Diabetes treatment update: new and not-so-new
The target readers of this writing is general public and yet one may be disappointed if one is merely looking for ‘practical advice’ (your doctor is still the best source) of managing one’s diabetes. All my medical writings strive to convey the concepts of medicine; in this case, diabetes and its management.
Welchol (a cholesterol-lowering drug) is a new class of anti-diabetic therapy
On January 23, 2008 FDA approved Welchol (colesevelam)—a bile acid sequestrant—to be used in combination with metformin, sulfonylurea, or insulin to improve blood sugar control.
Bile salts are sent to the intestines to help digest fats and are recycled back to the liver, by way of reabsorption into blood. Welchol binds bile acid in intestine to prevent its being taken back and has been used as a cholesterol-lowering drug. The liver ends up making more bile acids to replace what have been lost in the feces. The liver needs cholesterol to make bile; being diverged to make bile acids, less LDL cholesterol will be available to be released to the blood circulation.
When I began my practice in 1975 we had two classes of anti-diabetic agents: insulin and sulfonylurea (of which there were 3 drugs), and Welchol is the 10th class (each class has one to many drugs); pretty soon it will be more than my fingers can count. This is why I “can make it clearer, but I cannot make it simpler or shorter.” It is not recommended to read this article in one stretch; one can read selectively by browsing the headlines.
For those who are familiar with “one gene encodes one protein” theory, have you ever wonder why, in His grand design, DNA doesn’t make glucose (sugar) directly? The best theory of answer lies in the fact that sugar (carbohydrate) is far more complex a molecule for the beautiful, yet simple, DNA to make. The complexity of protein comes from its α helix and β sheet and its intricate folding. Glucose (sugar) is the fuel of life For the purpose of discussion, treat the glucose as the fuel that enters Krebs cycle (citric acid cycle)—the greatest furnace He ever designed—to burn to make energy (ATP) to keep us going. Although protein and fat, after some ‘manipulations’, can also enter this furnace; for the brain, protected by brain blood barrier, glucose is the only fuel available, with ketone as the only exception (I'm still contemplating its evolutionary significance.) And this partly explains why hypoglycemia (low blood sugar) can be dangerous. Paul Boyer (now 90 years of age) had a very splendid article with a title of “The ATP synthase—A Splendid Molecular Machine,” and his 1997 Nobel Lecture (in Chemistry) was “Energy, Life, and ATP.” This process completes the Krebs cycle in grand style. A grand Finale of Krebs cycle, if you will. Glucose is made by liver (gluconeogenesis) While we are not eating (unfortunately that doesn’t happen often) with no glucose intake, our liver, to a very limited extent, kidney, makes glucose, a process called gluconeogenesis; a process converting fats and proteins into glucose, and glucagon controls this process. This is why many anti-diabetic therapies target glucagon. Some diabetic patients deliberately went extended period of fasting before coming to the Lab and were disappointed that their blood glucose level failed to come down as expected, ‘betrayed’ by their liver. Liver making glucose is a life-sustaining process. Once the dietary glucose source stops, the body mobilizes converting glycogen (the stored form of glucose) back to glucose, but the supply may keep us going for 2 days only, it is the gluconeogenesis that enables us to survive for weeks either on hunger strike or stranded in the mountains. Concept of insulin resistance: It is a common knowledge that type 1 diabetes is due to absolute deficiency of insulin whereas relative insulin deficiency and insulin resistance contribute to type 2 diabetes. But, what is the insulin resistance? As I mention above, glucose is the fuel of life and it has to enter the cells to be burned. Insulin helps move glucose across cell membrane into cells in skeletal muscle, liver, and fat. So for the sake of simplicity, it is safe to say that the job of insulin is to ‘push’ glucose into cell, and if this job is not efficiently done, it is insulin resistance. Glitazones (Avandia, Actos): insulin sensitizers that improve cellular sensitivity to insulin A class of anti-diabetic therapy is glitazones (short for thiazolidinediones), which improve insulin action; glitazone binds to a nuclear receptor (PPAR gamma), activating various genes, resulting in facilitating glucose transport across cell membrane, thus tackling the heart of the problem of type 2 diabetes—insulin resistance. Development of glitazone (insulin sensitizer) is a triumph and beauty of science, thus it is particularly sad to learn that Avandia (rosiglitazone) was implicated in increasing risks for heart attack based on meta-analysis of 42 clinical studies, published in NEJM 2007 June 14;356:2457. A report from Toronto published on JAMA 2007 December 12;298:2634 confirmed the same results. I am not aware of any plausible pathophysiological mechanism by which Avandia increases the cardiovascular risks, though. Greater caution is now recommended in using Avandia in diabetic patients at risk of heart attack. And you may have seen the advertisement of Avandia by the lawyers. Another insulin sensitizer in clinical use is pioglitazone (Actos), which was not so implicated. However, both Avandia and Actos can cause fluid retention and worsen congestive heart failure, especially in combined use with insulins. It so happens that PPAR gamma receptors (where glitazones can bind) are abundant in the cells lining renal collecting tubules, and stimulation of which leads to increase in sodium reabsorption, hence fluid retention. Increased incidence of fractures have been observed in female patients taking Avandia or Actos. The first glitazone (troglitazone or Rezulin) was withdrawn from the market in 2000, several years after its potential liver toxicity became known. It is recommended that liver enzymes should be checked periodically while taking glitazones, Avandia or Actos. Metformin is another insulin sensitizer and reduces making of glucose by liver The mechanism by which metformin (Glucophage) increases insulin sensitivity is unknown and and in less magnitude than glitazones. It reduces glucose production and output by the liver, thus achieving its blood sugar-lowering effect. Understanding its action, one wouldn’t be surprised to find that metformin rarely causes hypoglycemia, coupled with the fact that it is neutral with regard to weight gain, metformin has emerged as the first line drug of choice for the treatment of type 2 diabetes. Like glitazones, metformin requires the presence of insulin to work, therefore not to be used in type 1 diabetes However, metformin is not without its fair share of adverse effects, mainly gastrointestinal, such as diarrhea, nausea or vomiting. The most dread complication is lactic acidosis; serious and potentially fatal. Fortunately it rarely occurs and only in those with impaired renal function or compromised circulatory state. Caution should be exercised and contraindications scrutinized. Survey of the landscape of the existing diabetic therapies: all focus on insulin until recently Despite the vast array of the armamentarium of anti-diabetic therapies, optimal control without risking hypoglycemic (low blood sugar) reaction is still beyond the reach for many. All previously available options, including all oral hypoglycemic agents, focus on insulin: Sulfonylureas and meglitinides work by stimulating pancreatic insulin secretion. Glitazones (thiazolidinediones—Avandia and Actos) are insulin sensitizers helping cells to better glucose utilization. Biguanides (metformin) decreases glucose production by liver and also improves insulin sensitivity. Alpha-glucosidase inhibitors inhibiting the enzymes that break down the complex carbohydrates, are not directly related to insulin, but the efficacy is limited, and the minor, yet unpleasant adverse effects meet some resistance from patients. Sulfonylureas and meglitinides work by stimulating pancreatic insulin secretion The three first generation sulfonylureas are now virtually abandoned, glyburide and glipizide are the second generation agents and Prandin (repaglinide) and Starlix (nateglinide) are meglitinides. The drawbacks of these agents are that they may cause hypoglycemia and their efficacy tend to wane as years go by as type 2 diabetes is a progressive disease, the pancreatic beta cells function declines over time. Targeting glucagon matters in treating diabetes, why? In normal individual insulin is released by β-cells of pancreas in response to the rising blood glucose as we eat. Insulin travels to systemic circulation via portal vein, and it is the insulin level in portal vein that suppresses after meal glucagon secretion and reduces glucose output from the liver. Insulin injection can not achieve this deed (the injected insulin reaches the systemic circulation bypassing the portal vein), thus cannot adequately address the postprandial (after meal) hyperglycemia (high blood sugar). Three classes of drugs targeting glucagon and gastric (stomach) emptying: Januvia, Byetta, and Symlin In addition to insulin and glucagon, gut also produces hormones (incretins) regulating glucose metabolism, including glucagon-like peptide (GLP-1) and gastric inhibitory polypeptide (GIP). Once food gets into the lumen of intestine, which secretes incretins in anticipating the rising blood glucose level. Incretins achieve blood glucose-lowering effect by increasing insulin (by pancreatic beta-cells) and decreasing glucagon secretion (by pancreatic alpha-cells), and also delaying gastric emptying, all of which are conducive to better diabetes control. GLP-1 levels are decreased in type 2 diabetes. Another problem with endogenous incretins (GLP-1 or GIP) is that they are so short-lived, quickly degraded by DPP-IV enzymes that they can’t exert lasting beneficial effects to diabetics. Byetta (exenatide) is GLP-1 analog (one with somewhat similar structure) and thus mimics its action. It is approved for adjunctive use in type 2 diabetic patients receiving sulfonylurea, thiazolidinedione, or metformin. Most patients achieve some weight loss, but may pay the price of constant nausea. Currently available Byetta requires twice a day injections; but, this shortcoming will be amended by Byetta LAR that can be given once a week, and the Phase 3 data were made available in October 2007 and the results are encouraging. Januvia (sitagliptin) is the first DPP-IV inhibitor approved by FDA in October 2006. (Januvia inhibits DPP-IV enzymes that inactivates GLP-1, so GLP-1 can stay around longer to do its job.) Januvia achieves a 0.5-0.8% HbA1c reduction on average and unlike Byetta, Januvia is weight neutral. Several other DPP-IV inhibitors are currently in the Phase 3 trails—coming soon! This market will be crowded soon. Like Byetta, Januvia is also approved for use in type 2 diabetes only, although work on type 1 diabetes is under investigation. Amylin, like insulin, secreted by pancreatic beta cell in response to food intake, is deficient in type 1 diabetes and relatively deficient in type 2 diabetes. Amylin delays gastric emptying (thereby promotes satiety and decreases appetite) and suppresses glucagon secretion after meals, thereby reduces glucose production from liver—a glucagon-mediated process. Symlin (pramlintide) is an analog of amylin and was approved for use in both type 1 and type 2 diabetes taking insulin. Unfortunately a ‘black box’ warning (for potentially serious adverse effects) has been issued as some patients developed severe hypoglycemia (even though Symlin alone doesn't cause hypoglycemia), limiting its use to a very narrow niche (for those whose diabetes remain uncontrolled with multiple-dose intensive insulin regimen and are willing to take a few extra injections a day—Symlin is given through injections before meals; not many highly motivated brave souls are willing to do it.) Many with type 2 diabetes may eventually require insulin, why? Type 2 diabetes is a chronic and progressive disease, the pancreatic beta cells function declines over time, and may reach the state similar to type 1 diabetes, that is, absolute insulin deficiency. And when that happens, drugs requiring the presence of insulin to work also become useless, such as sulfonylurea (glyburide and glipizide), meglitinides (repaglinide or Prandin, nateglinide or Starlix), metformin (the only biguanide in clinical use), and glitazones (Avandia and Actos). Various side effects of blood sugar-lowering drugs and the underlying renal (kidney), hepatic (liver), or heart diseases also limit their use in many patients, resorting to the use of insulins. Using insulin is a science and can be an art While initiating insulin therapy, it is reasonable to begin with a once or twice a day regimen, consisting of basal insulins (NPH, glargine or detemir insulin); as simple as possible, there is no reason to scare patients away. One may rely on oral agents to take care of the after meals hyperglycemia. Life is not always simple, nor the insulin regimen; more complex and intense regimen often needed in order to achieve more optimal blood glucose and HbA1c control by adding short- or rapid-acting insulins (regular, aspart, lispro, or glulisine insulin) before meals to cover the surges of blood glucose after meals.
The above graph shows the time courses of basal insulins (long-acting); no peak is seen in insulin glargine (Lantus) whereas there is a peak for NPH insulin. It has been observed that nocturnal (night time) hypoglycemia occurs less often with the use of Lantus, which is best taken in the morning, although taken in the evening is acceptable. NPH insulin can be taken once or twice a day, and it is better to take it in the evening if once a day based on one study. Intensive insulin therapy (use of both basal insulin and postprandial insulin), inconvenient though it may be, is the best way to emulate the physiological insulin response to rising blood glucose levels.
The above graph shows twice a day regimen (before breakfast and supper) of intermediate-acting NPH insulin and rapid-acting lispro insulin (but, can be aspart, glulisine, or regular insulin) Rapid-acting insulin covers the after-meal blood glucose surge, while NPH acts as the basal insulin covering rest of the time in day time and during the night. Comparing with regular insulin, the rapid-acting insulins (lispro, aspart, glulisine) have a shorter duration of action, which theoretically may be an advantage of causing less hypoglycemia, as by the time lunch dose given, the action of morning dose is gone compltely. Comparing with regular insulin, rapid-acting insulin (lispro, aspart, or glulisine) has more rapid onset of action and a shorter duration of action. The above graph shows taking glargine (Lantus) bed time as basal insulin and rapid-acting aspart insulin (can be lispro, glulisine, or regular insulin) as prandial insulin covering after meals blood glucose surges. Starting dose of basal insulin for type 2 diabetes can be determined by mean fasting blood glucose level and the degree of obesity. Pre-mixed insulins, though convenient it may be in selected type 2 diabetes, is not recommended in type 1 diabetes. The drawbacks of taking insulins are hypoglycemia and the weight gain
inermediate- or long-acting insulins: short-acting or rapid-acting insulins:
Lantus (insulin glargine) Novolog (insulin aspart)
Levemir (insulin detemir) Humalog (insulin lispro)
NPH insulins Apidra (insulin glulisine)
Exubera is a rapid-acting inhaled insulin that was approved by FDA in Januray 2006 and Pfizer announced in October 2007 that it will no longer make Exubera; it was a business decision (the sale of Exubera never took off), rather than safety or efficacy issue.
Using HbA1c to estimate blood glucose control in diabetes
Hemoglobin (Hb) inside newly formed red blood cells enter circulation without glucose attached, and glucose can enter red cells freely and becomes irreversibly attached to Hb, that is, it is a one-way street, once glucose enters red cells, it cannot get out. And the amount of glucose entering red cells at any given time corresponds to the blood glucose concentration: the higher it is, the more enters.
Several million red cells perish and replaced every day, and since the life span of red cells is 120 days, the glycosylated Hb (HbA1c—the glucose-attached Hb) reflects the average blood glucose level of the past 3 or 4 months, in reality, it correlates best with mean blood glucose over the previous 8 to 12 weeks.
An HbA1c value of 7% or less is considered optimal control of diabetes, using an assay in which the upper limit of normal is 6%. And for those who experience no hypoglycemic reactions, it may be advisable to be more aggressive to reach 6.5% or even 6% if at all possible.
Aggressive in controlling diabetes: To be, or not to be, that is the question . . .
(Please refer to http://doctortsai.vox.com/library/posts/tags/dm/)
Microalbuminuria is the harbinger of diabetic renal disease
Increased urinary protein excretion is the earliest sign of diabetic nephropathy (diabetic renal disease). The conventionally used urine dipstick is not sensitive enough to detect the relatively small amount of protein, not becoming positive until protein excretion exceeds 300 to 500 mg/day.
A specific assay for albumin (a type of protein) can detect very small amount of albumin. An albumin excretion of 30-300 mg/day (normal individual should have less than 20 mg/day) is called microalbuminuria. So microalbumin is a misnomer; it simply means ‘very small amount of’ albumin. Values above 300 mg/day of albumin excretion is overt proteinuria, which most likely would progress to clinical renal disease, leading to impaired renal function.
Studies have shown that angiotensin converting enzyme (ACE) inhibitors can delay the progression of nephropathy in type 1 diabetes and angiotensin II receptor blockers (ARB) in type 2 diabetes. This is the official recommendation, but it is likely that ACEI and ARB can be interchangeable for either type 1 or type 2 diabetes, given the fact that both work at the same renin-angiotensin system (at different steps).
Blood sugar level is not the only thing a diabetic should be concerned, LDL (‘bad cholesterol’) level is as important, if not more
Any type 2 diabetics over age of 40 should consider taking ‘statin’ (the most popular cholesterol-lowering drug) regardless the blood cholesterol level, as it has been proven that it can reduce the coronary events. This goes along with the same concept that “if one has a heart attack, whatever your cholesterol level is too high” or “treating a diabetic like he or she has already had one heart attack” In fact, current recommendations of acceptable LDL level and blood pressure are the same for diabetics and those who have had a coronary event.
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