2020 糖尿病血糖控制 T2DM 選擇口服及注射藥物流程圖

AACE 2017 GLYCEMIC CONTROL ALGORITHM

流程圖
第一線用藥是 metformin.
再來評估是否有ASCVD動脈粥狀硬化的心血管疾病, 慢性腎病, 或心衰竭.
有上述疾病或危險因子的病患, 根據病情嚴重度, 給予不同的A1C指標.
根據病患是否以動脈粥狀硬化為主. 或者是心衰竭/慢性腎病為主做考量.
已經確診有 ASCVD或者有ASCVD危險因子, 給予GLP1RA, 如果腎功能還好, 也可以給 SGLT2i
ASCVD危險因子包括:
55歲以上, 有動脈硬化, 阻塞超過 50% (冠狀動脈,頸動脈,下肢動脈), 或者左心室肥大

以心衰竭或慢性腎病為考量的, 尤其是 HFrEF (EF<45%)
CKD 指 eGFR 30-60 以下, 或者 UACR > 30 mg/g , 尤其是 UACR > 300 mg/g 的患者
UACR= urine albumin-creatinine ratio, UACR，通常介於. 30~299 mg/g
如果eGFR 還好. 考慮給 SGLT2i
如果無法使用 SGLT2i (病患無法忍受副作用,或腎功能太差), 可考慮 GLP1RA

Figure 9.1 說明

Glucose-lowering medication in type 2 diabetes: overall approach. For appropriate context, see Fig. 4.1. ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease; CVOTs, cardiovascular outcomes trials; DPP-4i, dipeptidyl peptidase 4 inhibitor; eGFR, estimated glomerular filtration rate; GLP-1 RA, glucagon-like peptide 1 receptor agonist; HF, heart failure; SGLT2i, sodium–glucose cotransporter 2 inhibitor; SU, sulfonylurea; TZD, thiazolidinedione. Adapted from Davies and colleagues 

ASCVD 這組, 經過治療之後如果血糖仍控制不良, 需要加入其他藥物

或病患無法忍受GLP1RA or SGLT2i, 

- 使用 GLP1RA的患者可加上 SGLT2i

- 沒有使用 GLP1RA的病患可考慮DPP4i

- 基礎胰島素

- TZD 胰島素增敏劑

- SU

心衰竭或慢性腎病為主的這組病患, 如果血糖控制仍不良

*心衰竭病患避免使用 TZD

- 使用 SGLT2i 的患者可以加上 GLP1RA

- 心衰竭患者如果沒有使用 GLP1RA的, 可選 DPP4i (不要選 saxagliptin) 

- 基礎胰島素

- SU

2020 糖尿病血糖控制 3 第一型DM非胰島素治療

Noninsulin Treatments for Type 1 Diabetes

有研究評估使用胰島素治療的第一型DM病患, 輔助使用注射型及口服的降血糖藥物的效果
使用胰島素治療再加上pramlintide 普蘭林肽, 隨機研究顯示能降低A1C 0% -0.3%, 降低體重 1-2 公斤


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.

第一型DM患者, 注射胰島素的同時使用 metformin, 可稍微降低體重及血脂肪, 但無法降低 A1C

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). 

第一型DM患者使用胰島素治療加上 GLP-1RA liraglutide 及 exenatide, 可降低 0.2% A1C (很微量), 降低體重 3 公斤,
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).

胰島素治療加上 SGLT2i, 相較於單純只用胰島素, 可以改善A1C 及體重. 但第一型DM患者使用 SGLT2i 會增加 2-4 倍酮酸中毒機率, 輔助藥物的危險及利益仍需進一步評估
目前只有 pramlintide 證實對第一型DM有益處.
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.

Pramlintide 普蘭林肽是由Amylin Pharmaceuticals 開發的可注射的胰島澱粉樣多肽類似物藥物

pramlintide，是 amylin的類似物，amylin與胰島素都是由胰臟的 β細胞分泌，血中 amylin增加時，會抑制升糖素、減緩胃排空、刺激飽食中樞，因而能降低血糖，也能降低體重，必須皮下注射使用。

在臨床試驗的表現：一篇收納 656位糖尿病病患的 RCT，追蹤 52週，發現使用 pramlintide (120 μg SC BID)的組別體重平均降低 1.4 kg，比起使用 placebo組增加 0.7 kg，達到統計學上顯著差異 (P<0.05)。

2020 糖尿病血糖控制 10 第二型DM的組合注射藥物治療

Combination Injectable Therapy
If basal insulin has been titrated to an acceptable fasting blood glucose level (or if the dose is >0.5 units/kg/day) and A1C remains above target, consider advancing to combination injectable therapy (Fig. 9.2). This approach can use a GLP-1 RA added to basal insulin or multiple doses of insulin. The combination of basal insulin and GLP-1 RA has potent glucose-lowering actions and less weight gain and hypoglycemia compared with intensified insulin regimens (84–86). Two different once-daily fixed-dual combination products containing basal insulin plus a GLP-1 RA are available: insulin glargine plus lixisenatide and insulin degludec plus liraglutide.

Intensification of insulin treatment can be done by adding doses of prandial to basal insulin. Starting with a single prandial dose with the largest meal of the day is simple and effective, and it can be advanced to a regimen with multiple prandial doses if necessary (87). Alternatively, in a patient on basal insulin in whom additional prandial coverage is desired, the regimen can be converted to two doses of a premixed insulin. Each approach has advantages and disadvantages. For example, basal/prandial regimens offer greater flexibility for patients who eat on irregular schedules. On the other hand, two doses of premixed insulin is a simple, convenient means of spreading insulin across the day. Moreover, human insulins, separately, self-mixed, or as premixed NPH/regular (70/30) formulations, are less costly alternatives to insulin analogs. Figure 9.2 outlines these options, as well as recommendations for further intensification, if needed, to achieve glycemic goals. When initiating combination injectable therapy, metformin therapy should be maintained while sulfonylureas and DPP-4 inhibitors are typically discontinued. In patients with suboptimal blood glucose control, especially those requiring large insulin doses, adjunctive use of a thiazolidinedione or an SGLT2 inhibitor may help to improve control and reduce the amount of insulin needed, though potential side effects should be considered. Once a basal/bolus insulin regimen is initiated, dose titration is important, with adjustments made in both mealtime and basal insulins based on the blood glucose levels and an understanding of the pharmacodynamic profile of each formulation (pattern control). As people with type 2 diabetes get older, it may become necessary to simplify complex insulin regimens because of a decline in self-management ability (see Section 12 “Older Adults,” https://doi.org/10.2337/dc20-S012).

2020 糖尿病血糖控制 9 第二型DM的胰島素治療

Insulin Therapy
Many patients with type 2 diabetes eventually require and benefit from insulin therapy (Fig. 9.2). See the section insulin injection technique above, for guidance on how to administer insulin safely and effectively. The progressive nature of type 2 diabetes should be regularly and objectively explained to patients, and providers should avoid using insulin as a threat or describing it as a sign of personal failure or punishment. Rather, the utility and importance of insulin to maintain glycemic control once progression of the disease overcomes the effect of other agents should be emphasized. Educating and involving patients in insulin management is beneficial. For example, instruction of patients in self-titration of insulin doses based on self-monitoring of blood glucose improves glycemic control in patients with type 2 diabetes initiating insulin (58). Comprehensive education regarding self-monitoring of blood glucose, diet, and the avoidance and appropriate treatment of hypoglycemia are critically important in any patient using insulin.

Basal Insulin
Basal insulin alone is the most convenient initial insulin regimen and can be added to metformin and other oral agents. Starting doses can be estimated based on body weight (0.1–0.2 units/kg/day) and the degree of hyperglycemia, with individualized titration over days to weeks as needed. The principal action of basal insulin is to restrain hepatic glucose production and limit hyperglycemia overnight and between meals (59,60). Control of fasting glucose can be achieved with human NPH insulin or a long-acting insulin analog. In clinical trials, long-acting basal analogs (U-100 glargine or detemir) have been demonstrated to reduce the risk of symptomatic and nocturnal hypoglycemia compared with NPH insulin (61–66), although these advantages are modest and may not persist (67). Longer-acting basal analogs (U-300 glargine or degludec) may convey a lower hypoglycemia risk compared with U-100 glargine when used in combination with oral agents (68–74). Despite evidence for reduced hypoglycemia with newer, longer-acting basal insulin analogs in clinical trial settings, in practice these effects may be modest compared with NPH insulin (75).

The cost of insulin has been rising steadily over the past two decades, at a pace several fold that of other medical expenditures (76). This expense contributes significant burden to patients as insulin has become a growing “out-of-pocket” cost for people with diabetes, and direct patient costs contribute to treatment nonadherence (76). Therefore, consideration of cost is an important component of effective management. For many patients with type 2 diabetes (e.g., individuals with relaxed A1C goals, low rates of hypoglycemia, and prominent insulin resistance, as well as those with cost concerns), human insulin (NPH and regular) may be the appropriate choice of therapy, and clinicians should be familiar with its use (75). Human regular insulin, NPH, and 70/30 NPH/regular products can be purchased for considerably less than the AWP and NADAC prices listed in Table 9.3 at select pharmacies.

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Table 9.3
Median cost of insulin products in the U.S. calculated as AWP (54) and NADAC (55) per 1,000 units of specified dosage form/product

Prandial Insulin
Many individuals with type 2 diabetes require doses of insulin before meals, in addition to basal insulin, to reach glycemic targets. A dose of 4 units or 10% of the amount of basal insulin at the largest meal or the meal with the greatest postprandial excursion is a safe estimate for initiating therapy. The prandial insulin regimen can then be intensified based on patient needs (see Figure 9.2). People with type 2 diabetes are generally more insulin resistant than those with type 1 diabetes, require higher daily doses (∼1 unit/kg), and have lower rates of hypoglycemia (77). Titration can be based on home glucose monitoring or A1C. With significant additions to the prandial insulin dose, particularly with the evening meal, consideration should be given to decreasing basal insulin. Meta-analyses of trials comparing rapid-acting insulin analogs with human regular insulin in patients with type 2 diabetes have not reported important differences in A1C or hypoglycemia (78,79).

Concentrated Insulins
Several concentrated insulin preparations are currently available. U-500 regular insulin is, by definition, five times more concentrated than U-100 regular insulin. Regular U-500 has distinct pharmacokinetics with delayed onset and longer duration of action, has characteristics more like an intermediate-acting (NPH) insulin, and can be used as two or three daily injections (80). U-300 glargine and U-200 degludec are three and two times as concentrated as their U-100 formulations, and allow higher doses of basal insulin administration per volume used. U-300 glargine has a longer duration of action than U-100 glargine but modestly lower efficacy per unit administered (81,82). The FDA has also approved a concentrated formulation of rapid-acting insulin lispro, U-200 (200 units/mL). These concentrated preparations may be more convenient and comfortable for patients to inject and may improve adherence in those with insulin resistance who require large doses of insulin. While U-500 regular insulin is available in both prefilled pens and vials (a dedicated syringe was approved in July 2016), other concentrated insulins are available only in prefilled pens to minimize the risk of dosing errors.

Inhaled Insulin
Inhaled insulin is available for prandial use with a limited dosing range; studies in people with type 1 diabetes suggest rapid pharmacokinetics (7). A pilot study found evidence that compared with injectable rapid-acting insulin, supplemental doses of inhaled insulin taken based on postprandial glucose levels may improve blood glucose management without additional hypoglycemia or weight gain (83), although results from a larger study are needed for confirmation. Inhaled insulin is contraindicated in patients with chronic lung disease, such as asthma and chronic obstructive pulmonary disease, and is not recommended in patients who smoke or who recently stopped smoking. All patients require spirometry (FEV1) testing to identify potential lung disease prior to and after starting inhaled insulin therapy.

2020 糖尿病血糖控制 1 大綱

Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2020

Abstract

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes” includes the ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc20-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc20-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

第一型DM患者的藥物治療建議
1. 多數第一型DM患者應採用每天多次注射的治療 (隨餐胰島素及基礎胰島素), 或連續性皮下胰島素注射
2. 多數第一型DM患者,  應使用短效胰島素類似物, 以減少低血糖風險
3. 第一型DM患者, 應接受訓練調整胰島素劑量, 根據吃入的碳水化合物, 餐前血糖, 以及將從事的身體活動.

PHARMACOLOGIC THERAPY FOR TYPE 1 DIABETES

Recommendations

9.1 Most people with type 1 diabetes should be treated with multiple daily injections of prandial and basal insulin, or continuous subcutaneous insulin infusion. A

9.2 Most individuals with type 1 diabetes should use rapid-acting insulin analogs to reduce hypoglycemia risk. A

9.3 Patients with type 1 diabetes should be trained to match prandial insulin doses to carbohydrate intake, premeal blood glucose, and anticipated physical activity. C

第二型DM的藥物治療流程圖

2. 第一型DM的胰島素治療Insulin therapy
3. 第一型DM非胰島素治療

4. 第一型DM的手術治療

5. 第二型DM的藥物治療

6. 第二型DM初始治療

7. 第二型DM組合治療
8. 第二型DM心血管研究
9. 第二型DM胰島素治療
10. 第二型DM組合注射藥物治療 

2020 糖尿病血糖控制 8 第二型DM的組心血管研究

Cardiovascular Outcomes Trials
There are now multiple large randomized controlled trials reporting statistically significant reductions in cardiovascular events in patients with type 2 diabetes treated with an SGLT2 inhibitor (empagliflozin, canagliflozin, dapagliflozin) or GLP-1 RA (liraglutide, semaglutide, dulaglutide); see Section 10 “Cardiovascular Disease and Risk Management” (https://doi.org/10.2337/dc20-S010) for details. The subjects enrolled in the cardiovascular outcome trials using empagliflozin, canagliflozin, liraglutide, and semaglutide had A1C ≥7%, and more than 70% were taking metformin at baseline. Thus, a practical extension of these results to clinical practice is to use these drugs preferentially in patients with type 2 diabetes and established ASCVD or indicators of high ASCVD risk. For these patients, incorporating one of the SGLT2 inhibitors or GLP-1 RAs that have been demonstrated to have cardiovascular disease benefit is recommended (Table 9.1). In cardiovascular outcomes trials, empagliflozin, canagliflozin, dapagliflozin, liraglutide, semaglutide, and dulaglutide all had beneficial effects on indices of CKD. See Section 11 “Microvascular Complications and Foot Care” (https://doi.org/10.2337/dc20-S011) for a detailed discussion on how CKD may impact treatment choices. Additional large randomized trials of other agents in these classes are ongoing.

2020 糖尿病血糖控制 7 第二型DM的組合治療

Combination Therapy
Because type 2 diabetes is a progressive disease in many patients, maintenance of glycemic targets with monotherapy is often possible for only a few years, after which combination therapy is necessary. Current recommendations have been to use stepwise addition of medications to metformin to maintain A1C at target. This allows a clearer assessment of the positive and negative effects of new drugs and reduces patient risk and expense (42); based on these factors, sequential addition of oral agents to metformin has been the standard of care. However, there is data to support initial combination therapy for more rapid attainment of glycemic goals (43,44), and a recent clinical trial has demonstrated that this approach is superior to sequential addition of medications for extending primary and secondary failure (45). In the VERIFY trial, participants receiving the initial combination of metformin and the dipeptidyl peptidase 4 (DPP-4) inhibitor vildagliptin had a slower decline of glycemic control compared with metformin alone and to vildagliptin added sequentially to metformin. These results have not been generalized to oral agents other than vildagliptin, but they suggest that more intensive early treatment has some benefits and should be considered through a shared decision-making process with patients, as appropriate. Moreover, since the absolute effectiveness of most oral medications rarely exceeds 1%, initial combination therapy should be considered in patients presenting with A1C levels 1.5–2.0% above target.

The choice of medication added to metformin is based on the clinical characteristics of the patient and their preferences. Important clinical characteristics include the presence of established ASCVD or indicators of high ASCVD risk, other comorbidities, and risk for specific adverse drug effects, as well as safety, tolerability, and cost. Although there are numerous trials comparing dual therapy with metformin alone, there is little evidence to support one combination over another. A comparative effectiveness meta-analysis suggests that each new class of noninsulin agents added to initial therapy with metformin generally lowers A1C approximately 0.7–1.0% (46,47). If the A1C target is not achieved after approximately 3 months, metformin can be combined with any one of the preferred six treatment options: sulfonylurea, thiazolidinedione, DPP-4 inhibitor, SGLT2 inhibitor, GLP-1 RA, or basal insulin; the choice of which agent to add is based on drug-specific effects and patient factors (Fig. 9.1 and Table 9.1).

For patients with established ASCVD or indicators of high ASCVD risk (such as patients ≥55 years of age with coronary, carotid, or lower-extremity artery stenosis >50% or left ventricular hypertrophy), established kidney disease, or heart failure, an SGLT-2 inhibitor or GLP-1 RA with demonstrated CVD benefit (Table 9.1, Table 10.3B, Table 10.3C) is recommended as part of the glucose-lowering regimen independent of A1C and in consideration of patient-specific factors (Figure 9.1). For patients without established ASCVD, indicators of high ASCVD risk, HF, or CKD, the choice of a second agent to add to metformin is not yet guided by empiric evidence. Rather, drug choice is based on avoidance of side effects, particularly hypoglycemia and weight gain, cost, and patient preferences (48). Similar considerations are applied in patients who require a third agent to achieve glycemic goals; there is very little trial-based evidence to guide this choice. In all cases, treatment regimens need to be continuously reviewed for efficacy, side effects, and patient burden (Table 9.1). In some instances, patients will require medication reduction or discontinuation. Common reasons for this include ineffectiveness, intolerable side effects, expense, or a change in glycemic goals (e.g., in response to development of comorbidities or changes in treatment goals). Section 12 “Older Adults”(https://doi.org/10.2337/dc20-S012) has a full discussion of treatment considerations in older adults, a setting where changes of glycemic goals and de-escalation of therapy is common.

Although most patients prefer oral medications to drugs that need to be injected, the eventual need for the greater potency of injectable medications is common, particularly in people with a longer duration of diabetes. The addition of basal insulin, either human NPH or one of the long-acting insulin analogs, to oral agent regimens is a well-established approach that is effective for many patients. In addition, recent evidence supports the utility of GLP-1 RAs in patients not reaching glycemic targets with use of non-GLP-1 RA oral agent regimens. While most GLP-1 RA products are injectable, an oral formulation of semaglutide is now commercially available (49). In trials comparing the addition of an injectable GLP-1 RAs or insulin in patients needing further glucose lowering, the efficacy of the two treatments was similar (50–52). However, GLP-1 RAs in these trials had a lower risk of hypoglycemia and beneficial effects on body weight compared with insulin, albeit with greater gastrointestinal side effects. Thus, trial results support injectable GLP-1 RAs as the preferred option for patients requiring the potency of an injectable therapy for glucose control (Fig. 9.2). However, high costs and tolerability issues are important barriers to the use of GLP-1 RAs.

Cost for diabetes medicine has increased dramatically over the past two decades, and an increasing proportion is now passed on to patients and their families (53). Table 9.2 provides cost information for currently approved noninsulin therapies. Of note, prices listed are average wholesale prices (AWP) (54) and National Average Drug Acquisition Costs (NADAC) (55), separate measures to allow for a comparison of drug prices but do not account for discounts, rebates, or other price adjustments often involved in prescription sales that affect the actual cost incurred by the patient. Medication costs can be a major source of stress for patients with diabetes and contribute to worse adherence with medications (56); cost-reducing strategies may improve adherence in some cases (57).

2020 糖尿病血糖控制 6 第二型DM的初始治療

Initial Therapy
Metformin should be started at the time type 2 diabetes is diagnosed unless there are contraindications; for many patients this will be monotherapy in combination with lifestyle modifications. Metformin is effective and safe, is inexpensive, and may reduce risk of cardiovascular events and death (35). Metformin is available in an immediate-release form for twice-daily dosing or as an extended-release form that can be given once daily. Compared with sulfonylureas, metformin as first-line therapy has beneficial effects on A1C, weight, and cardiovascular mortality (36); there is little systematic data available for other oral agents as initial therapy of type 2 diabetes. The principal side effects of metformin are gastrointestinal intolerance due to bloating, abdominal discomfort, and diarrhea; these can be mitigated by gradual dose titration. The drug is cleared by renal filtration, and very high circulating levels (e.g., as a result of overdose or acute renal failure) have been associated with lactic acidosis. However, the occurrence of this complication is now known to be very rare, and metformin may be safely used in patients with reduced estimated glomerular filtration rates (eGFR); the FDA has revised the label for metformin to reflect its safety in patients with eGFR ≥30 mL/min/1.73 m2 (37). A recent randomized trial confirmed previous observations that metformin use is associated with vitamin B12 deficiency and worsening of symptoms of neuropathy (38). This is compatible with a recent report from the Diabetes Prevention Program Outcomes Study (DPPOS) suggesting periodic testing of vitamin B12 (39).

In patients with contraindications or intolerance to metformin, initial therapy should be based on patient factors; consider a drug from another class depicted in Fig. 9.1. When A1C is ≥1.5% (12.5 mmol/mol) above the glycemic target (see Section 6 “Glycemic Targets,” https://doi.org/10.2337/dc20-S006, for selecting appropriate targets), many patients will require dual combination therapy to achieve their target A1C level (40). Insulin has the advantage of being effective where other agents are not and should be considered as part of any combination regimen when hyperglycemia is severe, especially if catabolic features (weight loss, hypertriglyceridemia, ketosis) are present. It is common practice to initiate insulin therapy for patients who present with blood glucose levels ≥300 mg/dL (16.7 mmol/L) or A1C >10% (86 mmol/mol) or if the patient has symptoms of hyperglycemia (i.e., polyuria or polydipsia) or evidence of catabolism (weight loss) (Fig. 9.2). As glucose toxicity resolves, simplifying the regimen and/or changing to oral agents is often possible. However, there is evidence that patients with uncontrolled hyperglycemia associated with type 2 diabetes can also be effectively treated with a sulfonylurea (41).

2020 糖尿病血糖控制 5 第二型DM的藥物治療

PHARMACOLOGIC THERAPY FOR TYPE 2 DIABETES

Recommendations
建議Metformin 做為起始藥物,
9.4 Metformin is the preferred initial pharmacologic agent for the treatment of type 2 diabetes. A

開始使用metformin後, 如果病患可容忍且沒有禁忌症, 應持續使用, 其他藥物, 包含胰島素, 可與 metformin 並用
9.5 Once initiated, metformin should be continued as long as it is tolerated and not contraindicated; other agents, including insulin, should be added to metformin. A

對於特定病患, 可考慮早期使用組合治療, 可以延緩治療失敗的時間
9.6 Early combination therapy can be considered in some patients at treatment initiation to extend the time to treatment failure. A

有些狀況建議早期使用胰島素: 有進行性異化作用(大分子分解為小分子,體重減輕), 有高血糖症狀, 或 A1C > 10%, 或血糖超過 300.
9.7 The early introduction of insulin should be considered if there is evidence of ongoing catabolism (weight loss), if symptoms of hyperglycemia are present, or when A1C levels (>10% [86 mmol/mol]) or blood glucose levels (≥300 mg/dL [16.7 mmol/L]) are very high. E

以病患為中心的治療策略選擇藥物, 考量因素包括: 心血管共病症, 低血糖風險, 體重增減, 副作用機率, 以及病患喜好.
9.8 A patient-centered approach should be used to guide the choice of pharmacologic agents. Considerations include cardiovascular comorbidities, hypoglycemia risk, impact on weight, cost, risk for side effects, and patient preferences (Table 9.2 and Figure 9.1). E

第二型DM病患如果已經確診動脈粥粥狀硬化的心血管疾病, 或有心血管疾病危險因子, 慢性腎病, 心衰竭, 可考慮 SGLT2i 或 GLP1RA, 這兩類藥物對心血管疾病有益處.
9.9 Among patients with type 2 diabetes who have established atherosclerotic cardiovascular disease or indicators of high risk, established kidney disease, or heart failure, a sodium–glucose cotransporter 2 inhibitor or glucagon-like peptide 1 receptor agonist with demonstrated cardiovascular disease benefit (Table 9.1, Table 10.3B, Table 10.3C) is recommended as part of the glucose-lowering regimen independent of A1C and in consideration of patient-specific factors (Figure 9.1). A

第二型DM病患, 如果血糖需降低的幅度大於口服藥物的降血糖作用, 選擇 GLP1RA 優於胰島素.
9.10 In patients with type 2 diabetes who need greater glucose lowering than can be obtained with oral agents, glucagon-like peptide 1 receptor agonists are preferred to insulin when possible. B

第二型DM病患如果沒有達到治療目標, 應及早使用組合治療
9.11 Intensification of treatment for patients with type 2 diabetes not meeting treatment goals should not be delayed. B

應常規檢視病患的處方, 及病患用藥行為 (每 3-6 個月), 根據特定因素調整藥物
9.12 The medication regimen and medication-taking behavior should be reevaluated at regular intervals (every 3–6 months) and adjusted as needed to incorporate specific factors that impact choice of treatment (Fig. 4.1 and Table 9.1). E

美國糖尿病學會/歐洲糖尿病共識研究, 建議以病患為中心的治療策略, 考量治療效果與病患的關鍵因子, 來選擇最適合的治療方式
1. 已罹患重要的共病症(例如動脈粥狀硬化的心血管疾病 ASCVD), 具 ASCVD 危險因子, 慢性腎病, 心衰竭
2. 低血糖風險
3. 是否影響體重
4. 副作用
5. 費用
6. 病患喜好(例如有人堅持不打胰島素)

The American Diabetes Association/European Association for the Study of Diabetes consensus report “Management of Hyperglycemia in Type 2 Diabetes, 2018” and the 2019 update (33,34) recommend a patient-centered approach to choosing appropriate pharmacologic treatment of blood glucose (Fig. 9.1). This includes consideration of efficacy and key patient factors: 1) important comorbidities such as atherosclerotic cardiovascular disease (ASCVD) and indicators of high ASCVD risk, chronic kidney disease (CKD), and heart failure (HF) (see Section 10 “Cardiovascular Disease and Risk Management,” https://doi.org/10.2337/dc20-S010, and Section 11 “Microvascular Complications and Foot Care,” https://doi.org/10.2337/dc20-S011), 2) hypoglycemia risk, 3) effects on body weight, 4) side effects, 5) cost, and 6) patient preferences.

不管用哪一種藥, 都要對病患強調, 改變生活習慣以促進健康,
Lifestyle modifications that improve health (see Section 5 “Facilitating Behavior Change and Well-being to Improve Health Outcomes,” https://doi.org/10.2337/dc20-S005) should be emphasized along with any pharmacologic therapy. Section 12 “Older Adults” (https://doi.org/10.2337/dc20-S012) and Section 13 “Children and Adolescents” (https://doi.org/10.2337/dc20-S013) have recommendations specific for older adults and for children and adolescents with type 2 diabetes, respectively; Section 10 “Cardiovascular Disease and Risk Management” (https://doi.org/10.2337/dc20-S010) and Section 11 “Microvascular Complications and Foot Care” (https://doi.org/10.2337/dc20-S011) have recommendations for the use of glucose-lowering drugs in the management of cardiovascular and renal disease, respectively.

抗糖尿病藥物與腎功能考量

Metformin eGFR < 30 禁用

SGLT2i 需根據腎功能調整劑量

GLP1RA 需根據腎功能調整劑量, 開始服用或增加劑量要小心, 可能造成腎損傷

DPP4i 根據腎功能調整劑量, 但 linagliptin 在腎衰竭不用減量

TZD 有可能造成體液滯留, 所以通常不建議使用於腎衰竭病患

SU: 不建議使用 glyburide, 可使用glipizide 及 glimepiride , 要保守, 避免低血糖

胰島素: 不管是人類胰島素或胰島素類似物, 需根據腎功能減低劑量, 根據每次的治療反應調整劑量. 

2020 糖尿病血糖控制 4 第一型DM患者的手術治療

SURGICAL TREATMENT FOR TYPE 1 DIABETES

胰臟及胰島移植 
第一型DM患者, 經成功移植胰臟及胰島細胞可以讓血糖正常化, 減輕小血管併發症

Pancreas and Islet Transplantation

Successful pancreas and islet transplantation can normalize glucose levels and mitigate microvascular complications of type 1 diabetes. 

但接受移植的患者需要終身免疫抑制治療, 以避免排斥反應, 或免疫性胰島破壞再發.
However, patients receiving these treatments require life-long immunosuppression to prevent graft rejection and/or recurrence of autoimmune islet destruction. 

考量免疫抑制治療前在的不良反應, 胰臟移植僅限於第一型DM患者, 做腎臟移植時同步進行, 或接受過腎臟移植, 或酮酸中毒再發, 或嚴重低血糖
Given the potential adverse effects of immunosuppressive therapy, pancreas transplantation should be reserved for patients with type 1 diabetes undergoing simultaneous renal transplantation, following renal transplantation, or for those with recurrent ketoacidosis or severe hypoglycemia despite intensive glycemic management (32). 

隨著持續血糖監控的改善, 封閉式幫浦感應系統, 以及能提供無低血糖警覺性的病患另一種策略的裝置, 單純胰臟及胰島細胞移植的角色, 需要重新思考. 
With the advent of improved continuous glucose monitors, closed-loop pump-sensor systems, and devices that offer alternative approaches for patients with hypoglycemia unawareness, the role of pancreas transplantation alone, as well as islet transplant, will need to be reconsidered.

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.

CKD 慢性腎病分期 簡介

2015台灣慢性腎臟病臨床診療指引
慢性腎病篩檢及追蹤頻率
STAGE OF CHRONIC KIDNEY DISEASE

CKD 可以eGFR分期, 但如果只用 eGFR 分期, eGFR > 60 不算 CKD, ，eGFR<60（3~5 期）才會被認定為 CKD 病人。

如果沒有腎臟損傷證據, G1 G2 不符合 CKD 定義

2012 年美國腎臟基金會 KDIGO 指引 CKD 定義﹕腎臟結構或功能異常超過三個月，並且對健康造成影響。

所以加上對健康造成影響之條件，是因為有些人雖然有腎臟結構或功能異常，但不
一定都對健康造成影響；

經由統合分析一般人及心臟血管危險族群的 GFR、白蛋白尿對死亡率、心臟血管死亡率、CKD 進展及腎衰竭之影響
KDIGO 仍維持 GFR<60 ml/min/1.73m2
白蛋白血清肌酸酐比值（ACR）≧ 30 mg/g
這兩項臨界值。

血清胱蛋白（cystatin C）
其濃度幾乎全仰賴 GFR
Cystatin C 的產生，個人差異性比血清肌酸酐少
在 GFR 輕微下降至70 到 90 ml/min/m2 時，濃度就已經上升
在高GFR 情況下，cystatin C 比血清肌酸酐更適合作為 GFR 指標。

KDIGO 同時建議，對沒有明確腎臟損傷標記、但以血清肌酸酐為基礎的 eGFR 值在 45 ∼ 59 ml/min/1.73m2 間病人，可檢測血清胱蛋白，以確定 CKD 診斷。

建議 CKD 篩檢的對象應包含
DM、高血壓、心血管疾病（Cardiovascular disease，簡稱 CVD）、泌尿道系統構造異常、自體免疫疾病可能有腎臟侵犯者、家族有腎臟病病史等
尤其是鼓勵 DM 病人接受 CKD 篩檢，其成本效益非常高。

CKD 高風險族群 (風險不一定是成因)
1. DM
2. Hypertension
3. CVD 心臟血管疾病
4. 家族病史
5. 高血脂
6. 草藥使用者
7. 急性腎損傷病史
8. 老年人
9. 過重,肥胖, 或代謝症候群
10. 長期使用止痛藥
11. 吸菸
12. 生活型態 ，相較於高體能活動量的個案，中度體能活動量的族群發生糖尿病或高血壓相關腎病變 RR 較高 , RR=3.7（95% CI為 1.0–14.2）
13. 高尿酸血症或痛風

參考資料
Time-Centered Approach to Understanding Risk Factors for the Progression of CKD
KIDNEY FAILURE RISK EQUATION

慢性腎病患者, 經過多久時間, 會出現腎衰竭症狀, 需要洗腎或做腎臟移植
CKD 可依照 eGFR 分成五期
第三期 eGFR 30-60 又可以分成 3a 45-59 和 3b 44-30

CKD 成因
45% 是糖尿病末期腎病變
25% 是高血壓控制不良
15% 是免疫疾病或遺傳問題
15% 其他

CKD 進展至下一期的時間. 

例如, Stage 3a 進展至 3b 的時間是 7.9年. 但血糖控制不良會比較快進展成 3b, 時間減少 1.8 年. 

台灣國健署 慢性腎臟病健康管理手冊

轉貼~妊娠高血糖~劉漢文醫師

劉漢文醫師寫的

(1) 製造乳汁需要碳水化合物，所以應該要吃適量澱粉類食物。如果飲食控制下，血糖還是高，表示需要血糖藥物幫忙。
(2) 妊娠糖尿病或糖尿病母親的新生兒低血糖，是因為懷孕時母體的高血糖刺激胎兒的胰島細胞分泌胰島素。出生後因為不再處於高血糖環境，原本胰島素的分泌量就變成相對太多，才導致短暫的低血糖。
(3) 母親打的胰島素不會穿過胎盤，不是懷孕時打的胰島素造成胎兒低血糖。哺乳時的母親打胰島素，會有一些跑到乳汁中，但是不會讓胎兒低血糖 (否則大家就用口服胰島素控制糖尿病就好啦！)。而且有研究報告顯示乳汁中的胰島素似乎有降低新生兒將來發生第一型糖尿病的機率。
(4) 懷孕時如果飲食控制下血糖仍高，還是建議用胰島素治療。口服血糖藥 metformin 或 sulfonylurea 類藥物會通過胎盤，還是有一些些機會影響胎兒 (sulfonylurea 可能有新生兒低血糖或巨嬰，metformin 可能讓早產機會稍微增加)。
(5) 母親如果口服血糖藥 metformin，約 0.5% 的劑量出現在乳汁中。研究顯示對新生兒沒有影響。Metformin 的作用方式不會傷肝、不會傷腎、不會低血糖，所以不用太擔心。
(6) 大部分 sulfonylurea 類藥物會出現在乳汁中，因為這類藥物有低血糖風險，哺乳期間通常不建議使用。

妊娠糖尿病與糖尿病人的孕期照護

建議有妊娠糖尿病的婦 女，於產後 6-12 週時， 接受 75g 葡萄糖耐受試 驗，以篩檢是否有糖尿病。

妊娠期糖尿病的血糖控制目標 

針對 PDM，建議在打算懷孕時，就開始嚴格控制血糖，理想上 是讓糖化血色素 <6.5%。觀察性研究的結果顯示，當糖化血色素低 於 6-6.5% 時，發生胎兒異常的機會較低 [623, 637-639]。因此美國 糖尿病學會建議，可以糖化血色素低於 < 6-6.5% 做為 PDM 的治療 目標，並根據個人狀況，考慮更嚴格 (<6%) 或是稍寬鬆 (<7%) 的目 標。 在懷孕過程中，無論是 PDM 或 GDM，都建議孕婦利用血糖機 每日自我監測血糖四次以上 ( 例如一次空腹加上三餐餐後一小時或 兩小時 )。建議目標為空腹 ≤ 95 mg/dl；餐後一小時 ≤ 140 mg/dl； 社團法人中華民國糖尿病學會 183 

第二十章 妊娠糖尿病與糖尿 病人的孕期照護

餐後兩小時 ≤ 120 mg/dl[640]。若控制穩定則可適度減少自我監測 次數。臨床上，接近九成的 GDM 病人可以藉由生活型態調整達到 良好的控制 [617, 621, 629, 635]。 值得注意的是，懷孕期間糖化血色素會下降 [641, 642]，因此 在訂定目標時要考量到這一點，或是可以測定糖化白蛋白 ( 原理請 見第十章 )。在健康的孕婦，整個孕期糖化血色素的範圍介於 4.5% - 5.7%，糖化白蛋白的範圍介於 11.5% - 15.7% 之間 [643]。懷孕期糖 化白蛋白的目標值，目前相關的研究不多，有一篇研究發現，當糖 化白蛋白高於上述的範圍 (≥15.8%) 時，胎兒發生巨嬰、低血糖、呼 吸疾病、低血鈣等問題的機會顯著增加 [644]。然而，後續的研究 指出，糖化白蛋白的目標應該更低，介於 13.6-14.7% 之間 [645]。 在有更多的研究結果之前，本指引建議依據正常孕婦的參考值，以及日本糖尿病學會的建議，以糖化白蛋白 < 15.8% 做為妊娠期糖尿 病的控制目標。

7. 妊娠時期糖尿病的藥物治療： 針對孕前已罹患糖尿病的孕婦 (PDM)，有藥物治療需要時，建 議使用胰島素控制孕期血糖。另外針對子癲前症高危險族群，包括 184 社團法人中華民國糖尿病學會 PDM，2018 年 ADA 指引建議在妊娠第 12 週後至生產給予低劑量 aspirin(80 mg/day) 做預防 [651]，由於目前缺乏本土族群資料，在 仔細評估有無合併其他子癲前症危險因子以及進行相關檢查後 ( 例 如 uterine artery doppler 等 )，可考慮使用。至於診斷為妊娠糖尿 病 (GDM) 的孕婦，在非藥物治療未達理想時，胰島素可做為安全 有效的第一線藥物治療。近年來，越來越多的數據顯示，口服的 metformin 與 glyburide 也可用於治療妊娠糖尿病。藥物的細節如 下： (1) 胰島素：所有市面上流通的胰島素都不會通過胎盤，相關 藥物懷孕分級請見表三。在基礎胰島素使用選擇上，可選擇 NPH 或 insulin detemir；兩者比較起來，insulin detemir 有較少的低血糖 發生率。針對餐後血糖的控制，可選用 RI、insulin aspart 或 insulin lispro。比較起來，速效胰島素 insulin lispro 與 insulin aspart 在 控制餐後血糖與減少低血糖的表現，比短效胰島素 RI 為佳 [621, 635]。 (2)Metformin：此藥物會通過胎盤 [651]，因此不建議在 PDM 使用。如果是因為多囊性卵巢症候群導致的不孕症，在使用 metformin 後順利懷孕，因為對於減少流產與預防妊娠糖尿病沒有 好處，因此受孕後沒有必要繼續使用 metformin [652]。Metformin 用於治療妊娠糖尿病時，對於孕婦體重以及餐後血糖的控制較胰島 素為佳、發生新生兒低血糖的機會也稍低，但是使用 metformin 會 使早產的風險增加 [653, 654]。此外，目前並沒有長期追蹤的結果， 所以 metformin 對胎兒的長期安全性，還有賴更多的研究來證實。 (3)Glyburide：此藥物也會通過胎盤 [655]，因此也不建議用於 PDM。文獻中指出，glyburide 用於控制體重與血糖的效果，跟胰 島素相當，但是有較高的機率發生新生兒低血糖及巨嬰症，因此在 安全性上不如胰島素 [654, 656, 657]。