Answer: Current recommendations for the pharmacologic management of type 2 diabetes include the use of multiple strategies for hyperglycemic control in untreated and poorly controlled patients. The effectiveness of medications depends not only on the intrinsic characteristics of the drugs but also on the duration of diabetes, baseline glucose levels, previous therapy, and other factors. Therefore, treatment regimens must be individualized for each patient, balancing the potential for lowering HbA1c and providing long-term benefits against safety concerns. Physicians must also consider potential adverse effects, tolerability, ease of use, long-term adherence, expense, and the nonglycemic effects of available medications.
Recommendations set by the ADA/European Association for the Study of Diabetes (EASD), the American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE), and the Canadian Diabetes Association (CDA) are similar in their emphasis on lifestyle modification and the importance of treating fasting and postprandial glucose levels.1-3 These organizations recommend reducing A1c levels to <7% or ≤6.5% in most patients with type 2 diabetes who have minimal vascular risk factors. Less stringent targets should be considered for patients with long-standing type 2 diabetes, those with multiple comorbidities, and those at high risk for hypoglycemic events.
The recommendations differ in their specific treatment approaches, however. ADA/EASD guidelines offer a stepwise approach to intensifying therapy, starting with metformin for initial monotherapy. If patients have not achieved an HbA1c of less than 7% after 2 to 3 months, therapy should be intensified by adding one of several treatment options. Tier 1 options include a sulfonylurea or insulin, while Tier 2 therapies include pioglitazone or a glucagon-like peptide-1 (GLP-1) agonist.
The AACE/ACE guidelines offer a more detailed treatment algorithm according to baseline HbA1c. Initial monotherapy options for patients with a baseline HbA1c of 6%-7% include metformin, a thiazolidinedione, a secretagogue, a DPP-4 inhibitor, or an α-glucosidase inhibitor. The algorithm also prioritizes medication choices according to risk of hypoglycemia, safety, efficacy, simplicity, and anticipated degree of patient adherence. DPP-4 inhibitors are included as first- or second-line options due, in part, to their glucose-dependent mechanism of action that complements the actions of other oral antidiabetic drugs. As in the ADA/EASD guidelines, patients who have not achieved target HbA1c after 2-3 months of monotherapy should be transitioned to combination therapy.
Patients with baseline HbA1c of 7%-8% can receive combination therapy from the start. Potential regimens include metformin plus a thiazolidinedione, a DPP-4 inhibitor, a secretagogue, or an α-glucosidase inhibitor. Patients may also receive triple combination therapy. If triple therapy fails to achieve glycemic control, insulin therapy is recommended. Initial combination therapy is also recommended for patients with higher HbA1c values, in the range of 7.6% to 9.0%. Those patients with HbA1c values greater than 9% should receive combination or triple therapy as initial treatment.
Recent FDA safety warnings may curtail the use of thiazolidinediones in patients with type 2 diabetes, however. The thiazolidinedione rosiglitazone is available through restricted access programs only, after an increased risk of ischemic cardiovascular events was observed in patients taking the drug.4 In June 2011, the FDA issued a safety warning regarding the long-term use of the thiazolidinedione pioglitazone, due to an increased risk of bladder cancer in patients with type 2 diabetes who had been taking pioglitazone for more than 1 year.5
Given the complexity of available guidelines and potential concerns regarding the safety of antidiabetic agents, a better understanding of the pharmacotherapeutic treatment options and their potential side effects is crucial to improving diabetes care and outcomes. For example, the human incretin hormone GLP-1 has been shown to decrease blood glucose by several pathways: via the regulation of insulin and glucagon, inhibition of gastric emptying, and suppression of appetite.6 The normal physiologic response to GLP-1 is impaired in type 2 diabetes. These findings supported the introduction of two GLP-1–based therapeutic classes: the GLP-1 receptor agonists and the DPP-4 inhibitors. Whereas GLP-1 receptor agonists directly stimulate human GLP-1 receptors, DPP-4 inhibitors act by slowing the rapid degradation of endogenous GLP-1 by the enzyme DPP-4. GLP-1 receptor agonists thereby provide pharmacologic levels of GLP-1 receptor stimulus, whereas DPP-4 inhibitors act by preserving physiologic levels of endogenous GLP-1.
Two GLP-1 agonists have been approved and are currently available in the United States. Others are under clinical investigation. Exenatide, which is given by subcutaneous injection, was the first FDA-approved GLP-1 agonist for use in patients with type 2 diabetes in addition to the oral medicines metformin and sulfonylureas. Exenatide is also approved for use as add-on therapy in type 2 diabetes patients not adequately controlled on thiazolidinediones. A long-acting release (LAR) formulation of exenatide that is administered once a month is currently under investigation and has shown promising results in a phase 2 study.7
Liraglutide is the second GLP-1 agonist to be approved by the FDA. In the LEAD (Liraglutide Effect and Action in Diabetes) studies, liraglutide showed equivalent or greater improvements in HbA1c than the corresponding comparator treatments.8
Currently, three DPP-4 inhibitors are FDA-approved for use in the Unites States. Sitagliptin was approved in 2006; this was followed by the approval of saxagliptin in 2009. Saxagliptin once daily is indicated as an adjunct to diet and exercise, as monotherapy or in combination with commonly prescribed oral antidiabetic medications such as metformin, a sulfonylurea, or a thiazolidinedione to significantly reduce HbA1c levels. In February 2011, the FDA labeling for saxagliptin was updated regarding its use in renally impaired patients based on its demonstrated efficacy and safety in diabetic patients with renal impairment.9 Both saxagliptin and sitagliptin have been associated with durable glycemic control as add-on therapy regardless of gender, body-mass index, and other patient parameters, with some studies suggesting that these agents may also be effective in upfront settings and as part of a triple-drug combination in patients failing combination therapy. In November 2010, the FDA approved a fixed-dose formulation of saxagliptin and extended-release metformin based on results of two clinical trials and bioequivalence studies.10 This once-daily combination may help simplify therapy for better adherence. More recently, the DPP-4 inhibitor linagliptin was approved in May 2011 as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. It has demonstrated clinically relevant and statistically significant reductions in A1c (28% vs. 11%) and fasting plasma glucose levels (difference: -21.1) when given as add-on therapy in type 2 diabetes patients who are inadequately controlled with metformin.11,12 In addition, it demonstrated significant improvement in HbA1c in combination with pioglitazone, sulfonylurea, and metformin plus sulfonylurea compared with placebo. There was no significant difference in body weight between linagliptin and placebo in combination with sulfonylurea. Although some weight increase was seen when linagliptin was combined with pioglitazone, it was lower than that seen with pioglitazone alone (1.2 kg vs. 2.3 kg).
A primary consideration in selecting antidiabetic regimens is the risk of hypoglycemia, a significant potential cause of morbidity and mortality in diabetic patients receiving medical treatment. Hypoglycemic events tend to occur more frequently in patients who require intensive therapy for poorly controlled disease13 and are commonly associated with the use of insulin-based treatment in type 2 settings. Poor awareness of hypoglycemia has been associated with a higher frequency of more severe hypoglycemic events.14 Incretin mimetics and DPP-4 inhibitors are among the therapies associated with a lower risk of hypoglycemia, along with biguanides, thiazolidinediones, and alpha-glucosidase inhibitors.15
A successful multimodal diabetes management program incorporates more than just effective pharmacotherapy, however. Given that persistence and patient adherence to therapy may be the biggest obstacles to glycemic control, it is crucial for physicians to become more aware of resources that have proven benefit in motivating and coaching patients to take control of their own care on a daily basis. Diabetic educators, pharmacists, hospital support groups, ADA, and other programs are available to patients, and physician recommendations of these programs will significantly improve patient participation. Communication with patients at every visit to reinforce motivation for self-care is crucial to persistent and successful outcomes.
In addition, physicians should seek to simplify treatment regimens whenever possible to improve adherence—simpler regimens are easier to adhere to. Results of a meta-analysis showed that patients who were on fixed-dose regimens were more likely to adhere to therapy than those on regimens with multiple drug components.16 This analysis included studies in a variety of chronic conditions for which long-term or lifelong therapy may be required, including diabetes.
In addition to improving adherence, outcomes in patients with type 2 diabetes can be improved by managing concomitant conditions. For example, patients with type 2 diabetes have a significantly higher risk for cardiovascular disease than those without diabetes. In fact, the risk of a cardiovascular event or death in a patient with diabetes is similar to that in a patient with existing heart disease and no diabetes.17 The majority of deaths in patients with type 2 diabetes—the sixth leading cause of death in the United States—have been attributed to cardiovascular disease.17,18 Accordingly, reducing cardiovascular risks should be a primary goal of diabetes treatment. Treatment strategies to reduce cardiovascular disease in patients with diabetes include antiplatelet therapy and the aggressive control of lipids and hypertension.19
Finally, the significance of lifestyle interventions, such as maintaining normal body weight and regular physical exercise cannot be overemphasized when considering outcomes in patients with type 2 diabetes. Long-term follow-up data from the Finnish Diabetes Prevention Study (DPS) demonstrated that modest lifestyle changes alone could prevent progression to diabetes in subjects with impaired glucose tolerance.20 The DPS lifestyle intervention was designed to achieve 5 goals: (1) weight reduction of 5% or more; (2) <30% of daily energy intake from fat; (3) <10% of energy intake from saturated fat; (4) fiber intake ≥15 g per 1,000 calories; and (5) moderately intensive exercise ≥30 minutes per day. Study participants who implemented lifestyle interventions achieved 58% reduction in progression to diabetes over a median follow-up of 4 years. Interestingly, no subjects who achieved four or five of the goals progressed to diabetes during the DPS. Over the long-term follow-up, only 2% of subjects who had achieved four or five targets developed diabetes. However, 50% of control subjects developed diabetes.
Regardless of the treatment regimen chosen for managing patients with type 2 diabetes, effectively controlling the disease and protecting against micro- and macrovascular complications requires the involvement of physicians, nurses, dieticians, and others. The patient must also play an active role in therapeutic decision-making, self-management to control risk factors, monitoring treatment effectiveness, and maintaining lifestyle changes.
