Diabetes mellitus type 2

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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 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]

Impaired glucose metabolism refers to impaired fasting glucose and impaired glucose tolerance.

Clinical practice guidelines address the care of patients with diabetes mellitus type 2.[4]

Prevalence

United States

Prevalence of Diagnosed and Undiagnosed Diabetes Among People Aged 20 Years or Older, United States, 2007 [5]

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%


(PD) Image: National Diabetes Information Clearinghouse. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
See: [1] and [2]

Etiology

Diabetes mellitus type 2 is characterized by insulin resistance, high insulin levels, and declining function of insulin-secreting cells of the pancreatic islets (beta-cells).

Diabetes mellitus type 2 is associated with the Metabolic syndrome X (Abdominal obesity-metabolic syndrome).[6]

Genetics

Diabetes mellitus type 2 is genetically heterogeneous and variations are labeled NIDDM2, NIDDM3, NIDDM4.[7]

Maturity-onset diabetes of the young (MODY)

Maturity-onset diabetes of the young (MODY) is "an autosomal dominant form of diabetes typically occurring before 25 years of age and caused by primary insulin secretion defects. Despite its low prevalence, MODY is not a single entity but represents genetic, metabolic, and clinical heterogeneity"[8] Several mutations may cause MODY and these variations are labeled MODY1, MODY2, ... MODY9. Because these mutations may cause diabetes at a later ge and other conditions can cause early diabetes, it has been suggestions to label these mutations "autosomal dominant noninsulin-dependent."[9]

Diagnosis

The World Health Organization definition of diabetes is for a single raised glucose reading with symptoms, otherwise raised values on two occasions, of either[10]:

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

An alternative algorithm that diagnoses diabetes with high sensitivity and specificity:[11]

  • Fasting plasma glucose ≥ 7.0mmol/l (126mg/dl)
    • Diabetes is diagnosed
or

Glycosylated hemoglobin A

HbA1c levels 5.5% may rule out while levels 7.0% may rule in diabetes.[12]

Regarding a single cutoff, a glycosylated hemoglobin A value of ≥ 6.5% may be used to diagnose.[13][14]

Impaired fasting glucose

Impaired fasting glucose is defined as:[10][15]

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

Impaired glucose tolerance

Impaired glucose tolerance is defined as[10][15]:

Screening and prevention

A cost-benefit analysis suggests that screening should start between age 30 and 45 and be repeated every 3 to 5 years.[16]

Clinical practice guidelines

US Preventive Services Task Force

Regarding the mass screening for diabetes, in 2014 the U.S. Preventive Services Task Force draft recommendations were:[17]

  • Appropriate tests are "measuring hemoglobin A1c or fasting plasma glucose or with an oral glucose tolerance test"
  • Regarding who to screen: "Risk factors include age of 45 years or older, overweight or obesity, or a first-degree relative with diabetes. Women with a history of gestational diabetes or polycystic ovarian syndrome are also at increased risk. Certain racial/ethnic minorities, including African Americans, American Indians/Alaska Natives, Asian Americans, Hispanics/Latinos, and Native Hawaiians/Pacific Islanders, are also at increased risk compared with whites."
  • Regarding confirmation of positive screening: "The diagnosis of IFG, IGT, and type 2 diabetes must be confirmed unless symptoms are present. Repeat testing using the same test on a different day is the preferred method of confirmation. If diagnosis cannot be confirmed by the results of two tests, but at least one test indicates high risk, clinicians may wish to follow the patient closely and retest in 3 to 6 months"
  • Regarding rescreening: "every 3 years may be a reasonable approach for adults at low risk with normal blood glucose levels. For adults at high risk or those who have near abnormal test values, repeat annual screening may be warranted."
Prior recommendations

In 2008 the U.S. Preventive Services Task Force concluded:[18] [19]

  • "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.[20]

In 2003, U.S. Preventive Services Task Force concluded that the benefits are:[21][22]

  • 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.[23]

The USPSTF recommended:

  • "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.

Canadian Task Force on Preventive Health Care

The Canadian Task Force on Preventive Health Care recommends:[24] Based on Finnish Diabetes Risk Score else Canadian Diabetes Risk Assessment Questionnaire], frequency of screening with glycosylated hemoglobin A:

Other practice guidelines

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".[25]

The American College of Endocrinology announced in 2008 clinical practice guidelines for the treatment of prediabetes.[26]

Accuracy of tests for early detection

Various testing strategies are available[27][28], including [[clinical prediction rule]s].[29][30]

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[22]:

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.[33][34] 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:

Glycosylated hemoglobin A values are not perfect.[35]

Clinical prediction rule

A clinical prediction rule based on age, gender, family medical history, hypertension, body mass index, and physical activity predicted diabetes with accuracy of:[29]

A second clinical prediction rule, QDSCORE®, may "predict the 10-year risk of developing Type 2 diabetes in the UK".[30]

Benefit of early detection

Major randomized controlled trials (RCTs) and meta-analyses of RCTs for
the prevention of diabetes mellitus type 2[36][37][38][39][40][41][42][43][44][45][46]
Study/year Population Intervention Comparison Outcomes Results
ADDITION-Europe Study
2011[36]
Cluster trial		 3057 patients
• Diabetes diagnosed by mass screening		 Multifactorial interventions aimed at:
• Health care providers
• Patients		 Usual care • Glycosylated hemoglobin A
• Clinical endpoints		 Hazard ratio 0.83, statistically insignificant
NAVIGATOR Study
2010[37]		 9306 patients
• Impaired glucose tolerance
• Coronary heart disease or risk factors		 Valsartan up to 160 mg daily for five years Placebo Diagnosis of diabetes mellitus type 2 "relative reduction of 14% in the incidence of diabetes but did not reduce the rate of cardiovascular events"
NAVIGATOR Study
2010[38]		 9306 patients
• Impaired glucose tolerance
• Coronary heart disease or risk factors		 Nateglinide up to 60 mg three times daily for five years Placebo Diagnosis of diabetes mellitus type 2 "did not reduce the incidence of diabetes or the coprimary composite cardiovascular outcome"
Finnish Diabetes Prevention Study
2001[39]
2006[40]		 522 patients
• 40 to 65 years old
• BMI at least 25
• Impaired glucose tolerance		 Lifestyle changes for 3.2 years:
• diet
• exercise		 General information about diet and exercise at given at base line and annually Diagnosis of diabetes mellitus type 2 "Type 2 diabetes can be prevented by changes in the lifestyles of high-risk subjects"[39]
• "Lifestyle intervention in people at high risk for type 2 diabetes resulted in sustained lifestyle changes and a reduction in diabetes incidence, which remained after the individual lifestyle counseling was stopped."[40]
Diabetes Prevention Program (DPP)
2002[47][41][42]		 3234 patients
• 30 or more years old
• Impaired glucose tolerance or impaired fasting glucose
 Metformin (850 mg twice daily) for 2.8 years Placebo • Death or diagnosis of diabetes mellitus type 2[41]
• Vascular disease events[42]		 • "Lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk"
• Did not reduce vascular disease
STOP-NIDDM
2003[43]		 1429 patients
• 40 to 70 more years old
• Impaired glucose tolerance
• BMI 25 - 40		 Acarbose 100 mg of acarbose 3 times a day Placebo Vascular disease events "This study suggests that treating IGT patients with acarbose is associated with a significant reduction in the risk of cardiovascular disease and hypertension"
DREAM
2006[44]		 5269 patients
• 30 or more years old
• Impaired glucose tolerance or impaired fasting glucose
 Rosiglitazone (8 mg per day) for 3 years Placebo • Death or diagnosis of diabetes mellitus type 2
• Vascular disease events
• Carotid ultrasonography (results not reported)[48]
• "Rosiglitazone at 8 mg daily for 3 years substantially reduces incident type 2 diabetes and increases the likelihood of regression to normoglycaemia"
• Rosiglitazone did not significantly decrease death
• Rosiglitazone increased heart failure
• Rosiglitazone did not reduce vascular disease
DREAM
2006[44]		 5269 patients
• 30 or more years old
• Impaired glucose tolerance or impaired fasting glucose
 Ramipril (up to 15 mg per day) for 3 years Placebo Death or diagnosis of diabetes mellitus type 2
• Vascular disease events		 "ramipril for 3 years does not significantly reduce the incidence of diabetes or death but does significantly increase regression to normoglycemia"
Salpeter meta-analysis
2008[45]		 4570 patients in 31 randomized controlled trials including Diabetes Prevention Program Research Group[41] Metformin Placebo or no treatment Varioius outcomes Metformin treatment in persons at risk for diabetes improves weight, lipid profiles, and insulin resistance, and reduces new-onset diabetes by 40%.
Voglibose Ph-3 Study
2009[46]		 1780 patients
• 30 to 70 years old
• Impaired glucose tolerance
• At least one risk factor for diabetes		 Voglibose 0.2 mg three times a day orally Placebo Diagnosis of diabetes mellitus type 2 "Voglibose, in addition to lifestyle modification, can reduce the development of type 2 diabetes in high-risk Japanese individuals with impaired glucose tolerance."

Treatment

Treatment goals

Remission

In selected patients, dieting to loose approximately 3% of body weight can remit mild, assymptomatic diabetes in approximately 50% of patients according to one trial.[49]

Intensive insulin treatment with a goal of normoglycaemia can cause diabetes in newly diagnosed patients to remit in one of four patients after one year of follow-up.[50] However, there was no control group that did not receive intensive therapy.

Prior uncontrolled cases series have reported similar results.[51][52][53][54]

These studies have been summaried by Retnakaran.[55]

Chronic care of outpatients

For most patients the goal of treatment should be a Hb A1c of 7.0%. The benefit of intensive therapy is not certain.[56] Below is a summary of clinical practice guidelines and randomized controlled trials that support this recommendation.

In older patients with life expectancy of less than 5 years:

Practice guidelines

For most patients, clinical practice guidelines recommend a goal Hb A1c of 7.0%[59][60][61].

Previously the American Diabetic Association (ADA) clinical practice guideline suggested a goal of 6.0%:[62]

  • "The A1C goal for patients in general is an A1C goal of <7%."
  • "The A1C goal for the individual patient is an A1C as close to normal (<6%) as possible without significant hypoglycemia."

The current ADA recommendation is from a consensus statement of 7% following the results of the trials below that suggest no benefit from goals below 7%.[63]

Clinical practice guidelines by the National Institute for Health and Clinical Excellence recommend starting metformin or a sulfonylurea is Hb A1c is more than 6.5%; however, a thiazolidinedione or insulin should not be added unless the Hb A1c is more than 7.5%.[64][65] These guidelines have been summarized.[66]

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."[67]

Evidence from trials
(CC) Photo: Robert Badgett
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 goal fasting blood glucose of below 108 mg/dl (6 mmol/L) over 10 years resulting in an Hb A1c of 7% over 10 years was found in the United Kingdom Prospective Diabetes Study (UKPDS 33) randomized controlled trial. Intensive control reduced diabetic complications in one out of every 20 patients (number needed to treat = 20).[68]

A goal fasting blood glucose of below 108 mg/dl (6 mmol/L) over 10 years resulting in an Hb A1c of 7.4% over 10.7 years in the metformin group compared to 8.0% in the conventional group in the UK Prospective Diabetes Study (UKPDS 34) randomized controlled trial. Metformin reduced cardiovascular disease in one out of every 11 patients (number needed to treat = 11).[69]

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.[70] Although the treatment group averaged an Hb A1c of 6.9%, the goal was 6.0%.[71]

A Hb A1c goal of 6.5% over 5 years was found in the ADVANCE randomized controlled trial not to reduce mortality using a protocol whose first step was a sulfonylurea (gliclazide). The intervention group had 0.9% less nephropathy, but more severe hypoglycemia.[72]

A Hb A1c goal of 6% over 3.5 years was found in the ACCORD randomized controlled trial found to increase serious complications.[73][74]

The ORIGIN trial used basal insulin supplementation to reduce the Hb A1c from 6.4% to 6.2%. There was no benefit on cardiac outcomes but there was an increase in hypoglycemia and weight gain.[75]

The PROACTIVE study used pioglitazone.[76]

The older University Group Diabetes Program (UGDP) also found no benefit in a controversial randomized controlled trial.[77][78][79][80][81] The UGDP randomized approximately 1000 patients to one of five treatment groups and followed from 1962 to 1975: phenformin, tolbutamide, small fixed-dose insulin (ISTD) based on body-surface area (averaged 14 units per day), variable-dose insulin (ISTD) (averaged 45 units per day), n (IVAR), or placebo. The trial found statistically significant increase in cardiovascular deaths among the patients treated with tolbutamide and so this group was stopped in 1969. The phenformin group was also stopped early due to increased mortality. The ISTD group had no reduction in blood glucose. The IVAR group had a reduction in the IVAR group of about 2.0 mmol/L (36 mg/dL) which correlates to a 1% difference in the level of Hb A1c.[82] Problems in the trial include: 1) "25% of placebo and tolbutamide-treated subjects dropped out or changed medication during the trial[79], 2) glucose values were only checked quarterly[80], 3) smoking history was not measured[80] 4) reduced fraction of males in the IVAR group (IVAR=22%; placebo=31%).

Inpatients

Clinical practice guidelines are available by the American College of Physicians (ACP) and a consensus group[83] are available. The ACP recommends:[84]

  1. "ACP recommends not using intensive insulin therapy to strictly control blood glucose in non–surgical intensive care unit (SICU)/medical intensive care unit (MICU) patients with or without diabetes mellitus (Grade: strong recommendation, moderate-quality evidence)."
  1. "ACP recommends not using intensive insulin therapy to normalize blood glucose in SICU/MICU patients with or without diabetes mellitus (Grade: strong recommendation, high-quality evidence)."
  1. "ACP recommends a target blood glucose level of 7.8 to 11.1 mmol/L (140 to 200 mg/dL) if insulin therapy is used in SICU/MICU patients (Grade: weak recommendation, moderate-quality evidence)."

This recommendation was updated without changes in 2013.[85]

Intensive care
For more information, see: Intensive care#Glucose control.

Two clinical practice guidelines are available; however, both of these guidelines were developed without broad representation of stakeholders.[86] 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:[87]

  • "Critically ill patients, between 80 to 110 mg/dL (grade A recommendation)"

A clinical practice guideline from the American Diabetes Association (ADA) states[61]

  • "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)"

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.[88]

Since the meta-analysis, two negative randomized controlled trials have been published.[89][90]

Non-intensive care

Two clinical practice guidelines are available; however, both of these guidelines were developed without broad representation of stakeholders.[86] This may lead to overly aggressive clinical recommendations. A meta-analysis has addressed this issue.[91]

A clinical practice guideline from the American Association of Clinical Endocrinologists (AACE) recommends the following target blood glucose levels:[87]

  • "Preprandial, less than 110 mg/dL (grade C recommendation)"
  • "Peak postprandial, less than 180 mg/dL (grade B recommendation)"

A clinical practice guideline from the American Diabetes Association (ADA) states[61]

  • "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)"
Intraoperative care

Regarding [[perioperative care|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."[92]

Pediatrics

Lower blood sugars may be beneficial in the intensive care of children.[93]

Self monitoring of blood glucose

It is unclear if self-monitoring of blood glucose improves outcomes[94], especially among "reasonably well controlled non-insulin treated patients with type 2 diabetes."[95] Self-monitoring may reduce quality of life.[96]

Diet

A low glycemic index diet may reduce the HbA1c.[97]

Available classes of antidiabetic drugs

Sulfonylureas

For more information, see: Sulfonylureas.

Sulfonylureas are insulin secretagogues. They cause weight gain.

  • Glipizide is mainly excreted by the liver
  • Glyburide is excreted by both liver and kidneys.

Meglitinides

Meglitinides stimulate insulin release. Examples include nateglinide, repaglinide, and their analogs. These are associated with weight gain.[98]

Biguanides

Biguanides are insulin sensitizers and include metformin and phenformin.

SGLT2 inhibitors

SGLT2 inhibitors (Gliflozin) inhibit renal sodium-glucose transport protein 2 (SGLT2)leading reduced reabsorption of glucose in the kidney. Examples include dapagliflozin, empagliflozin, canagliflozin.

Thiazolidinediones

Thiazolidinediones (TZDs) are insulin sensitizers and include rosiglitazone, pioglitazone, and troglitazone. Rosiglitazone is safer than pioglitazone according to a systematic review published in 2011.[99]

α-glucosidase inhibitors

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

Peptide analogs

In general, these do not cause weight gain.[98]

Incretin therapy can reduce the glycosylated hemoglobin[100] but may increase cancer[101][102] and pancreatitis[101].

  • Incretin mimetics. Incretin is an insulin secretagogue.
    • Glucagon-like peptide (GLP) analogs (subcutaneous administration)
      • Exenatide (Byetta®,Bydureon®) which can be given twice daily (Byetta®) or once weekly (Bydureon®).[103]
      • Liraglutide (Victoza®) may be more effective than the peptide analog sitagliptin because GLP-1 receptor agonists do not rely on endogenous incretin secretion that DPP-4 inhibitors require.[104]
    • Gastric inhibitory peptide (GIP) analogs
      • None are FDA approved
  • Incretin enhancement by dipeptidyl peptidase-4 (DPP-4) inhibitors[105]
    • Alogliptin (SYR-322) is an oral inhibitor of DPP-4[106]
    • Saxagliptin (Onglyza®) is taken orally
    • Sitagliptin (Januvia®) is taken orally

Amylin therapy

Insulins

For more information, see: insulin.


Selecting an antidiabetic drug

Oral drugs

If dietary changes are not successful, medication is needed.

Metformin is usually the first drug according to clinical practice guidelines.[59] Metformin and second-generation sulfonylureas and are excellent choices according to a systematic review of randomized controlled trials.[107] 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."[108] While thiazolidinediones such as rosiglitazone are effective, they may increase drug toxicity such as heart failure and fractures.

For patients with heart failure, metformin may be the best choice.[109]

Insulin regimens

If antidiabetic drugs fail, insulin therapy may be necessary. The initial insulin regimen can be chosen based on the patient's blood glucose profile.[110] When insulin is started, "insulin secretagogues (sulfonylurea or glinides) should be discontinued, or tapered and then discontinued, since they are not considered to be synergistic."[59]

Bedtime insulin

Initially, adding bedtime insulin to patients failing oral medications is more effective and with less weight gain than using multiple dose insulin.[111] Nightly insulin combines better with metformin that with sulfonylureas.[112] 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.[113]

Multiple dose insulin

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.[111][112] 4 units can be added for each 18 mg/dl over 180 mg/dl.[111] A typical final dose is about 45 units per day.[111] More complicated estimations to guide initial dosage of insulin are:[114]

  • 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.[115][116][117]. 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".[116] A guide to titrating fixed ratio insulin is available (http://www.annals.org/cgi/content/full/145/2/125/T4).[110]

Treatment of associated diseases

Treating to a goal of LDL-C < 70 mg/dl and systolic blood pressure to < 115 mm Hg may cause regression of carotid initial media thickness in a randomized controlled trial.[121]

Aspirin

Aspirin may not be justified just because a patients had diabetes.[122]

Angiotensin-converting enzyme inhibitors

The HOPE study suggests that diabetics should be treated with angiotensin-converting enzyme inhibitors (specifically ramipril 10 mg/d) if they have one of the following [123]:

After treatment with ramipril for 5 years the number needed to treat was 50 patients to prevent one cardiovascular death.

Initially, other angiotensin-converting enzyme inhibitors were thought to be not be as effective.[124] However, subsequent studies have shown the apparent benefit of ramipril independent of blood pressure reduction was more likely due to the administration of ramipril at night and recording blood pressures during the day when the least effect of ramipril was present.[125][126]

Hypertension

Randomized controlled trials of treating hypertension in patients with diabetes mellitus type 2[127][128]
Trial Population Intervention Comparison Outcome Comments
ACCORD[127]
2010		 4,733 patients Systolic pressure goal of less than 120 mm Hg for 4.7 years Systolic pressure goal of less than 140 mm Hg Mortality Insignificantly increased
ADVANCE[128]
2007		 11,140 patients Fixed combination of perindopril and indapamide that achieved blood pressure of 136/73 for 4.3 years Achieved blood pressure of 130/73 Mortality Significantly reduced

According to clinical practice guidelines, when treating hypertension in the diabetic patients, the goal blood pressure is 130/80 which is lower than in non-diabetic patients.[129] However, a subsequent randomized controlled trial found no benefit in treating to a level of 120 mm Hg.[127]

"In subjects with type 2 diabetes and hypertension but with normoalbuminuria, the use of trandolapril plus verapamil and trandolapril alone decreased the incidence of microalbuminuria to a similar extent. The effect of verapamil alone was similar to that of placebo," according to the BENEDICT randomized controlled trial.[130]

Hypercholesterolemia

Various clinical practice guidelines have addressed the treatment of hypercholesterolemia. The American College of Physicians has addressed hypercholesterolemia in patients with diabetes [131][132]. 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")[132].
  • 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).[133]

Whether diabetes is an equivalent risk factor to having an existing myocardial infarction is debated.[134]

Treating to a goal of LDL-C < 70 mg/dl and systolic blood pressure to < 115 mm Hg may cause regression of carotid initial media thickness in a randomized controlled trial.[135]

Obesity

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).[136] In this trial 73% of the patients who remitted their diabetes versus 13% of the patients in the control group.

Complications

Hypoglycemia

For more information, see: Hypoglycemia.

Hypoglycemia from intensive therapy is associated with cardiovascular adverse outcomes.[137]

Diabetic foot

For more information, see: Diabetic foot.


Neuropathy

For more information, see: Diabetic neuropathy.


Nephropathy

Hyperglycemic hyperosmolar nonketotic coma

For more information, see: Hyperglycemic hyperosmolar nonketotic coma.


Diabetic ketoacidosis

For more information, see: Diabetic ketoacidosis.


References

  1. ↑ Anonymous (2024), Diabetes Mellitus, Type 2 (English). Medical Subject Headings. U.S. National Library of Medicine.
  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. ↑ American Diabetes Association (2011). "Standards of medical care in diabetes--2011.". Diabetes Care 34 Suppl 1: S11-61. DOI:10.2337/dc11-S011. PMID 21193625. PMC PMC3006050. Research Blogging.
  5. ↑ National Diabetes Information Clearinghouse. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). (2007) National Diabetes Statistics, 2007.
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  118. ↑ Horvath K, Jeitler K, Berghold A, Ebrahim Sh, Gratzer T, Plank J, Kaiser T, Pieber T, Siebenhofer A (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.
  119. ↑ Esposito K, Ciotola M, Maiorino MI, et al. (October 2008). "Addition of neutral protamine lispro insulin or insulin glargine to oral type 2 diabetes regimens for patients with suboptimal glycemic control: a randomized trial". Ann. Intern. Med. 149 (8): 531–9. PMID 18936501. [e]
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  135. ↑ 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.
  136. ↑ 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).
  137. ↑ Zoungas S, Patel A, Chalmers J, de Galan BE, Li Q, Billot L et al. (2010). "Severe hypoglycemia and risks of vascular events and death.". N Engl J Med 363 (15): 1410-8. DOI:10.1056/NEJMoa1003795. PMID 20925543. Research Blogging.

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