Interpretation of the 2021 ADA "Diagnosis and Treatment Standards for Diabetes" Guidelines-SGLT-2i Treatment Status Changes

*The professional part involved in this article is only for medical professionals to read and refer to.
What are the updates this year? In December 2020, the American Diabetes Association (ADA) issued the 2021 version of the Guidelines for Diabetes Diagnosis and Treatment.

The new version of the guidelines has updated the content related to the drug treatment of type 2 diabetes (T2DM).
In the treatment path of hypoglycemic drugs for T2DM patients, the guidelines will distinguish and distinguish T2DM patients with heart failure (HF) and chronic kidney disease (CKD).
In detail, the treatment strategies of hypoglycemic drugs are respectively recommended.

In T2DM patients with atherosclerotic cardiovascular disease (ASCVD), HF, and CKD, sodium-glucose cotransporter 2 inhibitors (SGLT-2i) are the preferred drugs recommended by the guidelines.

Figure 1 2021 ADA Guidelines: The 2021 ADA Guidelines for Type 2 Diabetes Hypoglycemic Drug Treatment Pathways are the same as previous guidelines.
They emphasize patient-centered, comprehensive consideration of efficacy and individual factors of patients to select appropriate treatment methods, including: 1) ASCVD and High ASCVD risk indicators, CKD and HF and other comorbidities; 2) risk of hypoglycemia; 3) impact on body weight; 4) side effects; 5) cost; 6) patient preference.

Metformin is the starting drug for T2DM treatment recommended by the guidelines.
However, in special circumstances, such as a confirmed cardiovascular disease (CVD) or increased risk of CVD or CKD, it can be combined or replaced with other hypoglycemic drugs.

At the same time, for T2DM patients with diagnosed ASCVD or high risk of ASCVD, HF, CKD, it is recommended to add SGLT-2i or glucagon-like peptide 1 receptor agonist (GLP-1 RA), which has a clear benefit of CVD, to reduce blood sugar The treatment plan does not need to consider the use of glycosylated hemoglobin (HbA1c) and metformin.

Guidelines recommendation: For T2DM patients with diagnosed ASCVD or CKD, it is recommended to use SGLT-2i or GLP-1 RA with cardiovascular (CV) benefits as a hypoglycemic regimen that reduces the risk of CV complex events.

 Evidence level: A For T2DM patients with confirmed ASCVD or multiple high-risk ASCVD risk factors, or patients with diabetic nephropathy, SGLT-2i with evidence of CV benefit is recommended to reduce the risk of major CV adverse events and hospitalization for heart failure (HHF) .

Evidence level: A.
For T2DM patients with high-risk factors or diagnosed ASCVD, the status of SGLT-2i is improved in the 2021 ADA guidelines, and it is listed as the same recommendation as GLP-1 RA (see Figure 2).

The guidelines point out that SGLT-2i with clear CV benefits in ASCVD patients with T2DM include empagliflozin and canagliflozin.

Figure 2 Comparison of the treatment path of the 2020 and 2021 ADA guidelines for T2DM patients with diagnosed and high-risk ASCVD.
Empagliflozin Cardiovascular Outcome Trial The EMPA-REG OUTCOME study is a randomized, double-blind trial, in 7020 patients with CVD Evaluate the effect of empagliflozin on cardiovascular outcomes compared with placebo in patients with type 2 diabetes.

The average age of study participants was 63 years old, 57% of patients had diabetes with a duration of >10 years, and 99% of patients were diagnosed with CVD.

The results of EMPA-REG OUTCOME showed that during a median follow-up of 3.
1 years, treatment with empagliflozin reduced the risk of myocardial infarction, stroke and cardiovascular death composite endpoint by 14% (HR 0.
86, 95% CI 0.
74-0.
99, superiority P = 0.
04) and reduced the risk of death from CV by 38% (HR 0.
62, 95% CI 0.
49-0.
77, P <0.
001) [1].

Therefore, the U.
S.
Food and Drug Administration approved the addition of indications for empagliflozin to reduce the risk of cardiovascular death. The CANVAS project includes two randomized, double-blind trials to evaluate the effect of canagliflozin on cardiovascular outcomes in T2DM patients with high CV event risk and CKD.
The two studies included 10142 patients.

The average age of the study participants was 63 years old, and 66% had a history of cardiovascular disease.

The average follow-up was 3.
6 years.

Data compiled by the CANVAS study found that compared with placebo, canagliflozin can significantly reduce the risk of myocardial infarction, stroke, and cardiovascular death composite endpoint by 14% (HR 0.
86, 95% CI 0.
75-0.
97).

[2] In the cardiovascular outcome study of dapagliflozin, the results suggest that dapagliflozin failed to significantly reduce the risk of major cardiovascular events compared with placebo (HR 0.
93, 95% CI 0.
84-1.
03, P=0.
17) .

[3] Guidelines recommendation: For T2DM patients with confirmed HF and reduced ejection fraction, SGLT-2i is recommended to reduce the risk of HF deterioration and CV death.

Evidence level: A.
For T2DM patients with diabetic nephropathy, patients with eGFR≥30mL/min/1.
73m2 and urine protein-creatinine ratio>30mg/g, consider using SGLT-2i.

Evidence level: A.
For T2DM patients with diabetic nephropathy, patients with eGFR≥30mL/min/1.
73m2 and urine protein-creatinine ratio>30mg/g, consider using SGLT-2i to reduce the risk of CV.

Evidence level: A is different from the previous version.
In the T2DM hypoglycemic treatment pathway diagram, the 2021 ADA guidelines separately list the treatment pathways for T2DM patients with HF and T2DM patients with CKD.

(Figure 3) Figure 3 Comparison of treatment paths between 2020 and 2021 ADA guidelines for T2DM patients with HF and CKD.
For patients with confirmed HF, especially patients with HF with reduced ejection fraction (HFrEF) (shown as left ventricular ejection) Score <45%), it is recommended to use SGLT-2i, which has proven beneficial in this population. In the SGLT-2i Cardiovascular Outcome Trial (CVOT), empagliflozin, canagliflozin and dapagliflozin can reduce the risk of HF.

In the EMPA-REG OUTCOME trial, compared with placebo, the addition of empagliflozin on the basis of standard treatment reduced the risk of HHF by 35% [1], and the effect was consistent in patients with or without HF at baseline [4].

In the CANVAS study and the DECLARE-TIMI 58 trial, compared with placebo, the use of canagliflozin and dapagliflozin reduced the risk of HHF by 33% and 27%, respectively [2,3].

In the DAPA-HF study, the effect of dapagliflozin on the primary endpoint (composite endpoint of worsening HF or CV death) was evaluated in 4744 patients with HFrEF, and 45% of them had a history of T2DM.

The results of the study suggest that dapagliflozin significantly reduces the risk of the primary endpoint event by 26% (HR 0.
74, 95% CI 0.
65-0.
85), and the effect has nothing to do with whether the patient has T2DM.

[5] Therefore, the guidelines recommend that for T2DM patients with HFrEF, the use of proven benefit SGLT-2i to reduce the risk of HF worsening and CV death.

The recently released EMPEROR-Reduced study shows the clinical benefit of SGLT-2i empagliflozin for patients with chronic HFrEF.
The research shows that compared with placebo, empagliflozin can significantly reduce chronic HFrEF patients with or without T2DM The composite endpoint risk of HF hospitalization or CV death was 25% (HR: 0.
75; 95% CI: 0.
65-0.
86).

[6] In T2DM patients with CKD, if the patient has diabetic nephropathy (DKD) and proteinuria, it is recommended to prefer SGLT-2i for hypoglycemic therapy.
If it is intolerable or contraindicated in SGLT-2i, consider using GLP-1 RA treatment; for other T2DM patients with CKD and an increased risk of CV events, it is recommended to use GLP-1 RA or SGLT-2i treatment with proven CVD benefit. The results of EMPA-REG OUTCOME showed that compared with placebo, empagliflozin reduced new or worsening nephropathy (progression to urine albumin/creatinine ratio> 300 mg/g·Cr, doubling of serum creatinine, end-stage renal disease [ESRD] Or the composite endpoint of ESRD death) the risk is 39%, and the risk of reducing serum creatinine with eGFR≤45 mL/min/1.
73 m2 is 44%.

[7] Canagliflozin reduces the risk of proteinuria progression by 27%, and reduces the risk of eGFR decline, ESRD or ESRD death composite event risk by 40%.

[2] In terms of the mechanism of action, the effect of SGLT-2i on the kidney seems to be independent of the hypoglycemic effect.
SGLT-2i can reduce renal tubular glucose reabsorption, reduce body weight, reduce systolic blood pressure and intraglomerular pressure, and reduce albuminuria And slow down the decrease of glomerular filtration rate (GFR) [2,7,8-10].

Not only that, recent data supports that SGLT-2i can reduce renal oxidative stress by >50%, slow down the increase in angiotensinogen and reduce the activity of NLRP3 inflammasomes [11-13].

In addition, for patients whose HbA1c treatment does not reach the target, when performing combination therapy, drugs that minimize the risk of hypoglycemia and minimize weight gain or weight reduction should be selected according to the patient's individual situation.

SGLT-2i has its special hypoglycemic mechanism.
By inhibiting the reabsorption of glucose by the proximal renal tubules of the kidney, it promotes the excretion of glucose from the urine and reduces blood sugar.
SGLT-2i excretion of sugar is based on the patient's blood glucose level and renal function.
Yes, so the risk of using SGLT-2i to treat hypoglycemia is low.

While excreting sugar through urine, it also reduces the accumulation of energy in the body, which can reduce weight to a certain extent.

ASCVD, HF and CKD are common comorbidities of diabetes.
SGLT-2i has significant benefits for these T2DM patients with CV and kidney disease.
It can improve the patient's CV and kidney outcomes and reduce the risk of death.

At the same time, its low risk of hypoglycemia and weight reduction make SGLT-2i the preferred drug for combination therapy in the comprehensive management of T2DM.

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Diabetes Care.
2021 Jan;44(Suppl 1):S111 -S124.