Pharmacovigilance Study of Diabetes Mellitus Patients with Cardiovascular Complication in Bangladesh

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Pharmacovigilance Study of Diabetes Mellitus Patients with Cardiovascular Complication in Bangladesh

Chapter 1

Literature Review

1.1 Introduction

Diabetes comes from Greek, and it means a siphon. Aretus the Cappadocian, a Greek physician during the second century A.D., named the condition diabainein. He described patients who were passing too much water (polyuria) – like a siphon. The word became “diabetes” from the English adoption of the Medieval Latin diabetes.

In 1675 Thomas Willis added mellitus to the term, although it is commonly referred to simply as diabetes. Mel in Latin means honey; the urine and blood of people with diabetes has excess glucose, and glucose is sweet like honey. Diabetes mellitus could literally mean “siphoning off sweet water”.

In ancient China people observed that ants would be attracted to some people’s urine, because it was sweet. The term “Sweet Urine Disease” was coined. ^[1]

Diabetes (diabetes mellitus) is classed as a metabolism disorder. Metabolism refers to the way our bodies use digested food for energy and growth. Most of what we eat is broken down into glucose. Glucose is a form of sugar in the blood – it is the principal source of fuel for our bodies.

When our food is digested the glucose makes its way into our bloodstream. Our cells use the glucose for energy and growth. However, glucose cannot enter our cells without insulin being present – insulin makes it possible for our cells to take in the glucose.

Insulin is a hormone that is produced by the pancreas. After eating, the pancreas automatically releases an adequate quantity of insulin to move the glucose present in our blood into the cells, and lowers the blood sugar level.

A person with diabetes has a condition in which the quantity of glucose in the blood is too elevated (hyperglycemia). This is because the body does not produce enough insulin, produces no insulin, or has cells that do not respond properly to the insulin the pancreas produces. This results in too much glucose building up in the blood. This excess blood glucose eventually passes out of the body in urine. So, even though the blood has plenty of glucose, the cells are not getting it for their essential energy and growth requirements.

Diabetes is a metabolic disorder that is characterized by high blood glucose and either insufficient or ineffective insulin. 5.9% of the population in the United States has diabetes, and diabetes is the seventh leading cause of death in our country. Diabetes is a chronic disease without a cure, however, with proper management and treatment, diabetics can live a normal, healthy lives.^[1]

1.2 Diabetes

Diabetes mellitus is a group of metabolic diseases characterized by high blood sugar (glucose) levels that result from defects in insulin secretion, or its action, or both. Diabetes mellitus, commonly referred to as diabetes (as it will be in this article) was first identified as a disease associated with “sweet urine,” and excessive muscle loss in the ancient world. Elevated levels of blood glucose (hyperglycemia) lead to spillage of glucose into the urine, hence the term sweet urine.^[2]

· Normally, blood glucose levels are tightly controlled by insulin, a hormone produced by the pancreas. Insulin lowers the blood glucose level. When the blood glucose elevates (for example, after eating food), insulin is released from the pancreas to normalize the glucose level. In patients with diabetes, the absence or insufficient production of insulin causes hyperglycemia. Diabetes is a chronic medical condition, meaning that although it can be controlled, it lasts a lifetime.^{[2] [3]}

Figure 1: Diabetes can lead to heart and blood vessel disease

1.3 Cardiovascular Disease

Cardiovascular disease is a class of diseases that involve the heart or blood vessels (arteries and veins).^[4] Cardiovascular disease refers to any disease that affects the cardiovascular system, principally cardiac disease, vascular diseases of the brain and kidney, and peripheral arterial disease.^[5] The causes of cardiovascular disease are diverse but atherosclerosis and/or hypertension are the most common.

1.4 Diabetes Mellitus with cardiovascular disease

This statement examines the cardiovascular complications of diabetes mellitus and considers opportunities for their prevention. These complications include coronary heart disease (CHD), stroke, peripheral arterial disease, nephropathy, retinopathy, and possibly neuropathy and cardiomyopathy. Because of the aging of the population and an increasing prevalence of obesity and sedentary life habits in the United States, the prevalence of diabetes is increasing. Thus, diabetes must take its place alongside the other major risk factors as important causes of cardiovascular disease (CVD). In fact, from the point of view of cardiovascular medicine, it may be appropriate to say, “Diabetes is a cardiovascular disease.” ^[6]

1.4.1 Diabetes as a Major Risk Factor

A large body of epidemiological and pathological data documents that diabetes is an independent risk factor for CVD in both men and women. Women with diabetes seem to lose most of their inherent protection against developing CVD. CVDs are listed as the cause of death in ?65% of persons with diabetes. Diabetes acts as an independent risk factor for several forms of CVD. To make matters worse, when patients with diabetes develop clinical CVD, they sustain a worse prognosis for survival than do CVD patients without diabetes. These considerations have convinced the Scientific Advisory and Coordinating Committee of the American Heart Association (AHA) that diabetes mellitus deserves to be designated a major risk factor for CVD. This formal designation commits the AHA to a greater emphasis on diabetes as a risk factor in its scientific and educational programs. This statement provides the scientific rationale for the decision to classify diabetes as a major risk factor for CVD. ^[8]

1.4.2 Diabetes and Specific CVD

Atherosclerotic

Both type 1 diabetes and type 2 diabetes is independent risk factors for CHD. Moreover, myocardial ischemia due to coronary atherosclerosis commonly occurs without symptoms in patients with diabetes. As a result, multivessel atherosclerosis often is present before ischemic symptoms occur and before treatment is instituted. A delayed recognition of various forms of CHD undoubtedly worsens the prognosis for survival for many diabetic patients. ^[7]

1.4.3 Diabetic Cardiomyopathy

One reason for the poor prognosis in patients with both diabetes and ischemic heart disease seems to be an enhanced myocardial dysfunction leading to accelerated heart failure (diabetic cardiomyopathy). Thus, patients with diabetes are unusually prone to congestive heart failure. Several factors probably underlie diabetic cardiomyopathy: severe coronary atherosclerosis, prolonged hypertension, chronic hyperglycemia, microvascular disease, glycosylation of myocardial proteins, and autonomic neuropathy. Improved glycemic control, better control of hypertension, and prevention of atherosclerosis with cholesterol-lowering therapy may prevent or mitigate diabetic cardiomyopathy. An early clinical trial suggested that sulfonyl ureas used for control of hyperglycemias are cardiotoxic and may exacerbate diabetic cardiomyopathy. This side effect, however, was not confirmed in a recent large clinical trial. ^[11]

Fig 2: Cardiovascular Disease and diabetes cardiovascular disease and diabetes

1.4.4 Stroke

Mortality from stroke is increased almost 3-fold when patients with diabetes are matched to those without diabetes. The most common site of cerebrovascular disease in patients with diabetes is occlusion of small paramedial penetrating arteries. Diabetes also increases the likelihood of severe carotid atherosclerosis. Patients with diabetes, moreover, are likely to suffer irreversible brain damage with carotid emboli that otherwise would produce only transient ischemic attacks in persons without diabetes. Approximately 13% of patients with diabetes >65 years old have had a stroke. ^[13]

1.4.5 Renal Disease

Renal disease is a common and often severe complication of diabetes. Approximately 35% of patients with type 1 diabetes of 18 years’ duration will have signs of diabetic renal involvement. Up to 35% of new patients beginning dialysis therapy have type 2 diabetes. End-stage renal disease (ESRD) appears to be especially common among Hispanics, blacks, and Native Americans with diabetes. For patients with diabetes who are on renal dialysis, mortality rates probably exceed 20% per year. When diabetes is present, CVD is the leading cause of death among patients with ESRD. ^[15]

1.5 Classification of Diabetes Mellitus: ^{[2] [3]}

The three main types of diabetes mellitus (DM) are:

• Type 1 DM results from the body’s failure to produce insulin, and presently requires the person to inject insulin. (Also referred to as insulin-dependent diabetes mellitus (IDDM) or “juvenile” diabetes)
• Type 2 DM results from insulin resistance, a condition in which cells fail to use insulin properly, sometimes combined with an absolute insulin deficiency. (Formerly referred to as noninsulin-dependent diabetes mellitus (NIDDM) or “adult-onset” diabetes)
• Gestational diabetes is when pregnant women, who have never had diabetes before, have a _high blood glucose level during pregnancy. It may precede development of type 2 DM.

1.5.1 Type 1 diabetes (T1D): The body stops producing insulin or produces too little insulin to regulate blood glucose level.

• Type 1 diabetes involves about 10% of all people with diabetes in the United States.
• Type 1 diabetes is typically diagnosed during childhood or adolescence. It used to be referred to as juvenile-onset diabetes or insulin-dependent diabetes mellitus.
• Type 1 diabetes can occur in an older individual due to destruction of the pancreas by alcohol, disease, or removal by surgery. It also results from progressive failure of the pancreatic beta cells, the only cell type that produces significant amounts of insulin.
• People with type 1 diabetes require insulin treatment daily to sustain life.

1.5.2Type 2 diabetes (T2D): Although the pancreas still secretes insulin, the body of someone with type 2 diabetes is partially or completely unable to use this insulin. This is sometimes referred to as insulin resistance. The pancreas tries to overcome this resistance by secreting more and more insulin. People with insulin resistance develop type 2 diabetes when they fail to secrete enough insulin to cope with their higher demands.

• At least 90% of adult individuals with diabetes have type 2 diabetes.
• Type 2 diabetes is typically diagnosed in adulthood, usually after age 45 years. It used to be called adult-onset diabetes mellitus, or non-insulin-dependent diabetes mellitus. These names are no longer used because type 2 diabetes does occur in younger people, and some people with type 2 diabetes require insulin therapy.
• Type 2 diabetes is usually controlled with diet, weight loss, exercise, and oral medications. However, more than half of all people with type 2 diabetes require insulin to control their blood sugar levels at some point in the course of their illness.

1.5.3 Gestational diabetes (GDM) is a form of diabetes that occurs during the second half of pregnancy.

• Although gestational diabetes typically resolves after delivery of the baby, a woman who develop gestational diabetes is more likely than other women to develop type 2 diabetes later in life.
• Women with gestational diabetes are more likely to have large babies.

Metabolic syndrome(also referred to as syndrome X) is a set of abnormalities in which insulin-resistant diabetes (type 2 diabetes) is almost always present along with hypertension (high blood pressure), high fat levels in the blood (increased serum lipids, predominant elevation of LDL cholesterol, decreased HDL cholesterol, and elevated triglycerides), central obesity, and abnormalities in blood clotting and inflammatory responses. A high rate of cardiovascular disease is associated with metabolic syndrome.

1.6 Diabetes Causes

1.6.1 Causes of type 1 diabetes

In type 1 diabetes, your immune system which normally fights harmful bacteria or viruses attacks and destroys your insulin-producing cells in the pancreas. This leaves you with little or no insulin. Instead of being transported into your cells, sugar builds up in your bloodstream. Type 1 is thought to be caused by a combination of genetic susceptibility and environmental factors, though exactly what those factors are is still unclear. ^[17]

1.6.2 Causes of prediabetes and type 2 diabetes

In prediabetes — which can lead to type 2 diabetes — and in type 2 diabetes, your cells become resistant to the action of insulin, and your pancreas is unable to make enough insulin to overcome this resistance. Instead of moving into your cells, sugar builds up in your bloodstream. Exactly why this happens is uncertain, although as in type 1 diabetes, it’s believed that genetic and environmental factors play a role in the development of type 2. Being overweight is strongly linked to the development of type 2 diabetes, but not everyone with type 2 is overweight.

1.6.3 Causes of gestational diabetes

During pregnancy, the placenta produces hormones to sustain your pregnancy. These hormones make your cells more resistant to insulin. As your placenta grows larger in the second and third trimesters, it secretes more of these hormones — making it even harder for insulin to do its job.

Normally, your pancreas responds by producing enough extra insulin to overcome this resistance. But sometimes your pancreas can’t keep up. When this happens, too little glucose gets into your cells and too much stays in your blood. This is gestational diabetes.^{[16] [17]}

1.7 Connection between diabetes, heart disease, and stroke

If you have diabetes, you are at least twice as likely as someone who does not have diabetes to have heart disease or a stroke. People with diabetes also tend to develop heart disease or have strokes at an earlier age than other people. If you are middle-aged and have type 2 diabetes, some studies suggest that your chance of having a heart attack is as high as someone without diabetes who has already had one heart attack. Women who have not gone through menopause usually have less risk of heart disease than men of the same age. But women of all ages with diabetes have an increased risk of heart disease because diabetes cancels out the protective effects of being a woman in her child-bearing years. ^[18]

People with diabetes who have already had one heart attack run an even greater risk of having a second one. In addition, heart attacks in people with diabetes are more serious and more likely to result in death. High blood glucose levels over time can lead to increased deposits of fatty materials on the insides of the blood vessel walls. These deposits may affect blood flow, increasing the chance of clogging and hardening of blood vessels (atherosclerosis).^[19]

Figure 3: Connection between diabetes, heart disease, and stroke

1.8 Risk factors for heart disease and stroke in people with diabetes ^[19]

Diabetes itself is a risk factor for heart disease and stroke. Also, many people with diabetes have other conditions that increase their chance of developing heart disease and stroke. These conditions are called risk factors. One risk factor for heart disease and stroke is having a family history of heart disease. If one or more members of your family had a heart attack at an early age (before age 55 for men or 65 for women), you may be at increased risk.

You can’t change whether heart disease runs in your family, but you can take steps to control the other risk factors for heart disease listed here:

• Having central obesity. Central obesity means carrying extra weight around the waist, as opposed to the hips. A waist measurement of more than 40 inches for men and more than 35 inches for women means you have central obesity. Your risk of heart disease is higher
• because abdominal fat can increase the production of LDL (bad) cholesterol, the type of blood fat that can be deposited on the inside of blood vessel walls.^{[19] [21]}

• Having abnormal blood fat (cholesterol) levels.– LDL cholesterol can build up inside your blood vessels, leading to narrowing and hardening of your arteries-the blood vessels that carry blood from the heart to the rest of the body. Arteries can then become blocked. Therefore, high levels of LDL cholesterol raise your risk of getting heart disease.- Triglycerides are another type of blood fat that can raise your risk of heart disease when the levels are high.

  – HDL (good) cholesterol removes deposits from inside your blood vessels and takes them to the liver for removal. Low levels of HDL cholesterol increase your risk for heart disease. ^[19][21]

· Having high blood pressure. If you have high blood pressure, also called hypertension, your heart must work harder to pump blood. High blood pressure can strain the heart, damage blood vessels, and increase your risk of heart attack, stroke, eye problems, and kidney problems.

• Smoking. Smoking doubles your risk of getting heart disease. Stopping smoking is especially important for people with diabetes because both smoking and diabetes narrow blood vessels. Smoking also increases the risk of other long-term complications, such as eye problems. In addition, smoking can damage the blood vessels in your legs and increase the risk of amputation.^[21]

1.9 Diabetes Symptoms ^[22]

Diabetes symptoms vary depending on how high your blood sugar is elevated. Some people, especially those with prediabetes or type 2 diabetes, may not experience symptoms initially. In type 1 diabetes, however, symptoms tend to come on quickly and be more severe. Some of the signs and symptoms of type 1 and type 2 diabetes include:

• Increased thirst
• Frequent urination
• Extreme hunger
• Unexplained weight loss
• Presence of ketones in the urine (ketones are a byproduct of the breakdown of muscle and fat that happens when there’s not enough insulin)
• Fatigue
• Blurred vision
• Slow-healing sores
• Mild high blood pressure
• Frequent infections, such as gum or skin infections and vaginal or bladder infections

Although type 1 diabetes can develop at any age, it typically appears during childhood or adolescence. Type 2 diabetes, the most common type, can develop at any age and is often preventable

1.10 Complications of diabetes ^[2]

Both type 1 and type 2 diabetes ultimately lead to high blood sugar levels, a condition called hyperglycemia. Over a long period of time, hyperglycemia damages the retina of the eye, the blood vessels of the kidneys, the nerves, and other blood vessels.

• Damage to the retina from diabetes (diabetic retinopathy) is a leading cause of blindness.
• Damage to the kidneys from diabetes (diabetic nephropathy) is a leading cause of kidney failure.
• Damage to the nerves from diabetes (diabetic neuropathy) is a leading cause of foot wounds and ulcers, which frequently lead to foot and leg amputations.
• Damage to the nerves in the autonomic nervous system can lead to paralysis of the stomach (gastroparesis), chronic diarrhea, and an inability to control heart rate and blood pressure during postural changes.
• Diabetes accelerates atherosclerosis, (the formation of fatty plaques inside the arteries), which can lead to blockages or a clot (thrombus). Such changes can then lead to heart attack, stroke, and decreased circulation in the arms and legs (peripheral vascular disease).
• Diabetes predisposes people to elevated blood pressure, high levels of cholesterol and triglycerides. These conditions both independently and together with hyperglycemia, increase the risk of heart disease, kidney disease, and other blood vessel complications.

Diabetes can contribute to a number of acute (short-lived) medical problems.

• Many infections are associated with diabetes, and infections are frequently more dangerous in someone with diabetes because the body’s normal ability to fight infections is impaired. To compound the problem, infections may worsen glucose control, which further delays recovery from infection.
• Hypoglycemia or low blood sugar, occurs intermittently in most people with diabetes. It can result from taking too much diabetes medication or insulin (sometimes called an insulin reaction), missing a meal, exercising more than usual, drinking too much alcohol, or taking certain medications for other conditions. It is very important to recognize hypoglycemia and be prepared to treat it at all times. Headache, feeling dizzy, poor concentration, tremor of the hands, and sweating are common symptoms of hypoglycemia. A person can faint or have a seizure if blood sugar level becomes too low.
• Diabetic ketoacidosis (DKA) is a serious condition in which uncontrolled hyperglycemia (usually due to complete lack of insulin or a relative deficiency of insulin) over time creates a buildup of ketones (acidic waste products) in the blood. High levels of ketones can be very harmful. This typically happens to people with type 1 diabetes who do not have good blood glucose control. Diabetic ketoacidosis can be precipitated by infection, stress, trauma, missing medications like insulin, or medical emergencies such as a stroke and heart attack.
• Hyperosmolar hyperglycemic nonketotic syndrome is a serious condition in which the blood sugar level gets very high. The body tries to get rid of the excess blood sugar by eliminating it in the urine. This increases the amount of urine significantly, and often leads to dehydration so severe that it can cause seizures, coma, and even death. This syndrome typically occurs in people with type 2 diabetes who are not controlling their blood sugar levels, who have become dehydrated, or who have stress, injury, stroke, or are taking certain medications, like steroids.

1.10.1Other Complications

• Uncontrolled diabetes often leads to biochemical imbalances that can cause acute life-threatening events, such as diabetic ketoacidosis and hyperosmolar—nonketotic—coma.
• People with diabetes are more susceptible to many other illnesses. Once they acquire these illnesses, they often have worse prognoses. For example, they are more likely to die with pneumonia or influenza than people who do not have diabetes.
• People with diabetes ages 60 years or older are 2 to 3 times more likely to report an inability to walk one-quarter of a mile, climb stairs, or do housework compared with people without diabetes in the same age group.
• People with diabetes are twice as likely to have depression, which can complicate diabetes management, than people without diabetes. In addition, depression is associated with a 60 percent increased risk of developing type 2 diabetes.

As indicated above, diabetes can affect many parts of the body and can lead to serious complications such as blindness, kidney damage, and lower-limb amputations. Working together, people with diabetes, their support network, and their health care providers can reduce the occurrence of these and other diabetes complications by controlling the levels of blood glucose, blood pressure, and blood lipids, and by receiving other preventive care practices in a timely manner.

1.11 Preventing Diabetes Complications ^[20]

Glucose Control

• Studies in the United States and abroad have found that improved glycemic control benefits people with either type 1 or type 2 diabetes. In general, every percentage point drop in A1C blood test results, for example, from 8.0 to 7.0 percent, can reduce the risk of microvascular complications—eye, kidney, and nerve diseases—by 40 percent. The absolute difference in risk may vary for certain subgroups of people.
• In patients with type 1 diabetes, intensive insulin therapy has long-term beneficial effects on the risk of cardiovascular disease.

Blood Pressure Control

• Blood pressure control reduces the risk of cardiovascular disease—heart disease or stroke—among people with diabetes by 33 to 50 percent and the risk of microvascular complications—eye, kidney, and nerve diseases—by about 33 percent.
• In general, for every 10 mmHg reduction in systolic blood pressure, the risk for any complication related to diabetes is reduced by 12 percent.
• No benefit of reducing systolic blood pressure below 140 mmHg has been demonstrated in randomized clinical trials.
• Reducing diastolic blood pressure from 90 mmHg to 80 mmHg in people with diabetes reduces the risk of major cardiovascular events by 50 percent.

Control of Blood Lipids

• Improved control of LDL, or bad, cholesterol can reduce cardiovascular complications by 20 to 50 percent.

Preventive Care Practices for Eyes, Feet, and Kidneys

• Detecting and treating diabetic eye disease with laser therapy can reduce the development of severe vision loss by an estimated 50 to 60 percent.
• About 65 percent of adults with diabetes and poor vision can be helped by appropriate eyeglasses.
• Comprehensive foot care programs—ones that include risk assessment, foot-care education and preventive therapy, treatment of foot problems, and referral to specialists—can reduce amputation rates by 45 to 85 percent.
• Detecting and treating early diabetic kidney disease by lowering blood pressure can reduce the decline in kidney function by 30 to 70 percent. Treatment with particular medications for hypertension called angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) is more effective in reducing the decline in kidney function than is treatment with other blood pressure lowering drugs.
• In addition to lowering blood pressure, ARBs and ACE inhibitors reduce proteinuria, a risk factor for developing kidney disease, by about 35 percent.

1.12 Metabolic syndrome and it linked to heart disease:

Metabolic syndrome is a grouping of traits and medical conditions that puts people at risk for both heart disease and type 2 diabetes. It is defined by the National Cholesterol Education Program as having any three of the following five traits and medical conditions:

Traits and Medical Conditions	Definition
Elevated waist circumference	Waist measurement of 40 inches or more in men 35 inches or more in women
Elevated levels of triglycerides	150 mg/dL or higher or Taking medication for elevated triglyceride levels
Low levels of HDL (good) cholesterol	Below 40 mg/dL in men Below 50 mg/dL in women or Taking medication for low HDL cholesterol levels
Elevated blood pressure levels	130 mm Hg or higher for systolic blood pressure or 85 mm Hg or higher for diastolic blood pressure or Taking medication for elevated blood pressure levels
Elevated fasting blood glucose levels	100 mg/dL or higher or Taking medication for elevated blood glucose levels

Table: Metabolic syndrome and it linked to heart disease

1.13 Prevent or delay heart disease and stroke. ^[23]

Even if you are at high risk for heart disease and stroke, you can help keep your heart and blood vessels healthy. You can do so by taking the following steps:

• Make sure that your diet is “heart-healthy.” Meet with a registered dietitian to plan a diet that meets these goals:
  • Include at least 14 grams of fiber daily for every 1,000 calories consumed. Foods high in fiber may help lower blood cholesterol. Oat bran, oatmeal, whole-grain breads and cereals, dried beans and peas (such as kidney beans, pinto beans, and black-eyed peas), fruits, and vegetables are all good sources of fiber. Increase the amount of fiber in your diet gradually to avoid digestive problems.
  • Cut down on saturated fat. It raises your blood cholesterol level. Saturated fat is found in meats, poultry skin, butter, dairy products with fat, shortening, lard, and tropical oils such as palm and coconut oil. Your dietitian can figure out how many grams of saturated fat should be your daily maximum amount.
  • Keep the cholesterol in your diet to less than 300 milligrams a day. Cholesterol is found in meat, dairy products, and eggs.
  • Keep the amount of trans fat in your diet to a minimum. It’s a type of fat in foods that raises blood cholesterol. Limit your intake of crackers, cookies, snack foods, commercially prepared baked goods, cake mixes, microwave popcorn, fried foods, salad dressings, and other foods made with partially hydrogenated oil. In addition, some kinds of vegetable shortening and margarines have trans fat. Check for trans fat in the Nutrition Facts section on the food package.
• Make physical activity part of your routine. Aim for at least 30 minutes of exercise most days of the week. Think of ways to increase physical activity, such as taking the stairs instead of the elevator. If you haven’t been physically active recently, see your doctor for a checkup before you start an exercise program.
• Reach and maintain a healthy body weight. If you are overweight, try to be physically active for at least 30 minutes a day, most days of the week. Consult a registered dietitian for help in planning meals and lowering the fat and calorie content of your diet to reach and maintain a healthy weight. Aim for a loss of no more than 1 to 2 pounds a week.
• If you smoke, quit. Your doctor can help you find ways to quit smoking.
• Ask your doctor whether you should take aspirin. Studies have shown that taking a low dose of aspirin every day can help reduce the risk of heart disease and stroke. However, aspirin is not safe for everyone. Your doctor can tell you whether taking aspirin is right for you and exactly how much to take.
• Get prompt treatment for transient ischemic attacks (TIAs). Early treatment for TIAs, sometimes called mini-strokes, may help prevent or delay a future stroke. Signs of a TIA are sudden weakness, loss of balance, numbness, confusion, blindness in one or both eyes, double vision, difficulty speaking, or a severe headache.

1.14 Types of heart and blood vessel disease occur in people with diabetes

Two major types of heart and blood vessel disease, also called cardiovascular disease, are common in people with diabetes: coronary artery disease (CAD) and cerebral vascular disease. People with diabetes are also at risk for heart failure. Narrowing or blockage of the blood vessels in the legs, a condition called peripheral arterial disease, can also occur in people with diabetes.

1.14.1 Coronary Artery Disease

Coronary artery disease, also called ischemic heart disease, is caused by a hardening or thickening of the walls of the blood vessels that go to your heart. Your blood supplies oxygen and other materials your heart needs for normal functioning. If the blood vessels to your heart become narrowed or blocked by fatty deposits, the blood supply is reduced or cut off, resulting in a heart attack.^[24]

1.14.2 Cerebral Vascular Disease

Cerebral vascular disease affects blood flow to the brain, leading to strokes and TIAs. It is caused by narrowing, blocking, or hardening of the blood vessels that go to the brain or by high blood pressure.

Stroke

A stroke results when the blood supply to the brain is suddenly cut off, which can occur when a blood vessel in the brain or neck is blocked or bursts. Brain cells are then deprived of oxygen and die. A stroke can result in problems with speech or vision or can cause weakness or paralysis. Most strokes are caused by fatty deposits or blood clots-jelly-like clumps of blood cells-that narrow or block one of the blood vessels in the brain or neck. A blood clot may stay where it formed or can travel within the body. People with diabetes are at increased risk for strokes caused by blood clots.

A stroke may also be caused by a bleeding blood vessel in the brain. Called an aneurysm, a break in a blood vessel can occur as a result of high blood pressure or a weak spot in a blood vessel wall.

TIAs

TIAs are caused by a temporary blockage of a blood vessel to the brain. This blockage leads to a brief, sudden change in brain function, such as temporary numbness or weakness on one side of the body. Sudden changes in brain function also can lead to loss of balance, confusion, blindness in one or both eyes, double vision, difficulty speaking, or a severe headache. However, most symptoms disappear quickly and permanent damage is unlikely. If symptoms do not resolve in a few minutes, rather than a TIA, the event could be a stroke. The occurrence of a TIA means that a person is at risk for a stroke sometime in the future. See page 3 for more information on risk factors for stroke.

Heart Failure

Heart failure is a chronic condition in which the heart cannot pump blood properly-it does not mean that the heart suddenly stops working. Heart failure develops over a period of years, and symptoms can get worse over time. People with diabetes have at least twice the risk of heart failure as other people. One type of heart failure is congestive heart failure, in which fluid builds up inside body tissues. If the buildup is in the lungs, breathing becomes difficult.

Blockage of the blood vessels and high blood glucose levels also can damage heart muscle and cause irregular heartbeats. People with damage to heart muscle, a condition called cardiomyopathy, may have no symptoms in the early stages, but later they may experience weakness, shortness of breath, a severe cough, fatigue, and swelling of the legs and feet. Diabetes can also interfere with pain signals normally carried by the nerves, explaining why a person with diabetes may not experience the typical warning signs of a heart attack.

Peripheral Arterial Disease

Another condition related to heart disease and common in people with diabetes is peripheral arterial disease (PAD). With this condition, the blood vessels in the legs are narrowed or blocked by fatty deposits, decreasing blood flow to the legs and feet. PAD increases the chances of a heart attack or stroke occurring. Poor circulation in the legs and feet also raises the risk of amputation. Sometimes people with PAD develop pain in the calf or other parts of the leg when walking, which is relieved by resting for a few minutes. ^[24]

1.15 Treatment options for heart disease

Treatment for heart disease includes meal planning to ensure a heart-healthy diet and physical activity. In addition, you may need medications to treat heart damage or to lower your blood glucose, blood pressure, and cholesterol. If you are not already taking a low dose of aspirin every day, your doctor may suggest it. You also may need surgery or some other medical procedure.^[25]

1.15.1 How will I know whether I have had a stroke?

The following signs may mean that you have had a stroke:

• sudden weakness or numbness of your face, arm, or leg on one side of your body
• sudden confusion, trouble talking, or trouble understanding
• sudden dizziness, loss of balance, or trouble walking
• sudden trouble seeing out of one or both eyes or sudden double vision
• sudden severe headache

If you have any of these symptoms, call 911 right away. You can help prevent permanent damage by getting to a hospital within an hour of a stroke. If your doctor thinks you have had a stroke, you may have tests such as a neurological examination to check your nervous system, special scans, blood tests, ultrasound examinations, or x rays. You also may be given medication that dissolves blood clots. ^[25][26]

1.15.2 Treatment options for stroke?

At the first sign of a stroke, you should get medical care right away. If blood vessels to your brain are blocked by blood clots, the doctor can give you a “clot-busting” drug. The drug must be given soon after a stroke to be effective. Subsequent treatment for stroke includes medications and physical therapy, as well as surgery to repair the damage. Meal planning and physical activity may be part of your ongoing care. In addition, you may need medications to lower your blood glucose, blood pressure, and cholesterol and to prevent blood clots. ^[26]

Points to Remember

• If you have diabetes, you are at least twice as likely as other people to have heart disease or a stroke.
• Controlling the ABCs of diabetes-A1C (blood glucose), blood pressure, and cholesterol-can cut your risk of heart disease and stroke.
• Choosing foods wisely, being physically active, losing weight, quitting smoking, and taking medications (if needed) can all help lower your risk of heart disease and stroke.
• If you have any warning signs of a heart attack or a stroke, get medical care immediately-don’t delay. Early treatment of heart attack and stroke in a hospital emergency room can reduce damage to the heart and the brain.

Fig 4: Intensive diabetes treatment and cardiovascular disease in patients

1.16 Fact sheet: Diabetes and Cardiovascular Disease (CVD) ^[27]

It is well established that diabetes is a major risk factor for cardiovascular disease (CVD), a term that refers to disease of the heart and circulatory system. Both type 1 and type 2 diabetes are closely linked to CVD and it is the main cause of death in people with diabetes.

1.15.1 Major clinical manifestations of CVD

These can be divided into three groups:

1. Those affecting the heart and coronary circulation (coronary heart disease – CHD)

A thickening of the walls in the coronary arteries or the occurrence of a blood clot in the coronary arteries will prevent blood reaching the heart, causing strain on the heart, which can ultimately lead to angina, myocardial infarction, or sudden death.

2. Those affecting the brain and cerebral circulation

An interruption of blood supply to the brain (as a result of cerebral haemorrhage or a cerebral thrombosis) will lead to a stroke, a sudden loss of function of part of the brain resulting in death (infarction) of an area within the brain.

3. Those affecting the lower limbs and feet (peripheral vascular disease)

Peripheral vascular disease often results from a narrowing of the vessels that carry blood to leg and arm muscles. The loss of blood supply can cause gangrene (death of tissue which can ultimately lead to amputation) and intermittent claudication.

Facts:

• Cardiovascular disease is the major cause of death in diabetes, accounting for some 50% of all diabetes fatalities, and much disability.1
• On average, people with type 2 diabetes will die 5-10 years before people without diabetes and most of this excess mortality is due to cardiovascular disease.2
• People with type 2 diabetes are over twice as likely to have a heart attack or stroke as people who do not have diabetes. Indeed, people with type 2 diabetes are as likely to suffer a heart attack as people without diabetes who have already had a heart attack.3
• Strokes occur twice as often in people with diabetes and hypertension as in those with hypertension alone.3
• People with diabetes are 15-40 times more likely to have a lower limb amputation compared to the general population.3
• People with diabetes have two to four times the risk of developing atherosclerosis compared to people without diabetes.3
• The treatment of cardiovascular disease accounts for a large part of the huge healthcare costs attributable to type 2 diabetes, that have been estimated to account for 10-12% of European health care expenditure.
• Part of the cardiovascular risk associated with IGT and diabetes is undoubtedly due to their association with other cardiovascular risk factors such as hypertension, high LDL-cholesterol and low HDL-cholesterol and smoking.
• Lifestyle changes that improve blood glucose control e.g. weight loss, dietary changes and increased physical activity are also likely to improve these other cardiovascular risk factors.

Glossary

Angina: a pain in the chest due to reduced blood supply to the heart.

Myocardial infarction (also called a heart attack): an interruption of blood supply to the area of the heart muscle due to narrowed or blocked vessels.

Sudden death: the result from the sudden abrupt loss of heart function.

Atherosclerosis: the clogging of the arteries that in this case nourish the heart. For people with diabetes, too much glucose in the blood contributes to atherosclerosis.

Stroke: a sudden loss of function of part of the brain due to the interruption of its blood supply, resulting in death (infarction) of an area within the brain.

Gangrene: death of tissue due to a loss of blood supply which can ultimately lead to amputation.

Intermittent claudication: a pain usually in the calves when walking, due to impaired blood supply to the calf muscles which results from atherosclerosis.

Diabetes and Cardiovascular Disease: Time to Act

In 2001, IDF produced a publication on diabetes and cardiovascular disease aimed at raising awareness of the link between the two conditions and recommending courses of action to prevent or delay cardiovascular complications of diabetes.

Diabetes and Cardiovascular Disease: Time to Act is directed at decision makers in the health and social policy sectors, with the aim of raising awareness and influencing policy. It also serves to sensitize healthcare professionals to the need for the aggressive management of all cardiovascular risk factors in people with diabetes.

1.17 Global Prevalence of Diabetes ^[26]

Estimates for the year 2000 and projections for 2030

The prevalence estimates were applied to population estimates for individual countries for 2000 and 2030, which were produced by the United Nations Population Division ^[28]. Conventional, albeit simplistic, definitions of developed countries (Europe including former socialist economies, North America, Japan, Australia, and New Zealand) and less developed countries (all other countries) were used. In keeping with previous estimates, prevalence of diabetes was assumed to be similar in urban and rural areas of developed countries ^[31]. For developing countries, urbanization was used as a proxy measure of the increased risk of diabetes associated with altered diet, obesity, decreased physical activity, and other factors such as stress, which are assumed to differ between urban and rural populations. For most developing countries, the prevalence of diabetes in rural areas was assumed to be one-half that of urban areas, based on the ratio observed in a number of population studies and as used in previous estimates ^[30]. For some populations in developing countries (small islands and populations for which prevalence data were derived from studies combining urban and rural populations), a single estimate of diabetes prevalence was used. In the current estimates, on the advice of local experts, the prevalence of diabetes in rural areas was assumed to be one-quarter that of urban areas for Bangladesh, Bhutan, India, the Maldives, Nepal, and Sri Lanka ^[29].

Figure — Global diabetes prevalence by age and sex for 2000

1.17.1 Diagnosed and Undiagnosed Diabetes among People Ages 20 Years or Older, United States, 2010

Group	Number or percentage who have diabetes
Ages 20 years or older	25.6 million, or 11.3 percent, of all people in this age group
Ages 65 years or older	10.9 million, or 26.9 percent, of all people in this age group
Men	13.0 million, or 11.8 percent, of all men ages 20 years or older
Women	12.6 million, or 10.8 percent, of all women ages 20 years or older
Non-Hispanic whites	15.7 million, or 10.2 percent, of all non-Hispanic whites ages 20 years or older
Non-Hispanic blacks	4.9 million, or 18.7 percent, of all non-Hispanic blacks ages 20 years or older

Table: Diagnosed and Undiagnosed Diabetes among People Ages 20 Years or Older, United States, 2010

1.17.2Diagnosed and Undiagnosed Diabetes

Figure 5: 2005–2008 National Health and Nutrition Examination Survey

1.17.3 Country and regional data on diabetes ^[32]

WHO South-East Asia Region

Prevalence of diabetes in the WHO South-East Asia Region

Country	2000	2030
Bangladesh	3,196,000	11,140,000
Bhutan	35,000	109,000
Dem. People’s Rep. of Korea	367,000	635,000
India	31,705,000	79,441,000
Indonesia	8,426,000	21,257,000
Maldives	6,000	25,000
Myanmar	543,000	1,330,000
Nepal	436,000	1,328,000
Sri Lanka	653,000	1,537,000
Thailand	1,536,000	2,739,000
Total	46,903,000	119,541,000

1.18 When to Seek Medical Care

If a person has diabetes and experiences any of the following, call a health care professional:

• Experiencing diabetes symptoms: this may mean that the person’s blood sugar level is not being controlled despite treatment
• Blood sugar levels, when tested, are consistently high (more than 200 mg/dL): Persistently high blood sugar levels are the root cause of all of the complications of diabetes.
• The patient’s blood sugar level is often low (less than 70 mg/dL): this may mean that the diabetes management strategy is too aggressive. It also may be a sign of infection or other stress on the body’s organs such as kidney failure, liver failure, adrenal gland failure, or the concomitant use of certain medications.
• An injury to the foot or leg, no matter how minor: even the tiniest cut or blister can become very serious in a person with diabetes. Early diagnosis and treatment of problems with the feet and lower extremities, along with regular diabetic foot care, are critical in preserving the function of the legs and preventing amputation.
• Low-grade fever (less than 101.5 F or 38.6 C): Fever is a sign of infection. In patients with diabetes, many common infections can potentially be more dangerous for them than for other people. Note any symptoms, such as painful urination, redness or swelling of the skin, abdominal pain, chest pain, or cough, that may indicate where the infection is located.
• Nausea or vomiting, but can keep liquids down: The health care professional may adjust medications while the patient is sick, and will probably recommend an urgent office visit or a visit to the emergency department. Persistent nausea and vomiting can be a sign of diabetic ketoacidosis, a potentially life-threatening condition, as well as several other serious illnesses.
• Small sore(s) (ulcer) on the foot or le:. Any non-healing sore or ulcer on the feet or legs of someone with diabetes needs to be seen by a medical professional right away. A sore less than 1 inch across, not draining pus, and not exposing deep tissue or bone, can safely be evaluated by a health care professional, as long as the patient does not have fever and their blood sugar levels are under control.

When you call a health care professional, tell them that you or someone you know has diabetes and are concerned.

• The patient will probably be referred to a nurse who will ask questions and make a recommendation about what to do.
• Be prepared for this conversation. Have a list of medications, medical problems, allergies to medicines, and a blood sugar diary handy by the phone.
• The nurse may need any or all of this information to decide both the urgency of the patient’s condition and how best to recommend treatment for the problem.^[23]

1.18.1 Diabetic emergencies

The following situations can become 911 medical emergencies and warrant an immediate visit to a hospital emergency department.

• The person with a severe diabetic complication may travel to the emergency department by car or ambulance.
• A companion should go along to speak for the person if the person is not able to speak for him or herself with the emergency care professional.
• Bring a list of medical problems, medications, allergies to medications, and the person’s blood sugar diary to the emergency department. This information will help the emergency care professional diagnose the problem and treat it appropriately.

The following are signs and symptoms of diabetic complications that warrant emergency care.

• Altered mental status: Lethargy, agitation, forgetfulness, or just strange behavior can be a sign of very low or very high blood sugar levels. If a person has diabetes with an altered mental status:
  • Try giving them some fruit juice (about 6 ounces) or cake icing if the person is awake enough to swallow normally without choking. Avoid giving things such as hard candy that can lodge in the throat. The health care provider can prescribe glucose wafers or gels that melt under the tongue.
  • Does not wake up and behave normally within about 15 minutes, call 911.
  • Is not a known diabetic, these symptoms can be signs of stroke, drug intoxication, alcohol intoxication, oxygen starvation, and other serious medical conditions? Call 911 immediately.
• Nausea or vomiting: If the patient is known to have diabetes and cannot keep food, medications, or fluids down at all, they may have diabetic ketoacidosis, hyperosmolar hyperglycemic nonketotic syndrome, or another complication of diabetes. If the person:
  • Has not already taken the latest insulin dose or oral diabetes medicine, do not take it without talking to a medical professional.
  • Already has low blood sugar levels, taking additional insulin or medication will drive the blood sugar level down even further, possibly to dangerous levels.
• Fever above 101.5 F (38.6 C): If the primary health care professional cannot see the patient right away, seek emergency care for a person with diabetes with a high fever. Note any other symptoms such as cough, painful urination, abdominal pain, or chest pain.
• High blood sugar level: If the patient’s blood sugar level is above 400 mg/dL, and the primary health care professional cannot see them right away, go to the closest emergency department. Very high blood sugar levels can be a sign of diabetic ketoacidosis or hyperosmolar hyperglycemic nonketotic syndrome, depending on the type of diabetes the person has. Both of these conditions can be fatal if not treated promptly.
• Large sores or ulcers on the feet or legs: If the person has diabetes, a non-healing sore larger than 1 inch in diameter can be a sign of a potentially limb-threatening infection.
  • Other signs and symptoms that merit immediate care are exposed bone or deep tissue in the wound, large areas of surrounding redness and warmth, swelling, and severe pain in the foot or leg.
  • If left untreated, such a sore may ultimately require amputation of the limb.
• Cuts or lacerations: Any cut penetrating all the layers of skin, especially on the legs, is a potential danger to a person with diabetes. Prop