Professional Documents
Culture Documents
2022 ADA-EASD Hyperglycemia
2022 ADA-EASD Hyperglycemia
CONSENSUS REPORT
The American Diabetes Association and the European Association for the Study
of Diabetes convened a panel to update the previous consensus statements on
the management of hyperglycemia in type 2 diabetes in adults, published since
2006 and last updated in 2019. The target audience is the full spectrum of the
professional health care team providing diabetes care in the U.S. and Europe. A 1
Leicester Diabetes Research Centre, University
systematic examination of publications since 2018 informed new recommenda- of Leicester, Leicester, U.K.
2
tions. These include additional focus on social determinants of health, the health Leicester National Institute for Health Research
care system, and physical activity behaviors, including sleep. There is a greater Biomedical Research Centre, University Hospitals
of Leicester NHS Trust, Leicester, U.K.
emphasis on weight management as part of the holistic approach to diabetes 3
Division of Endocrinology, Diabetes and
management. The results of cardiovascular and kidney outcomes trials involving Hypertension, Brigham and Women’s Hospital,
sodium–glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor Harvard Medical School, Boston, MA
4
agonists, including assessment of subgroups, inform broader recommendations National Heart, Lung, and Blood Institute,
Bethesda, MD
for cardiorenal protection in people with diabetes at high risk of cardiorenal dis- 5
American Diabetes Association, Arlington, VA
ease. After a summary listing of consensus recommendations, practical tips for 6
Duke Clinical Research Institute, Duke University
implementation are provided. School of Medicine, Durham, NC
7
Department of Medicine, Johns Hopkins University
School of Medicine, Baltimore, MD
8
Kidney and Hypertension Unit, Joslin Diabetes
Type 2 diabetes is a chronic complex disease, and management requires multifacto- Center, Harvard Medical School, Boston, MA
9
rial behavioral and pharmacological treatments to prevent or delay complications Department of Clinical and Experimental Medicine,
University of Pisa, Pisa, Italy
and maintain quality of life (Fig. 1). This includes management of blood glucose lev- 10
Clinical and Experimental Endocrinology, KU
els, weight, cardiovascular risk factors, comorbidities, and complications. This necessi- Leuven, Leuven, Belgium
tates that care be delivered in an organized and structured way, such as described in 11
Universit
a Cattolica del Sacro Cuore, Rome, Italy
12
the chronic care model, and includes a person-centered approach to enhance en- Fondazione Policlinico Universitario A. Gemelli
gagement in self-care activities (1). Careful consideration of social determinants of IRCCS, Rome, Italy
13
Division of Diabetes and Nutritional Sciences,
health and the preferences of people living with diabetes must inform individualiza- School of Cardiovascular and Metabolic Medicine
tion of treatment goals and strategies (2). and Sciences, King’s College London, London, U.K.
14
This consensus report addresses the approaches to management of blood glucose Steno Diabetes Center Copenhagen, Herlev,
levels in nonpregnant adults with type 2 diabetes. The principles and approach for Denmark
15
Department of Clinical Medicine, University of
achieving this are summarized in Fig. 1. These recommendations are not generally Copenhagen, Copenhagen, Denmark
applicable to individuals with diabetes due to other causes, for example, monogenic 16
Department of Endocrinology, Medical University—
diabetes, secondary diabetes, and type 1 diabetes, or to children. Sofia, Sofia, Bulgaria
2 Consensus Report Diabetes Care
DATA SOURCES, SEARCHES, AND stakeholder input, the recommendations of microvascular complications (11,12),
STUDY SELECTION presented herein reflect the values and and early intervention is essential (13).
The writing group members were ap- preferences of the consensus group. The greatest absolute risk reduction comes
pointed by the American Diabetes Associ- from improving very elevated glycemic lev-
ation (ADA) and European Association for THE RATIONALE, IMPORTANCE, els, and a more modest reduction results
the Study of Diabetes (EASD). The group AND CONTEXT OF GLUCOSE- from near normalization of plasma glucose
largely worked virtually, with regular tele- LOWERING TREATMENT levels (2,14). The impact of glucose control
conferences from September 2021, a Fundamental aspects of diabetes care in- on macrovascular complications is less
3-day workshop in January 2022, and a clude promoting healthy behaviors through certain but is supported by multiple meta-
face-to-face 2-day meeting in April 2022. medical nutrition therapy (MNT), physical analyses and epidemiological studies. Be-
The writing group accepted the 2012 (3), activity, and psychological support, as well cause the benefits of intensive glucose
2015 (4), 2018 (5), and 2019 (6) editions as weight management and tobacco/sub- control emerge slowly while the harms
17
Diabetes Centre, Clinical Research and Evidence- 05787-2) and Diabetes Care (https://doi.org/10.2337/ Committee on Clinical Affairs and approved by its
Based Medicine Unit, Aristotle University Thessaloniki, dci22-0034) by the European Association for the Study Executive Board. The article was reviewed for
Thessaloniki, Greece of Diabetes and American Diabetes Association. ADA by its Professional Practice Committee.
18
Harris Manchester College, University of Oxford,
A consensus report of a particular topic contains This article contains supplementary material online
Oxford, U.K
19 a comprehensive examination and is authored by at https://doi.org/10.2337/figshare.20800537.
University of North Carolina School of Medicine,
an expert panel and represents the panel’s
Chapel Hill, NC © 2022 by the American Diabetes Association
collective analysis, evaluation and opinion. M.J.D.
Corresponding author: John B. Buse, jbuse@ and the European Association for the Study of
and J.B.B. were co-chairs for the Consensus
med.unc.edu Diabetes. Readers may use this article as long as
Report Writing Group. V.R.A., B.S.C., R.A.G., J.G.,
Received 2 August 2022 and accepted 4 August the work is properly cited, the use is educational
N.M.M., and S.E.R. were the writing group
2022 and not for profit, and the work is not altered.
members for ADA. S.D.P., C.M., G.M., P.R., T.T.,
More information is available at https://www.
This article is being simultaneously published in and A.T. were the writing group members for
diabetesjournals.org/journals/pages/license.
Diabetologia (https://doi.org/10.1007/s00125-022- EASD. The article was reviewed for EASD by its
diabetesjournals.org/care
Figure 1—Decision cycle for person-centered glycemic management in type 2 diabetes. Adapted from Davies et al. (5) with permission. BGM, blood glucose monitoring; BP, blood pressure; CGM, continuous
glucose monitoring; CKD, chronic kidney disease; CVD, atherosclerotic cardiovascular disease; DSMES, diabetes self-management education and support; HF, heart failure.
Davies and Associates
3
how language matters. Language in dia- The best outcomes from DSMES are must be addressed to improve health out-
betes care should be neutral, free of achieved through programs with a theory- comes. Five social determinants of health
stigma, and based on facts; be strength- based and structured curriculum and with areas have been identified: socioeconomic
based (focus on what is working), respect- contact time of over 10 h (26). While on- status (education, income, and occupa-
ful, and inclusive; encourage collaboration; line programs may reinforce learning, a tion), living and working conditions, multi-
and be person-centered (18). People living comprehensive approach to education us- sector domains (e.g., housing, education,
with diabetes should not be referred to as ing multiple methods may be more effec- and criminal justice system), sociocultural
“diabetics” or described as “noncompliant” tive (26). Emerging evidence demonstrates context (e.g., shared cultural values, practi-
or blamed for their health condition. the benefits of telehealth or web-based ces, and experiences), and sociopolitical
DSMES programs (33), and these were context (e.g., societal and political norms
Diabetes Self-Management Education used with success during the coronavirus that are root-cause ideologies and policies
and Support disease 2019 (COVID-19) pandemic (34–36). underlying health disparities) (46). More
DSMES is a key intervention, as important
improve risk factors for cardiometabolic management (57). Additionally, time causes of therapeutic inertia are multi-
disease and quality of life (50). above and below range are useful varia- factorial, occurring at the levels of the
bles for the evaluation of treatment regi- practitioner, person with diabetes, and/
Glucose Management: Monitoring mens. Particular attention to minimizing or health care system (66). Interventions
Glycemic management is primarily as- the time below range in those with hypo- targeting therapeutic inertia have facili-
sessed with the HbA1c test, which was glycemia unawareness may convey bene- tated improvements in glycemic manage-
the measure used in trials demonstrating fit. If using the ambulatory glucose profile ment and timely insulin intensification
the benefits of glucose lowering (2,52). to assess glycemic management, a goal (67,68). For example, the involvement of
As with any laboratory test, HbA1c mea- parallel to an HbA1c level of <53 mmol/ multidisciplinary teams that include non-
surement has limitations (2,52). There mol (<7%) for many is time in range of physician providers with authorization
may be discrepancies between HbA1c re- >70%, with additional recommendations to prescribe (e.g., pharmacists, specialist
sults and an individual’s true mean blood to aim for time below range of <4% and nurses, and advanced practice providers)
time at <3.0 mmol/L (<54 mg/dL) of
CV, cardiovascular; CVOT, cardiovascular outcomes trial; DKA, diabetic ketoacidosis; DKD, diabetic kidney disease; DPP-4, dipeptidyl peptidase 4; eGFR, estimated glomerular filtration rate; GI, gastroin-
testinal; GIP, gastric inhibitory polypeptide; GLP-1 RA, glucagon-like peptide 1 receptor agonist; HF, heart failure; NASH, nonalcoholic steatohepatitis; MACE, major adverse cardiovascular events; SGLT2,
sodium-glucose cotransporter 2; SQ, subcutaneous; T2DM, type 2 diabetes mellitus. *For agent-specific dosing recommendations, please refer to manufacturers’ prescribing information.
1
Tsapas et al. (223). 2Tsapas et al. (224).
Diabetes Care
maintained is important for weight loss lifestyle programs may be considered for Physical Activity Behaviors, Including
(5,6,22,72–74). glycemic benefit and can be adapted for Sleep
A network analysis comparing trials of specific cultural indications (83–87). Physical activity behaviors significantly
nine dietary approaches of >12 weeks’ du- The Diabetes Remission Clinical Trial impact cardiometabolic health in type 2
ration demonstrated reductions in HbA1c (DiRECT) demonstrated greater remis- diabetes (Fig. 2) (96–117). Regular aero-
from –9 to –5.1 mmol/mol (–0.82% to sion of diabetes with a weight manage- bic exercise (i.e., involving large muscle
–0.47%) with all approaches compared ment program than with usual best groups and rhythmic in nature) improves
with a control diet. Greater glycemic ben- practice care in adults with type 2 dia- glycemic management in adults with type 2
efits were seen with the Mediterranean diabetes, resulting in less daily time in hyper-
betes within 6 years of diagnosis. The
diet and low-carbohydrate diet (75). The glycemia and reductions of 7 mmol/mol
structured, primary care-led intensive
greater glycemic benefits of low-carbohy- (0.6%) in HbA1c (118), and induces clini-
weight management program involved to-
drate diets (<26% of energy) at 3 and cally significant benefits in cardiorespira-
tal diet replacement (3,452–3,569 kJ/day
tory fitness (101,110,119). These glycemic
insulin sensitivity and reduce energy intake (95% CI 34%, 53%) following metabolic Recent data have increased confidence
(117,125). However, “catch-up” weekend surgery in people with type 2 diabetes and in the safety of the SGLT2i drug class
sleep alone is not enough to reverse the a BMI <30 kg/m2 (136), significantly (141,142). Their use is associated with in-
impact of insufficient sleep (126). higher than that achieved with traditional creased risk for mycotic genital infections,
medical management (137). However, there which are reported to be typically mild
Weight Management Beyond is a strong association between duration of and treatable. While SGLT2i use can in-
Lifestyle Interventions diabetes and the likelihood of postoperative crease the risk of diabetic ketoacidosis
Medications for Weight Loss in Type 2 Diabetes diabetes remission. People with more re- (DKA), the incidence is low, with a modest
Weight loss medications are effective ad- cently diagnosed diabetes are more likely incremental absolute risk (142). The SGLT2i
juncts to lifestyle interventions and healthy to experience remission after metabolic cardiovascular outcome trials (CVOTs) have
behaviors for management of weight and surgery, and the likelihood of remission reported DKA rates of 0.1–0.6% compared
have also been found to improve glucose decreases significantly with duration of di- with rates of <0.1–0.3% with placebo
weight (5,6,164). Beyond improving HbA1c provided when initiating GLP-1 RA therapy. considered at treatment initiation to ex-
in adults with type 2 diabetes, specific GLP-1 RA promote a sense of satiety, facili- tend the time to treatment failure (176).
GLP-1 RA have also been approved for re- tating reduction in food intake. It is impor- Metformin should not be used in people
ducing risk of MACE in adults with type 2 tant to help people distinguish between with an eGFR <30 ml/min per 1.73 m2,
diabetes with established CVD (dulaglu- nausea, a negative sensation, and satiety, and dose reduction should be considered
tide, liraglutide, and subcutaneous sema- a positive sensation that supports weight when the eGFR is <45 ml/min per 1.73 m2
glutide) or multiple cardiovascular risk loss. Mindful eating should be encouraged: (177). Metformin use may result in lower
factors (dulaglutide) (Table 1) and for eating slowly, stopping eating when full serum vitamin B12 concentrations and
chronic weight management (subcutane- and not eating when not hungry. Smaller worsening of symptoms of neuropathy;
ous liraglutide titrated to 3.0 mg once meals or snacks, decreasing intake of high- therefore, periodic monitoring and supple-
daily; subcutaneous semaglutide titrated fat and spicy foods, moderating alcohol in- mentation are generally recommended if
to 2.4 mg once weekly). This is discussed take, and increasing water intake are also levels are deficient, particularly in those
recommended. Slower or flexible dose
approved tirzepatide, a GIP and GLP-1 RA, have raised concerns, although findings on the education and support provided
for once-weekly subcutaneous administra- from systematic reviews have found no in- to facilitate self-management (5,6). Care-
tion to improve glucose control in adults crease in all-cause mortality rates com- ful consideration should be given to the
with type 2 diabetes as an addition to pared with other active treatments (191). pharmacokinetic and pharmacodynamic
healthy eating and exercise. In the Phase The incidence of cardiovascular events profiles of the available insulins as well
III clinical trial program, tirzepatide dem- was comparable in those treated with a as the matching of the dose and timing
onstrated superior glycemic efficacy to sulfonylurea or pioglitazone in the Thiazoli- to an individual’s physiological require-
placebo (183,184), subcutaneous sema- dinediones or Sulfonylureas and Cardiovas- ments. Numerous formulations of insulin
glutide 1.0 mg weekly (185), insulin de- cular Accidents Intervention Trial (TOSCA.IT) are available, with advances in therapy
gludec (186), and insulin glargine (187). (193), and no difference in the incidence geared toward better mimicking physio-
For HbA1c, placebo-adjusted reductions of MACE was found in people at high logical insulin release patterns. Chal-
of 21 mmol/mol (1.91%), 21 mmol/mol cardiovascular risk treated with glimepiride lenges of insulin therapy include weight
or linagliptin (194), a medication whose
formulated as premixes, combining mix- is seen with subcutaneous semaglutide Liraglutide exhibited a lower risk than the
tures of the insulin with protamine sus- followed by the other GLP-1 RA and pooled effect of the other three medica-
pension and the rapid-acting insulin. SGLT2i, and the greatest reduction in tions on a composite cardiovascular out-
Analog-based mixtures may be timed in blood pressure is seen with the SGLT2i come comprising MACE, revascularization,
closer proximity to meals. Education on the and GLP-1 RA classes (224). As discussed or HF or unstable angina requiring hospi-
impact of dietary nutrients on glucose levels above, the novel GIP and GLP-1 RA tir- talization (245,246).
to reduce the risk of hypoglycemia while zepatide was associated with greater
using mixed insulin is important. Insulins glycemic and weight loss efficacy than PERSONALIZED APPROACH TO
with different routes of administration (in- semaglutide 1 mg weekly (185). TREATMENT BASED ON
haled, bolus-only insulin delivery patch INDIVIDUAL CHARACTERISTICS
pump) are also available (211–213). Combination Therapy AND COMORBIDITIES:
The underlying pathophysiology of type 2 RECOMMENDED PROCESS FOR
GLUCOSE-LOWERING
Figure 3—Use of glucose-lowering medications in the management of type 2 diabetes. ACEi, angiotensin-converting enzyme inhibitor; ACR, albumin/creatinine ratio; ARB, angiotensin receptor blocker; ASCVD,
atherosclerotic cardiovascular disease; CGM, continuous glucose monitoring; CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease; CVOT, cardiovascular outcomes trial; DPP-4i, dipep-
tidyl peptidase 4 inhibitor; eGFR, estimated glomerular filtration rate; GLP-1 RA, glucagon-like peptide 1 receptor agonist; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart
failure with reduced ejection fraction; HHF, hospitalization for heart failure; MACE, major adverse cardiovascular events; MI, myocardial infarction; SDOH, social determinants of health; SGLT2i, sodium-glucose co-
transporter 2 inhibitor; T2D, type 2 diabetes; TZD, thiazolidinedione.
Davies and Associates
13
composite primary outcome of progres- diabetes and worsening HF, sotagliflozin in the overall population versus placebo
sion to renal replacement therapy, eGFR reduced the total number of cardiovascu- (142,249). Regarding GLP-1 RA, a meta-
of <15 ml/min per 1.73 m2, a doubling lar deaths or hospitalizations or urgent analysis of relevant CVOTs demonstrated
of serum creatinine level, or death from visits for HF compared with placebo re- the favorable effect of GLP-1 RA versus
cardiovascular or kidney causes. The Da- gardless of ejection fraction (150). All placebo on MACE and its individual com-
pagliflozin and Prevention of Adverse these data corroborate the salutary drug ponents, including stroke, HHF, and a
Outcomes in Chronic Kidney Disease class effects of SGLT2i on HF-related out- composite kidney outcome including se-
(DAPA-CKD) trial recruited participants comes in the setting of HF, irrespective of vere albuminuria (250,251). It should be
with and without type 2 diabetes with ejection fraction or diabetes status. noted, however, that the overall effect
an eGFR of 25–75 ml/min per 1.73 m2 Finally, among GLP-1 RA, the Effect of estimate for HHF seems to have been
and a urinary albumin/creatinine ratio Efpeglenatide on Cardiovascular Out- driven by CVOTs of albiglutide and efpe-
(UACR) of 20–500 mg/mmol [200–5,000 comes (AMPLITUDE-O) trial demonstrated glenatide, which are not available for
implemented support the credibility of albumin excretion rate [UACR <3.0 mg/ and data on efficacy, safety, and outcome
the conclusions favoring use of SGLT2i or mmol (<30 mg/g)], moderate albuminuria benefits considering within-class heteroge-
GLP-1 RA in individuals with compelling [UACR 3.0–30 mg/mmol (30–300 mg/g)], neity. No CVOT is available that focuses
indications independent of the use of and severe albuminuria [UACR $30 mg/ on people with type 2 diabetes who are
metformin. mmol ($300 mg/g)]) (252). In addition, no at low cardiovascular risk. Some infer-
Similarly, other subgroup analyses have modification of the effect estimates for ences about the effect of glucose-lower-
explored the role of baseline cardiovascu- MACE, cardiovascular death or HHF, and ing medications as primary cardiovascular
lar risk as a potential effect modifier re- the composite kidney outcome was ob- prevention in populations with low car-
garding the effect of treatment on MACE, served for SGLT2i in subgroup meta- diovascular risk can be made from net-
HHF, or kidney outcomes. Consistency of analyses based on history of HF (142). work meta-analyses, suggesting that no
findings from between-trial and within- Regarding GLP-1 RA, a subgroup meta- agent or drug class has a notable benefi-
trial comparisons, formal statistical testing analysis found that their effect on MACE cial effect on cardiovascular events in low-
population (266). Therefore, recommen- infarction, stroke, and lower extremity Sex Differences
dations for the selection of medications amputation over a 5-year period was In women with reproductive potential,
to improve cardiovascular and kidney most notable in people with diabetes the use of highly effective contraception
outcomes do not differ for older people. aged 18–44 years (275). Younger people should be ensured, such as long-acting re-
Older age should not be an obstacle to with type 2 diabetes should be consid- versible contraception (intrauterine device
treatment of individuals with established ered at very high risk for complications or progesterone implant), prior to pre-
or high risk for CVD. However, medica- and treated correspondingly. Early use scribing medications that may adversely
tion choices for people who are frail or of combination therapy may be consid- affect a fetus. Diabetes significantly in-
who have multiple comorbidities may re- ered, as the Vildagliptin Efficacy in Combi- creases the risk of cardiovascular compli-
quire modification for safety and tolera- nation with Metformin for Early Treatment cations in both sexes, and CVD causes
bility. People with diabetes should also of Type 2 Diabetes (VERIFY) trial findings most hospitalizations and deaths in
understand and be able to appropriately suggest that this approach provides supe- women and men with diabetes (280,281).
to reduce NASH activity; pioglitazone sessions/week. Balance training ses- • In general, selection of medications to
therapy and metabolic surgery may also sions are particularly encouraged for improve cardiovascular and kidney out-
improve hepatic fibrosis (188,292–298). older individuals or those with limited comes should not differ for older people.
Although not licensed for this pur- mobility/poor physical function. • In younger people with diabetes
pose, it has therefore been suggested • Metabolic surgery should be consid- (<40 years), consider early combina-
that people with type 2 diabetes at in- ered as a treatment option in adults tion therapy.
termediate to high risk of fibrosis should with type 2 diabetes who are appro- • In women with reproductive potential,
be considered for treatment with piogli- priate surgical candidates with a BMI counseling regarding contraception and
tazone and/or a GLP-1 RA with evidence $40.0 kg/m2 (BMI $37.5 kg/m2 in taking care to avoid exposure to medi-
of benefit (291,299). Although SGLT2i people of Asian ancestry) or a BMI of cations that may adversely affect a fe-
therapy has also been shown to reduce 35.0–39.9 kg/m2 (32.5–37.4 kg/m2 in tus are important.
elevated levels of liver enzymes and he- people of Asian ancestry) who do not
achieve durable weight loss and im-
Figure 4—Holistic person-centered approach to T2DM management. 1“Cardiovascular Disease and Risk Management” in Standards of Medical Care in Diabetes—2022 (141). ACEi, angiotensin-converting en-
zyme inhibitor; ARB, angiotensin receptor blockers; ASCVD, atherosclerotic cardiovascular disease; BP, blood pressure; CKD, chronic kidney disease; CV, cardiovascular; eGFR, estimated glomerular filtration
rate; GLP-1 RA, glucagon-like peptide 1 receptor agonist; HF, heart failure; SGLT2i, sodium-glucose cotransporter 2 inhibitor; T2D, type 2 diabetes.
Diabetes Care
care, comorbid conditions, degree of hy- approach to diabetes. Mental illness, in- Facilitating Healthy Behaviors and
perglycemia, risks of complications, and cluding depression, is associated with an Weight Management
susceptibility to medication side effects. increased risk of diabetes and with Promotion of healthy behaviors is central
Attention should be given to how the bal- poorer prognosis but may also compli- to the holistic management of type 2 di-
ance of risks and benefits of each inter- cate diabetes management and be a bar- abetes and should be addressed at the
vention is communicated to each person rier to self-management. time of diagnosis and throughout the
living with diabetes. Risk estimator tools, course of diabetes. Healthy behaviors in-
especially for CVD risk, may also be help- Practical Tips for Clinicians
clude healthy nutrition, regular physical
ful, but when using these tools one must • Consider each person living with dia- activity, adequate sleep, and smoking
be aware that they work best when they betes an individual with specific con- cessation. Health behaviors should al-
are derived from and/or are validated in text, risks, and preferences. ways be assessed and addressed when
a population similar to the population in • Health care systems should monitor glycemic targets are not met and when
new pharmacotherapy or interventions
loss, particularly GLP-1 RA with high symptoms, and treatment of hypogly- events are more likely to experience a
weight loss efficacy, should be considered, cemia when undertaking physical ac- benefit over intermediate time frames
as they can often provide 10–15% weight tivity or adopting a specific nutritional than those with cardiovascular risk factors
loss or more. Metabolic surgery, which is plan; prescribe glucagon in people at only. Through shared decision-making,
most effective when performed early dur- risk for severe hypoglycemia. considering an individual’s lifelong CVD
ing diabetes, can be considered in those • DSMES and MNT can help the person risk, introduction of a GLP-1 RA or SGLT2i
without a sufficient response to nonsurgi- living with diabetes to identify and ad- with proven cardiovascular benefit into
cal weight loss interventions based on dress barriers to implementing health- the regimen for a person with CVD risk
the specific context and preferences and ier behaviors. factors can be considered in the context
should be accompanied by health behav- See Supplementary Fig. 2. of increased treatment burden and po-
ior interventions. The benefits of meta- tential side effects with lower absolute
bolic surgery need to be balanced against Choice of Glucose-Lowering risk reduction.
Medication
update (5,6), other classes of agents are agents with complementary mechanisms safety, and organ protection. While most
useful in combination with metformin or of action should be pursued. Tradition- people with diabetes require intensifica-
when metformin is contraindicated or ally, a stepwise approach was advocated, tion of glucose-lowering medications,
not tolerated. Selection of other glucose- in which a new agent is added to the ex- some require medication reduction or
lowering agents will be determined by isting regimen, but evidence is growing discontinuation, particularly if the ther-
the balance between the glucose-lowering to support a more proactive approach in apy is ineffective or associated with side
efficacy and the side effect profile of the many by combining glucose-lowering effects such as hypoglycemia or when
individual agents (see Table 1). agents from initial diagnosis (6). glycemic goals have changed because of
Special attention needs to be given to Early use of combinations of agents a change in clinical circumstances (e.g.,
populations in which hypoglycemia is most allows tighter glucose control than development of comorbidities or even
dangerous, for example, people with monotherapy with the individual agents, healthy ageing). Medication should be
frailty, in whom agents without risk of and thus combinations of agents are in- stopped, or the dose reduced, if there are
Practical Tips for Clinicians control as defined by HbA1c and time in is necessary to ensure evolving evidence
• The use of a GLP-1 RA should be con- range (3.9–10.0 mmol/L [70–180 mg/dL]), reaches people living with type 2 diabetes.
sidered prior to initiation of insulin. fewer hyperglycemic and hypoglycemic Policy makers have a responsibility to en-
• When initiating insulin, start with a episodes, and improvements in diabetes sure that evidence-based interventions are
basal insulin and intensify the dose in distress (336,337). available and affordable to all. Interven-
a timely fashion, titrating to achieve As with other wearables, for example, tions to improve diabetes must also in-
an individualized fasting glycemic tar- those collecting steps walked or monitor- clude the health system (including the
get set for every person. ing dietary intake, medication dose ad- microsystems within a system) and gov-
• When insulin is initiated, continue or- ministered, or sleep quality, use of CGM ernmental agencies. Policy makers, to-
gan-protective glucose-lowering medi- has also been proposed as a motivational gether with all stakeholders, should
cations and metformin. tool for those with type 2 diabetes not reflect on care delivery. How, where, and
• Refer for DSMES when initiating insulin on insulin therapy, but the evidence on by whom is care delivered? Who coordi-
or advancing to basal–bolus therapy.
a year of identification of the severe systematically integrated with published being treated with therapies that
acute respiratory syndrome coronavirus 2 evidence to drive quality improvement have been inadequately studied in
(SARS-CoV-2) virus, preventive and thera- (344–346). Precision medicine initiatives, pregnancy, it is essential to describe
peutic products were not only developed whether omics-based or focused on social the reproductive safety of recom-
and tested but also administered on a determinants of health, aim to optimally mended approaches. Similarly, there
massive scale. The annual global mortal- target interventions based on the wide have been inadequate studies of
ity rate directly attributable to diabetes heterogeneity of the population affected frail older people and those aged
is approximately 1.5 million people, with by diabetes. Precision medicine has tre- >75 years with regard to under-
540 million people affected (340,341). mendous but largely unrealized promise. standing both appropriate targets
Although not as spectacular as the im- When these efforts are driven by real- and interventions to minimize harms
pact of COVID-19 on the health of soci- world data, causal inference study design and maximize quality of life. Sex bal-
ety, diabetes is sure and steady in its and analysis create greater confidence in ance is another dimension where
our present studies fail to be repre-
• Glucose monitoring. Further studies to person-centered decision-making and sup- and Sanofi, an advisory board member and
understand the role and optimal im- port informed by an understanding of local speaker for AstraZeneca, an advisory board
member for Janssen, Lexicon, Pfizer, and ShouTi
plementation of CGM and/or episodic resources and individual social determi- Pharma, and as a speaker for Napp Pharma-
CGM in type 2 diabetes are needed. nants of health. Combined with consistent ceuticals, Novartis, and Takeda Pharmaceuticals
• Comorbidities. There are numerous efforts to improve health behaviors (nutri- International. Her institution has received grants
studies underway to understand the tion, activity, sleep, and self-monitoring) from Novo Nordisk, Sanofi, Eli Lilly, Boehringer
role of interventions in the setting Ingelheim, AstraZeneca, and Janssen. V.R.A. has
and to provide DSMES, these form the
served as a consultant for Applied Therapeutics,
of NAFLD and cognitive impairment. foundation of diabetes management. In Duke, Fractyl, Novo Nordisk, Pfizer, and Sanofi.
NAFLD is highly prevalent, and thus this context, acceptance of, adherence to, V.R.A.’s spouse is an employee of Janssen and a
understanding the impact of interven- and persistence with medical and behav- former employee of Merck. V.R.A.’s employer in-
tions on person-centered outcomes ioral interventions to support cardiorenal stitution has received research funding for her
and costs is essential. Cognitive impair- role as investigator on clinical trials from Ap-
health, cardiovascular risk reduction, and plied Therapeutics, Medpace, Eli Lilly, Fractyl,
ment is a major burden to people with
Boehringer Ingelheim, Eli Lilly, Fortress Biotech, microvascular complications in patients with type 2 www.diabetes.org.uk/resources-s3/2017-11/
Janssen, Mellitus Health, Moderna, Pendulum Ther- diabetes: a meta-analysis of randomised control- structuredpatiented.pdf
apeutics, Praetego, ReachMD, Stability Health, and trials. Therapie 2021;77:413–423 24. National Institute for Health and Clinical
Zealand Pharma. He is a member of the advisory 12. Agrawal L, Azad N, Bahn GD, et al.; VADT Excellence. Diabetes in adults. Quality statements 2
board for Boehringer Ingelheim, Eli Lilly, Mellitus Study Group. Long-term follow-up of intensive and 3. Quality standard [QS6]. London, U.K.,
Health, Moderna, Novo Nordisk, Pendulum glycaemic control on renal outcomes in the National Institute for Health and Clinical Excellence,
Therapeutics, Praetego, Stability Health, vTv Ther- Veterans Affairs Diabetes Trial (VADT). Diabetologia 2016. Accessed 18 August 2022. Available from
apeutics, and Zealand Pharma. His employer re- 2018;61:295–299 www.nice.org.uk/guidance/qs6
ceives research funding from Dexcom, Eli Lilly, 13. Lind M, Imberg H, Coleman RL, Nerman O, 25. Chrvala CA, Sherr D, Lipman RD. Diabetes
NovaTarg, Novo Nordisk, Sanofi, Tolerion, and Holman RR. Historical HbA1c values may explain self-management education for adults with type 2
vTv Therapeutics. He is an investor in Mellitus the type 2 diabetes legacy effect: UKPDS 88. diabetes mellitus: a systematic review of the effect
Health, Pendulum Therapeutics, and PhaseBio. Diabetes Care 2021;44:2231–2237 on glycemic control. Patient Educ Couns 2016;99:
Author Contributions. All authors were re- 14. Riddle MC, Gerstein HC, Holman RR, et al. 926–943
sponsible for drafting the article and revising it A1C targets should be personalized to maximize 26. Pillay J, Armstrong MJ, Butalia S, et al.
critically for important intellectual content. All benefits while limiting risks. Diabetes Care Behavioral programs for type 2 diabetes mellitus:
38. Lee MK, Lee DY, Ahn HY, Park CY. A novel user monitoring of blood glucose on glucose control randomised controlled trial. Prim Care Diabetes
utility score for diabetes management using in patients with non-insulin-treated type 2 2017;11:474–481
tailored mobile coaching: secondary analysis of a diabetes: a meta-analysis of randomized controlled 69. Tabesh M, Magliano DJ, Koye DN, Shaw JE.
randomized controlled trial. JMIR Mhealth Uhealth trials. J Diabetes Sci Technol 2018;12:183–189 The effect of nurse prescribers on glycaemic
2021;9:e17573 55. Young LA, Buse JB, Weaver MA, et al.; control in type 2 diabetes: a systematic review
39. Ahlqvist E, Storm P, K€ar€aj€am€aki A, et al. Monitor Trial Group. Glucose self-monitoring in and meta-analysis. Int J Nurs Stud 2018;78:37–43
Novel subgroups of adult-onset diabetes and non-insulin-treated patients with type 2 diabetes 70. Murphy ME, Byrne M, Galvin R, Boland F,
their association with outcomes: a data-driven in primary care settings: a randomized trial. Fahey T, Smith SM. Improving risk factor
cluster analysis of six variables. Lancet Diabetes JAMA Intern Med 2017;177:920–929 management for patients with poorly controlled
Endocrinol 2018;6:361–369 56. National Institute for Health and Care Excellence. type 2 diabetes: a systematic review of healthcare
40. Pigeyre M, Hess S, Gomez MF, et al. Type 2 diabetes in adults: management. Overview. interventions in primary care and community
Validation of the classification for type 2 diabetes NICE guideline [NG28]. London, U.K., National Institute settings. BMJ Open 2017;7:e015135
into five subgroups: a report from the ORIGIN for Health and Clinical Excellence. Accessed 28 July 71. American Diabetes Association. Introduction:
trial. Diabetologia 2022;65:206–215 2022. Available from www.nice.org.uk/guidance/ng28 Standards of Medical Care in Diabetes—2022.
41. American Diabetes Association Professional 57. Lu J, Ma X, Zhou J, et al. Association of time Diabetes Care 2022;45(Suppl. 1):S1–S2
hypoglycaemia: a randomized controlled trial. Diabet Diabetes–2021. Diabetes Care 2021;44(Suppl. 1): function: a growing problem. Diabetology 2022;
Med 2018;35:588–594 S40–S52 3:30–45
83. O’Neil PM, Miller-Kovach K, Tuerk PW, et al. 97. Lee SWH, Ng KY, Chin WK. The impact of 113. Smyth A, Jenkins M, Dunham M, Kutzer Y,
Randomized controlled trial of a nationally sleep amount and sleep quality on glycemic Taheri S, Whitehead L. Systematic review of clinical
available weight control program tailored for control in type 2 diabetes: a systematic review practice guidelines to identify recommendations
adults with type 2 diabetes. Obesity (Silver Spring) and meta-analysis. Sleep Med Rev 2017;31: for sleep in type 2 diabetes mellitus management.
2016;24:2269–2277 91–101 Diabetes Res Clin Pract 2020;170:108532
84. Mottalib A, Salsberg V, Mohd-Yusof BN, 98. Schipper SBJ, Van Veen MM, Elders PJM, 114. Zuraikat FM, Makarem N, Redline S,
et al. Effects of nutrition therapy on HbA1c et al. Sleep disorders in people with type 2 Aggarwal B, Jelic S, St-Onge MP. Sleep regularity
and cardiovascular disease risk factors in diabetes and associated health outcomes: a and cardiometabolic heath: is variability in sleep
overweight and obese patients with type 2 review of the literature. Diabetologia 2021;64: patterns a risk factor for excess adiposity and
diabetes. Nutr J 2018;17:42 2367–2377 glycemic dysregulation? Curr Diab Rep 2020;20:38
85. Chee WSS, Gilcharan Singh HK, Hamdy O, 99. Navarro DJ, Alpert PT, Cross C. The impact of 115. International Diabetes Federation. (2017) The
et al. Structured lifestyle intervention based on a shift work on diabetes self-management activities. IDF Consensus Statement on sleep apnoea and
trans-cultural diabetes-specific nutrition algorithm J Dr Nurs Pract 2019;12:66–72 type 2 diabetes. Brussels, Belgium, International
126. Depner CM, Melanson EL, Eckel RH, et al. Ad 140. Aminian A, Kashyap SR, Wolski KE, et al. cloudfront.net/50fd68b9-106b-4550-b5d0-
libitum weekend recovery sleep fails to prevent Patient-reported outcomes after metabolic surgery 12b045f8b184/0be9cb1b-3b33-41c7-bfc2-
metabolic dysregulation during a repeating pattern versus medical therapy for diabetes: insights from 04c9f718e442/0be9cb1b-3b33-41c7-bfc2-
of insufficient sleep and weekend recovery sleep. the STAMPEDE randomized trial. Ann Surg 2021; 04c9f718e442_viewable_rendition__v.pdf
Curr Biol 2019;29:957–967.e4 274:524–532 157. Merck. Prescribing information for STEGLATRO.
127. Draznin B, Aroda VR, Bakris G, et al.; 141. American Diabetes Association Professional Readington, NJ, Merck, 2017. Accessed 20 June 2022.
American Diabetes Association Professional Practice Practice Committee. 10. Cardiovascular disease and Available from www.accessdata.fda.gov/drugsatfda_
Committee. 8. Obesity and weight management for risk management: Standards of Medical Care in docs/label/2017/209803s000lbl.pdf
the prevention and treatment of type 2 diabetes: Diabetes–2022. Diabetes Care 2022;45(Suppl. 1): 158. Mistry S, Eschler DC. Euglycemic diabetic
Standards of Medical Care in Diabetes–2022. S144–S174 ketoacidosis caused by SGLT2 inhibitors and a
Diabetes Care 2022;45(Suppl. 1):S113–S124 142. McGuire DK, Shih WJ, Cosentino F, et al. ketogenic diet: a case series and review of
128. Davies M, Færch L, Jeppesen OK, et al.; Association of SGLT2 inhibitors with cardiovascular literature. AACE Clin Case Rep 2020;7:17–19
STEP 2 Study Group. Semaglutide 2.4 mg once a and kidney outcomes in patients with type 2 159. Kosiborod MN, Esterline R, Furtado RHM, et al.
week in adults with overweight or obesity, and diabetes: a meta-analysis. JAMA Cardiol 2021;6: Dapagliflozin in patients with cardiometabolic risk
type 2 diabetes (STEP 2): a randomised, double- 148–158 factors hospitalised with COVID-19 (DARE-19): a
and the risk of diabetic retinopathy. Diabetes diabetes (SURPASS-1): a double-blind, randomised, cardiovascular and renal risk: the CARMELINA
Obes Metab 2018;20:889–897 phase 3 trial. Lancet 2021;398:143–155 randomized clinical trial. JAMA 2019;321:69–79
171. Bethel MA, Diaz R, Castellana N, Bhattacharya 184. Dahl D, Onishi Y, Norwood P, et al. Effect of 196. Kahn SE, Haffner SM, Heise MA, et al.;
I, Gerstein HC, Lakshmanan MC. HbA1c change and subcutaneous tirzepatide vs placebo added to ADOPT Study Group. Glycemic durability of
diabetic retinopathy during GLP-1 receptor agonist titrated insulin glargine on glycemic control in rosiglitazone, metformin, or glyburide monotherapy.
cardiovascular outcome trials: a meta-analysis and patients with type 2 diabetes: the SURPASS-5 N Engl J Med 2006;355:2427–2443
meta-regression. Diabetes Care 2021;44:290–296 randomized clinical trial. JAMA 2022;327:534– 197. Dormandy JA, Charbonnel B, Eckland DJA,
172. He L, Wang J, Ping F, et al. Association of 545 et al.; PROactive Investigators. Secondary prevention
glucagon-like peptide-1 receptor agonist use with 185. Frıas JP, Davies MJ, Rosenstock J, et al.; of macrovascular events in patients with type 2
risk of gallbladder and biliary diseases: a systematic SURPASS-2 Investigators. Tirzepatide versus diabetes in the PROactive Study (PROspective
review and meta-analysis of randomized clinical semaglutide once weekly in patients with type 2 pioglitAzone Clinical Trial In macroVascular Events): a
trials. JAMA Intern Med 2022;182:513–519 diabetes. N Engl J Med 2021;385:503–515 randomised controlled trial. Lancet 2005;366:
173. Crowley MJ, McGuire DK, Alexopoulos AS, 186. Ludvik B, Giorgino F, J odar E, et al. Once- 1279–1289
et al. Effects of liraglutide on cardiovascular weekly tirzepatide versus once-daily insulin 198. Kernan WN, Viscoli CM, Furie KL, et al.; IRIS
outcomes in type 2 diabetes patients with and degludec as add-on to metformin with or Trial Investigators. Pioglitazone after ischemic
basal and prandial insulin analogues for the 224. Tsapas A, Karagiannis T, Kakotrichi P, et al. a systematic review and meta-analysis. J Clin
treatment of type 2 diabetes: a network meta- Comparative efficacy of glucose-lowering medications Med 2019;8:E45
analysis of randomized controlled trials. Endocrine on body weight and blood pressure in patients 237. Castellana M, Cignarelli A, Brescia F, Laviola
2021;74:508–517 with type 2 diabetes: a systematic review and L, Giorgino F. GLP-1 receptor agonist added to
211. Chan J, Cheng-Lai A. Inhaled insulin: a network meta-analysis. Diabetes Obes Metab insulin versus basal-plus or basal-bolus insulin
clinical and historical review. Cardiol Rev 2017; 2021;23:2116–2124 therapy in type 2 diabetes: a systematic review
25:140–146 225. Abdul-Ghani M, Puckett C, Adams J, et al. and meta-analysis. Diabetes Metab Res Rev
212. Bergenstal RM, Peyrot M, Dreon DM, et al.; Durability of triple combination therapy versus 2019;35:e3082
Calibra Study Group. Implementation of basal- stepwise addition therapy in patients with new- 238. Min SH, Yoon JH, Hahn S, Cho YM. Efficacy
bolus therapy in type 2 diabetes: a randomized onset T2DM: 3-year follow-up of EDICT. Diabetes and safety of combination therapy with an
controlled trial comparing bolus insulin delivery Care 2021;44:433–439 a-glucosidase inhibitor and a dipeptidyl peptidase-4
using an insulin patch with an insulin pen. 226. Matthews DR, Paldanius PM, Proot P, inhibitor in patients with type 2 diabetes mellitus: a
Diabetes Technol Ther 2019;21:273–285 Chiang Y, Stumvoll M; VERIFY study group. systematic review with meta-analysis. J Diabetes
213. Heinemann L, Parkin CG. Rethinking the Glycaemic durability of an early combination Investig 2018;9:893–902
viability and utility of inhaled insulin in clinical therapy with vildagliptin and metformin versus 239. Cai X, Gao X, Yang W, Han X, Ji L. Efficacy
with the FREEDOM cardiovascular outcomes 264. European Medicines Agency. Guideline on 278. Mishriky BM, Powell JR, Wittwer JA, et al.
trial. Diabetes Metab Syndr 2022;16:102382 clinical investigation of medicinal products in the Do GLP-1RAs and SGLT-2is reduce cardiovascular
251. Shaman AM, Bain SC, Bakris GL, et al. Effect treatment or prevention of diabetes mellitus. events in black patients with type 2 diabetes? A
of the glucagon-like peptide-1 receptor agonists Amsterdam, Netherlands, European Medicines systematic review and meta-analysis. Diabetes
semaglutide and liraglutide on kidney outcomes Agency, 2012. Accessed 18 August 2022. Available Obes Metab 2019;21:2274–2283
in patients with type 2 diabetes: pooled analysis from www.ema.europa.eu/docs/en_GB/document_ 279. Food and Drug Administration. Diversity
of SUSTAIN 6 and LEADER. Circulation 2022; library/Scientific_guideline/2012/06/WC500129256. plans to improve enrollment of participants from
145:575–585 pdf underrepresented racial and ethnic populations
252. Neuen BL, Young T, Heerspink HJL, et al. 265. Food and Drug Administration. Draft in clinical trials; draft guidance for industry;
SGLT2 inhibitors for the prevention of kidney guidance for industry on diabetes mellitus: availability. Silver Spring, MD, Food and Drug
failure in patients with type 2 diabetes: a developing drugs and therapeutic biologics for Administration, 2022. Accessed 22 June 2022.
systematic review and meta-analysis. Lancet treatment and prevention–guidance document. Available from www.fda.gov/regulatory-nformation/
Diabetes Endocrinol 2019;7:845–854 Silver Spring, MD, Food and Drug Administration, isearch-fda-guidance-documents/diversity-plans-
253. Sattar N, Lee MMY, Kristensen SL, et al. 2008. Accessed 22 June 2022. Available from improve-enrollment-participants-underrepresented-
Cardiovascular, mortality, and kidney outcomes www.regulations.gov/document/FDA-2008-D-0118- racial-and-ethnic-populations
global public health agenda for NAFLD: a cardiovascular and renal outcomes: an expl- 320. Downes MJ, Bettington EK, Gunton JE,
consensus statement. Nat Rev Gastroenterol oratory analysis of the EMPA-REG OUTCOME trial. Turkstra E. Triple therapy in type 2 diabetes; a
Hepatol 2022;19:60–78 Diabetes Care 2020;43:3007–3015 systematic review and network meta-analysis.
291. Kanwal F, Shubrook JH, Adams LA, et al. 306. Levengood TW, Peng Y, Xiong KZ, et al.; PeerJ 2015;3:e1461
Clinical care pathway for the risk stratification Community Preventive Services Task Force. Team- 321. Lee CMY, Woodward M, Colagiuri S. Triple
and management of patients with nonalcoholic based care to improve diabetes management: a therapy combinations for the treatment of type 2
fatty liver disease. Gastroenterology 2021;161: community guide meta-analysis. Am J Prev Med diabetes–a network meta-analysis. Diabetes Res
1657–1669 2019;57:e17–e26 Clin Pract 2016;116:149–158
292. Newsome PN, Buchholtz K, Cusi K, et al.; 307. Chamnan P, Simmons RK, Sharp SJ, Griffin 322. Lukashevich V, Del Prato S, Araga M,
NN9931-4296 Investigators. A placebo-controlled SJ, Wareham NJ. Cardiovascular risk assessment Kothny W. Efficacy and safety of vildagliptin in
trial of subcutaneous semaglutide in nonalcoholic scores for people with diabetes: a systematic patients with type 2 diabetes mellitus inadequately
steatohepatitis. N Engl J Med 2021;384:1113–1124 review. Diabetologia 2009;52:2001–2014 controlled with dual combination of metformin and
293. Musso G, Cassader M, Paschetta E, Gambino 308. Srikanth V, Sinclair AJ, Hill-Briggs F, Moran sulphonylurea. Diabetes Obes Metab 2014;16:
R. Thiazolidinediones and advanced liver fibrosis in C, Biessels GJ. Type 2 diabetes and cognitive 403–409
nonalcoholic steatohepatitis: a meta-analysis. JAMA dysfunction–towards effective management of 323. Hong AR, Lee J, Ku EJ, et al. Comparison of
334. Eberle C, Stichling S. Effect of telemetric patients with type 2 diabetes treated with basal projections for 2045. Diabetes Res Clin Pract
interventions on glycated hemoglobin A1c and insulin: a randomized clinical trial. JAMA 2021; 2022;183:109119
management of type 2 diabetes mellitus: sys- 325:2262–2272 342. Falcetta P, Aragona M, Bertolotto A, et al.
tematic meta-review. J Med Internet Res 2021; 338. Effective Practice and Organisation of Care Insulin discovery: a pivotal point in medical
23:e23252 (EPOC). (2015) EPOC taxonomy. London, U.K., history. Metabolism 2022;127:154941
335. Dicembrini I, Mannucci E, Monami M, Pala 2015. Accessed 29 July 2022. Available from 343. Beran D, Lazo-Porras M, Mba CM, Mbanya
L. Impact of technology on glycaemic control in https://epoc.Cochrane.org/epoc-taxonomy JC. A global perspective on the issue of access to
type 2 diabetes: A meta-analysis of randomized 339. Chan JCN, Lim LL, Wareham NJ, et al. The insulin. Diabetologia 2021;64:954–962
trials on continuous glucose monitoring and Lancet Commission on diabetes: using data to 344. Horwitz LI, Kuznetsova M, Jones SA.
continuous subcutaneous insulin infusion. Diabetes transform diabetes care and patient lives. Lancet Creating a learning health system through rapid-
Obes Metab 2019;21:2619–2625 2021;396:2019–2082 cycle, randomized testing. N Engl J Med 2019;
336. Evans M, Welsh Z, Ells S, Seibold A. The 340. World Health Organization. Diabetes. 381:1175–1179
impact of flash glucose monitoring on glycaemic Geneva, Switzerland, World Health Organization, 345. McGinnis JM, Fineberg HV, Dzau VJ.
control as measured by HbA1c: a meta-analysis 2021. Accessed 1 August 2022. Available from Advancing the learning health system. N Engl J
of clinical trials and real-world observational www.who.int/news-room/fact-sheets/detail/ Med 2021;385:1–5