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).