Consensus update on multiple medications for elderly patients pays attention to the safety of antidiabetic drugs in elderly patients

The trend of aging of the elderly population in China is becoming more and more obvious
.

With the increase of age, the decline of physiological function and the deterioration of organ function, the coexistence of multiple diseases in the elderly has increased significantly
.

Diabetes is a common chronic disease of the elderly.
The latest data show that the number of elderly diabetic patients ≥65 years old in China is about 35.
5 million, accounting for 1/4 of the global elderly diabetic patients, ranking first in the world, and showing an upward trend1
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The pharmacokinetic and pharmacodynamic changes caused by age-related physiological changes, drug-drug interactions and the risk of drug-disease interactions in multi-drug combination therapy, make the elderly with co-morbidities tolerate drugs and Safety has been significantly reduced, and the incidence of adverse drug reactions has increased, 2 not only may affect the efficacy of hypoglycemic drugs, but may also increase the risk of adverse reactions such as hypoglycemia1
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The newly released "Experts Consensus on the Safety Management of Multiple Drugs in the Elderly and Elderly Patients with Comorbidity" (referred to as the "Consensus on the Safety of Elderly Drugs") 2 includes the potential inappropriate prescription and management of multiple drugs such as the endocrine system and drug interactions, and summarizes them for clinical use.
The choice of medication for hypoglycemic therapy in elderly patients provides more reference opinions
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The effect of changes in physiological function of elderly patients on drug metabolism.
Aging can cause the deterioration of the structure and function of the liver and kidney in the elderly, and is also an important reason for the increased risk of drug interactions: the number of liver cells in the elderly over 80 years old is reduced by about 40% compared with those in 40 years old.
, The liver blood flow is also reduced, the function of liver cells to synthesize proteins is reduced, and the activity of various enzymes is weakened, which slows down the metabolism of drugs in the body; the kidney weight of the elderly is reduced by about 20% to 30% compared with the 40-year-old, and the glomerular sclerosis is about Up to 10%, renal blood flow is reduced, renal concentration and dilution function is reduced, drug excretion is slowed, and at the same time, the role of regulating acid, alkali and water and electrolyte metabolism is weakened, renal reserve is reduced, and the endocrine glands of the elderly are easily damaged by the toxic effects of drugs; The response to stimuli is reduced, hormone synthesis and secretion are reduced, and the lipid content in the visceral fat and skeletal muscle cells of the elderly increases, resulting in insulin resistance
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2 Potentially inappropriate prescription and management of endocrine multi-drugs and drug interactions 1.
Sulfonylureas hypoglycemic drugs: (1) Sulfonylureas and CYP2C9 inhibitors (fluconazole, amiodarone, fluvastatin) and CYP2C19 Combination of inhibitors (voriconazole, omeprazole), etc.
, can increase the risk of hypoglycemia events and other adverse reactions; (2) Sulfonylureas and CYP2C9 inducers (carbamazepine, rifampicin, phenobarbital) or CYP2C19 The combination of inducers (phenytoin and rifampicin) can accelerate the metabolism of sulfonylureas, leading to hyperglycemia
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2.
ɑ-glycosidase inhibitor: the combination of acarbose and warfarin can increase the INR of prothrombin and increase the risk of bleeding
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3.
Glinides: Repaglinide is metabolized by CYP2C8 and CYP3A4, and when combined with clopidogrel, the latter significantly inhibits CYP2C8, which can increase the blood concentration of repaglinide by 5 times and cause severe hypoglycemia
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4.
Dipeptidyl peptidase IV (DPP-4) inhibitors: (1) Saxagliptin is metabolized by CYP3A4, and its strong inhibitors ketoconazole, itraconazole, azalaver, ritonavir, The combined use of clarithromycin and telithromycin can significantly increase the blood concentration of saxagliptin and should be used in a reduced dose; (2) the combined use of saxagliptin and carbamazepine accelerates its metabolism and significantly reduces the hypoglycemic effect; ( 3) Sitagliptin is metabolized by CYP3A4 and CYP2C8, combined with digoxin can increase the blood pressure concentration of digoxin, it should be used with caution; (4) Vidagliptin combined with angiotensin converting enzyme inhibitor (ACEI) will increase Risk of angioedema
.

5.
Thiazolidinediones: (1) Rosiglitazone and pioglitazone are metabolized by CYP2C8, and its inhibitors gemfibrozil and clopidogrel slow their metabolism and increase the blood concentration; (2) CYP2C8 inducer Rifol Equality accelerates drug metabolism and reduces efficacy; (3) Combined use with insulin may increase the risk of edema and heart failure
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6.
Sodium-glucose cotransporter 2 (SGLT-2) inhibitors: (1) dapagliflozin, empagliflozin, and canagliflozin are almost not metabolized by CYP450 enzymes and have fewer drug interactions; (2) It is estimated that patients with glomerular filtration rate (eGFR)<30ml/(min·1.
73m^2) should be treated with dapagliflozin and canagliflozin, and patients with eGFR<45ml/(min·1.
73m^2) should be treated with empagliflozin It can increase the blood concentration of the drug and should be cautious; (3) Combination of canagliflozin and rifampicin increases the risk of hypoglycemia, and combination with digoxin can increase the concentration of digoxin; (4) Concomitant genitourinary system Older patients with infection and hypovolemia should not use SGLT-2 inhibitors
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Hypoglycemic drugs and treatment pathways for elderly patients The "Guidelines for the Diagnosis and Treatment of Diabetes in the Elderly in China (2021 Edition)" put forward the principles of drug treatment for elderly patients with type 2 diabetes (T2DM): (1) Give priority to drugs with lower risk of hypoglycemia; (2) Choose simple, highly compliant drugs to reduce the risk of multiple medications; (3) Weigh the benefit-risk ratio to avoid overtreatment; (4) Pay attention to factors such as liver and kidney function, heart function, complications, and accompanying diseases
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1 Combining the mechanism and characteristics of various hypoglycemic drugs, the guide recommends a non-insulin treatment path diagram for elderly T2DM patients, with metformin, DPP-4 inhibitors, and SGLT-2 inhibitors as the first-level recommended drugs; glucagon-like peptides -1 receptor agonists, ɑ-glycosidase inhibitors and glinides are recommended as secondary drugs; sulfonylureas and other oral hypoglycemic agents are recommended as tertiary drugs
.

MET: metformin; SGLT-2i: sodium-glucose cotransporter 2 inhibitor; DPP-4i: dipeptidyl peptidase-4 inhibitor; GLP-1 RA: glucagon-1 receptor agonist; AGI : Α-glycosidase inhibitors; SU: sulfonylureas; TZD: thiazolidinediones; Glinides: Glinides; HF: heart failure; ASCVD: atherosclerotic cardiovascular disease; CKD: chronic kidney disease Figure 1.
Pathway diagram of non-insulin therapy for elderly patients with T2DM.
Among the three non-insulin therapy drugs recommended at the first level of the guideline, metformin needs to be titrated from a small dose and administered twice a day, which has gastrointestinal adverse reactions and reduces The effect of body weight, and the need to adjust the dose or stop according to renal function, for elderly diabetic patients with cognitive decline, poor compliance, impaired renal function, or sarcopenia, attention should be paid when using it
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SGLT-2 inhibitors are not suitable for the hypoglycemic treatment of patients with severe renal impairment; in addition, SGLT-2 inhibitors increase the risk of urinary and reproductive system infections and diabetic ketoacidosis; at the same time, they can reduce weight Elderly patients with sarcopenia may increase the risk of malnutrition, weakness and falls
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In contrast, DPP-4 inhibitors generally do not have hypoglycemia when used alone, have a neutral effect on body weight, and have less gastrointestinal reactions.
They are more suitable for the majority of elderly patients
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1 It is worth mentioning that among the five DPP-4 inhibitors that have been on the market in China, only about 10% of linagliptin is metabolized by the liver and about 5% is excreted by the kidneys.
It can be used in elderly people with any liver and kidney function.
The patient does not need to adjust the drug dose, and the remaining 4 DPP-4 inhibitors need to be adjusted or stopped according to liver and kidney function1
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In addition, Linagliptin is a weak to moderate inhibitor of CYP isoenzyme CYP3A4, but it has no inhibition on other CYP isoenzymes, nor is it an inducer of CYP isoenzymes
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3 At the same time, according to relevant research results, it is believed that Linagliptin is unlikely to interact with other P-glycoprotein substrates at therapeutic concentrations
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3 There is no need to adjust the dose when linagliptin is used in combination with digoxin, ritonavir, and rifampin
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3 Elderly patients with coexistence of multiple diseases and multiple medications have an increased risk of drug interactions.
Therefore, when formulating a hypoglycemic plan for elderly patients, hypoglycemic drugs with low risk of drug interaction and good safety should be selected
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It can be seen from the guidelines for the management of blood sugar reduction in elderly diabetic patients in China and the consensus on the safety of multiple drugs that DPP-4 inhibitors are more suitable due to their low risk of hypoglycemia, neutral effect on weight, and less gastrointestinal reactions.
For elderly patients
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Among them, the DPP-4 inhibitor linagliptin can be used in elderly patients with any liver and kidney function without adjusting the drug dose, and studies have shown that the risk of drug interaction is small when multiple drugs are used, or it may become the preferred drug for elderly diabetic patients Choose one
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References: 1.
Chinese Guidelines for Diagnosis and Treatment of Diabetes in the Elderly (2021 Edition) [J].
Chinese Journal of Diabetes,2021,13(01):14-46.
2.
National Key Research and Development Project (2018YFC2002400) Research Group.
Multiple medications for elderly and elderly patients with comorbidities Expert consensus on safety management[J].
Chinese Journal of Healthcare and Medicine,2021,23(05):548-554.
3.
Linagliptin Instructions