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*It is only for medical professionals to read for reference.
Does a single drug of metformin control blood sugar not up to standard? Let's take a look at this first! Metformin has been used clinically for more than 60 years.
It is currently one of the most widely used oral hypoglycemic drugs in the world and is the core drug for the prevention and control of diabetes in the world [1]
.
At present, domestic and foreign guidelines recommend metformin as the first-line cornerstone drug for the treatment of type 2 diabetes (T2DM)
.
When the blood glucose control is not up to standard after metformin monotherapy, clinicians often think of choosing the following three options [2]: ￭ increase the dose of metformin; ￭ combine with other hypoglycemic drugs with different mechanisms; ￭ switch to other hypoglycemic drugs, such as dipeptidyl peptidase 4 (DPP-4) inhibitors, and the like
.
So, in clinical practice, how to choose the above three options? In March 2021, Yoshio Nagai and other scholars from Santa Mariana Medical University in Japan published a paper entitled "Effects of Increasing Metformin Dose vs Adding/Switching to Dipeptidyl Peptidase-4 Inhibitors on Glycemic Control in Patients with Type 2 Diabetes" in Diabetes Therapy magazine [2], may be able to give the answer
.
Retrospective cohort study: PK from three schemes This is a retrospective cohort study based on the Japanese claims database.
Among 2,726,437 T2DM patients, 494 eligible patients were screened out.
These patients were in the initial low-dose metformin ( ≥500mg/d but <1000mg/d) After treatment, the program was adjusted, and the above three programs were used respectively.
The research team divided these patients into a primary research group and a secondary research group
.
The main research groups are: 1.
Incremental group (increased dose of metformin, n=226); 2.
Combination group (combined with DPP-4 inhibitor, n=240); 3.
Conversion group (converted to DPP-4 inhibitor , N=28)
.
The secondary research group was subdivided into the following three groups from the main research group: 1.
From the incremental group, patients with an average dose of metformin ≥1000 mg/d and no other hypoglycemic drug prescription records (n=106) were screened out; 2 .
From the combination group, patients with an average dose of metformin less than 1000 mg/d and no other hypoglycemic drug prescription records (n=171) were selected from the combination group; 3.
From the conversion group, only DPP-4 inhibitor treatment and no other hypoglycemic drugs were selected.
Patients with prescription records (n=14)
.
The primary end point was the change in HbA1c level from baseline at 12±3 months after the adjustment program
.
The secondary endpoints were the change in HbA1c levels from baseline at 3±1 months and 6±1 months after the adjustment plan, and the proportion of HbA1c reaching the target (<6.
5% or 7%) at 12±3 months
.
PK result 1: When the blood glucose control is not up to standard after metformin monotherapy, it is not a good plan to switch to DPP-4 inhibitor [2]
.
Incremental group: HbA1c was significantly reduced by 0.
91% in the main study group, and HbA1c was significantly reduced by 0.
84% in the secondary study group; combined group: HbA1c was significantly reduced by 1.
06%, and HbA1c was significantly reduced by 0.
67% in the secondary study group; conversion group : HbA1c was significantly reduced by 0.
37%, and HbA1c was significantly reduced by 0.
42% in the secondary study group
.
Comparing the propensity scores after pairing: the HbA1c decrease in the main study group from high to low was the combined group (-1.
06%), the incremental group (-0.
91%), and the conversion group (-0.
37%).
There was significant difference between the groups Differences; in the secondary study group, HbA1c decreased from high to low to incremental group (-0.
84%), combined group (-0.
67%), and conversion group (-0.
42%).
There were significant differences among the groups
.
The first hint from this study: When the blood sugar control is not up to standard after metformin monotherapy, switching to a DPP-4 inhibitor is obviously not a good plan
.
Figure 1 HbA1c changes after treatment in the main study group (left); HbA1c changes after treatment in the secondary study group (right) PK result 2: When the blood glucose control after metformin monotherapy is not up to standard, increasing the dose of metformin is a better plan, not only The hypoglycemic effect is the best and safer [2]
.
We see that in the main research group, the combined group is better than the incremental group; in the secondary research group, the incremental group is better than the combined group
.
Why does this happen? Further analysis found that the original key point was the difference in the dosage of metformin [2]
.
At 12 months of treatment, in the main study group, the average dose of metformin in the incremental group was only 938.
6 mg/d, so the efficacy could not reach the level of the combined group; in the secondary study group, the average dose of metformin in the incremental group increased , Reaching 1127.
6mg/d[2]
.
This research observation once again confirms the results of the early dose study of metformin: in the dose range of 500-2000 mg/d, the hypoglycemic effect of metformin is positively correlated with the dose [3]
.
Metformin 500mg/d can reduce HbA1c by 0.
6% (eliminating the placebo effect), and 2000mg/d can reduce HbA1c by 2.
0% [3]
.
Another ADOPT study showed that in newly diagnosed T2DM patients, metformin (2000 mg/d) monotherapy can maintain the average HbA1c level of subjects below 7% within 4 years [4]
.
When the patient can tolerate it, the best single-dose (2000mg/d) metformin treatment will not only make blood glucose reach the target as soon as possible, but also get good control for a longer period of time, and has a better cost-benefit ratio.
.
In addition, in terms of safety observed in this study, the estimated glomerular filtration rate (eGFR) of the combined group decreased more than that of the incremental group (-4.
26ml/min/1.
73m2vs-1.
25ml/min/1.
73m2) It can be seen that the metformin incremental program is safer, because metformin itself does not damage the kidneys [1], and studies have suggested that metformin may have a renal protective effect [6]
.
In addition, patients in all groups did not experience hypoglycemia
.
The clinical application strategy of metformin: start with a small dose and apply in sufficient amount.
The "Expert Consensus on the Clinical Application of Metformin (2018 Edition)" pointed out that the efficacy of metformin has a dose-dependent effect [1], use as soon as possible and in sufficient amount [1].
Generally speaking, The minimum recommended dose of metformin that takes effect is 500 mg/d, and the best effective dose is 2000 mg/d [1].
In order to reduce the gastrointestinal adverse reactions of metformin, it is necessary to adhere to "start with a small dose, gradually increase the dose, and apply in sufficient amount.
" The clinical application strategy: take metformin 500-1000mg/d at the beginning, increase to the optimal effective dose of 2000mg/d or the maximum tolerated dose after 1-2 weeks [1], and then consider whether it is necessary after 3 months of adequate use Combine with other hypoglycemic drugs
.
Summary: Metformin is a first-line drug for the treatment of T2DM, and its efficacy has a dose-dependent effect.
Low-dose application is a clinical problem that needs to be resolved
.
Metformin can be started in small doses, gradually increased, and applied to the best effective dose of 2000mg/day as soon as possible.
This not only enables patients to reach the target blood sugar as soon as possible, but also can be well controlled for a longer period of time, and has good safety
.
Therefore, when the blood sugar level does not reach the target after metformin monotherapy, don't rush to add or change the medicine.
First, use a sufficient dose of 2000mg/day of metformin
.
References: [1] Mu Yiming, Ji Linong, Li Chunlin, et al.
Chinese Journal of Diabetes, 2019, 027(003):161-173.
[2] Nagai Y, Kazumori K, Takeshima T, et al.
Diabetes Ther, 2021 , 12(3):897-911.
[3] Garber AJ, Duncan TG, Goodman AM, et al.
Am J Med, 1997, 103: 491-497.
[4] Kahn SE, Haffner SM, Heise MA, et al.
N Engl J Med, 2006, 355: 2427-2443.
[5] Diabetes Branch of Chinese Medical Association.
Chinese Journal of Diabetes, 2021, 13(4):315-408.
[6] Muskiet MH, Smits MM, Morsink LM, et al.
Nat Rev Nephrol, 2014, 10:88-103.
"This article is only used to provide scientific information to medical and health professionals, and does not represent the position of the platform.
" For submission/reprint/business cooperation, please contact: pengsanmei@yxj .
org.
cn
Does a single drug of metformin control blood sugar not up to standard? Let's take a look at this first! Metformin has been used clinically for more than 60 years.
It is currently one of the most widely used oral hypoglycemic drugs in the world and is the core drug for the prevention and control of diabetes in the world [1]
.
At present, domestic and foreign guidelines recommend metformin as the first-line cornerstone drug for the treatment of type 2 diabetes (T2DM)
.
When the blood glucose control is not up to standard after metformin monotherapy, clinicians often think of choosing the following three options [2]: ￭ increase the dose of metformin; ￭ combine with other hypoglycemic drugs with different mechanisms; ￭ switch to other hypoglycemic drugs, such as dipeptidyl peptidase 4 (DPP-4) inhibitors, and the like
.
So, in clinical practice, how to choose the above three options? In March 2021, Yoshio Nagai and other scholars from Santa Mariana Medical University in Japan published a paper entitled "Effects of Increasing Metformin Dose vs Adding/Switching to Dipeptidyl Peptidase-4 Inhibitors on Glycemic Control in Patients with Type 2 Diabetes" in Diabetes Therapy magazine [2], may be able to give the answer
.
Retrospective cohort study: PK from three schemes This is a retrospective cohort study based on the Japanese claims database.
Among 2,726,437 T2DM patients, 494 eligible patients were screened out.
These patients were in the initial low-dose metformin ( ≥500mg/d but <1000mg/d) After treatment, the program was adjusted, and the above three programs were used respectively.
The research team divided these patients into a primary research group and a secondary research group
.
The main research groups are: 1.
Incremental group (increased dose of metformin, n=226); 2.
Combination group (combined with DPP-4 inhibitor, n=240); 3.
Conversion group (converted to DPP-4 inhibitor , N=28)
.
The secondary research group was subdivided into the following three groups from the main research group: 1.
From the incremental group, patients with an average dose of metformin ≥1000 mg/d and no other hypoglycemic drug prescription records (n=106) were screened out; 2 .
From the combination group, patients with an average dose of metformin less than 1000 mg/d and no other hypoglycemic drug prescription records (n=171) were selected from the combination group; 3.
From the conversion group, only DPP-4 inhibitor treatment and no other hypoglycemic drugs were selected.
Patients with prescription records (n=14)
.
The primary end point was the change in HbA1c level from baseline at 12±3 months after the adjustment program
.
The secondary endpoints were the change in HbA1c levels from baseline at 3±1 months and 6±1 months after the adjustment plan, and the proportion of HbA1c reaching the target (<6.
5% or 7%) at 12±3 months
.
PK result 1: When the blood glucose control is not up to standard after metformin monotherapy, it is not a good plan to switch to DPP-4 inhibitor [2]
.
Incremental group: HbA1c was significantly reduced by 0.
91% in the main study group, and HbA1c was significantly reduced by 0.
84% in the secondary study group; combined group: HbA1c was significantly reduced by 1.
06%, and HbA1c was significantly reduced by 0.
67% in the secondary study group; conversion group : HbA1c was significantly reduced by 0.
37%, and HbA1c was significantly reduced by 0.
42% in the secondary study group
.
Comparing the propensity scores after pairing: the HbA1c decrease in the main study group from high to low was the combined group (-1.
06%), the incremental group (-0.
91%), and the conversion group (-0.
37%).
There was significant difference between the groups Differences; in the secondary study group, HbA1c decreased from high to low to incremental group (-0.
84%), combined group (-0.
67%), and conversion group (-0.
42%).
There were significant differences among the groups
.
The first hint from this study: When the blood sugar control is not up to standard after metformin monotherapy, switching to a DPP-4 inhibitor is obviously not a good plan
.
Figure 1 HbA1c changes after treatment in the main study group (left); HbA1c changes after treatment in the secondary study group (right) PK result 2: When the blood glucose control after metformin monotherapy is not up to standard, increasing the dose of metformin is a better plan, not only The hypoglycemic effect is the best and safer [2]
.
We see that in the main research group, the combined group is better than the incremental group; in the secondary research group, the incremental group is better than the combined group
.
Why does this happen? Further analysis found that the original key point was the difference in the dosage of metformin [2]
.
At 12 months of treatment, in the main study group, the average dose of metformin in the incremental group was only 938.
6 mg/d, so the efficacy could not reach the level of the combined group; in the secondary study group, the average dose of metformin in the incremental group increased , Reaching 1127.
6mg/d[2]
.
This research observation once again confirms the results of the early dose study of metformin: in the dose range of 500-2000 mg/d, the hypoglycemic effect of metformin is positively correlated with the dose [3]
.
Metformin 500mg/d can reduce HbA1c by 0.
6% (eliminating the placebo effect), and 2000mg/d can reduce HbA1c by 2.
0% [3]
.
Another ADOPT study showed that in newly diagnosed T2DM patients, metformin (2000 mg/d) monotherapy can maintain the average HbA1c level of subjects below 7% within 4 years [4]
.
When the patient can tolerate it, the best single-dose (2000mg/d) metformin treatment will not only make blood glucose reach the target as soon as possible, but also get good control for a longer period of time, and has a better cost-benefit ratio.
.
In addition, in terms of safety observed in this study, the estimated glomerular filtration rate (eGFR) of the combined group decreased more than that of the incremental group (-4.
26ml/min/1.
73m2vs-1.
25ml/min/1.
73m2) It can be seen that the metformin incremental program is safer, because metformin itself does not damage the kidneys [1], and studies have suggested that metformin may have a renal protective effect [6]
.
In addition, patients in all groups did not experience hypoglycemia
.
The clinical application strategy of metformin: start with a small dose and apply in sufficient amount.
The "Expert Consensus on the Clinical Application of Metformin (2018 Edition)" pointed out that the efficacy of metformin has a dose-dependent effect [1], use as soon as possible and in sufficient amount [1].
Generally speaking, The minimum recommended dose of metformin that takes effect is 500 mg/d, and the best effective dose is 2000 mg/d [1].
In order to reduce the gastrointestinal adverse reactions of metformin, it is necessary to adhere to "start with a small dose, gradually increase the dose, and apply in sufficient amount.
" The clinical application strategy: take metformin 500-1000mg/d at the beginning, increase to the optimal effective dose of 2000mg/d or the maximum tolerated dose after 1-2 weeks [1], and then consider whether it is necessary after 3 months of adequate use Combine with other hypoglycemic drugs
.
Summary: Metformin is a first-line drug for the treatment of T2DM, and its efficacy has a dose-dependent effect.
Low-dose application is a clinical problem that needs to be resolved
.
Metformin can be started in small doses, gradually increased, and applied to the best effective dose of 2000mg/day as soon as possible.
This not only enables patients to reach the target blood sugar as soon as possible, but also can be well controlled for a longer period of time, and has good safety
.
Therefore, when the blood sugar level does not reach the target after metformin monotherapy, don't rush to add or change the medicine.
First, use a sufficient dose of 2000mg/day of metformin
.
References: [1] Mu Yiming, Ji Linong, Li Chunlin, et al.
Chinese Journal of Diabetes, 2019, 027(003):161-173.
[2] Nagai Y, Kazumori K, Takeshima T, et al.
Diabetes Ther, 2021 , 12(3):897-911.
[3] Garber AJ, Duncan TG, Goodman AM, et al.
Am J Med, 1997, 103: 491-497.
[4] Kahn SE, Haffner SM, Heise MA, et al.
N Engl J Med, 2006, 355: 2427-2443.
[5] Diabetes Branch of Chinese Medical Association.
Chinese Journal of Diabetes, 2021, 13(4):315-408.
[6] Muskiet MH, Smits MM, Morsink LM, et al.
Nat Rev Nephrol, 2014, 10:88-103.
"This article is only used to provide scientific information to medical and health professionals, and does not represent the position of the platform.
" For submission/reprint/business cooperation, please contact: pengsanmei@yxj .
org.
cn
