SGLT2 Inhibitors as Add On Therapy: Q&A

Combination therapy with antihyperglycemic agents that address several of the multiple metabolic defects that underlie type 2 diabetes is a proven strategy.  Dual or triple therapy has the advantage of preventing compensatory mechanisms and may produce an additive reduction in A1c.  

In randomized controlled studies, agents in the class of sodium glucose co-transport 2 inhibitors (SGLT2I) have been effective in further reducing hyperglycemia when combined with traditional agents (eg, metformin, sulfonlyureas, and thiazolidinediones) and with newer agents (eg, dipeptidyl peptidase-4 inhibitors [DPP-4Is]).  Check your math with a few add-on questions. (Find references on last page.)

1. Approximately how many people with T2DM in the US do not meet the American Diabetes Association (ADA) recommended goal of A1c <7.0%?

A. 25%

B. 30%

C. 40%

D. 50%

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Answer: D. 50%

The progressive nature of T2DM often means that many patients fail to attain adequate glycemic control, and ultimately require add-on therapy. Several guidelines recommend dual or triple therapy, but the clinical trial evidence regarding the optimal approach to dual or triple combination therapy remains limited.¹ Delay in achieving optimal glycemic control has been linked to increased risk for microvascular and macrovascular complications.²

2. Combined SGLT2I/DPP-4I therapy produces a synergistic effect that represents the addictive value of each separate agent on lowering A1c.

A. True

B. False

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Answer: B. False

Clinical trials have suggested that combining SGLT2Is with DPP-4Is does not have a synergistic effect
on lowering A1c. The effect on A1c is much smaller than the additive effect of each separate agent. For example, a trial of combined therapy with empagliflozin plus linaglipitin found that reductions from baseline HbA1c with empagliflozin plus linagliptin were not significantly different compared empagliflozin 25 mg alone.³ Similarly, a trial of saxagliptin plus dapagliflozin added to a background of metformin found that the overall additional benefit of adding saxaglitpin to dapagliflozin was very small, about 0.28%.⁴

3. DPP-4Is  _____ endogenous glucose production (EGP), while SGLT2Is  ____ EGP.

A. Increase, decrease

B. Decrease, increase

C. Increase, increase

D. Decrease, decrease

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Answer: B. Decrease, increase

Inhibition of SGLT2 receptors stimulates EGP, with the amount of the increase correlating with the amount of glucose lost through the urine. This also results in a large increase in plasma glucagon concentration. In contrast, DPP-4Is primarily act by suppressing glucagon secretion, thereby inhibiting EGP. The lack of synergistic effect when combining DPP-4Is with SGLT2Is (see question 2) may perhaps be explained by the fact that inhibition of EGP by DPP-4Is may not be strong enough to compensate for the stimulatory effect on EGP produced by SGLT2Is.⁴

4. Adding the SGLT2I dapagliflozin to metformin may have a similar effect on mean change in A1c as adding which of the following to metformin?

A. DPP-4Is

B. Thiazolidinediones

C. Sulphonylureas

D. All of the above

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Answer: D. All of the above

A recent systematic literature review and meta-analysis analyzed 6 RCTs involving patients inadequately controlled on metformin monotherapy who received add-on therapy with various other antidiabetes drugs (DPP-4Is, thiazolidinediones, sulphonylureas, and dapagliflozin). Trials of GLP-1 analogues were excluded because they did not meet inclusion criteria. The study found similar mean changes from baseline A1c after one year of treatment across comparators. Risk of hypoglycemia was also similar.⁵

5. The decrease in A1c seen after adding 100 mg canagliflozin to metformin is  ____  adding glimepiride to metformin.

A. Less than

B. About the same as

C. Similar to

D. None of the above

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Answer: C. Similar to

A recent 52-week phase 3 RCT  looked at adding 100 mg  or 300 mg canagliflozin vs. glimepiride  to metformin.  Results showed that 100 mg canagliflozin reduces A1c by 0.81%, which is similar to the effect of glimepiride  (least-squares mean difference -0.01% [95% CI -0.11 to 0.09]). And, adding 300 mg canagliflozin to metformin reduces A1c by 0.93%, which was greater than the effect of glimepiride (least-mean squares difference -0.12% [-0.22 to -0.02]).⁶

6. Adding an SGLT2I to metformin may have a less deteriorating effect on renal functioning compared to adding glipizide.

A. True

B. False

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Answer: A. True

According to a recent analysis of four year extension data, adding dapagliflozin to metformin was not associated with deterioration in glomerular filtration, whereas adding glipizide to metformin was. At four years, 0.6% of patients who received dapagliflozin plus metformin experienced renal impairment, compared to 1.2% of patients who received glipizide.⁷ Though initiation of SGLT2 inhibitor therapy has been associated with transient decreases in estimated glomerular filtration rates, this attenuates over time and may be related to volume loss. Dysfunctional SGLT2 upregulation may occur in T2DM, contributing to increased renal glucose reabsorption and hyperglycemia. SGLT2 inhibitors may address this issue, and may have the potential to be nephroprotective, though further research is needed.⁸

References:

• Inzucchi SE, Bergenstal RM, Buse JB, et al. American Diabetes Association (ADA); European Association for the Study of Diabetes (EASD).  Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012;35:1364-1379.
• Vasilakou D, Karagiannis T, Athanasiadou E, et al. Sodium–glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meat-analysis.  Ann Intern Med 2013;159:262-274.
• Lewin A, DeFronzo RA, Patel S, et al. Initial combination of empagliflozin and linagliptin in subjects with type 2 diabetes. Diabetes Care. 2015 Mar;38(3):394-402. doi: 10.2337/dc14-2365. Epub 2015 Jan 29.
• Abdul-Ghani M.  Where does combination therapy with an SGLT2 inhibitor plus a DPP_4 inhibitor fit in the management of type 2 diabetes? Diabetes Care; 38:373-375. doi 10.2337/dc14-2517
• Goring S, Hawkins N, Wygant G, et al. Dapagliflozin compared with other oral anti-diabetes treatments when added to metformin monotherapy: a systematic review and network meta-analysis. Diabetes Obes Metab. 2014 May;16(5):433-42. doi: 10.1111/dom.12239. Epub 2013 Dec 16.
• Cefalu WT, Leiter LA, Yoon KH, et al. 1.   Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet. 2013 Sep 14;382(9896):941-50. doi: 10.1016/S0140-6736(13)60683-2. Epub 2013 Jul 12.
• Del Prato S, Nauck M, Duran-Garcia S, et al. Long-term glycemic response and tolerability of dapaglflozin versus a sulphonylurea as add=on therapy to metformin in type 2 diabetes patients: 4-year data.  Diabetes Obes Metab. 2015 Published online Mar 4. doi: 10.1111/dom.12459.
• Wilding JPH. The role of the kidneys in glucose homeostasis in type 2 diabetes: Clinical implications and therapeutic significance through sodium glucose co-transporter 2 inhibitors.  Metabolism. 2014;63:1228-1237.