Protracted battle for hypoglycemic, pay attention to the effectiveness and safety of long-term treatment of hypoglycemic drugs

*Only for medical professionals to read for reference.
Quick overview of the content of this article: Long-term hypoglycemic treatment has complex factors, and attention should be paid to the effectiveness and safety of long-term clinical treatment of hypoglycemic drugs.

Post-marketing monitoring studies (PMS), as a supplement to clinical registration studies, can more fully reflect the long-term clinical use of drugs.

Three PMS conducted in Asian populations suggest that long-term clinical use of dipeptidyl peptidase-4 inhibitor (DPP-4i) linagliptin is safe and sustainable and effective in reducing blood sugar.

DPP-4i Linagliptin can achieve a safe and effective hypoglycemic effect in patients with type 2 diabetes (T2DM) of all ages (including elderly patients).

The effect of DPP-4i linagliptin is not affected by the patient's renal function status, and linagliptin does not affect the patient's renal function level during long-term monitoring.

Diabetes is a long-term chronic disease.
Diabetic patients usually need long-term use of hypoglycemic drugs to control blood sugar in order to avoid or reduce the risk of acute complications such as ketoacidosis and chronic complications such as cardiovascular disease and renal dysfunction.
Life expectancy improves the quality of life of patients.

However, in the course of clinical treatment, there are many factors that will affect the patient's long-term treatment compliance and treatment effect, including adverse drug reactions, aging, decreased liver and kidney function, and multiple combined medications.

At the same time, observational studies suggest that patients with renal insufficiency and increasing age are the main factors affecting drug prescription errors [1].

Therefore, it is particularly important to evaluate the long-term safety and effectiveness of drugs in the clinical environment.

The new hypoglycemic drug DPP-4i has become one of the fastest-growing hypoglycemic drugs in the world in recent years due to its unique mechanism of action and good safety [2].
Among them, linagliptin is rarely metabolized by the liver and kidneys.
Excretion does not need to adjust the dose according to the liver and kidney function of the patient, and it is applicable to a wider range of patients; a number of phase III clinical studies have shown that linagliptin has good safety and effectiveness in patients with type 2 diabetes (T2DM) [3- 12], the risk of hypoglycemia is low, and it shows long-term cardiovascular and renal safety [13-14].

However, the observation period of these studies is relatively short, generally 52 weeks.
The patients are limited to clinical conditions and cannot fully reflect the long-term clinical use [12].

What is the efficacy and safety of long-term treatment with Linagliptin in the clinic? Will the patient’s aging and decreased renal function affect the treatment of linagliptin? What is the performance of linagliptin combined with other hypoglycemic drugs? Let’s take a look at several recently published long-term PMS results of DPP-4i Linagliptin in Asian populations.

A 3-year prospective, observational PMS study conducted in a Japanese population of T2DM patients to evaluate the safety (2235 cases in the safety analysis set) and effectiveness (2054 cases in the effectiveness analysis set) of linagliptin.

The average age of the patients was 66.
7±12.
5 years.

The included patients were all T2DM patients who were initially treated with linagliptin, and 82.
3% of the patients maintained linagliptin monotherapy during the study period [15].

Studies have shown that in the safety analysis, the incidence of adverse drug reactions (ADR) was 10.
7%, and 1.
6% of patients (n=35) had severe ADRs (Table 1).

In addition, the incidence of ADR (hypoglycemia, pancreatitis, hypersensitivity, etc.
) of particular concern is low (0~0.
8%) (Table 2).

This study did not find any drug-related adverse events of pancreatitis or pemphigoid that are currently attracting attention.

Table 1.
The incidence of ADR and severe ADR.
Table 2.
ADR of special concern.
In the effectiveness analysis, linagliptin can continuously improve the blood glucose control of T2DM patients, and the glycosylated hemoglobin (HbA1c) was reduced by 0.
67% from the baseline at the last observation; From 26 to 156 weeks, the patient's average HbA1c was stable at 6.
69% to 6.
76% (Figure 1a).

Fasting blood glucose (FPG) was reduced by an average of 20.
41 mg/dL compared with baseline; FPG was steadily controlled at -18.
26 to -23.
12 mg/dL (Figure 1b).

Figure 1.
Repeated measures analysis of mixed model of HbA1c and FPG over time.
82.
3% of patients in the study maintained linagliptin monotherapy, with a median duration of 153.
7 weeks, and HbA1c from baseline (7.
28±1.
25%) to the last observation (6.
67±0.
93%) an average decrease of 0.
61%, linagliptin monotherapy can reduce blood sugar steadily for a long time, and the overall compliance is good.

In this study, 40.
4% were patients <65 years old; 59.
6% were patients ≥65 years old.
The incidence of hypoglycemia in the entire study and in all age groups (including the elderly) was low.
There are significant differences, and the hypoglycemic effect is consistent in patients ≥65 years of age and under the age of 65.

In addition, the results of group analysis based on different estimated glomerular filtration rate (eGFR) levels suggest that the safety and effectiveness of long-term use of linagliptin are not affected by the state of renal function, and long-term medication does not affect the patient’s kidneys.
Function (Figure 2).

[16] Figure 2.
Changes in eGFR of eGFR subgroups over time during the study period.
In clinical use, linagliptin is often combined with other hypoglycemic drugs.
Another 3-year prospective and observational PMS developed in Japan Studies have shown the safety (3372 cases) and effectiveness (3029 cases) of linagliptin combined with other hypoglycemic drugs in the treatment of patients with T2DM [17].

The average age of patients in the safety analysis set was 66.
5±12.
4 years (61.
1% of patients were ≥65 years old). Studies have shown that in the safety analysis, the incidence of any ADR was 11.
39%.
The most common ADRs were diabetes progression (n=42, 1.
25%), hypertension (n=28, 0.
83%), and hypoglycemia (n=27).
, 0.
80%), constipation (n=20, 0.
59%), hyperuricemia (n=18, 0.
53%) and increased HbA1c (n=18, 0.
53%).

There was no significant difference in the incidence of ADR in the subgroups of hypoglycemic drugs with different baseline backgrounds and subgroups of each age.

2.
49% of patients (n=84) had severe ADR.

Of particular concern, the incidence of ADR is low, and there is no occurrence of interstitial lung disease (Table 3).

Table 3.
ADRs of particular concern are listed as "Clinically Significant Adverse Reactions" in the Japanese package insert; ADR: Adverse Drug Reactions In the effectiveness analysis, linagliptin can continuously improve the blood glucose control of T2DM, and HbA1c at the last observation was 0.
49 lower than the baseline %.

HbA1c decreased at 12 weeks and continued throughout the observation period.

The average range of HbA1c varies from -0.
57% to -0.
46% (Figure 3).

The decreasing trend of HbA1c was consistent in all subgroups.

The average change of FPG was 15.
27±59.
96 mg/dL (95% CI, -19.
54 ~ -11.
00 mg/dL), and the change trend of FPG over time was similar to that of HbA1c.

Figure 3.
Changes in HbA1c The latest release of a 6-year prospective, observational PMS study to evaluate the safety (safety analysis set 3119 cases) and effectiveness of linagliptin in the treatment of T2DM patients in South Korea ( Validity analysis set 2171 cases) [18].

The average age of the patients was 61 years old, and 91.
7% of them were treated with linagliptin combined with other hypoglycemic drugs.

The study showed that in the safety analysis, the incidence of ADR was 1.
8%. The most common ADRs are gastrointestinal diseases (n=21, 0.
7%), metabolic and nutritional disorders (n=14, 0.
5%), and neurological diseases (n=7, 0.
2%).

ADR of special concern occurred in 12 patients, of which 11 had hypoglycemia (10 of which received sulfonylureas combined with linagliptin), and 1 had skin damage.

The patient had no hepatobiliary disease, pancreatic disease, or symptoms related to heart disease.

In the effectiveness analysis, linagliptin can continuously improve the blood glucose control of T2DM, and the average HbA1c during the study period was significantly reduced by 0.
8%.

The 6-year PMS study in South Korea has a longer observation period and the results are similar to the 3-year PMS study in Japan, suggesting that Linagliptin has longer-term safety and effectiveness in patients with T2DM.

Two 3-year PMS studies in Japan and a 6-year PMS study in South Korea suggest that long-term clinical use of DPP-4i linagliptin monotherapy or combined with other hypoglycemic drugs is safe and sustainable and effective in reducing blood sugar.

Linagliptin has a low risk of treating hypoglycemia, small gastrointestinal side effects, simple medication, no need to adjust the dosage according to the patient's liver and kidney function, and little interaction with other drugs.

PMS studies suggest that linagliptin can be safe and effective in lowering blood sugar in a wide range of age groups.
Two Japanese PMS studies included nearly 60% of elderly diabetic patients.
The results of the study can better reflect the effectiveness of linagliptin in the treatment of elderly patients.
Advantages, the 2021 "Guidelines for Diagnosis and Treatment of Diabetes in the Elderly in China" will also use DPP-4i as the first-level recommended drug for non-insulin therapy [19].

In addition, studies suggest that the level of renal function in patients does not affect the effectiveness and safety of linagliptin, and it has been observed that long-term use of linagliptin does not affect the level of eGFR in patients.

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