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Second- and Third-Line Pharmacotherapy for Type 2 Diabetes: Update [Internet]

Second- and Third-Line Pharmacotherapy for Type 2 Diabetes: Update [Internet]

CADTH Optimal Use Report - Canadian Agency for Drugs and Technologies in Health

Version: July 2013

BACKGROUND

Type 2 diabetes mellitus is a progressive disease and many patients will eventually require treatment with exogenous insulin to maintain glycemic control. Insulin therapy for patients with type 2 diabetes is typically initiated with a basal insulin. Clinical practice guidelines typically recommend intensification of an insulin regimen for most patients inadequately controlled with basal insulin, such as through the use of a biphasic insulin or a basal-bolus insulin regimen. Two dipeptidyl peptidase-4 (DPP-4) inhibitors, saxagliptin (Onglyza) and sitagliptin (Januvia) were recently given approval by Health Canada for use in combination with basal or biphasic insulin when these insulins do not provide adequate glycemic control. In addition, the GLP-1 analogue exenatide (Byetta) has been approved by Health Canada for use in combination with insulin glargine, and liraglutide (Victoza) has Food and Drug Administration approval for use in combination with insulin. The regulatory status of combination use of incretins and insulin is summarized in Table 1.

DISCUSSION

For patients who are inadequately controlled with insulin, the included RCTs demonstrated that the addition of a DPP-4 inhibitor results in an improvement in A1C of approximately 0.5% relative to placebo (range 0.3% to 0.6%). One study demonstrated an improvement of 0.7% with a GLP-analogue compared with placebo. A single trial directly comparing the addition of a DPP-4 inhibitor against intensification of insulin (i.e., increased dose) found a larger benefit on A1C with the former strategy, although this study was associated with a number of limitations. Overall, there was insufficient RCT evidence to accurately compare the addition of an incretin agent versus intensification of insulin for patients who are inadequately controlled with their existing insulin regimen.

CRITICAL APPRAISAL

The primary limitation of the available evidence is the absence of well-designed trials comparing the addition of an incretin with intensified insulin for patients inadequately controlled on their existing insulin regimen. The only trial that directly compared the addition of a DPP-4 inhibitor against an intensified insulin regimen was conducted exclusively in Korea, had a small sample size (N = 124), and used an open-label design. As well, the rate and extent of insulin titration may have been somewhat conservative in this trial than in clinical practice, potentially biasing results in favour of sitagliptin. All of the placebo-controlled trials were double-blind, with well-reported methodology. Sample sizes were appropriate for assessing the primary end point (i.e., hemoglobin A1C); however, the persistence of efficacy cannot be accurately assessed beyond six months in the included studies, as all of the trials were relatively short in duration (range 24 to 30 weeks).

CONCLUSIONS AND IMPLICATIONS FOR DECISION- OR POLICY-MAKING

Based on the updated systematic review, there was insufficient evidence to evaluate the comparative efficacy of third-line treatments added to metformin and a sulfonylurea in terms of clinically important long-term complications of diabetes. Compared with continued treatment with metformin and a sulfonylurea, addition of DPP-4 inhibitors, GLP-1 analogues, TZDs, and insulins produced statistically significant reductions in A1C; whereas, meglitinides and alpha-glucosidase inhibitors did not. Insulins and TZDs were all associated with an increase in body weight, DPP-4 inhibitors and alpha-glucosidase inhibitors were not associated with significant weight gain, and GLP-1 analogues were associated with weight loss. The various insulin-containing strategies were typically associated with a greater risk of hypoglycemia relative to other active comparators, although the risk of severe hypoglycemia was low across all drug classes. Further studies of adequate size and duration are required to assess comparative efficacy in terms of durability of antihyperglycemic effect, long-term complications of diabetes, and quality of life.

Project in Brief

Key Messages For most adult patients with type 2 diabetes, when proper diet and exercise are not enough to control hyperglycemia: Start oral therapy with metformin. Add a sulfonylurea to metformin when metformin alone is not enough to adequately control hyperglycemia. Add neutral protamine Hagedorn (NPH) insulin when metformin and a sulfonylurea are not enough to adequately control hyperglycemia. OR Add a DPP-4 inhibitor to metformin and a sulfonylurea in the rare instances when insulin is not an option. Optimize the dose of the drug at each stage of therapy before moving to the next. Proper diet and exercise should be encouraged at every stage. *Patients experiencing significant hypoglycemia during efforts to reach target glycated hemoglobin (A1C) with NPH insulin may benefit from a switch to a long-acting insulin analogue (i.e., insulin glargine or insulin detemir).

BACKGROUND

In August 2010, the Canadian Agency for Drugs and Technologies in Health (CADTH) published a systematic review and network meta-analysis assessing the comparative safety and efficacy of all available classes of antihyperglycemic therapies added to metformin in patients with type 2 diabetes who were experiencing inadequate glycemic control on metformin monotherapy., The results of this review indicated that there were no apparent differences in efficacy (as measured by glycated hemoglobin [hemoglobin A1C]) across the available drug classes, although there were differences in the risk of hypoglycemia and changes in body weight. A cost-utility analysis performed using the results of the systematic review found sulfonylureas to be the most cost-effective second-line treatment option., Based on these analyses, the Canadian Optimal Medication Prescribing and Utilization Service (or COMPUS) Expert Review Committee (or CERC) recommended that most patients requiring a second treatment after metformin should be prescribed a sulfonylurea.

RECOMMENDATIONS

Recommendation 1 The Canadian Drug Expert Committee (CDEC) recommends that a sulfonylurea be added to metformin for most adults with type 2 diabetes inadequately controlled on metformin alone.

SUMMARY OF RECOMMENDATIONS

Recommendation 1 The Canadian Drug Expert Committee (CDEC) recommends that a sulfonylurea be added to metformin for most adults with type 2 diabetes inadequately controlled on metformin alone. Recommendation 2 The Canadian Drug Expert Committee (CDEC) recommends that insulin NPH be added for most adults with type 2 diabetes inadequately controlled on metformin and a sulfonylurea. Recommendation 3 In circumstances where patients with type 2 diabetes are unable to use insulin as a third-line option, the Canadian Drug Expert Committee (CDEC) recommends that a DPP-4 inhibitor may be added to metformin and sulfonylurea therapy.

RESEARCH GAPS

Direct or indirect comparisons assessing the relative efficacy of different antihyperglycemic drugs for the prevention of macrovascular and microvascular diabetes-related complications. Due to the relatively short duration of the included trials, it was impossible to accurately determine whether there were differences in the durability of antihyperglycemic effects across the various drug classes.

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