[Endocrinology] Insulin – Its Physiologic Effects and Their Mechanisms

October 8, 2015 Diabetes, Physiology and Pathophysiology No comments , , , , , , , , ,

Regular-and-NPH-insulin-vials-with-doctors-prescriptionGeneral Considerations

Hormones are chemical products, released in very small amounts from the cell, that exert a biologic action on a target cell.

Chemical Structures of Hormones

There types of hormones, including protein/peptide, steroid hormones, and amino acid-derived hormones. Let’s talk them below. Based on their chemical structure, hormones can be classified into peptides/proteins (i.e., insulin, glucagon, ACTH), steroids, and amino acid derivatives/amines.

Protein or peptide hormones constitute the majority of hormones. These are molecules ranging from 3 to 200 amino acid residues. They are synthesized as preproxhormones and undergo post-translational processing. They are stored in secretory granules before being released by exocytosis. Steroid hormones are derived from cholesterol and are synthesized in the adrenal cortex, gonads, and placenta. They are lipid soluble, circulate bound to binding proteins in plasma, and cross the plasma membrane to bind to intracellular cytosolic or nuclear receptors.

Vitamin D and its metabolites are also considered steroid hormones. Amino acid-derived hormones are those hormones that are synthesized from the amino acid tyrosine and include the catecholamines norepinephrine, epinephrine, and dopamine; as well as the thyroid hormones.d Hormone structure, to a great extent, dictates the location of the hormone receptor, with amines and peptide hormones binding to receptors in the cell surface and steroid hormones being able to cross plasma membranes and bind to intracellular receptors. An exception to this generalization is thyroid hormone, an amino acid-derived hormone that is transported into the cell in order to bind to its nuclear receptor.

Hormone Effects

Depending on where the biologic effect of a hormone is elicited in relation to where the hormone was released, its effects can be classified in 1 of 3 ways. 1.The effect is endocrine when a hormone is released into the circulation and then travels in the blood to produce a biologic effect on distant target cells. 2.The effect is paracrine when a hormone released from 1 cell produces a biologic effect on a neighboring cell, which is frequently a cell in the same organ or tissue. and 3.The effect is autocrine when a hormone produces a biologic effect on the same cell that released it.Screen Shot 2015-11-21 at 7.06.54 PM

Hormone Transport

Hormones released into the circulation can circulate either freely or bound to carrier proteins, also known as binding proteins. This binding proteins serves as a reservoir for the hormone and prolong the hormone’s half-life, the time during which the concentration of a hormone decreases to 50% of its initial concentration. However, the free or unbound hormone is the active form of the hormone, which binds to the specific hormone receptor. Thus, hormone binding to its carrier protein serves to regulate the activity of the hormone by determining how much hormone is free to exert a biologic action.

Most carrier proteins are globulins and are synthesized in the liver. Some of the biding protein are specific for a given protein, such as cortisol-binding proteins. However, proteins such as globulins and albumin are known to bind hormones as well. Because for the most part these proteins are synthesized in the liver, alterations in hepatic function may result in abnormalities in binding-protein levels and my indirectly affect total hormone levels (also see the thread of The Plasma Protein Concentration And The Interpretation Of TDM Report by Tom Hsiung).

In general, the majority of amines, peptides, and protein (hydrophilic) hormones circulate in their free form. However, a notable exception to this rule is the binding of the insulin-like growth factors to 1 of 6 different high-affinity binding proteins. Steroid and thyroid (lipophilic) hormones circulate bound to specific transport protein.

Hormone Clearance

Once hormones are released into the circulation, they can bind to their specific receptor in a target organ, they can undergo metabolic transformation by the liver, or they can undergo urinary excretion. Also they can be degraded at their target cell through internalization of the hormone-receptor complex followed by lysosomal degradation of the hormone. Only a very small fraction of total hormone production is excreted intact in the urine and feces.

Hormone Receptors and Signal Transduction

Hormone receptors are classified depending on their cellular localization, as cell membrane or intracellular receptors. Peptides and catecholamines are unable to cross the cell membrane lipid bilayer and in general bind to cell membrane receptors, with the exception of thyroid hormones as mentioned above. Steroid hormones are lipid soluble, cross the plasma membrane, and bind to intracellular receptors.

Cell Membrane Receptors Binding of hormones to cell membrane receptors and formation of the hormone-receptor complex initiates a signaling cascade of intracellular events, resulting in a specific biologic response.

Cell membrane receptors can be divided into two subcategories of receptors, that are, ligand-gated ion channels and receptors that regulate activity of intracellular proteins. Ligand-gated ion channels/receptors are functionally coupled to ion channels, and with hormone binding they produce a conformational change that opens ion channels on the cell membrane, producing ion fluxes in the target cell. The cellular effects occur within seconds of hormone binding. Detail information about ligand-gated ion channels/receptors could be found at this thread Ligand- And Voltage-gated Channels (Receptors) by Tom Hsiung.

The other subcategory of cell membrane receptors is a little bit complex, including G protein-coupled receptors and receptor protein tyrosine kinases, both of which are transmembrane proteins that transmit signals to intracellular targets when activated. Ligand binding to the receptor on the cell surface and activation of the associated protein initiate a signaling cascade of events that activates intracellular proteins and enzymes and that can include effects on gene transcription and expression. Intracellular Receptors Receptors in this category belong to the steroid receptor superfamily. These receptors are transcription factors that have binding sites for the hormone (ligand) and for DNA and function as ligand (hormone)-regulated transcription factors.

Hormone-receptor complex formation and binding to DNA result in either activation or repression of gene transcription. Binding to intracellular hormone receptors requires that the hormone be hydrophobic and cross the plasma membrane. Steroid hormones and the steroid derivative vitamin D3 fulfill this requirement, whereas thyroid hormones must be actively transported into the cell. This distribution of the unbound intracellular hormone receptor can be cytosolic or nuclear. Hormone-receptor complex formation with cytosolic receptors produces a conformational change that allows the hormone-receptor complex to enter the nucleus and bind to specific DNA sequences to regulate gene transcription. Once in the nucleus, the receptors regulate transcription by binding, generally as dimers, to hormone response elements normally located in regulatory regions of target genes. In all cases, hormone binding leads to a nearly complete nuclear localization of the hormone-receptor complex. Unbound intracellular receptors may be located in the nucleus, as in the case of thyroid hormone receptors. The unoccupied thyroid receptor represses transcription of genes. Binding of thyroid hormone to the receptor activates gene transcription. Screen Shot 2015 09 23 at 4 26 58 PM

Hormone Receptor Regulation

Two ways exist for the receptor regulation, including desensitization and receptor downregulation. Two types of receptors are involved in the process of desensitization and receptor downregulation, G protein-coupled receptors and receptor protein tyrosine kinases, where both happen to G protein-coupled receptors and only downregulation happens to receptor protein tyrosine kinases, respectively. Note that the process of desensitization and downregulation are reversible. Hormone receptors can also undergo upregulation. Upregulation of receptors involves an increase in the number of receptors for the particular hormone and frequently occurs when the prevailing levels of the hormone have been low of some time.

Characteristics of Hormone-Receptor Binding (Also see the thread The Properties of Drugs – Receptor Rationale by Tom Hsiung)

The binding of hormones and their receptors have phenomenon of spareness, where the maximal biologic response to a hormone can be achieved without reaching 100% hormone-receptor occupancy. Frequently, the hormone-receptor occupancy needed to produce a biologic response in a given target cell is very low, for example, insulin-mediated cellular effects occurs when less than 3% of the total number of receptors in adipocytes is occupied.

Control of Hormone Release

The secretion of hormones involves synthesis or production of the hormone and its release from the cell. Plasma levels of hormones oscillate throughout the day, showing peaks and troughs that are hormone specific. This variable pattern of hormone release is determined by the interaction and integration of multiple control mechanisms, which include 1) hormonal, 2) neural, 3) nutritional, and 4) environmental factors that regulate the constitutive (basal) and stimulated (peak levels) secretion of hormones. The periodic and pulsatile release of hormones is critical in maintaining normal endocrine function and in exerting physiologic effects at the target organ. Although the mechanisms that determine the pulsatility and periodicity of hormone release are not completely understood for all the different hormones, 3 general mechanisms can be identified as common regulators of hormone release including: neural control, hormonal control, and nutrient or ion regulation.

Neural Control

Control and integration by the central nervous system is a key component of hormonal regulation and is mediated by direct neurotransmitter control of endocrine hormone release. Neural control plays an important role in the regulation of central (e.g., pituitary) and peripheral (e.g., adrenal glands) endocrine hormone release. Endocrine organs such as the pancreas receive sympathetic and parasympathetic input, which contributes to the regulation of insulin and glucagon release.

Hormonal Control

Hormone release from an endocrine organ is frequently controlled by another hormone. When the outcome is stimulation of hormone release, the hormone that exerts that effect is referred to as a tropic hormone (feed-forward mechanismas) is the case for most of the hormones produced and released from the anterior pituitary. Hormones can also supress another hormone's release (negative feedback regulation).

Nutrient or Ion Regualtion

Plasma levels of nutrients or ions can also regulate hormone release. In all cases, the particular hormone regulates the concentration of the nutrient or ion in plasma either directly or indirectly. Examples of nutrient and ion regulation of hormone release include the control of insulin release by plasma glucose levels and the control of parathyroid hormone release by plasma calcium and phosphate levels.


screen-shot-2016-10-11-at-3-26-17-pmIn several instances, release of 1 hormone can be influenced by more than 1 of these mechanisms. For example, insulin release is regulated by nutrients (plasma levels of glucose and amino acids), neural (sympathetic and parasympathetic stimulation), and hormonal (somatostatin) mechanisms. The ultimate function of these control mechanisms is to allow the neuroendocrine system to adapt to a changing environment, integrate signals, and maintain homeostasis.

The Clincial Art of Assessment of Endocrine Function

In general, disorders of the endocrine system result from 1) alterations in hormone secretion or 2) target cell responsiveness to hormone action. Alterations in target cell response can be caused by increased or decreased biologic responsiveness to a particular hormone. The initial approach to assessment of endocrine function is measurement of plasma hormone levels.

Interpretation of Hormone Measurements

Hormone concentrations in biologic fluids are measured using immunoassays. These assays rely on the ability of specific antibodies to recognize specific hormones. Specificity for hormone measurement depends on the ability of the antibodies to recognize antigenic sites of the hormone. Hormone levels can be measured in plasma, serum, urine, or other biologic samples. Hormone determinations in urine collected over 24 hours provide an integrated assessment of the production of a hormone or metabolite, which vary considerably throughout the day as is the case for cortisol.

Because of the variability in ciculating hormone levels resulting from pulsatile release, circadian rhythms, sleep/wake cycle, and nutritional status, interpretation of isolated plasma hormone measurements should always be done with caution and with understanding of the integral components of the hormone axis in question. Plasma hormone measurements reflect endocrine function only when interpreted in the right context. Some general aspects that should be considered when interpreting hormone measurements are: 1) Hormone levels should be evaluated with their appropraite regulatory factors; 2) stimultaneous elevation of pairs (elevation of both the hormone and the substrate that it regulates) suggests a hormone-resistance state; 3) Urinary excretion of hormone or hormone metabolites over 24 hours, in individuals with normal renal function, may be a better estimate of hormone secretion than one-time plasma-level measurement; 4) target hormone excess should be evaluated with the appropriate tropic hormone to rule out ectopic hormone production, which is usually caused by a hormone-secreting tumor.

The possible interpretations of altered hormone and regulatory factor pairs are summarized in Table 1-1. Increased tropic hormone levels with low target hormone levels indicate primary failure of the target endocrine organ. Increased tropic hormone levels with increased target gland hormone levels indicate autonomous secretion of tropic hormone or inability of target gland hormone to suppress tropic hormone release (impaired negative feedback mechanisms). Low tropic hormone levels with low target gland hormone levels indicate a tropic hormone deficiency, as seen with pituitary failure. Low tropic hormone levels with high target gland hormone levels indicate autonomous hormone secretion by the target endocrine organ.

Dynamic Measurements of Hormone Secretion

In some cases, detection of abnormally high or low hormone concentrations may not be sufficient to conclusively establish the site of endocrine dysfunction. Dynamic measures of endocrine function provide more information than that obtained from hormone-pair measurements and rely on the integrity of the feedback control mechanisms that regulate hormone release. These tests of endocrine function are based on either stimulation or suppression of the endogenous hormone production.

Stimulation tests are designed to determine the capacity of the target gland to respond to its control mechanism, either a tropic hormone or a substrate that stimulates its release. Suppression tests are used to determine whether the negative feedback mechanisms that control that hormone's release are intact.

Hormone-Receptor Measurements

The measurement of hormone-receptor presence, nunber, and affinity has become a useful diagnostic tool, particularly in instituting hormone therapy for the treatment of some tumors. Receptor measurements made in tissue samples obtained surgically allow determination of tissue responsiveness to hormone and prediction of tumor responsiveness to hormone therapy.screen-shot-2016-10-11-at-4-40-22-pm

Insulin Synthesis of Insulin And The Significance of C-Peptide

Proinsulin consists of an amino-terminal beta-chain, a carboy-terminal alpha-chain, and a connecting peptide, known as the C-peptide, that links the alpha- and beta-chains. In the endoplasmic reticulum, proinsulin is processed by specific endopeptidases, which cleave the C-peptide exposing the end of the insulin chain that interacts with the insulin receptor, generating the mature form of insulin. Insulin and the free C-peptide are packaged into secretory granules in the Golgi. These secretory granules accumulate in the cytoplasm in 2 pools: a readily releasable (5%) and a reserve pool of the granules (more than 95%).

On stimulation, the beta-cell releases insulin in a biphasic pattern; initially from the readily releasable pool followed by the reserve pool of granules. Only a small proportion of the cellular stores of insulin are released even under maximal stimulatory conditions. Insulin circulates in its free form, has a half-life of 3-8 minutes, and is degraded predominantly by the liver, with more than 50% of insulin degraded during its first pass. Additional degradation of insulin occurs in the kidneys as well as at target tissues by insulin proteases following endocytosis of the receptor-bound hormone. Because exocytosis of secretory granule content results in the release of equal amounts of insulin and C-peptide into the portal circulation. The importance of C-peptide is that unlike insulin, it is not readily degraded in the liver. Thus, the relatively long half-life of the peptide (35 minutes) allows its release to be used as an index of the secretory capacity of the endocrine pancreas.

Regulation of Insulin Secretion

The pancreatic beta-cell functions as a neuroendocrine integrator that senses and responds to changes in plasma levels of energy substrates (glucose and amino acids), hormones (insulin, glucagon-like peptide I, somatostatin, and eninephrine), and neurotransmitters (norepinephrine and acetylcholine) by increasing or decreasing insulin release. A brief mechanisms of the sensing and responding of beta-cell are summarized in the figure below. The key role to regulate the secretion of insulin (stored in the vesicles) is the intracellular concentration of free calcium, which depends on the voltage-dependent Ca2+ channel crossing on the membrane of the beta-cell. So the depolarization of beta-cell’s membrane, caused by the ATP-sensitive K+ channel (target of sulfonylurea anti-diabetic drugs) enhances the influx of calcium and the resultant increased secretion of insulin.

PS: The increased ATP/ADP ratio leads to inhibition and closure of the ATP-sensitive K+ channels (the target of sulfonylurea drugs), resulting in plasma membrane depolarization and opening of the voltage-dependent Ca2+ channels
Screen Shot 2015 09 23 at 8 42 10 PM

Insulin Receptor and The Signal After Binding

The insulin receptor is part of the insulin-receptor family, which includes the insulin-like growth-factor receptor. The insulin receptor is a heterotetrameric glycoprotein membrane receptor composed of 2 alpha- and 2 beta-subunits, linked by disulfide bonds, which belongs to the enzymes including receptor tyrosine kinases (detail here http://www.tomhsiung.com/wordpress/2014/11/transmembrane-enzymes-including-receptors/). The extracellular alpha-chain is the site for insulin binding. The intracellular segment of the beta-chain has intrinsic tyrosine kinase activity, which on insulin binding, undergoes autophosphorylation on tyrosine residues. The activated receptor phosphorylates tyrosine residues of several proteins known as insulin receptor substrates 1 through 4 (IRS-1-4), facilitating the interaction of the insulin receptor with intracellular substrates. Signal transduction by the insulin receptor is not limited to its activation at the cell surface.

The activated ligand-receptor complex is internalized into endosomes. Endocytosis of activated receptors is thought to enhance the insulin receptor tyrosine kinase activity on substrates that are distant from those readily accessible at the plasma membrane. Following acidification of the endosomal lumen, insulin dissociates from its receptor, ending the insulin receptor-mediated phosphorylation events, and promoting the degradation of insulin by proteases such as the acidic insulinase. The insulin receptor can then be recycled into the cell surface, where it becomes available for insulin binding again. The number of available insulin receptors is modulated by exercise, diet, insulin, and other hormones.

Chronic exposure to high insulin level, obesity, and excess growth hormone all lead to a downregulation of insulin receptors. In contrast, exercise and fasting upregulate the number of receptors, improving insulin responsiveness.

Insulin Effects At Target Organs

The effects of insulin at target organs can be divided into three categories from the perspective of time, including early effects, intermediate effects, and long-term effects. Insulin produces a wide variety of effects that range from immediate (within seconds), such as the modulation of ion (K+) and glucose transport into the cellearly (within minutes), such as the regulation of metabolic enzyme activitymoderate (within minutes to hours), such as the modulation of enzyme synthesis; to delayed (within hours to days), such as the effects on growth and cellular differentiationOverall, the actions of insulin at target organs are anabolic and promote the synthesis of carbohydrate, fat, and protein, and these effects are mediated through binding to the insulin receptor.Screen Shot 2015-09-24 at 7.59.16 PMEarly Effects (metabolic enzyme activity/in fat and muscle cells)

Although the expression of insulin receptors is widespread, the specific effects of insulin on skeletal muscle glucose utilization dominate insulin action. The movement of glucose into the cell is mediated by glucose transporters, accurately, the GLUT 4, most of which is sequestered intracellularly in the absence of insulin or other stimuli such as exercise.Insulin binding to its receptor results in increased GLUT 4 translation through targeted exocytosis and decreased rate of its endocytosis.

Intermediate Effects (enzyme synthesis/in muscle, fat, and liver)

The intermediate effects of insulin are mediated by modulation of protein phosphorylation of enzymes involved in metabolic process in muscle, fat, and, liver. In fat, insulin inhibit its lipolysis and ketogenesis by triggering the dephosphorylation of hormone sensitive lipase and stimulates lipogenesis by activating acetyl coenzyme A (acetyl-CoA) carboxylase. Dephosphorylation of hormone-sensitive lipase inhibits the breakdown of triglycerides to fatty acids and glycerol, the rate-limiting step in the release of free fatty acids mediated by lipolysis.

This process thereby reduces the amount of substrate that is available for ketogenesis. In the liver, insulin stimulates the gene expression of enzymes involved in glucose utilization (e.g., glucokinase, pyruvate kinase) and lipogenic enzymes and inhibits the gene expression of enzymes involved in glucose production (e.g., phosphoenolpyruvate carboxykinase and glucose-6-phosphatase). Insulin stimulates glycogen synthesis by increasing phosphatase activity, leading to the dephosphorylation of glycogen phosphorylase and glycogen synthase. In addition, insulin-mediated dephosphorylation of inhibitory sites on hepatic acetyl-CoA carboxylase increases the production of malonylcoenzyme A and simultaneously reduces the rate at which fatty acids can enter hepatic mitochondria for oxidation and ketone body production. In muscle, insulin stimulates glucose uptake and favors protein synthesis though phosphorylation of a serine/threonine protein kinase known as mammalian target of rapamycin (mTOR). In addition, insulin favors lipid storage in muscle as well as in adipose tissue.

Long-Term Effects

Sustained insulin stimulation enhances the synthesis of lipogenic enzymes and the repression of gluconeogenci enzymes. The growth promoting and mitogenic effects of insulin are long-term response mediated through the MAPK pathway.

Insulin Resistance

Insulin resistance (IR) implies there is target level resistance to the physiological actions of insulin. This resistance is seen at peripheral tissues especially muscle, adipose tissue and liver. The end results of IR are: 1) Decreased peripheral uptake of glucose; 2) inadequate supression of hepatic glucose production; and 3) increased lipolysis. Clinically, the IR is apparent when an appropriate dose of insulin fails to lower plasma glucose to the same extent as seen in controls. Biochemically, the presence of relatively higher fasting and post-secretagogue insulin values are indicative of IR. The impairment of insulin action can be measured by euglycaemic hyperinsulinaemic clamp studies as well as the minimal and homeostasis model assessment (HOMA) methods. In euglycaemic hyperinsulinaemic clamp, a fixed amount of insulin is infused intravenously and a titrated infusion of intravenous glucose is administered to maintain normoglycaemia. A low rate of exogenous glucose infusion indicates insulin resistance. Glucose disposal in clamp studies typically measures up to 7 mg/kg/min in controls while in overweight T2DM it is observed to be much lower, (around 2.5 mg/kg/min).

Mechanisms for Insulin Resistance

Cellular Mechanism of insulin resistance are summarized in Table 25.2.2.screen-shot-2016-10-07-at-7-57-32-pm

In muscles, the sketeal muscles require insulin for optimal glucose uptake and utilization. In T2DM, available insulin fails to recruit more GLU-4 for facilitated glucose transportaiton across the cell membrane. Therefore, the entry of glucose into the myocytes is only through mass action. This results in reduction in glucose uptake from the standard 60 G to 44 G in 3 to 5 hours after a stipulated glucose load. The insulin mediated glucose utilization by the muscles is also impaired in T2DM. Both these factors combined together contribute to the elevated postprandial blood glucose levels seen so frequently in early stages of T2DM.

In the adipose tissue, the resistance of adipocytes to insulin action leads to increased lipolysis resulting in elevated FFAs in circulation and tissues. Leptin is a protein secreted by adipose tissue. In rodents it inhibits neuropeptide neurones, (they stimulate feeding) to the hypothalamus. Its defects give rise to over feeding an dobesity in rodents. The role of leptin in human T2DM is unclear. Adipose tissue also secrets the cytokine TNFalpha, which may cause insulin resistance by inhibiting tyrosine kinase activity of the insulin receptor and decreasing the expression of glucose transporter (GLUT-4). IL-6 secreted by adipose tissue and other cells also induces insulin resistance. The protein adiponectin is secreted by fat cells and ameliorates insulin resistance probably by increasing fat oxidation. Its level is low in obesity. The role of the protein resistin which is also secreted by adipocytes and implicated in IR is not very clear as yet. Moreover, in obesity there is often an increased sympathetic over activity which leads to increased lipolysis, reduced muscle blood flow and thus decreased glucose delivery. Recently it has been observed that foetal and postnatal overnutrition in the first 5 to 10 years which leads to obesity results in IR and metabolic syndrome in later life.

In the liver, both glycogenolysis and gluconeogensis are under the influence of insulin. In patients with IR, there is impaired restraining effect of insulin on gluconeogeenesis and hepatic glucose production (HGP). In T2DM, the requirement of insulin for the control of HGP is nearly double the amount required in normal subjects. Moreover, loss of first phase of insulin secretion seen even at the stage of IGT also contributes to the failure of prompt postload supression of gluconeogenesis. The end result is elevated post-absorptive (fasting) and postprandial (PP) blood sugar values.

The Management of Hypertension (Clinical Evaluation)

September 12, 2015 Cardiology, Diabetes, Infectious Diseases, Pharmacotherapy, Therapeutics No comments , , , , , , , ,

Frequently, the only sign of essential hypertension is elevated BP. The rest of the physical examination may be completely normal. However, a complete medical evaluation including a comprehensive medical history, physical examination, and laboratory and/or diagnostic test is recommended after diagnosis to identify secondary causes, identify other CV risk factors or comorbid conditions that may define prognosis and/or guide therapy, and assess for the presence of absence of hypertension-associated target-organ damage.

For the patients who have been diagnosed with hypertension, we should ask a few questions that are necessary to make a clinical evaluation for these patients. Here is an example of a patient with hypertension.

D.C. is a 44-year-old black man who presents to his primary care provider concerned about high BP. At an employee health screening last month he was told he has stage 1 hypertension. His medical history is significant for allergic rhinitis. His BP was 144/84 and 146/86 mm Hg last year during an employee health screening at work. D.C.’s father had hypertension and died of an MI at age 54. His mother had diabetes and hypertension and died of a stroke at age 68. D.C. smokes on pack per day of cigarettes and thinks his BP is high because of job-related stress. He does not engage in any regular exercise and does not restrict his diet in any way, although he knows he should lose weight.

Physical examination show he is 175 cm tall, weighs 108 kg (BMI, 35.2 kg/m2), BP is 148/88 mm Hg (left arm) and 146/86 mm Hg (right arm) while sitting, heart rate is 80 beats/minute. Six months ago, his BP values were 152/88 mm Hg and 150/84 mm Hg when he was seen by his primary-care provider for allergic rhinitis. Funduscopic examination reveals mild arterial narrowing and arteriovenous nicking, with no exudates or hemorrhages. The other physical examination findings are essentially normal.

D.C.’s fasting laboratory serum values are as follows:

Blood urea nitrogen, 24 mg/dL

Creatinine, 1.0 mg/dL

Glucose, 105 mg/dL (Fasting?)

Potassium, 4.4 mEq/L

Uric acid, 6.5 mg/dL

Total cholesterol, 196 mg/dL

Low-density lipoprotein cholesterol, 141 mg/dL

High-density lipoprotein cholesterol, 32 mg/dL

Triglycerides, 170 mg/dL

An electrocardiogram is normal except for left ventricular hypertrophy.

PS: Normal values are marked in green and abnormal values are marked in orange.

Clinical Presentation

Question 1 What is the clinical presentation D.C.?

All the information above could be the part of D.C.’s clinical presentation. Besides, we could classify the stage of D.C.’s hypertension as shown below.

D.C. has uncontrolled stage 1 hypertension. He has had elevated BP values, measured in clinical environments, and meets the diagnostic criteria for hypertension because two or more of his BP measurements are elevated on separate days. SBP values are consistently stage 1, whereas DBP values are all in the prehypertension range. The higher of the two classifications is used to classify hypertension.

Question 2 Why does D.C. have hypertension?

D.C. has essential hypertension; therefore, the exact cause is not known. He has several characteristics (e.g., family history of hypertension, obesity) that may have increased his chance of developing hypertension. Race and sex also influence the prevalence of hypertension Across all age groups, black have a higher prevalence of hypertension than do whites and Hispanics. Similar to other form of CV disease, hypertension is more server, more like to include hypertension-associated complications, and occurs at an earlier age in black patients.

Patient Evaluation and Risk Assessment

The presence of absence of hypertension-associated complications as well as other major CV risk factors (Table 14-5) must be assessed in D.C. Also, secondary cause of hypertension (Table 14-3), if suggested by history and clinical examination findings, should be identified and managed accordingly. The presence of concomitant medical conditions (e.g., diabetes) should be assessed, and lifestyle habits should be evaluated so that they can be used to guide therapy.

  • Hypertension-associated complications
  • Secondary causes of hypertension
  • Concomitant medical conditions

Question 3 Dose D.C. has secondary cause of hypertension?

The most common secondary causes of hypertension are list in Table 3-1. Patients with secondary hypertension might have signs or symptoms suggestive of the underlying disorders.

Table 3-1 Secondary Causes of Hypertension.

  • Patients with pheochromocytoma may have a history of paroxysmal headaches, sweating, tachycardia, and palpitations. Over half of these patients suffer from episodes of orthostatic hypotension.
  • In primary hyperaldosteronism symptoms related to hypokalemia usually include muscle cramps and muscle weakness.
  • Patients with Cushing’s syndrome may complain of weight gain, polyuria, edema, menstrual irregularities, recurrent acne, or muscle weakness and have several classic physical features (e.g., moon face, buffalo hump, hirsutism).
  • Patient with coarctation of the aorta may have higher BP in the arms than in legs and diminished or even absent femoral pulses.
  • Patient with renal artery stenosis may have an abdominal systolic-diastolic bruit.

Also, routine laboratory tests may also help identify secondary hypertension. For example, Baseline hypokalemia may suggest mineralocorticoid-induced hypertension. Protein, red blood cells, and casts in the urine may indicate renovascular disease. Some laboratory tests are used specifically to diagnose secondary hypertension. These include plasma norepinephrine and urinary metanephrine for pheochromocytoma, plasma and urinary aldosterone concentrations for primary hyperaldosteronism, and plasma rennin activity, captopril stimulation test, renal vein renin, and renal artery angiography for renoascular disease.

Certain drugs and other products can result in drug-induced hypertension. For some patients, the addition of these agents can be the cause of elevated BP or can exacerbate underlying hypertension. Identify a temporal relationship between starting the suspected agent and developing elevated BP is most suggestive of drug-induced BP elevation.

Question 4 Which hypertension-associated complications are present in D.C.?

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A complete physical examination to evaluate hypertension-associated complications includes examination of the optic funds; auscultation for carotid, abdominal, and femoral bruits; palpation of the thyroid gland; heart and lung examination; abdominal examination for enlarged kidney, masses, and abnormal aortic pulsation; lower extremity palpation for edema and pulses; and neurologic assessment. Routine laboratory assessment after diagnosis should include the following: EKG; urinalysis; fasting glucose; hematocrit; serum potassium, creatinine, and calcium; and fasting lipid panel. Optional testing may include measurement of urinary albumin excretion or albumin-to-creatinine ratio, or additional tests specific for secondary causes if suspected.

Question 5 What other forms of hypertension-associated complications is D.C. at risk for?

Hypertension adversely affects many organ systems, including the heart, brain, kidneys, peripheral circulation, and eyes (Table 14-5). Damage to these systems resulting from hypertension is termed hypertension-associated complications, target-organ damage, or CV disease. There are often misconceptions about the term CV disease and CAD. CV disease encompasses the broad scope of all forms of hypertension-associated complications. CAD is simply a subset of CV disease and refers specifically to disease related to the coronary vasculature, including ischemic heart disease and MI.

Hypertension can affect the heart either indirectly, by promoting atherosclerotic changes, or directly, via pressure-related effects. Hypertension can promote CV disease and increase the risk for ischemic events, such as angina and MI. Antihypertensive therapy has been shown to reduce the risk of these coronary events. Hypertension also promotes the development of LVH, which is a myocardial (cellular) change, not an arterial change. These two conditions often coexist, however. It is commonly believed that LVH is a compensatory mechanism of the heart in response to the increased resistance caused by elevated BP (more accurately, the afterload). Recall the definition of afterload, that is, wall tension=(pressure * radius)/(wall thickness). LVH is a strong and independent risk factor for CAD, left ventricular dysfunction, and arrhythmia. LVH does not indicate the presence of left ventricular dysfunction, but is a risk for progression to left ventricular dysfunction, which is considered a hypertension-associated complication. This may be caused by ischemia, excessive LVH, or pressure overload. Ultimately, left ventricular dysfunction results in a decrease ability to contract (systolic dysfunction).

Hypertension is one of the most frequent causes of cerebrovascular disease. Cerebrovascular signs can manifest as transient ischemic attacks, ischemic strokes, multiple cerebral infarcts, and hemorrhages. Residual functional deficits caused by stroke are among the most devastating forms of hypertension-associated complications. Clinical trials have demonstrated that antihypertensive therapy can significantly reduce the risk of both initial and recurrent stroke. A sudden, prolonged increase in BP also can cause hypertensive encephalopathy, which is classified as a hypertensive emergency.

The GFR is used to estimate kidney function, which declines with aging. This rate of decline is greatly accelerated by hypertension. Hypertension is associated with nephrosclerosis, which is caused by increased intraglomerular pressure. It is unknown whether a primary kidney lesion with ischemia causes systemic hypertension or whether systemic hypertension directly causes glomerular capillary damage by increasing intraglomerular pressure. Regardless, CKD, whether mild or severe, can progress to kidney failure (stage 5 CKD) and the need for dialysis. Studies have demonstrated that controlling hypertension is the most important strategy to slow the rate of kidney function decline, but it may not be entirely effective in slowing the progression of renal impairment in all patients.

In hypertension, stage 3 CKD or worse is considered a hypertension-associated complication (GFR values of <60 mL/min/1.73 m2). An estimated GFR of less than 60 mL/min/1.73 m2 corresponds approximately to a serum concentration of greater than 1.5 mg/dL in an average man and greater than 1.3 mg/dL in an average woman. This level of kidney compromise lowers an individual’s BP goal to less than 130/80 mm Hg according to multiple guidelines. The presence of persistent albuminuria (>300 mg albumin in a 24-hour urine collection or 200 mg albumin/g creatinine on a spot urine measurement) also indicates significant CKD, for which achieving the more aggressive BP goal is a strategy to minimize the rate of progression to kidney failure.

Peripheral arterial disease, a non coronary form of atherosclerotic vascular disease, is considered a hypertension-associated complication. It is equivalent in CV risk to CHD. Risk factor reduction, BP control, and anti platelet agent(s) are needed to decrease progression. Complications of peripheral arterial disease can include infection and necrosis, which in some cases require revascularization procedures or extremity amputation.

Hypertension causes retinopathies that can progress to blindness. Retinopathy is evaluated according to the Keith, Wagener, and Barker funduscopic classification system. Grade 1 is characterized by narrowing of the arterial diameter, indicating vasoconstriction. Arteriovenous nicking is the hallmark of grade 2, indicating atherosclerosis. Longstanding, untreated hypertension can cause cotton wool exudates and flame hemorrhages (grade 3). In severe cases, papilledema occurs, and this is classified as grade 4.

Question 6 Which major CV risk factors are present in D.C.?

As shown in Table 14-5, major CV risk factors include advanced age (>55 years for men, >65 years for women), cigarette smoking, diabetes mellitus, dyslipidemia, family history of premature atherosclerotic vascular disease (men <55 years or women <65 years) in primary relatives, hypertension, kidney disease (microablubuminuria or estimated GFR <60 mL/min/1.73 m2), obesity (BMI >=30 kg/m2), and physical inactivity.

PS: Estimated GFR calculated from online calculator for D.C. is 105 mL/min/1.73 m(online calculator: http://www.davita.com/gfr-calculator/).

So according to D.C.’s clinical presentation, he has major CV risk factors that are marked in orange, that is, 5 factors in total, including the essential hypertension.

Question 7 What is D.C.’s BP goal and how can Framingham risk scoring influence BP goal determination?

D.C. is a primary prevention patient because he does not yet have any hypertension-associated compilations (or compelling indications). He has multiple CV risk factors, so controlling his BP is of paramount importance to reduce the risk of developing hypertension-associated complications. The JNC-8 guidelines recommend the initial BP goal for hypertension patients with age of <60 years should be 140/90 mm Hg, which has grade A evidence (strong recommendation) for patients from 30 through 59 years of age, and grade E (expert opinion) for those from 18 through 29 years of age. So D.C.’s initial BP goal should be below 140/90 mm Hg.

The framingham risk scoring system is available as an online calculator at NIH site of http://cvdrisk.nhlbi.nih.gov/calculator.asp. According to D.C.’s clinical presentation, he will has a CV risk of  14% in a next 10-year period of expectation before we intervention, which means in a population cohort such as D.C., 14 in 100 individuals will develop CV diseases after a period of 10-year, if we don’t treat these CV risk factors (if these risk factors worsen, the incidence of developing CV diseases would be higher). If we treat D.C.’s current hypertension target the BP goal, with other interventions that target D.C.’s rest risk factors like habit of smoking, etc., the incidence of developing CV diseases would be attenuated (In D.C.’s example, the incidence would decrease to 5%, that is 5 in 100 of individuals will develop CV diseases in a period of 10-year). Compare the results without/with interventions to D.C.

Screen Shot 2015-09-12 at 3.26.52 PM Screen Shot 2015-09-12 at 3.28.34 PM

The intervention above does not include the management of dyslipidemia. According to the latest AHA guideline, four types of patients need the intervention for dyslipidemia, including: 1.secondary prevention in individuals with clinical ASCVD; 2. primary prevention in individuals with primary elevations of LDL-C >=190 mg/dL; 3.primary prevention in individuals with diabetes 40 to 75 years of age who have LDL-C 70 to 189 mg/dL; and 4.primary prevention in individual without diabetes and with estimated 10-year ASCVD risk>=7.5%, 40 to 75 years of age who have LDL-C 70 to 189 mg/dL. (References: http://www.tomhsiung.com/wordpress/2014/07/the-management-of-dyslipidemia/). So we need to calculate D.C.’s ASCVD risk from another tool developed by ACC/AHA (American College of Cardiology/American Heart Association), which is available as iOs apps. So the result of ASCVD risk of D.C. is 9.7% (>=7.5%) without any intervention, whereas ASCVD risk is 8.6% (still >=7.5%) with interventions of antihypertensive therapy and smoke cessation. Therefore, the dyslipidemia should be treated for D.C.

PS: ASCVD includes coronary heart disease (CHD), stroke, and peripheral arterial disease, all of presumed atherosclerotic origin.


The Management of Dyslipidemia

July 26, 2014 Cardiology, Diabetes, Pharmacotherapy, Pharmacy Education, Therapeutics No comments , , ,

Let's talk about ATP IV first, then we shall discuss how to detect, evaluate, and manage patients with lipid disorders.

This thread is based on the latest clinical guideline (Circulation. 2014:S1-S45) for therapy of dyslipidemia to reduce atherosclerotic cardiovascular risk in adults (>21 years of age) and the guideline is based on the Full Panel Report. Because RCT data were used to identify those most likely to benefit from cholesterol-lowering statin therapy, the recommendations will be of value to primary care clinicians as well as specialists concerned with ASCVD prevention.

These recommendations in the guideline are intended to provide a strong, evidence-based foundation for the treatment of cholesterol for the primary and secondary prevention of ASCVD in women and men. Of note, to manage the patients with dyslipidemia successfully and appropriately, besides the guideline clinicians should also know the detection, evaluation, and treatment of lipid disorders of these patients, with strategies for each specific individual.

Basically, the latest guideline or ATP IV is quite different from any previous guidelines such as ATP III. The latest ATP IV guideline only focus on the treatment of dyslipidemia to reduce risk of ASCVD, based on evidence-based medicine, RCTs.

PS: ASCVD includes coronary heart disease (CHD), stroke, and peripheral arterial disease, all of presumed atherosclerotic origin.

In the figure on the left are new changes in ATP IV guideline. Here we shall keep in mind for those ones:

1.This guideline is based on a comprehensive set of data from RCTs from which 4 statin benefit groups were identify that focus efforts to reduce ASCVD event in secondary and primary prevention;

2.This guideline identifies high-intensity and moderate-intensity statin therapy for use in secondary and primary prevention;

3. The Expert Panel was unable to find RCT evidence to support continued use of specific LDL-C or non-HDL-C treatment target;(For secondary prevention the Expert Panel reviewed 19 RCTs to answer the question of specific LDL-C and non-HDL-C targets. No data were identified for treatment or titration to a specific LDL-C goal in adults with clinical ASCVD since no any RCTs compared 2 LDL-C treatment targets [<100 mg/dL or <70 mg/dL]. For primary prevention the Expert Panel reviewed 6 RCTs but did not find any RCTs that evaluated titration of all individuals in a treatment group to specific LDL-C targets <100 mg/dL or <70 mg/dL)

4.Nonstatin therapies, as compared with statin therapy, do not provide acceptable ASCVD risk-reduction benefits relative to their potential for adverse effects in the routine prevention of ASCVD. For safety of nonstatin please refer to the thread here http://forum.tomhsiung.com/pharmacotherapy/465-atp-4-guideline-for-dyslipidemia.html

There are more updates in ATP IV guideline. They are listed at left side.

The Management of Lipid Disorders


All adults older than age 20 year should have plasma levels of cholesterol, triglyceride, LDL-C, and HDL-C measured after a 12-hour overnight fast, at least once every five years. If the profile is obtained in the nonfasted state, only total cholesterol and HDL-C will be usable because LDL-C is usually a calculated value. If total cholesterol is >=200 mg/dL, or if HDL-C is <40 mg/dL, a followup fasting lipoprotein profile should be obtained.

Patient Evaluation

After a lipid abnormality is confirmed, we shall try efforts to define the category of the lipid disorder and to rule out any possible secondary causes of the hyperlipidemia. The Fredrickson classfication can be helpful in this regard.

Thereafter, major components of the evaluation are the history, physical examination, and laboratory investigations. A complete history and physical exam should assess:

(1) presence or absence of cardiovascular risk factors or definite cardiovascular disease in the individual; Major risk factors for ASCVD include: Age >=45 years (male) or>=55 years or premature menopause without estrogen replacement (female); High total choesterol; Low HDL-C; Hypertension, or use of antihypertensive therapy; Diabetes; Current smoking.

Additional factors contributing to ASCVD risk including: Family history of premature CHD (definite myocardial infarction or sudden death before 55 years of age in father or other male first-degree relative, or before 65 years of age in mother or other female first-degree relative); Primary LDL-C >=160 mg/dL or other evidence of genetic hyperlipidemias; High-sensitivity C-reactive protein >=2 mg/L, coronary artery calcium score >=300 Agatston units or >=75th percentile for age, sex, and ethnicity; Ankle-brachial index <0.9; or Elevated lifetime risk of ASCVD (see in following text).

(2) family history of premature cardiovascular disease or lipid disorders;

(3) presence or absence of secondary causes of lipid abnormalities, including concurrent medications (see http://forum.tomhsiung.com/physiology-and-pathophysiology/471-the-secondary-causes-of-dyslipidemia.html);

(4) presence or absence of xanthomas or abdominal pain, or history of pancreatitis, renal or liver disease, peripheral vascular disease, abdominal aortic aneurysm, or cerebral vascular disease (carotid bruits, stroke, or transient ischemic attack).

(5) baseline lab value such as fasting lipid profile, liver function, renal function, and creatine kinase;

(6) history of previous statin intolerance or muscle disorders;

(7) whether the individual had comorbidities, possible concurrent medications and DDIs.

To evaluate the potential risk for ASCVD, ATP IV guideline suggest using the new Pooled Cohort Risk Assessment Equations developed by the Risk Assessment Work Group to estimate the 10-year ASCVD risk (defined as first-occurrence nonfatal and fatal MI and nonfatal and fatal stroke) or the lifetime ASCVD risk (more detail see Pharmacy Profession Forum at http://forum.tomhsiung.com/pharmacotherapy/467-how-to-estimate-the-risk-of-ascvd-the-latest-equations.html). The predicted 10-year ASCVD risk is defined as first-occurrence nonfatal and fatal MI and nonfatal and fatal stroke.

Estimates of 10-year risk for ASCVD are based on data from multiple community-based populations and are applicable to African-American and non-Hispanic white men and women 40 through 79 years of age. For other ethnic groups, we recommend use of the equations for non-Hispanic whites, though these estimates may underestimate the risk for persons from some race/ethnic groups, especially American Indians, some Asian Americans (e.g., of south Asian ancestry), and some Hispanics (e.g., Puerto Ricans), and may overestimate the risk for others, including some Asian Americans (e.g., of east Asian ancestry) and some Hispanics (e.g., Mexican Americans)Estimates of lifetime risk for ASCVD are provided for adults 20 through 59 years of age and are shown as the lifetime risk for ASCVD for a 50-year old without ASCVD who has the risk factor values entered into the spreadsheet. The estimates of lifetime risk are most directly applicable to non-Hispanic whites. We recommend the use of these values for other race/ethnic groups, though as mentioned above, these estimates may represent under- and overestimates for persons of various ethnic groups. Because the primary use of these lifetime risk estimates is to facilitate the very important discussion regarding risk reduction through lifestyle change, the imprecision introduced is small enough to justify proceeding with lifestyle change counseling informed by these results.

Note that 10-year risk estimation is only calculated for the 40 to 79 year range. Life-time risk estimation is only calculated for the 20 to 59 year range.

Also there is iPad app of this new tool, completely free – https://itunes.apple.com/us/app/ascvd-risk-estimator/id808875968?mt=8.

General Approach

Therapeutic lifestyle change (TLC) should be implemented in all patients prior to considering drug therapy. Many persons should be given a three-month trial (two visits spaced 6 Weeks apart) of TLC unless patients are at very high risk.

PS: Very high risk for ASCVD is defined as the presence of established CVD plus one or more of:
1. multiple major risk factors (especially diabetes)
2. severe and poorly controlled risk factors (especially continued cigarette smoking)
3. multiple risk factors of the metabolic syndrome (especially high triglycerides >=200 mg/dL plus non-HDL-C>=130 mg/dL with low HDL-C [<40 mg/dL])
4. on the basis of PROVE IT, patients with acute coronary syndromes.

However, this criteria is derived from ATP III guideline. The ATP IV guideline has changed largely and according to a clinical pharmacy specialist/BCPS/Cardiology, whose name is Brent Reed, the very high risk category is no longer valid in the new guidelines (Clinical Practice Guideline of ATP IV).

If drug therapy to further reduce lipid profile is necessary, before initiation of drug therapy the patient shall be evaluation, not only the potential risk for ASCVD, but also ASCVD risk-reduction benefits, adverse effects, DDIs, and patient preferences (e.g., comorbidities, age >75 years, etc.)

In the latest ATP IV guideline, generally, four groups of patients would definitely benefit from statin therapy (ASCVD risk reduction clearly outweighs the risk of adverse events based on a strong body of evidence). They are 1.secondary prevention in individuals with clinical ASCVD; 2. primary prevention in individuals with primary elevations of LDL-C >=190 mg/dL; 3.primary prevention in individuals with diabetes 40 to 75 years of age who have LDL-C 70 to 189 mg/dL; and 4.primary prevention in individual without diabetes and with estimated 10-year ASCVD risk>=7.5%, 40 to 75 years of age who have LDL-C 70 to 189 mg/dL. Patient with heart failure or hemodialysis are excluded and no suggestion would be made to these two cohorts.

PS: clinical ASCVD is defined by the inclusion criteria for the secondary-prevention statin RCTs, which include acute coronary syndromes, a history of Mi, stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease presumed to be of atherosclerotic origin.

Also, moderate evidence supports the use of statin for primary prevention in individuals with 5% to <7.5% 10-year ASCVD risk, 40 to 75 years of age with LDL-C 70 to 189 mg/dL. Selected individuals with <5% 10-year ASCVD risk, or <40 or >75 years of age may also benefit from statin therapy, but in these circumstances clinicians shall consider the potential ASCVD risk reduction benefits, adverse effects, DDIs, and patient preferences.

Nonpharmacologic Therapy

It must be emphasized that lifestyle modification (i.e., heart-healthy diet, regular exercise habits, avoidance of tobacco products, and maintenance of a healthy weight) remains a crucial component of health promotion and ASCVD risk reduction, both prior to and in concert with the use of cholesterol-lowering drug therapies. Individualized diet counseling that provides acceptable substitutions for unhealthy foods and ongoing reinforcement by a registered dietitian are necessary for maximal effect.

Generally, lifestyle modification includes stopping excessive dietary intake of cholesterol and saturated fatty acids, weight control, increasing physical activity, increasing intake of soluble fiber, intake of fish oil supplementation, fat substitutes, and plant sterols & stanols.

Excessive dietary intake of cholesterol and saturated fatty acids leads to decreased hepatic clearance of LDL and deposition of LDL and oxidized LDL in peripheral tissues. Compared with polyunsaturated and saturated fat, intake of cholesterol has been found to have a greater effect on the concentration of LDL. Note that changes in blood lipid levels may change before three months, but may require a longer period time too. If all of the recommended dietary changes from NCEP are made, the estimated reduction, on average, in LDL-C would range from 20-30%.

Thus, ideally, lifestyle modification shall reduced intake of saturated fats and cholesterol. Weight control plus increased physical activity reduces risk beyond LDL-C and non-HDL lowering, but also can raises HDL.

Increased intake of soluble fiber can result in useful adjunctive reductions in total and LDL cholesterol. However, increased fiber intake has little or no effect on HDL-C or triglyceride concentrations. It is unclear whether the reduction in CHD risk associated with large amount of cold water, oily fish is the same with commercially prepared fish oil products. Note that fish oil supplementation has fairly large effect in reducing triglycerides and VLDL-C but it either has no effect on total and LDL-C or may cause elevations in these fractions.

Fat substitutes is similar in composition to triglycerides, but is not hydrolyzed in the gastrointestinal tract by pancreatic lipase, and, consequently, is not taken up by the intestinal mucosa. However, the absorption of lipophilic drugs or vitamins (A, D, E, and K) would be kept in the tract and excreted in the feces.

Plant sterols and stanols have demonstrated LDL-lowering effect in recent studies. The two are efficaciously comparable.

Pharmacotherapy Therapy

Nonstatin therapies, as compared with statin therapy, do not provide acceptable ASCVD risk-reduction benefits relative to their potential for adverse effects in the routine prevention of ASCVD. For patients with clinical ASCVD and within age of 75 years, high-intensity statin therapy should be initiated if they are not on statin therapy, or the intensity shall be increased in those receiving a low- or moderate-intensity statin therapy unless they have a history of intolerance to high-intensity statin therapy or other characteristics that could influence safety. If high-intensity statin therapy would otherwise be used, either when high-intensity statin therapy is contraindicated or when characteristics predisposing to statin-associated adverse effects are present, moderate-intensity statin should be used as the second option, if tolerated.

Dosage of Statin TherapyPatients with clinical ASCVD

For patients with clinical ASCVD and >75 years of age, RCTs data of high-intensity versus moderate-intensity statin therapy is few. However, there was no clear evidence of an additional reduction in ASCVD events from high-intensity statin therapy. In contrast, individuals >75 years of age did experience a reduction in ASCVD events in  moderate-intensity statin therapy, as compared with control. Thus, moderate-intensity statin therapy should be considered for individual >75 years of age with clinical ASCVD.

Although atorvastatin 40 mg reduces LDL-C by approximately >=50%, this dose was used in only 1 RCT if the participant was unable to tolerate atorvastatin 80 mg/dL. Whether an individual receiving atorvastatin 40 mg should be uptitrated to atorvastatin 80 mg shall be based on the potential for adverse effects, DDIs, and patient preferences.

Patients with LDL-C >=190 mg/dL

For patient >=21 years of age without clinical ASCVD but with LDL-C >=190 mg/dL (primary), severe elevation of LDL-C have a high lifetime risk for ASCVD events. Thus, at age 21, these individuals should receive statin therapy if they have not already been diagnosed and treated before. Patients with primary elevations of LDL-C >=190 mg/dL require even more substantial reductions in their LDL-C levels and intensive management of other risk factors to reduce their ASCVD event rates. Therefore, it is reasonable to use high-intensity statin therapy to achieve at least 50% reduction. It is recognized that maximal statin therapy might not be adequate to lower LDL-C sufficiently to reduce ASCVD event risk in individuals with primary severe elevations of LDL-C. In addition to a maximally tolerated dose of statin, nonstatin cholesterol level medications are often needed to lower LDL-C to acceptable levels in these individuals. It is also important that secondary causes, if it were exist, can contribute to the degree and severity of LDL-C >=190 mg/dL. Therefore these secondary causes should be corrected if possible.

Patients with diabetes and LDL-C is between 70 and 189 mg/dL

A high level of evidence supports the use of moderate-intensity statin therapy in persons with diabetes who are 40 to 75 years of age. The only trial of high-intensity statin therapy in primary prevention was performed in a population without diabetes. However, a high level of evidence existed for event reduction with statin therapy in individuals with a >=7.5% estimated 10-year ASCVD risk who did not have diabetes to recommend high-intensity statin therapy preferentially for individuals with diabetes and a >=7.5% estimated 10-year ASCVD risk. This consideration for those with diabetes who are 40 to 75 years of age recognizes that these individuals are at substantially increased lifetime risk for ASCVD events and death. Moreover, individuals with diabetes experience greater morbidity and worse survival after the onset of clinical ASCVD. For patients with diabetes but the 10-year ASCVD risk <7.5% moderate-intensity is recommended.

In patients with diabetes who are <40 years of age or >75 years of age, or whose LDL-C is <70 mg/dL, statin therapy should be individualized on the basis of considerations of ASCVD risk-reduction benefits, the potential for adverse effects and drug-drug interactions, and patient preferences.

Patients without diabetes and with LDL-C between 70 and 189 mg/dL

In individuals 40 to 75 years of age with LDL-C 70 to 189 mg/dL who do not have clinical ASCVD or diabetes, initiation of statin therapy based on estimated 10-year ASCVD risk is recommended, regardless of sex, race, or ethnicity. A high level of evidence for an ASCVD restriction benefit from initiation of moderate- or high-intensity statin therapy in individuals 40 to 75 years of age with >=7.5% estimated 10-year ASCVD risk was found. The reduction in ASCVD risk clearly outweighs the potential for adverse effects. Thus, it is recommended that individuals 40 to 75 years of age, who are not already candidates for statin therapy on the basis of the presence of clinical ASCVD, diabetes, or LDL-C >=190 mg/dL, receive statin therapy if they have a >=7.5% estimated 10-year risk for ASCVD and LDL-C 70 to 189 mg/dL.

For patients in this group (age 40-75) with estimated risk of 5-7.5%, although a similar level of evidence of a reduction in ASCVD events from moderate- and high-intensity statin therapy is present, the potential for adverse effects may outweigh the potential for ASCVD risk-reduction benefit when high-intensity statin therapy is used. Thus, it is recommended that moderate-intensity statin therapy should be used in this cohort since ASCVD risk-reduction benefit from moderate-intensity statin therapy clearly exceeds the potential for adverse effects.

For patients in this group (age 40-75) with estimated risk of <5%, patients 21 to 39 years of age, patients >75 years of age, or patients with LDL-C <70 mg/dL, the decision to initiate statin therapy and the starting dosage should based on ASCVD risk-reduction benefits, adverse effects, DDIs, and patient preferences.

Combination Therapy

No evidence support the routine use of nonstatin drugs combined with statin therapy to further reduce ASCVD events. However, high-risk patients who have a less than-anticipated response to statins, who are unable to tolerate a less-than-recommended intensity of a statin, or who are completely statin intolerant, may be added a nonstatin cholesterol level therapy. High-risk patients include those with ASCVD, those with LDL-C >=190 mg/dL, and those with diabetes 40-75 years of age. Due to that the potential benefits and safety are not clear in combination therapy, ASCVD risk-reduction benefits, adverse effects, DDIs, and patient preferences should be considered.


Once pharmacotherapy for dyslipidemia initiates, clinicians should monitor the efficacy, safety, adherence of the choosen regimen. To monitor the efficacy, the evidence is less clear with regard to the most appropriate tests for determining whether an anticipated therapeutic response to statin therapy has occurred on the maximally tolerated dose. However, it is reasonable to use following as indicators of anticipated therapeutic response for the monitor of statin therapy. The percent LDL-C reduction may not only indicate adherence, but also may reflect biological variability in the response to statin therapy.

1.High-intensity statin therapy generally results in an average LDL-C reduction of >=50% from the untreated baseline.

2.Moderate intensity statin therapy generally results in an average LDL-C reduction of 30% to <50% from the untreated baseline.

3.If the baseline levels of LDL-C of the patients are unknown and already on a statin, an LDL-C of <100 mg/dL was observed in most individuals receiving high-intensity statin therapy in RCTs.

The most important issue in statin safety is to manage the muscle symptoms. The recommendation is list in the table below.

Statin Safety RecommendationsSome recommendation shall be emphasized here.

Routine measurement of creatine kinase is not recommended. To monitor it when patients have symptoms and signs of muscle problems.

If the 2 consecutive values of LDL-C are <40 mg/dL, clinicians shall consider decreasing the statin dose. This recommendation was based on the approach taken in 2 RCTs. However, no data were identified that suggest an excess of adverse events occurred when LDL-C levels were below this level.

The frequency of monitor should be every 3 to 12 months as clinical indicated, with the first re-check 4 to 12 Weeks after initiation of statin therapy.


Feb 11 2016

Major cardiovascular risk factors

  • Advanced age (>55 years for men, >65 years for women)
  • Cigarette smoking (no information available)
  • Diabetes mellitus
  • Dyslipidemia (no information available)
  • Familiy history of premature atherosclerotic vascular disease (men <55 years or women <65 years) in primary relatives
  • Hypertension
  • Kidney disease (microalbuminuria or estimate GFR <60 mL/min/1.73 m2)
  • Obesity (BMI >=30 kg/m2)
  • Physical inactivity (no information available)

Additional cardiovascular rsik factors

  • Family history of premature CHD (definite myocardial infarction or sudden death before 55 years of age in father or other male first-degree relative, or before 65 years of age in mother or other female first-degree relative)
  • Primary LDL-C >=160 mg/dL or other evidence of genetic hyperlipidemias
  • High-sensitivity C-reactive protein >=2 mg/L, coronary artery calcium score >=300 Agatston units or >=75th percentile for age, sex, and ethnicity
  • Ankle-brachial index <0.9
  • Elevated lifetime risk of ASCVD

Nutrition Recommendations and Interventions for Diabetes (Part One)

March 25, 2014 Diabetes No comments , , ,

ACCPEffectiveness of MNT (Medical Nutrition Therapy)

Clinical trials/outcome studies of MNT have reported decreases in HbA1c of ~1% in type 1 diabetes and 1-2% in type 2 diabetes, depending on the duration of diabetes. Meta-analysis of studies in nondiabetic, free-living subjects and expert committees report that MNT reduce LDL cholesterol by 15-25 mg/dl. After initiation of MNT, improvements were apparent in 3-6 months. Meta-analysis and expert committees also support a role for lifestyle modification in treating hypertension.

Goals of MNT for Prevention and Treatment of Diabetes

1. With Pre-Diabetes

To decrease the risk of diabetes and cardiovascular disease (CVD) by promoting healthy food choices and physical activity leading to moderate weight loss that is maintained.

2. With Diabetes

Achieve and maintain: Blood glucose levels in the normal range or as close to normal as is safely possible A lipid and lipoprotein profile that reduces the risk for vascular disease Blood pressure levels in the normal range or as close to normal as is safely possible.

To prevent, or at least slow, the rate of development of the chronic complications of diabetes by modifying nutrient intake and lifestyle.

To address individual nutrition needs, taking into account personal and cultural preferences and willingness to change.

To maintain the pleasure of eating by only limiting food choices when indicated by scientific evidence.

Nutrition Recommendations and Interventions for The Management of Diabetes (Secondary Prevention)

The nutrition has a direct relationship with obesity, and obesity has a correlation with insulin resistance.Overweight and Disease Risk As the figure shown, disease risk increases with obesity class.

There are several types of foods including carbohydrate, dietary fat and cholesterol, protein, macronutrients, alcohol, micronutrients, and chromium other minerals and herbs. In this post we will discuss the management of these foods in diabetes.


Control of blood glucose in an effort to achieve normal or near-normal levels is a primary goal of diabetes management. Food and nutrition interventions that reduce postprandial blood glucose excursions are important in this regard, since dietary carbohydrate is the major determinant of postprandial glucose levels.

Monitoring carbohydrate, whether by carbohydrate counting, exchanges, or experienced-based estimation remains a key strategy in achieving glycemic control. In the figure below there are the glycemic index and glycemic load of common foods.

Low-carbohydrate diets might seem to be a logical approach to lowering postprandial glucose. However, foods that contain carbohydrate are important sources of energy, fiber, vitamins, and minerals and are important in dietary palatability. Therefore, these foods are important components fo the diet for individuals with diabetes.

Blood glucose concentration following a meal is primarily determined by the rate of appearance of glucose in the blood stream (digestion and absorption) and its clearance from the circulation. Insulin secretory response normally maintains blood glucose in a narrow range, but in individuals with diabetes, defects in insulin action, insulin secretion, or both impair regulation of postprandial glucose in response to dietary carbohydrate. Both the quantity and the type or source of carbohydrates found in foods influence postprandial glucose levels.

For carbohydrate, the amount and type of carbohydrate digested and absorbed determined the rate of appearance of glucose in blood stream. As noted in 2004 ADA statement, the average minimum carbohydrate requirement is about 130 g/day. However, several clinical trials found low-carbohydrate have no significant difference reduction in fasting glucose and A1C compared with other types of diet styles (e.g., low-fat).

In rationale, the amount of carbohydrate ingested is usually the primary determinant of postprandial response, but the type of carbohydrate also affects this response. The glycemic index of foods was developed to comare the postprandial responses to constant amount of different carbohydrate-containing foods. The glycemic index of a food is the increase above fasting in the blood glucose area over 2 h after ingestion of a constant amount of that food (usually a 50–g carbohydrate portion) divided by the response to a reference food (usually glucose or white bread). The glycemic loads of foods, meals, and diets are calculated by multiplying the glycemic index of constituent foods by the amounts of carbohydrate in each food and then totaling the values for all foods.

GI and GLRelationship between Glycemic Index and Glycemic Load

The GI and GL of a food are related by the amount of available carbohydrates in a fixed serving of the food.

The glycemic load of a food is calculated by multiplying the absolute GI value by the grams of available carbohydrate in the serving, and then dividing by 100. Or:

GL = GI * Available Carbs (grams) / 100

Reversing the equation:

GI = GL *100 / Available Carbs (grams)

Note that Available Carbs is equal to the total carbohydrate content minus the fiber content.

For example, a 225 g (1 cup) serving of Bananas with a GI of 52 and a carbohydrate content of 45.5 g (51.4 g total carbohydrate – 5.9 g fiber) makes the calculation GL = 52 * 45.5 / 100 = 24, so the GL is 24.

For one serving of a food, a GL greater than 20 is considered high, a GL of 11-19 is considered medium, and a GL of 10 or less is considered low.

Several randomized clinical trials have reported that low-glycemic index diets reduce glycemia in diabetic subjects, but other clinical trials have not confirmed this effect. Nevertheless, a recent meta-analysis of low-glycemic index diet trials in diabetic subjects showed that such diets produced a 0.4% decrement in A1C when compared with high-glycemic index diets.

Fiber-containing foods such as legumes, fiber-rich cereals, fruits, vegetables, and whole grain products are encouraged in people with diabetes. Generally, to reach the fiber intake goals of 14 g/1,000 kcal is a first priority for people with diabetes.

Substantial evidence from clinical studies demonstrates that dietary sucrose does not increase glycemia more than isocaloric amounts of starch. Thus, intake of sucrose and sucrose-containing foods by people with diabetes does not need to be restricted because of concern about aggravating hyperglycemia. Sucrose can be substituted for other carbohydrate sources in the meal plan or, if added to the meal plan, adequately covered with insulin or another glucose-lowering medication.

In individuals with diabetes, fructose produces a lower postprandial glucose response when it replaces sucrose or starch in the diet; however, this benefit is tempered by concern that fructose may adversely affect plasma lipids. Thus, the ingestion of fructose is not recommended but there is, however, no reason to recommended that people with diabetes avoid naturally occuring fructose in fruits, vegetables, and other foods.

Dietary fat and cholesterol

The primary goal with respect to dietary fat in individuals with diabetes is to limit saturated fatty acids, trans fatty acids, and cholesterol intakes so as to reduce risk of CVD. Saturated and trans fatty acids are the principal dietary determinants of plasma LDL cholesterol. In nondiabetic individuals, reducing saturated and trans fatty acids and cholesterol intakes decreases plasma total and LDL cholesterol. Despite reducing saturated fatty acids may also reduce HDL cholesterol, the ratio of LDL cholesterol to HDL cholesterol is not adversely affected.

The target is to limit saturated fat acids to <7% of total energy, to minimize trans fatty acids intake, and to limit dietary cholesterol to <200 mg/day.

With the limit of ingestion of saturated fatty acids and trans fatty acids, some other foods such as monounsaturated fatty acids, polyunsaturated fatty acids, plant sterol, and stanol esters can lower plasma LDL.

The Management of Hyperglycemic Crises in Diabetes

November 11, 2013 Critical Care, Diabetes, Pharmacotherapy, Therapeutics No comments , , , ,

Diabetic ketoacidosis (DKA) and the hyperosmolar hyperglycemic state (HHS) are the two most serious acute metabolic complications of diabetes. The triad of uncontrolled hyperglycemia, metabolic acidosis (SAG elevated metabolic acidosis), and increased total body ketone concentration characterizes DKA. HHS is characterized by severe hyperglycemia, hyperosmolality, and dehydration in the absence of significant ketoacidosis.



In DKA, hyperglycemia develops as a result of three processes: increased gluconeogenesis, accelerated glycogenolysis, and imaired glucose utilization by peripheral tissues.

The mechanisms of these three processes include: reduced effective insulin concentrations and increased concentrations of counterregulatory hormones (catecholamines, cortisol, glucagon, and growth hormone) lead to hyperglycemia and ketosis.

The combination of insulin deficiency and increased counterregulatory hormones in DKA lead to the release of free fatty acids into the circulation from adipose tissue (lipolysis) and to unrestrained hepatic fatty acid oxidation in the liver to ketone bodies (β-hydroxybutyrate and acetoacetate), with resulting ketonemia and metabolic acidosis.


The pathogenesis of HHS is not as well understood as that of DKA, but a greater degree of dehydration (due to osmotic diuresis) and differences in insulin availability distinguish it from DKA. Although relative insulin deficiency is clearly present in HHS, endogenous insulin secretion (reflected by C-peptide levels) appears to be greater than in DKA, where it is negligible. Insulin levels in HHS are inadequate to facilitate glucose utilization by insulin-sensitive tissues but adequate to prevent lipolysis and subsequent ketogenesis.

Figure 1. Pathogenesis of DKA and HHS

Precipitating Factors

The most common precipitating factor in the developmemt of DKA and HHS is infection. Other precipitating factors include discontinuation of or inadequate insulin therapy, pancreatitis, myocardial infarction, cerebrovascular accident, and drugs.

However, an increasing number of DKA cases without precipitating cause have been reported in patients with diabetes.

On admission, leukocytosis with cell counts in the 10,000-15,000 mm3 range is the rule in DKA and may not be indicative of an infectious process. However, leukocytosis with cell counts >25,000 mm3 may designate infection and require further evaluation.


The key diagnostic feature in DKA is the elevation in circulating total blood ketone concentration and hyperglycemia. If available, measurement of β-hydroxybutyrate may be useful for diagnosis. For hyperglycemia, however, a wide range of plasma glucose can be present on admission.

While HHS is characterized by severe hyperglycemia, hyperosmolality, and dehydration in the absence of significant ketoacidosis. Studies on serum osmolality and mental alteration have established a positive linear relationship between osmolality and mental obtundation. The occurrence of stupor or coma in a diabetic patient in the absence of definitive elevation of effective osmolality (≥320 mOsm/kg) demands immediate consideration of other causes of mental status change.

PS: The effective osmolality can be calculated as: [sodium ion (mEq/L) × 2 + glucose (mg/dL)/18]. For example, a given serum sodium ion concentration of 100 mEq/L, with a serum glucose concentration of 750 mg/dL, the effective osmolality should be [100 × 2 + 750/18] = 241.67 mOsm/kg. Note that the BUN/urea concentration is not taken into account becaue it is freely permeable and its accumulation dose not induce major changes in intracellular volume or osmotic gradient across the cell membrane.

Diagnostic Criteria for DKA and HHS


Fluid and Electrolyte Correction

Successful treatment of DKA and HHS requires correction of dehydration, hyperglycemia, and electrolyte imbalances; identification of comorbid precipitating events; and above all, frequent patient monitoring. Generally, the treatment strategies include fluid therapy (necessary), insulin therapy (necessary), potassium correction (necessary), pH correction (if necessary), and phosphate correction (if necessary).

Initial fluid therapy for both DKA and HHS is fluid replacement with 0.9% NaCl infused at a rate of 15-20 ml · kg body wt-1 · h-1 or  1-1.5 l during the first hour. Thereafter if the corrected serum sodium is low, 0.9% NaCl should be administered at a rate of 250-500 ml/h. Conversely, if the corrected serum after the fluid replacement of the initial first hour is normal or elevated, 0.45% NaCl infused at a rate of 250-500 ml/h is the strategy. Subsequent choice for fluid replacement depends on hemodynamics, the state of hydration, serum electrolyte levels, and urinary output.

Once the plasma glucose is ~ 200 mg/dL (DKA) or ~ 300 mg/dL (HHS), the fluid replacement should be changed to 5% dextrose with 0.45% NaCl at the drip rate of 150-250 ml/hr.

Despite total-body potassium depletion, mild-to-moderate hyperkalemia is common in patients with hyperglycemic crises. Insuilin therapy, correction of acidosis (alkali replacement enhance the risk of increased potassium waste), and volume expansion decrease serum potassium concentration. To prevent hypokalemia, potassium replacement is initiated after serum levels fall below the upper level of normal for the particular laboratory (5.0-5.2 mEq/L). The treatment goal of potassium replacement is to maintain srum potassium levels within the normal range of 4-5 mEq/L. Generally, 20-30 mEq potassium in each liter of infusion fluid is sufficient to get this goal. Rarely, DKA patients may present with significant hypokalemia. In such cases, potassium replacement should begin with fluid therapy (note that in such cases insulin therapy should be delayed until serum potassium restores to >3.3 mEq/Ll).

Despite whole-body phosphate deficits in DKA, serum phosphate is often normal or increased at presentation. Phosphate concentration decreases with inslulin therapy. However, prospective randomized studies have failed to show any beneficial effect of phosphate replacement on the clinical outcome in DKA, and overzealous phosphate therapy can cause severe hypocalcemia. But, to avoid potential cardiac and skeletal muscle weakness and respiratory depression due to hypophosphatemia, careful phosphate replacement may sometimes be indicated in patients with cardiac dysfunction and in those with serum phosphate concentration <1.0 mg/dL. When needed, 20-30 mEq/L potassium phosphate can be added to replacement fluids. For HHS, no studies are available on the use of phosphate.

The maximal rate of phosphate replacement generally regarded as safe to treat severe hypophosphatemia is 4.5 mmol/h.

Insulin Therapy

Low-dose regular insulin by intravenous infusion have demonstrated it effectiveness and benefit in the treatment of both DKA and HHS. Regular insulin should be given to patients with DKA or HHS on admission, but, for patients with significant hypokalemia on admission, insulin treatment should be delayed until patassium concentration is restored to >3.3 mEq/L. Regular insulin should be administered intravenously at a continuous dose of 0.1 U/kg/hr, with a prior IV bolus dose of 0.1 U/kg. If serum glucose dose not fall by at leaset 10% in the first hour, we should give 0.14 U/kg as IV bolus, then continue previous Rx.

Once the plasma glucose is ~ 200 mg/dL (DKA) or ~ 300 mg/dL (HHS), the rate of intravenously continuous regular insulin should be decreased to 0.02-0.05 U/kg/hr. Thereafter, the rate of insulin administration or the concentration of dextrose may need to be adjusted to maintain glucose values between 150 and 200 mg/dL in DKA or 250 and 300 mg/dL in HHS until they are resolved.

Transition to subcutaneous insulin. Once DKA or HHS is resolved, subcutaneous insulin theray can be started and continuous intravenous insulin should be allow a overlap of 1-2 h before discontinuation due to prevention recurrence of hyperglycemia or ketoacidosis during the transition period from IV insulin to SC insulin. Patients with known diabetes may be given insulin at the dosage they were receiving before the onset of DKA so long as it was controlling glucose properly. In insulin-naïve patients, a multidose insulin regimen should be started at a dose of 0.5-0.8 units · kg-1 · day-1.

Acid-Base Disorders

Prospective randomized study failed to show either beneficial or deleterious changes in morbidity or mortality with bicarbonate therapy in DKA patients with an admission arterial pH between 6.9 and 7.1. Nine small studies in a total of 434 patients with diabetic ketoacidosis (217 treated with bicarbonate and 178 without alkali therapy) support the notion that bicarbonate therapy for DKA offers no advantage in improving cardiac or neurologic functions or in the rate of recovery of hyperglycemia and ketoacidosis. However, due to the reason that severe acidosis may lead to a numerous adverse vascular effects, it is recommended that adult patients with a pH <6.9 should receive 100 mmol sodium bicarbonate in 400mml sterile water (an isotonic solution) with 20 mEq KCl (due to that alkali therapy enhance the risk of increased potassium wasting) administered at a rate of 200 ml/h for 2 hours until the venous pH is >7.0. If the pH is still <7.0 after this is infused, it is recommended repeating infusion every 2 h unitl pH reaches >7.0.

Recovery criteria

Criteria for resolution of ketoacidosis include a blood glucose <200 mg/dL and two of the following criteria: a serum bicarbonate level ≥15 mEq/L, a venous pH >7.3, and a calculated anion gap ≤12 mEq/L (DKA belongs to elevated anion gap metabolic acidosis).

Criteria for resolution of HHS is associated with normal osmolality and regain of normal mental status.