Seven categories of oral hypoglycemic drugs: the latest renal function requirements, hypoglycemic efficacy, and contraindications for use, summarized in one article

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 Introduction: Oral hypoglycemic drugs are the most commonly used "weapons" in clinical treatment of diabetes.
There are seven categories in total, and endocrinologists should be familiar with them
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According to the latest published guidelines/instructions, this article summarizes the contents of "renal function and drug application, mechanism of action, hypoglycemic efficacy, and additional benefits" for teachers' reference
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Renal function classification and application of oral hypoglycemic agentsFig.
1 KDIGO classification of chronic kidney diseaseFig.
2 Application of various oral hypoglycemic agents under different renal function conditions 1.
Metformin The biguanide drugs currently used clinically are mainly metformin hydrochloride
.

1.
Mechanism of action Lowers blood sugar by reducing hepatic glucose output and improving peripheral insulin resistance
.

2.
Hypoglycemic efficacy Clinical studies carried out in China's type 2 diabetes (T2DM) population show that the hypoglycemic efficacy of metformin is a 0.
7%-1.
0% decrease in HbA1c
.

In the dose range of 500-2000 mg/d, the efficacy of metformin showed a dose-dependent effect, and the efficacy was independent of body weight
.

Medication Note that the use of metformin alone does not increase the risk of hypoglycemia, but the risk of hypoglycemia can be increased when metformin is used in combination with insulin or insulin secretagogues
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➤ Gastrointestinal reactions: The main adverse reactions of metformin are gastrointestinal reactions
.

Efficacy and overall gastrointestinal adverse event rates were similar between the extended-release and regular tablets
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Starting with a small dose and increasing it gradually is an effective way to reduce its adverse effects
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Continued dose increases of metformin in patients already tolerated low doses of metformin did not increase gastrointestinal adverse effects
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➤Metformin and lactic acidosis: The relationship is uncertain
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➤Vitamin B12 deficiency: Long-term use of metformin can cause a decrease in vitamin B12 levels
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Long-term use of metformin can determine the serum vitamin B12 level once a year, such as lack of vitamin B12 should be properly supplemented
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➤ Renal insufficiency and drug use: Biguanides are contraindicated in renal insufficiency [serum creatinine level >132.
6umol/L (1.
5 mg/dl) in men, >123.
8umol/L (1.
4 mg/dl) in women or estimated renal Patients with spherical filtration rate (eGFR) <45 ml·min⁻¹·(1.
73 m²)⁻¹], hepatic insufficiency, severe infection, hypoxia, or undergoing major surgery
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For those who are taking metformin, when the eGFR is between 45 and 59 ml·min⁻¹·(1.
73 m²)⁻¹, there is no need to stop using it, and the dosage can be appropriately reduced to continue using it
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➤Contrast agent and drug use: If iodinated contrast agent is used in angiography, metformin should be temporarily discontinued, and the drug can be continued after at least 48 hours after the examination and the renal function has not deteriorated
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2.
Sulfonylureas Sulfonylureas are insulin secretagogues.
The sulfonylureas currently listed in China are mainly Glibenclamide, Glimepiride, Gliclazide, Glipizide and Glimequin.
ketones
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1.
Mechanism of action The main mechanism of action is to reduce blood sugar by stimulating the pancreatic β cells to secrete insulin, increasing insulin levels in the body
.

2.
Hypoglycemic effect Sulfonylureas can reduce HbA1c by 1.
0%~1.
5% (after removing the placebo effect)
.

Precautions for medication ➤ Hypoglycemia: sulfonylureas can cause hypoglycemia if used improperly, especially in elderly patients and those with hepatic and renal insufficiency; ➤ Weight gain: sulfonylureas can also cause weight gain; ➤ Renal insufficiency Use with drugs: Patients with mild renal insufficiency who use sulfonylureas should choose Gliquidone
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3.
Glinides Glinides are non-sulfonylurea insulin secretagogues, and repaglinide, nateglinide and mitiglinide are listed in China
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1.
Mechanism of action and hypoglycemic efficacy These drugs mainly reduce postprandial blood sugar by stimulating the early phase secretion of insulin, and also have a certain effect on reducing fasting blood sugar, which can reduce HbA1c by 0.
5% to 1.
5%
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These drugs need to be taken immediately before meals and can be used alone or in combination with other hypoglycemic drugs (except sulfonylureas)
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In the newly diagnosed T2DM population in China, the combination of repaglinide and metformin can reduce HbA1c more significantly than repaglinide alone, but the risk of hypoglycemia is significantly increased
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The common adverse reactions of medication attention are hypoglycemia and weight gain, but the risk and degree of hypoglycemia are less than that of sulfonylureas
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Glinides can be used in patients with renal insufficiency
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Fourth, thiazolidinediones (TZDs) TZDs reduce blood sugar mainly by increasing the sensitivity of target cells to insulin action
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At present, the TZDs listed in China mainly include rosiglitazone and pioglitazone and their compound preparations with metformin
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1.
Hypoglycemic efficacy The results of clinical research in T2DM patients in China show that TZD can reduce HbA1c by 0.
7% to 1.
0% (after removing the placebo effect)
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Medication precautions ➤ Hypoglycemia: TZD does not increase the risk of hypoglycemia when used alone, but can increase the risk of hypoglycemia when used in combination with insulin or insulin secretagogues
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➤ Weight gain: Weight gain is a common adverse reaction of TZD, and it is more pronounced when combined with insulin
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➤ Edema: Edema is a common adverse reaction of TZD, which is more obvious when combined with insulin
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➤ Fractures and heart failure: TZD use was associated with an increased risk of fractures and heart failure
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This class of drugs should be contraindicated in patients with heart failure (New York Heart Association (NYHA) cardiac function class II or above), active liver disease or elevated aminotransferase greater than 2.
5 times the upper limit of normal, severe osteoporosis and a history of fractures
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5.
α-Glucosidase Inhibitors The domestic marketed α-glucosidase inhibitors include acarbose, voglibose and miglitol
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1.
Hypoglycemic mechanism α-glucosidase inhibitors reduce postprandial blood glucose by inhibiting the absorption of carbohydrates in the upper small intestine, and are suitable for patients with elevated postprandial blood glucose with carbohydrates as the main food component
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It is recommended that patients swallow it 2-3 times a day, immediately before meals or chew it with the first mouthful of food
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2.
Hypoglycemic efficacy The results of a systematic review of clinical studies conducted in T2DM populations including Chinese showed that α-glucosidase inhibitors could reduce HbA1c by 0.
50% and reduce body weight
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The hypoglycemic efficacy of 300 mg of acarbose per day in newly diagnosed diabetic patients was comparable to that of 1500 mg of metformin per day
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Medication attention ➤ Gastrointestinal reactions: The common adverse reactions of α-glucosidase inhibitors are gastrointestinal reactions (such as abdominal distension, gas, etc.
)
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Starting with a small dose and gradually increasing the dose is an effective way to reduce adverse reactions
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➤ Hypoglycemia: Hypoglycemia usually does not occur with this drug alone
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If hypoglycemia occurs in patients taking α-glucosidase inhibitors, glucose or honey should be used for treatment, and consumption of sucrose or starchy foods is less effective in correcting hypoglycemia
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6.
Dipeptidyl peptidase IV inhibitor (DPP-4i) The DPP-4i currently listed in China are sitagliptin, saxagliptin, vildagliptin, linagliptin and alogliptin
.

1.
Hypoglycemic mechanism DPP-4i reduces the inactivation of GLP-1 in vivo by inhibiting dipeptidyl peptidase IV (DPP-4), and increases the level of endogenous GLP-1
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GLP-1 increases insulin secretion and inhibits glucagon secretion in a glucose concentration-dependent manner
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2.
The clinical research results of hypoglycemic efficacy in T2DM patients in China show that the hypoglycemic efficacy of DPP‑4i (after removing the placebo effect) is to reduce HbA1c by 0.
4%~0.
9%, and its hypoglycemic effect is related to the baseline HbA1c, that is, the baseline The higher the HbA1c level, the greater the absolute magnitude of lowering blood glucose and HbA1c
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Multiple meta-analyses have shown that the 5 DPP‑4i have similar glycemic lowering efficacy across different treatment regimens or different populations after removing the placebo effect
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Medication Note that the use of DPP-4i alone does not increase the risk of hypoglycemia
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The effect of DPP‑4i on body weight is neutral
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➤ Renal insufficiency and drug use: When using sitagliptin, saxagliptin, alogliptin and vildagliptin in patients with renal insufficiency, attention should be paid to reducing the drug dose according to the drug instructions
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No dose adjustment is required for the use of linagliptin in patients with hepatic or renal insufficiency
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7.
Sodium-glucose co-transporter 2 inhibitor (SGLT2i) The SGLT2i currently listed in China include dapagliflozin, empagliflozin, canagliflozin and itogliflozin
.

1.
Hypoglycemic mechanism SGLT2i can inhibit the reabsorption of glucose by the kidney, lower the renal glucose threshold, and thus promote the excretion of urine glucose
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2.
Hypoglycemic efficacy SGLT2i monotherapy can reduce HbA1c by 0.
5%-1.
2%, and combined therapy on the basis of metformin can reduce HbA1c by 0.
4%-0.
8%
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SGLT2i also has certain weight loss and antihypertensive effects
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3.
Cardiorenal benefits SGLT2i has demonstrated cardiovascular and renal benefits in a series of large cardiovascular and renal outcomes studies, including the Empagliflozin Cardiovascular Outcomes Study (EMPA‑REG OUTCOME), Canagliflozin Cardiovascular Vascular Assessment Study (CANVAS), Effect of Dapagliflozin on Cardiovascular Events (DECLARE‑TIMI 58), Evaluating the Efficacy and Safety of Itogliflozin on Cardiovascular Outcomes (VERTISCV) Trial, Dapagliflozin and Heart Failure Adverse Outcomes Prevention (DAPA‑HF) study, Canagliflozin and Clinical Evaluation of Renal Endpoints in Diabetic Patients with Nephropathy (CRENDENCE)
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Main benefits: ➤MACE endpoint: Empa-REGOUTCOME and CANVAS studies show that empagliflozin and canagliflozin reduce the risk of MACE (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) by 14%; ➤ Cardiac Endpoints of hospitalization for failure: Empagliflozin, canagliflozin, dapagliflozin and itogliflozin were all effective in reducing heart failure hospitalizations in patients with T2DM in the EMPA‑REG OUTCOME, CANVAS, DECLARE‑TIMI 58 and VERTIS CV studies Risks; ➤ Renal outcome endpoints: Canagliflozin reduces the risk of primary renal endpoints (end-stage renal disease, serum creatinine doubling, renal or cardiovascular death) by 30% in the CRENDENCE study; dapagliflozin and prevention of adverse chronic kidney disease outcomes The (DAPA‑CKD) study showed that dapagliflozin reduced the risk of the primary endpoint (≥50% reduction in eGFR, end-stage renal disease, or death from renal failure) by 39%
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Medication Note that SGLT2i monotherapy does not increase the risk of hypoglycemia, but it increases the risk of hypoglycemia when used in combination with insulin or insulin secretagogues
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Therefore, the dose of insulin or insulin secretagogues should be down-regulated when SGLT2i is used in combination with insulin or insulin secretagogues
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➤SGLT2i and genitourinary tract infections: The common adverse reactions of SGLT2i are urinary and reproductive system infections and adverse reactions related to hypovolemia; ➤SGLT2i and diabetic ketoacidosis (DKA): Rare adverse reactions of SGLT2i include DKA
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DKA can occur when blood sugar is mildly elevated or normal, and there are many DKA-inducing factors or people at high risk of DKA
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If DKA is suspected, SGLT2i should be discontinued and the patient evaluated for immediate treatment
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In addition, acute kidney injury should also be alerted during the medication process
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➤ Hepatic insufficiency and drug use: SGLT2i does not require dose adjustment in patients with mild to moderate hepatic impairment (Child-Pugh class A, B), and is not recommended in patients with severe hepatic impairment (Child-Phgh class C) use
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➤ Renal insufficiency and drug use: SGLT2i is not used in patients with eGFR<30 ml min⁻¹·(1.
73 m²)⁻¹
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References: [1] Diabetes Society of Chinese Medical Association.
Guidelines for the Prevention and Treatment of Type 2 Diabetes in China (2020 Edition) [J].
Chinese Journal of Diabetes, 2021, 13(4): 315-409.
DOI: 10.
3760/cma.
j.
cn115791-20210221-00095.
[2] China Clinical Guidelines for the Prevention and Treatment of Type 2 Diabetes in the Elderly Guidelines (2022 Edition) [J].
Chinese Journal of Internal Medicine, 2022, 61(1): 12-50.
DOI: 10.
3760/cma.
j.
cn112138-20211027-00751.
[3] Related drug instructions.