ITC Type 2 Diabetes 2019

Annals of Internal Medicine䊛
In the Clinic®
Type 2 Diabetes Screening and Prevention
Diagnosis and Evaluation
Treatment
T
ype 2 diabetes is a prevalent illness that
causes major vascular, renal, and neuro-
logic complications. Prevention and treat-
ment of diabetes and its complications are of Practice Improvement
paramount importance. Many new treatments
have emerged over the past 5–10 years. Recent
evidence shows that newer treatments may sub-
stantially reduce risk for cardiac and renal dis-
ease, suggesting that it may be necessary to
change existing treatment paradigms. This re-
view summarizes the evidence supporting dia-
betes prevention and treatment, focusing on
aspects that are commonly in the purview of
primary care physicians.
CME/MOC activity available at Annals.org.
Physician Writer doi:10.7326/AITC201911050

Sandeep Vijan, MD
From University of Michigan, CME Objective: To review current evidence for screening, prevention, diagnosis, evaluation,
Ann Arbor, Michigan. treatment, and practice improvement of in the clinic: type 2 diabetes.
Funding Source: American College of Physicians.
Disclosures: Dr. Vijan, ACP Contributing Author, has nothing to disclose. The form can be viewed
at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M19-1836.
With the assistance of additional physician writers, the editors of Annals of Internal Medicine
develop In the Clinic using MKSAP and other resources of the American College of
Physicians.
In the Clinic does not necessarily represent official ACP clinical policy. For ACP clinical
guidelines, please go to https://www.acponline.org/clinical_information/guidelines/.
© 2019 American College of Physicians
Downloaded from https://annals.org by Hospital Pablo Tobon, Julio Cesar Julio Cesar Valencia Maturana on 11/04/2019
Diabetes is among the most com- renal disease in the United States (3).
mon illnesses encountered by inter- In addition, it is a substantial risk fac-
nists. An estimated 30.3 million per- tor for atherosclerotic disease, which
sons (9.4%) in the United States have is the leading cause of morbidity,
diabetes, and only 23.1 million of mortality, and expenditures in per-
these cases have been diagnosed sons with diabetes.
1. Centers for Disease Con-
trol and Prevention. Na- (1). Incidence is increasing because
tional Diabetes Statistics of the aging and changing ethnic
Report. Atlanta: Centers Although care and complication
for Disease Control and mix of the population and because rates showed improvements
Prevention; 2017. Ac-
cessed at www.cdc.gov of increasing obesity. On the basis through 2010 (4), there has re-
/diabetes/data/statistics of current trends, prevalence is ex-
/statistics-report.html on cently been a concerning resur-
11 June 2019. pected to nearly double by 2050 (2).
2. Boyle JP, Thompson TJ, gence in rates of complications,
Gregg EW, et al. Projec- particularly among younger
tion of the year 2050
Diabetes is a leading cause of vision
burden of diabetes in the loss, amputation, and end-stage adults (5).
US adult population:
dynamic modeling of
incidence, mortality, and
prediabetes prevalence.
Popul Health Metr. 2010;
8:29. [PMID: 20969750]
Screening and Prevention
3. American Diabetes Associ- Should we screen for type 2 trial in the United Kingdom,
ation. 1. Improving care
and promoting health in diabetes? screening for diabetes among
populations: Standards of Current data suggest that about high-risk persons did not lead to
Medical Care in Diabetes-
2019. Diabetes Care. 1 in 4 persons with type 2 diabe- changes in outcomes during 10
2019;42:S7-S12. [PMID:
30559227]
tes are unaware of their disease years of follow-up (7). Evidence
4. Gregg EW, Williams DE, (1). Diabetes has a long asymp- from modeling studies is incon-
Geiss L. Changes in
diabetes-related complica- tomatic phase, during which sistent, and whether screening is
tions in the United States some people develop early com-
[Letter]. N Engl J Med. likely to substantially improve
2014;371:286-7. [PMID: plications, such as background
25014698] outcomes or be cost-effective
5. Gregg EW, Hora I, Benoit
retinopathy or microalbuminuria.
SR. Resurgence in Some groups have therefore sug- when applied broadly is unclear
diabetes-related complica-
gested that screening should be (8 –10). There is thus a lack of
tions. JAMA. 2019;321:
1867-8. [PMID: done every 3 years in persons consensus on who should be
30985875]
6. American Diabetes Associ- older than 45 years and in those screened, the magnitude of ben-
ation. 2. Classification and
diagnosis of diabetes:
younger than 45 years who have efit (if any), and how often
Standards of Medical Care risk factors (see the Box: Risk Fac- screening should be done.
in Diabetes-2019. Diabe-
tes Care. 2019;42:S13- tors for Type 2 Diabetes) (6).
S28. [PMID: 30559228]
7. Simmons RK, Echouffo-
In a cluster randomized trial in 33 practices in
Tcheugui JB, Sharp SJ,
However, no clinical trials have the United Kingdom, 15 089 patients who
et al. Screening for type 2 shown that screening improves were at high risk for diabetes on the basis of
diabetes and population
mortality over 10 years health outcomes. In a large-scale responses to questionnaires were invited for
(ADDITION-Cambridge): a
cluster-randomised con- screening. Seventy-three percent were screened,
trolled trial. Lancet. 2012; and 3% were ultimately diagnosed with previ-
380:1741-8. [PMID:
23040422] ously unknown diabetes. After 9.6 years of
8. Kahn R, Alperin P, Eddy D, Risk Factors for Type 2 Diabetes follow-up, there was no difference in overall (haz-
et al. Age at initiation and
frequency of screening to
• Age >45 years ard ratio [HR], 1.06 [95% CI, 0.90 –1.25]), cardio-
detect type 2 diabetes: a • First-degree relative with type vascular (HR, 1.02 [CI, 0.75–1.38]), or diabetes-
cost-effectiveness analysis. 2 diabetes
Lancet. 2010;375:1365- • African American, Hispanic, related (HR, 1.26 [CI, 0.75–2.10]) mortality
74. [PMID: 20356621] between patients who were screened and
9. The cost-effectiveness of Asian, Pacific Islander, or
screening for type 2 dia- Native American race/ethnicity those who were not (7).
betes. CDC Diabetes Cost- • History of gestational diabetes
Effectiveness Study Group, or delivery of infant weighing
Centers for Disease Con- Who is likely to benefit from
trol and Prevention. ≥9 lb
JAMA. 1998;280:1757- • Polycystic ovary syndrome screening?
63. [PMID: 9842951] • Overweight, especially
10. Hofer TP, Vijan S, Hay-
abdominal obesity Diabetes screening is most likely
ward RA. Estimating the
microvascular benefits of • Cardiovascular disease, to improve outcomes in patients
screening for type 2 hypertension, dyslipidemia, or with risk factors for cardiovascu-
diabetes mellitus. Int J other features of metabolic
Technol Assess Health
syndrome lar disease, particularly if treat-
Care. 2000;16:822-33.
[PMID: 11028137] ment goals differ for those with
姝 2019 American College of Physicians ITC66 In the Clinic Annals of Internal Medicine 5 November 2019
and without diabetes. For exam- years. The intervention involved personal coun-
ple, lipid management guide- seling sessions to encourage a reduction in total
lines suggest a risk-based ap- and saturated fat intake to less than 30% and
proach using a risk calculator for 10% of energy consumed, respectively; an in-
crease in fiber intake; and moderate exercise for
initiation of lipid-lowering ther- 11. Grundy SM, Stone NJ,
at least 30 minutes per day (12). Bailey AL, et al. 2018
apy. However, lipid-lowering AHA/ACC/AACVPR/AAPA/
ABC/ACPM/ADA/AGS/
therapy is recommended for all The Diabetes Prevention Program, a random- APhA/ASPC/NLA/PCNA
patients with diabetes, regard- ized controlled trial that involved 3234 U.S. guideline on the man-
agement of blood cho-
less of underlying risk (11). Thus, patients with prediabetes (mean age, 51 lesterol: a report of the
American College of
knowledge of diabetes status years; mean body mass index, 34 kg/m2), Cardiology/American
alters the likelihood of recom- showed that a lifestyle modification program Heart Association Task
Force on Clinical Practice
aimed at a 7% weight loss reduced the cumu- Guidelines. Circulation.
mending treatment and may ar-
lative incidence of diabetes from 29% to 14% 2019;139:e1082-e1143.
gue for screening of patients who [PMID: 30586774]
over 3 years (relative risk, 0.42 [CI, 0.34 – 12. Tuomilehto J, Lindström
would otherwise not be candi- 0.52]) compared with placebo (13). Ten-year J, Eriksson JG, et al;
Finnish Diabetes Preven-
dates for lipid-lowering therapy. follow-up found persistence of the initial ef- tion Study Group. Pre-
However, to date there have been vention of type 2 diabe-
fect of lifestyle modification, although the tes mellitus by changes
no formal evaluations of the effects rates in both groups were similar after the in lifestyle among sub-
jects with impaired glu-
of diabetes screening on lipid treat- study period, implying that the intervention cose tolerance. N Engl J
must be maintained for benefit to continue Med. 2001;344:1343-
ment recommendations. 50. [PMID: 11333990]
(14). 13. Knowler WC, Barrett-
Connor E, Fowler SE,
Diabetes is more likely to be de- et al; Diabetes Preven-
A randomized controlled trial involving 577 tion Program Research
tected in persons with risk factors Chinese adults with impaired glucose toler- Group. Reduction in the
incidence of type 2 dia-
for it (Box: Risk Factors for Type 2 ance assigned to diet, exercise, both, or nei- betes with lifestyle inter-
ther found that incidence of diabetes over 6 vention or metformin. N
Diabetes). However, beyond the Engl J Med. 2002;346:
increased prevalence of disease, years was 68% among persons in the “neither” 393-403. [PMID:
11832527]
there is no consistent evidence group, 44% in the diet group, 41% in the ex- 14. Knowler WC, Fowler SE,
ercise group, and 46% in the “both” group. All Hamman RF, et al; Dia-
supporting improved clinical out- betes Prevention Pro-
3 interventions resulted in statistically signifi- gram Research Group.
comes with screening, and rec- 10-year follow-up of
cant reductions in progression to diabetes
ommendations are based largely diabetes incidence and
(15). weight loss in the Diabe-
on expert opinion. tes Prevention Program
Outcomes Study. Lancet.
Some medications can prevent 2009;374:1677-86.
[PMID: 19878986]
diabetes onset in patients with 15. Pan XR, Li GW, Hu YH,
Can type 2 diabetes be et al. Effects of diet and
prediabetes. exercise in preventing
prevented? NIDDM in people with
In the medication group of the Diabetes Pre- impaired glucose toler-
Several high-quality randomized ance. The Da Qing IGT
trials have shown that changes in vention Program, metformin (850 mg twice and Diabetes Study.
Diabetes Care. 1997;20:
diet and exercise lead to sub- daily) reduced cumulative incidence of diabe- 537-44. [PMID:
stantial reductions in progression tes from 29% to 22% over 3 years (relative risk, 9096977]
16. Chiasson JL, Josse RG,
0.69 [CI, 0.57– 0.83]), a significant reduction Gomis R, et al; STOP-
to type 2 diabetes in persons
but smaller than that observed with the life- NIDDM Trail Research
with “prediabetes,” defined as style intervention (13). Ten-year follow-up
Group. Acarbose for
prevention of type 2
impaired fasting glucose level or again showed persistence of the initial effect, diabetes mellitus: the
STOP-NIDDM ran-
impaired glucose tolerance. although the rates in the metformin and pla- domised trial. Lancet.
2002;359:2072-7.
These programs achieved mod- cebo groups were similar after the study [PMID: 12086760]
est weight loss (generally 5%–7%) period (14). 17. Gerstein HC, Yusuf S,
Bosch J, et al; DREAM
but were markedly effective. (Diabetes REduction
In the randomized, double-blind, international Assessment with ramipril
and rosiglitazone Medi-
STOP-NIDDM (Study to Prevent Non-Insulin- cation) Trial Investigators.
In a randomized, unblinded, controlled trial of Dependent Diabetes Mellitus), which involved Effect of rosiglitazone on
the frequency of diabetes
522 overweight Finnish patients with im- 1429 patients with impaired glucose toler- in patients with impaired
paired glucose tolerance (mean age, 55 years), ance, acarbose (100 mg 3 times daily) reduced glucose tolerance or
impaired fasting glucose:
an intervention aimed at a 5% reduction in incidence of diabetes from 42% to 32% com- a randomised controlled
weight decreased the incidence of newly diag- pared with placebo. The relative risk reduction trial. Lancet. 2006;368:
1096-105. [PMID:
nosed type 2 diabetes from 23% to 11% over 3 over 3 years was 25% (16). 16997664]
5 November 2019 Annals of Internal Medicine In the Clinic ITC67 姝 2019 American College of Physicians
The DREAM (Diabetes Reduction Assessment screening is generally necessary
with ramipril and rosiglitazone Medication) to identify the high-risk prediabe-
trial randomly assigned 5269 adults without tes population. However, be-
previous cardiovascular disease but with im- cause lifestyle and dietary
paired fasting glucose level, impaired glucose modification are likely to benefit
tolerance, or both to rosiglitazone, 8 mg/d, or everyone regardless of diabetes
18. Sussman JB, Kent DM,
Nelson JP, et al. Improv- placebo and to rosiglitazone, up to 15 mg/d, status, the advantages of labeling
ing diabetes prevention
with benefit based tai-
or placebo. After a median of 3 years, 11.6% of patients as “prediabetic” are un-
lored treatment: risk patients who received rosiglitazone developed certain. The most reasonable op-
based reanalysis of Dia-
betes Prevention Pro- diabetes or died versus 26.0% of those who
gram. BMJ. 2015;350:
tion is to consider screening in
received placebo (HR, 0.40 [CI, 0.35– 0.46]).
h454. [PMID: persons who are at particularly
25697494] Cardiovascular event rates were statistically
19. American Diabetes Asso- high risk (those with multiple risk
ciation. 5. Lifestyle man- similar in both groups (17).
agement: Standards of
factors) and to implement pre-
Medical Care in ventive measures, such as medi-
Diabetes-2019. Diabetes
Care. 2019;42:S46-S60. The implications of diabetes cation therapy and lifestyle modi-
[PMID: 30559231]
20. Intensive blood-glucose
screening for prevention have fication, in persons with high-risk
control with sulphony- not been fully elucidated, but prediabetes (18).
lureas or insulin com-
pared with conventional
treatment and risk of
complications in patients
with type 2 diabetes
Screening and Prevention... Little trial evidence shows clinical benefit
(UKPDS 33). UK Prospec- from broad-based screening programs for type 2 diabetes. The single
tive Diabetes Study (UK-
PDS) Group. Lancet.
large-scale trial did not show benefit at 10 years, and modeling studies
1998;352:837-53. have yielded inconsistent results. However, programs aimed at modest
[PMID: 9742976]
21. Chudyk A, Petrella RJ.
weight loss can prevent diabetes in persons with prediabetes, and
Effects of exercise on medication may be indicated for those who cannot achieve lifestyle
cardiovascular risk factors
in type 2 diabetes: a
goals. Because diet and exercise programs tend to be beneficial re-
meta-analysis. Diabetes gardless of blood glucose levels, screening may be best for persons at
Care. 2011;34:1228-37.
[PMID: 21525503]
particularly high risk, especially to identify those who may benefit from
22. Malanda UL, Welschen medications to prevent diabetes (18). Guidelines for lifestyle change
LM, Riphagen II, et al.
Self-monitoring of blood
suggest that loss of about 7% of body weight and 150 minutes of exer-
glucose in patients with cise per week are enough to substantially reduce diabetes risk.
type 2 diabetes mellitus
who are not using insu-
lin. Cochrane Database
Syst Rev. 2012;1:
CD005060. [PMID:
CLINICAL BOTTOM LINE
22258959]
23. Balkau B, Hu G, Qiao Q,
et al; DECODE Study
Group. Prediction of the
risk of cardiovascular
mortality using a score
that includes glucose as
Diagnosis and Evaluation
a risk factor. The DECODE What are the diagnostic criteria with a threshold of 6.5% or
Study. Diabetologia.
2004;47:2118-28. for type 2 diabetes in higher being diagnostic for dia-
[PMID: 15662552] nonpregnant adults?
24. Holman RR, Paul SK, betes (6). Other tests can also
Bethel MA, et al. 10-year Clinicians should confirm the di- be used, including measurement
follow-up of intensive
glucose control in type 2 agnosis of diabetes in persons of fasting plasma glucose
diabetes. N Engl J Med.
2008;359:1577-89.
with classic symptoms (polyuria, levels, with a level of 7.0 mmol/L
[PMID: 18784090] polydipsia, polyphagia, and
25. Duckworth W, Abraira C, (126 mg/dL) or higher confirmed
Moritz T, et al; VADT weight loss) or evidence of com-
Investigators. Glucose by testing on a different day be-
control and vascular plications (retinopathy, nephrop-
complications in veterans athy, neuropathy, impotence, ing diagnostic for diabetes. Alter-
with type 2 diabetes. N
Engl J Med. 2009;360: acanthosis nigricans, or frequent natively, diabetes can be diag-
129-39. [PMID:
19092145] infections). Many tests can be nosed in persons with classic
26. Reaven PD, Emanuele
NV, Wiitala WL, et al; used to diagnose type 2 diabe- symptoms and a nonfasting
VADT Investigators. In- glucose level of 11.1 mmol/L
tensive glucose control in tes; however, because of ease of
patients with type 2 use and reliability, the current (200 mg/dL) or higher confirmed
diabetes - 15-year follow-
up. N Engl J Med. 2019; recommendation is to measure by a second test. Finally, an oral
380:2215-24. [PMID:
31167051] hemoglobin A1c (HbA1c) levels, glucose tolerance test (OGTT)
Table 1. Diagnostic Criteria for Type 2 Diabetes 27. Qaseem A, Wilt TJ, Kan-
sagara D, et al; Clinical
Diagnosis Hemoglobin A1c Level, % Fasting Plasma Glucose Level Guidelines Committee of
the American College of
Physicians. Hemoglobin
mmol/L mg/dL A1c targets for glycemic
control with pharmaco-
Prediabetes 5.7–6.4 5.6–6.9 100–125 logic therapy for non-
Diabetes ≥6.5 ≥7.0 ≥126 pregnant adults with
type 2 diabetes mellitus:
a guidance statement
update from the Ameri-
can College of Physi-
could be used, with a 2-hour ment of cardiovascular, cerebro- cians. Ann Intern Med.
2018;168:569-76.
plasma glucose level of 11.1 vascular, and erectile dysfunc- [PMID: 29507945]
mmol/L (200 mg/dL) considered tion. The initial evaluation should 28. Gerstein HC, Miller ME,
Byington RP, et al; Action
diagnostic for diabetes. include blood pressure measure- to Control Cardiovascular
Risk in Diabetes Study
ment and inspection for possible Group. Effects of inten-
Prediabetes can be diagnosed in sive glucose lowering in
diabetes complications via car- type 2 diabetes. N Engl J
persons with an HbA1c level of diovascular, neurologic, skin, and Med. 2008;358:2545-
59. [PMID: 18539917]
5.7%– 6.4%, a fasting glucose foot examinations. Laboratory 29. ACCORD Study Group.
Nine-year effects of 3.7
level of 5.6 – 6.9 mmol/L (100-125 tests should assess levels of glu- years of intensive glyce-
mg/dL), or a 2-hour plasma glucose control (HbA1c level), cho- mic control on cardiovas-
cular outcomes. Diabetes
cose level of 7.8 –11.0 mmol/L lesterol levels, and nephropathy Care. 2016;39:701-8.
[PMID: 26822326]
(140-199 mg/dL) on an OGTT (urinary microalbumin– creatinine 30. Patel A, MacMahon S,
(Table 1). ratio and serum creatinine). Liver Chalmers J, et al; AD-
VANCE Collaborative
function testing should be con- Group. Intensive blood
glucose control and
What should the initial sidered in those who are likely to vascular outcomes in
patients with type 2
evaluation of patients with need lipid-lowering therapy and diabetes. N Engl J Med.
newly diagnosed type 2 because nonalcoholic fatty liver 2008;358:2560-72.
[PMID: 18539916]
diabetes include? disease is prevalent among pa- 31. Vijan S, Sussman JB,
Yudkin JS, et al. Effect of
Clinicians should conduct a de- tients with type 2 diabetes. At patients' risks and prefer-
tailed history and physical exami- diagnosis, ophthalmologic as- ences on health gains
with plasma glucose
nation, including review of diet sessment should be done to level lowering in type 2
diabetes mellitus. JAMA
and physical activity and assess- evaluate for retinopathy. Intern Med. 2014;174:
1227-34. [PMID:
24979148]
32. Effect of intensive blood-
Diagnosis and Evaluation... Type 2 diabetes is common and should be glucose control with
metformin on complica-
considered when patients present with suggestive symptoms (such as tions in overweight pa-
polyuria or polydipsia), signs (such as acanthosis nigricans), or compli- tients with type 2 diabe-
tes (UKPDS 34). UK
cations (such as retinopathy) of the disease. The diagnosis can be con- Prospective Diabetes
Study (UKPDS) Group.
firmed by HbA1c levels of 6.5% or higher or fasting plasma glucose lev- Lancet. 1998;352:854-
els above 7.0 mmol/L (>126 mg/dL) on 2 occasions at least 1 day apart. 65. [PMID: 9742977]
33. Inzucchi SE, Kosiborod
Random plasma glucose levels and an OGTT can also be used to diag- M, Fitchett D, et al. Im-
nose type 2 diabetes. Newly diagnosed patients should be examined provement in cardiovas-
cular outcomes with
for hypertension, as well as neurologic, ophthalmologic, and podiatric empagliflozin is inde-
complications. The initial laboratory evaluation should include an as- pendent of glycemic
control [Letter]. Circula-
sessment of glucose control, a lipid profile, and measurement of urinary tion. 2018;138:1904-7.
microalbumin– creatinine ratio. [PMID: 30354665]
34. Zinman B, Wanner C,
Lachin JM, et al; EMPA-
REG OUTCOME Investiga-
CLINICAL BOTTOM LINE tors. Empagliflozin, car-
diovascular outcomes,
and mortality in type 2
2015;373:2117-28.
[PMID: 26378978]
35. Wanner C, Inzucchi SE,
Lachin JM, et al; EMPA-
REG OUTCOME Investiga-
tors. Empagliflozin and
progression of kidney
disease in type 2 diabe-
tes. N Engl J Med. 2016;
375:323-34. [PMID:
27299675]
Treatment
What are the components of frequency of home monitoring
36. Perkovic V, Jardine MJ, nondrug therapy for patients has not been formally evaluated
Neal B, et al; CREDENCE
with type 2 diabetes? and is usually at the discretion of
Trial Investigators. Cana-
gliflozin and renal out- Lifestyle changes, primarily diet the patient and provider. Its role
comes in type 2 diabetes
and nephropathy. N Engl and exercise, are the corner- in guiding oral therapy is unclear;
J Med. 2019;380:2295-
stones of management of type 2 a formal evidence review found a
306. [PMID: 30990260]
37. Wiviott SD, Raz I, Bonaca diabetes and should be consid- small reduction in HbA1c levels at
MP, et al; DECLARE–TIMI
58 Investigators. Dapa- ered first-line therapy unless se- 6 months, but this benefit sub-
gliflozin and cardiovascu-
vere hyperglycemia requires im- sided by 12 months, suggesting
lar outcomes in type 2
mediate medical treatment. No that self-monitoring has no sus-
2019;380:347-57.
[PMID: 30415602] one diet or exercise regimen is tained effect (22).
38. Marso SP, Daniels GH,
Brown-Frandsen K, et al; appropriate for all patients with Patients are generally advised to
LEADER Steering Com-
mittee. Liraglutide and
diabetes, and an individualized monitor fasting and preprandial
cardiovascular outcomes assessment should be used to glucose levels. However, post-
in type 2 diabetes. N
Engl J Med. 2016;375: develop a feasible strategy. The prandial measurement may be
311-22. [PMID:
27295427] American Diabetes Association helpful in persons with elevated
39. Marso SP, Bain SC, Con- lifestyle management guidelines HbA1c levels despite normal fast-
soli A, et al; SUSTAIN-6
Investigators. Semaglu- (19) can be accessed at http: ing levels. Observational data
tide and cardiovascular
outcomes in patients //care.diabetesjournals.org suggest that postprandial glu-
with type 2 diabetes. N /content/42/Supplement_1/S46.
Engl J Med. 2016;375: cose excursions may be tied to
1834-44. [PMID: cardiovascular risk (23), leading
27633186] In a study of patients with newly diagnosed
40. Husain M, Birkenfeld AL, some experts to recommend rou-
Donsmark M, et al; PIO- type 2 diabetes, diet initially reduced HbA1c
NEER 6 Investigators. levels by 2.25%. However, control deteriorated
tine postprandial monitoring.
Oral semaglutide and
over time, and most patients eventually re- However, thus far no trials have
cardiovascular outcomes
in patients with type 2 quired drug therapy (20). shown that treatment of these
2019;381:841-51.
excursions reduces cardiovascu-
[PMID: 31185157] A meta-analysis of 34 randomized trials that lar risk.
41. Gerstein HC, Colhoun
HM, Dagenais GR, et al;
compared exercise (aerobic with or without re-
REWIND Investigators. sistance training) versus no exercise in pa- What is the target HbA1c level?
Dulaglutide and cardio-
vascular outcomes in tients with type 2 diabetes showed that exer- No single HbA1c target applies to
type 2 diabetes (RE- cise significantly improved glycemic control all patients with type 2 diabetes.
WIND): a double-blind,
randomised placebo- and reduced waist circumference and blood Most organizations and quality
controlled trial. Lancet. pressure, even though neither weight nor
2019;394:121-30. measurement groups advocate a
[PMID: 31189511] body mass index was significantly reduced
42. Gerstein HC, Colhoun target of 7% or less for most pa-
(21).
HM, Dagenais GR, et al; tients, based on the results of the
REWIND Investigators.
Dulaglutide and renal What is the role of home UKPDS (U.K. Prospective Diabe-
outcomes in type 2 dia-
betes: an exploratory glucose monitoring? tes Study) (20). However, the re-
analysis of the REWIND sults from the UKPDS and other
randomised, placebo- Home glucose monitoring allows
controlled trial. Lancet. studies of intensive glucose con-
2019;394:131-8. [PMID: patients and providers to assess
31189509]
trol are inconsistent.
43. Pi-Sunyer X, Astrup A,
glucose control longitudinally,
Fujioka K, et al; SCALE can provide real-time feedback In the UKPDS, patients with newly diagnosed
Obesity and Prediabetes
NN8022-1839 Study on the effects of glucose treat- diabetes were randomly assigned to more ver-
Group. A randomized,
ments, and should be used for sus less intensive glucose control. Patients in
controlled trial of 3.0 mg
of liraglutide in weight testing if symptoms of hypergly- the intensive group achieved an HbA1c level of
management. N Engl J 7.0% compared with 7.9% among those in the
Med. 2015;373:11-22. cemia or hypoglycemia are pres-
[PMID: 26132939] control group. Persons maintaining better con-
44. White WB, Cannon CP,
ent. It is considered part of the
trol had reduced risk for early, asymptomatic
Heller SR, et al; EXAM- standard of care for persons re- microvascular outcomes but did not have clear
INE Investigators.
Alogliptin after acute ceiving insulin therapy to allow benefits for either cardiovascular outcomes
coronary syndrome in
patients with type 2 sensible dose adjustments, par- or symptomatic microvascular complications,
diabetes. N Engl J Med. ticularly with shorter-acting insu- such as vision loss, amputation, or end-stage
2013;369:1327-35.
[PMID: 23992602] lin preparations. The optimum renal disease (20). In a 20-year follow-up
study, the group initially assigned to intensive els were 6.4% and 7.5%. The trial was stopped
control had lower rates of myocardial infarction early because of a 22% increase in total mor-
(16.8 vs. 19.6 per 1000 patient-years) and tality in the intensive control group (5.0% vs.
death (26.8 vs. 30.3 per 1000 patient-years), 4.0%; P = 0.04). The overall main end point
even though differences in glycemic control (nonfatal myocardial infarction, nonfatal
were not maintained between groups (24). stroke, and cardiovascular death) did not differ 45. Scirica BM, Bhatt DL,
Braunwald E, et al;
between groups. Hypoglycemia and weight SAVOR-TIMI 53 Steering
The VADT (Veterans Affairs Diabetes Trial) stud-
gain were also more prevalent in the intensive Committee and Investi-
ied 1791 veterans with diabetes (mean age, gators. Saxagliptin and
control group (28). Long-term follow-up of this cardiovascular outcomes
60.4 years; mean diabetes duration, 11.5
population suggested an ongoing increase in in patients with type 2
years; 40% with a prior cardiovascular event). diabetes mellitus. N Engl
risk for cardiovascular events (29). J Med. 2013;369:1317-
The group assigned to intensive control had a 26. [PMID: 23992601]
target HbA1c level that was 1.5% lower than in ADVANCE (Action in Diabetes and Vascular Dis- 46. Green JB, Bethel MA,
Armstrong PW, et al;
the control group. The achieved levels were ease: Preterax and Diamicron - MR Controlled TECOS Study Group.
6.9% in the intensive group and 8.4% in the Evaluation), a multinational study of 11 140 Effect of sitagliptin on
cardiovascular outcomes
control group. No significant effects on the pri- patients with diabetes (mean age, 66 years; in type 2 diabetes. N
mary end point (a composite of cardiovascular mean diabetes duration, 8 years; 32% with a Engl J Med. 2015;373:
232-42. [PMID:
events, heart failure, vascular surgery, and am- prior cardiovascular event), comprised an in- 26052984]
putation), total mortality, or microvascular 47. Home PD, Pocock SJ,
tensive control group with a target HbA1c level Beck-Nielsen H, et al;
events were found (25). In a 15-year follow-up of 6.5% or lower and a control group. The RECORD Study Team.
Rosiglitazone evaluated
study, patients randomly assigned to intensive HbA1c level was 6.5% in the intensive control for cardiovascular out-
control did not have lower rates of mortality group and 7.3% in the control group. The in- comes in oral agent
combination therapy for
(HR, 1.02 [CI, 0.88 –1.18]) or cardiovascular tensive control group had reduced nephropa- type 2 diabetes (RE-
disease (HR, 0.91 [CI, 0.78 –1.06]). However, thy (4.1% vs. 5.2%; P = 0.006), but there were CORD): a multicentre,
randomised, open-label
during a median of 7.1 years while HbA1c lev- no differences in cardiovascular events or trial. Lancet. 2009;373:
els differed between groups, there was a re- mortality (30). 2125-35. [PMID:
19501900]
duction in cardiovascular events (HR, 0.83 [CI, 48. Mahaffey KW, Hafley G,
0.70 – 0.99]) (26). Interpretation and reconciliation Dickerson S, et al. Re-
sults of a reevaluation of
of the results of the major cardiovascular outcomes
These results are not fully in ac- glucose-lowering trials are diffi- in the RECORD trial. Am
Heart J. 2013;166:240-
cord with each other but suggest cult. Moderate glucose control 249.e1. [PMID:
that there may be a small benefit (mean HbA1c level of 7%) may 23895806]
49. Holman RR, Farmer AJ,
to cardiovascular risk with treat- eventually provide small benefit Davies MJ, et al; 4-T
Study Group. Three-year
ment to an HbA1c level of about in decreasing cardiovascular efficacy of complex insu-
7%. This possible benefit, plus a events and mortality and in early lin regimens in type 2
presumed eventual benefit in asymptomatic microvascular out- 2009;361:1736-47.
[PMID: 19850703]
microvascular outcomes that will comes. It is likely but has not 50. Buse JB, Wolffenbuttel
likely take more than 20 years to been proved that longer-term BH, Herman WH, et al.
DURAbility of Basal ver-
realize, has led the American Col- benefit in symptomatic microvas- sus Lispro mix 75/25
insulin Efficacy (DURA-
lege of Physicians to suggest an cular outcomes, such as vision BLE) trial 24-week re-
HbA1c goal between 7% and 8% loss, end-stage renal disease, sults: safety and efficacy
of insulin lispro mix
for most patients (27). However, and amputation, will eventually 75/25 versus insulin
glargine added to oral
despite the aforementioned evi- occur, but only in the distant fu- antihyperglycemic drugs
dence, some experts advocate ture because such benefits have in patients with type 2
diabetes. Diabetes Care.
more aggressive targets for gly- not been demonstrated even in 2009;32:1007-13.
[PMID: 19336625]
cemic control or treatment to studies with 20 years of follow- 51. Hayward RA, Manning
near-normal glucose levels when up. More aggressive control (for WG, Kaplan SH, et al.
Starting insulin therapy
possible (HbA1c level <6%). example, HbA1c target <6.5%), at in patients with type 2
diabetes: effectiveness,
least in the shorter term, does complications, and re-
In ACCORD (Action to Control Cardiovascular source utilization. JAMA.
not seem to provide substantial
Risk in Diabetes), a study of 10 251 U.S. pa- 1997;278:1663-9.
benefit and may increase mortal- [PMID: 9388085]
tients with diabetes (mean age, 62.2 years; 52. Yki-Järvinen H, Ryysy L,
median diabetes duration, 10 years; 35% with ity due to higher rates of cardio- Nikkilä K, et al. Compari-
vascular events. Further, it is un- son of bedtime insulin
a prior cardiovascular event), the group as- regimens in patients
signed to intensive therapy had target HbA1c clear whether specific subgroups with type 2 diabetes
mellitus. A randomized,
levels less than 6.0%, whereas the group as- of patients are more prone to controlled trial. Ann
signed to conventional therapy had target lev- harms or benefits as the result of Intern Med. 1999;130:
389-96. [PMID:
els ranging from 7.0%–7.9%. The achieved lev- aggressive control. 10068412]
The most logical conclusion from available to treat type 2 diabetes.
these studies is that moderate Studies that may help to guide
control (HbA1c level of 7%– 8%, the selection of treatments for
which may vary depending on patients with type 2 diabetes are
diabetes duration) will probably outlined here.
provide the majority of achiev-
53. Billings LK, Doshi A,
Gouet D, et al. Efficacy able benefit for most people with The UKPDS found that, in pa-
and safety of IDegLira
type 2 diabetes because most of tients who exceeded ideal body
versus basal-bolus insu-
lin therapy in patients them are older than 65 years and weight by 20%, metformin was
with type 2 diabetes
uncontrolled on met- are therefore less likely to benefit superior to sulfonylureas and in-
formin and basal insulin: from intensive control given sulin in reducing mortality de-
the DUAL VII randomized
clinical trial. Diabetes the long time horizon but are spite identical levels of glycemic
Care. 2018;41:1009-16.
[PMID: 29483185] also more likely to experience control (32). Metformin was also
54. Cushman WC, Evans treatment-related harms. How- associated with lower rates of
GW, Byington RP, et al;
ACCORD Study Group. ever, because younger or other- hypoglycemia and weight gain
Effects of intensive
blood-pressure control in
wise healthy patients with a lon- than insulin or sulfonylureas. Met-
type 2 diabetes mellitus. ger life expectancy (≥20 years) formin should not be used in per-
N Engl J Med. 2010;
362:1575-85. [PMID: may eventually realize benefit sons with severe renal insuffi-
20228401] from more intensive control (for
55. Whelton PK, Carey RM, ciency (glomerular filtration rate
Aronow WS, et al. 2017 example, HbA1c level <7%), gly- <30 mL/min/1.73 m2), acute de-
ACC/AHA/AAPA/ABC/
ACPM/AGS/APhA/ASH/ cemic targets should be adjusted compensated heart failure, or
ASPC/NMA/PCNA guide- depending on life expectancy severe liver disease.
line for the prevention,
detection, evaluation, and comorbid conditions. Evi-
and management of If metformin is contraindicated or
high blood pressure in
dence from modeling studies
adults: a report of the suggests that the time horizon for not tolerated, the choice of oral
American College of
Cardiology/American benefit may cause the burden of agent should be dictated by pa-
Heart Association Task therapy (particularly injectable tient preferences regarding po-
Force on Clinical Practice
Guidelines. Circulation. agents) to outweigh the benefits tential adverse effects, efficacy,
2018;138:e484-e594.
[PMID: 30354654]
for many patients with type 2 and cost. Although there was lit-
56. Qaseem A, Wilt TJ, Rich diabetes (31). tle known difference between
R, et al; Clinical Guide-
lines Committee of the
When should treatment drug classes in the past, more
American College of
Physicians and the Com- include drugs? recent data show that some drug
mission on Health of the
Public and Science of the Once an HbA1c goal has been classes provide benefit in cardio-
American Academy of
established, pharmacologic man- vascular and renal outcomes. Of
Family Physicians. Phar-
macologic treatment of agement should be instituted if note, this benefit may be inde-
hypertension in adults
aged 60 years or older to diet and exercise do not achieve pendent of glucose control (33).
higher versus lower
blood pressure targets: a the goal. In general, aside from In the EMPA-REG trial, 7020 patients with type
clinical practice guideline patients with mild HbA1c eleva-
from the American Col- 2 diabetes and high cardiovascular risk were
lege of Physicians and tions, if diet and exercise do not randomly assigned to placebo or to 10 or 25
the American Academy
of Family Physicians. Ann accomplish the targeted reduc- mg of the sodium– glucose cotransporter-2
Intern Med. 2017;166:
430-7. [PMID:
tion in glycemic values within (SGLT-2) inhibitor empagliflozin. The pooled
28135725] approximately 6 – 8 weeks, phar- empagliflozin group had a composite cardio-
57. Heart Protection Study vascular risk of 10.5% versus 12.1% in the pla-
Collaborative Group. macologic therapy should be
MRC/BHF Heart Protec- initiated. Patients with severe hy- cebo group (HR, 0.86 [CI, 0.74 – 0.99]). There
tion Study of cholesterol
lowering with simvasta- perglycemia or symptoms may was also a significant reduction in all-cause
tin in 20,536 high-risk
require pharmacologic interven- mortality (5.7% vs. 8.3%; HR, 0.68 [CI, 0.57–
individuals: a ran-
0.82]), with the difference largely explained by
domised placebo- tion immediately, sometimes with
controlled trial. Lancet. reductions in cardiovascular mortality (34). Re-
2002;360:7-22. [PMID: insulin.
12114036] nal outcomes also improved in this trial, with
58. LaRosa JC, Grundy SM, How should physicians select lower rates of doubling of serum creatinine
Waters DD, et al; Treat-
ing to New Targets (TNT) therapies from among the level and initiation of renal replacement ther-
Investigators. Intensive apy (35).
lipid lowering with ator- many drug options other than
vastatin in patients with
stable coronary disease. insulin? In the CREDENCE (Canagliflozin and Renal
N Engl J Med. 2005; Table 2 provides an overview of
352:1425-35. [PMID:
Events in Diabetes With Established Nephrop-
15755765] the classes of noninsulin agents athy Clinical Evaluation) trial, 4401 patients
who had type 2 diabetes, a glomerular filtra- A trial randomly assigned 9340 patients with 59. Cannon CP, Braunwald E,
McCabe CH, et al; Prava-
tion rate of 30 – 89 mL/min/1.73 m2, and albu- type 2 diabetes and high cardiovascular risk to statin or Atorvastatin Evalu-
minuria and were using renin–angiotensin the glucagon-like peptide-1 (GLP-1) receptor ation and Infection
Therapy-Thrombolysis in
blockade were randomly assigned to canagli- agonist liraglutide or placebo. Over 3.8 years, Myocardial Infarction 22
flozin or placebo. There was a significant re- Investigators. Intensive
there was a lower rate of a composite of cardio- versus moderate lipid
duction in the composite end point of end- vascular events with liraglutide (13.0% vs. lowering with statins after
stage renal disease, doubling of creatinine acute coronary syndromes.
14.9%; HR, 0.87 [CI, 0.78 – 0.97]), including a N Engl J Med. 2004;350:
level, or death due to renal or cardiovascular reduction in total mortality (8.2% vs. 9.6%; HR, 1495-504. [PMID:
15007110]
causes (43.2 vs. 61.2 per 1000 patient-years; 0.85 [CI, 0.74 – 0.97]) and cardiovascular mor- 60. Ginsberg HN, Elam MB,
HR, 0.70 [CI, 0.59 – 0.82]). Reductions were tality (4.7% vs. 6.0%; HR, 0.78 [CI, 0.66 – Lovato LC, et al; ACCORD
Study Group. Effects of
seen in renal outcomes, including end-stage 0.93]) (38). combination lipid ther-
renal disease, and in cardiovascular outcomes apy in type 2 diabetes
mellitus. N Engl J Med.
(36). A trial randomly assigned 3297 patients with 2010;362:1563-74.
type 2 diabetes and high cardiovascular risk [PMID: 20228404]
In the DECLARE–TIMI 58 (Dapagliflozin Effect 61. Cannon CP, Blazing MA,
(83.0% with prior cardiovascular or chronic kid- Giugliano RP, et al;
on Cardiovascular Events–Thrombolysis in IMPROVE-IT Investiga-
ney disease) to once-weekly semaglutide or
Myocardial Infarction 58) trial, 17 160 patients tors. Ezetimibe added to
placebo. Patients who received semaglutide statin therapy after acute
with type 2 diabetes (10 186 without baseline coronary syndromes. N
cardiovascular disease) were randomly as- had lower risk for a composite cardiovascular Engl J Med. 2015;372:
signed to dapagliflozin or placebo, with a pri- end point (6.6% vs. 8.9%; HR, 0.74 [CI, 0.58 – 2387-97. [PMID:
26039521]
mary outcome of cardiovascular death, myo- 0.95]). There were no differences in mortality. 62. Schwartz GG, Steg PG,
Rates of nephropathy were reduced in the Szarek M, et al; ODYSSEY
cardial infarction, or stroke and a second OUTCOMES Committees
composite of cardiovascular death and hospi- semaglutide group (3.8% vs. 6.1%; HR, 0.64 and Investigators. Aliro-
cumab and cardiovascu-
talization for heart failure (37). Secondary out- [CI, 0.46 – 0.88]), but rates of worsening reti- lar outcomes after acute
comes included a composite renal failure out- nopathy requiring treatment were higher coronary syndrome. N
Engl J Med. 2018;379:
come and all-cause mortality. The trial found (2.0% vs. 1.8%; HR, 1.76 [CI, 1.11–2.78]) (39). 2097-107. [PMID:
no difference in the primary outcome but re- In a trial of oral semaglutide versus placebo, a 30403574]
ductions in hospitalization for heart failure composite cardiovascular end point was not
(HR, 0.73 [CI, 0.61– 0.88]) and renal end significantly reduced, but total mortality was
points (HR, 0.76 [CI, 0.67– 0.87]). (1.4% vs. 2.8%; HR, 0.51 [CI, 0.31– 0.84]),
Table 2. Noninsulin Medications Available in the United States for Type 2 Diabetes
Drug Class Name Initial Dose Maximum Dose Usual Dose
Biguanides Metformin 500 mg twice daily or 2550 mg/d 500–1000 mg twice daily
850 mg/d
Metformin extended release 500 mg/d 2000 mg/d 1500–2000 mg/d
Sulfonylureas Glimepiride 1–2 mg/d 8 mg/d 4 mg/d
Glipizide 2.5–5 mg/d 40 mg/d 10–20 mg/d (or twice daily)
Glipizide sustained release 5 mg/d 20 mg/d 5–20 mg/d (or twice daily)
Glyburide 2.5–5 mg/d 20 mg/d 5–20 mg/d (or twice daily)
Glyburide micronized 0.75–3 mg/d 12 mg/d 3–12 mg/d (or twice daily)
Thiazolidinediones Pioglitazone 15–30 mg/d 45 mg/d 15–45 mg/d
Rosiglitazone 4 mg/d (or twice daily) 8 mg/d 4–8 mg/d (or twice daily)
␣-Glucosidase inhibitors Acarbose 25 mg/d (with meals) 100 mg 3 times daily 50–100 mg 3 times daily
Miglitol 25 mg/d (with meals) 100 mg 3 times daily 25–100 mg 3 times daily
Nonsulfonylurea insulin Repaglinide 0.5 mg before meals 4 mg before meals (16 mg/d); 0.5–4 mg with meals
secretagogues wait 1 wk between dose
increases
Nateglinide 120 mg 3 times daily before 120 mg 3 times daily before 60–120 mg 3 times daily
meals (60 mg 3 times daily meals before meals
if near glycemic goals)
Dipeptidyl peptidase-4 inhibitors Sitagliptin 100 mg/d 100 mg/d 100 mg/d
Saxagliptin 2.5 mg/d 5 mg/d 5 mg/d
Linagliptin 5 mg/d 5 mg/d 5 mg/d
Alogliptin 25 mg/d 25 mg/d 25 mg/d
Sodium–glucose cotransporter-2 Canagliflozin 100 mg/d 300 mg/d 100–300 mg/d
inhibitors Empagliflozin 10 mg/d 25 mg/d 10–25 mg/d
Dapagliflozin 5 mg/d 10 mg/d 5–10 mg/d
Ertugliflozin 5 mg/d 15 mg/d 5–15 mg/d
Glucagon-like peptide-1 agonists* Exenatide 5 mcg twice daily (≤60 min 10 mcg twice daily 5–10 mcg/d
before meals)
Exenatide extended release 2 mg once per week 2 mg once per week 2 mg once per week
Liraglutide 0.6 mg/d 1.8 mg/d 1.2 mg/d
Dulaglutide 0.75 mg/wk 1.5 mg/wk 0.75–1.5 mg/wk
Lixisenatide 10 mcg/d 20 mcg/d 20 mcg/d
Semaglutide 0.25 mg/wk 1 mg/wk 0.5 mg/wk
Semaglutide (oral) 7 mg/d 14 mg/d 7–14 mg/d
* All are injectable aside from oral semaglutide.
driven primarily by a reduction in cardiovascu- cular benefits seen with met-
lar mortality (40). formin, SGLT-2 inhibitors, and
GLP-1 receptor agonists (44 – 46).
The REWIND trial compared dulaglutide with
placebo in 9901 persons with type 2 diabetes Sulfonylureas can cause hypogly-
and high cardiovascular risk (31.5% had a cemia and weight gain (20) and
prior cardiovascular event; the remainder had have less convincing evidence of
various combinations of cardiovascular risk fac- cardiovascular benefits than other
63. Bowman L, Mafham M, tors) (41). The primary outcome was a compos- drugs. Thiazolidinediones can in-
Wallendszus K, et al; ite of nonfatal myocardial infarction, nonfatal
ASCEND Study Collabora-
crease risk for heart failure and
tive Group. Effects of stroke, or cardiovascular death. Dulaglutide fracture, although they probably
aspirin for primary pre- led to a reduction in cardiovascular outcomes
vention in persons with do not increase total cardiovascu-
diabetes mellitus. N Engl (HR, 0.88 [CI, 0.79 – 0.99]). In a post hoc ex- lar events (47, 48). Short-acting
J Med. 2018;379:1529-
39. [PMID: 30146931]
ploratory analysis, the investigators also agents, such as ␣-glucosidase in-
64. Sussman JB, Vijan S, found a reduction in renal end points (HR,
Choi H, et al. Individual hibitors (acarbose, miglitol) and
and population benefits
0.85 [CI, 0.77– 0.93]), primarily new-onset
nonsulfonylurea insulin secreta-
of daily aspirin therapy: a macroalbuminuria (42).
proposal for personaliz- gogues (nateglinide, repaglinide),
ing national guidelines.
Circ Cardiovasc Qual Taken together, these data are administered before meals
Outcomes. 2011;4:268- strongly suggest that newer and may be useful in persons with
75. [PMID: 21487091]
65. Vijan S, Hofer TP, Hay- agents, particularly SGLT-2 inhibi- inconsistent mealtimes. Several
ward RA. Cost-utility
analysis of screening tors and GLP-1 receptor agonists, combination formulations of oral
intervals for diabetic reduce total mortality, primarily agents are available and may pro-
retinopathy in patients
with type 2 diabetes through a reduction in cardiovas- vide advantages in convenience or
mellitus. JAMA. 2000;
283:889-96. [PMID: cular mortality. These agents cost for some patients. Adverse
10685713] should therefore be strongly con- effects should also be considered
66. Brenner BM, Cooper ME,
de Zeeuw D, et al; RE- sidered as first-line agents in per- when choosing agents.
NAAL Study Investiga-
tors. Effects of losartan sons unable to take metformin;
on renal and cardiovas- choices between them may be When should physicians
cular outcomes in pa-
tients with type 2 diabe- dictated by patient preferences consider insulin therapy?
tes and nephropathy. N
Engl J Med. 2001;345: (injectable vs. oral agents, adverse Patients who are unable to
861-9. [PMID: effect profile) and individual risk achieve glycemic goals with non-
11565518]
67. Hansson L, Lindholm LH, factors. For example, liraglutide is insulin medications, whether
Niskanen L, et al. Effect
of angiotensin-
approved by the U.S. Food and alone or in combination, are can-
converting-enzyme inhi- Drug Administration as a weight didates for insulin therapy. Other
bition compared with
conventional therapy on loss medication and may be partic- indications include a desire for
cardiovascular morbidity
and mortality in hyper-
ularly helpful in patients with rapid reduction of blood glucose
tension: the Captopril obesity (43). levels in persons with severe
Prevention Project
(CAPPP) randomised symptoms; some experts recom-
trial. Lancet. 1999;353: Most patients with diabetes have mend early initiation for persons
611-6. [PMID:
10030325]
worsening glycemic control over with markedly elevated HbA1c
68. Parving HH, Lehnert H, time. Increasing the dose of exist- levels at diagnosis because of the
Bröchner-Mortensen J,
et al; Irbesartan in Pa- ing oral agents is generally the possibility of prolonging ␤-cell
tients with Type 2 Diabe-
tes and Microalbumin-
first step to maintain control, but function (29).
uria Study Group. The the response from dose escala-
effect of irbesartan on
the development of tion is limited. Patients therefore Many insulin formulations are
diabetic nephropathy in
patients with type 2
often require the addition of 1 or available, separated primarily by
diabetes. N Engl J Med. more oral agents. On the basis their onset of action and duration
2001;345:870-8. [PMID:
11565519] of the aforementioned trials, (Table 3). No particular regimen
69. Garber AJ, Abrahamson SGLT-2 inhibitors and GLP-1 re- is clearly superior; in 1 random-
MJ, Barzilay JI, et al.
Consensus statement by ceptor agonists should both be ized trial, median HbA1c levels
the American Association
of Clinical Endocrinolo- considered for second- and/or were similar among biphasic,
gists and American Col- third-line treatment as needed. prandial, and basal insulin, al-
lege of Endocrinology on
the comprehensive type Dipeptidyl peptidase-4 inhibitors though rates of hypoglycemia
2 diabetes management
algorithm - 2019 execu- are reasonable options for glu- were lowest in the basal insulin
tive summary. Endocr
Pract. 2019;25:69-100.
cose control, although trials have group (49). Most patients have a
[PMID: 30742570] not demonstrated the cardiovas- 1%–2% decrease in HbA1c levels
after starting insulin therapy (50, acting analogues, such as deglu- However, aggressive treatment
51). When intensive glycemic dec. Typical starting doses of to a blood pressure target of
control is planned, a fasting glu- insulin are 0.1– 0.2 U/kg of body 120/80 mm Hg does not lead to
cose level below 6.7 mmol/L weight. improved diabetes outcomes
(<120 mg/dL) is a reasonable compared with a target of
goal. The primary risks of insulin Some patients need twice-daily
140/90 mm Hg (54). Despite
therapy are hypoglycemia and insulin to achieve glycemic tar-
this, the current guidelines from
weight gain (20). Patients must gets, but more frequent injec-
the American College of Cardi-
be warned about these possibili- tions (such as preprandial injec-
tions) are often not necessary for ology and the American Heart
ties and educated to recognize Association suggest a blood
and treat hypoglycemia. persons with type 2 diabetes.
However, if HbA1c levels remain pressure target of 130/80 mm
elevated despite normal fasting Hg for patients with diabetes
At the start of insulin therapy,
glucose levels, prandial insulin (55), although other organiza-
most patients can be treated with
may be considered. For those tions, including the American
a once-daily injection. Those
receiving high doses of insulin, College of Physicians, recom-
without hypoglycemia can often
the U-500 (highly concentrated) mend a target of 140/90 mm Hg
be effectively treated with a sin-
formulation can be used. (56).
gle bedtime dose of neutral
protamine Hagedorn (NPH) or Fixed-dose combinations, such Current evidence is not clear on
basal analogue insulin combined as basal insulin and GLP-1 recep- the optimal choice of drugs for
with an oral agent, such as met- tor agonists, are also available. blood pressure control. All drug
formin. This can reduce insulin These achieve glycemic control classes are effective, although
dosing to once daily at bedtime, similar to that with basal plus many patients use angiotensin-
which is often more acceptable prandial insulin injections but are converting enzyme (ACE) inhibi-
to patients (52). associated with lower rates of tors or angiotensin-receptor
hypoglycemia and often avoid
In patients with normal fasting blockers (ARBs) as the initial
the weight gain associated with
glucose levels or high risk for hy- agent for blood pressure control
insulin (53).
poglycemia, a basal analogue because of their beneficial renal
may be the first choice, although Aside from glycemic control, effects. Other agents should be
they are considerably more ex- what other clinical added as needed to achieve
pensive than NPH insulin. Evi- interventions reduce blood pressure goals, with
dence suggests lower rates of complications? choices dictated by comorbid
hypoglycemia with basal ana- Hypertension is a major risk fac- conditions, adverse effects, and
logues, particularly newer, long- tor for diabetes complications. patient preferences.
Table 3. Onset and Mechanisms of Action of Various Types of Insulin

Class Onset of Action Peak of Action Duration of Action
Rapid-acting (insulin analogues lispro, aspart, glulisine) ≤30 min 0.5–3 h 3–5 h
Short-acting (human regular) 0.5–1 h 2–5 h Up to 12 h
Concentrated insulin (U-500) 0.5–1 h 6–8 h Up to 24 h
Intermediate-acting (human NPH) 1.5–4 h 4–12 h Up to 24 h
Long-acting (insulin analogues glargine, detemir, degludec) 0.8–4 h Relatively peakless Up to 24–42 h
Ultra-long-acting (glargine U-300) 6h Relatively peakless Up to 5 d to steady state
Human insulin mixtures
70% NPH/30% regular 0.5–2 h 2–12 h Up to 24 h
50% NPH/50% regular 0.5–2 h 2–5 h Up to 24 h
Analogue mixtures
75% lispro protamine/25% lispro <15 min 1–2 h Up to 24 h
50% lispro protamine/50% lispro <15 min 1–2 h Up to 24 h
70% aspart protamine/30% aspart 10–20 min 1–4 h Up to 24 h
Inhaled insulin (Afrezza [MannKind]) 12–15 min 1h 2.5–3 h
NPH = neutral protamine Hagedorn.
Use of lipid-lowering agents is events of 1.1% but an increase in For patients with stable disease,
also a priority in patients with bleeding risk of 0.9%, suggesting this can be reduced to every 6
diabetes. For primary preven- no net benefit (63). Although the months (3).
tion, recent guidelines suggest evidence is not clear, consider-
using a risk-based approach to ation of underlying cardiovascu- When should a specialist be
select patients for lipid-lowering lar and bleeding risk may identify consulted?
therapy. Nearly all patients with patients who are most likely to Meta-analyses show that diabe-
diabetes who are older than 40 benefit from aspirin therapy (64). tes education by a certified edu-
years meet treatment thresholds Patients with a history of heart cator is effective in improving
and are therefore likely to bene- disease should take 75–325 mg many key domains in diabetes
fit from statin therapy, regard- of aspirin per day. care, including glycemic control,
less of their initial low-density although the durability of these
lipoprotein cholesterol level Retinal examination reduces inci- effects is not clear.
(11). Optimal low-density lipo- dence of vision loss in patients
protein cholesterol targets, par- with type 2 diabetes. The fre- Consultation with an endocrinol-
ticularly in primary prevention, quency of examination for pa- ogist is helpful for addressing
are not well established; how- tients without high-risk retinal questions about diagnosis or
ever, most trial evidence sug- when glucose management be-
lesions can range from 1–3 years
gests that moderate statin doses comes difficult (for example, in
depending on underlying risk
are recommended for most pa- patients with highly labile blood
(65). Measurement of the urinary
tients with type 2 diabetes (57). glucose levels). Patients who are
microalbumin– creatinine ratio
For secondary prevention, statin pregnant or are contemplating
allows detection of early diabetic pregnancy should be referred
use should be encouraged in
nephropathy; albuminuria is also for assistance with glucose con-
almost all patients. There is evi-
a risk factor for cardiovascular trol because poor control is
dence that higher-dose statins
disease. Clinical trials have associated with adverse fetal
(for example, simvastatin or ator-
shown that treatment of albumin- outcomes.
vastatin, 80 mg) may be more
effective than lower-dose statins uria with ACE inhibitors or ARBs
reduces risk for progression to Ophthalmologic examination,
in patients with existing coronary
end-stage renal disease (66 – 68). whether by an ophthalmologist
artery disease (58, 59). Combi-
As noted earlier, newer classes of or optometrist or via retinal pho-
nation therapy with statins and
glucose-lowering agents, particu- tography, should be done every
fibrates does not seem to im-
larly SGLT-2 inhibitors, also show 1–3 years depending on prior
prove cardiovascular outcomes
impressive reductions in renal examination results and level of
in patients with diabetes (60),
disease outcomes (35, 36). Neu- glucose control. Other condi-
although ezetimibe may have
ropathy screening and foot care tions, such as known retinopathy,
modest additional benefit in
are essential in reducing risk for glaucoma, and cataracts, may
high-risk patients already using a
statin (61). Newer agents, such amputation. Painful neuropathy is necessitate more frequent
as proprotein convertase subtili- examination.
uncommon in type 2 diabetes
sin/kexin type 9 inhibitors, may but can be treated with various Nephrologic evaluation is re-
also offer modest benefit in agents (Table 4). quired for patients with a glomer-
high-risk patients who are al- ular filtration rate less than 30
ready receiving maximal toler- How frequently should mL/min/1.73 m2. Earlier referral
ated statin doses, but these physicians see patients with can be considered, although in-
agents are injectable and expen- type 2 diabetes, and what terventions to reduce progres-
sive (62). should be included in sion center around risk factor
The benefit of aspirin therapy in follow-up visits? control and use of ACE inhibitors
preventing cardiovascular dis- There is no direct evidence on or ARBs as outlined earlier. Refer-
ease in patients with type 2 dia- the ideal frequency of visits for ral should also be considered if
betes is unclear. A recent ran- patients with type 2 diabetes. the origin of renal insufficiency is
domized controlled study of Expert opinion and the recom- unclear. Patients with hyperkale-
aspirin in patients with type 2 mended frequency of monitoring mia, acidemia, or difficulty with
diabetes found an absolute re- of HbA1c levels suggest that controlling blood pressure may
duction in serious vascular quarterly visits are reasonable. also benefit.
Table 4. Therapies to Reduce Neuropathy Symptoms*
Agent Notes
Tricyclic antidepressants RCT evidence shows efficacy
Start with small bedtime dose and titrate to efficacy
Anticholinergic adverse effects common; use with particular caution in elderly persons
Duloxetine Approved for diabetic neuropathy by the U.S. Food and Drug Administration
Not appropriate with liver disease or substantial alcohol use
Capsaicin cream RCT evidence shows efficacy
Causes burning sensation that often decreases over time
Antiepileptic agents Carbamazepine, gabapentin, and pregabalin have RCT evidence of efficacy
RCT = randomized controlled trial.

* There are no data on the relative efficacy of the medications listed. Patient preference should be considered for dosing and
administration, along with comorbid conditions and adverse effect profiles, to determine initial choice of agent.
Podiatric evaluation is helpful When should patients with ketoacidosis or hyperosmolar

for management of lesions, such type 2 diabetes be hospitalized? coma requires hospitalization for
as calluses or deformities, which management. Diabetes compli-
Some patients with severe, symp- cations may require hospitaliza-
require intervention to reduce tomatic hyperglycemia may re- tion; for example, cellulitis or
risk for foot ulcers and quire hospitalization, particularly osteomyelitis may require intra-
amputation. at the time of diagnosis. Diabetic venous antibiotics or surgery.
Treatment... The goal of treating type 2 diabetes is to achieve glycemic

targets on an individual basis according to life expectancy and patient
preferences. Patients should achieve at least moderate control (HbA1c
level <8.0% in most cases) to minimize hyperglycemia and because mi-
crovascular risk increases exponentially above this level. More aggres-
sive targets (for example, <7.0%) should be reserved for patients with a
long life expectancy because reductions in advanced diabetes compli-
cations take 15–20 years to accrue.
CLINICAL BOTTOM LINE
Practice Improvement
What measures do U.S.
stakeholders use to evaluate
Quality Measures for Diabetes
the quality of care for patients
Eye examination
with type 2 diabetes? • Percentage of patients who received a retinal or dilated eye examination by
The National Committee on an eye care professional (optometrist or ophthalmologist) during the
Quality Assurance, through the reporting year or during the prior year if patient has low risk for retinopathy
Healthcare Effectiveness Data (not taking insulin, HbA1c level <8.0%, and no evidence of retinopathy in the
prior year)
and Information Set program,
HbA1c management
recommends several measures
• Percentage of patients who have had ≥1 HbA1c test in the measurement year
of diabetes care (see the Box:
HbA1c management control
Quality Measures for Diabetes).
• Percentage of patients whose most recent HbA1c level was <8.0% (good
It is important to note that these control)
recommendations do not per- • Percentage of patients whose most recent HbA1c level was >9.0% (poor
fectly align with clinical targets. control)
• Percentage of patients whose most recent HbA1c level was <7.0% (selected
What do professional population likely to benefit from tight control)
organizations recommend Blood pressure management
regarding the care of patients • Percentage of patients with blood pressure <140/90 mm Hg documented in
the past year
with type 2 diabetes?
Medical attention for nephropathy (use of an ACE inhibitor/ARB or screen-
Several professional associations
ing for albuminuria)
publish guidelines for diabetes
care. These guidelines do not
always agree on all aspects, and
The American Diabetes Associa- 3 years in adults who are at in-
the nature of the organization
tion releases standards of diabe- creased risk for diabetes (see the
inevitably influences its recom-
tes care annually. The standards Box: Risk Factors for Type 2 Dia-
mendations. The following orga-
are broad and encompass most betes). This recommendation is
nizations are 4 of the most com-
relevant areas of screening, pre- based on the evidence support-
monly cited sources.
vention, and management (3). ing the efficacy of diabetes pre-
The American College of Physi- vention programs. More detail
The American Association of
cians conducted systematic re- and finalized recommendations
Clinical Endocrinologists up-
views of the evidence to inform can be accessed at www.us
dated its guidelines in 2019 (69).
guidelines on glucose manage- preventiveservicestaskforce.org
ment in patients with type 2 dia- The U.S. Preventive Services Task /Page/Document/Recommendation
betes (27). Blood pressure con- Force recommends screening for StatementFinal/screening-for
trol is discussed in a separate elevated blood glucose level -abnormal-blood-glucose-and-type
guideline (56). (not specifically diabetes) every -2-diabetes.
In the Clinic Patient Information
https://medlineplus.gov/howtopreventdiabetes.html
Tool Kit https://medlineplus.gov/spanish/howtopreventdiabetes

.html
Information in English and Spanish on how to prevent
diabetes from the National Institutes of Health
MedlinePlus.
www.niddk.nih.gov/health-information/diabetes
Type 2 Diabetes /overview/what-is-diabetes
www.niddk.nih.gov/health-information/informacion
-de-la-salud/diabetes/informacion-general/que-es
Information for patients in English and Spanish on types
of diabetes from the National Institute of Diabetes and
Digestive and Kidney Diseases.
IntheClinic
www.niddk.nih.gov/health-information/diabetes
/overview/managing-diabetes
Information for patients on managing diabetes from the
National Institute of Diabetes and Digestive and Kidney
Diseases.
https://professional.diabetes.org/search/site?f%5B0%5D
=im_field_dbp_ct%3A32&retain-filters=1
Patient education library from the American Diabetes
Association, in English and other languages.
Information for Health Professionals

https://professional.diabetes.org/content-page/practice
-guidelines-resources
The 2019 Standards of Medical Care in Diabetes from the
American Diabetes Association, updated yearly.
http://diabetes.acponline.org
Latest information on type 2 diabetes from the American
College of Physicians Diabetes Monthly.
www.niddk.nih.gov/health-information
/communication-programs/ndep/health-professionals
Information for health professionals on diabetes from the
National Institute of Diabetes and Digestive and Kidney
Diseases.
WHAT YOU SHOULD KNOW In the Clinic
Annals of Internal Medicine
ABOUT TYPE 2 DIABETES
What Is Type 2 Diabetes?
Diabetes is a common condition where there is
too much sugar in your blood. Insulin is a hor-
mone that turns sugar into energy. Most people
with diabetes make some insulin, but it does not
work to keep the blood sugar under control.
This is called type 2 diabetes. High sugar levels
in your blood over time may lead to:
• Vision loss
• Kidney damage
• Nerve damage
• Foot ulcers
• Heart disease
• Possible amputation from infections
What Are the Signs and • Your provider will check your blood pressure,
Symptoms? cholesterol levels, and kidney function.
• You will need an eye examination to check for
• Extreme thirst and/or hunger any problems.
• Fatigue
• Frequent need to urinate How Is It Treated?
• Unexpected weight loss
• Blurred vision People with diabetes need to improve blood
• Tingling or numbness in the hands or feet sugar control in their bodies.
Some people with diabetes may not have symptoms • Lifestyle changes, such as losing weight and
at first and do not know they have the disease. exercising regularly, improve blood sugar
control without medication.
What Are Other Risk Factors? • If lifestyle changes do not improve blood
sugar control, you may need medicine.
• Age 45 years or older • There are many different types of medicines
• African American, Hispanic, Asian, Pacific for type 2 diabetes, including several new oral
Islander, or Native American race/ethnicity and injectable medicines. Not all people with
• Being overweight or obese
Patient Information
type 2 diabetes need to take injectable
• Having a close relative with type 2 diabetes medicines or check their blood sugar at home.
• A history of diabetes in pregnancy • Talk to your provider about what your average
blood sugar target (HbA1c level) should be.
Can I Prevent It? • Make sure your blood pressure and cholesterol
A healthy diet and regular exercise may prevent are controlled to help prevent complications.
type 2 diabetes. Even a small amount of weight • The best treatment plan for you is one that you
loss and 30 minutes of exercise a day can can afford and will stick with. Talk about the
reduce your risk. cost and convenience of treatment plans with
your health care provider.
How Is It Diagnosed?
• Your health care provider will ask you about Questions for My Doctor
your medical history, including your current • Do I need to change my diet and start exercising?
diet and exercise regimen, and do a physical • What is an optimal blood sugar target (HbA1c
examination. level) for me?
• Diabetes is diagnosed by measuring the level • Do I have to check my blood sugar? When,
of sugar in your blood. You may need to fast and how often?
before some tests. • What are the symptoms of low blood sugar? What
• Your hemoglobin A1c (HbA1c) level is assessed should I do when I have these symptoms?
with a simple blood test that measures your • How should I care for my feet?
average blood sugar over the past 3 months • How often should I make follow-up visits?
and does not require fasting. • Do I need to see other medical specialists?
For More Information

American College of Physicians
www.acponline.org/practice-resources/patient-education/online
-resources/diabetes
American Diabetes Association

www.diabetes.org/diabetes/type-2

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Annals of Internal Medicine䊛

Type 2 Diabetes Screening and Prevention

Diagnosis and Evaluation

CME/MOC activity available at Annals.org.

Physician Writer doi:10.7326/AITC201911050

* All are injectable aside from oral semaglutide.

Table 3. Onset and Mechanisms of Action of Various Types of Insulin

NPH = neutral protamine Hagedorn.

RCT = randomized controlled trial.

Podiatric evaluation is helpful When should patients with ketoacidosis or hyperosmolar

Treatment... The goal of treating type 2 diabetes is to achieve glycemic

CLINICAL BOTTOM LINE

Tool Kit https://medlineplus.gov/spanish/howtopreventdiabetes

Information for Health Professionals

For More Information

American Diabetes Association

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