Annals of Internal Medicine䊛 In the Clinic®
Type 2 Diabetes
D
iabetes is one of the most common illnesses encountered by internists. Currently, an estimated 29.1 million people in the United States have diabetes, and only 21.0 million of these cases have been diagnosed (1). The incidence of diabetes is increasing because of the aging and changing ethnic mix of the population and because of increasing obesity. Based on current trends, it is expected that the prevalence of diabetes will nearly double by 2050 (2).
Screening and Prevention Diagnosis and Evaluation Treatment Practice Improvement Tool Kit Patient Information
The CME quiz is available at www.annals.org/intheclinic.aspx. Complete the quiz to earn up to 1.5 CME credits.
Physician Writer Sandeep Vijan
CME Objective: To review current evidence for prevention, screening, diagnosis, treatment, and patient information of type 2 diabetes. Funding source: American College of Physicians. Disclosures: Dr. Vijan, ACP Contributing Author, has disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms .do?msNum=M14-2388. With the assistance of additional physician writers, Annals of Internal Medicine editors develop In the Clinic using resources of the American College of Physicians, including ACP Smart Medicine and MKSAP (Medical Knowledge and Self-Assessment Program). © 2015 American College of Physicians
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Although care and complication rates are clearly improving (3), complications are still common, and diabetes is among the leading causes of vision loss, amputation, and end-stage renal disease
in the United States (4). In addition, it is a substantial risk factor for atherosclerotic disease, which is the leading cause of morbidity, mortality, and expenditures in diabetic persons.
Screening and Prevention 1. Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2014 [Internet]. [cited 2014 Oct 14]. Available from: www.cdc.gov /diabetes/pubs/statsreport14.htm 2. Boyle JP, Thompson TJ, Gregg EW, Barker LE, Williamson DF. Projection of the year 2050 burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence. Popul Health Metr. 2010;8:29. [PMID: 20969750] 3. Gregg EW, Williams DE, Geiss L. Changes in diabetes-related complications in the United States [Letter]. N Engl J Med. 2014;371:286-7. [PMID: 25014698] 4. American Diabetes Association. Standards of medical care in diabetes--2014. Diabetes Care. 2014;37 Suppl 1:S14-80. [PMID: 24357209] 5. American Diabetes Association. Standards of medical care in diabetes--2013. Diabetes Care. 2013;36 Suppl 1:S11-66. [PMID: 23264422] 6. Simmons RK, EchouffoTcheugui JB, Sharp SJ, Sargeant LA, Williams KM, Prevost AT, et al. Screening for type 2 diabetes and population mortality over 10 years (ADDITIONCambridge): a clusterrandomised controlled trial. Lancet. 2012;380: 1741-8. [PMID: 23040422] 7. Kahn R, Alperin P, Eddy D, Borch-Johnsen K, Buse J, Feigelman J, et al. Age at initiation and frequency of screening to detect type 2 diabetes: a costeffectiveness analysis. Lancet. 2010;375:136574. [PMID: 20356621] 8. The cost-effectiveness of screening for type 2 diabetes. CDC Diabetes CostEffectiveness Study Group, Centers for Disease Control and Prevention. JAMA. 1998;280:175763. [PMID: 9842951] 9. Hofer TP, Vijan S, Hayward RA. Estimating the microvascular benefits of screening for type 2 diabetes mellitus. Int J Technol Assess Health Care. 2000;16:822-33. [PMID: 11028137]
姝 2015 American College of Physicians
Should we screen for type 2 diabetes? Current data suggest that about 1 in 4 persons with diabetes are unaware of their disease (1). Diabetes has a fairly long asymptomatic phase, during which some patients will develop early disease complications, such as background retinopathy or microalbuminuria. Some groups have therefore suggested that screening should be done every third year in persons older than 45 years as well as in those younger than 45 who have diabetes risk factors (see the Box: Risk Factors for Type 2 Diabetes) (4, 5). However, at present no definitive evidence shows that screening improves health outcomes. In a single, large-scale screening trial in the United Kingdom, screening for diabetes among high-risk persons did not lead to changes in outcomes in 10 years of follow-up (6). Evidence from modeling studies is inconsistent, and it is unclear whether screening is likely to substantially improve outcomes or to be costeffective when applied broadly (7–9). There is thus a lack of consensus on who should be screened, the magnitude of benefit (if any), and how often screening should be done. In a cluster randomized trial in 33 practices in England, 15 089 patients who were at high risk for diabetes based on questionnaires were invited for screening; 73% agreed, and 3% were ultimately diagnosed with previously unknown diabetes. After 9.6 years of follow-up, there was no difference in mortality between patients who were screened and those who
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In the Clinic
were not (hazard ratio [HR], 1.06 [95% CI, 0.90 –1.25]), nor in cardiovascular (HR, 1.02 [CI, 0.75–1.38) or diabetes-related (HR, 1.26 [CI, 0.75–2.10]) mortality.
Which patients are likely to benefit from screening?
Risk Factors for Type 2 Diabetes Age >45 years First-degree relative with type 2 diabetes African American, Hispanic, Asian, Pacific Islander, or Native-American ethnicity History of gestational diabetes or delivery of infant weighing ≥9 lb The polycystic ovary syndrome Overweight, especially abdominal obesity Cardiovascular disease, hypertension, dyslipidemia, or other features of the metabolic syndrome
Diabetes screening is most likely to improve outcomes in patients with risk factors for cardiovascular disease, particularly if treatment goals differ for those with and without diabetes. While previous recommendations suggested screening for diabetes in persons with hypertension, recent studies suggest that blood pressure treatment goals should be the same for those with and without diabetes (10), limiting the rationale for screening in persons with hypertension. Recent guidelines for the management of lipids suggest a risk-based approach to initiation of lipidlowering therapy, using a risk
Annals of Internal Medicine
3 March 2015
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/933271/ by a University of California San Diego User on 04/27/2017
Table 1. Diagnostic Criteria for Type 2 Diabetes Diagnosis
Hemoglobin A1c Level, %
Prediabetes Diabetes
5.7–6.4 ≥6.5
calculator that includes the presence of diabetes as a risk factor (11). Knowledge of diabetes status alters the likelihood of recommending treatment and may argue for screening the population who would otherwise not be candidates for lipid-lowering therapy; however, at present there are no formal evaluations of the effects of diabetes screening on lipid treatment recommendations. Diabetes is more likely to be detected in persons with risk factors for the disease (Table 1). However, beyond the increased prevalence of disease, there is no consistent evidence supporting improved clinical outcomes with screening, and recommendations are based largely on expert opinion.
Can type 2 diabetes be prevented? Several high-quality randomized trials show that lifestyle changes in diet and exercise lead to substantial reductions in the incidence of type 2 diabetes in persons with “prediabetes,” defined as having impaired fasting glucose or impaired glucose tolerance. These programs achieved modest weight loss (generally 5%–7% of body weight) but were markedly effective. In a randomized, unblinded, controlled trial of 522 overweight Finnish patients with impaired glucose tolerance (mean age, 55 years), an intervention aimed at a 5% reduction in weight decreased the incidence of newly diagnosed type 2 diabetes over 3 years, from 23% to 11%. The intervention involved personal counseling sessions to encourage a reduction in total and saturated fat intake to less than
3 March 2015
Fasting Plasma Glucose Level mmol/L
mg/dL
5.55–6.94 ≥7.0
100–125 ≥126
30% and 10% of energy consumed, respectively; an increase in fiber intake; and moderate exercise for at least 30 minutes per day (12). The Diabetes Prevention Project, a randomized, controlled trial that involved 3234 U.S. patients with prediabetes (mean age, 51 years; mean body mass index, 34 kg/m2), showed that a lifestyle modification program aimed at a 7% weight loss reduced the cumulative incidence of diabetes over 3 years, from 29% to 14% (relative risk [RR], 0.42 [CI, 0.34 – 0.52]) compared with placebo (13). Ten-year follow-up found persistence of the initial effect of lifestyle, although after the study period the rates in the lifestyle and placebo groups were similar, implying that the intervention must be maintained for benefit to continue (14). A randomized, controlled trial that involved 577 Chinese adults with impaired glucose tolerance assigned to diet, exercise, both, or neither found that the incidence of diabetes over 6 years was 68% among persons in the “neither” group, 44% in the diet group, 41% in the exercise group, and 46% in the “both” group. All 3 interventions resulted in statistically significant reductions in the progression to diabetes (15).
Some medications can prevent diabetes onset in patients with prediabetes. In the medication group of the Diabetes Prevention Project, metformin (850 mg twice daily) reduced the cumulative incidence of diabetes from 29% to 22% over 3 years (RR, 0.69 [CI, 0.57– 0.83], a significant but smaller reduction than that observed with the lifestyle intervention in this trial (13). Ten-year follow-up again showed persistence of initial effect, although after the study period the rates in the metformin and placebo group were similar (14). In the randomized, double-blind, international Study to Prevent NonInsulin-Dependent Diabetes Mellitus, which involved 1429 patients with impaired glucose tolerance, acarbose (100 mg 3 times daily) reduced the incidence of diabetes
Annals of Internal Medicine
In the Clinic
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10. Cushman WC, Evans GW, Byington RP, Goff DC Jr, Grimm RH Jr, Cutler JA, et al; ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362:157585. [PMID: 20228401] 11. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/ AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014; 129:S1-45. [PMID: 24222016] 12. Tuomilehto J, Lindstro¨m J, Eriksson JG, Valle TT, Ha¨ma¨la¨inen H, IlanneParikka P, et al; Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344:1343-50. [PMID: 11333990] 13. Knowler WC, BarrettConnor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393403. [PMID: 11832527] 14. Knowler WC, Fowler SE, Hamman RF, Christophi CA, Hoffman HJ, Brenneman AT, et al; Diabetes Prevention Program Research Group. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet. 2009;374:1677-86. [PMID: 19878986] 15. Pan XR, Li GW, Hu YH, Wang JX, Yang WY, An ZX, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care. 1997;20: 537-44. [PMID: 9096977]
姝 2015 American College of Physicians
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from 42% to 32% compared with placebo. The relative risk reduction over 3 years was 25% (16). The DREAM trial (Diabetes Reduction Assessment with ramiripril and rosiglitazone Medication) randomly assigned 5269 adults without previous cardiovascular disease but with impaired fasting glucose, impaired glucose tolerance, or both to rosiglitazone 8 mg per day or placebo and to rosiglitazone up to 15 mg per day or placebo. After a median 3 years, 11.6% of patients who received rosiglitazone developed diabetes or died compared with 26.0% of patients who received placebo (HR, 0.40 [CI, 0.35 to 0.46]). Cardiovascular event rates were statistically similar in both groups (17). The implications of prevention for diabetes screening have not been fully elucidated,
but screening is generally necessary to identify the high-risk prediabetes population. However, because lifestyle and dietary modification are likely to benefit everyone regardless of diabetes status, the advantages of labeling patients as “prediabetic” is uncertain. The most likely option is to consider screening in persons who are at particularly high-risk (that is, those with multiple factors as discussed in Table 1) and to implement prevention, perhaps with medication therapy as well as lifestyle modification, in persons with high-risk prediabetes. There are national resources being put in place to help disseminate lifestyle changes for at-risk patients; more detail is available at www.cdc.gov/diabetes/prevention /index.htm.
Screening and Prevention... Little direct evidence shows clinical benefit from broad-based screening programs for type 2 diabetes. The single large-scale trial did not show mortality benefits at 10 years, and modeling studies have yielded inconsistent results. Diabetes can clearly be prevented in persons who have prediabetes with programs aimed at modest weight loss, and medication may be indicated for those who cannot achieve lifestyle goals. However, because diet and exercise programs tend to be universally beneficial, screening may best be preserved for persons at particularly high risk, largely to identify those who may benefit from medications to prevent diabetes. Guidelines for lifestyle change suggest that loss of about 7% of body weight and 150 minutes of exercise per week are enough to substantially reduce diabetes risk.
CLINICAL BOTTOM LINE
Diagnosis and Evaluation 16. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M; STOP-NIDDM Trail Research Group. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet. 2002;359:2072-7. [PMID: 12086760] 17. Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N, et al; DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet. 2006;368: 1096-105. [PMID: 16997664]
姝 2015 American College of Physicians
What are the diagnostic criteria for type 2 diabetes in nonpregnant adults? Clinicians should confirm the diagnosis of diabetes in persons with classic symptoms (polyuria, polydipsia, polyphagia, and weight loss) or in those with evidence of diabetes complications (retinopathy, nephropathy, neuropathy, impotence, acanthosis nigricans, or frequent infections). There are many tests that can be used to diagnose type 2 diabetes; however, due to ease of use and reliability, the current recommendation is to measure hemoglobin A1c (HbA1c) levels, with a threshold of ≥6.5% being diagnostic for dia-
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In the Clinic
betes (4). Other tests can also be used, including measuring fasting plasma glucose levels, with a level of ≥126 mg/dL confirmed by testing on a different day being diagnostic for diabetes. Alternatively, diabetes can be diagnosed in persons with classic symptoms and a nonfasting glucose ≥200 mg/dL, again confirmed by a second test. Finally, an oral glucose tolerance test (OGTT) could be used, with a 2-hour plasma glucose level of 200 mg/dL considered diagnostic for diabetes. Prediabetes can be diagnosed in persons with an HbA1c level 5.7%– 6.4%, fasting glucose levels 100 to 125 mg/dL, or an OGTT
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with a 2-hour plasma glucose level140 –199 mg/dL (Table 1).
What should the initial evaluation of patients with newly diagnosed type 2 diabetes include? Providers should conduct a detailed history and physical examination, including review of diet; physical activity; and assessment of cardiovascular, cerebrovascular, and erectile dysfunction. The initial evaluation should include blood pressure measurement and inspection for possible
diabetes complications via cardiovascular, neurologic, skin, and foot examinations. Laboratory tests should assess levels of glucose control (HbA1c level), cholesterol levels, and nephropathy (urine microalbumin– creatinine ratio and serum creatinine), along with liver function testing for persons who are likely to need lipid-lowering therapy. At diagnosis, ophthalmologic assessment should be done to evaluate for retinopathy.
Diagnosis and Evaluation... Type 2 diabetes is common and should be considered when patients present with suggestive symptoms (e.g., polyuria or polydipsia), signs (e.g., acanthosis nigricans), or complications of disease (e.g., retinopathy). The diagnosis can be confirmed by HbA1c levels measuring ≥6.5% or higher or by fasting plasma glucose levels >7.0 mmol/L (126 mg/dL) on 2 occasions at least 1 day apart. Random plasma glucose levels and OGTT can also be used to diagnose type 2 diabetes. Newly diagnosed patients should be examined for hypertension, as well as neurologic, ophthalmologic, and podiatric complications. The initial laboratory evaluation should include an assessment of glucose control, a lipid profile, and measurement of the urine microalbumin– creatinine ratio.
CLINICAL BOTTOM LINE
Treatment What are the components of nondrug therapy for patients with type 2 diabetes? Lifestyle changes, primarily diet and exercise, are the cornerstones of managing type 2 diabetes and should be considered first-line therapy for patients unless severe hyperglycemia requires immediate medical treatment. No one diet or exercise regimen applies to all patients with diabetes, and an individualized assessment should be used to develop a feasible strategy. The American Diabetes Association nutrition guidelines can be accessed at http://care .diabetesjournals.org/content /37/Supplement_1/S120.full.
3 March 2015
In a study of patients with newly diagnosed type 2 diabetes, diet initially reduced HbA1c levels by 2.25 percentage points. However, control deteriorated over time and most patients eventually required drug therapy (18). A meta-analysis of 14 randomized trials that compared exercise with no exercise and involved a total of 377 patients with type 2 diabetes showed that exercise significantly improved glycemic control, reduced visceral adipose tissue, and reduced plasma triglycerides even in the absence of weight loss (19).
What is the role of home glucose monitoring? Home glucose monitoring allows patients and providers to assess glucose control longitudinally and can provide real-time feedback on the effect of glucose treatments. Home monitoring is
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18. 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. 1998;352:837-53. [PMID: 9742976]
姝 2015 American College of Physicians
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considered part of the standard of care for persons receiving insulin therapy to allow sensible dose adjustments and to help determine whether symptoms are due to hyperglycemia or hypoglycemia. The optimum frequency of home monitoring has not been formally evaluated and is usually left to the discretion of the patient and provider. The role of home glucose monitoring in guiding oral therapy is less clear; a formal evidence review found a small reduction in HbA1c levels at 6 months, but this benefit subsided by 12 months, suggesting that self-monitoring has no sustained effect (20). Patients are generally advised to monitor fasting and premeal glucose levels. However, postprandial measurement may be helpful in persons with elevated HbA1c levels despite normal fasting levels. Some observational data suggest that postmeal glucose excursions may be tied to cardiovascular risk, leading some experts to recommend routine postprandial monitoring. However, thus far no trials have shown that treatment of these excursions reduces cardiovascular risk.
19. Thomas DE, Elliott EJ, Naughton GA. Exercise for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2006: CD002968. [PMID: 16855995] 20. Malanda UL, Welschen LM, Riphagen II, Dekker JM, Nijpels G, Bot SD. Self-monitoring of blood glucose in patients with type 2 diabetes mellitus who are not using insulin. Cochrane Database Syst Rev. 2012;1: CD005060. [PMID: 22258959]
姝 2015 American College of Physicians
What is the target HbA1c level? There is no clear single HbA1c target that applies to all patients with type 2 diabetes. Most organizations and quality measurement groups advocate a target ≤7% for most patients, based on the results of the U.K. Prospective Diabetes Study (UKPDS) (18); however, this was a study of newly diagnosed patients, who typically have milder disease. By the end of the study (10 years), mean HbA1c levels were close to 8% in the intensive-therapy group— only a minority of patients was able to maintain a level
Type 2 Diabetes
D
iabetes is one of the most common illnesses encountered by internists. Currently, an estimated 29.1 million people in the United States have diabetes, and only 21.0 million of these cases have been diagnosed (1). The incidence of diabetes is increasing because of the aging and changing ethnic mix of the population and because of increasing obesity. Based on current trends, it is expected that the prevalence of diabetes will nearly double by 2050 (2).
Screening and Prevention Diagnosis and Evaluation Treatment Practice Improvement Tool Kit Patient Information
The CME quiz is available at www.annals.org/intheclinic.aspx. Complete the quiz to earn up to 1.5 CME credits.
Physician Writer Sandeep Vijan
CME Objective: To review current evidence for prevention, screening, diagnosis, treatment, and patient information of type 2 diabetes. Funding source: American College of Physicians. Disclosures: Dr. Vijan, ACP Contributing Author, has disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms .do?msNum=M14-2388. With the assistance of additional physician writers, Annals of Internal Medicine editors develop In the Clinic using resources of the American College of Physicians, including ACP Smart Medicine and MKSAP (Medical Knowledge and Self-Assessment Program). © 2015 American College of Physicians
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/933271/ by a University of California San Diego User on 04/27/2017
Although care and complication rates are clearly improving (3), complications are still common, and diabetes is among the leading causes of vision loss, amputation, and end-stage renal disease
in the United States (4). In addition, it is a substantial risk factor for atherosclerotic disease, which is the leading cause of morbidity, mortality, and expenditures in diabetic persons.
Screening and Prevention 1. Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2014 [Internet]. [cited 2014 Oct 14]. Available from: www.cdc.gov /diabetes/pubs/statsreport14.htm 2. Boyle JP, Thompson TJ, Gregg EW, Barker LE, Williamson DF. Projection of the year 2050 burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence. Popul Health Metr. 2010;8:29. [PMID: 20969750] 3. Gregg EW, Williams DE, Geiss L. Changes in diabetes-related complications in the United States [Letter]. N Engl J Med. 2014;371:286-7. [PMID: 25014698] 4. American Diabetes Association. Standards of medical care in diabetes--2014. Diabetes Care. 2014;37 Suppl 1:S14-80. [PMID: 24357209] 5. American Diabetes Association. Standards of medical care in diabetes--2013. Diabetes Care. 2013;36 Suppl 1:S11-66. [PMID: 23264422] 6. Simmons RK, EchouffoTcheugui JB, Sharp SJ, Sargeant LA, Williams KM, Prevost AT, et al. Screening for type 2 diabetes and population mortality over 10 years (ADDITIONCambridge): a clusterrandomised controlled trial. Lancet. 2012;380: 1741-8. [PMID: 23040422] 7. Kahn R, Alperin P, Eddy D, Borch-Johnsen K, Buse J, Feigelman J, et al. Age at initiation and frequency of screening to detect type 2 diabetes: a costeffectiveness analysis. Lancet. 2010;375:136574. [PMID: 20356621] 8. The cost-effectiveness of screening for type 2 diabetes. CDC Diabetes CostEffectiveness Study Group, Centers for Disease Control and Prevention. JAMA. 1998;280:175763. [PMID: 9842951] 9. Hofer TP, Vijan S, Hayward RA. Estimating the microvascular benefits of screening for type 2 diabetes mellitus. Int J Technol Assess Health Care. 2000;16:822-33. [PMID: 11028137]
姝 2015 American College of Physicians
Should we screen for type 2 diabetes? Current data suggest that about 1 in 4 persons with diabetes are unaware of their disease (1). Diabetes has a fairly long asymptomatic phase, during which some patients will develop early disease complications, such as background retinopathy or microalbuminuria. Some groups have therefore suggested that screening should be done every third year in persons older than 45 years as well as in those younger than 45 who have diabetes risk factors (see the Box: Risk Factors for Type 2 Diabetes) (4, 5). However, at present no definitive evidence shows that screening improves health outcomes. In a single, large-scale screening trial in the United Kingdom, screening for diabetes among high-risk persons did not lead to changes in outcomes in 10 years of follow-up (6). Evidence from modeling studies is inconsistent, and it is unclear whether screening is likely to substantially improve outcomes or to be costeffective when applied broadly (7–9). There is thus a lack of consensus on who should be screened, the magnitude of benefit (if any), and how often screening should be done. In a cluster randomized trial in 33 practices in England, 15 089 patients who were at high risk for diabetes based on questionnaires were invited for screening; 73% agreed, and 3% were ultimately diagnosed with previously unknown diabetes. After 9.6 years of follow-up, there was no difference in mortality between patients who were screened and those who
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In the Clinic
were not (hazard ratio [HR], 1.06 [95% CI, 0.90 –1.25]), nor in cardiovascular (HR, 1.02 [CI, 0.75–1.38) or diabetes-related (HR, 1.26 [CI, 0.75–2.10]) mortality.
Which patients are likely to benefit from screening?
Risk Factors for Type 2 Diabetes Age >45 years First-degree relative with type 2 diabetes African American, Hispanic, Asian, Pacific Islander, or Native-American ethnicity History of gestational diabetes or delivery of infant weighing ≥9 lb The polycystic ovary syndrome Overweight, especially abdominal obesity Cardiovascular disease, hypertension, dyslipidemia, or other features of the metabolic syndrome
Diabetes screening is most likely to improve outcomes in patients with risk factors for cardiovascular disease, particularly if treatment goals differ for those with and without diabetes. While previous recommendations suggested screening for diabetes in persons with hypertension, recent studies suggest that blood pressure treatment goals should be the same for those with and without diabetes (10), limiting the rationale for screening in persons with hypertension. Recent guidelines for the management of lipids suggest a risk-based approach to initiation of lipidlowering therapy, using a risk
Annals of Internal Medicine
3 March 2015
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/933271/ by a University of California San Diego User on 04/27/2017
Table 1. Diagnostic Criteria for Type 2 Diabetes Diagnosis
Hemoglobin A1c Level, %
Prediabetes Diabetes
5.7–6.4 ≥6.5
calculator that includes the presence of diabetes as a risk factor (11). Knowledge of diabetes status alters the likelihood of recommending treatment and may argue for screening the population who would otherwise not be candidates for lipid-lowering therapy; however, at present there are no formal evaluations of the effects of diabetes screening on lipid treatment recommendations. Diabetes is more likely to be detected in persons with risk factors for the disease (Table 1). However, beyond the increased prevalence of disease, there is no consistent evidence supporting improved clinical outcomes with screening, and recommendations are based largely on expert opinion.
Can type 2 diabetes be prevented? Several high-quality randomized trials show that lifestyle changes in diet and exercise lead to substantial reductions in the incidence of type 2 diabetes in persons with “prediabetes,” defined as having impaired fasting glucose or impaired glucose tolerance. These programs achieved modest weight loss (generally 5%–7% of body weight) but were markedly effective. In a randomized, unblinded, controlled trial of 522 overweight Finnish patients with impaired glucose tolerance (mean age, 55 years), an intervention aimed at a 5% reduction in weight decreased the incidence of newly diagnosed type 2 diabetes over 3 years, from 23% to 11%. The intervention involved personal counseling sessions to encourage a reduction in total and saturated fat intake to less than
3 March 2015
Fasting Plasma Glucose Level mmol/L
mg/dL
5.55–6.94 ≥7.0
100–125 ≥126
30% and 10% of energy consumed, respectively; an increase in fiber intake; and moderate exercise for at least 30 minutes per day (12). The Diabetes Prevention Project, a randomized, controlled trial that involved 3234 U.S. patients with prediabetes (mean age, 51 years; mean body mass index, 34 kg/m2), showed that a lifestyle modification program aimed at a 7% weight loss reduced the cumulative incidence of diabetes over 3 years, from 29% to 14% (relative risk [RR], 0.42 [CI, 0.34 – 0.52]) compared with placebo (13). Ten-year follow-up found persistence of the initial effect of lifestyle, although after the study period the rates in the lifestyle and placebo groups were similar, implying that the intervention must be maintained for benefit to continue (14). A randomized, controlled trial that involved 577 Chinese adults with impaired glucose tolerance assigned to diet, exercise, both, or neither found that the incidence of diabetes over 6 years was 68% among persons in the “neither” group, 44% in the diet group, 41% in the exercise group, and 46% in the “both” group. All 3 interventions resulted in statistically significant reductions in the progression to diabetes (15).
Some medications can prevent diabetes onset in patients with prediabetes. In the medication group of the Diabetes Prevention Project, metformin (850 mg twice daily) reduced the cumulative incidence of diabetes from 29% to 22% over 3 years (RR, 0.69 [CI, 0.57– 0.83], a significant but smaller reduction than that observed with the lifestyle intervention in this trial (13). Ten-year follow-up again showed persistence of initial effect, although after the study period the rates in the metformin and placebo group were similar (14). In the randomized, double-blind, international Study to Prevent NonInsulin-Dependent Diabetes Mellitus, which involved 1429 patients with impaired glucose tolerance, acarbose (100 mg 3 times daily) reduced the incidence of diabetes
Annals of Internal Medicine
In the Clinic
ITC3
10. Cushman WC, Evans GW, Byington RP, Goff DC Jr, Grimm RH Jr, Cutler JA, et al; ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362:157585. [PMID: 20228401] 11. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/ AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014; 129:S1-45. [PMID: 24222016] 12. Tuomilehto J, Lindstro¨m J, Eriksson JG, Valle TT, Ha¨ma¨la¨inen H, IlanneParikka P, et al; Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344:1343-50. [PMID: 11333990] 13. Knowler WC, BarrettConnor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393403. [PMID: 11832527] 14. Knowler WC, Fowler SE, Hamman RF, Christophi CA, Hoffman HJ, Brenneman AT, et al; Diabetes Prevention Program Research Group. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet. 2009;374:1677-86. [PMID: 19878986] 15. Pan XR, Li GW, Hu YH, Wang JX, Yang WY, An ZX, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care. 1997;20: 537-44. [PMID: 9096977]
姝 2015 American College of Physicians
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from 42% to 32% compared with placebo. The relative risk reduction over 3 years was 25% (16). The DREAM trial (Diabetes Reduction Assessment with ramiripril and rosiglitazone Medication) randomly assigned 5269 adults without previous cardiovascular disease but with impaired fasting glucose, impaired glucose tolerance, or both to rosiglitazone 8 mg per day or placebo and to rosiglitazone up to 15 mg per day or placebo. After a median 3 years, 11.6% of patients who received rosiglitazone developed diabetes or died compared with 26.0% of patients who received placebo (HR, 0.40 [CI, 0.35 to 0.46]). Cardiovascular event rates were statistically similar in both groups (17). The implications of prevention for diabetes screening have not been fully elucidated,
but screening is generally necessary to identify the high-risk prediabetes population. However, because lifestyle and dietary modification are likely to benefit everyone regardless of diabetes status, the advantages of labeling patients as “prediabetic” is uncertain. The most likely option is to consider screening in persons who are at particularly high-risk (that is, those with multiple factors as discussed in Table 1) and to implement prevention, perhaps with medication therapy as well as lifestyle modification, in persons with high-risk prediabetes. There are national resources being put in place to help disseminate lifestyle changes for at-risk patients; more detail is available at www.cdc.gov/diabetes/prevention /index.htm.
Screening and Prevention... Little direct evidence shows clinical benefit from broad-based screening programs for type 2 diabetes. The single large-scale trial did not show mortality benefits at 10 years, and modeling studies have yielded inconsistent results. Diabetes can clearly be prevented in persons who have prediabetes with programs aimed at modest weight loss, and medication may be indicated for those who cannot achieve lifestyle goals. However, because diet and exercise programs tend to be universally beneficial, screening may best be preserved for persons at particularly high risk, largely to identify those who may benefit from medications to prevent diabetes. Guidelines for lifestyle change suggest that loss of about 7% of body weight and 150 minutes of exercise per week are enough to substantially reduce diabetes risk.
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Diagnosis and Evaluation 16. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M; STOP-NIDDM Trail Research Group. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet. 2002;359:2072-7. [PMID: 12086760] 17. Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N, et al; DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet. 2006;368: 1096-105. [PMID: 16997664]
姝 2015 American College of Physicians
What are the diagnostic criteria for type 2 diabetes in nonpregnant adults? Clinicians should confirm the diagnosis of diabetes in persons with classic symptoms (polyuria, polydipsia, polyphagia, and weight loss) or in those with evidence of diabetes complications (retinopathy, nephropathy, neuropathy, impotence, acanthosis nigricans, or frequent infections). There are many tests that can be used to diagnose type 2 diabetes; however, due to ease of use and reliability, the current recommendation is to measure hemoglobin A1c (HbA1c) levels, with a threshold of ≥6.5% being diagnostic for dia-
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betes (4). Other tests can also be used, including measuring fasting plasma glucose levels, with a level of ≥126 mg/dL confirmed by testing on a different day being diagnostic for diabetes. Alternatively, diabetes can be diagnosed in persons with classic symptoms and a nonfasting glucose ≥200 mg/dL, again confirmed by a second test. Finally, an oral glucose tolerance test (OGTT) could be used, with a 2-hour plasma glucose level of 200 mg/dL considered diagnostic for diabetes. Prediabetes can be diagnosed in persons with an HbA1c level 5.7%– 6.4%, fasting glucose levels 100 to 125 mg/dL, or an OGTT
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with a 2-hour plasma glucose level140 –199 mg/dL (Table 1).
What should the initial evaluation of patients with newly diagnosed type 2 diabetes include? Providers should conduct a detailed history and physical examination, including review of diet; physical activity; and assessment of cardiovascular, cerebrovascular, and erectile dysfunction. The initial evaluation should include blood pressure measurement and inspection for possible
diabetes complications via cardiovascular, neurologic, skin, and foot examinations. Laboratory tests should assess levels of glucose control (HbA1c level), cholesterol levels, and nephropathy (urine microalbumin– creatinine ratio and serum creatinine), along with liver function testing for persons who are likely to need lipid-lowering therapy. At diagnosis, ophthalmologic assessment should be done to evaluate for retinopathy.
Diagnosis and Evaluation... Type 2 diabetes is common and should be considered when patients present with suggestive symptoms (e.g., polyuria or polydipsia), signs (e.g., acanthosis nigricans), or complications of disease (e.g., retinopathy). The diagnosis can be confirmed by HbA1c levels measuring ≥6.5% or higher or by fasting plasma glucose levels >7.0 mmol/L (126 mg/dL) on 2 occasions at least 1 day apart. Random plasma glucose levels and OGTT can also be used to diagnose type 2 diabetes. Newly diagnosed patients should be examined for hypertension, as well as neurologic, ophthalmologic, and podiatric complications. The initial laboratory evaluation should include an assessment of glucose control, a lipid profile, and measurement of the urine microalbumin– creatinine ratio.
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Treatment What are the components of nondrug therapy for patients with type 2 diabetes? Lifestyle changes, primarily diet and exercise, are the cornerstones of managing type 2 diabetes and should be considered first-line therapy for patients unless severe hyperglycemia requires immediate medical treatment. No one diet or exercise regimen applies to all patients with diabetes, and an individualized assessment should be used to develop a feasible strategy. The American Diabetes Association nutrition guidelines can be accessed at http://care .diabetesjournals.org/content /37/Supplement_1/S120.full.
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In a study of patients with newly diagnosed type 2 diabetes, diet initially reduced HbA1c levels by 2.25 percentage points. However, control deteriorated over time and most patients eventually required drug therapy (18). A meta-analysis of 14 randomized trials that compared exercise with no exercise and involved a total of 377 patients with type 2 diabetes showed that exercise significantly improved glycemic control, reduced visceral adipose tissue, and reduced plasma triglycerides even in the absence of weight loss (19).
What is the role of home glucose monitoring? Home glucose monitoring allows patients and providers to assess glucose control longitudinally and can provide real-time feedback on the effect of glucose treatments. Home monitoring is
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18. 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. 1998;352:837-53. [PMID: 9742976]
姝 2015 American College of Physicians
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considered part of the standard of care for persons receiving insulin therapy to allow sensible dose adjustments and to help determine whether symptoms are due to hyperglycemia or hypoglycemia. The optimum frequency of home monitoring has not been formally evaluated and is usually left to the discretion of the patient and provider. The role of home glucose monitoring in guiding oral therapy is less clear; a formal evidence review found a small reduction in HbA1c levels at 6 months, but this benefit subsided by 12 months, suggesting that self-monitoring has no sustained effect (20). Patients are generally advised to monitor fasting and premeal glucose levels. However, postprandial measurement may be helpful in persons with elevated HbA1c levels despite normal fasting levels. Some observational data suggest that postmeal glucose excursions may be tied to cardiovascular risk, leading some experts to recommend routine postprandial monitoring. However, thus far no trials have shown that treatment of these excursions reduces cardiovascular risk.
19. Thomas DE, Elliott EJ, Naughton GA. Exercise for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2006: CD002968. [PMID: 16855995] 20. Malanda UL, Welschen LM, Riphagen II, Dekker JM, Nijpels G, Bot SD. Self-monitoring of blood glucose in patients with type 2 diabetes mellitus who are not using insulin. Cochrane Database Syst Rev. 2012;1: CD005060. [PMID: 22258959]
姝 2015 American College of Physicians
What is the target HbA1c level? There is no clear single HbA1c target that applies to all patients with type 2 diabetes. Most organizations and quality measurement groups advocate a target ≤7% for most patients, based on the results of the U.K. Prospective Diabetes Study (UKPDS) (18); however, this was a study of newly diagnosed patients, who typically have milder disease. By the end of the study (10 years), mean HbA1c levels were close to 8% in the intensive-therapy group— only a minority of patients was able to maintain a level
