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Diabetes mellitus type 2 is a "subclass of diabetes mellitus that is characterized initially by insulin resistance and hyperinsulinemia; and eventually by glucose intolerance; hyperglycemia; and overt diabetes. Type II diabetes mellitus is no longer considered a disease exclusively found in adults. Patients seldom develop ketosis but often exhibit obesity."[1]

The U.S. Centers for Disease Control and Prevention provides a slightly more expanded description:[2]

Type 2 diabetes was previously called non–insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes. In adults, type 2 diabetes accounts for about 90% to 95% of all diagnosed cases of diabetes. It usually begins as insulin resistance, a disorder in which the cells do not use insulin properly. As the need for insulin rises, the pancreas gradually loses its ability to produce it. Type 2 diabetes is associated with older age, obesity, family history of diabetes, history of gestational diabetes, impaired glucose metabolism, physical inactivity, and race/ethnicity. African Americans, Hispanic/Latino Americans, American Indians, and some Asian Americans and Native Hawaiians or Other Pacific Islanders are at particularly high risk for type 2 diabetes and its complications. Type 2 diabetes in children and adolescents, although still rare, is being diagnosed more frequently among American Indians, African Americans, Hispanic/Latino Americans, and Asians/Pacific Islanders. [3]

Prevalence in United States

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Prevalence of Diagnosed and Undiagnosed Diabetes Among People Aged 20 Years or Older, United States, 2007 [4]

Category
Number of People Affected
Percent of All People on Category Affected
Age 20 years or older
23.5 million
10.7%
Age 60 years or older
12.0 million
23.1%
Men
12.0 million
11.2%
Women
11.5 million
10.2%
Non-Hispanic whites
14.9 million
9.8%
Non-Hispanic blacks
3.7 million
14.7%


See: [1] and [2]

Diagnosis

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The World Health Organization definition of diabetes is for a single raised glucose reading with symptoms, otherwise raised values on two occasions, of either[5]:

  • fasting plasma glucose ≥ 7.0mmol/l (126mg/dl)
or

 ♦ Impaired fasting glucose

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Impaired fasting glucose is defined as:[5][6]

  • Fasting glucose level > 5.6 mmol/l (100 mg/dl) and < 6.9 mmol/l (125mg/dl).

 ♦ Impaired glucose tolerance

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Impaired glucose tolerance is defined as[5][6]:

Screening and prevention

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Regarding the mass screening for diabetes, in 2008 the US Preventive Services Task Force concluded:[7] [8]

  • " Screen for type 2 diabetes in asymptomatic adults with sustained blood pressure (either treated or untreated) greater than 135/80 mm Hg. (B recommendation)"
  • "Current evidence is insufficient to assess the balance of benefits and harms of routine screening in asymptomatic adults with blood pressure of 135/80 mm Hg or lower. (I statement)"

Screening obese patients may also be beneficial.[9]

Prior guidelines

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In 2003, US Preventive Services Task Force concluded:[10][11]

  • "The USPSTF recommends screening for type 2 diabetes in adults with hypertension or hyperlipidemia." This was a grade B recommendation
  • "The evidence is insufficient to recommend for or against routinely screening asymptomatic adults for type 2 diabetes, impaired glucose tolerance, or impaired fasting glucose" (italics by CZ), this was a grade I recommendation when published in 2003.

Accuracy of tests for early detection

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Various testing strategies are available[12][13], including a clinical prediction rule.[14]

Fasting plasma glucose

The fasting plasma glucose > 7.0 mmol/L (126 mg/dL), compared to a 2-hour postload glucose level of at least 11.1 mmol/L (≥ 200 mg/dL) as a reference standard, has[11]:

Random capillary blood glucose

A random capillary blood glucose > 6.7 mmol/L (120 mg/dL) has:

Glycosylated hemoglobin

Glycosylated hemoglobin A (Hb A1c) values that are elevated (over 5%), but not in the diabetic range (not over 7.0%) are predictive of subsequent clinical diabetes in US female health professionals.[17] In this study, 177 of 1061 patients with Hb A1c value less than 6% became diabetic within 5 years compared to 282 of 26281 patients with a Hb A1c value of 6.0% or more. This equates to a Hb A1c value of 6.0% or more having:

Benefit of early detection

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According to the US Preventive Services Task Force[10][11], the benefits are:

  • In hypertensive patients, identifying diabetes would lower the goal diastolic pressure to ≤ 80 mm Hg.
  • In hypercholesterolemia patients, identifying diabetes would affect decision making due to changes in calculating cardiovascular risk in the ATP3 clinical practice guideline.[18]

The American College of Endocrinology recently announced guidelines for the treatment of prediabetes.[19]

Since publication of the USPSTF statement, a randomized controlled trial of prescribing acarbose to patients who do not have overt diabetes, but are a "high-risk population of men and women between the ages of 40 and 70 years with a body mass index (BMI), calculated as weight in kilograms divided by the square of height in meters, between 25 and 40. They were eligible for the study if they had IGT according to the World Health Organization criteria, plus impaired fasting glucose (a fasting plasma glucose concentration of between 100 and 140 mg/dL or 5.5 and 7.8 mmol/L) found a number needed to treat of 44 (over 3.3 years) to prevent a major cardiovascular event[20].

Subsequently in 2005, an evidence report by the Agency for Healthcare Research and Quality (AHRQ) concluded that "there is evidence that combined diet and exercise, as well as drug therapy (metformin, acarbose), may be effective at preventing progression to DM in IGT subjects".[21]

Life-style changes[22] can delay the onset of diabetes. Life-style changes can reduce cardiovascular risk factors.[23]


Metformin can improve "weight, lipid profiles, and insulin resistance, and reduces new-onset diabetes by 40%." according to a meta-analysis.[24] The meta-analysis also concluded that "the long-term effect on morbidity and mortality should be assessed in future trials."[24] This meta-analysis includes an earlier randomized controlled trial that found that metformin can delay the onset of diabetes[25].

The DREAM study has reported that rosiglitazone[26] but not ramipril[27] can delay the onset of diabetes. Although the DREAM study performed carotid ultrasounds on 20% of patients, these results have not been reported.[28]

Treatment

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Treatment goals

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Remission

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An initial randomized controlled trial found that intensive insulin treatment with a goal of normoglycaemia can cause diabetes to remit in one of four patients after one year of follow-up.[29]

Chronic care of outpatients

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For most patients the goal of treatment should be a Hb A1c of 7.0%. Below is a summary of clinical practice guidelines and randomized controlled trials that support this recommendation.

Practice guidelines
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For most patients, clinical practice guidelines recommend a goal Hb A1c of 7.0%[30][31]. Previously the American Diabetic Association has suggested a goal of 6.0%[32] but their current recommendation of 7% is align with the more recent ACCORD trial that targeted 6% (see below) has halted early due to increased harm in the intervention group.[33]

Clinical practice guidelines by the National Institute for Health and Clinical Excellence recommend a goal Hb A1c of 7.5%.[34][35] These guidelines have been summarized.[36]

In older patients, clinical practice guidelines by the American Geriatrics Society states "for frail older adults, persons with life expectancy of less than 5 years, and others in whom the risks of intensive glycemic control appear to outweigh the benefits, a less stringent target such as 8% is appropriate."[37]

Evidence from trials
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Forest Plot showing meta-analysis of randomized controlled trials of differing target glucose control and mortality for diabetes mellitus type 2. Note the heterogeneity due to increased death when the glycosylated hemoglobin A (Hb A1c) target was 6.0% in the ACCORD trial

A Hb A1c goal of 7% over 10 years was found in the UK Prospective Diabetes Study (UKPDS 33) randomized controlled trial to reduce diabetic complications in one out of every 20 patients (number needed to treat = 20).[38]

A Hb A1c of 6.9% over 6 years was found in the VA Diabetes Trial (VADT) randomized controlled trial to have no significant effect on diabetic complications.[39] Although the treatment group averaged an Hb A1c of 6.9%, the goal was 6.0%.[40]

A Hb A1c goal of 6.5% over 5 years was found in the ADVANCE randomized controlled trial not to reduce mortality. The intervention group had 0.9% less nephropathy, but more severe hypoglycemia.[41]

A Hb A1c goal of 6% over 3.5 years was found in the ACCORD randomized controlled trial found to increase serious complications.[33][42]

Inpatients

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Practice guidelines
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Two clinical practice guidelines are available; however, both of these guidelines were developed without broad representation of stakeholders.[43] This may lead to overly aggressive clinical recommendations.

A clinical practice guideline from the American Association of Clinical Endocrinologists (AACE) recommends the following target blood glucose levels:[44]

  • "Preprandial, less than 110 mg/dL (grade C recommendation)"
  • "Peak postprandial, less than 180 mg/dL (grade B recommendation)"
  • "Critically ill patients, between 80 to 110 mg/dL (grade A recommendation)"

A clinical practice guideline from the American Diabetes Association (ADA) states[31]

  • "Critically ill patients: blood glucose levels should be kept as close to 110 mg/dl (6.1 mmol/l) as possible and generally <140 mg/dl (7.8 mmol/l). (A) These patients require an intravenous insulin protocol that has demonstrated efficacy and safety in achieving the desired glucose range without increasing risk for severe hypoglycemia. (E)"
  • "Non–critically ill patients: there is no clear evidence for specific blood glucose goals. Since cohort data suggest that outcomes are better in hospitalized patients with fasting glucose <126 mg/dl and all random glucoses <180–200, these goals are reasonable if they can be safely achieved. Insulin is the preferred drug to treat hyperglycemia in most cases. (E)"
  • "Due to concerns regarding the risk of hypoglycemia, some institutions may consider these blood glucose levels to be overly aggressive for initial targets. Through quality improvement, glycemic goals should systematically be reduced to the recommended levels. (E)"

Older versions (2007) of these clinical practice guidelines were more aggressive regarding non-critically ill patients:

  • "Non-critically ill patients: premeal blood glucose levels should be kept as close to 90 to 130 mg/dL (5.0 to 7.2 mmol/L; midpoint of range 110 mg/dL) as possible given the clinical situation and postprandial blood glucose levels <180 mg/dL. Insulin should be used as necessary. (E)"
Evidence from trials
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Adults

Randomized controlled trials of tight glucose control in the critical care and perioperative care settings have produced mixed results. A meta-analysis of trials in the critical care setting concludes there is no benefit to tight control.[45]

Since the meta-analysis, an additional negative randomized controlled trial has been published.[46]

Regarding surgical patients in a critical care setting, a large randomized controlled trial (1548 patients) concluded "intensive insulin therapy to maintain blood glucose at or below 110 mg per deciliter reduces morbidity and mortality among critically ill patients in the surgical intensive care unit."[47] However, other trials have not found this benefit according to a meta-analysis.[48] This trial has been criticized for the following reasons:[48]

  1. "The trial was stopped early for an unexpectedly large treatment effect, which can overestimate the efficacy of treatment or result in a false-positive finding;"
  2. "The relative reduction in mortality for a decrease of 50 mg/dL in morning glucose levels seems biologically implausible and exceeds that for any other intervention in critically ill patients;"
  3. "The mortality rate in the control group was much higher than that noted in tertiary care medical centers in the United States. On admission to the ICU, all patients received 200 to 300 g/d of intravenous dextrose followed by enteral or parenteral nutrition, an unusual practice considering the deleterious effects of parenteral nutrition; at least in part, the difference in outcomes between the 2 arms in this study might have reflected the harm of maintaining the control group as hyperglycemic rather than the benefit of strict glucose control in the intervention group."

Regarding medical patients in a critical care setting, a large randomized controlled trial that compared a goal blood glucose level of 80 to 110 mg per deciliter (4.4 to 6.1 mmol per liter) to a goal blood glucose level of between 180 and 200 mg per deciliter (10 and 11 mmol per liter) concluded "intensive insulin therapy significantly reduced morbidity but not mortality among all patients in the medical ICU. Although the risk of subsequent death and disease was reduced in patients treated for three or more days, these patients could not be identified before therapy."[49] Tight control may protect renal function.[50]

Among medical patients with septic shock, intensive insulin therapy and pentastarch increased adverse events in a randomized controlled trial.[51]

A meta-analysis was published in 2006 that did not include the two trials above that were published later that did not reduce mortality.[52] This meta-analysis concluded that tight control was beneficial in surgical critical care. However, in addition to not including the two more recent negative trials, this meta-analysis overlooked the problems with the largest trial[47] that were noted by the other meta-analysis.[48]

Regarding intraoperative control of glucose, a randomized controlled trial concluded "the increased incidence of death and stroke in the intensive treatment group raises concern about routine implementation of this intervention."[53]

Pediatrics

Lower blood sugars may be beneficial in the intensive care of children.[54]

Self monitoring of blood glucose

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It is unclear if self-monitoring of blood glucose improves outcomes among "reasonably well controlled non-insulin treated patients with type 2 diabetes."[55] Self-monitoring may reduce quality of life.[56]

Diet

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A low glycemic index diet may reduce the HbA1c.[57]

Available classes of antidiabetic drugs

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Sulfonylureas

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Main resource: Sulfonylureas

Sulfonylureas are insulin secretagogues.

Biguanides

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Biguanides are insulin sensitizers and include metformin and phenformin.

Thiazolidinediones

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Thiazolidinediones (TZDs) are insulin sensitizers and include rosiglitazone, pioglitazone, and troglitazone.

α-glucosidase inhibitors

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α-glucosidase inhibitors reduce carbohydrate absorption and include acarbose and miglitol.

Meglitinides

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Meglitinides stimulate insulin release. Examples include nateglinide, repaglinide, and their analogs.

Peptide analogs

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Insulins

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Main resource: insulin

Selecting an antidiabetic drug

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Oral drugs

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If dietary changes are not successful, medication is needed. A systematic review of randomized controlled trials found that metformin and second-generation sulfonylureas and are excellent choices.[59] Confirming the role of metformin, the initial choice of anti-diabetic drug has been compared in a randomized controlled trial which found "cumulative incidence of monotherapy failure at 5 years of 15% with rosiglitazone, 21% with metformin, and 34% with glyburide."[60] Rosiglitazone had more weight gain and edema.[60] Rosiglitazone may increase risk of death from cardiovascular causes.[61] Pioglitazone[62] and rosiglitazone may increase the risk of fractures.[63] Pioglitazone, an insulin sensitizer, may reduce atherosclerosis compared to sulfonylureas which are insulin secretagogues.[64]

For patients with heart failure, metformin may be the best choice.[65]

Insulin regimens

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If antidiabetic drugs fail, insulin therapy may be necessary. The initial insulin regimen can be chosen based on the patient's blood glucose profile.[66]

Bedtime insulin
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Initially, adding bedtime insulin to patients failing oral medications is more effective and with less weight gain than using multiple dose insulin.[67] Nightly insulin combines better with metformin that with sulfonylureas.[68] The initial dose of nightly insulin (measured in IU/d) should be equal to the fasting blood glucose level (measured in mmol/L). If the fasting glucose is reported in mg/dl, multiple by 0.05551 (or divided by 18) to convert to mmol/L.[69]

Multiple dose insulin
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When nightly insulin is insufficient, multiple doses are required.

Typical total daily dosage of insulin is 0.6 U/kg with starting doses of 0.25 U/kg.[67][68] 4 units can be added for each 18 mg/dl over 180 mg/dl.[67] A typical final dose is about 45 units per day.[67] More complicated estimations to guide initial dosage of insulin are:[70]

  • For men, [(fasting plasma glucose [mmol/liter]–5)x2] x (weight [kg]÷(14.3xheight [m])–height [m])
  • For women, [(fasting plasma glucose [mmol/liter]–5)x2] x (weight [kg]÷(13.2xheight [m])–height [m])
  • Premixed insulin with a fixed ratio of short and intermediate acting insulin; this tends to be more effective than long acting insulin, but is associated with more hypoglycemia.[71][72][73]. Initial total daily dosage of biphasic insulin can be 10 units if the fasting plasma glucose values are less than 180 mg/dl or 12 units when the fasting plasma glucose is above 180 mg/dl".[72] A guide to titrating fixed ratio insulin is available (http://www.annals.org/cgi/content/full/145/2/125/T4).[66]

Treatment of associated diseases

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Treating to a goal of LDL-C < 70 mg/dl and systolic blood pressure to < 115 mm Hg may cause regression of carotid intial media thickness in a randomized controlled trial.[75]

ACE inhibitors

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The HOPE study suggests that diabetics should be treated with ACE inhibitors (specifically ramipril 10 mg/d) if they have one of the following [76]:

After treatment with ramipril for 5 years the number needed to treat was 50 patients to prevent one cardiovascular death. Other ACE inhibitors may not be as effective.[77]

Hypertension

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When treating hypertension in the diabetic patients, the goal blood pressure is 130/80 which is lower than in non-diabetic patients.[78]

Hypercholesterolemia

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Various clinical practice guidelines have addressed the treatment of hypercholesterolemia. The American College of Physicians has addressed hypercholesterolemia in patients with diabetes [79]. Their recommendations are:

  • Recommendation 1: Lipid-lowering therapy should be used for secondary prevention of cardiovascular mortality and morbidity for all patients (both men and women) with known coronary artery disease and type 2 diabetes.
  • Recommendation 2: Statins should be used for primary prevention against macrovascular complications in patients (both men and women) with type 2 diabetes and other cardiovascular risk factors.
  • Recommendation 3: Once lipid-lowering therapy is initiated, patients with type 2 diabetes mellitus should be taking at least moderate doses of a statin (the accompanying evidence report states "simvastatin, 40 mg/d; pravastatin, 40 mg/d; lovastatin, 40 mg/d; atorvastatin, 20 mg/d; or an equivalent dose of another statin")[80].
  • Recommendation 4: For those patients with type 2 diabetes who are taking statins, routine monitoring of liver function tests or muscle enzymes is not recommended except in specific circumstances.

Statin therapy prevents major vascular events in about 1 of every 24 patients with [diabetes who use the treatment for 5 years if they are similar to the patients in the meta-analysis by Kearney et al (Number needed to treat is 24).[81]

Treating to a goal of LDL-C < 70 mg/dl and systolic blood pressure to < 115 mm Hg may cause regression of carotid intial media thickness in a randomized controlled trial.[82]

Obesity

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Bariatric surgery remits diabetes mellitus type 2 in more than 1 of every two people after 2 years if they are similar to the patients in the randomized controlled trial / meta-analysis by Dixon et al (Number needed to treat is 1.74).[83] In this trial 73% of the patients who remitted their diabetes versus 13% of the patients in the control group.

Complications

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Diabetic foot

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Main resource: Diabetic foot

Neuropathy

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Main resource: Diabetic neuropathy

Nephropathy

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References

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  1. ↑ Template:MeSH
  2. ↑ National Center for Chronic Disease Prevention and Health Promotion. (2008) What is Diabetes?
  3. ↑ National Center for Chronic Disease Prevention and Health Promotion. (2008) What is Diabetes?
  4. ↑ National Diabetes Information Clearinghouse. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). (2007) National Diabetes Statistics, 2007.
  5. ↑ 5.0 5.1 5.2 .World Health Organization. "Definition, diagnosis and classification of diabetes mellitus and its complications: Report of a WHO Consultation. Part 1. Diagnosis and classification of diabetes mellitus". Retrieved 2007-05-29.
  6. ↑ 6.0 6.1 "Diagnosis and classification of diabetes mellitus". Diabetes Care 28 Suppl 1: S37-42. 2005. PMID 15618111. 
  7. ↑ Norris, Susan L.; Devan Kansagara; Christina Bougatsos; Rongwei Fu (2008-06-03). "Screening Adults for Type 2 Diabetes: A Review of the Evidence for the U.S. Preventive Services Task Force". Ann Intern Med 148 (11): 855-868. PMID 18519930. http://www.annals.org/cgi/content/abstract/148/11/855. Retrieved 2008-06-03. 
  8. ↑ Norris, Susan L.; Devan Kansagara; Christina Bougatsos; Rongwei Fu (2008-06-03). "Screening Adults for Type 2 Diabetes: A Review of the Evidence for the U.S. Preventive Services Task Force". Ann Intern Med 148 (11): 855-868. PMID 18519931. http://www.annals.org/cgi/content/abstract/148/11/855. Retrieved 2008-06-03. 
  9. ↑ Hoerger TJExpression error: Unrecognized word "etal". (2007). "Cost-effectiveness of screening for pre-diabetes among overweight and obese U.S. adults". Diabetes Care 30 (11): 2874–9. doi:10.2337/dc07-0885. PMID 17698614. 
  10. ↑ 10.0 10.1 U.S. Preventive Services Task Force (2003). "Screening for type 2 diabetes mellitus in adults: recommendations and rationale". Ann. Intern. Med. 138 (3): 212-4. PMID 12558361. http://www.annals.org/cgi/content/full/138/3/212.  National Guidelines Clearinghouse: Complete Summary Cite error: Invalid <ref> tag; name "pmid12558361" defined multiple times with different content
  11. ↑ 11.0 11.1 11.2 Harris R; Donahue K; Rathore SS; Frame P; Woolf SH; Lohr KN (2003). "Screening adults for type 2 diabetes: a review of the evidence for the U.S. Preventive Services Task Force". Ann. Intern. Med. 138 (3): 215-29. PMID 12558362. http://www.annals.org/cgi/content/full/138/3/215. 
  12. ↑ "Strategies to identify adults at high risk for type 2 diabetes: the Diabetes Prevention Program". Diabetes Care 28 (1): 138–44. 2005. PMID 15616247. 
  13. ↑ Icks AExpression error: Unrecognized word "etal". (2004). "Cost-effectiveness analysis of different screening procedures for type 2 diabetes: the KORA Survey 2000". Diabetes Care 27 (9): 2120–8. PMID 15333472. 
  14. ↑ Heikes KE; Eddy DM; Arondekar B; Schlessinger L (May 2008). "Diabetes Risk Calculator: a simple tool for detecting undiagnosed diabetes and pre-diabetes". Diabetes Care 31 (5): 1040–5. doi:10.2337/dc07-1150. PMID 18070993. http://care.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=18070993. 
  15. ↑ 15.0 15.1 Ziemer DCExpression error: Unrecognized word "etal". (2008). "Random Plasma Glucose in Serendipitous Screening for Glucose Intolerance: Screening for Impaired Glucose Tolerance Study 2". J Gen Intern Med. doi:10.1007/s11606-008-0524-1. PMID 18335280. 
  16. ↑ 16.0 16.1 Rolka DBExpression error: Unrecognized word "etal". (2001). "Performance of recommended screening tests for undiagnosed diabetes and dysglycemia". Diabetes Care 24 (11): 1899-903. PMID 11679454. 
  17. ↑ Pradhan AD; Rifai N; Buring JE; Ridker PM (2007). "Hemoglobin A1c predicts diabetes but not cardiovascular disease in nondiabetic women". Am. J. Med. 120 (8): 720-7. doi:10.1016/j.amjmed.2007.03.022. PMID 17679132. 
  18. ↑ "10-year CVD Risk Calculator (Risk Assessment Tool for Estimating 10-year Risk of Developing Hard CHD (Myocardial Infarction and Coronary Death) Version)". Retrieved 2007-11-14.
  19. ↑ July 23, 2008 Diabetes Experts Recommend One-Two Punch for Treating Patients with Pre-Diabetes. American College of Endocrinology
  20. ↑ Chiasson JL; Josse RG; Gomis R; Hanefeld M; Karasik A; Laakso M (2003). "Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial". JAMA 290 (4): 486-94. doi:10.1001/jama.290.4.486. PMID 12876091.  ACP Journal Club review
  21. ↑ Santaguida PLExpression error: Unrecognized word "etal". (2005). "Diagnosis, prognosis, and treatment of impaired glucose tolerance and impaired fasting glucose". Evidence report/technology assessment (Summary) (128): 1-11. PMID 16194123. http://www.ahrq.gov/clinic/epcsums/impglusum.htm. 
  22. ↑ Lindström J; Ilanne-Parikka P; Peltonen M; Aunola S; Eriksson JG; Hemiö K; Hämäläinen H; Härkönen P et al. (2006). "Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish Diabetes Prevention Study". Lancet 368 (9548): 1673-9. doi:10.1016/S0140-6736(06)69701-8. PMID 17098085. ACP Journal Club review
  23. ↑ Thoolen BExpression error: Unrecognized word "etal". (2007). "Effectiveness of a self-management intervention in patients with screen-detected type 2 diabetes". Diabetes Care 30 (11): 2832–7. doi:10.2337/dc07-0777. PMID 17666461. 
  24. ↑ 24.0 24.1 Salpeter SR; Buckley NS; Kahn JA; Salpeter EE (2008). "Meta-analysis: metformin treatment in persons at risk for diabetes mellitus". Am. J. Med. 121 (2): 149–157.e2. doi:10.1016/j.amjmed.2007.09.016. PMID 18261504. 
  25. ↑ Knowler WC; Barrett-Connor E; Fowler SE; Hamman RF; Lachin JM; Walker EA; Nathan DM (2002). "Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin". N. Engl. J. Med. 346 (6): 393-403. doi:10.1056/NEJMoa012512. PMID 11832527.  ACP Journal Club review
  26. ↑ Gerstein HCExpression error: Unrecognized word "etal". (2006). "Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial". Lancet 368 (9541): 1096–105. doi:10.1016/S0140-6736(06)69420-8. PMID 16997664. 
  27. ↑ Bosch JExpression error: Unrecognized word "etal". (2006). "Effect of ramipril on the incidence of diabetes". N. Engl. J. Med. 355 (15): 1551–62. doi:10.1056/NEJMoa065061. PMID 16980380. 
  28. ↑ Gerstein HC; Yusuf S; Holman R; Bosch J; Pogue J (2004). "Rationale, design and recruitment characteristics of a large, simple international trial of diabetes prevention: the DREAM trial". Diabetologia 47 (9): 1519–27. doi:10.1007/s00125-004-1485-5. PMID 15322749. 
  29. ↑ Weng JExpression error: Unrecognized word "etal". (May 2008). "Effect of intensive insulin therapy on beta-cell function and glycaemic control in patients with newly diagnosed type 2 diabetes: a multicentre randomised parallel-group trial". Lancet 371 (9626): 1753–60. doi:10.1016/S0140-6736(08)60762-X. PMID 18502299. http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(08)60762-X. 
  30. ↑ Qaseem A, Vijan S, Snow V, Cross JT, Weiss KB, Owens DK, et al. Glycemic Control and Type 2 Diabetes Mellitus: The Optimal Hemoglobin A1c Targets. A Guidance Statement from the American College of Physicians. Ann Intern Med. 2007 Sep 18;147(6):417-422. Full text
  31. ↑ 31.0 31.1 American Diabetes Association (January 2008). "Standards of medical care in diabetes--2008". Diabetes Care 31 Suppl 1: S12–54. doi:10.2337/dc08-S012. PMID 18165335. http://care.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=18165335.  Complete summary from National Guidelines Clearinghouse Cite error: Invalid <ref> tag; name "pmid18165335" defined multiple times with different content
  32. ↑ "Standards of medical care in diabetes--2006". Diabetes Care 29 Suppl 1: S4–42. 2006. PMID 16373931. 
  33. ↑ 33.0 33.1 Anonymous (February 6, 2008). "For Safety, NHLBI Changes Intensive Blood Sugar Treatment Strategy in Clinical Trial of Diabetes and Cardiovascular Disease". National Institutes of Health (NIH). Retrieved 2008-02-07.
  34. ↑ Home P; Mant J; Diaz J; Turner C (June 2008). "Management of type 2 diabetes: summary of updated NICE guidance". BMJ 336 (7656): 1306–8. doi:10.1136/bmj.39560.442095.AD. PMID 18535074. PMC 2413390. http://bmj.com/cgi/pmidlookup?view=long&pmid=18535074. 
  35. ↑ "NICE guidance by type". Retrieved 2008-08-26.
  36. ↑ Anonymous. "NICE guidelines for diabetes mellitus, type 2". Daily POEMS. Essential Evidence Plus. Retrieved 2008-08-26.
  37. ↑ Brown AF; Mangione CM; Saliba D; Sarkisian CA (2003). "Guidelines for improving the care of the older person with diabetes mellitus". Journal of the American Geriatrics Society 51 (5 Suppl Guidelines): S265–80. doi:10.1046/j.1532-5415.51.5s.1.x. PMID 12694461. http://www.americangeriatrics.org/products/positionpapers/JAGSfinal05.pdf. 
  38. ↑ "Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group". Lancet 352 (9131): 837–53. 1998. doi:10.1016/S0140-6736(98)07019-6. PMID 9742976.  Review by ACP Journal Club
  39. ↑ "(VADT) Intense Blood Glucose Control Yields no Significant Effect on CVD Reduction in VA Diabetes Trial". American Diabetes Association. June 8, 2008. Retrieved 2008-08-06.
  40. ↑ Abraira CExpression error: Unrecognized word "etal". (2003). "Design of the cooperative study on glycemic control and complications in diabetes mellitus type 2: Veterans Affairs Diabetes Trial". Journal of diabetes and its complications 17 (6): 314–22. PMID 14583175. http://linkinghub.elsevier.com/retrieve/pii/S1056872702002775. 
  41. ↑ "Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes". N. Engl. J. Med. 358 (24): 2560–2572. June 2008. doi:10.1056/NEJMoa0802987. PMID 18539916. http://content.nejm.org/cgi/pmidlookup?view=short&pmid=18539916&promo=ONFLNS19. 
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  43. ↑ Mulrow CD, Lohr KN (April 2001). "Proof and policy from medical research evidence". J Health Polit Policy Law 26 (2): 249–66. PMID 11330080. http://jhppl.dukejournals.org/cgi/pmidlookup?view=long&pmid=11330080. 
  44. ↑ AACE Diabetes Mellitus Clinical Practice Guidelines Task Force (2007). "American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus". Endocr Pract 13 Suppl 1: 1–68. PMID 17613449. http://aace.metapress.com/openurl.asp?genre=article&issn=1530-891X&volume=13%20Suppl%201&issue=&spage=1.  Complete summary from National Guidelines Clearinghouse
  45. ↑ Soylemez Wiener R; Wiener DC; Larson RJ (August 2008). "Benefits and risks of tight glucose control in critically ill adults: a meta-analysis". JAMA 300 (8): 933–44. doi:10.1001/jama.300.8.933. PMID 18728267. http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=18728267. 
  46. ↑ Arabi YMExpression error: Unrecognized word "etal". (December 2008). "Intensive versus conventional insulin therapy: a randomized controlled trial in medical and surgical critically ill patients". Crit. Care Med. 36 (12): 3190–7. doi:10.1097/CCM.0b013e31818f21aa. PMID 18936702. http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?doi=10.1097/CCM.0b013e31818f21aa. 
  47. ↑ 47.0 47.1 van den Berghe GExpression error: Unrecognized word "etal". (2001). "Intensive insulin therapy in the critically ill patients". N. Engl. J. Med. 345 (19): 1359–67. PMID 11794168. http://content.nejm.org/cgi/content/full/345/19/1359. 
  48. ↑ 48.0 48.1 48.2 Gandhi GYExpression error: Unrecognized word "etal". (April 2008). "Effect of perioperative insulin infusion on surgical morbidity and mortality: systematic review and meta-analysis of randomized trials.7". Mayo Clin. Proc. 83 (4): 418–30. PMID 18380987. http://www.mayoclinicproceedings.com/Abstract.asp?AID=4644&Abst=Abstract&UID=. 
  49. ↑ Van den Berghe GExpression error: Unrecognized word "etal". (2006). "Intensive insulin therapy in the medical ICU". N. Engl. J. Med. 354 (5): 449–61. doi:10.1056/NEJMoa052521. PMID 16452557. http://content.nejm.org/cgi/content/full/354/5/449. 
  50. ↑ Schetz M; Vanhorebeek I; Wouters PJ; Wilmer A; Van den Berghe G (2008). "Tight blood glucose control is renoprotective in critically ill patients". J. Am. Soc. Nephrol. 19 (3): 571-8. doi:10.1681/ASN.2006101091. PMID 18235100. http://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=18235100. 
  51. ↑ Brunkhorst FMExpression error: Unrecognized word "etal". (2008). "Intensive insulin therapy and pentastarch resuscitation in severe sepsis". N. Engl. J. Med. 358 (2): 125–39. doi:10.1056/NEJMoa070716. PMID 18184958. 
  52. ↑ Pittas AG; Siegel RD; Lau J (2006). "Insulin therapy and in-hospital mortality in critically ill patients: systematic review and meta-analysis of randomized controlled trials". JPEN J Parenter Enteral Nutr 30 (2): 164–72. PMID 16517961. http://pen.sagepub.com/cgi/pmidlookup?view=long&pmid=16517961. 
  53. ↑ Gandhi GYExpression error: Unrecognized word "etal". (2007). "Intensive intraoperative insulin therapy versus conventional glucose management during cardiac surgery: a randomized trial". Ann. Intern. Med. 146 (4): 233–43. PMID 17310047. http://www.annals.org/cgi/content/full/146/4/233. 
  54. ↑ Vlasselaers et al. (2009) Lancet. Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study. doi:10.1016/S0140-6736(09)60044-1
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  56. ↑ O'Kane, M. J., Bunting, B., Copeland, M., Coates, V. E., & on behalf of the ESMON study group. (2008). Efficacy of self monitoring of blood glucose in patients with newly diagnosed type 2 diabetes (ESMON study): randomised controlled trial. BMJ, bmj.39534.571644.BE. doi:10.1136/bmj.39534.571644.BE
  57. ↑ Jenkins, David J. A.; Cyril W. C. Kendall; Gail McKeown-Eyssen; Robert G. Josse; Jay Silverberg; Gillian L. Booth; Edward Vidgen; Andrea R. Josse et al. (2008-12-17). "Effect of a Low-Glycemic Index or a High-Cereal Fiber Diet on Type 2 Diabetes: A Randomized Trial". JAMA 300 (23): 2742-2753. doi:10.1001/jama.2008.808. http://jama.ama-assn.org/cgi/content/abstract/300/23/2742. Retrieved 2008-12-17. 
  58. ↑ Template:DailyMed
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  74. ↑ Horvath K; Jeitler K; Berghold A; Ebrahim Sh; Gratzer T; Plank J; Kaiser T; Pieber T et al. (2007). "Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus". Cochrane database of systematic reviews (Online) (2): CD005613. PMID 17443605. 
  75. ↑ Howard, B. V., Roman, M. J., Devereux, R. B., Fleg, J. L., Galloway, J. M., Henderson, J. A., et al. (2008). Effect of Lower Targets for Blood Pressure and LDL Cholesterol on Atherosclerosis in Diabetes: The SANDS Randomized Trial. JAMA, 299(14), 1678-1689. doi:10.1001/jama.299.14.1678.
  76. ↑ Yusuf S; Sleight P; Pogue J; Bosch J; Davies R; Dagenais G (2000). "Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators". N. Engl. J. Med. 342 (3): 145-53. PMID 10639539. 
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  82. ↑ Howard, B. V., Roman, M. J., Devereux, R. B., Fleg, J. L., Galloway, J. M., Henderson, J. A., et al. (2008). Effect of Lower Targets for Blood Pressure and LDL Cholesterol on Atherosclerosis in Diabetes: The SANDS Randomized Trial. JAMA, 299(14), 1678-1689. doi:10.1001/jama.299.14.1678.
  83. ↑ John B. Dixon et al., “Adjustable Gastric Banding and Conventional Therapy for Type 2 Diabetes: A Randomized Controlled Trial,” JAMA 299, no. 3 (January 23, 2008).
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Diabetes and your heart

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