Insulin: Let his target innovate, I'm from the middle of the column

In recent years, the field of anti-diabetic has developed many new targets and new treatment mechanisms, of which GLP-1, DPP-4, SGLT2 and other target drugs have achieved the most resultsBut insulin is still the most direct and effective means of reducing sugar, in addition to type I diabetes patients must use insulin treatment, late-stage type 2 diabetes patients and patients with oral hypoglycemic drugs still need to control blood sugar through insulin, so insulin drugs are still the most important means of dealing with diabetes today, insulin and its mechanism
the pancreas is an important digestive organ of the human body, including the secretion of digestive enzymes mainly of external secretion cells and catheter system, and a variety of endocrine cells composed of isletsInsulin is a protein hormone secreted by the islet beta cells in the human pancreas, stimulated by endogenous or exogenous substances such as glucose, lactose, ribose, argininine, glucagon, etc., and is the only hypoglycemic hormone in the bodyInsulin function sits in animals of different races (people, cattle, sheep, pigs, etc.) with much the same function, but with slight differences in compositioninsulin is the last line of defense for patients with diabetes in late-stage medication, and it is necessary to use drugs in the middle and late stages and can not be replacedOnce the patient's blood sugar is not well controlled for a long time, it is likely to lead to serious complicationsChart 1: History of insulin development
insulin consists of two peptide chains A and B, human insulin A chain has 11 kinds of 21 amino acids, B chain has 15 kinds of 30 amino acids, molecular weight 5800The two peptide chains are connected by two disulfur bonds, and the other amino acid components are the same for insulin of different genus except 4, 8, 9 and 10 and B-chains 3, 9, 29 and 30the molecular weight and structure of insulin are highly complex compared to small molecular compounds, and their biological function is highly correlated with the way peptide chains are folded and modified, which greatly improves the difficulty of research and developmentChart 2: Insulin structureinsulin is still the best treatment drug, type I diabetes patients must use insulin injection therapy, and oral medications including metabolites, alpha-glucosein assinas, sulfonylurea, greina, thorades, etcon the treatment of type 2 diabetes is only to aid or strengthen insulin, improve biological activity and so onstudies show that insulin-reinforced blood sugar in the early stage of diabetes can significantly reduce the risk of complications such as myocardial infarction, microvascular complications, peripheral vascular disease, and significantly reduce diabetes-related mortalityChart 3: Insulin sugar reduction is most effective
insulin promotes the intake and utilization of glucose in whole body tissue cells, inhibits the decomposition of glycogen and glycogen isogenesis, promotes the synthesis and storage of fat, reduces the free fatty acids in the blood, and inhibits the decomposition and oxidation of fat; Chart 4: Insulin secretion and its mechanism of action
II, insulin iteration history
insulin after four iterations, animal-derived insulin (first generation), recombinant human insulin (second generation), recombinant insulin analogues (third generation) and ultra-long-acting insulin (fourth generation) animal-derived insulin is extracted from the pancreas of pigs and cattle and is prone to the production of antibodies Pig insulin in the B chain 30 by alanine instead of sucine, bovine insulin and human insulin have 3 amino acids different, A8 and B30 is not sucine, but alanine, A10 bit isolenine is replaced by proline At present, basically eliminated by clinical, because of cheap, in China also exists in the primary medical institutions, such as township hospitals, village health rooms, the market accounted for about 1%, only Wanbang animal insulin sporadic sales recombinant human insulin is a high-purity human insulin synthesized by yeast or E coli fermentation, whose structure is the same as the body's own secretion of insulin, allergic reactions are greatly reduced Products to Novo Nordisk, Lilly, Tonghua Dongbao-based, including short-acting insulin, medium-effect insulin and part of the premixed insulin Recombinant human insulin is currently commonly used insulin drugs, but the big city hospitals have entered a mature period, the incremental market is mainly at the county level and below the town hospitals, less developed areas of small and medium-sized hospitals insulin analog is the use of genetic engineering technology to modify the insulin peptide chain, change the amino acid combination in certain parts, to simulate the physiological state of insulin secretion rhythm Compared with human insulin, insulin analogues are closer to biological insulin secretion in terms of actability time, peak time and duration of action, are superior to human insulin in reducing the potential risk of hypoglycemia, and have achieved new levels that traditional human insulin cannot achieve in terms of quick effect and long-acting Chart 5: The history of insulin iteration is divided into short-acting insulin, long-acting insulin and premixed insulin, depending on the time of effect, mode, and duration Short-acting insulin works fast, immediate injection before meals, early peak time, short duration, long-acting insulin constant speed release into blood, long-term effect, good repeatability, provide stable insulin concentration; premixed insulin takes into account the patient's need for basic and meal time insulin, medium fast-acting insulin meets the needs of insulin at mealtime, glymin insulin meets the needs of basic insulin, corresponding to different needs of patients, there are a variety of insulin mixing (premixed insulin), but there is no obvious advantage Chart 6: Long, Short and Premixed Insulin Action Characteristics
3, Insulin Market Size and Pattern
The current domestic second-generation insulin sales growth slowly, the market pattern into stock competition, while the increase in insulin sales amount in the last 5 years almost came from the third generation of insulin, the amount of three-generation insulin sales has increased from 5,036 million yuan in 2013 to 11.192 billion yuan in 2017 Chart 7: China's second-generation/third-generation insulin sales amount (BILLION) and growth rate (%) recombinant human insulin (second generation) recombinant human insulin global market growth declined, but the market competition pattern is stable At the same time, domestic second-generation insulin sales are not optimistic, sales have all but stalled, sales in 2017 sales rose by only 1% Second-generation insulin use is concentrated in the second- and third-tier primary medical market, it is expected that the total amount of the national second-generation insulin market is still more than three generations of insulin, but the third-generation products to replace the second-generation products occupy the main market is an inevitable trend according to evaluate Pharma, the global second-generation insulin market share in 2016 was 68%, 29% and 3%, respectively, according to Evaluate Pharma Domestic second-generation insulin is still dominated by foreign investment, but has gradually ceded market share According to IMS data, in 2016 Novo Nordisk, Tonghua Dongbao, Lilly, and Federal Pharma had a market share of 59.1%, 20.8%, 13.8% and 5.1% of the second-generation insulin market in China, respectively With the continuous improvement of the level of new agricultural co-financing, as well as the changeofs of the second-generation insulin into the new version of the national base drug catalog, the grass-roots market will be an important incremental source of second-generation insulin in China in the next 3-5 years insulin analogues (three generations) because of good medicinal properties, hospitals in cities and above in China, and county hospitals in developed areas, three generations of insulin has gradually replaced the second generation of insulin, occupying a dominant position quick-acting insulin analogues are effective in reducing post-meal blood sugar and reducing the occurrence of hypoglycemia, while long-acting insulin analogues have no significant spikes, providing patients with a stable base insulin As a result, insulin analogues are priced in the market much higher than human insulin, with a large profit margin three generations of insulin, domestic enterprises currently only Gan Li Pharmaceutical has products on the market, the market share of 10.2%, the share increased year by year Therefore, for national products, the room for import substitution is still huge Federal Pharmaceuticals, Tonghua Dongbao, Haizheng Pharmaceuticals and Jiangsu Wanbang are currently declaring three generations of insulin varieties, which are expected to compete for market share after the market Chart 8: 2016 China's Ganli Pharmaceutical Market accounted for 10.2% Schedule 1: Each generation insulin summary Schedule 2: Advances of insulin in the winter (domestic pharmaceutical companies, first five) Schedule 3: Progress of insulin (domestic pharmaceutical companies, first three) Schedule 4: Dite insulin Progress (Domestic Pharmaceutical Companies, Top 4) Schedule 5: Progress of insulin glargine (domestic pharmaceutical companies, top five) Source: China Diabetes Prevention and Control Guide (2017 Edition), IDF, Prospective Industry Research Institute, EvaluatePharm, IMS, CDE, Guojin Securities, Changjiang Securities, Dongxing Securities