1Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
2Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
3Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
4Division of Endocrinology and Metabolism, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
5Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
6Division of Endocrinology & Metabolism, Department of Medicine, Gyeongsang National University Changwon Hospital, Gyeongsang National University College of Medicine, Changwon, Korea
7Division of Endocrinology and Metabolism, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
8Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
9Department of Endocrinology and Metabolism, Kyung Hee University College of Medicine, Kyung Hee University Hospital, Seoul, Korea
10Division of Endocrinology and Metabolism, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea
11Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
12Division of Endocrinology and Metabolism, Department of Internal Medicine, Chosun University College of Medicine, Gwangju, Korea
13Division of Endocrinology & Metabolism, Department of Internal Medicine, Sejong General Hospital, Bucheon, Korea
14Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Korea
15Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Soonchunhyang University College of Medicine, Cheonan, Korea
16Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
17Division of Endocrinology and Metabolism, Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
18Institute for Evidence-based Medicine, Cochrane Korea, Department of Preventive Medicine, Korea University College of Medicine, Seoul, Korea
19Division of Vitreous and Retina, Department of Ophthalmology, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea
20Department of Pediatrics, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
21Division of Infectious Diseases, Department of Internal Medicine, Korea University College of Medicine, Korea University Ansan Hospital, Ansan, Korea
Copyright © 2021 Korean Diabetes Association
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
CONFLICTS OF INTEREST
No potential conflict of interest relevant to this article was reported.
FUNDING
This work was supported by the Korean Diabetes Association.
1. A1C level ≥6.5%a or |
2. Fasting plasma glucose of ≥126 mg/dL for >8 hoursa or |
3. 2 hours plasma glucose of ≥200 mg/dL during 75 g oral glucose tolerance testa or |
4. Classic symptoms of hyperglycemia (polyuria, polydipsia, unexplained weight loss) with a random plasma glucose of ≥200 mg/dL |
Cardiovascular disease | Present | Absent |
---|---|---|
A1C, % | <6.5a | <6.5a |
Blood pressure, mm Hg | <130/80 | <140/85 |
LDL-C, mg/dL | <70 | <100b |
Triglycerides, mg/dL | <150 | <150 |
HDL-C, mg/dL | >40 (men), >50 (women) |
A1C, glycosylated hemoglobin; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol.
a A1C target should be individualized according to the patient’s clinical condition,
b Target LDL-C is also <70 mg/dL in the presence of target organ damage or cardiovascular risk factors.
Classification | BMI, kg/m2 | Lifestyle therapy | Medical therapya | Bariatric surgeryb |
---|---|---|---|---|
Normal | 18.5–22.9 | - | - | - |
Overweight | 23.0–24.9 | ⊙ | - | - |
Class I obesity | 25.0–29.9 | ⊙ | ◎ | - |
Class II obesity | 30.0–34.9 | ⊙ | ◎ | ◎ |
Class III obesity | ≥35.0 | ⊙ | ◎ | ◎ |
Variable | EMPA-REG OUTCOME | DECLARE-TIMI 58 | DAPA-HFa | VERTIS-CV | DAPA-CKD | EMPEROR-R |
---|---|---|---|---|---|---|
No. of patients enrolled | 7,020 | 17,160 | 4,744 | 8,246 | 4,304 | 3,730 |
Drug | Empagliflozin | Dapagliflozin | Dapagliflozin | Ertugliflozin | Dapagliflozin | Empagliflozin |
Median follow-up, yr | 3.1 | 4.2 | 1.5 | 3 | 2.4 | 1.3 |
Mean baseline A1C, % | 8.1 | 8.3 | NA | 8.2 | NA | NA |
Mean duration of diabetes, yr | NA | 11 | NA | 13 | NA | NA |
Baseline statin use, % | 77 | 75 | NA | 82.3 | 65 | NA |
Baseline CVD/HF, % | 99 | 41 | Not reported | 100 | 37 | Not reported |
Baseline HF, % | 10 | 10 | 100 | 23.7 | 10.8 | 100 |
MACE outcomeb | 0.86 (0.74–0.99) | 0.93 (0.84–1.03) | Not reported | 0.97 (0.85–1.11) | Not reported | Not reported |
Hospitalization for HF or CV death | 0.66 (0.55–0.79) | 0.83 (0.73–0.95) | 0.75 (0.65– 0.85) | 0.88 (0.75–1.03) | 0.71 (0.55–0.92) | 0.75 (0.65–0.86) |
CV death | 0.62 (0.49–0.77) | 0.98 (0.82–1.17) | 0.82 (0.69– 0.98) | 0.92 (0.77–1.11) | 0.81 (0.58–1.12) | 0.92 (0.75–1.12) |
Fatal or nonfatal MI | 0.87 (0.70–1.09) | 0.89 (0.77–1.01) | Not reported | 1.04 (0.86–1.26) | Not reported | Not reported |
Fatal or nonfatal stroke | 1.18 (0.89–1.56) | 1.01 (0.84–1.21) | Not reported | 1.06 (0.82–1.37) | Not reported | Not reported |
All-cause mortality | 0.68 (0.57–0.82) | 0.93 (0.82–1.04) | 0.83 (0.71–0.97) | 0.93 (0.80–1.08) | 0.69 (0.53–0.88) | 0.92 (0.77–1.10) |
HF hospitalization | 0.65 (0.50–0.85) | 0.73 (0.61–0.88) | 0.70 (0.59– 0.83) | 0.70 (0.54–0.90) | Not reported | 0.69 (0.59–0.81) |
Renal composite endpoint | 0.54 (0.40–0.75) | 0.53 (0.43–0.66) | 0.71 (0.44–1.16) | 0.81 (0.63–1.04) | 0.61 (0.51–0.72) | 0.50 (0.32–0.77) |
ESKD | 0.45 (0.21–0.97) | 0.31 (0.13–0.79) | 1.00 (0.50–1.99) | 0.81 (0.63–1.04) | 0.64 (0.50–0.82) | Not reported |
Renal death | Not reported | 0.60 (0.22–1.65) | NA | NA | NA | Not reported |
Values are presented as hazard ratio (95% confidence interval).
SGLT2, sodium-glucose cotransporter 2; A1C, glycosylated hemoglobin; NA, not available; CVD, cardiovascular disease; HF, heart failure; MACE, major adverse cardiovascular events; CV, cardiovascular; MI, myocardial infarction; ESKD, end-stage kidney disease.
a 58.2% of patients enrolled in DAPA-HF did not have diabetes mellitus. All patients enrolled in DAPA-HF had HF with reduced ejection fraction,
b Mean duration of diabetes was not provided for EMPA-REG OUTCOME, but 57% of patients enrolled had diabetes for more than 10 years.
REWIND | LEADER | SUSTAIN-6 | |
---|---|---|---|
Patients enrolled | 9,901 | 9,340 | 3,297 |
Drug | Dulaglutide | Liraglutide | Semaglutide SC |
Dose | 1.5 mg per week | 1.8 mg or max tolerated dose per day | 0.5 mg or 1 mg per week |
Median duration of follow-up, yr | 5.4 | 3.8 | 2.1 |
Mean baseline A1C, % | 7.2 | 8.7 | 8.7 |
Mean duration of diabetes, yr | 9.5 | 12.8 | 13.9 |
Baseline statin use, % | 66 | 72 | 73 |
Baseline prevalence of ASCVD/HF, % | 31 | 81 | 72 |
Baseline prevalence of HF, % | 9 | 18 | 24 |
Primary outcome, 3-MACEa | 0.88 (0.79–0.99) | 0.87 (0.78–0.97) | 0.74 (0.58–0.95) |
CV death | 0.91 (0.78–1.06) | 0.78 (0.66–0.93) | 0.98 (0.65–1.48) |
Fatal or nonfatal MIb | 0.96 (0.79–1.15) | 0.86 (0.73–1.00) | 0.74 (0.51–1.08) |
Fatal or nonfatal strokeb | 0.76 (0.62–0.94) | 0.86 (0.71–1.06) | 0.61 (0.38–0.99) |
All-cause mortality | 0.90 (0.80–1.01) | 0.85 (0.74–0.97) | 1.05 (0.74–1.50) |
HF hospitalizationc | 0.93 (0.77–1.12)c | 0.87 (0.73–1.05) | 0.86 (0.48–1.55) |
Renal composite outcomed | 0.85 (0.77–0.93) | 0.78 (0.67–0.92) | 0.64 (0.46–0.88) |
Values are presented as hazard ratio (95% confidence interval).
GLP-1, glucagon-like peptide-1; SC, subcutaneous; A1C, glycosylated hemoglobin; ASCVD, atherosclerotic cardiovascular disease; HF, heart failure; 3-MACE, 3-point major adverse cardiovascular event; CV, cardiovascular; MI, myocardial infarction.
a Three-point MACE is a composite of CV death, MI, or stroke,
b The risk estimates and 95% CIs for SUSTAIN-6 is for nonfatal MI (excluding fatal MI) or nonfatal stroke (excluding fatal stroke). The effect estimates for the composite endpoints of fatal or nonfatal MI and fatal or nonfatal stroke were not available in the primary manuscripts,
c Urgent HF visit or hospitalization for HF,
d The renal composite outcome reported in a recent meta-analysis was a composite of the development of macroalbuminuria, doubling of serum creatinine, a ≥40% decline in estimated glomerular filtration rate (eGFR), development of end-stage kidney disease, or death due to renal causes. For SUSTAIN-6, the renal composite was persistent macroalbuminuria, persistent doubling of serum creatinine with an eGFR <45 mL/min/1.73 m2 or need for continuous renal replacement therapy.
Evidence level | |
RCT | Systematic reviews, meta-analyses, randomized controlled trials |
NRS | Non-randomized controlled studies |
Others | Case series |
Expert opinion | Expert opinions from consensus of the Committee of Clinical Practice Guidelines of the KDA |
Range of recommendation | |
General | If the recommendation could be applied to most of subjects |
Limited | If the recommendation could be applied to specific subjects or in specific conditions |
1. A1C level ≥6.5% |
2. Fasting plasma glucose of ≥126 mg/dL for >8 hours |
3. 2 hours plasma glucose of ≥200 mg/dL during 75 g oral glucose tolerance test |
4. Classic symptoms of hyperglycemia (polyuria, polydipsia, unexplained weight loss) with a random plasma glucose of ≥200 mg/dL |
Cardiovascular disease | Present | Absent |
---|---|---|
A1C, % | <6.5 |
<6.5 |
Blood pressure, mm Hg | <130/80 | <140/85 |
LDL-C, mg/dL | <70 | <100 |
Triglycerides, mg/dL | <150 | <150 |
HDL-C, mg/dL | >40 (men), >50 (women) |
Classification | BMI, kg/m2 | Lifestyle therapy | Medical therapy |
Bariatric surgery |
---|---|---|---|---|
Normal | 18.5–22.9 | - | - | - |
Overweight | 23.0–24.9 | ⊙ | - | - |
Class I obesity | 25.0–29.9 | ⊙ | ◎ | - |
Class II obesity | 30.0–34.9 | ⊙ | ◎ | ◎ |
Class III obesity | ≥35.0 | ⊙ | ◎ | ◎ |
Variable | EMPA-REG OUTCOME | DECLARE-TIMI 58 | DAPA-HF |
VERTIS-CV | DAPA-CKD | EMPEROR-R |
---|---|---|---|---|---|---|
No. of patients enrolled | 7,020 | 17,160 | 4,744 | 8,246 | 4,304 | 3,730 |
Drug | Empagliflozin | Dapagliflozin | Dapagliflozin | Ertugliflozin | Dapagliflozin | Empagliflozin |
Median follow-up, yr | 3.1 | 4.2 | 1.5 | 3 | 2.4 | 1.3 |
Mean baseline A1C, % | 8.1 | 8.3 | NA | 8.2 | NA | NA |
Mean duration of diabetes, yr | NA | 11 | NA | 13 | NA | NA |
Baseline statin use, % | 77 | 75 | NA | 82.3 | 65 | NA |
Baseline CVD/HF, % | 99 | 41 | Not reported | 100 | 37 | Not reported |
Baseline HF, % | 10 | 10 | 100 | 23.7 | 10.8 | 100 |
MACE outcome |
0.86 (0.74–0.99) | 0.93 (0.84–1.03) | Not reported | 0.97 (0.85–1.11) | Not reported | Not reported |
Hospitalization for HF or CV death | 0.66 (0.55–0.79) | 0.83 (0.73–0.95) | 0.75 (0.65– 0.85) | 0.88 (0.75–1.03) | 0.71 (0.55–0.92) | 0.75 (0.65–0.86) |
CV death | 0.62 (0.49–0.77) | 0.98 (0.82–1.17) | 0.82 (0.69– 0.98) | 0.92 (0.77–1.11) | 0.81 (0.58–1.12) | 0.92 (0.75–1.12) |
Fatal or nonfatal MI | 0.87 (0.70–1.09) | 0.89 (0.77–1.01) | Not reported | 1.04 (0.86–1.26) | Not reported | Not reported |
Fatal or nonfatal stroke | 1.18 (0.89–1.56) | 1.01 (0.84–1.21) | Not reported | 1.06 (0.82–1.37) | Not reported | Not reported |
All-cause mortality | 0.68 (0.57–0.82) | 0.93 (0.82–1.04) | 0.83 (0.71–0.97) | 0.93 (0.80–1.08) | 0.69 (0.53–0.88) | 0.92 (0.77–1.10) |
HF hospitalization | 0.65 (0.50–0.85) | 0.73 (0.61–0.88) | 0.70 (0.59– 0.83) | 0.70 (0.54–0.90) | Not reported | 0.69 (0.59–0.81) |
Renal composite endpoint | 0.54 (0.40–0.75) | 0.53 (0.43–0.66) | 0.71 (0.44–1.16) | 0.81 (0.63–1.04) | 0.61 (0.51–0.72) | 0.50 (0.32–0.77) |
ESKD | 0.45 (0.21–0.97) | 0.31 (0.13–0.79) | 1.00 (0.50–1.99) | 0.81 (0.63–1.04) | 0.64 (0.50–0.82) | Not reported |
Renal death | Not reported | 0.60 (0.22–1.65) | NA | NA | NA | Not reported |
REWIND | LEADER | SUSTAIN-6 | |
---|---|---|---|
Patients enrolled | 9,901 | 9,340 | 3,297 |
Drug | Dulaglutide | Liraglutide | Semaglutide SC |
Dose | 1.5 mg per week | 1.8 mg or max tolerated dose per day | 0.5 mg or 1 mg per week |
Median duration of follow-up, yr | 5.4 | 3.8 | 2.1 |
Mean baseline A1C, % | 7.2 | 8.7 | 8.7 |
Mean duration of diabetes, yr | 9.5 | 12.8 | 13.9 |
Baseline statin use, % | 66 | 72 | 73 |
Baseline prevalence of ASCVD/HF, % | 31 | 81 | 72 |
Baseline prevalence of HF, % | 9 | 18 | 24 |
Primary outcome, 3-MACE |
0.88 (0.79–0.99) | 0.87 (0.78–0.97) | 0.74 (0.58–0.95) |
CV death | 0.91 (0.78–1.06) | 0.78 (0.66–0.93) | 0.98 (0.65–1.48) |
Fatal or nonfatal MI |
0.96 (0.79–1.15) | 0.86 (0.73–1.00) | 0.74 (0.51–1.08) |
Fatal or nonfatal stroke |
0.76 (0.62–0.94) | 0.86 (0.71–1.06) | 0.61 (0.38–0.99) |
All-cause mortality | 0.90 (0.80–1.01) | 0.85 (0.74–0.97) | 1.05 (0.74–1.50) |
HF hospitalization |
0.93 (0.77–1.12)c | 0.87 (0.73–1.05) | 0.86 (0.48–1.55) |
Renal composite outcome |
0.85 (0.77–0.93) | 0.78 (0.67–0.92) | 0.64 (0.46–0.88) |
RCT, randomized controlled trial; NRS, non-randomized controlled study; KDA, Korean Diabetes Association.
A1C should be measured in a standardized manner. A1C, glycosylated hemoglobin. In the absence of apparent hyperglycemia, require repeated verification on different days but can be confirmed immediately if more than two abnormal results are obtained from the same sample.
A1C, glycosylated hemoglobin; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol. A1C target should be individualized according to the patient’s clinical condition, Target LDL-C is also <70 mg/dL in the presence of target organ damage or cardiovascular risk factors.
Values are presented as range. ⊙, be recommended; ◎, be considered. BMI, body mass index. If lifestyle therapy fails, If nonsurgical treatment fails.
Values are presented as hazard ratio (95% confidence interval). SGLT2, sodium-glucose cotransporter 2; A1C, glycosylated hemoglobin; NA, not available; CVD, cardiovascular disease; HF, heart failure; MACE, major adverse cardiovascular events; CV, cardiovascular; MI, myocardial infarction; ESKD, end-stage kidney disease. 58.2% of patients enrolled in DAPA-HF did not have diabetes mellitus. All patients enrolled in DAPA-HF had HF with reduced ejection fraction, Mean duration of diabetes was not provided for EMPA-REG OUTCOME, but 57% of patients enrolled had diabetes for more than 10 years.
Values are presented as hazard ratio (95% confidence interval). GLP-1, glucagon-like peptide-1; SC, subcutaneous; A1C, glycosylated hemoglobin; ASCVD, atherosclerotic cardiovascular disease; HF, heart failure; 3-MACE, 3-point major adverse cardiovascular event; CV, cardiovascular; MI, myocardial infarction. Three-point MACE is a composite of CV death, MI, or stroke, The risk estimates and 95% CIs for SUSTAIN-6 is for nonfatal MI (excluding fatal MI) or nonfatal stroke (excluding fatal stroke). The effect estimates for the composite endpoints of fatal or nonfatal MI and fatal or nonfatal stroke were not available in the primary manuscripts, Urgent HF visit or hospitalization for HF, The renal composite outcome reported in a recent meta-analysis was a composite of the development of macroalbuminuria, doubling of serum creatinine, a ≥40% decline in estimated glomerular filtration rate (eGFR), development of end-stage kidney disease, or death due to renal causes. For SUSTAIN-6, the renal composite was persistent macroalbuminuria, persistent doubling of serum creatinine with an eGFR <45 mL/min/1.73 m2 or need for continuous renal replacement therapy.