Diabetes mellitus (DM) is defined as a metabolic disorder of multiple etiologies, characterized by chronic hyperglycemia with disturbances of carbohydrate, fat and protein metabolism. It results from defects in insulin secretion, insulin action (resistance), or both.1
Developing guidelines for the management of DM should be given a priority in health care as the disease is a common, serious and costly health problem.2 According to the Ad Hoc Diabetes Reporting Group,3 Saudi Arabia is a high-prevalence country (12-23.7%).45 DM usually leads to many complications6 and, as a result, the economic burden of the disease is enormous.7 Good control is associated with reduced morbidity and mortality.8 Diabetic patients should be managed by a team rather than one physician. Lack of consistent care causes confusion in patients and reduces their compliance. Finally, the emotional cost on the patient and his family is huge, as the disease is commonly associated with anxiety, impotence, disturbed family life, and increased fatigue and irritability.9
The criteria for the diagnosis of DM and impaired glucose tolerance have changed many times over the last decade. These changes were based on the epidemiological studies that looked at the association between different glucose levels and the incidence of complications.10 The most recent criteria are summarized in Figure 1.1112
The management of patients with diabetes is classified in the current review under the following categories: a) Non-Pharmacological, b) Pharmacological, c) Monitoring of glycemic control, d) Prevention, e) Clinic organization and f) Referral and admission.
i. Psycho-Social Aspects.
The psycho-social impact of the disease should not be underestimated. Doctors should learn the communication skills as well as the skills of breaking bad news to patients when informing them of the diagnosis for the first time. These skills will no doubt enhance their ability to detect and treat psychological disorders associated with diabetes.
The patient may experience various degrees of anxiety and fear of complications, or may be affected socially as a result of the stigma or embarrassment leading to his/her isolation and low self-esteem.13
Social support from a family network or other sources, such as a diabetes support organization, and emotional well-being are crucial in achieving effective self-management of diabetes.14
Improvements in glycemic control are associated with the improvement in quality of life, provided there is no increase in hypoglycemic symptoms. Severe hypoglycemia may adversely affect the quality of life among patients treated with insulin, particularly newly diagnosed patients; multiple insulin injections were not found to adversely affect the quality of life.15
ii. Health Education
Diabetes education is the cornerstone of the care of diabetic patients who aspire to achieve successful health-related outcomes. In this respect, the role of the physician as “the coordinator”, is essential to ensure that the quality of diabetes education is delivered through a coordinated systematic approach. The instructional team should be composed of at least a trained nurse and a physician.
The following health education guidelines need to be considered13 (Appendix 1):
- The patient must be taught self-care to be his (her) own doctor, dietician and laboratory technician (health promotion approach).
- Suitably trained nurses and dieticians are possibly in a better position to deliver patient education than the physician; so they should be utilized properly for that purpose.
- The education of the team members is of paramount importance and should precede the implementation of the protocol.
iii. Physical activity
Several long-term studies have demonstrated a consistent beneficial effect of regular physical activity on carbohydrate metabolism and insulin sensitivity, and their benefits can be maintained for at least 5 years. These studies employed physical activity regimens, three to four times a week, in 30-60-minute sessions. Improvements in HbA1c were generally 10-20% of baseline and were most marked in patients with Type 2 diabetes, particularly the most insulin resistant.16
A combination of physical activity and wise food choices can help to reach the target weight and maintain it.16 Patients should be informed that any type of exercise is useful, including walking to the mosque or the grocery, performing the house work and walking around the house.
Many Type 2 diabetic patients are overweight and insulin resistant; therefore, medical nutrition therapy should concentrate on lifestyle changes that result in reduced energy intake along with exercise. Healthy lifestyle strategies help in the control of blood sugar, dyslipidemia, and blood pressure. These strategies should therefore, be implemented at an early stage after the diagnosis of diabetes. It is recommended that a competent dietitian be included in the out-patient management of diabetic patients.
Studies on healthy subjects and those at risk of developing type 2 diabetes, support the importance of including foods containing carbohydrate, particularly from whole grains, fruits, vegetables, and low-fat milk in the diet of people with diabetes.17
In type 2 diabetic patients, there is a strong evidence that the ingestion of very large amounts of fibers are necessary to confer metabolic benefits on glycemic control, hyperinsulinemia, and plasma lipids.18
The component of the diet that has the greatest influence on blood glucose is carbohydrate. Other macronutrients in the diet such as fat and protein, can influence the postprandial blood glucose level, however. The total amount of carbohydrate consumed is a strong predictor of glycemic response, and, thus, monitoring total grams of carbohydrate, whether by use of exchanges or carbohydrate counting, remains a key strategy in achieving glycemic control.19 A recent meta-analysis found that the low glycemic index diet, as compared to high glycemic index diet had a significant effect on improving glycemic control.20
Protein intake should account for 15-20% of average energy intake. In individuals with microalbuminuria, reduction of protein to 0.8-1.0 g per kg body weight per day while in individuals with overt nephropathy, reduction to 0.8 g per kg body weight per day may slow the progression of nephropathy.18
Nowadays, artificial sweeteners especially aspartame are added to a wide variety of drinks and drugs, and according to the current literature, the possible risk of cancer seems negligible and there is no convincing evidence that they are carcinogenic.21
b. Pharmacological Management Guideline
A stepwise approach is recommended to lower and maintain HbA1c to as close to physiological levels as possible (Figure 2)22 It was shown, beyond doubt, that a lower threshold for starting insulin in type 2 patients is associated with reduced long term complications.23 The early addition of insulin when maximum sulfonylurea therapy is inadequate, can significantly improve glycemic control without promoting increased hypoglycemia or weight gain.24 All therapies should be used in the context of continuing lifestyle intervention. Agreement to diet therapy should be discussed with people with diabetes and monitored when the level of glucose control is problematic. If the patient is not complying with diet or drugs, then his motivation towards following the recommended action should take precedence over increasing the drug dose. Insulin therapy is a necessary part of management for the majority of people with type 2 diabetes who survive the disease for 5 to15 years.11 Therefore, it is important to prepare people with type 2 diabetes, well in advance, that insulin will almost certainly be required at some stage, due to the progressive nature of the disease. Insulin Glargine is a good choice for patients who suffer from frequent hypoglycemic attacks as it causes significantly less nocturnal hypoglycemia than NPH, thereby, reducing a leading barrier to initiating insulin.25 If fasting glucose is normal, while daytime glucose levels are above target levels, an intermediate-acting insulin, 6 to 10 units at breakfast time, should be added. Metformin should be continued when insulin is added. The combination therapy with Metformin and insulin improves glycemic control and reduces insulin requirements.26 The decision to start on conservative management (e.g. diet, exercise) or oral hypoglycemic drugs or insulin depends on many factors14 as shown in Figure 3.
c. Monitoring of Glycemic Control
i. Blood Glucose Targets
HbA1c levels should be as close to physiological levels as possible, preferably less than 7%. Regular monitoring of HbA1c results in improvement of metabolic control, and fewer hospitalizations prompted by poorly controlled glucose levels.27 Lower HbA1c targets are particularly advisable for young people, in the first few years after diagnosis of diabetes, in the presence of complications of diabetes or multiple risk factors such as hypertension and hyperlipidemia1 and when the risk of hypoglycemia is minimal as in patients on insulin sensitizers (e.g. the Metformin or Glitazone) and those on alpha-glucosidase inhibitors such as Acarbose. Higher HbA1c targets may be advisable for older people who are frail or have significant co-morbidities, for those with hypoglycemic unawareness and who suffer frequent hypoglycemic episodes as well as for those at risk of severe hypoglycemia (on insulin or insulin secretagogue) who live alone or have poor social supports.1
ii. For which patients is self-monitoring of Blood Glucose (SMBG) is advisable?
Type 1 and type 2 patients requiring insulin128 should be encouraged to check their blood sugar themselves and record the measurements on a chart.
Prevention is an important issue in the management of diabetic patients. It should include all the three levels of prevention: primary, secondary and tertiary.
I. Primary Prevention
i. Control of other Risk Factors
In the past, type 2 diabetes affected primarily individuals older than 40 years of age. However, the increasing prevalence of childhood obesity has led to a marked increase in type 2 diabetes in adolescents and young adults.
A large number of epidemiological studies have shown that obesity and a sedentary lifestyle are independently related to the chances of developing diabetes. Data from the Nurses’ Health Study suggest that the lowest risk of diabetes occurs in individuals who have a BMI <21, with increasing prevalence as the obesity levels increase.29
Similarly, several intervention studies have found that weight loss and increased physical activity help prevent or delay the development of type 2 diabetes among person with IGT.3031
b. Blood lipid (Table 1)
For patients with diabetes mellitus ‘Coronary Heart Disease (CHD) risk equivalent’, the overall goal is an LDL-C level [less than 2.6 mmol/l (<100 mg/dl)].32 Triglycerides (TGs) are also considered a risk factor of CHD.3233 The target of TGs should be less than 1.7 mmol/l (150 mg/dl). If TGs are less than 5.7 mmol/l (500 mg/dl), it is recommended LDL-C to be lowered first; but if TGs are higher then TGs be lowered with the use of fibrates and nicotinic acid to prevent pancreatitis.32 Lipids should be measured annually or more frequently if not under control.
c. Blood pressure
The benefits of good blood pressure control in patients with diabetes exceed the benefits of tight glycemic control and extend not only to the prevention of macrovascular disease, but also to the prevention of microvascular complications.3435
In one study, patients with diabetes who were randomized to a target diastolic blood pressure of 80 mmHg or less had a 50% reduction in major cardiovascular events compared with those with a target diastolic blood pressure of 90 or less.36 Two studies (The LIFE and the ALLHAT)3738 have demonstrated that adequate BP control improves CVD outcomes, especially stroke, when aggressive BP targets are achieved. It is, therefore, recommended that blood pressure in diabetic patients should be controlled to levels of 130/80 mm Hg or lower.35
Both Angiotensin-converting enzyme (ACE) inhibitors and Angiotensin receptor blockers (ARB) are considered the first-line antihypertensive therapy for patients with both diabetes and hypertension; both agents have been shown to reduce long term complications.3940
Most diabetic patients with hypertension require combination therapy to achieve optimal blood pressure goals. Thiazide-type diuretics are beneficial in diabetic patients, either alone or as part of a combined regimen.
ii. Care of Patients with Impaired Glucose Tolerance (IGT)
There is growing evidence that at above normal glucose levels but below the diabetes diagnostic threshold, nowadays referred to as pre-diabetes, there is a substantially increased risk of cardiovascular disease (CVD) and death. In those individuals, CVD risk factors are also more prevalent.
When obese subjects with IGT received intensive individualized instruction on weight reduction, food intake, and guidance on increasing physical activity (intervention group), there was a 58% relative reduction in the incidence of diabetes after an average follow-up of 3.2 years.30 Furthermore, Metformin was shown to reduce the risk of diabetes by 31%.31 Similarly, Acarbose and Troglitazone reduced the risk of DM by 32% and 56%, respectively.41
iii. Aspirin Therapy
Meta-analyses of studies among diabetic patients support the view that low – dose aspirin therapy should be prescribed as a secondary prevention strategy, and as a primary prevention strategy (if no contraindications exist) in adults with diabetes who are at high risk of cardiovascular events.42 Furthermore, trials had demonstrated a significant benefit of aspirin versus no aspirin in reducing the composite end-point of cardiovascular deaths, stroke, or myocardial infarction among high-risk individuals, including those with diabetes.43
iv. Smoking cessation
Studies of diabetic patients who smoked had found a heightened risk of morbidity, premature death, macrovascular and microvascular complications of DM as compared to non-smokers; smoking may have a role in the development of type 2 diabetes.44 Education of diabetic patients on the adverse effects of smoking is of paramount importance and counseling smokers to quit this habit was found to be cost-effective.45
Patients with diabetes are at high risk for complications, hospitalization, and death from influenza and pneumococcal disease. The risk is greater among patients with end organ complications of cardiac and renal disease.46
Vaccinating individuals at high risk before the influenza season each year is the most effective measure for reducing the negative impact of influenza on their health. Therefore, the influenza vaccine should be recommended for patients with diabetes, aged ≥6 months.46
II. Secondary Prevention
Early diagnosis and screening
Checking fasting blood sugar is a relatively cheap and simple procedure. The incidence and prevalence of DM in Saudi Arabia increases significantly after the age of 30 years. Therefore, we recommend the screening for DM among asymptomatic Saudi patients aged 30 years and above. Screening is more important among obese individuals who have a first degree relative with diabetes, are hypertensive ≥140/90, have been diagnosed with gestational diabetes mellitus (GDM), have dyslipidaemia and those with impaired glucose tolerance (IGT) or impaired fasting glucose (IFG).47
III. Tertiary Prevention
Screening for complications
a. Diabetic Nephropathy
It is defined as increased urinary albumin excretion (UAE) in the absence of other renal diseases.48 Around 40% of type 2 diabetic patients suffer some sort of nephropathy, which increases the risk of death, mainly resulting from cardiovascular diseases.
Microalbuminuria is defined as albumin excretion rate (AER) of 30 to 300 mg/d, and overt proteinuria, as an AER greater than 300 mg/d. Urinary albumin to creatinine ratio (ACR), from first-morning voided samples, correlates well with 24-hour urinary albumin level.49 Therefore, it has been recommended for routine screening of patients with DM. Microalbuminuria is also defined as urinary ACR ≥ to 2.5 mg/mmol (men) and ≥ to 3.5 mg/mmol (women), while proteinuria is defined as urinary ACR ≥ 30 mg/mmol.50
Screening for microalbuminuria should be requested for all Type 2 diabetes at the time of diagnosis and annually thereafter.4850 Patients with albuminuria of any degree should undergo an evaluation for the presence of co-morbid associations, especially retinopathy and macrovascular disease.
The following strategies were found to be effective for the control of diabetic nephropathy:48 achieving the best metabolic control (HbA1c <7%), treating hypertension (<130/80 mmHg or <125/75 mmHg if proteinuria >1.0 g/24h and increased serum creatinine), using drugs like ACE-inhibitors or angiotensin II receptor blockers and treating dyslipidemia (LDL cholesterol <2.6 mmol/l).
b. Diabetic Neuropathy
About half of all people with diabetes suffer some degree of diabetic neuropathy which is usually present as either a polyneuropathy or a mononeuropathy.51
i. Peripheral neuropathy
Diabetic peripheral neuropathy may present with positive symptoms including pain, burning, and numbness, or negative symptoms, such as loss of sensation, as the disease progresses. The most common form of diabetic neuropathy is a polyneuropathy characterized by the loss of peripheral sensation.
Neurological assessment of lower limbs should be performed for newly diagnosed diabetic patients and then annually or according to the presenting symptoms.51 In order to confirm the diagnosis, such patients are referred for nerve conduction studies.
Based on randomized controlled trials, the drug, gabapentin showed good efficacy, a favourable side-effect profile with lack of drug interactions and therefore it remains the first choice treatment in painful diabetic neuropathy, especially in the elderly.52
ii. Autonomic neuropathy
Diabetic autonomic neuropathy (DAN) is a serious common complication. It is associated with an increased risk of cardiovascular mortality as well as multiple symptoms and impairments.
DAN may affect many body systems especially gastrointestinal [GI] and genitourinary tracts and the cardiovascular system. Constipation is the most common lower-GI symptom but may alternate with episodes of diarrhea.53
In men, DAN may cause loss of penile erection and/or retrograde ejaculation. There is no curative therapy for DAN and usually symptomatic treatment is given.
c. Diabetic Retinopathy
Diabetic retinopathy (DR) and diabetic macular edema (DME) are common microvascular complications in patients with diabetes and may have a sudden and debilitating impact on visual acuity (VA), eventually leading to blindness.
Early detection of retinal abnormalities is essential in preventing DR/DME and loss of vision.
Ophthalmoscopy is a useful screening procedure, easy to perform and accessible to ophthalmologists and other physicians, and requires no specialized equipment. Compared with fundus photography, ophthalmoscopy by an experienced examiner was found to agree with grading by fundus photography in more than 85% of cases. In the hands of non-ophthalmologist, ophthalmoscopy was less sensitive than fundus photography in detecting both any DR and sight-threatening DR (sensitivity 63 vs. 79% and 66 vs. 87%, respectively).54
The screening of all diabetic patients by an ophthalmologist should be undertaken annually or at short intervals based on retinal findings.
d. Coronary Heart Disease (CHD)
Diabetes is associated with a 2- to 4-fold increase in the risk of developing coronary artery disease. The risk of a myocardial infarction in patients with diabetes and no evidence of coronary artery disease, matches that of patients without diabetes who have had a previous myocardial infarction.55
It was recommended that a noninvasive cardiac testing be performed for asymptomatic persons with diabetes who have peripheral arterial disease (PAD) or cerebrovascular disease, those with major or minor electrocardiographic (ECG) changes at rest, or those with ≥2 CVD risk factors. Various screening tests have been suggested and these include: thallium stress test, stress echocardiogram, or stress ECG.56
The goals of early detection are not clearly defined in any of the currently available guidelines. In fact, there are few data on which to base recommendations for clinical practice for selecting the screening test for asymptomatic persons with diabetes.56
There is convincing evidence, from population-based studies, that the ankle-brachial blood pressure index (ABI) is a useful noninvasive measure for the detection of sub-clinical PAD and that a low ABI may provide incremental information beyond that provided by cardiovascular risk factor measurements, “especially in people aged 50 years and older or those who appear to be at intermediate or higher risk for CVD, such as cigarette smokers or individuals with diabetes”.57
e. Diabetic foot
Foot ulcers are a significant complication of diabetes mellitus and often precede lower-extremity amputation. The most frequent underlying etiologies are neuropathy, trauma, deformity, high plantar pressures, and peripheral arterial disease.58
All individuals with diabetes should receive an annual foot examination to identify high-risk foot conditions. The examination should include the assessment of protective sensation, foot structure, vascular status, and skin integrity. People at high-risk for diabetic foot should be evaluated more frequently and proper foot care strategies such as the use of footwear and debridement of callus offered. These strategies have been reported to decrease the incidence of lower extremity amputation by 49–85%.59
Because foot ulcers are usually contaminated, culture of noninfected wounds is generally not recommended.60 Polymicrobial infections predominate in severe diabetic foot infections and include a variety of aerobic gram-positive cocci, gram-negative rods, and anaerobes which necessitate aggressive intervention61 including proper antibiotic therapy with flucloxacillin, ciprofloxacin and metronidazole.
e. Clinic Organization
As a general guideline for a stable type 2 patient, three-monthly appointments are acceptable. The patient may visit earlier for repeat prescriptions or for other reasons. Newly-diagnosed patients usually need shorter appointment intervals. A check-list as a reminder for physicians should be developed to improve the care of diabetic patients (an example in appendix 2).
f. Threshold for referral and Admission
The indications for referral vary among physicians based on their competence and interest and between different sittings based on the availability of medications, other facilities and supporting staff such as diabetic educators, social workers, dieticians etc. Concerning the decision for admission, while nothing was discussed in many of the guidelines revised, we believe that the majority of physicians agree on certain clear indications such as in cases presenting with ketoacidosis, non-ketotic hyperosmolar coma, certain cases of diabetic foot and patients with severe infections or septicaemia. Other reasons for admission could be uncontrolled diabetes mellitus due to social reasons and adjustment problems. While there is no clear threshold for admission, the following factors may have an influence on the doctor's decision to admit such as the presence of other acute illnesses (e.g. pneumonia) or chronic illnesses (e.g. Bronchial Asthma).
The authors greatly appreciate and thank Dr. Aseem Al-Fada (Consultant Diabetologist, King Saud University) for his comments on this review.
1. New Zealand guidelines Group. . Management of type 2 diabetes: Evidence-based best practice guideline New Zealand Guidelines Group (NZGG). 2003 (www.nzgg.org.nz
2. Murata GH, Shah JH, Hoffman RM, Wendel CS, Adam KD, Solvas PA, et al Intensified Blood Glucose Monitoring improves glycemic control in stable, insulin treated veterans with type 2 diabetes: The diabetes outcome in veterans study (DOVES) Diabetes care. 2003;26(6):1759–63
3. King H, Rewers M. Global estimates for prevalence of diabetes mellitus and impaired glucose tolerance in adults. WHO Ad Hoc Diabetes Reporting Group Diabetes Care. 1993;16(1):157–77
4. Al-Nuaim A, Al-Rubeaan K, Al-Mazrou Y, Khoja T, Al-Attas O, Al-Daghari N. National chronic metabolic diseases survey 1995 Jointly published by Ministry of Health and King Saud University. Riyadh Kingdom of Saudi Arabia
5. Al-Nozha MM, Al-Maatouq MA, Al-Mazrou YY, Al-Harthi SS, Arafah MR, Khalil MA, et al Diabetes mellitus in Saudi Arabia Saudi Med J. 2004;25(11):1603–10
6. Famuyiwa OO, Sulaimani RA, Laajam MA, Al-Jasser SJ, Mekki MO, et al Diabetes Mellitus in Saudi Arabia: The clinical pattern and complications in 1,000 patients Ann Saudi Med. 1992;12(2):140–51
7. Al-Shehri ST. Direct costs of Diabetes Mellitus: Estimation of direct cost of health services offered to adult diabetic patients in Ministry of Health Centers in Al-Khobar area [dissertation] 1995 Al-Khobar King Faisal University
8. . UK prospective diabetes study group. Intensive BS control with sulphonylurea or insulin compared with conservative treatment and risks of complications in patients with type 2 Diabetes Mellitus Lancet. 1990;352:837–53
9. Surridge DHC, Williams EDL, Lawson JS. Psychiatric Aspects of Diabetes Mellitus Br J Psychiatry. 1994;145:269–76
10. . Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus Diabetes Care. 1997;20(7):1183–97
11. . National Institute of Clinical Excellence. Management of type 2 Diabetes (Management of blood glucose) Guidelines G National Institute of Clinical Excellence. 2002 (www.nice.org.uk
12. . American Diabetes Association. Diagnosis and classification of diabetes mellitus. Clinical practice recommendations 2004 Diabetes care. 2004;27(Supplement 1):S5–S10
13. Al-Faris EA. Guidelines for the Management of Diabetic Patients in the Health Centers of Saudi Arabia Journal of Family and Community Medicine. 1997;4(1):12–20
14. . American Diabetes Association. Physician's guide to insulin dependent (type I) diabetes diagnosis and treatment. American Diabetes Association, Inc., Alexandria, Virginia 22314 1988:15–28
15. The Diabetes Control and Complications Trial Research Group. . Influence of intensive diabetes treatment on quality-of-life outcomes in the diabetes control and complications tria Diabetes Care. 1996;19(3):195–203
16. Sigal RJ, Kenny GP, Wasserman DH, Castaneda-Sceppa C. Physical Activity/Exercise and Type 2 Diabetes Diabetes Care. 2004;27(10):2518–39
17. Franz MJ, Bantle JP, Beebe CA, Brunzell JD, Chiasson JL, Garg A, et al Evidence-based nutrition principles and recommendations for the treatment and prevention of diabetes and related complications Diabetes Care. 2002;25(1):148–98
18. . American Diabetes Association. Clinical Practice Recommendations 2002 Diabetes Care. 2002;25(Suppl. 1):S1–S147
19. Sheard NF, Clark NG, Brand-Miller JC, Franz MJ, Pi-Sunyer FX, Mayer-Davis E, et al Dietary carbohydrate (amount and type) in the prevention and management of diabetes: a statement by the american diabetes association Diabetes Care. 2004;27(9):2266–71
20. Brand-Miller J, Hayne S, Petocz P, Colagiuri S. Low-glycemic index diets in the management of diabetes: a meta-analysis of randomized controlled trials Diabetes Care. 2003;26(8):2261–7
21. . National Institutes of Environmental Health Sciences: 9th
National Toxicology Report on Carcinogens 2000 Washington, DC DHHS, NIH
22. . Canadian Diabetes Association. Clinical practice guidelines Clinical practice guidelines experts committee. 2003
23. Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, et al Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study Diabetes Res Clin Pract. 1995;28(2):103–17
24. Wright A, Burden AC, Paisey RB, Cull CA, Holman RRU.K. Prospective Diabetes Study Group. . Sulfonylurea inadequacy: efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the U.K. Prospective Diabetes Study (UKPDS 57) Diabetes Care. 2002;25(2):330–336
25. Riddle MC, Rosenstock J, Gerich J. Insulin Glargine 4002 Study Investigators. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients Diabetes care. 2003;26(11):3080–6
26. Ponssen HH, Elte JW, Lehert P, Schouten JP, Bets D. Combined metformin and insulin therapy for patients with type 2 diabetes mellitus Clin Ther. 2000;22(6):709–18
27. Larsen ML, Horder M, Mogensen EF. Effect of long-term monitoring of glycosylated hemoglobin levels in insulin-dependent diabetes mellitus N Engl J Med. 1990;323(15):1021–5
28. Coster S, Gulliford MC, Seed PT, Powrie JK, Swaminathan R. Self-monitoring in type 2 diabetes mellitus: Meta-analysis Diabet Med. 2000;17(11):755–61
29. Carey VJ, Walters EE, Colditz GA, Solomon CG, Willett WC, Rosner BA, et al Body fat distribution and risk of non-insulin-dependent diabetes mellitus in women: the Nurses’ Health Study Am J Epidemiol. 1997;145:614–9
30. Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, et al Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance N Engl J Med. 2001;344(18):1343–50
31. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DMDiabetes Prevention Program Research Group. . Reduction in the incidence of type 2 diabetes with life-style intervention or metformin N Engl J Med. 2002;346(6):393–403
32. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, et al Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines Circulation. 2004;110(2):227–239
33. Robins SJ, Rubins HB, Faas FH, Schaefer EJ, Elam MB, Anderson JW, et al Insulin resistance and cardiovascular events with low HDL cholesterol: the Veterans Affairs HDL Intervention Trial (VA-HIT) Diabetes Care. 2003;26(5):1513–7
34. UK Prospective Diabetes Study Group. . Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38 BMJ. 1998;317(7160):703–13
35. Arauz-Pacheco C, Parrott MA, Raskin P. American Diabetes Association. Treatment of hypertension in adults with diabetes Diabetes Care. 2003;26(Suppl 1):S80–S82
36. Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, et al Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group Lancet. 1998;351(9118):1755–62
37. Lindholm LH, Ibsen H, Dahlof B, Devereux RB, Beevers G, de Faire U, et al Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol Lancet. 2002;359(9311):1004–10
38. Cushman WC, Ford CE, Cutler JA, Margolis KL, Davis BR, Grimm RH, et al Success and predictors of blood pressure control in diverse North American settings: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT) J Clin Hypertens (Greenwich). 2002;4(6):393–404
39. . American Diabetes Association. Standards of Medical Care in Diabetes Diabetes Care. 2005;28:S4–S36
40. Berl T, Hunsicker LG, Lewis JB, Pfeffer MA, Porush JG, Rouleau JL, et al Cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial of patients with type 2 diabetes and overt nephropathy Ann Intern Med. 2003;138:542–9
41. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso MSTOP-NIDDM Trail Research Group. . Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomized trial Lancet. 2002;359(9323):2072–7
42. Colwell JA. American Diabetes Association. Aspirin therapy in diabetes (Position Statement) Diabetes Care. 2003;26(Suppl. 1):S87–S88
43. Sacco M, Pellegrini F, Roncaglioni MC, Avanzini F, Tognoni G, Nicolucci APPP Collaborative Group. . Primary prevention of cardiovascular events with low-dose aspirin and vitamin E in type 2 diabetic patients: results of the Primary Prevention Project (PPP) trial Diabetes Care. 2003;26(12):3264–72
44. Haire-Joshu D, Glasgow RE, Tibbs TL. Smoking and diabetes (Technical Review) Diabetes Care. 1999;22(11):1887–98
45. . U.S. Preventive Services Task Force: Counseling to prevent tobacco use Guide to Clinical Preventive Services. 19962nd ed Baltimore, MD Williams & Wilkins:597–609
46. . Advisory Committee on Immunization Practices (ACIP). Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP) MMWR 46 Recomm Rep. 1997;46(RR-9):1–25
47. . American Diabetes Association. Screening for diabetes (Position Statement) Diabetes Care. 2002;25(Suppl. 1):S21–S25
48. Gross JL, de Azevedo MJ, Silveiro SP, Canani LH, Caramori ML, and Zelmanovitz T. Diabetic Nephropathy: Diagnosis, Prevention, and Treatment Diabetes Care. 2005;28:164–76
49. Schwab SJ, Christensen L, Dougherty K, Klahr S. Quantitation of proteinuria by use of protein to creatinine ratios in single urine samples Arch Intern Med. 1987;147:943–4
50. . The American Diabetes association. Diabetic Nephropathy Diabetes Care. 2002;25:S85–S89
51. Sima AA, Thomas PK, Ishii D, Vinik A. Diabetic neuropathies Diabetologia. 1997;40(suppl 3):B74–B77
52. Adriaensen H, Plaghki L, Mathieu C, Joffroy A, Vissers K. Critical review of oral drug treatments for diabetic neuropathic pain-clinical outcomes based on efficacy and safety data from placebo-controlled and direct comparative studies Diabetes Metab Res Rev. 2005;21(3):231–40
53. Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic Autonomic Neuropathy Diabetes Care. 2003;26:1553–79
54. Ciulla TA, Amador AG, Zinman B. Diabetic Retinopathy and Diabetic Macular Edema: Pathophysiology, screening, and novel therapies Diabetes Care. 2003;26:2653–64
55. Saito I, Folsom AR, Brancati FL, Duncan BB, Chambless LE, McGovern PG. Nontraditional risk factors for coronary heart disease incidence among persons with diabetes: the Atherosclerosis Risk in Communities (ARIC) Study Ann Intern Med. 2000;133(2):81–91
56. . American Diabetes Association. Consensus development conference on the diagnosis of coronary heart disease in people with diabetes: 10-11 February 1998, Miami, Florida Diabetes Care. 1998;21(9):1551–9
57. Smith SC Jr, Greenland P, Grundy SM. AHA Conference Proceedings: Prevention conference V: beyond secondary prevention: identifying the high-risk patient for primary prevention: executive summary: American Heart Association Circulation. 2000;101:111–6
58. Reiber GE, Vileikyte L, Boyko EJ, del Aguila M, Smith DG, Lavery LA, et al Causal pathways for incident lower-extremity ulcers in patients with diabetes from two settings Diabetes Care. 1999;22:157–62
59. Apelqvist J, Larsson J. What is the most effective way to reduce incidence of amputation in the diabetic foot? Diabetes Metab Res Rev. 2000;16(Suppl.1):S75–S83
60. . American Diabetes Association. Consensus Development Conference on Diabetic Foot Wound Care: 7-8 April 1999, Boston, Massachusetts Diabetes Care. 1999;22:1354–60
61. Caballero E, Frykberg RG. Diabetic foot infections J Foot Ankle Surg. 1998;37:248–55