Changing the treatment paradigm to achieve best practice goals for type 2 diabetes mellitus

Elaine Y L Tsui 崔綺玲, Rosie T T Young 楊紫芝

HK Pract 2005;27:339-343

Summary

Current diabetes management involves not only tight glycaemic control, but also aggressive multi-factorial intervention of cardiovascular risk, along with patient focussed diabetes self management education through a multidisciplinary team approach. These have been shown to reduce the morbidity and mortality of complications secondary to the disease. With increasing understanding of the basic pathophysiology of type 2 diabetes, and the rapid development of numerous pharmacological agents targeting different sites of defect, a more proactive approach in achieving and maintaining near normal glycaemia has become a reality. Together with a comprehensive diabetes assessment and complications screening programme, the health care team could provide simple and practical measures in effectively managing various aspects of this common yet complicated disease.

摘要

現行的糖尿病治療不僅需要嚴謹的血糖控制，還要從多方面積極地改善心血管病的風險。 並以病人為本的精神，利用多學科小組方式，向糖尿病人提供自我護理的知識。實証顯示， 這些措施可減低由糖尿病引起的併發症病發率和死亡率。隨著對二型糖尿病的基本病理生理學了解日益增加， 和多種針對不同機能缺陷的藥物快速開發，以較進取的方法去達致和維持近乎正常的血糖水平已可實現。 透過全面的糖尿病評估和併發症篩查，醫療小組能為這常見而複雜的疾病，在各方面提供簡單和實用的有效治療方法。

Introduction

Diabetes is a worldwide problem and its incidence is reaching epidemic proportions. Data from World Health Organization¹ revealed that the projected prevalence of diabetes by year 2030 will be at an alarming figure of over 370 million adults. There are also increasing reports of type 2 diabetes in children and adolescents, most of whom are obese.²

The most feared long term consequences of diabetes mellitus are its microvascular and macrovascular complications, the major cause of morbidity and mortality in this group of patients. The importance of glycaemic control in reducing these complications have been clearly demonstrated by the Diabetes Complications and Control Trial (DCCT) ³ and United Kingdom Prospective Diabetes Study (UKPDS).⁴ Although several ongoing clinical studies also demonstrated the relationship between lower HbA1c values and reduced macrovascular complications, glycaemic control alone is unlikely to significantly reduce the alarming morbidity and mortality from these complications. The combination of aggressive glycaemic control and global cardiovascular risk reduction will be the new perspective for physicians taking care of patients with diabetes.

Glycaemic control

Glycaemic control is fundamental to the management of diabetes. Over recent years, there has been an ever-decreasing glycaemic goal for people with diabetes. Table 1 shows that the current recommended glycaemic goals^5-7 are HbA1c < 6.5 - 7 %. As shown in the UKPDS,⁴ in patients with type 2 diabetes, every 1% increase in HbA1c would result in 21% increase in any diabetes-related endpoints, 14% increase in risk of myocardial infarction, 13% increase in stroke and 37% increase in risk of microvascular complications. There appeared to be no threshold value for this linear relationship.

With improved understanding of the basic pathophysiology of type 2 diabetes, it is now agreed that the disease process is complex and involves both insulin resistance and b cell dysfunction.⁸ Insulin resistance is usually present before the diagnosis of type 2 diabetes. As b cell dysfunction progresses, the diagnosis of type 2 diabetes is usually made when about 50% of b cells are destroyed. Currently available oral hypoglycaemic agents target distinct sites as part of their primary mechanism of action. They can be divided into 4 main groups⁹:

Conservative treatment of glycaemia involves stepwise progression from lifestyle modification, oral monotherapy, oral combination therapy and in the end, adding insulin (Figure 1). However, as shown in the UKPDS,⁴ the secondary failure rate of monotherapy in the treatment of type 2 diabetes is 5 - 10 % per year, reasons being decreasing b cell function, increasing obesity and decreasing exercise thus increasing insulin resistance, non-compliance and intercurrent illness. It is now recognised that in order to minimize complications, one should employ a more proactive and aggressive approach: beginning with lifestyle modification, and progressing to early combination oral therapy, and if necessary, adding insulin therapy in order to achieve a HbA1c target of < 7 % (Figure 2). This early combination approach¹¹ has the advantages of targeting different pathophysiological sites via different mechanism of drug action, reducing side effects (eg. weight gain, hypoglycaemia) and toxicity with lower dosage of individual medication while efficaciously reducing HbA1c to target. Fixed dose combination therapy (eg. Glibenclamide/Metformin, Rosiglitazone/Metformin) further enhances compliance by reducing the actual number of pills taken.

It is now also clear that glycaemic control in individuals with type 2 diabetes requires the treatment of both fasting hyperglycaemia and postprandial glucose spikes.¹² This underscores the importance of home blood glucose monitoring in patients with type 2 diabetes. In the position statement from the American Diabetes Association,⁵ it states that self monitoring of blood glucose should be an integral component of DM therapy, and that HbA1c testing should be performed at least twice a year in patients who are meeting goals and who have stable glycaemic control, and quarterly in those whose therapy has changed or who are not meeting glycaemic goals.

Two emerging therapies for type 2 diabetes that are recently approved by USA, FDA are Exenatide and Pramlintide.

Exenatide is a Glucagon-like-peptide 1 (GLP 1) mimetic that has diverse mechanism of action: reducing glucagon secretion, promoting satiety, decreasing gastric emptying, stimulating glucose dependent insulin secretion and b cell differentiation and secretion. It is the first insulin secretatogue that does not cause hypoglycaemia, and it may actually facilitate weight loss. It is approved as an adjunctive therapy for type 2 patients¹³ who have not achieved satisfactory glycaemic control on metformin and/or sulphonylurea. It is formulated for self administration as a fixed dose subcutaneous injection twice a day and has major side effects of nausea and vomiting.

Pramlintide is a synthetic analog of human amylin, a naturally occurring neuroendocrine hormone synthesized by pancreatic b cells that contributes to glucose control during the post-prandial period. It has diverse mechanism of action: suppressing glucagon secretion thus reducing hepatic glucose output after meals; slowing gastric emptying; modulating appetite, resulting in decreased food intake. It has been shown to decrease mean HbA1c, mean body weight and insulin dosage in patients with type 2 diabetes currently on insulin.¹⁴

Beyond glycaemic control.

Patients with type 2 diabetes and no known cardiovascular disease have the same cardiovascular risk as individuals without diabetes who have had a prior cardiovascular event.^15-17 Outcomes after cardiovascular events are significantly worse in patients with diabetes and about 7 out of 10 patients with type 2 diabetes will die from a cardiovascular event or its complications.^18-20 The majority of patients with type 2 diabetes have coexisting cardiovascular risk factors, including hypertension, dyslipidaemia, central obesity and microalbuminuria.²¹ Targeting glycaemic control alone will not significantly reduce the morbidity and mortality from macrovascular disease in this group of patients. A large body of clinical evidence supports aggressive cardiovascular risk management in patients with type 2 diabetes.

Towards global cardiovascular risk reduction

Weight management

All patients with type 2 diabetes should strive to maintain a healthy body weight²² within the normal BMI for their ethnic group. This should be done through lifestyle modification and if necessary, pharmacological intervention.

Dyslipidaemia

Patients with type 2 diabetes typically have lipid profile characterized by elevated triglycerides, low HDL, modestly elevated LDL, elevated levels of small dense LDL particles and elevated levels of lipoprotein (a).²³ The American Diabetes Association5 and National Cholesterol Education Program Adult Treatment Panel III16 have both identified lipid goals for patients with diabetes, as shown in Table 2. First line therapy is lifestyle changes. Pharmacological therapies for LDL reduction include HMG-CoA reductase inhibitor (statin) and/or cholesterol absorption inhibitors. Treatment options for lowering triglycerides and raising HDL include fibrates and niacin.

Blood pressure

Lowering blood pressure is another key component of global cardiovascular risk reduction in people with diabetes and insulin resistance. Blood pressure goal is 130/80. Blood pressure control often requires 2 or more antihypertensive agents. Clinical data support the use of an ACE inhibitor as first line therapy for the prevention of microalbuminuria in patients with diabetes and hypertension.⁵ In patients >55 years of age, with or without hypertension but with another cardiovascular risk factor such as history of cardiovascular disease (CVD), dyslipidaemia, microalbuminuria, or smoking, an ACE inhibitor (if not contraindicated) should be considered to reduce the risk of cardiovascular events.⁵

Anti-platelet therapy

Low dose coated aspirin ( 75 - 162 mg ) is recommended as a primary prevention strategy in those with type 2 diabetes at increased cardiovascular risk, including those who are >40 years of age or who have additional risk factors (family history of CVD, hypertension, smoking, dyslipidaemia, or albuminuria).⁵

Smoking cessation

Studies of individuals with diabetes consistently found an increased risk of morbidity and premature death associated with the development of macrovascular complications among smokers.²⁴ Smoking is also related to the premature development of microvascular complications of diabetes and may have a role in the development of type 2 diabetes. All patients with diabetes should be advised not to smoke.²⁵

Multidisciplinary team approach, patient education and comprehensive complication screening programme

People with diabetes should receive medical care from a physician-coordinated team.²⁶ Such team includes, but is not limited to physicians, nurse practitioners, dieticians, pharmacists, podiatrists and mental health professionals with expertise and a special interest in diabetes. The patient, his/her family, together with the physician and other members of the health care team, should formulate individualized management plan. An integral component of this management plan is diabetes self management education (DSME)⁵ which aims to provide adequate education to help the patient develop problem-solving skills in the various aspects of diabetes management. This patient centred multi-disciplinary team can first identify the problems including presence of complications and other health and social problem, then set up realistic individualized goals and finally implement a targeted treatment plan in a coordinated fashion.

An annual comprehensive diabetes assessment and complications screening programme is recommended for all patients with type 2 diabetes, regardless of their form of treatment (Table 3). This serves to identify the glycaemic control, presence/absence of macrovascular or microvascular complications, cardiovascular and other risk factors, based on which management could be modified if necessary.

Conclusion

The new treatment paradigm of type 2 diabetes has shifted from "physician-based" "glucose-centred" approach to that of multi-disciplinary team approach targeting multifactorial intervention. This comprehensive management scheme would hopefully help our patients enjoy a healthy and happy life while having to live with diabetes.

Disclosure: Professor R. Young attended the Rosiglitazone GOLD programme at the end of 2004.

Key messages

1. Current management of type 2 diabetes involves glycaemic control and aggressive multifactorial intervention of cardiovascular risk factors.
2. A multi disciplinary team approach delivering patient focussed self management education and comprehensive assessment and complications screening programme have become the standard of care.
3. Numerous pharmacological agents targeting different sites of defect will hopefully make "near normal glycaemia" become a reality.