DIABETES MELLITUS

INTRODUCTION

Diabetes Mellitus is a group of metabolic disorder characterized by hyperglycaemia associated with abnormalities in carbohydrate, fat and protein metabolism resulting in chronic complications.

It is a serious and economically devastating illness that is reaching epidemic proportions in both industrialized and developing countries and poses a major threat to public health in the 21^st century. Diabetes was the fifth leading cause of death in the US in the year 2000. Diabetes is associated with an increased incidence of stroke, heart failure, new-onset blindness, limb amputations, End-Stage Renal Disease (ESRD), birth complications and sexual dysfunction. Persons with diabetes often have associated Cardio Vascular Disease (CVD) risk factors including hypertension, dyslipidaemia, and obesity.

Diabetes is one of the leading causes of morbidity and mortality due to specific microangiopathy and the associated macroangiopathy. It is the leading cause of blindness and visual impairment in adults in the western hemisphere and the risk of cardiovascular disease is two to five times in persons with diabetes, as compared to normal adults. For the purpose of rational management, it is appropriate to classify diabetes as the following.

• Type 1 (also called Insulin-Dependent Diabetes Mellitus or IDDM),
• Type 2 (also called Non-Insulin-Dependent Diabetes Mellitus or NIDDM).

Other specific types of diabetes are :

• Genetic defects of b-cell function (eg.MODY)
• Genetic defects in insulin action
• Diseases of the endocrine pancreas
• Endocrinopathies
• Drug or chemical induced
• Infections
• Gestational Diabetes Mellitus (GDM)

Gestational Diabetes Mellitus

Defined as any degree of glucose intolerance that has its onset or is first detected during pregnancy.

• Occurs in approximately 2% - 4% of pregnant women, generally during the second or third trimester.
• Occurrence of GDM increases future risk for developing type 2 diabetes.

CHART 1: DIFFERENCE BETWEEN TYPE 1 AND TYPE 2 DIABETES

Characteristics	Type 1	Type 2
Other names	Previously : insulin-dependent diabetes mellitus (IDDM) : juvenile-onset diabetes mellitus	Previously : non-insulin-dependent diabetes mellitus (NIDDM): adult onset diabetes mellitus
% of diabetic population	5-10%	90%
Age of onset	Usually <30 yr, peaks at 12-14 yr, rare before 6 months, some adults develop type 1 during the fifth decade	Usually >40 yr, but increasing prevalence among obese children.
Pancreatic function	Usually none, although some residual C-peptide can sometimes be detected at diagnosis, especially in adults	Insulin present in low, "normal", or high amounts
Pathogenesis	Associated with certain HLA types; presence of islet cell antibodies suggests autoimmune process	Defect in insulin secretion, tissue resistance to insulin; ↑ hepatic glucose output.

CHART 1: continued

Family history	Generally not strong	Strong
Obesity	Uncommon unless "overinsulinized" with exogenous insulin	Common (60-90%)
History of ketoacidosis	Often present	Rare, except in circumstances of unusual stress (eg.infection)
Clinical presentation	Moderate to severe symptoms that generally progress relatively rapidly (days to weeks): polyuria, polydipsia, fatigue, weight loss, ketoacidosis	Mild polyuria, fatigue, often diagnosed on routine physical or dental examination
Treatment	Insulin Diet Exercise	Diet Exercise Oral antidiabetic agents and insulin

PREVALENCE

The prevalence of diagnosed diabetes has increased dramatically over the past 40 years both in the US and worldwide. In 1985, there were approximately 30 million people with diabetes worldwide; by 1995, this number had escalated to 135 million and by 2025, it is projected that there will be an increase in the incidence of diabetes, affecting 300 million people. Most of the expected increase will be in type 2 diabetes, which accounts for >90% of cases of diabetes, while the incidence of type 1 diabetes is anticipated to remain stable. By 2025 the countries with largest number of people with diabetes will be in India (>57 million, prevalence 6%), China (>37 million, prevalence 3.4%), and the United States (>21 million, prevalence 8.9%).

REVIEW OF MANAGEMENT OF DIABETES

Three methods of treatment are available for diabetic patients: diet alone, oral hypoglycaemic drugs, and insulin. Approximately 50% of new cases of diabetes can be controlled adequately by diet alone, 20-30% will require insulin. Regardless of aetiology, the type of treatment required is determined by the circulating plasma insulin concentration. In clinical practice the age and weight of the patient at diagnosis are closely related to the plasma insulin and usually indicate the type of treatment required.

Fig 1: Long-term treatment of diabetes

DIETARY MANAGEMENT

Dietary measures are required in the treatment of all diabetic patients to achieve the overall therapeutic goal: i.e. normal metabolism. The aims of dietary treatment are the following.

• Abolish symptoms of hyperglycaemia.
• Reduce overall blood glucose and minimize fluctuations.
• Achieve weight reduction in obese patients to reduce insulin resistance, hyperglycaemia and dyslipidaemia.
• Avoid hypoglycaemia associated with therapeutic agents

(Insulin, sulfonylureas).

• Avoid weight gain associated with therapeutic agents

(Insulin, sulfonylureas, thiazolidinediones).

• Avoid 'atherogenic' diets or those, which may aggravate diabetic complications

(e.g. high protein intake in nephropathy).

TYPES OF DIABETIC DIET

Two basic types of diet are used in the treatment of diabetes: low-energy, weight-reducing diets and weight maintenance diets.

Low-energy, weight-reducing diets

Dietary prescriptions, which cause a daily deficit of 500kcal, provide a realistic diet and induce a weekly weight loss of around 0.5kg. Rapid weight reduction may provoke loss of lean body tissue, and care must be taken in the elderly to avoid the omission of essential nutrients, vitamins and minerals. Caloric restriction is essential for the obese diabetic patient treated with insulin and most oral agents, to try to minimize the weight gain, which these can promote. In such individuals, the omission of snacks between meals is often necessary.

Weight maintenance diets

These are necessary for individuals with a normal Body Mass Index (BMI) and should be high in carbohydrate and low in fat, with particular attention being paid to the type of fat ingested.

ORAL DRUG TREATMENT OF TYPE 2 DIABETES MELLITUS

The main stay of treatment for patients with type 2 diabetes who fail diet therapy are the oral antidiabetic agents. There are 5 classes of oral antidiabetic agents available in the United States: Sulfonylureas, biguanides, alpha-glucosidase inhibitors, thiazolid-inediones and non-sulfonylurea secretagogues. They have differences and similarities with respect to their pharmacology and role in diabetes.

The oral antidiabetic drug classes differ in their sites and mechanisms of action to lower plasma glucose. The sulfonylureas and non sulfonylurea (non-SU) Secretagogues primarily work in the pancreas to stimulate insulin release. The biguanides primarily work in the liver to decrease glucose production. The alpha-glucosidase inhibitors primarily work in the small intestine to slow carbohydrate absorption. The thiazolidinediones (TZDs) primarily work in the peripheral tissues and act as insulin sensitizers.Chart 2 lists the mechanism and site of action for each class of drugs.

Chart 2

The oral antidiabetic agents also differ in their effects on the patient's lipid profile. Sulfonylureas, non-SU secretagogues, and alpha-glucosidase inhibitors do not appreciably affect the lipid profile. Biguanides can improve the complete lipid profile, whereas TZDs can improve some lipid levels while adversely affecting the others. Chart 3 lists the effects the oral antidiabetic agents have on lipid profile.

Chart 3

Sulfonylureas

Sulfonylureas are classified as first and second-generation agents based on when they became available. The generations differ in their potency, Pharmacokinetics, and safety. The second-generation agents are more potent and in general have better pharmacokinetic and safety profiles. The first-generation agents include acetohexamide, chlorpropamide, tolazamide, and tolbutamide. The second-generation agents include glimepiride, glipizide, and glyburide. It is well known that sulfonylureas (available since 1954) lower plasma glucose primarily by increasing the release of insulin from functioning pancreatic b-cells. One concern with these agents is the loss of efficacy over time, which may be related to the potential to exhaust b-cell function. Because these agents increase plasma levels of insulin, they may cause of hypoglycaemia. The addition of other antidiabetic agents can further increase the risk of hypoglycaemia.

Biguanides

Metformin (available since 1995) is the only biguanide available in the United States. It is in the same class of drugs as phenformin, which was available but was removed from the United States and European markets in the 1970s because of its association with lactic acidosis. The long-term benefit of metformin was shown in the United Kingdom Prospective Diabetes Study, (UKPDS). Metformin has several mechanism of action, but its primary mechanism for lowering plasma glucose is to decrease hepatic gluconeogenesis. To a smaller extent, it also improves insulin sensitivity of peripheral tissues. Recent studies suggest that metformin may reduce the risk of cancer in diabetic patients.

Alpha-glucosidase Inhibitors

The alpha-glucosidase inhibitors (available since 1996) include acarbose and miglitol. These agents decrease the rate of ingested carbohydrate absorption in the small intestine. They act as competitive, reversible inhibitors of alpha-glucosidases (hydrolase enzymes found in the brush border of the small intestine), and alpha-amylase (found in the pancreas). Inhibition of these enzymes slows digestion of carbohydrates, which results in slower absorption and a reduction in postprandial plasma glucose levels.

TZDs (Thiazolidinediones)

TZDs (available since 1997) include pioglitazone and rosiglitazone. These agents act primarily to improve insulin sensitivity of muscle and adipose tissue. To a lesser extent, these agents decrease hepatic glucose production. TZDs are selective and potent agonists for the proxisome proliferator-activated receptor-gamma (PPARg) nuclear receptors. The action of these agents requires the presence of insulin. A study by found rosiglitazone to decrease the proinsulin-insulin ratio in patients with type 2 diabetes mellitus, indicating an improvement in b-cell function.

Non-SU Secretagogues

The non-SU secretagogues include repaglinide (which is a member of the meglitinide family) and nateglinide (which is a derivative of d-phenylalanine). Like the sulfonylureas, the non-SU secretagogues (available since 1998) lower plasma glucose by increasing the release of insulin from functioning pancreatic b-cells. The mechanism is exactly same as the sulfonylureas, except the non-SU secretagogues bind to different receptors on the b-cells. Unlike SU, non-SU secretagogues have a very short half-life and duration of action, so they stimulate insulin secretion for brief periods. Therefore, they are dose with meals and are most helpful in decreasing postprandial hyperglycaemia. The quick "on and off" helps to decrease the incidence of hypoglycaemia compared to SU.

EFFICACY

All 5 classes of oral antidiabetic agents lower fasting plasma glucose and A1c, but they do so to different extents. Chart 5 lists the efficacy in lowering fasting plasma glucose and A1c for the 5 classes of antidiabetic agents.

In general, sulfonylureas, biguanides, and non-SU secretagogues lower fasting plasma glucose and A1c to a similar extent.

Chart 5

Insulin

Insulin is required for treatment of all patients with IDDM and many patients with NIDDM. No single standard exists for patterns of administration of insulin, and treatment plans vary from physician to physician and, with a given physician, for different patients. Three treatment regimens will be described: Conventional, Multiple subcutaneous injections (MSI), and Continuous subcutaneous insulin infusion (CSII). MSI or CSII is required in intensive treatment schedules designed to protect against complications. Conventional insulin therapy involves the administration of one or two injections a day of intermediate-acting insulin such as Zinc insulin (Lente insulin) or Isophane insulin (NPH) with or without the addition of small amounts of regular insulin.

Insulin is considered the most effective treatment for lowering extremely high glucose. This is important because inhibition of glucotoxicity may be beneficial in preserving functional b-cell mass. Oral agents do not work as quickly or lower glucose enough to effectively address glucotoxicity in many patients.

Insulin therapy may actually protect against endothelial damage. Observational and interventional evidence consistently indicates that glycaemic control with insulin therapy in the hospital setting can improve clinical outcomes. demonstrated that the unfavourable long-term prognosis for myocardial infarction could be improved by insulin treatment.

CHART 6: CONVENTIONAL (STANDARD) PREPARATIONS OF INSULIN ( Tripathi KD 2003)

Type	Appearance	Onset (hr)	Peak (hr)	Duration (hr)	Can be mixed with
Short Acting
Regular (soluble) insulin	Clear	0.5-1	2-4	6-8	All preparations
Prompt Insulin Zinc Suspension (amorphous) or semilente	Cloudy	1	3-6	12-16	Regular, Lente preparations
Intermediate Acting
Insulin zinc Suspension or Lente (ultra: Semi: 7:3)	Cloudy	1-2	8-10	20-24	Regular, semilente
Neutral Protamine Hagedorn (NPH) or Isophane Insulin	Cloudy	1-2	8-10	20-24	Regular
Long Acting
Extended Insulin Zinc Suspension (Crystalline) or Ultralente	Cloudy	4-6	14-18	24-36	Regular, semilente
Protamine Zinc Insulin (PZI)	Cloudy	4-6	14-20	24-36	Regular

PATIENT EDUCATION IN DIABETES

Pharmacists Role

Pharmacists in all practice settings are in a key position to start providing care to people, who have diabetes or are at risk of developing it, or to expand and improve their care. Pharmacy programs for patients with diabetes involve activities ranging from identifying and referring at-risk patients, to supporting American Diabetes Association - recognized multi-disciplinary diabetes care programs.

Pharmacists can help identify patients with diabetes through screening and should target patients at high risk, people with a family history of the disease, and women with a history of gestational diabetes or who delivered a baby weighing more than nine pounds. Patient education should be provided immediately after diagnosis, at a second stage at which time a patient assessment can be performed, and at a third stage during which patients can receive continuing education to reinforce concepts and motivational boost. One of the pharmacist's most important roles is the referral of patients to the other members of the diabetes care team. Although the role of the pharmacist in monitoring diabetes is not well defined, it might include such things as ascertaining whether physician visits and testing to assess long-term glycaemic control.

The pharmacist can play an important role in diabetes care by screening patients at risk for diabetes, assessing patient health status and adherence to standards of care, educating patients to empower them to care for themselves, referring patients to other health care professionals as appropriate, and monitoring outcomes. Providing diabetes management services requires communication skills, and a commitment of time, effort, and resources. Pharmacists who obtain training in diabetes management reap rewards in professional satisfaction and financial reimbursement.

Patient involvement is paramount for the successful care of diabetes. Patients require education and information about a wide range of subjects. The following areas are to be considered for patient education.

1. The disease

• Signs and symptoms

1. Hyperglycaemia

• Signs, symptoms and treatments

1. Hypoglycaemia

• Signs, symptoms and treatments

1. Exercise

• Benefits and effect on blood glucose control

1. Diet
2. Insulin therapy

• Injection technique
• Types of insulin
• Onset and peak actions
• Storage
• Stability

1. Urine testing

• Glucose
• Ketones

1. Home blood glucose testing

• Technique
• Interpretation

1. Oral hypoglycaemic agents

• Mode of action
• Dosing
• Need for multiple therapies

1. Foot care
2. Management during illness
3. Cardiovascular risk factors

• Smoking
• Hypertension
• Obesity
• Hyperlipidaemia

1. Regular medical and ophthalmologic examinations

The patient must be involved in the decision making process and must learn as much about the disease and associated complications as possible. Emphasis should be placed on the evidence that indicates complications can be prevented or minimized with glycaemic control and management of risk factors for cardiovascular disease. Recognition of the need for proper patient education to empower them into self-care has generated certification in diabetes education.

CONCLUSION

The current approach to management of drug therapy in patients with type 2 diabetes is to begin insulin therapy if a combination of two oral agents fails to provide adequate glycaemic control. For every 10 units of insulin administered, an average of 1 kg of weight may be gained. This weight gain, associated with the lipotrophic effect of insulin, promotes greater insulin resistance in patients with severe disease. The result of escalating doses of insulin is a perpetual cycle of weight gain and uncontrolled diabetes. With the advent of the newer oral agents, combination therapy may delay insulin use in patients who traditionally would require insulin early in the course of the disease. Reasonable combinations of oral agents based on mechanism of action include sulfonylurea plus metformin, sulfonylurea plus an alpha-glucosidase inhibitor, sulfonylurea plus glitazone, repaglinide plus metformin, glitazone plus metformin, insulin plus metformin, and insulin plus glitazone. The frequency and timing of glucose monitoring should be individualized for each patient. The optimal frequency of self-monitoring of blood glucose in patients with type 2 diabetes is not known, but monitoring should be performed often enough to facilitate reaching treatment goals. Efforts should be made to substantially increase appropriate use of self-monitoring, providing both the patient and the practitioner with substantial information necessary to achieve glycaemic goals. When possible, sulfonylureas should be prescribed as initial therapy in non-obese patients since they are less expensive than the newer oral agents. Metformin is an excellent initial agent for obese patients (i.e., those greater than 120 percent of ideal body weight) or as add-on therapy in patients whose disease is not controlled with sulfonylurea therapy. An alpha-glucosidase inhibitor or glitazone may be an alternative to a sulfonylurea or metformin as add-on therapy in patients with uncontrolled disease or significant renal dysfunction.

As health care providers with knowledge of the illness, its treatments, and monitoring tools, pharmacists are vital members of the diabetic health care team in both the outpatient and the inpatient settings. Clinical pharmacists in all practice settings are in a key position to start providing care to people, who have diabetes or are at of developing it, or to expand and improve their care.