Treatment pathway
According to the treatment guidelines of the Division of Diabetes Mellitus under the Chinese Medical Association, type 2 diabetes should first be treated with lifestyle interventions and oral metformin. If patients do not achieve glycemic control with metformin alone, duplex treatment should be used. If patients do not achieve the desired standard after 3 months of duplex treatment, triple therapy (i.e., the addition of a glucose-lowering drug with a different mechanism to duplex treatment) should be initiated. If glycemic control is still not achieved with triple therapy, then the treatment regimen should be changed to multiple insulin therapy, which includes either basal insulin plus mealtime insulin or multiple daily premixed insulins[1].
However, the American Diabetes Association Standards for the Management of Diabetes recommend a combination approach to treat type 2 diabetes, rather than a stepwise escalation of therapy based on the patient's condition (Figure 1). Please see Figure 2 for information on insulin therapy for type 2 diabetes. The guidelines also suggest that overweight/obese adults who are at high risk for type 2 diabetes should aim to lose 7% of their initial body weight and maintain it, with a recommended weight loss rate of 1-2 pounds per week. It is recommended that they get at least 150 minutes of moderate-intensity physical activity (such as brisk walking) per week[2].
Figure 1 Pharmacological treatment of type 2 diabetes
Figure 2 Insulin therapy for type 2 diabetes
Metformin is recommended for the prevention of type 2 diabetes in adults with prediabetes and in women with a history of gestational diabetes. This is especially important for those aged 25-59 years with a BMI of 35 kg/m2 or greater, high fasting glucose (e.g., ≥ 110 mg/dL), and relatively high HbA1c (e.g., > 6.0%). Long-term use of metformin may lead to vitamin B12 deficiency. Therefore, it is advised to consider periodic testing of vitamin B12 levels, particularly in patients with anemia or peripheral neuropathy. Prediabetes is associated with an increased risk of cardiovascular disease. Hence, screening and treatment of modifiable risk factors for cardiovascular disease are recommended[2].
Insulin therapy for type 1 diabetes is shown in Figure 3[2].
MDI: multiple daily insulin injections; NPH: recombinant human insulin; LAA: long-acting insulin analogue; RAA: rapid-acting insulin analogue; URAA: ultra rapid-acting insulin analogue
Figure 3 Insulin therapy for type 1 diabet
The ideal insulin replacement regimen maintains blood glucose as close to the normal physiologic range as possible, while allowing flexibility in terms of mealtimes and activity levels. Typical insulin replacement regimens include several components:
Basal insulin to restrain gluconeogenesis and ketogenesis in the preprandial state;
Mealtime insulin to cover the intake of carbohydrate and other macronutrients;
Correction insulin to treat hyperglycaemia.
Most people with type 1 diabetes should use regimens that mimic physiology as closely as possible, irrespective of the presentation. This is best achieved with either multiple dose injection of subcutaneous basal insulin analogues and mealtime rapid-acting or ultra-rapid-acting insulin analogues, or with continuous subcutaneous insulin infusion of a rapid-acting insulin analogue via a pump, delivered as continuous basal insulin combined with manual mealtime boluses. In the US, inhaled human insulin is an alternative to subcutaneous rapid-acting analogues[2].
Although first-generation basal analogues and NPH insulin are frequently administered once daily, greater flexibility and better coverage of basal insulin needs may be achieved by administering them twice daily. Studies have demonstrated that the latest basal analogues may cause less hypoglycaemia than first-generation basal analogues and NPH insulin, while rapid-acting analogues achieve better mealtime coverage and less postprandial hypoglycaemia than short-acting (regular) human insulin. Insulin analogues are, therefore, considered the insulins of choice.
References：
[2] American Diabetes Association ADA Standards of Care. 2022 Edition
[3] Holt RIG, DeVries JH, Hess-Fischl A, et al. The management of type 1 diabetes in adults. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2021; 44: 2589–2625
Medication selection
Current oral hypoglycemic drugs for the treatment of type 2 diabetes can be divided into those whose main effect is to stimulate insulin secretion and those that lower blood glucose by other mechanisms. The former mainly include sulfonylureas, glinides, dipeptidyl peptidase-IV inhibitors (DPP-4i), and glucagon-like peptide-1 receptor agonists (GLP-1 RA), and the latter mainly include biguanides, thiazolidinediones (TZDs), α-glucosidase inhibitors, and sodium-glucose cotransport-2 inhibitors (SGLT-2i).
Glucose-lowering drugs that stimulate insulin secretion
Sulfonylureas:
Sulfonylureas are classified as insulin secretagogues and their primary mechanism of action is to stimulate pancreatic beta cells to secrete insulin, effectively lowering blood glucose levels. Currently, sulfonylureas are still listed as first-line oral hypoglycemic agents in many countries and regions. However, the third-generation product glimepiride can not only stimulate insulin secretion but also increase insulin sensitivity. Its long-acting nature reduces the risk of hypoglycemia, which has led to its gradual replacement by second-generation products such as glipizide and gliquidone.
Glinides:
Glinides are a newer class of short-acting non-sulfonylurea insulin secretagogues. They work by stimulating pancreatic beta cells to secrete insulin more rapidly and effectively after meals, thereby controlling postprandial hyperglycemia. The main glinides are repaglinide, mitiglinide and nateglinide. Glinides have several advantages over sulfonylureas, including rapid onset of action, short duration of action, and a lower risk of hypoglycemia. These drugs are mainly metabolized in the body by the liver and gallbladder, making them suitable for use in elderly patients with diabetes and those with mild to moderate hepatic and renal insufficiency.
DPP-4 inhibitors:
DPP-4 inhibitors work by inhibiting the activity of dipeptidyl peptidase-4 (DPP-4), which reduces the breakdown and inactivation of the incretin GLP-1 (glucagon-like peptide-1), leading to increased endogenous levels of GLP-1. GLP-1 plays a critical role in promoting insulin release from pancreatic β-cells in response to glucose levels, while suppressing glucagon secretion from pancreatic α-cells. This unique mechanism of action allows DPP-4 inhibitors to increase insulin levels and lower blood glucose while reducing the risk of hypoglycemia and weight gain. The most important DPP-4 inhibitors are sitagliptin, saxagliptin, and linagliptin.
GLP-1 receptor agonists：
Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are a class of drugs used to treat type 2 diabetes. GLP-1 is an incretin hormone produced in the L-cells of the intestine that stimulates insulin secretion after an oral glucose load or a meal. It can also inhibit the production of glucagon by pancreatic α-cells when blood glucose levels are high. GLP-1 receptor agonists mimic GLP-1 and attempt to revive insulin secretion. By acting on the GLP-1 receptor, people with T2DM may experience delayed gastric emptying and suppression of glucagon production in pancreatic α-cells when blood glucose levels are high. In addition, GLP-1 receptor agonists can help reduce the death of pancreatic β-cells while promoting their proliferation. The main GLP-1 RAs currently on the market are semaglutide, liraglutide, dulaglutide, etc.
Other mechanism class hypoglycemic drugs
Biguanides:
Biguanides, of which metformin is the most widely used representative drug in patients with type 2 diabetes, exert their hypoglycemic effects by various mechanisms. Metformin inhibits gluconeogenesis, thereby reducing hepatic glucose output and increasing glucose uptake and utilization in peripheral tissues. This results in improved insulin sensitivity and a significant reduction in blood glucose levels. In addition to its glucose-lowering effects, metformin has been shown to reduce body weight and reduce the risk of cardiovascular events. Because of its proven efficacy and compatibility with most other oral hypoglycemic agents, metformin is considered a first-line treatment for diabetes in current national and international guidelines. It serves as a foundation drug in combination therapy, making it a fundamental component of many diabetes treatment regimens.
Alpha-glucosidase inhibitors:
Alpha-glucosidase inhibitors, including acarbose and voglibose, act in the gut to control blood glucose levels. Although their sites of action are similar, their mechanisms of action are slightly different. Acarbose competitively inhibits α-glucosidase in the cells of the small intestinal wall, preventing the breakdown of starch into disaccharides and further conversion into monosaccharides. Voglibose, on the other hand, inhibits intestinal α-glucosidase, interrupting the process of breaking down disaccharides into monosaccharides. Both acarbose and voglibose are effective in controlling postprandial blood glucose levels, with no significant difference in control. However, voglibose causes fewer gastrointestinal side effects, such as bloating, than acarbose.
Thiazolidinediones (TZDs):
Thiazolidinediones (TZDs) are classified as insulin sensitizers because they effectively reduce insulin resistance and increase insulin action by selectively activating peroxisome proliferator-activated receptors (PPARγ). This mechanism leads to a significant reduction in blood glucose levels. The main TZDs available are rosiglitazone and pioglitazone. When used alone, TZDs usually do not cause hypoglycemia. However, combining them with insulin or insulin secretagogues can increase the risk of hypoglycemia and side effects such as weight gain and edema.
SGLT-2 inhibitors:
SGLT-2 inhibitors act independently of insulin secretion and primarily target the kidneys. By inhibiting sodium-glucose cotransporter-2 (SGLT-2), they inhibit glucose reabsorption in the kidneys, resulting in increased urinary glucose excretion. This mechanism effectively lowers blood glucose levels. Commonly prescribed SGLT-2 inhibitors include dapagliflozin, empagliflozin, and canagliflozin. SGLT-2 inhibitors have many benefits, such as improving glycated hemoglobin levels, promoting weight loss, lowering blood pressure, and protecting kidney function.
Insulin therapy
Insulin therapy is an important tool for controlling hyperglycemia. Patients with type 1 diabetes depend on insulin for life support and also need insulin to control hyperglycemia and reduce the risk of diabetic complications. While patients with type 2 diabetes can survive without insulin, it becomes necessary to administer insulin when oral hypoglycemic drugs fail to work or when there are contraindications to the use of oral drugs. In such cases, insulin is required to effectively manage hyperglycemia and minimize the risk of diabetic complications. In certain cases, particularly in patients with long-standing diabetes, insulin therapy may become the mainstay or even an essential approach to managing blood glucose levels.
Insulins can be divided into animal insulin, human insulin, and insulin analogs based on the difference in the source and chemical structure. According to the difference in action characteristics, insulins can be further divided into ultra-short-acting insulin analogs, regular (short-acting) insulins, intermediate-acting insulins, long-acting insulins, long-acting insulin analogs, premixed insulins, premixed insulin analogs, and dual insulin analogs.
Initiation of insulin therapy
(1) Individuals diagnosed with type 1 diabetes must begin insulin therapy immediately and will require lifelong insulin replacement therapy.
(2) In cases where patients with newly diagnosed type 2 diabetes experience pronounced symptoms of hyperglycemia, ketosis, or DKA, insulin therapy is the preferred treatment option. Once blood glucose levels are effectively managed and symptoms are significantly alleviated, the subsequent course of treatment will be determined based on the individual's condition.
(3) When patients with newly diagnosed diabetes are difficult to diagnose and cannot be clearly distinguished as having type 1 or type 2 diabetes, insulin therapy may be the preferred treatment. Once blood glucose levels are well managed, symptoms are significantly improved, and the diagnosis is established, subsequent treatment plans will be formulated based on the type of diabetes and specific condition of the patient.
(4) Patients diagnosed with type 2 diabetes may initiate combination therapy of oral hypoglycemic drugs and insulin if their blood glucose levels do not achieve the target based on lifestyle modifications and oral hypoglycemic treatments. Typically, if the HbA1c remains ≥7.0% after a 3-month treatment period with adequate oral hypoglycemic drugs, initiation of insulin therapy may be considered.
(5) In the management of diabetes (including newly diagnosed type 2 diabetes), insulin therapy should be initiated as early as possible if there is significant unexplained weight loss[1].
Choice of starting insulin therapy
Basal insulin and premixed insulin can be selected as the starting insulin for treatment based on the patient's specific conditions.
(1) Basal insulin: Basal insulin includes intermediate-acting insulin and long-acting insulin analogs. When only basal insulin is used for treatment, the original oral hypoglycemic drugs are maintained and insulin stimulants do not need to be stopped.
(2) Premixed insulin: Premixed insulin includes premixed human insulin and premixed insulin analogs. Depending on the patient's blood glucose level, a 1-2 times daily injection regimen is available. If HbA1c is relatively high, use a 2 times daily injection regimen[1].
On the basis of insulin initiation therapy, further optimization of the treatment plan is required if the patient's blood glucose level still does not reach the standard or if recurrent hypoglycemia occurs after adequate dose adjustment. Intensive insulin therapy, which may include mealtime plus basal insulin (1-3 times/day) or premixed insulin analogs (2-3 times/day), may be considered as part of the treatment strategy[1].
(1) Mealtime + basal insulin: Adjust the insulin dosage before three meals according to the blood glucose level before lunch, dinner, and bedtime respectively. Adjust the basal insulin dosage before bedtime according to the fasting blood glucose level, and adjust every 3-5 days, changing the dose by 1-4 U each time according to the blood glucose level, until the blood glucose standard is reached.
(2) Premixed insulin 2-3 times a day (premixed human insulin 2 times/day and premixed insulin analog 2-3 times/day): adjust the insulin dosage according to the blood glucose level before bedtime and three meals, and adjust the dosage once every 3-5 days until the blood glucose reaches the standard[1].
Image source: China's Type 2 Diabetes Prevention and Control Guidelines (2020 Edition)
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