CME (November 2007)
Monthly Self-Study Series

Clinical management of type 2 diabetes

The Hong Kong Diabetes Advisory Panel
(members listed at the end of the article)

Introduction

The worldwide prevalence of diabetes is increasing at a dramatic rate. Approximately 171 million people are currently estimated to have the disease and this number is projected to exceed 360 million by the year 2025 [¹]. Of particular concern are epidemiological data predicting a prevalence of more than 150 million people with diabetes in the Asia Pacific region by 2025, with 30% or more of the total number of patients worldwide inhabiting China and India alone [¹]. Factors contributing to this growing epidemic include lifestyle changes related to dietary habits and reduced physical activity, with an increase in obesity, due to westernization, urbanization and industrialization of developing countries [^1-3]. Consequently, the incidence of type 2 diabetes is also increasing in children and adolescents worldwide as well as in Asia, such that approximately 80% of Japanese children with diabetes now have the type 2 form of the disease [^1-5]. Early diagnosis and implementation of effective strategies to manage and treat patients with diabetes in clinical practice is essential to reduce this growing healthcare burden and preserve societal productivity and quality of life. This article focuses on the clinical management of type 2 diabetes as it is the most prevalent form of the disorder, accounting for approximately 85–95% of all cases of diabetes.

Screening for diabetes mellitus

Screening and early detection of diabetes is crucial to preventing and minimizing long-term complications and reducing the associated healthcare burden. A measurement of fasting plasma glucose (FPG), 2-hr oral glucose tolerance test (OGTT; 75-g glucose load) or both is used in most screening programmes to detect prediabetes or diabetes [⁶]. However, FPG is the preferred test for diagnosis of diabetes in children and non-pregnant adults as it is less costly, more reproducible and easier to administer than an OGTT. The screening criteria, recommended by the American Diabetes Association (ADA), to detect pre-diabetes or diabetes in non-pregnant adults are listed in Table 1 [⁶]. As the incidence of type 2 diabetes has increased substantially in adolescents during recent years, current guidelines also suggest screening children and youths who have risk factors for the development of type 2 diabetes (Table 1) [⁶]. This emphasis on periodic screening of children for type 2 diabetes as well as type 1 diabetes is also being promoted in campaigns surrounding World Diabetes Day 2007, which has a particular focus on increasing awareness of the need for early screening and diagnosis of diabetes in children.

Diagnosis of diabetes mellitus

The diagnostic criteria for diabetes mellitus in nonpregnant adults are shown in Table 2 [⁶]. A diagnosis of diabetes mellitus may be made on the basis of these criteria using one of the following tests: 1) FPG; 2) 2-hr post-load glucose OGTT; or 3) symptoms of diabetes plus casual plasma glucose (PG) concentration. For clinical purposes, the diagnosis of diabetes should always be confirmed by repeat testing on a subsequent day unless there is unequivocal hyperglycaemia or evidence of diabetes-associated complications. Although an OGTT is not feasible for routine clinical use, it may be required in the evaluation of patients with impaired fasting glucose (IFG) or when diabetes is still suspected despite a normal FPG. The use of HbA_1c is not currently recommended as a diagnostic test [^6-8].

Patients with hyperglycaemia that is insufficient to fulfil the diagnostic criteria for diabetes mellitus are classified as having pre-diabetes and exhibit either impaired glucose tolerance (IGT) or IFG, depending on the test used for diagnosis. Such individuals are at increased risk for developing diabetes and/or cardiovascular disease (CVD). Recently, the ADA revised the definition of IFG, lowering the threshold for a diagnosis of IFG to a FPG of 5.6 mmol/L (100 mg/dL) or greater (Table 3) [⁶], whereas joint guidelines from the Wor ld He a l th Or g ani z a t ion (WHO) and International Diabetes Federation (IDF) advocate a FPG of 6.1–6.9 mmol/L [⁸].

Management of type 2 diabetes and its complications

Glycaemic control and goals

Several prospective randomized clinical trials have demonstrated that decreasing glycaemia is an effective strategy to reduce the risk of long-term diabetesassociated microvascular, macrovascular and neuropathic complications [^9-15]. For example, in the Asia Pacific Cohort Studies Collaboration, a 1.0 mmol/L decrease in FPG was associated with a 21% reduction in the risk of stroke and a 23% decrease in coronary heart disease (CHD) risk [¹⁶]. Similarly, in the United Kingdom Prospective Diabetes Study (UKPDS), an average decrease in HbA_1c of 1.0% over 10 years resulted in a risk reduction of 21% for diabetes-related mortality and 14% for myocardial infarction (MI) (Figure) [¹⁴].

Figure. Reductions in the relative risk of microvascular and macrovascular complications associated with a 1% decrease in HbA_1c. *p < 0.0001 versus baseline; **p = 0.035. Adapted from Stratton IM, et al [¹⁴].

Current clinical practice guidelines from the ADA recommend tight blood glucose control and an HbA_1c goal for patients in general of 7.0% or less [⁶]. However, an HbA_1c level as close to normal (6.0% and less) as possible may be considered for individual patients, with monitoring for increased risk of hypoglycaemia. In contrast, the American Association of Clinical Endocrinologists (AACE), IDF and the Asian-Pacific Type 2 Diabetes Policy Group, as well as the local diabetes association Diabetes Hongkong, recommend a more stringent HbA_1c goal of 6.5% or less [^{7, 17}]. Postprandial PG may be monitored 1 to 2 hours after the start of a meal in those patients who achieve preprandial glucose goals but not HbA_1c goals [⁶]. The ADArecommended goals for preprandial and postprandial PG levels are 5.0–7.2 mmol/L and less than 10.0 mmol/L, respectively [⁶]. By comparison, Diabetes Hongkong and the WHO/IDF recently proposed a FPG goal of 4.0–6.0 mmol/L and postprandial PG level of 7.8–8.0 mmol/L or less [⁸].

Self-monitoring of blood glucose (SMBG) is an important component of effective diabetes management as it allows patients to: 1) evaluate their responses to therapy and adjust their medications accordingly; 2) prevent hypoglycaemia; 3) determine whether glycaemic goals are being attained; and 4) learn lifestyle factors that affect glycaemic control [^{6, 18, 19}]. For those patients who have difficulties in achieving and maintaining glycaemic and other targets, additional interventions may be needed, such as reinforcing patient education, utilizing a multidisciplinary healthcare team approach, modifying therapeutic regimens, changing SMBG schedules, and increasing the number of doctor visits [^{6, 20}]. Importantly, patients must be informed that any improvement in glycaemic control, albeit falling short of treatment goals, is beneficial.

Metabolic management with lifestyle interventions

Behavioural interventions that reverse weight gain and/or obesity have been demonstrated to have a beneficial effect on glycaemic control in patients with type 2 diabetes [^21-23]. Furthermore, increased physical activity, dietary modifications and modest weight loss (5–10%) have been shown to reduce the risk of progression of IGT to type 2 diabetes by up to 58% [^24-26]. In addition to beneficial effects on glycaemia, lifestyle interventions (weight loss, diet and exercise) are also associated with improvements in coincident CVD risk factors, such as BP and atherogenic lipid profiles [^{27, 28}].

Exercise. In the absence of any contraindications, such as CVD risk, uncontrolled hypertension, severe peripheral or autonomic neuropathy, or retinopathy, the Asian-Pacific guidelines recommend that patients with type 2 diabetes accumulate at least 150 minutes of walking per week [¹⁷]. Resistance exercises (3 days/week) that target all major muscle groups are also recommended in addition to aerobic exercise [^{6, 29}].

Diet. Common medical nutritional strategies for the management of type 2 diabetes include reducing caloric intake, decreasing total fat consumption (approximately 30% of total caloric intake) and saturated fat intake (less than 7% of total calories), minimizing intake of trans fats, and encouraging a dietary fibre intake of 14 g/1,000 kcal [^{6, 30}]. The distribution range of protein intake in individuals with diabetes is similar to that for the general population (10–35% of energy intake; average of approximately 10% of calories), usually not exceeding 20% of energy intake. The recommended range of carbohydrate intake is 45–65% of total calories (minimum 130 g/day) [³¹]. In general, the optimal combination of macronutrients (protein, fat, carbohydrate) as well as total caloric intake must be customized to the individual needs and weight management goals of each patient. Additionally, daily alcohol intake should be limited to one drink or less for women and two drinks or less for men [^{6, 30}].

Metabolic management with pharmacological interventions

The majority of patients with type 2 diabetes will require antidiabetic agents in addition to appropriate lifestyle interventions to sustain glycaemic control over the course of their disease. Apart from insulin, there are currently eight different classes of pharmacological agents available for the treatment of type 2 diabetes (Table 4). The properties, mechanisms of action and use of these agents have been reviewed in detail elsewhere [^{6, 7, 32-34}].

Treatment algorithms for the management of hyperglycaemia using pharmacological agents have recently been published in a joint statement of the ADA and the European Association for the Study of Diabetes (EASD) [³⁴], as well as by the AACE [⁷]. Recommendations for metabolic control are based on: 1) achieving and maintaining PG levels as early and as close to the non-diabetic range as possible; 2) early use of pharmacological therapies in addition to lifestyle modifications; and 3) rapid dose titration and addition or switching of therapy, aiming at an HbA_1c of 7% or less. A large number of studies have confirmed that most patients will require combination therapy to achieve and maintain glycaemic goals [^{6, 7, 34, 35}]. Specific recommendations [^{7, 34}] include:

1. Initiating both lifestyle interventions and treatment with metformin, unless contraindicated, at diagnosis.
2. If glycaemic goals are not achieved or sustained within 2 to 3 months of initiating metformin treatment, either insulin, a sulphonylurea or a thiazolidinedione should be added to the treatment regimen.
3. If the target HbA_1c level is either not achieved or sustained, insulin therapy should be initiated or intensified. Use of sulphonylureas should be discontinued at this stage as they are not synergistic when co-administered with insulin. However, if HbA_1c is close to goal (< 8.0%), a third oral antidiabetic agent may be used instead of insulin.

Cardiovascular disease

CVD is the predominant cause of morbidity and mortality in patients with diabetes mellitus, resulting in approximately 75–80% of deaths in this population. The incidence of CHD, stroke, reinfarction, congestive heart failure and death are increased approximately 2- to 4-fold in patients with type 2 diabetes mellitus compared with the general population [36]. Although type 2 diabetes itself is an independent risk factor for CVD, additional risk factors include dyslipidaemia, hypertension, smoking and a previous history of CHD. Therefore, estimating the risk of CVD and implementing appropriate risk reduction strategies forms an essential part of the management of patients with diabetes mellitus [³⁷].

Dyslipidaemia

The increased incidence of CV events observed in patients with type 2 diabetes is due, in part, to abnormalities in lipid profiles, including elevated triglyceride levels, decreased high-density lipoprotein cholesterol (HDL-C) levels and increases in pro-atherogenic small, dense LDL-C particles [³⁸]. Annual screening of lipids is recommended for all adults with diabetes mellitus [⁶]. However, lipids may be measured every 2 years in adults with low-risk lipid profiles (LDL-C < 100 mg/dL [2.6 mmol/L], HDL-C > 50 mg/dL [1.3 mmol/L] and triglycerides < 150 mg/dL [1.7 mmol/L]) [⁶].

The primary goal of management of dyslipidaemia is to lower LDL-C levels to less than 100 mg/dL (2.6 mmol/L) using lifestyle (diet, weight loss, exercise) and/or pharmacological interventions [⁶]. In those patients under 40 years of age without overt CVD but who are at increased CVD risk, lifestyle interventions may be used initially to achieve target LDL-C levels. However, statin therapy is recommended for all patients with overt CVD and in those patients over 40 years of age to achieve an LDL-C reduction of 30–40% regardless of baseline LDL-C levels [^{6, 37}]. The ADA-recommended treatment goals for HDL-C and triglycerides are shown in Table 5 [^{6, 37}]. Although combination therapy with statins and fibrates may be necessary to achieve all lipid targets, this strategy can be associated with an increased risk for abnormal transaminase levels, rhabdomyolysis or myositis, depending on the particular combination of drugs used [^39-42]. Other classes of lipid-lowering drugs, such as ezetimibe or sustained-release nicotinic acid, may be suitable for those patients who either fail to reach lipid targets or who have tolerability problems with statins and/or fibrates.

Smoking

Patients with diabetes who smoke are at increased risk for morbidity and premature death as sociated with macrovascular complications [⁴³]. Therefore, patients who smoke should be provided with counselling on smoking cessation as part of their routine diabetes care [^{6, 43}].

Antiplatelet agents

Several clinical trials have provided evidence for aspirin as a preventive measure for reducing CV events [^{44, 45}]. Therefore, low-dose aspirin prophylaxis (75–162 mg/day) is recommended in patients with diabetes who are at increased risk of CVD (age > 40 years, dyslipidaemia, hypertension, albuminuria, smoking, family history of CVD) [^{6, 45}]. Aspirin therapy is also recommended as a secondary prevention strategy for patients with diabetes and a history of stroke/transient ischaemic attack (TIA), MI, peripheral vascular disease (PVD), vascular bypass surgery, claudication and/or angina [⁶].

Hypertension

Clinical trials have clearly established the benefits of intensive BP control in reducing CVD risk as well as other diabetes-related endpoints and deaths among diabetic hypertensive patients [^{46, 47}]. Monitoring of BP is recommended at all visits for patients with type 2 diabetes, with confirmation of hypertension (systolic BP >= 130 mmHg, or diastolic BP >= 80 mmHg) obtained within 1 month of the initial reading [⁶]. Patients with persistent BP values greater than 130/80 mmHg should be treated with the aim of achieving the recommended BP goal of less than 130/80 mmHg. Initial treatment of patients diagnosed with mild hypertension (systolic BP 130-139 mmHg or diastolic BP 80-89 mmHg) involves lifestyle interventions (weight control, reducing sodium and alcohol intake, increasing physical activity). If the target BP is not attained after 3 months of lifestyle changes, then drug therapy should be initiated, preferably with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) and subsequent addition of a thiazide diuretic and/or calcium channel blocker, if needed [⁶]. Combination therapy with drugs from different classes is generally required to achieve BP goals in the majority of patients with diabetes [48].

Diabetic retinopathy

Among adult patients with type 2 diabetes mellitus, approximately 20–40% have signs of diabetic retinopathy (DR) and approximately 8% have a more severe form associated with visual impairment at first presentation [⁴⁹]. Several studies have demonstrated that intensive management of hyperglycaemia and BP has beneficial effects in preventing and/or delaying the onset of diabetic retinopathy (Figure) [^{14, 46, 50, 51}]. The ADA recommends that patients receive a comprehensive dilated retinal eye examination and assessment of visual acuity by an ophthalmologist soon after diagnosis of type 2 diabetes [⁶]. In general, eye exams should be repeated annually. More frequent exams, however, are required in cases of mild non-proliferative diabetic retinopathy (NPDR; every 6–12 months) or severe retinopathy (3–6 months). Early treatment of retinopathy laser photocoagulation surgery may be beneficial in preventing or reducing vision loss in patients with early stage proliferative DR and severe NPDR, but it does not reverse vision impairment [^52-54].

Diabetic nephropathy

Diabetic nephropathy is the leading cause of endstage renal disease worldwide, with a particularly high incidence (approximately 59%) among Asian patients with type 2 diabetes [^{55, 56}]. The ADA guidelines recommend testing patients at diagnosis and annually thereafter for microalbuminuria by assessing albuminto- creatinine ratios (ACR) in spot urine specimens and estimated glomerular filtration rates (GFR) derived from serum creatinine [⁶]. The simplified Modification of Diet in Renal Disease (MDRD) equation has now been validated in Chinese populations [⁵⁷] and may be used to assess renal function. A definitive diagnosis of micro- or macro-albuminuria is based on the presence of albuminuria in at least two of three specimens collected within a period of 3–6 months [⁶]. Significant declines in GFR, however, also occur in the absence of increased urinary albumin excretion in a substantial proportion of patients with diabetes [^{58, 59}]. Intensive management of hyperglycaemia and BP, together with restrictions in daily protein intake (to 0.8–1.0 g/kg in patients with diabetes and early-stage chronic kidney disease [CKD]; 0.8 g/kg in later stages of CKD) are recommended to improve renal function [⁶]. If hypertension is present in patients with diabetes and microalbuminuria, treatment with an ACE inhibitor or ARB is indicated [^{6, 60, 61}]. For those patients unable to tolerate ACE inhibitors or ARBs, b-adrenergic receptor blockers, non-dihydropyridine calcium channel blockers or diuretics may be used [^{6, 62}].

Diabetic foot care

Early recognition of neuropathy in patients with diabetes is essential as up to 50% of diabetic peripheral neuropathy (DPN) may be asymptomatic, placing patients at risk of insensate injuries and ulcers to their feet [^{6, 63}]. All patients should be assessed for neuropathy and receive foot examinations at diagnosis of diabetes and annually thereafter [⁶]. Visual foot inspections should be scheduled more frequently (every 3–6 months) in patients with high-risk conditions, such as peripheral neuropathy, severe nail pathology, evidence of increased pressure, bony deformity, altered biomechanics, PVD, and/or a history of ulcers or amputation [^{6, 63-65}]. Evaluation of the patient should include tests of pinprick sensation, temperature and vibration perception, and assessment of foot pulses [^{63, 65, 66}]. If there is a lack of sensation or mechanical foot changes, patients should be referred for special footwear, and to a qualified podiatrist, orthopaedist, or neurologist [^{6, 63}]. Patients should also receive counselling on risk factors and self-care of the diabetic foot, including frequent moisturizing of the skin to prevent skin fissures [^{6, 63}]. Although there are no therapeutic agents approved specifically for the treatment of DPN-related pain, symptomatic relief may be achieved with the use of tricyclic antidepressants, anticonvulsants, 5-hydroxytriptamine and norepinephrine inhibitors [⁶].

Follow-up

Once an individual patient management plan has been developed, physicians and other members of the multidisciplinary healthcare team should work with the patient to help them reach the recommended treatment goals (summarized in Table 5). All patients should undergo a comprehensive assessment for risk factors and complications at least every 12–18 months including lipids, renal and liver function, haematology, and eye and foot examinations. At each visit, the treatment plan should be reviewed periodically with patients, noting where targets have been met, reinforcing positive behaviours and identifying any barriers preventing patients from achieving their goals. Key elements for review include body weight, glycaemic control (including SMBG, FPG and/or postprandial PG and HbA_1c), BP control, frequency of hypoglycaemic episodes and precipitating factors, new symptoms, and compliance with drug treatment and lifestyle interventions. In a local study involving over 7,000 type 2 diabetic patients, followed up for an average period of 5 years, reaching two or more of the three targets (BP, HbA_1c, LDL-C) was associated with significant reductions in new-onset CHD [⁶⁷], consistent with the importance of multifaceted care on clinical outcomes [^68-71].

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