type 2 diabetes and a long life
expectancy; more relaxed goals for the glycated hemoglobin level may be
preferable in older patients with long-standing type 2 diabetes and
cardiovascular disease.
• Lifestyle modification and metformin are recommended as initial therapies for most patients with type 2 diabetes.
•
Several therapeutic agents are available when therapy in addition to
metformin is needed to control glycemia, but evidence is lacking to
support the choice of any one agent over another. Decisions should take
into account cost, side effects, and long-term safety and effects on
complications of diabetes.
Hasta cuando seguiremos aceptando estos consensos sin fundamentos cientificos ? La ciencia se rige por las pruebas, por el metodo inductivo-deductivo-abductivo, por la experimentacion, pero nunca por el consenso de "expertos" que no declaran sus conflictos de intereses.
Image via Wikipedia Fuente: Enrique Gavilan Via: Lista MEDFAM-APS España El JAMA acaba de publicar un artículo de análisis, que adjunto, intentando discutir las consecuencias que puede tener el reciente informe de expertos norteamericanos sobre detección precoz de hipercolesterolemia en niños y adolescentes (éste: http://www.nhlbi.nih.gov/guidelines/cvd_ped/summary.htm#chap9).
Sólo se salvan los bebés; a partir de los 2 añitos el sólo hecho de que tengas un padre con un infarto antes de los 55 años hace que te lleves como mínimo 2 pinchazos para medir la LDL. Y a partir de los 9 años, cribado universal...
La consecuencia lógica es que se prescriban estatinas a partir de la conjunción de dos astros y unos LDL de entre 130-160. Me quedo frío.
Y todo ello, por la simple aplicación de, de nuevo, silogismos fisiopatológicos y sin la más mínima evidencia, según el artículo del JAMA, de que esta estrategia aporte más beneficios que riesgos. Salvo por el uso indebido, una vez más, de variables surrogadas, como el LDL.
Vale la pena leer el artículo, vale la pena...
Cuando sale este tema de los colesteroles en los niños siempre me acuerdo de la anécdota que Petr Skranabek nos cuenta sobre la pequeña Ariel y el helado furtivo. Vale la pena leerlo...
el riesgo de padecer una cardiopatía isquémica, pero no lo elimina del todo. Los niveles bajos de colesterolHDL se asocian a un mayor riesgo de desarrollar esta enfermedad, por lo que se cree que los tratamientos capaces de aumentar estos niveles podrían conseguir reducciones adicionales del riesgo. Los inhibidores de la proteína transferidora de ésteres de colesterol (cholesteryl ester transfer protein - CETP) aumentan los niveles de HDL y algunos disminuyen también los de LDL.
Objetivo
Estudiar la seguridad y los efectos sobre las lipoproteínas del tratamiento con anacetrapib en pacientes con antecedentes de cardiopatía isquémica o alto riesgo de desarrollarla.
Se invittó a participar en el estudio DEFINE (Details of the Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib) a personas de 18-80 años con antecedentes de cardiopatía isquémica conocida o con alto riesgo de desarrollarla (riesgo estimado mediante las tablas de Framingham >20% a los 10 años), en tratamiento con estatinas con o sin otros tratamientos hipolipemiantes, y niveles de colesterol LDL de 50-100 mg/dL, colesterol HDL <60 mg/dL y triglicéridos ≤400 mg/dL. Se excluyó a los pacientes con insuficiencia cardíaca, un episodio agudo de cardiopatía isquémica o de AVC en los últimos 3 meses, con afectos de hepatopatías o nefropatías crónicas o en tratamiento con anticoagulantes orales.
Los participantes fueron distribuidos aleatoriamente y a doble ciego a tomar con la comida 100 mg/d de anacetrapib o placebo. Se decidió retirar del estudio a los pacientes que presentasen niveles de colesterol LDL <25 mg/dL en dos determinaciones consecutivas. Las variables de resultado principales fueron el porcentaje en la reducción del colesterol LDL a las 24 semanas de tratamiento y los efectos adversos (PA, hepáticos, musculares, electrolitos, eventos cardiovasculares y muertes por cualquier causa). Las variables secundarias fueron los niveles del colesterol LDL a las 76 semanas y de colesterol HDL, no HDL y las apolipoproteínas B y A-I a las 24 y 76 semanas.
Resultados
Se invittó a participar en el estudio DEFINE (Details of the Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib) a personas de 18-80 años con antecedentes de cardiopatía isquémica conocida o con alto riesgo de desarrollarla (riesgo estimado mediante las tablas de Framingham >20% a los 10 años), en tratamiento con estatinas con o sin otros tratamientos hipolipemiantes, y niveles de colesterol LDL de 50-100 mg/dL, colesterol HDL <60 mg/dL y triglicéridos ≤400 mg/dL. Se excluyó a los pacientes con insuficiencia cardíaca, un episodio agudo de cardiopatía isquémica o de AVC en los últimos 3 meses, con afectos de hepatopatías o nefropatías crónicas o en tratamiento con anticoagulantes orales.
Los participantes fueron distribuidos aleatoriamente y a doble ciego a tomar con la comida 100 mg/d de anacetrapib o placebo. Se decidió retirar del estudio a los pacientes que presentasen niveles de colesterol LDL <25 mg/dL en dos determinaciones consecutivas. Las variables de resultado principales fueron el porcentaje en la reducción del colesterol LDL a las 24 semanas de tratamiento y los efectos adversos (PA, hepáticos, musculares, electrolitos, eventos cardiovasculares y muertes por cualquier causa). Las variables secundarias fueron los niveles del colesterol LDL a las 76 semanas y de colesterol HDL, no HDL y las apolipoproteínas B y A-I a las 24 y 76 semanas.
Resultados
Participaron en el estudio 1.623 pacientes (fig. 1). Las características iniciales de los individuos asignados a los dos grupos eran parecidas. La edad media era de 62 años, el 77% eran varones y el 55% tenían antecedentes de cardiopatía isquémica. La media de colesterol LDL fue de 82 mg/dL y el del HDL, de 40,5 mg/dL.
Figura 1. Flujo de los participantes.
Se excluyeron 142 (17,6%) del grupo de tratamiento activo y 1 (0,1%) del grupo placebo por presentar niveles de colesterol LDL <25 mg/dL. Por lo demás, aproximadamente un 15% de los asignados al tratamiento activo y un 17% de los asignados al placebo interrumpieron el tratamiento por otros motivos. Al final del estudio se dispuso de los datos de más del 99% de los participantes.
A las 24 semanas, el colesterol LDL se redujo en un 40% y el HDL aumentó un 138% más en el grupo intervención que en el grupo placebo (figura 2).
Figura 2. Evolución de los niveles de colesterol LDL y HDL.
Los pacientes asignados al tratamiento con anacetrapib presentaron también cambios favorables en el colesterol no-HDL, los triglicéridos, las apolipoproteínas A y B y la lipoproteína(a) (fig. 3). Todos estos cambios se mantuvieron a las 76 semanas.
Figura 3. Cambio en el perfil lipídico respecto a los valores iniciales a las 24 semanas.
No se apreciaron diferencias estadísticamente significativas en la proporción de pacientes que tuvieron que interrumpir el tratamiento por efectos indeseables, en el porcentaje de pacientes que presentaron síntomas musculares, ni en la mayor parte de los parámetros analíticos monitorizados, con dos excepciones: menos pacientes en el grupo intervención que en el grupo placebo experimentaron elevaciones importantes de las transaminasas y los niveles de sodio disminuyeron algo más en los pacientes asignados al grupo placebo que en el grupo intervención.
Aunque no se encontraron diferencias estadísticamente significativas, se dieron menos eventos cardiovasculares en el grupo de tratamiento activo que en el grupo placebo, sobre todo a expensas de eventos coronarios no mortales. En cambio se dieron más muertes cardiovasculares y por todas las causas (tabla 1).
Tabla 1. Eventos cardiovasculares y mortalidad en los dos grupos (en %) (diferencias sin significación estadística).
Anacetrapib
Placebo
Eventos cardiovasculares mayores
2,0
2,6
Muertes de causa cardiovascular
0,5
0,1
IAM no mortal
0,7
1,1
Ingreso por angina inestable
0,1
0,7
AVC no mortal
0,6
0,6
Muertes totales
1,4
1,0
Conclusiones
Los autores concluyen que el tratamiento con anacetrapib tiene efectos muy potentes sobre el colesterol HDL y LDL, con un perfil de afectos adversos aceptable y sin los efectos adversos cardiovasculares que se observaron con el torcetrapib.
Conflictos de interés
Financiado por Merck.
Comentario
Hasta ahora, el tratamiento sobre el perfil lipídico se ha basado en intentar disminuir el nivel de colesterol LDL mediante las estatinas. Este enfoque ha demostrado su eficacia en la prevención cardiovascular primaria y secundaria. Sin embargo, un porcentaje elevado de pacientes en tratamiento hipolipemiante presentan nuevos eventos (lo que se incluye en el concepto de "riesgo cardiovascular residual").
Para intentar reducir este riesgo se han propuesto nuevos abordajes, como los tratamientos para elevar el colesterol HDL. Entre los fármacos capaces de conseguirlo se encuentran los inhibidores de la proteína transferidora de ésteres de colesterol. Se ha descartado la utilización del primer fármaco de este grupo que se probó en humanos, el torcetrapib, dado que en un ensayo clínico de 12 meses se detectó un incremento en la mortalidad por todas las causas y en el número de eventos cardiovasculares, al parecer ligado al hiperaldosteronismo detectado en el que en el grupo de tratamiento activo.
En estudios preclínicos, el anacetrapib había demostrado aumentar de forma importante los niveles de colesterol HDL y disminuir de forma significativa los del LDL sin que se detectasen efectos apreciables sobre la PA. En esta publicación, se detallan los resultados observados en un ensayo clínico a medio plazo. Los efectos sobre el colesterol HDL y el LDL son similares a la de los estudios previos, el fármaco se toleró razonablemente bien y no se detectaron indicios de hiperaldosteronismo. Sin embargo, a pesar de que no era el objetivo del estudio, se apreció una tendencia no significativa estadísticamente a una mayor mortalidad cardiovascular y total, por lo que es necesario disponer de estudios más amplios antes de poder decidir su utilidad en la clínica.
Bibliografía
Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJP, Komajda M et al. Effects of Torcetrapib in Patients at High Risk for Coronary Events. N Engl J Med 2007; 357: 2109-222. R TC (s) PDF (s)
Krishna R, Anderson MS, Bergman AJ, Jin B, Fallon M, Cote J et al. Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia and on 24-h ambulatory blood pressure in healthy individuals: two double-blind, randomised placebo-controlled phase I studies. Lancet 2007; 370: 1907-1914. R TC (s) PDF (s)
Chapman MJ, Le Goff W, Guerin M, Kontush A. Cholesteryl ester transfer protein: at the heart of the action of lipid-modulating therapy with statins, fibrates, niacin, and cholesteryl ester transfer protein inhibitors. Eur Heart J 2010; 31: 149-164. R TC PDF
