2020 糖尿病血糖控制 2 第一型DM的胰島素治療

Insulin Therapy
Because the hallmark of type 1 diabetes is absent or near-absent β-cell function, insulin treatment is essential for individuals with type 1 diabetes. In addition to hyperglycemia, insulinopenia can contribute to other metabolic disturbances like hypertriglyceridemia and ketoacidosis as well as tissue catabolism that can be life threatening. Severe metabolic decompensation can be, and was, mostly prevented with once or twice daily injections for the six or seven decades after the discovery of insulin. However, over the past three decades, evidence has accumulated supporting more intensive insulin replacement, using multiple daily injections of insulin or continuous subcutaneous administration through an insulin pump, as providing the best combination of effectiveness and safety for people with type 1 diabetes. The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive therapy with multiple daily injections or continuous subcutaneous insulin infusion (CSII) reduced A1C and was associated with improved long-term outcomes (1–3). The study was carried out with short-acting (regular) and intermediate-acting (NPH) human insulins. In this landmark trial, lower A1C with intensive control (7%) led to ∼50% reductions in microvascular complications over 6 years of treatment. However, intensive therapy was associated with a higher rate of severe hypoglycemia than conventional treatment (62 compared with 19 episodes per 100 patient-years of therapy). Follow-up of subjects from the DCCT more than 10 years after the active treatment component of the study demonstrated less macrovascular as well as less microvascular complications in the group that received intensive treatment.

Over the last 25 years, rapid-acting and long-acting insulin analogs have been developed that have distinct pharmacokinetics compared with recombinant human insulins: basal insulin analogs have longer duration of action with flatter, more constant plasma concentrations and activity profiles than NPH insulin; rapid-acting analogs (RAA) have a quicker onset and peak and shorter duration of action than regular human insulin. In people with type 1 diabetes, treatment with analog insulins is associated with less hypoglycemia and weight gain as well as lower A1C compared with human insulins (4–6). More recently, two new insulin formulations with enhanced rapid action profiles have been introduced. Inhaled human insulin has a rapid peak and shortened duration of action compared with RAA and may cause less hypoglycemia and weight gain (7), and faster-acting insulin aspart may reduce prandial excursions better than RAA (8); further investigation is needed to establish a clear place for these agents in diabetes management. In addition, new longer-acting basal analogs (U-300 glargine or degludec) may confer a lower hypoglycemia risk compared with U-100 glargine in patients with type 1 diabetes (9,10). Despite the advantages of insulin analogs in patients with type 1 diabetes, for some patients the expense and/or intensity of treatment required for their use is prohibitive. There are multiple approaches to insulin treatment, and the central precept in the management of type 1 diabetes is that some form of insulin be given in a planned regimen tailored to the individual patient to keep them safe, out of diabetic ketoacidosis, and avoid significant hypoglycemia, with every effort made to reach the patient’s glycemic targets.

Most studies comparing multiple daily injections with CSII have been relatively small and of short duration. However, a recent systematic review and meta-analysis concluded that pump therapy has modest advantages for lowering A1C (–0.30% [95% CI –0.58 to –0.02]) and for reducing severe hypoglycemia rates in children and adults (11). However, there is no consensus to guide the choice of injection or pump therapy in a given patient, and research to guide this decision-making is needed (12). The arrival of continuous glucose monitors to clinical practice has proven beneficial in specific circumstances. Reduction of nocturnal hypoglycemia in people with type 1 diabetes using insulin pumps with glucose sensors is improved by automatic suspension of insulin delivery at a preset glucose level (12–14). The U.S. Food and Drug Administration (FDA) has also approved the first hybrid closed-loop pump system. The safety and efficacy of hybrid closed-loop systems has been supported in the literature in adolescents and adults with type 1 diabetes (15,16), and recent evidence suggests that a closed-loop system is superior to sensor-augmented pump therapy for glycemic control and reduction of hypoglycemia over 3 months of comparison in children and adults with type 1 diabetes (17). Intensive insulin management using a version of CSII and continuous glucose monitoring should be considered in most patients. See Section 7 “Diabetes Technology” (https://doi.org/10.2337/dc20-S007) for a full discussion of insulin delivery devices.

In general, patients with type 1 diabetes require 50% of their daily insulin as basal and 50% as prandial. Total daily insulin requirements can be estimated based on weight, with typical doses ranging from 0.4 to 1.0 units/kg/day. Higher amounts are required during puberty, pregnancy, and medical illness. The American Diabetes Association/JDRF Type 1 Diabetes Sourcebook notes 0.5 units/kg/day as a typical starting dose in patients with type 1 diabetes who are metabolically stable, with half administered as prandial insulin given to control blood glucose after meals and the other half as basal insulin to control glycemia in the periods between meal absorption (18); this guideline provides detailed information on intensification of therapy to meet individualized needs. In addition, the American Diabetes Association position statement “Type 1 Diabetes Management Through the Life Span” provides a thorough overview of type 1 diabetes treatment (19).

Typical multidose regimens for patients with type 1 diabetes combine premeal use of shorter-acting insulins with a longer-acting formulation, usually at night. The long-acting basal dose is titrated to regulate overnight, fasting glucose. Postprandial glucose excursions are best controlled by a well-timed injection of prandial insulin. The optimal time to administer prandial insulin varies, based on the pharmacokinetics of the formulation (regular, RAA, inhaled), the premeal blood glucose level, and carbohydrate consumption. Recommendations for prandial insulin dose administration should therefore be individualized. Physiologic insulin secretion varies with glycemia, meal size, and tissue demands for glucose. To approach this variability in people using insulin treatment, strategies have evolved to adjust prandial doses based on predicted needs. Thus, education of patients on how to adjust prandial insulin to account for carbohydrate intake, premeal glucose levels, and anticipated activity can be effective and should be offered to most patients (20,21). For individuals in whom carbohydrate counting is effective, estimates of the fat and protein content of meals can be incorporated into their prandial dosing for added benefit (22).

Insulin Injection Technique
Ensuring that patients and/or caregivers understand correct insulin injection technique is important to optimize glucose control and insulin use safety. Thus, it is important that insulin be delivered into the proper tissue in the right way. Recommendations have been published elsewhere outlining best practices for insulin injection (23). Proper insulin injection technique includes injecting into appropriate body areas, injection site rotation, appropriate care of injection sites to avoid infection or other complications, and avoidance of intramuscular (IM) insulin delivery.

Exogenous-delivered insulin should be injected into subcutaneous tissue, not intramuscularly. Recommended sites for insulin injection include the abdomen, thigh, buttock, and upper arm. Because insulin absorption from IM sites differs according to the activity of the muscle, inadvertent IM injection can lead to unpredictable insulin absorption and variable effects on glucose, with IM injection being associated with frequent and unexplained hypoglycemia in several reports. Risk for IM insulin delivery is increased in younger, leaner patients when injecting into the limbs rather than truncal sites (abdomen and buttocks) and when using longer needles. Recent evidence supports the use of short needles (e.g., 4-mm pen needles) as effective and well tolerated when compared with longer needles, including a study performed in obese adults (24).

Injection site rotation is additionally necessary to avoid lipohypertrophy, an accumulation of subcutaneous fat in response to the adipogenic actions of insulin at a site of multiple injections. Lipohypertrophy appears as soft, smooth raised areas several centimeters in breadth and can contribute to erratic insulin absorption, increased glycemic variability, and unexplained hypoglycemic episodes. Patients and/or caregivers should receive education about proper injection site rotation and to recognize and avoid areas of lipohypertrophy. As noted in Table 4.1, examination of insulin injection sites for the presence of lipohypertrophy, as well as assessment of injection device use and injection technique, are key components of a comprehensive diabetes medical evaluation and treatment plan. As referenced above, there are now numerous evidence-based insulin delivery recommendations that have been published. Proper insulin injection technique may lead to more effective use of this therapy and, as such, holds the potential for improved clinical outcomes.

Noninsulin Treatments for Type 1 Diabetes
Injectable and oral glucose-lowering drugs have been studied for their efficacy as adjuncts to insulin treatment of type 1 diabetes. Pramlintide is based on the naturally occurring β-cell peptide amylin and is approved for use in adults with type 1 diabetes. Results from randomized controlled studies show variable reductions of A1C (0–0.3%) and body weight (1–2 kg) with addition of pramlintide to insulin (25,26). Similarly, results have been reported for several agents currently approved only for the treatment of type 2 diabetes. The addition of metformin to adults with type 1 diabetes caused small reductions in body weight and lipid levels but did not improve A1C (27,28). The addition of the glucagon-like peptide 1 (GLP-1) receptor agonists (RAs) liraglutide and exenatide to insulin therapy caused small (0.2%) reductions in A1C compared with insulin alone in people with type 1 diabetes and also reduced body weight by ∼3 kg (29). Similarly, the addition of a sodium–glucose cotransporter 2 (SGLT2) inhibitor to insulin therapy has been associated with improvements in A1C and body weight when compared with insulin alone (30,31); however, SGLT2 inhibitor use in type 1 diabetes is associated with a two- to fourfold increase in ketoacidosis. The risks and benefits of adjunctive agents continue to be evaluated, but only pramlintide is approved for treatment of type 1 diabetes.