Diabetes Metab J.  2023 Sep;47(5):575-594. 10.4093/dmj.2023.0282.

2023 Clinical Practice Guidelines for Diabetes Mellitus of the Korean Diabetes Association

• Choi JH
• Lee KA
• Moon JH
• Chon S
• Kim DJ
• Kim HJ
• Kim NH
• Seo JA
• Kim MK
• Lim JH
• Song Y
• Yang YS
• Kim JH
• Lee YB
• Noh J
• Hur KY
• Park JS
• Rhee SY
• Kim HJ
• Kim HM
• Ko JH
• Kim NH
• Kim CH
• Ahn J
• Oh TJ
• Kim SK
• Kim J
• Han E
• Jin SM
• Choi WS
• Moon MK
• Committee of Clinical Practice Guidelines
• Korean Diabetes Association

• KMID: 2546118
• DOI: http://doi.org/10.4093/dmj.2023.0282

Abstract

In May 2023, the Committee of Clinical Practice Guidelines of the Korean Diabetes Association published the revised clinical practice guidelines for Korean adults with diabetes and prediabetes. We incorporated the latest clinical research findings through a comprehensive systematic literature review and applied them in a manner suitable for the Korean population. These guidelines are designed for all healthcare providers nationwide, including physicians, diabetes experts, and certified diabetes educators who manage patients with diabetes or individuals at risk of developing diabetes. Based on recent changes in international guidelines and the results of a Korean epidemiological study, the recommended age for diabetes screening has been lowered. In collaboration with the relevant Korean medical societies, recently revised guidelines for managing hypertension and dyslipidemia in patients with diabetes have been incorporated into this guideline. An abridgment containing practical information on patient education and systematic management in the clinic was published separately.

Keyword

Diabetes mellitus; Practice guideline; Prediabetic state; Republic of Korea

Figure

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  Fig. 1. Pharmacologic treatment fOr Adults With Type 2 Diabetes Mellitus (T2dm). This Algorithm Stratifies The Glycemic Control Strategy In Patients With T2dm Based On A1c Levels And Underlying Comorbidities. Self-management Education And Monitoring For Diabetes Should Be Continuously Implemented From The Time Of Diagnosis In All Patients With T2dm. If The A1c Level Is >9.0% And Symptomatic Hyperglycemia Or Metabolic Decompensation Is Present, Insulin Therapy With Or Without Oral Antidiabetic Drugs (Oads) Is Recommended. If Established Atherosclerotic Cardiovascular Disease (Eascvd), Heart Failure (Hf), Or Chronic Kidney Disease (Ckd) Are Combined, Sodium-glucose Cotransporter 2 Inhibitor (Sglt2i) Or Glucagon-like Peptide-1 Receptor Agonist (Glp-1ra), Which Have Proven Benefits Under These Conditions, Are Preferred. If The A1c Difference Between The Current And Target A1c Level Is ≥1.5% Or The Current A1c Level Is ≥7.5%, Initial Combination Therapy Is Recommended. If The Current A1c Level Is <7.5%, Metformin Monotherapy Is The Preferred Option, Depending On The Patient’s Condition. However, Early Combination Therapy Should Be Considered To Reduce The Risk Of Treatment Failure. Injectable Therapy, Glp-1ra Or Insulin Is Recommended When Potent Glucose-lowering Efficacy Is Required. When Considering Injectable-based Combination Therapy, Glp-1ra Is Preferred. If The Glycemic Target Is Not Achieved With Glp-1ra Or Basal Insulin Alone, The Two Drugs Can Be Combined. If The Glycemic Target Is Not Achieved With Glp-1ra Or Basal Insulin, Intensive Insulin Therapy Such As Basal-plus, Premixed, Or Basal-bolus Regimen Should Be Initiated. Tzd, Thiazolidinedione; Dpp-4i, Dipeptidyl Peptidase-4 Inhibitor; Su, Sulfonylurea; Α-gi, Α-glucosidase Inhibitor. aEstablished Atherosclerotic Cardiovascular Disease: History Of Acute Coronary Syndrome Or Myocardial Infarction, Stable Or Unstable Angina, Coronary Heart Disease With Or Without Revascularization, Other Arterial Revascularization, Stroke, Or Peripheral Artery Disease Assumed To Be Atherosclerotic In Origin, bHf: Current Or Prior Symptoms Of Hf With Documented Hf With Reduced Ejection Fraction (Hfref, Left Ventricular Ejection Fraction [Lvef] ≤40) Or Hf With Preserved Ejection Fraction (Hfpef, Lvef >40), cChronic Kidney Disease: Estimated Glomerular Filtration Rate (Egfr) <60 Ml/Min/1.73 M2 Or Urine Albumin-creatinine Ratio ≥30 Mg/G, dDulaglutide, Liraglutide, Semaglutide, eDapagliflozin, Empagliflozin, fDapagliflozin, Empagliflozin, Ertugliflozin, gPioglitazone.

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  Fig. 2. Hypertension management in patients with diabetes. Blood pressure (BP) should be measured at every clinic visit, and home BP monitoring is recommended. The recommended target BP level is <140/90 mm Hg in adults with diabetes without cardiovascular disease (CVD) or associated risk factors. The recommended target BP is <130/80 mm Hg in diabetic adults with CVD, target organ damage (albuminuria, chronic kidney disease, retinopathy, and left ventricular hypertrophy), or risk factors for CVD. Adults with diabetes and a BP >120/80 mm Hg should undergo lifestyle modifications. Pharmacological therapy should be implemented if the target BP is not achieved. Angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) are preferred when accompanied with albuminuria or coronary artery disease. If the BP exceeds 160/100 mm Hg, initial combination therapy is recommended. If BP is not controlled by primary antihypertensive medications, combination therapy using other drugs with different mechanisms is recommended. aAlbuminuria, chronic kidney disease, retinopathy, left ventricular hypertrophy, bAge (men ≥45 years, women ≥55 years), smoking, obesity, dyslipidemia, family history of early-onset coronary heart disease.

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  Fig. 3. Lipid management in patients with diabetes. Serum lipid profiles should be obtained at the time of the first diagnosis of diabetes and at least once a year thereafter. Past history of cardiovascular disease (CVD) and target organ damage (albuminuria, estimated glomerular filtration rate <60 mL/min/1.73 m2, retinopathy, and left ventricular hypertrophy), the major risk factors for CVD (age, family history of early-onset coronary artery disease, hypertension, smoking, and high-density lipoprotein cholesterol [HDL-C] <40 mg/dL) and duration of diabetes should be investigated to determine the low-density lipoprotein cholesterol (LDLC) goal. Education on active lifestyle modifications should also be provided. Pharmacological therapy should be implemented if LDL-C goals are not achieved. Statins should be used as first-line therapy. Ezetimibe should be added if the goal is not achieved with the maximum tolerable dose of statin therapy. If diabetic patients with CVD do not achieve this goal even after treatment with a statin plus ezetimibe, combination therapy with a statin and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors should be considered. Adults with severe hypertriglyceridemia (triglyceride levels ≥500 mg/dL) were treated with fenofibrate or omega-3 fatty acids. aAge (men ≥45 years, women ≥55 years), family history of early-onset coronary heart disease, hypertension, smoking, HDL-C <40 mg/dL, bAlbuminuria, estimated glomerular filtration rate <60 mL/min/1.73 m2, retinopathy, and left ventricular hypertrophy, cTarget organ damage or three or more major risk factors for CVD.

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  Fig. 4. Management of diabetic kidney disease. Urine albumin/creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) should be evaluated in individuals with type 2 diabetes mellitus (T2DM) at the time of diagnosis and at least once yearly. Therefore, blood glucose levels and blood pressure should be optimally controlled. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) that have shown renal benefits should first be used to inhibit diabetic kidney disease (DKD) progression in patients with albuminuria or a reduced eGFR. DKD patients consume adequate protein amounts. Angiotensin-converting enzyme inhibitors (ACEis) or angiotensin II receptor blockers (ARBs) should be prescribed for patients with diabetes, hypertension, and albuminuria. Non-steroidal mineralocorticoid receptor antagonists (nsMRAs), such as finerenone, which has shown cardiac and renal benefits, can be considered in patients with T2DM with albuminuria, decreased eGFR, and normal blood potassium levels. Request consultation with nephrologists for those with unknown causes of kidney disease or progressive nephropathy.

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  Fig. 5. Evaluation of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM). All adults with T2DM should be evaluated for the presence of NAFLD. Liver function tests or abdominal ultrasound should be performed to evaluate NAFLD and to exclude secondary causes. Non-invasive and simple tests, such as the fibrosis index-4 (FIB-4) or the NAFLD fibrosis score (NFS), can be used to evaluate liver fibrosis. Vibration-controlled transient elastography should be considered when evaluating liver fibrosis in T2DM adults, excluding those in low-risk groups. aLow risk: FIB-4 <1.3, NFS <2.67, bLow risk: liver stiffness measurement <8.0 kPa, Enhanced Liver Fibrosis (ELF) score <10.5.

Reference

1. Bae JH, Han KD, Ko SH, Yang YS, Choi JH, Choi KM, et al. Diabetes fact sheet in Korea 2021. Diabetes Metab J. 2022; 46:417–26.

2. Hur KY, Moon MK, Park JS, Kim SK, Lee SH, Yun JS, et al. 2021 Clinical practice guidelines for diabetes mellitus of the Korean Diabetes Association. Diabetes Metab J. 2021; 45:461–81.

3. Lee KA, Kim DJ, Han K, Chon S, Moon MK; Committee of Clinical Practice Guideline of Korean Diabetes Association. Screening for prediabetes and diabetes in Korean nonpregnant adults: a position statement of the Korean Diabetes Association, 2022. Diabetes Metab J. 2022; 46:819–26.

4. Kim BY, Kang SM, Kang JH, Kang SY, Kim KK, Kim KB, et al. 2020 Korean Society for the Study of Obesity guidelines for the management of obesity in Korea. J Obes Metab Syndr. 2021; 30:81–92.

5. Kim HL, Lee EM, Ahn SY, Kim KI, Kim HC, Kim JH, et al. The 2022 focused update of the 2018 Korean Hypertension Society guidelines for the management of hypertension. Clin Hypertens. 2023; 29:11.

6. Yang YS, Kim HL, Kim SH, Moon MK. Lipid management in Korean people with type 2 diabetes mellitus: Korean Diabetes Association and Korean Society of Lipid and Atherosclerosis Consensus Statement. Diabetes Metab J. 2023; 47:1–9.

7. Yang YS, Han BD, Han K, Jung JH, Son JW. Obesity fact sheet in Korea, 2021: trends in obesity prevalence and obesity-related comorbidity incidence stratified by age from 2009 to 2019. J Obes Metab Syndr. 2022; 31:169–77.

8. Diabetes Control and Complications Trial Research Group, Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, et al. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993; 329:977–86.

9. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998; 352:837–53.

10. Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract. 1995; 28:103–17.

11. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-Year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008; 359:1577–89.

12. Hayward RA, Reaven PD, Wiitala WL, Bahn GD, Reda DJ, Ge L, et al. Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015; 372:2197–206.

13. Lee AK, Warren B, Lee CJ, McEvoy JW, Matsushita K, Huang ES, et al. The association of severe hypoglycemia with incident cardiovascular events and mortality in adults with type 2 diabetes. Diabetes Care. 2018; 41:104–11.

14. Writing Group for the DCCT/EDIC Research Group, Orchard TJ, Nathan DM, Zinman B, Cleary P, Brillon D, et al. Association between 7 years of intensive treatment of type 1 diabetes and long-term mortality. JAMA. 2015; 313:45–53.

15. Heinemann L, Freckmann G, Ehrmann D, Faber-Heinemann G, Guerra S, Waldenmaier D, et al. Real-time continuous glucose monitoring in adults with type 1 diabetes and impaired hypoglycaemia awareness or severe hypoglycaemia treated with multiple daily insulin injections (HypoDE): a multicentre, randomised controlled trial. Lancet. 2018; 391:1367–77.

16. Battelino T, Phillip M, Bratina N, Nimri R, Oskarsson P, Bolinder J. Effect of continuous glucose monitoring on hypoglycemia in type 1 diabetes. Diabetes Care. 2011; 34:795–800.

17. Seyed Ahmadi S, Westman K, Pivodic A, Olafsdottir AF, Dahlqvist S, Hirsch IB, et al. The association between HbA1c and time in hypoglycemia during CGM and self-monitoring of blood glucose in people with type 1 diabetes and multiple daily insulin injections: a randomized clinical trial (GOLD-4). Diabetes Care. 2020; 43:2017–24.

18. Beck RW, Riddlesworth TD, Ruedy K, Ahmann A, Haller S, Kruger D, et al. Continuous glucose monitoring versus usual care in patients with type 2 diabetes receiving multiple daily insulin injections: a randomized trial. Ann Intern Med. 2017; 167:365–74.

19. Vigersky RA, Fonda SJ, Chellappa M, Walker MS, Ehrhardt NM. Short- and long-term effects of real-time continuous glucose monitoring in patients with type 2 diabetes. Diabetes Care. 2012; 35:32–8.

20. Ehrhardt NM, Chellappa M, Walker MS, Fonda SJ, Vigersky RA. The effect of real-time continuous glucose monitoring on glycemic control in patients with type 2 diabetes mellitus. J Diabetes Sci Technol. 2011; 5:668–75.

21. Yoo HJ, An HG, Park SY, Ryu OH, Kim HY, Seo JA, et al. Use of a real time continuous glucose monitoring system as a motivational device for poorly controlled type 2 diabetes. Diabetes Res Clin Pract. 2008; 82:73–9.

22. Bolinder J, Antuna R, Geelhoed-Duijvestijn P, Kroger J, Weitgasser R. Novel glucose-sensing technology and hypoglycaemia in type 1 diabetes: a multicentre, non-masked, randomised controlled trial. Lancet. 2016; 388:2254–63.

23. Haak T, Hanaire H, Ajjan R, Hermanns N, Riveline JP, Rayman G. Flash glucose-sensing technology as a replacement for blood glucose monitoring for the management of insulin-treated type 2 diabetes: a multicenter, open-label randomized controlled trial. Diabetes Ther. 2017; 8:55–73.

24. Yaron M, Roitman E, Aharon-Hananel G, Landau Z, Ganz T, Yanuv I, et al. Effect of flash glucose monitoring technology on glycemic control and treatment satisfaction in patients with type 2 diabetes. Diabetes Care. 2019; 42:1178–84.

25. Haskova A, Radovnicka L, Petruzelkova L, Parkin CG, Grunberger G, Horova E, et al. Real-time CGM is superior to flash glucose monitoring for glucose control in type 1 diabetes: the CORRIDA Randomized Controlled Trial. Diabetes Care. 2020; 43:2744–50.

26. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015; 373:2117–28.

27. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016; 375:311–22.

28. Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019; 394:121–30.

29. Maloney A, Rosenstock J, Fonseca V. A model-based meta-analysis of 24 antihyperglycemic drugs for type 2 diabetes: comparison of treatment effects at therapeutic doses. Clin Pharmacol Ther. 2019; 105:1213–23.

30. Egede LE, Gebregziabher M, Echols C, Lynch CP. Longitudinal effects of medication nonadherence on glycemic control. Ann Pharmacother. 2014; 48:562–70.

31. Huber CA, Reich O. Medication adherence in patients with diabetes mellitus: does physician drug dispensing enhance quality of care?: evidence from a large health claims database in Switzerland. Patient Prefer Adherence. 2016; 10:1803–9.

32. Iglay K, Cartier SE, Rosen VM, Zarotsky V, Rajpathak SN, Radican L, et al. Meta-analysis of studies examining medication adherence, persistence, and discontinuation of oral antihyperglycemic agents in type 2 diabetes. Curr Med Res Opin. 2015; 31:1283–96.

33. McGovern A, Tippu Z, Hinton W, Munro N, Whyte M, de Lusignan S. Systematic review of adherence rates by medication class in type 2 diabetes: a study protocol. BMJ Open. 2016; 6:e010469.

34. Khunti K, Seidu S, Kunutsor S, Davies M. Association between adherence to pharmacotherapy and outcomes in type 2 diabetes: a meta-analysis. Diabetes Care. 2017; 40:1588–96.

35. Polonsky WH, Henry RR. Poor medication adherence in type 2 diabetes: recognizing the scope of the problem and its key contributors. Patient Prefer Adherence. 2016; 10:1299–307.

36. McGovern A, Tippu Z, Hinton W, Munro N, Whyte M, de Lusignan S. Comparison of medication adherence and persistence in type 2 diabetes: a systematic review and meta-analysis. Diabetes Obes Metab. 2018; 20:1040–3.

37. Lasalvia P, Barahona-Correa JE, Romero-Alvernia DM, Gil-Tamayo S, Castaneda-Cardona C, Bayona JG, et al. Pen devices for insulin self-administration compared with needle and vial: systematic review of the literature and meta-analysis. J Diabetes Sci Technol. 2016; 10:959–66.

38. ElSayed NA, Aleppo G, Aroda VR, Bannuru RR, Brown FM, Bruemmer D, et al. 4. Comprehensive medical evaluation and assessment of comorbidities: standards of care in diabetes-2023. Diabetes Care. 2023; 46(Suppl 1):S49–67.

39. Weng J, Li Y, Xu W, Shi L, Zhang Q, Zhu D, et al. Effect of intensive insulin therapy on beta-cell function and glycaemic control in patients with newly diagnosed type 2 diabetes: a multicentre randomised parallel-group trial. Lancet. 2008; 371:1753–60.

40. Kramer CK, Zinman B, Retnakaran R. Short-term intensive insulin therapy in type 2 diabetes mellitus: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2013; 1:28–34.

41. Holman RR, Thorne KI, Farmer AJ, Davies MJ, Keenan JF, Paul S, et al. Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes. N Engl J Med. 2007; 357:1716–30.

42. Matthews DR, Paldanius PM, Proot P, Chiang Y, Stumvoll M, Del Prato S, et al. Glycaemic durability of an early combination therapy with vildagliptin and metformin versus sequential metformin monotherapy in newly diagnosed type 2 diabetes (VERIFY): a 5-year, multicentre, randomised, double-blind trial. Lancet. 2019; 394:1519–29.

43. Yoo SJ, Chang SA, Sohn TS, Kwon HS, Lee JM, Moon S, et al. Long-term glycaemic durability of early combination therapy strategy versus metformin monotherapy in Korean patients with newly diagnosed type 2 diabetes mellitus. Diabetes Metab J. 2021; 45:954–9.

44. Schectman JM, Nadkarni MM, Voss JD. The association between diabetes metabolic control and drug adherence in an indigent population. Diabetes Care. 2002; 25:1015–21.

45. Yoon KH, Shin JA, Kwon HS, Lee SH, Min KW, Ahn YB, et al. Comparison of the efficacy of glimepiride, metformin, and rosiglitazone monotherapy in Korean drug-naive type 2 diabetic patients: the practical evidence of antidiabetic monotherapy study. Diabetes Metab J. 2011; 35:26–33.

46. Tsapas A, Avgerinos I, Karagiannis T, Malandris K, Manolopoulos A, Andreadis P, et al. Comparative effectiveness of glucose-lowering drugs for type 2 diabetes: a systematic review and network meta-analysis. Ann Intern Med. 2020; 173:278–86.

47. Nauck MA, Mirna AE, Quast DR. Meta-analysis of head-to-head clinical trials comparing incretin-based glucose-lowering medications and basal insulin: an update including recently developed glucagon-like peptide-1 (GLP-1) receptor agonists and the glucose-dependent insulinotropic polypeptide/GLP-1 receptor co-agonist tirzepatide. Diabetes Obes Metab. 2023; 25:1361–71.

48. DeVries JH, Bain SC, Rodbard HW, Seufert J, D’Alessio D, Thomsen AB, et al. Sequential intensification of metformin treatment in type 2 diabetes with liraglutide followed by randomized addition of basal insulin prompted by A1C targets. Diabetes Care. 2012; 35:1446–54.

49. Aroda VR, Bailey TS, Cariou B, Kumar S, Leiter LA, Raskin P, et al. Effect of adding insulin degludec to treatment in patients with type 2 diabetes inadequately controlled with metformin and liraglutide: a double-blind randomized controlled trial (BEGIN: ADD TO GLP-1 Study). Diabetes Obes Metab. 2016; 18:663–70.

50. Rosenstock J, Aronson R, Grunberger G, Hanefeld M, Piatti P, Serusclat P, et al. Benefits of lixilan, a titratable fixed-ratio combination of insulin glargine plus lixisenatide, versus insulin glargine and lixisenatide monocomponents in type 2 diabetes inadequately controlled on oral agents: the LixiLan-O Randomized Trial. Diabetes Care. 2016; 39:2026–35.

51. Blonde L, Rosenstock J, Del Prato S, Henry R, Shehadeh N, Frias J, et al. Switching to iGlarLixi versus continuing daily or weekly GLP-1 RA in type 2 diabetes inadequately controlled by GLP-1 RA and oral antihyperglycemic therapy: the LixiLan-G Randomized Clinical Trial. Diabetes Care. 2019; 42:2108–16.

52. Gough SC, Bode B, Woo V, Rodbard HW, Linjawi S, Poulsen P, et al. Efficacy and safety of a fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with its components given alone: results of a phase 3, open-label, randomised, 26-week, treat-to-target trial in insulin-naive patients with type 2 diabetes. Lancet Diabetes Endocrinol. 2014; 2:885–93.

53. Linjawi S, Bode BW, Chaykin LB, Courreges JP, Handelsman Y, Lehmann LM, et al. The efficacy of IDegLira (insulin Degludec/Liraglutide combination) in adults with type 2 diabetes inadequately controlled with a GLP-1 receptor agonist and oral therapy: DUAL III Randomized Clinical Trial. Diabetes Ther. 2017; 8:101–14.

54. Buse JB, Bergenstal RM, Glass LC, Heilmann CR, Lewis MS, Kwan AY, et al. Use of twice-daily exenatide in Basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial. Ann Intern Med. 2011; 154:103–12.

55. Seino Y, Min KW, Niemoeller E, Takami A; EFC10887 GETGOAL-L Asia Study Investigators. Randomized, double-blind, placebo-controlled trial of the once-daily GLP-1 receptor agonist lixisenatide in Asian patients with type 2 diabetes insufficiently controlled on basal insulin with or without a sulfonylurea (GetGoal-L-Asia). Diabetes Obes Metab. 2012; 14:910–7.

56. Riddle MC, Aronson R, Home P, Marre M, Niemoeller E, Miossec P, et al. Adding once-daily lixisenatide for type 2 diabetes inadequately controlled by established basal insulin: a 24-week, randomized, placebo-controlled comparison (GetGoal-L). Diabetes Care. 2013; 36:2489–96.

57. Riddle MC, Forst T, Aronson R, Sauque-Reyna L, Souhami E, Silvestre L, et al. Adding once-daily lixisenatide for type 2 diabetes inadequately controlled with newly initiated and continuously titrated basal insulin glargine: a 24-week, randomized, placebo-controlled study (GetGoal-Duo 1). Diabetes Care. 2013; 36:2497–503.

58. Yang W, Min K, Zhou Z, Li L, Xu X, Zhu D, et al. Efficacy and safety of lixisenatide in a predominantly Asian population with type 2 diabetes insufficiently controlled with basal insulin: the GetGoal-L-C randomized trial. Diabetes Obes Metab. 2018; 20:335–43.

59. Ahmann A, Rodbard HW, Rosenstock J, Lahtela JT, de Loredo L, Tornoe K, et al. Efficacy and safety of liraglutide versus placebo added to basal insulin analogues (with or without metformin) in patients with type 2 diabetes: a randomized, placebo-controlled trial. Diabetes Obes Metab. 2015; 17:1056–64.

60. Pozzilli P, Norwood P, Jodar E, Davies MJ, Ivanyi T, Jiang H, et al. Placebo-controlled, randomized trial of the addition of once-weekly glucagon-like peptide-1 receptor agonist dulaglutide to titrated daily insulin glargine in patients with type 2 diabetes (AWARD-9). Diabetes Obes Metab. 2017; 19:1024–31.

61. Rodbard HW, Lingvay I, Reed J, de la Rosa R, Rose L, Sugimoto D, et al. Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): a randomized, controlled trial. J Clin Endocrinol Metab. 2018; 103:2291–301.

62. Aroda VR, Rosenstock J, Wysham C, Unger J, Bellido D, Gonzalez-Galvez G, et al. Efficacy and safety of lixilan, a titratable fixed-ratio combination of insulin glargine plus lixisenatide in type 2 diabetes inadequately controlled on basal insulin and metformin: the LixiLan-L Randomized Trial. Diabetes Care. 2016; 39:1972–80.

63. Rosenstock J, Diamant M, Aroda VR, Silvestre L, Souhami E, Zhou T, et al. Efficacy and safety of lixilan, a titratable fixed-ratio combination of lixisenatide and insulin glargine, versus insulin glargine in type 2 diabetes inadequately controlled on metformin monotherapy: the LixiLan Proof-of-Concept Randomized Trial. Diabetes Care. 2016; 39:1579–86.

64. Buse JB, Vilsboll T, Thurman J, Blevins TC, Langbakke IH, Bottcher SG, et al. Contribution of liraglutide in the fixed-ratio combination of insulin degludec and liraglutide (IDegLira). Diabetes Care. 2014; 37:2926–33.

65. Lingvay I, Perez Manghi F, Garcia-Hernandez P, Norwood P, Lehmann L, Tarp-Johansen MJ, et al. Effect of insulin glargine up-titration vs insulin degludec/liraglutide on glycated hemoglobin levels in patients with uncontrolled type 2 diabetes: the DUAL V Randomized Clinical Trial. JAMA. 2016; 315:898–907.

66. Owens DR, Luzio SD, Sert-Langeron C, Riddle MC. Effects of initiation and titration of a single pre-prandial dose of insulin glulisine while continuing titrated insulin glargine in type 2 diabetes: a 6-month ‘proof-of-concept’ study. Diabetes Obes Metab. 2011; 13:1020–7.

67. Lankisch MR, Ferlinz KC, Leahy JL, Scherbaum WA; Orals Plus Apidra and LANTUS (OPAL) study group. Introducing a simplified approach to insulin therapy in type 2 diabetes: a comparison of two single-dose regimens of insulin glulisine plus insulin glargine and oral antidiabetic drugs. Diabetes Obes Metab. 2008; 10:1178–85.

68. Leahy JL. Insulin therapy in type 2 diabetes mellitus. Endocrinol Metab Clin North Am. 2012; 41:119–44.

69. Giugliano D, Maiorino MI, Bellastella G, Chiodini P, Ceriello A, Esposito K. Efficacy of insulin analogs in achieving the hemoglobin A1c target of <7% in type 2 diabetes: meta-analysis of randomized controlled trials. Diabetes Care. 2011; 34:510–7.

70. Davidson MB, Raskin P, Tanenberg RJ, Vlajnic A, Hollander P. A stepwise approach to insulin therapy in patients with type 2 diabetes mellitus and basal insulin treatment failure. Endocr Pract. 2011; 17:395–403.

71. Castellana M, Cignarelli A, Brescia F, Laviola L, Giorgino F. GLP-1 receptor agonist added to insulin versus basal-plus or basal-bolus insulin therapy in type 2 diabetes: a systematic review and meta-analysis. Diabetes Metab Res Rev. 2019; 35:e3082.

72. Rosenstock J, Nino A, Soffer J, Erskine L, Acusta A, Dole J, et al. Impact of a weekly glucagon-like peptide 1 receptor agonist, albiglutide, on glycemic control and on reducing prandial insulin use in type 2 diabetes inadequately controlled on multiple insulin therapy: a randomized trial. Diabetes Care. 2020; 43:2509–18.

73. McMurray JJ, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019; 381:1995–2008.

74. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020; 383:1413–24.

75. Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Bohm M, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021; 385:1451–61.

76. Heerspink HJ, Stefansson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020; 383:1436–46.

77. The EMPA-KIDNEY Collaborative Group, Herrington WG, Staplin N, Wanner C, Green JB, Hauske SJ, et al. Empagliflozin in patients with chronic kidney disease. N Engl J Med. 2023; 388:117–27.

78. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jodar E, Leiter LA, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016; 375:1834–44.

79. Omboni S, Gazzola T, Carabelli G, Parati G. Clinical usefulness and cost effectiveness of home blood pressure telemonitoring: meta-analysis of randomized controlled studies. J Hypertens. 2013; 31:455–68.

80. Emdin CA, Rahimi K, Neal B, Callender T, Perkovic V, Patel A. Blood pressure lowering in type 2 diabetes: a systematic review and meta-analysis. JAMA. 2015; 313:603–15.

81. ACCORD Study Group, Cushman WC, Evans GW, Byington RP, Goff DC Jr, Grimm RH Jr, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010; 362:1575–85.

82. SPRINT Research Group, Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015; 373:2103–16.

83. Buckley LF, Dixon DL, Wohlford GF 4th, Wijesinghe DS, Baker WL, Van Tassell BW. Intensive versus standard blood pressure control in SPRINT-Eligible participants of ACCORD-BP. Diabetes Care. 2017; 40:1733–8.

84. Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018; 71:e13–115.

85. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 ESC/ESH guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension: the Task Force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension. J Hypertens. 2018; 36:1953–2041.

86. Zhang W, Zhang S, Deng Y, Wu S, Ren J, Sun G, et al. Trial of intensive blood-pressure control in older patients with hypertension. N Engl J Med. 2021; 385:1268–79.

87. Turnbull F, Neal B, Algert C, Chalmers J, Chapman N, Cutler J, et al. Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed overviews of randomized trials. Arch Intern Med. 2005; 165:1410–9.

88. Bangalore S, Fakheri R, Toklu B, Messerli FH. Diabetes mellitus as a compelling indication for use of renin angiotensin system blockers: systematic review and meta-analysis of randomized trials. BMJ. 2016; 352:i438.

89. Lindholm LH, Ibsen H, Dahlof B, Devereux RB, Beevers G, de Faire U, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002; 359:1004–10.

90. Berl T, Hunsicker LG, Lewis JB, Pfeffer MA, Porush JG, Rouleau JL, et al. Cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial of patients with type 2 diabetes and overt nephropathy. Ann Intern Med. 2003; 138:542–9.

91. Palmer SC, Mavridis D, Navarese E, Craig JC, Tonelli M, Salanti G, et al. Comparative efficacy and safety of blood pressure-lowering agents in adults with diabetes and kidney disease: a network meta-analysis. Lancet. 2015; 385:2047–56.

92. Arnold SV, Bhatt DL, Barsness GW, Beatty AL, Deedwania PC, Inzucchi SE, et al. Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association. Circulation. 2020; 141:e779–806.

93. Brugts JJ, Yetgin T, Hoeks SE, Gotto AM, Shepherd J, Westendorp RG, et al. The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials. BMJ. 2009; 338:b2376.

94. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010; 376:1670–81.

95. Ahmed S, Cannon CP, Murphy SA, Braunwald E. Acute coronary syndromes and diabetes: is intensive lipid lowering beneficial?: results of the PROVE IT-TIMI 22 trial. Eur Heart J. 2006; 27:2323–9.

96. Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, Vogel RA, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004; 291:1071–80.

97. Shepherd J, Barter P, Carmena R, Deedwania P, Fruchart JC, Haffner S, et al. Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes: the Treating to New Targets (TNT) study. Diabetes Care. 2006; 29:1220–6.

98. Moon MK, Noh J, Rhee EJ, Park SH, Kim HC, Kim BJ, et al. Cardiovascular outcomes according to comorbidities and low-density lipoprotein cholesterol in Korean people with type 2 diabetes mellitus. Diabetes Metab J. 2023; 47:45–58.

99. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004; 364:685–96.

100. Cholesterol Treatment Trialists’ (CTT) Collaborators, Kearney PM, Blackwell L, Collins R, Keech A, Simes J, et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008; 371:117–25.

101. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015; 372:2387–97.

102. Hong N, Lee YH, Tsujita K, Gonzalez JA, Kramer CM, Kovarnik T, et al. Comparison of the effects of ezetimibe-statin combination therapy on major adverse cardiovascular events in patients with and without diabetes: a meta-analysis. Endocrinol Metab (Seoul). 2018; 33:219–27.

103. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017; 376:1713–22.

104. Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018; 379:2097–107.

105. ElSayed NA, Aleppo G, Aroda VR, Bannuru RR, Brown FM, Bruemmer D, et al. 10. Cardiovascular disease and risk management: standards of care in diabetes-2023. Diabetes Care. 2023; 46(Suppl 1):S158–90.

106. Stevens PE, Levin A; Kidney Disease: Improving Global Outcomes Chronic Kidney Disease Guideline Development Work Group Members. Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline. Ann Intern Med. 2013; 158:825–30.

107. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998; 317:703–13.

108. Kasiske BL, Lakatua JD, Ma JZ, Louis TA. A meta-analysis of the effects of dietary protein restriction on the rate of decline in renal function. Am J Kidney Dis. 1998; 31:954–61.

109. Wheeler ML, Dunbar SA, Jaacks LM, Karmally W, Mayer-Davis EJ, Wylie-Rosett J, et al. Macronutrients, food groups, and eating patterns in the management of diabetes: a systematic review of the literature, 2010. Diabetes Care. 2012; 35:434–45.

110. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993; 329:1456–62.

111. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001; 345:861–9.

112. Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet. 2000; 355:253–9.

113. Mauer M, Zinman B, Gardiner R, Suissa S, Sinaiko A, Strand T, et al. Renal and retinal effects of enalapril and losartan in type 1 diabetes. N Engl J Med. 2009; 361:40–51.

114. Bakris GL, Agarwal R, Anker SD, Pitt B, Ruilope LM, Rossing P, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med. 2020; 383:2219–29.

115. Pitt B, Filippatos G, Agarwal R, Anker SD, Bakris GL, Rossing P, et al. Cardiovascular events with finerenone in kidney disease and type 2 diabetes. N Engl J Med. 2021; 385:2252–63.

116. Agarwal R, Filippatos G, Pitt B, Anker SD, Rossing P, Joseph A, et al. Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis. Eur Heart J. 2022; 43:474–84.

117. Mann JF, Orsted DD, Brown-Frandsen K, Marso SP, Poulter NR, Rasmussen S, et al. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med. 2017; 377:839–48.

118. Kristensen SL, Rorth R, Jhund PS, Docherty KF, Sattar N, Preiss D, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol. 2019; 7:776–85.

119. European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. Diabetologia. 2016; 59:1121–40.

120. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018; 67:328–57.

121. Hossain N, Afendy A, Stepanova M, Nader F, Srishord M, Rafiq N, et al. Independent predictors of fibrosis in patients with non-alcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2009; 7:1224–9.

122. Hernaez R, Lazo M, Bonekamp S, Kamel I, Brancati FL, Guallar E, et al. Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis. Hepatology. 2011; 54:1082–90.

123. Xiao G, Zhu S, Xiao X, Yan L, Yang J, Wu G. Comparison of laboratory tests, ultrasound, or magnetic resonance elastography to detect fibrosis in patients with nonalcoholic fatty liver disease: a meta-analysis. Hepatology. 2017; 66:1486–501.

124. Siddiqui MS, Yamada G, Vuppalanchi R, Van Natta M, Loomba R, Guy C, et al. Diagnostic accuracy of noninvasive fibrosis models to detect change in fibrosis stage. Clin Gastroenterol Hepatol. 2019; 17:1877–85.

125. Bril F, McPhaul MJ, Caulfield MP, Clark VC, Soldevilla-Pico C, Firpi-Morell RJ, et al. Performance of plasma biomarkers and diagnostic panels for nonalcoholic steatohepatitis and advanced fibrosis in patients with type 2 diabetes. Diabetes Care. 2020; 43:290–7.

126. Lee BW, Lee YH, Park CY, Rhee EJ, Lee WY, Kim NH, et al. Non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus: a position statement of the Fatty Liver Research Group of the Korean Diabetes Association. Diabetes Metab J. 2020; 44:382–401.

127. Wong VW, Vergniol J, Wong GL, Foucher J, Chan HL, Le Bail B, et al. Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease. Hepatology. 2010; 51:454–62.

128. Karlas T, Petroff D, Sasso M, Fan JG, Mi YQ, de Ledinghen V, et al. Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing steatosis. J Hepatol. 2017; 66:1022–30.

129. Koutoukidis DA, Astbury NM, Tudor KE, Morris E, Henry JA, Noreik M, et al. Association of weight loss interventions with changes in biomarkers of nonalcoholic fatty liver disease: a systematic review and meta-analysis. JAMA Intern Med. 2019; 179:1262–71.

130. Keating SE, Hackett DA, George J, Johnson NA. Exercise and non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol. 2012; 57:157–66.

131. Musso G, Gambino R, Cassader M, Pagano G. A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease. Hepatology. 2010; 52:79–104.

132. Thoma C, Day CP, Trenell MI. Lifestyle interventions for the treatment of non-alcoholic fatty liver disease in adults: a systematic review. J Hepatol. 2012; 56:255–66.

133. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology. 2015; 149:367–78.

134. Musso G, Cassader M, Rosina F, Gambino R. Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomized trials. Diabetologia. 2012; 55:885–904.

135. Musso G, Cassader M, Paschetta E, Gambino R. Thiazolidinediones and advanced liver fibrosis in nonalcoholic steatohepatitis: a meta-analysis. JAMA Intern Med. 2017; 177:633–40.

136. Lee YH, Kim JH, Kim SR, Jin HY, Rhee EJ, Cho YM, et al. Lobeglitazone, a novel thiazolidinedione, improves non-alcoholic fatty liver disease in type 2 diabetes: its efficacy and predictive factors related to responsiveness. J Korean Med Sci. 2017; 32:60–9.

137. Tang W, Xu Q, Hong T, Tong G, Feng W, Shen S, et al. Comparative efficacy of anti-diabetic agents on nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus: a systematic review and meta-analysis of randomized and non-randomized studies. Diabetes Metab Res Rev. 2016; 32:200–16.

138. Li Y, Liu L, Wang B, Wang J, Chen D. Metformin in non-alcoholic fatty liver disease: a systematic review and meta-analysis. Biomed Rep. 2013; 1:57–64.

139. Seeberg KA, Borgeraas H, Hofso D, Smastuen MC, Kvan NP, Grimnes JO, et al. Gastric bypass versus sleeve gastrectomy in type 2 diabetes: effects on hepatic steatosis and fibrosis: a randomized controlled trial. Ann Intern Med. 2022; 175:74–83.

140. Lassailly G, Caiazzo R, Ntandja-Wandji LC, Gnemmi V, Baud G, Verkindt H, et al. Bariatric surgery provides long-term resolution of nonalcoholic steatohepatitis and regression of fibrosis. Gastroenterology. 2020; 159:1290–301.

141. Lee Y, Doumouras AG, Yu J, Brar K, Banfield L, Gmora S, et al. Complete resolution of nonalcoholic fatty liver disease after bariatric surgery: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2019; 17:1040–60.

142. Cusi K, Isaacs S, Barb D, Basu R, Caprio S, Garvey WT, et al. American Association of Clinical Endocrinology clinical practice guideline for the diagnosis and management of nonalcoholic fatty liver disease in primary care and endocrinology clinical settings: co-sponsored by the American Association for the Study of Liver Diseases (AASLD). Endocr Pract. 2022; 28:528–62.