In domestic and international diabetes guidelines, experts unanimously recommend metformin as the drug of choice in the diabetes treatment system, while in clinical practice many patients have many misunderstandings about metformin, this paper will evaluate the important position of metformin in the diabetes diagnosis and treatment system from the perspective of the relationship between diabetes and coronary heart disease.
I. Diabetes is the equal risk of coronary heart disease
The view that diabetes mellitus is an equivocal risk for coronary heart disease is well established, especially among medical professionals involved in diabetes and cardiology. This view is based on a wide range of evidence-based evidence. The first was the European Heart Study cross-sectional survey led by Prof. Bartnik M in 2003, which brought together nearly 5,000 patients with coronary heart disease from 110 study centers in 25 European countries and showed that 71% of patients with coronary heart disease were hyperglycemic, with 12% with newly diagnosed diabetes, 28% with abnormal fasting glucose and reduced glucose tolerance, and 31% with known diabetes. The percentage of known diabetes was 31%.
In 2005, a cross-sectional survey led by Prof. Hu Dayi conducted the same survey on 3513 patients with coronary heart disease in 52 hospitals in 7 cities in China, and the results showed that 77% of patients with coronary heart disease had hyperglycemia, and more than half of patients with hypertension also had hyperglycemia. A similar proportion of hyperglycemia was also found in emergency admissions and elective admissions, suggesting that it is not the stressful condition caused by myocardial infarction that triggers hyperglycemia. These two studies suggest a high proportion of hyperglycemia in the coronary heart disease group, suggesting that hyperglycemia may play an important role in the development of coronary heart disease.
On the other hand, from the perspective of type 2 diabetes regression, a large amount of evidence-based evidence proves that 70% of patients with type 2 diabetes die from cardiovascular disease, and the risk of death from coronary heart disease is 2-4 times higher in type 2 diabetes than in non-diabetics. Also some studies have shown that the incidence of cardiovascular events within one year after cardiac stenting is significantly higher in diabetic patients than in non-diabetic patients, while the long-term survival rate is significantly lower than in non-diabetic patients.
The most famous study is the East-West study in Finland, which enrolled 1373 non-diabetic patients and 1059 diabetic patients, followed them for 7 years and compared the incidence of fatal and non-fatal myocardial infarction in both groups. The results showed that diabetic patients with no prior history of myocardial infarction had the same risk of coronary heart disease death as nondiabetic patients with a history of myocardial infarction, after correcting for sex and age. Follow-up for 18 years showed a significantly higher mortality from coronary heart disease and acute infarction in those with combined diabetes. This is how the concept of diabetes mellitus as an equivocal risk for coronary heart disease was developed.
II. Intensive Glucose-Lowering and Cardiovascular Benefits
As mentioned above, since diabetes is so strongly associated with cardiovascular risk, it should be logical that careful glycemic control should largely prevent the risk of coronary heart disease events. However, a series of evidence-based studies followed that raised significant questions about this logical reasoning, with unsatisfactory results and even contradictory findings, throwing scientific and clinical thinking into disarray.
The first was the landmark study for type 1 diabetes, the Diabetes Control and Complications Study (DCCT), which saw significant intervention effects of intensive glucose lowering on microvascular complications including renal, fundus and peripheral neuropathy in the first 6.5 years of the study, but no benefit was seen for macrovascular disease such as cardiovascular disease, perhaps related to the younger age of enrollment in type 1 diabetes? Evidence-based studies on intensive glucose lowering and cardiovascular events in type 2 diabetes have shown similar results.
The first was the controversy in the 1970s about the effect of the U.S. University Group Diabetes Program (UGDP) treatment in terms of increased deaths (1%/year) due to coronary heart disease in patients treated with tosylbutamide and metformin. The UK Prospective Study of Diabetes (UKPDS) was designed in this context and is landmark because the question the project study sought to answer was: Does intensive glycemic control reduce microvascular complications?
Can intensive glucose lowering reduce the incidence of macrovascular disease and death in diabetes mellitus? Are there differences in the efficacy of different glucose lowering modalities with insulin, sulfonylureas, and metformin? Sulfonylureas may interfere with myocardial ischemic preadaptation, so does lowering glucose with sulfonylureas increase cardiovascular mortality? Does insulin therapy have an anti-atherosclerotic effect? The study also spanned the period 1977-1997 (including follow-up studies), with a mean intervention treatment duration of 11 years.
The aim was to observe the association between intensive glucose therapy (FBG<6.0 mmol/l,HbA1c<7.0%) and complications. The results showed a 0.9% difference in HbA1c between the intensive and conventional treatment groups at the end of the study 1< span="">0 years, and found similar results to DCCT, i.e., a significant reduction in microangiopathy, especially albuminuria, but not in macrovascular disease such as myocardial infarction and stroke, and no significant difference in diabetes-related death or all-cause death.
However, the advantage of metformin treatment was seen in a subgroup study in the overweight population, with 411 cases receiving conventional treatment and 1293 cases receiving intensive treatment, and the group receiving intensive treatment was further divided into a metformin treatment group (342 cases) and an insulin or sulfonylurea treatment group (951 cases), and treatment with metformin in the overweight population resulted in a 32% reduction in diabetes-related endpoints compared with conventional treatment (P=0.0023), a 42% reduction in the risk of diabetes-related death (P=0.017) a 36% reduction in the risk of all-cause mortality (P=0.011), and a 39% reduction in the risk of myocardial infarction (P=0.01), all of which were statistically significant.
Compared with insulin or sulfonylurea intensive glucose-lowering regimens, the metformin-treated group showed statistically significant benefits in macrovascular disease and risk of any diabetes-related endpoint, all-cause mortality, except for microangiopathy, for which no statistically significant benefit was seen with insulin or sulfonylurea treatment. Further analysis of treatment characteristics in the metformin group revealed no weight gain, less occurrence of hypoglycemia and no significant increase in fasting insulin levels with metformin treatment. It is suggested that the favorable outcome of metformin may not only be related to blood glucose reduction.
The subsequent ACCORD study attempted to further observe the relationship between glycemic control and complications by controlling HbA1c below 6.0% in the intensive treatment group and between 7.0% and 7.9% in the standard treatment group, only to find that the risk of all-cause mortality was significantly greater in the intensive treatment group than in the conventional treatment group and was forced to stop at 3.5 years, causing an uproar in the endocrine field.
The ADVANCE study set a target HbA1c value of <6.5% for the intensive glucose-lowering treatment group, and at the end of 5.5 years the mean HbA1c value was 7.3% in the standard treatment group and 6.5% in the intensive treatment group, a difference of 0.8%, but still no benefit was seen for macroangiopathy, and there was no statistical difference in the risk of all-cause mortality. Similarly the US Veterans Study VADT saw no evidence of benefit for cardiovascular events in the 11.5 year study with a large difference in HbA1c between the intensive and conventional treatment groups (HbA1c <6.0% or less in the intensive glucose treatment group compared to 8 - 9% in the standard group).
The above evidence-based evidence leads one to reflect on the large differences in cardiovascular protection between different modes of glucose lowering and whether hypoglycemic events or weight gain in the intensive treatment group offset the benefits of good glycemic control? VADT, PROACTIVE) and found that the average weight gain in the intensive treatment group was 2.5 kg, while the incidence of severe hypoglycemia almost doubled.
Therefore, in the cardiovascular prevention of type 2 diabetes, glucose lowering may be slightly less valuable than blood pressure, lipid and weight control, especially in obese type 2 diabetes to prevent the use of drugs that increase weight and hypoglycemic response may be wise.
Third, the evidence-based basis for metformin therapy as the drug of choice for type 2 diabetes mellitus
The application of guanidine can be traced back to the Middle Ages. 1920~1950, many guanidine derivatives such as phenylethylguanidine, butylguanidine and metformin were synthesized successively, but the application of metformin preparations was affected by coinciding with the emergence of insulin. It was not until 1957 that metformin was first used in clinical practice. Phenethidine and butylbiguanide have been withdrawn from the market due to the risk of lactic acidosis, and only metformin of the biguanide preparations is still in clinical use.
In 1995, a meta-analysis including 11 studies confirmed the efficacy of metformin, and in the same year metformin was officially approved by the FDA for the treatment of type 2 diabetes. 1998 UKPDS initially confirmed the clear cardioprotective effect of metformin, which pushed metformin to a new level in evidence-based medicine.
The UKPDS study found a metabolic memory effect in patients with newly diagnosed type 2 diabetes treated with metformin, with a 32% and 42% reduction in diabetes-related endpoint events and death, respectively, and a 36% and 39% reduction in the risk of all-cause death and myocardial infarction, respectively, after 20 years of treatment with metformin, and even though the difference in HbA1c between the two groups had disappeared during the follow-up phase at the end of the study, a A sustained cardiovascular benefit was seen in the intensive treatment group.
A 2012 meta-analysis of 35 studies showed that metformin was effective in further reducing HbA1c, either as monotherapy or in combination with other medications.The PRESTO study compared the efficacy of metformin with non-insulin sensitizer analogues for glucose-lowering patterns and confirmed that metformin It significantly reduced the risk of any clinical events, myocardial infarction and death.
Notably, the SPREAD study confirmed the benefit of metformin treatment for type 2 diabetes with coronary artery disease in China, with a 46% reduction in the risk of coronary events with metformin treatment compared to glipizide. Many studies have shown that there is a dose-dependent effect (500-2000mg/d) on the hypoglycemic efficacy of metformin, and the optimal effective dose is 2000mg/d. The current dose used in China is generally insufficient, and studies have shown that metformin has comparable efficacy in lowering HbA1c in obese and non-obese type 2 diabetic patients;
Metformin is the drug of choice for the treatment of patients with type 2 diabetes. The above research evidence establishes metformin as the cornerstone of first-line use in type 2 diabetes. Although the “Comparative study of the efficacy of acarbose and metformin in the treatment of newly diagnosed T2DM patients” was published in 2014, which demonstrated for the first time that acarbose and metformin have similar efficacy and safety, there is still insufficient evidence that acarbose and metformin have similar cardioprotective effects. However, the evidence on the similar cardioprotective effects of acarbose and metformin is still insufficient, so the evidence for acarbose to replace metformin as a first-line agent is not sufficient.
In view of the good cardioprotective effect of metformin, major national and international guidelines indicate that metformin should be retained throughout the treatment of type 2 diabetes in the absence of specific contraindications.
Other reasons for metformin as a first-line drug are its potential antitumor effects, and there is a large body of research literature showing that metformin treatment can improve the outcome of various malignancies in combination with type 2 diabetes, which needs to be further studied.
Fourth, metformin use precautions
No drug is perfect, and metformin is no exception, although it has been pushed to the status of first-line drug by major guidelines.
But in the specific use of the process should pay attention to the following matters.
1, about renal safety: according to the 2014 China diabetic nephropathy prevention and treatment expert consensus that generally in chronic kidney disease (CKD) stage 3a or more should generally reduce the dose, eGFR < 45 ml/(min・1.73 m2) discontinued, because of renal failure metformin and lactic acid easy to accumulate. 2014 China metformin clinical application expert consensus that should be estimated by Glomerular filtration rate (eGFR) level should be adjusted: eGFR≥60 ml/(min-1.73 m2) can be used safely; eGFR 45-60 ml/(min-1.73 m2) should be used with caution; eGFR<45 ml/(min-1.73 m2) should be discontinued.
In patients with normal renal function, it is not necessary to discontinue metformin before imaging, but it should be discontinued for 48-72 h after using contrast agent under the guidance of the doctor, and the drug can be continued after the review of normal renal function; in patients with abnormal renal function, it should be temporarily discontinued for 48 h before using contrast agent and general anesthesia, and then it should be discontinued for 48-72 h, and the drug can be continued after the review of normal renal function.
2, acute heart failure and sleep apnea syndrome or other chronic hypoxic states are likely to cause lactic acidosis, attention should be paid to detect the blood lactate concentration. But the fact is that the risk of worsening heart failure caused by insulin in heart failure patients in ICU wards is much greater than that of metformin. Although heart failure is listed as a contraindication but there is no evidence-based evidence that metformin causes heart failure, and the 2014 ADA Diabetes Guidelines also state that metformin can be used in patients with stable CHF if renal function is normal.
3, Hepatic safety: Metformin should be avoided in patients with serum transaminases exceeding 3 times the upper limit of normal.
4, age-appropriate population: according to metformin expert consensus that metformin can be used in children aged l0 and above, older diabetic patients over 65 years old and under 10 years old are not recommended to use the maximum agent, and should start with a small dose, and calculate the eGFR of individual patients to guide the use of drugs, reasonable application of metformin treatment in older diabetic patients can achieve good glucose-lowering effect, less hypoglycemic risk is beneficial to the elderly, but regular monitoring of renal function is required (1 check in 3-6 months). Metformin is the only oral drug approved by the US FDA that can be used in type 1 diabetes patients at present.
5, gastrointestinal reactions and hepatic and renal toxicity: metformin’s main adverse reactions are gastrointestinal reactions, mostly occurring in the early stages of treatment (the vast majority occurring in the first l0 weeks). With the extension of treatment time, patients can gradually tolerate or symptoms disappear. The gastrointestinal reactions can be reduced by starting with a small dose, gradually increasing the dose, adjusting the dose when appropriate, and taking the non-slow-release formulation with meals in small doses.
Metformin does not have hepatic or renal toxicity, but only a high percentage of excretion in the kidneys, which is essentially different from the nephrotoxicity of aminoglycoside antibiotics. This is often a place where diabetic patients and their families are prone to misunderstand.
6.Treatment of polycystic ovary syndrome (PCOS): PCOS is not an indication for metformin, but metformin has been applied at home and abroad to treat PCOS for more than ten years. The American Society of Endocrinology recommends metformin as a therapeutic agent for patients with PCOS combined with type 2 diabetes or IGT, where lifestyle interventions (first-line treatment) have failed or where menstruation is irregular and contraceptives cannot be applied (second-line treatment).
7. Pregnancy use: for obese pregnant women with obvious tendency of insulin resistance, the use of insulin therapy is not the best choice, metformin in the FDA pregnancy drug classification for class B drugs, China’s pharmacovigilance department has not approved metformin for women during pregnancy.
8., metformin and vitamin B12 deficiency: there is evidence of vitamin B12 deficiency in patients taking oral metformin, and should be properly supplemented with vitamin B12.
9., Contraindications.
(1) Serum creatinine level, male ≥ 132 μmol/L (1.5 mg/d1), female ≥ 124 μmol/L (1.4 mg/d1), or eGFR < 45 ml/(min・1.73 m2) is prohibited;
(2) CHF and other serious cardiac or pulmonary disorders requiring drug therapy;
(3) Severe infections and trauma, major surgical procedures, clinical hypotension and hypoxia, etc;
(4) Known allergy to metformin hydrochloride;
(5) Acute or chronic metabolic acidosis, including diabetic ketoacidosis with or without coma;
(6) Alcoholics;
(7) Those receiving intravascular iodinated contrast should be temporarily discontinued;
(8) Those with uncorrected vitamin B12 and folic acid deficiency.
In short, in the elderly or adolescents or patients with complex conditions should read the drug instructions carefully before using the drug, pay attention to drug interactions, such as patients with atrial fibrillation anticoagulated with Warfarin, such as oral metformin may enhance the anticoagulant effect of Warfarin causing increased risk of bleeding.