8. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2018

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

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

• Consider educating individuals with type 1 diabetes on matching prandial insulin doses to carbohydrate intake, premeal blood glucose levels, and anticipated physical activity. E

• Individuals with type 1 diabetes who have been successfully using continuous subcutaneous insulin infusion should have continued access to this therapy after they turn 65 years of age. E

Insulin is the mainstay of therapy for individuals with type 1 diabetes. Generally, the starting insulin dose is based on weight, with doses ranging from 0.4 to 1.0 units/kg/day of total insulin with higher amounts required during puberty. 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 higher weight-based dosing required immediately following presentation with ketoacidosis (1), and provides detailed information on intensification of therapy to meet individualized needs. The American Diabetes Association (ADA) position statement “Type 1 Diabetes Management Through the Life Span” additionally provides a thorough overview of type 1 diabetes treatment (2).

Education regarding matching prandial insulin dosing to carbohydrate intake, premeal glucose levels, and anticipated activity should be considered, and selected individuals who have mastered carbohydrate counting should be educated on fat and protein gram estimation (3–5). Although most studies of multiple daily injections versus continuous subcutaneous insulin infusion (CSII) have been small and of short duration, a systematic review and meta-analysis concluded that there are minimal differences between the two forms of intensive insulin therapy in A1C (combined mean between-group difference favoring insulin pump therapy –0.30% [95% CI –0.58 to –0.02]) and severe hypoglycemia rates in children and adults (6). A 3-month randomized trial in patients with type 1 diabetes with nocturnal hypoglycemia reported that sensor-augmented insulin pump therapy with the threshold suspend feature reduced nocturnal hypoglycemia without increasing glycated hemoglobin levels (7). The U.S. Food and Drug Administration (FDA) has also approved the first hybrid closed-loop system pump. The safety and efficacy of hybrid closed-loop systems has been supported in the literature in adolescents and adults with type 1 diabetes (8,9).

Intensive management using CSII and continuous glucose monitoring should be encouraged in selected patients when there is active patient/family participation (10–12).

The Diabetes Control and Complications Trial (DCCT) clearly showed that intensive therapy with multiple daily injections or CSII delivered by multidisciplinary teams of physicians, nurses, dietitians, and behavioral scientists improved glycemia and resulted in better long-term outcomes (13–15). The study was carried out with short-acting and intermediate-acting human insulins. Despite better microvascular, macrovascular, and all-cause mortality outcomes, intensive therapy was associated with a high rate of severe hypoglycemia (61 episodes per 100 patient-years of therapy). Since the DCCT, a number of rapid-acting and long-acting insulin analogs have been developed. These analogs are associated with less hypoglycemia, less weight gain, and lower A1C than human insulins in people with type 1 diabetes (16–18). Longer-acting basal analogs (U-300 glargine or degludec) may additionally convey a lower hypoglycemia risk compared with U-100 glargine in patients with type 1 diabetes (19,20).

Rapid-acting inhaled insulin used before meals in patients with type 1 diabetes was shown to be noninferior when compared with aspart insulin for A1C lowering, with less hypoglycemia observed with inhaled insulin therapy (21). However, the mean reduction in A1C was greater with aspart (–0.21% vs. –0.40%, satisfying the noninferiority margin of 0.4%), and more patients in the insulin aspart group achieved A1C goals of ≤7.0% (53 mmol/mol) and ≤6.5% (48 mmol/mol). Because inhaled insulin cartridges are only available in 4-, 8-, and 12-unit doses, limited dosing increments to fine-tune prandial insulin doses in type 1 diabetes are a potential limitation.

Postprandial glucose excursions may be better controlled by adjusting the timing of prandial (bolus) insulin dose administration. The optimal time to administer prandial insulin varies, based on the type of insulin used (regular, rapid-acting analog, inhaled, etc.), measured blood glucose level, timing of meals, and carbohydrate consumption. Recommendations for prandial insulin dose administration should therefore be individualized.

Pramlintide, an amylin analog, is an agent that delays gastric emptying, blunts pancreatic secretion of glucagon, and enhances satiety. It is FDA-approved for use in adults with type 1 diabetes. It has been shown to induce weight loss and lower insulin doses. Concurrent reduction of prandial insulin dosing is required to reduce the risk of severe hypoglycemia.

Adding metformin to insulin therapy may reduce insulin requirements and improve metabolic control in patients with type 1 diabetes. In one study, metformin was found to reduce insulin requirements (6.6 units/day, P < 0.001), and led to small reductions in weight and total and LDL cholesterol but not to improved glycemic control (absolute A1C reduction 0.11%, P = 0.42) (22). A randomized clinical trial similarly found that, among overweight adolescents with type 1 diabetes, the addition of metformin to insulin did not improve glycemic control and increased risk for gastrointestinal adverse events after 6 months compared with placebo (23). The Reducing With Metformin Vascular Adverse Lesions in Type 1 Diabetes (REMOVAL) trial investigated the addition of metformin therapy to titrated insulin therapy in adults with type 1 diabetes at increased risk for cardiovascular disease and found that metformin did not significantly improve glycemic control beyond the first 3 months of treatment and that progression of atherosclerosis (measured by carotid artery intima-media thickness) was not significantly reduced, although other cardiovascular risk factors such as body weight and LDL cholesterol improved (24). Metformin is not FDA-approved for use in patients with type 1 diabetes.

Due to their potential protection of β-cell mass and suppression of glucagon release, glucagon-like peptide 1 (GLP-1) receptor agonists (25) and dipeptidyl peptidase 4 (DPP-4) inhibitors (26) are being studied in patients with type 1 diabetes but are not currently FDA-approved for use in patients with type 1 diabetes.

Sodium–glucose cotransporter 2 (SGLT2) inhibitors provide insulin-independent glucose lowering by blocking glucose reabsorption in the proximal renal tubule by inhibiting SGLT2. These agents provide modest weight loss and blood pressure reduction in type 2 diabetes. There are three FDA-approved agents for patients with type 2 diabetes, but none are FDA-approved for the treatment of patients with type 1 diabetes (2). SGLT2 inhibitors may have glycemic benefits in patients with type 1 or type 2 diabetes on insulin therapy (27). The FDA issued a warning about the risk of ketoacidosis occurring in the absence of significant hyperglycemia (euglycemic diabetic ketoacidosis) in patients with type 1 or type 2 diabetes treated with SGLT2 inhibitors. Symptoms of ketoacidosis include dyspnea, nausea, vomiting, and abdominal pain. Patients should be instructed to stop taking SGLT2 inhibitors and seek medical attention immediately if they have symptoms or signs of ketoacidosis (28).

Pancreas and islet transplantation have been shown to normalize glucose levels but require life-long immunosuppression to prevent graft rejection and recurrence of autoimmune islet destruction. 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 (29).

• Metformin, if not contraindicated and if tolerated, is the preferred initial pharmacologic agent for the treatment of type 2 diabetes. A

• Long-term use of metformin may be associated with biochemical vitamin B12 deficiency, and periodic measurement of vitamin B12 levels should be considered in metformin-treated patients, especially in those with anemia or peripheral neuropathy. B

• Consider initiating insulin therapy (with or without additional agents) in patients with newly diagnosed type 2 diabetes who are symptomatic and/or have A1C ≥10% (86 mmol/mol) and/or blood glucose levels ≥300 mg/dL (16.7 mmol/L). E

• Consider initiating dual therapy in patients with newly diagnosed type 2 diabetes who have A1C ≥9% (75 mmol/mol). E

• In patients without atherosclerotic cardiovascular disease, if monotherapy or dual therapy does not achieve or maintain the A1C goal over 3 months, add an additional antihyperglycemic agent based on drug-specific and patient factors (Table 8.1). A

• A patient-centered approach should be used to guide the choice of pharmacologic agents. Considerations include efficacy, hypoglycemia risk, history of atherosclerotic cardiovascular disease, impact on weight, potential side effects, renal effects, delivery method (oral versus subcutaneous), cost, and patient preferences. E

• In patients with type 2 diabetes and established atherosclerotic cardiovascular disease, antihyperglycemic therapy should begin with lifestyle management and metformin and subsequently incorporate an agent proven to reduce major adverse cardiovascular events and cardiovascular mortality (currently empagliflozin and liraglutide), after considering drug-specific and patient factors (Table 8.1). A*

• In patients with type 2 diabetes and established atherosclerotic cardiovascular disease, after lifestyle management and metformin, the antihyperglycemic agent canagliflozin may be considered to reduce major adverse cardiovascular events, based on drug-specific and patient factors (Table 8.1). C*

• Continuous reevaluation of the medication regimen and adjustment as needed to incorporate patient factors (Table 8.1) and regimen complexity is recommended. E

• For patients with type 2 diabetes who are not achieving glycemic goals, drug intensification, including consideration of insulin therapy, should not be delayed. B

• Metformin should be continued when used in combination with other agents, including insulin, if not contraindicated and if tolerated. A

See Section 12 for recommendations specific for children and adolescents with type 2 diabetes. The use of metformin as first-line therapy was supported by findings from a large meta-analysis, with selection of second-line therapies based on patient-specific considerations (30). An ADA/European Association for the Study of Diabetes position statement “Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach” (31) recommended a patient-centered approach, including assessment of efficacy, hypoglycemia risk, impact on weight, side effects, costs, and patient preferences. Renal effects may also be considered when selecting glucose-lowering medications for individual patients. Lifestyle modifications that improve health (see Section 4 “Lifestyle Management”) should be emphasized along with any pharmacologic therapy.

Metformin monotherapy should be started at diagnosis of type 2 diabetes unless there are contraindications. Metformin is effective and safe, is inexpensive, and may reduce risk of cardiovascular events and death (32). Compared with sulfonylureas, metformin as first-line therapy has beneficial effects on A1C, weight, and cardiovascular mortality (33). Metformin may be safely used in patients with estimated glomerular filtration rate (eGFR) as low as 30 mL/min/1.73 m², and the FDA recently revised the label for metformin to reflect its safety in patients with eGFR ≥30 mL/min/1.73 m² (34). Patients should be advised to stop the medication in cases of nausea, vomiting, or dehydration. Metformin is associated with vitamin B12 deficiency, with a recent report from the Diabetes Prevention Program Outcomes Study (DPPOS) suggesting that periodic testing of vitamin B12 levels should be considered in metformin-treated patients, especially in those with anemia or peripheral neuropathy (35).

In patients with metformin contraindications or intolerance, consider an initial drug from another class depicted in Fig. 8.1 under “Dual Therapy” and proceed accordingly. When A1C is ≥9% (75 mmol/mol), consider initiating dual combination therapy (Fig. 8.1) to more expeditiously achieve the target A1C level. Insulin has the advantage of being effective where other agents may not be and should be considered as part of any combination regimen when hyperglycemia is severe, especially if catabolic features (weight loss, ketosis) are present. Consider initiating combination insulin injectable therapy (Fig. 8.2) when blood glucose is ≥300 mg/dL (16.7 mmol/L) or A1C is ≥10% (86 mmol/mol) or if the patient has symptoms of hyperglycemia (i.e., polyuria or polydipsia). As the patient’s glucose toxicity resolves, the regimen may, potentially, be simplified.

Although there are numerous trials comparing dual therapy with metformin alone, few directly compare drugs as add-on therapy. A comparative effectiveness meta-analysis (36) suggests that each new class of noninsulin agents added to initial therapy generally lowers A1C approximately 0.7–1.0%. If the A1C target is not achieved after approximately 3 months and patient does not have atherosclerotic cardiovascular disease (ASCVD), consider a combination of metformin and any one of the preferred six treatment options: sulfonylurea, thiazolidinedione, DPP-4 inhibitor, SGLT2 inhibitor, GLP-1 receptor agonist, or basal insulin (Fig. 8.1); the choice of which agent to add is based on drug-specific effects and patient factors (Table 8.1). For patients with ASCVD, add a second agent with evidence of cardiovascular risk reduction after consideration of drug-specific and patient factors (see p. S77 cardiovascular outcomes trials). If A1C target is still not achieved after ∼3 months of dual therapy, proceed to a three-drug combination (Fig. 8.1). Again, if A1C target is not achieved after ∼3 months of triple therapy, proceed to combination injectable therapy (Fig. 8.2). Drug choice is based on patient preferences (37), as well as various patient, disease, and drug characteristics, with the goal of reducing blood glucose levels while minimizing side effects, especially hypoglycemia. If not already included in the treatment regimen, addition of an agent with evidence of cardiovascular risk reduction should be considered in patients with ASCVD beyond dual therapy, with continuous reevaluation of patient factors to guide treatment (Table 8.1).

Table 8.2 lists drugs commonly used in the U.S. Cost-effectiveness models of the newer agents based on clinical utility and glycemic effect have been reported (38). Table 8.3 provides cost information for currently approved noninsulin therapies. Of note, prices listed are average wholesale prices (AWP) (39) and National Average Drug Acquisition Costs (NADAC) (40) and do not account for discounts, rebates, or other price adjustments often involved in prescription sales that affect the actual cost incurred by the patient. While there are alternative means to estimate medication prices, AWP and NADAC were utilized to provide two separate measures to allow for a comparison of drug prices with the primary goal of highlighting the importance of cost considerations when prescribing antihyperglycemic treatments. The ongoing Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) will compare four drug classes (sulfonylurea, DPP-4 inhibitor, GLP-1 receptor agonist, and basal insulin) when added to metformin therapy over 4 years on glycemic control and other medical, psychosocial, and health economic outcomes (41).

Rapid-acting secretagogues (meglitinides) may be used instead of sulfonylureas in patients with sulfa allergies or irregular meal schedules or in those who develop late postprandial hypoglycemia when taking a sulfonylurea. Other drugs not shown in Table 8.1 (e.g., inhaled insulin, α-glucosidase inhibitors, colesevelam, bromocriptine, and pramlintide) may be tried in specific situations but considerations include modest efficacy in type 2 diabetes, frequency of administration, potential for drug interactions, cost, and/or side effects.

There are now three large randomized controlled trials reporting statistically significant reductions in cardiovascular events for two SGLT2 inhibitors (empagliflozin and canagliflozin) and one GLP-1 receptor agonist (liraglutide) where the majority, if not all patients, in the trial had ASCVD. The empagliflozin and liraglutide trials demonstrated significant reductions in cardiovascular death. Exenatide once-weekly did not have statistically significant reductions in major adverse cardiovascular events or cardiovascular mortality but did have a significant reduction in all-cause mortality. In contrast, other GLP-1 receptor agonists have not shown similar reductions in cardiovascular events (Table 9.4). Whether the benefits of GLP-1 receptor agonists are a class effect remains to be definitively established. See antihyperglycemic therapies and cardiovascular outcomes in Section 9 “Cardiovascular Disease and Risk Management” and Table 9.4 for a detailed description of these cardiovascular outcomes trials. Additional large randomized trials of other agents in these classes are ongoing.

Of note, these studies examined the drugs in combination with metformin (Table 9.4) in the great majority of patients for whom metformin was not contraindicated or not tolerated. For patients with type 2 diabetes who have ASCVD, on lifestyle and metformin therapy, it is recommended to incorporate an agent with strong evidence for cardiovascular risk reduction especially those with proven benefit on both major adverse cardiovascular events and cardiovascular death after consideration of drug-specific patient factors (Table 8.1). See Fig. 8.1 for additional recommendations on antihyperglycemic treatment in adults with type 2 diabetes.

Many patients with type 2 diabetes eventually require and benefit from insulin therapy. The progressive nature of type 2 diabetes should be regularly and objectively explained to patients. Providers should avoid using insulin as a threat or describing it as a sign of personal failure or punishment.

Equipping patients with an algorithm for self-titration of insulin doses based on self-monitoring of blood glucose improves glycemic control in patients with type 2 diabetes initiating insulin (42). Comprehensive education regarding self-monitoring of blood glucose, diet, and the avoidance of and appropriate treatment of hypoglycemia are critically important in any patient using insulin.

Basal insulin alone is the most convenient initial insulin regimen, beginning at 10 units per day or 0.1–0.2 units/kg/day, depending on the degree of hyperglycemia. Basal insulin is usually prescribed in conjunction with metformin and sometimes one additional noninsulin agent. When basal insulin is added to antihyperglycemic agents in patients with type 2 diabetes, long-acting basal analogs (U-100 glargine or detemir) can be used instead of NPH to reduce the risk of symptomatic and nocturnal hypoglycemia (43–48). Longer-acting basal analogs (U-300 glargine or degludec) may additionally convey a lower hypoglycemia risk compared with U-100 glargine when used in combination with oral antihyperglycemic agents (49–55). While there is evidence for reduced hypoglycemia with newer, longer-acting basal insulin analogs, people without a history of hypoglycemia are at decreased risk and could potentially be switched to human insulin safely. Thus, due to high costs of analog insulins, use of human insulin may be a practical option for some patients, and clinicians should be familiar with its use (56). Table 8.4 provides AWP (39) and NADAC (40) information (cost per 1,000 units) for currently available insulin and insulin combination products in the U.S. There have been substantial increases in the price of insulin over the past decade and the cost-effectiveness of different antihyperglycemic agents is an important consideration in a patient-centered approach to care, along with efficacy, hypoglycemia risk, weight, and other patient and drug-specific factors (Table 8.1) (57).

Many individuals with type 2 diabetes may require mealtime bolus insulin dosing in addition to basal insulin. Rapid-acting analogs are preferred due to their prompt onset of action after dosing. In September 2017, the FDA approved a new faster-acting formulation of insulin aspart. The recommended starting dose of mealtime insulin is 4 units, 0.1 units/kg, or 10% of the basal dose. If A1C is <8% (64 mmol/mol) when starting mealtime bolus insulin, consideration should be given to decreasing the basal insulin dose.

Premixed insulin products contain both a basal and prandial component, allowing coverage of both basal and prandial needs with a single injection. NPH/Regular 70/30 insulin, for example, is composed of 70% NPH insulin and 30% regular insulin. The use of premixed insulin products has its advantages and disadvantages, as discussed below in combination injectable therapy.

Several concentrated insulin preparations are currently available. U-500 regular insulin, by definition, is five times as concentrated as U-100 regular insulin and has a delayed onset and longer duration of action than U-100 regular, possessing both prandial and basal properties. 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. The FDA has also approved a concentrated formulation of rapid-acting insulin lispro, U-200 (200 units/mL). These concentrated preparations may be more comfortable for the patient and may improve adherence for patients 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 FDA approved in July 2016), other concentrated insulins are available only in prefilled pens to minimize the risk of dosing errors.

Inhaled insulin is available for prandial use with a more limited dosing range. It 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. It requires spirometry (FEV₁) testing to identify potential lung disease in all patients prior to and after starting 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. 8.2). When initiating combination injectable therapy, metformin therapy should be maintained while other oral agents may be discontinued on an individual basis to avoid unnecessarily complex or costly regimens (i.e., adding a fourth antihyperglycemic agent). In general, GLP-1 receptor agonists should not be discontinued with the initiation of basal insulin. Sulfonylureas, DPP-4 inhibitors, and GLP-1 receptor agonists are typically stopped once more complex insulin regimens beyond basal are used. In patients with suboptimal blood glucose control, especially those requiring large insulin doses, adjunctive use of a thiazolidinedione or SGLT2 inhibitor may help to improve control and reduce the amount of insulin needed, though potential side effects should be considered. Once an 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).

Studies have demonstrated the noninferiority of basal insulin plus a single injection of rapid-acting insulin at the largest meal relative to basal insulin plus a GLP-1 receptor agonist relative to two daily injections of premixed insulins (Fig. 8.2). Basal insulin plus GLP-1 receptor agonists are associated with less hypoglycemia and with weight loss instead of weight gain but may be less tolerable and have a greater cost (58,59). In November 2016, the FDA approved two different once-daily fixed-dual combination products containing basal insulin plus a GLP-1 receptor agonist: insulin glargine plus lixisenatide and insulin degludec plus liraglutide. Other options for treatment intensification include adding a single injection of rapid-acting insulin analog (lispro, aspart, or glulisine) before the largest meal or stopping the basal insulin and initiating a premixed (or biphasic) insulin (NPH/Regular 70/30, 70/30 aspart mix, 75/25 or 50/50 lispro mix) twice daily, usually before breakfast and before dinner. Each approach has its advantages and disadvantages. For example, providers may wish to consider regimen flexibility when devising a plan for the initiation and adjustment of insulin therapy in people with type 2 diabetes, with rapid-acting insulin offering greater flexibility in terms of meal planning than premixed insulin. If one regimen is not effective (i.e., basal insulin plus GLP-1 receptor agonist), consider switching to another regimen to achieve A1C targets (i.e., basal insulin plus single injection of rapid-acting insulin or premixed insulin twice daily) (60,61). Regular human insulin and human NPH/Regular premixed formulations (70/30) are less costly alternatives to rapid-acting insulin analogs and premixed insulin analogs, respectively, but their pharmacodynamic profiles may make them less optimal.

Fig. 8.2 outlines these options, as well as recommendations for further intensification, if needed, to achieve glycemic goals. If a patient is still above the A1C target on premixed insulin twice daily, consider switching to premixed analog insulin three times daily (70/30 aspart mix, 75/25 or 50/50 lispro mix). In general, three times daily premixed analog insulins have been found to be noninferior to basal-bolus regimens with similar rates of hypoglycemia (62). If a patient is still above the A1C target on basal insulin plus single injection of rapid-acting insulin before the largest meal, advance to a basal-bolus regimen with ≥2 injections of rapid-acting insulin before meals. Consider switching patients from one regimen to another (i.e., premixed analog insulin three times daily to basal-bolus regimen or vice-versa) if A1C targets are not being met and/or depending on other patient considerations (60,61). Metformin should be continued in patients on combination injectable insulin therapy, if not contraindicated and if tolerated, for further glycemic benefits.