Sugar coating on a bitter pill Multiple drugs are needed to keep diabetes under control
By Lucio Victor Jr.
In a patient with diabetes mellitus (DM), the complicating presence of hypertension and dyslipidemia increases the likelihood of stroke and heart disease. Although there is no single cure for the deadly triad of DM, hypertension, and dyslipidemia, it is possible to battle each with the proper medication and to achieve target levels of control.
Hyperglycemia results from defects in insulin secretion, insulin action, or both. Dr. Mary Anne Lim-Abrahan, professor of endocrinology at the University of the Philippines-Philippine General Hospital, notes that as hyperglycemia becomes chronic, long-term damage to the eyes, kidneys, nerves, heart, and blood vessels ensues. Symptoms characteristically called the three Ps-polyuria, polydipsia, and polyphagia-with unexplained weight loss and sometimes blurring of vision are indicators of marked hyperglycemia. Long-term complications include retinopathy that ultimately leads to loss of vision; nephropathy that develops into renal failure; peripheral neuropathy that poses a risk to foot ulcers and leads to amputation; and autonomic neuropathy that causes gastrointestinal, genitourinary, cardiovascular, and sexual dysfunction. Warns Lim-Abrahan: "For diabetics the chance of dying from heart disease is 75 percent. This is mostly in the form of myocardial infarction, followed by congestive heart failure, and then stroke. Usually when you diagnose diabetes mellitus for the first time there are already other complications. About 50 percent of type 2 diabetes patients already have hypertension and 30 to 40 percent have a lipid problem at the time of diagnosis." The United Kingdom Prospective Diabetes Study established that the lowering of blood glucose levels and achie-ving a median glycosylated hemoglobin level (HbA1c) of 7.0 percent decreased the overall microvascular complication rate by 25 percent. They also lowered the risks of diabetic retinopathy, nephro-pathy, and neuropathy. The study noted that every percentage point decrease in HbA1c levels translated into a 35-percent risk reduction in complications, a 25-percent reduction in diabetes related deaths, a seven-percent reduction in all cause mortality, and an 18-percent reduction in combined fatal and nonfatal MI. Also, lowering blood pressure to a mean of 144/82 mm Hg significantly reduced stroke, diabetes-related deaths, heart failure, microvascular complications, and visual loss.
In type 1 DM, the problem is that the beta cells do not produce insulin. Glycemic control is achieved with insulin infusion. On the other hand, the main culprit implicated in type 2 DM is insulin resistance. This occurs when a seemingly normal concentration of insulin is unable to elicit a normal biological response from the target organ or tissue. Pharmacologic intervention in type 2 DM is achieved by using insulin secretagogues and sensitizers. Secretagogues like sulfonylureas and meglitinides stimulate pancreatic insulin secretion by binding to ATP sensitive potassium channels. This action reduces potassium conductance that leads to depolarization of the cell membrane. This depolarization is picked up by voltage sensitive calcium channels that open up and take calcium ions into the beta cells. As calcium enters the cell, insulin is pumped out. First-generation sulfonylureas, except for chlorpropamide, are hardly available anymore. Now preferred are the more potent second-generation gliclazide, glyburide, glimeperide, glipizide, and glibenclamide. Meglitinides, on the other hand, like nateglinide and repaglinide, have a faster onset of action in lowering postprandial glucose levels. Insulin sensitizers like rosiglitazone and troglitazone make peripheral tissues and target organs sensitive to whatever insulin is present in the system. Also known as thiazolidinediones, these agents induce specific enzymes that ensure normal concentrations of insulin will induce a corresponding biological response in the target organs and tissues particularly the skeletal muscles. Insulin sensitizers can be used alongside insulin or oral hypoglycemic therapy. Other antidiabetic agents are the alpha glucosidase inhibitors and biguanides. Alpha glucosidase inhibitors antagonize the effects of the enzyme alpha glucosidase, which is found on the brush border of the intestinal villi. This enzyme normally breaks down complex carbohydrates into simple sugar as these traverse the ileal and colonic segments of the gut. However, by inhibiting alpha glucosidase, complex carbohydrates are not broken down into simple sugar along the ileal and colonic segments. This lowers postprandial blood glucose. Acarbose and Voglibose fall in this drug category. Biguanides block hepatic glucose release, preventing the conversion of liver glycogen into glucose during fasting. Biguanides like metformin do not elevate insulin levels; they cause significant reduction in LDL and total cholesterol while increasing HDL levels. And because they do not induce weight gain, they are ideal for overweight or obese patients Lastly, insulin therapy remains essential in a diabetic's therapy, considering that up to 50 percent of type 2 diabetics suffer from insulin deficiency. In fact, insulin is the only pharmacologic agent that can be used in diabetic emergencies like hyperosmolar states and ketoacidosis. Insulin is particularly indicated when glycemic goals are not achieved with oral hypoglycemic agents. It also finds use among pregnant diabetics, those undergoing surgery, and those who have renal or hepatic disease, allergy to oral hypoglycemic agents, hyperglycemia despite maximum doses of oral agents; decompensation due to intercurrent events. For the hypertensive diabetic, more drugs are needed to manage their blood pressure. Lim-Abrahan notes that the JNC VI and WHO/ISH recommend that ACE inhibitors be used as initial therapy for hypertensive diabetics. This is largely because ACE inhibitors reduce renal, coronary, and cardiovascular disease progression in DM and have a renal protective mechanism. Lim-Abrahan says that ACE inhibitors may be given to normotensive diabetics with albuminuria and may be used in combination with thiazide diuretics or beta blockers in those with congestive heart failure. An alternative to ACE inhibitors is angiotensin-II-receptor blocker (ARB). Although acting on another mechanism within the renin-angiotensin system, ARBs confer generally the same benefits as ACE inhibitors do. ARBs are usually reserved for diabetic patients on ACE inhibitors who develop cough. For patients with both hypertension and angina, Lim-Abrahan says a beta-blocker has to be added to ACE inhibitor or ARB. This improves blood pressure control while addressing angina. She warns though that giving a beta-blocker to a diabetic patient with peripheral vascular disease (PVD) could aggravate the claudication so nitrates may have to be used for the angina. Also, in the diabetic patient with hypertension and congestive heart failure, a diuretic is advised alongside an ACE inhibitor. Aspirin also finds a niche in the diabetic patient's therapy and is mainly recommended as secondary prevention in diabetic patients with large vessel disease, PVD, claudication, angina, and previous MI or stroke. Lim-Abrahan also warns that research has shown that hypertensive individuals on long-term, high-dose beta- blockers run the risk of developing increased glucose tolerance. Conversely, persons with impaired glucose tolerance attributed to any etiology are likely to develop DM sooner or later if precautionary and preventive measures are not taken. Also, patients on insulin therapy should also be wary of using beta-blockers because it can prolong hypoglycemic episodes or blunt the body's response to hypoglycemia. Other hypertensive patients have been shown to benefit from long-acting calcium channel-blockers more specifically the nondihydropyridine. Diltiazem and Verapamil have shown significant results in cardiovascular endpoints. A novel agent used in diabetic patients to prevent coronary artery disease, MI, PVD, CVD, and stroke is folic acid. According to Dr. Susan Yu-Gan, endocrinology consultant at the Metropo-litan Hospital, a daily dose of 0.65 mg can reduce or maintain homocysteine levels at the normal range of five to 15 mmol/L. Patients with homocysteine levels above the normal range have a higher relative risk of developing MI. Anecdotal reports show folic acid supplementation can unmask an underlying vitamin B12 deficiency so it would be logical to give vitamin B12 at a dose of 1mg/kg/day. Aside from folate, oral contraceptives and estrogen replacement therapy have also been used to reduce homocysteine levels.
Another problem is dyslipidemia, manifesting as hypercholesterolemia or hypertriglyceridemia. Gan says LDL has to be brought down to below 100mg/dL, triglycerides to less than 200mg/dL, better if below 150mg/dL. HDL level should be above 45mg/dL, but Lim-Abrahan notes that increasing it beyond 55 mg/dL could bring more benefits. The two agree that high triglyceride levels can be managed with a bile-acid binding resin or fibric acid derivative (fibrate), while hypercholesterolemia can be managed with a statin. In diabetic patients who present with both hypertriglyceridemia and hypercholesterolemia, it may be prudent to start the patient on a fibrate, notes Lim-Abrhan. However, fibrates and statins can be used concomitantly. Fibrates have been shown to be more effective in increasing HDL levels. Lim-Abrahan believes that obesity gives rise to dyslipidemia in many diabetics, hence losing weight is important. "Patients do not have to go back to their original weight but of course the more weight they lose, the better," she says.
Dr. Lim-Abrahan laments that many diabetic patients do not get proper treatment for several reasons, including financial. Also, many fail to modify their diets and lifestyles despite knowing that these are important in glycemic control. "Smoking is a no-no. It causes peri-pheral vasoconstriction, is a cardiovascular risk, and if a patient has PVD it will aggravate the claudication, worsen ischemia, and cause hypercoaguability of the blood favoring thrombosis," she warns. "Alcohol may be allowed if very well controlled. Still you shouldn't encourage [diabetic patients] to drink." Diet for diabetic individuals should be low in fat and salt, and free of simple sugars. High-fiber diets, complex carbohydrates, and monounsaturated and polyunsaturated fats are encouraged. Small frequent meals are all right but patients should not skip meals or fast for prolonged periods. Isotonic and isometric exercises with weight reduction for overweight and obese individuals are important. The American Diabetes Association recommends constant follow-up of diabe-tic patients. Capillary blood glucose moni-toring should be done at least daily, routine laboratory tests such as HbA1c testing, quarterly or at least twice a year. Lipid profile, microalbuminuria, ophthalmologic examination, and doppler of lower extremities should be performed yearly.
"Mahirap mag-convince sa tao to diet and change lifestyle," laments Lim-Abrahan. Physicians face difficulty managing diabetic patients because they usually do not want to be told what to do about diet and lifestyle. "These patients usually expect the medication to do everything." More than that, "kalaban mo dito ang ibang entrepreneurs of fast foods, commercial foods, and junk foods, and the government, which tends to favor rapid urbanization and allows [the presence of] these businesses that sell calorie-dense foods," she adds. She also takes potshots at the Cocacolonization (which entices people to eat more junk food) and Nintendonization (which encourages children to just sit in front of the television instead of playing outdoors) of the population. "These two contribute to the increase in the incidence of type 2 DM in the younger population," she notes. Unfortunately, oral hypoglycemic agents are not advisable for persons below eighteen, making diabetes management even harder among them. |
