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Dipeptidyl peptidase-4 inhibitors or sodium glucose co-transporter-2 inhibitors as an add-on to insulin therapy: A comparative review.

The gradual decline in β-cell function is inevitable in type 2 diabetes mellitus and therefore, substantial proportions of patients require insulin subsequently, in order to achieve optimal glucose control. While weight gain, hypoglycemia, and fluid retention especially during dose intensification is a known limitation to insulin therapy, these adverse effects also reduce patient satisfaction and treatment adherence. It is also possible that the benefits of intensive control achieved by insulin therapy, perhaps get nullified by the weight gain and hypoglycemia. In addition, improvement in plasma glucose or glycated hemoglobin (HbA1c) itself is associated with weight gain. Notably, studies have already suggested that reduction in body weight by ~3-5%, may allow a significantly better glycemic control. Thus, a class of drugs, which can reduce HbA1c effectively, yet are weight neutral or preferably reduce body weight, could be the most sought out strategy as an add-on therapy to insulin. While sulfonylureas (SUs) are associated with weight gain and hypoglycemia, pioglitazone increases body weight and fluid retention. Moreover, SUs are not recommended once premix or prandial insulin is commenced. The addition of newer agents, such as glucagon-like peptide-1 receptor agonist to insulin certainly appears to be an effective tool in reducing both HbA1c and body weight as is evident across the studies; however, this approach incurs an additional injection as well as cost. Dipeptidyl peptidase-4 inhibitors (DPP-4I) and sodium-glucose co-transporter-2 inhibitors (SGLT-2I) are other exciting options, as an add-on to insulin therapy primarily because these are oral drugs and do not possess any intrinsic potential of hypoglycemia. Furthermore, these are either weight neutral or induce significant weight loss. This review article aims to comparatively analyze the safety and efficacy of DPP-4I and SGLT-2I, as an add-on therapy to insulin.

The general recommendation is to continue SU with basal insulin and to reduce SU dosage, once the basal insulin titration is intensified. In addition, to discontinue SU, once prandial or premix insulin is commenced. [5] Nevertheless, SU causes weight gain and can potentiate the risk of hypoglycemia when used as an add-on to insulin. [3,6] Pioglitazone as an add-on to insulin has been associated with weight gain, edema, and increased risk of congestive heart failure. [6,7] Glucagon-like peptide-1 receptor agonists (GLP-1RA) are other potentially effective add-on agent to the insulin that lowers glucose and body weight simultaneously. [8][9][10][11] However; this approach will incur an additional injection and cost. Single co-formulation of basal insulin with GLP-1RA such as IDegLira (insulin degludec with liraglutide) and LixiLan (insulin glargine with lixisenatide) can minimize the number of pricks. [12] Newer class of OAD, such as dipeptidyl peptidase-4 inhibitors (DPP-4I) and sodium-glucose co-transporter-2 inhibitors (SGLT-2I) are other exciting option to improve glycemic control as add-on agents to insulin therapy. DPP-4I improves glycemic control, by enhancing concentrations of active incretin such as GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), both of which increase insulin secretion from the β-cells in a glucose-dependent manner. Moreover, there could perhaps be several other novel mechanisms by which DPP-4I improve glycemic control. [13] While DPP-4I significantly reduced glucagon during hyperglycemia, it does not compromise glucagon secretion during hypoglycemia and hence it has an ideal effect on glucagon dynamics. This GIP-mediated augmentation of glucagon secretion could be a plausible defense mechanism against hypoglycemia and makes this class a logical option of add-on agent to insulin therapy. [14,15] Moreover, DPP-4I are weight neutral, safe in elderly and patients with renal impairment. Furthermore, DPP-4I are cardiac neutral drug, as seen in different cardio-vascular outcome trials (CVOT) such as saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus (SAVOR-TIMI), Alogliptin after acute coronary syndrome in patients with type 2 diabetes (EXAMINE), and effect of sitagliptin on cardiovascular outcomes in type 2 diabetes (TECOS) trials. It is important to note that 41.6% patient in SAVOR-TIMI, 30.3% in EXAMINE and 23.5% of patients in TECOS trial were already receiving concomitant insulin therapy in these high-risk CV disease cohort. [16][17][18] This indirectly suggests no safety signals with DPP-4I and insulin combination therapy. Furthermore, as DPP-4I reduces postprandial glucose (PPG) predominantly, it will produce a complementary effect with basal insulin, in effectively managing overall glycemic control. Based on these characteristics, DPP-4I as an add-on to insulin therapy is expected to improve glycemic control without any apparent increase in hypoglycemia risk and weight gain.
SGLT-2I are newly approved OAD, which induces urinary glucose excretion by inhibiting renal glucose reabsorption and thereby reduces plasma glucose. [19] This β-cell independent mechanism of action of SGLT-2I protects them from hypoglycemia. Moreover, an increase in urinary glucose excretion leads to osmotic diuresis and additionally creates a negative calorie balance. Both calorie loss and osmotic diuresis induced by SGLT-2I has the potential to counter the insulin-induced weight gain and fluid retention. The lower rate of hypoglycemia which occurs due to the decrease in renal threshold for glucose or via insulin-independent mechanism also makes SGLT-2I a near-ideal partner to insulin. In addition, SGLT-2I can modulate other risk factors beyond glycemia including a reduction in blood pressure (BP), weight, visceral adiposity, hyperinsulinemia, arterial stiffness, albuminuria, uric acid levels, and oxidative stress. [20] Notably, a recently concluded CVOT with SGLT-2I empagliflozin (EMPA-REG), found a significant reduction in CV death and all-cause mortality. Interestingly, 48% of the patients in EMPA-REG outcome trial were concomitantly receiving insulin with empagliflozin and found similar benefit in CV outcomes. [21] These collective characteristics of weight loss, minimal hypoglycemia, BP reduction, osmotic diuresis, and unprecedented CV outcome makes SGLT-2I, a potentially useful add-on agent to insulin. However, it is worthwhile to mention that SGLT-2I are not indicated in moderate to severe renal impairment and precaution is required while using these agents in elderly patients on concomitant volume depleting therapies. The increase in glucagon and endogeneous glucose production with SGLT-2I can also offset its glycemic benefit and is a potentially concern. Furthermore, euglycemic ketoacidosis (EuDKA) has been reported with SGLT-2I, especially in long-standing insulinopenic T2DM, although its prevalence appears pretty low. [22,23] Moreover, urogenital infection which many diabetics and elderly patients are prone to, are commonly observed side effects with SGLT-2I, owing to its mechanism of action.
With this background information, this review will analyze the comparative safety and efficacy of DPP-4I or SGLT-2I as an add-on therapy to insulin.

Review methODs
The studies with DPP-4 inhibitors or SGLT-2 inhibitors as an add-on to insulin therapy were identified by conducting a literature search using an electronic database of PubMed, Scopus, and Cochrane review till September 2015. Several key MeSH words were used to retrieve efficacy and safety data of both DPP-4I and SGLT-2I as an add-on therapy to insulin. The eligibility/inclusion criteria for the studies included in this systematic review were patients more than 18 years of age with T2DM, receiving DPP-4I or SGLT-2I as an add-on to insulin, without any gender or ethnic origin bias. The studies had to report at least one outcome of interest.

Dapagliflozin plus insulin
Wilding et al., in a randomized, double-blind, placebo-controlled, multi-centric, proof-of-concept, 12-week study (n = 75), evaluated dapagliflozin 10 mg as add-on to insulin versus placebo keeping insulin dose fixed. The study found −0.61% reduction in HbA1c with dapagliflozin compared to placebo (increase in HbA1c by 0.09%), despite 50% baseline reduction in the total daily insulin dosage in both arms. Interestingly, 65.2% of patients had a HbA1c reduction of ≥0.5% in dapagliflozin arm, compared to 15.8% in the placebo group at week 12. Placebo-subtracted body weight reduction was −2.6 kg and systolic BP (SBP) reduction was − 10 mm of Hg in dapagliflozin arm, although P value was not reported. Surprisingly, no case of urinary tract infection (UTI) or genital tract infection (GTI) reported in dapagliflozin arm, compared to 4.3% cases in the placebo arm. Although rates of hypoglycemia was higher in dapagliflozin arm (29 vs. 13%, P value not reported), compared to placebo. This could have happened perhaps due to the fixed insulin regime, not being allowed to lower the dose of insulin in dapagliflozin arm. [37] In another larger (n = 808), longer (48-weeks), randomized, placebo-controlled and multi-centric study, Wilding et al. studied the effect of dapagliflozin 10 mg as add-on to insulin, without reducing the baseline insulin dose. This 48-weeks study (24-weeks randomized, with further 24-weeks extension period) found that addition of dapagliflozin 10 mg (N = 178), significantly reduced the HbA1c (−1.0% vs. −0.47%, difference −0.54%; both P < 0.001), compared to placebo. Notably, the adjusted proportion of patients who required at least 10% lesser dose from the baseline was significantly higher in dapagliflozin 10 mg arm (18.6% vs. 10.5% in control, P = 0.024), compared to control. Overall, a significantly lower dose of insulin required in dapagliflozin 10 mg arm (−11.2 IU, P < 0.001), compared to placebo. Significant reduction in body weight also observed in dapagliflozin arm (−1.6 vs. 0.8 kg, difference − 2.43 kg; both P < 0.001), compared to placebo. Notably, reported events of UTI were 2-times and GTI 5-times higher in dapagliflozin-treated arm, although no P value reported. [38] In the 56-weeks extension (total 104 weeks) of the same study of Wilding et al. significant reduction in HbA1c (difference −0.35%, P = 0.0007) and body weight (difference −3.3 kg, P < 0.0001) were observed with dapagliflozin versus placebo. Similarly, proportion of patient requiring mean daily insulin dose reduction of ≥10% was significantly higher in dapagliflozin arm (17 vs. 7%, difference 10%, P = 0.0022), compared to control. Furthermore, the mean difference of change in total insulin daily dose was significantly lower in dapagliflozin 10 mg arm (−0.8 vs. 18.3 IU, difference −19.2 IU, P < 0.0001), compared to control. Significant reduction in body weight observed in dapagliflozin arm (−1.5 vs. 1.8 kg,  difference −3.3 kg, P < 0.0001) compared to control. While no difference in hypoglycemia observed in this study, hypotension was higher in dapagliflozin arm. Both UTI and GTI were 2-to 5-times higher in dapagliflozin arm (although P value not reported). [39] In both of these study, UTI and GTI events were more commonly observed in women, mainly as a single episode, categorized as mild to moderate, and mostly occurred in the first 24 weeks of treatment. The reported cases were based primarily on symptoms (not by culture studies) and managed easily with standard treatment. [38,39] In a Dutch healthcare setting, van Haalen et al. found significant reduction of HbA1c (−1.01 vs. −0.47%; P < 0.05) and body weight (−1.61 vs. −0.82 kg; P < 0.05) in dapagliflozin versus placebo at week 48. A significant placebo-subtracted reduction of body weight (−2.4 kg, P < 0.05) also observed with dapagliflozin. Moreover, dapagliflozin in combination with insulin was found to be cost-effective using Cardiff diabetes model. [40]

Canagliflozin plus insulin
Deveneni et al., in a phase 1b, 4-week dose-finding study (n = 29), found significant reduction in HbA1C with canagliflozin 100 mg QD and 300 mg BD, as an add-on therapy to insulin versus placebo (−0.73, −0.92% vs. −0.19%; both P < 0.05), although hypoglycemic event rate were higher in canagliflozin arm. [41] Dumas et al., in an exploratory analysis (n = 278) of Canagliflozin Cardiovascular Assessment Study (CANVAS), found that addition of canagliflozin 100 and 300 mg add-on to basal insulin markedly reduced HbA1c (−0.76, −0.79% vs. 0.10%, P value not reported), compared to placebo, although the hypoglycemic event rates were higher in canagliflozin arm. [42] Neal et al., in a randomized, placebo-controlled, two-point outcome (week 18 and 52), insulin substudy (N = 2072) of CANVAS, studied the efficacy and safety of canagliflozin as an add-on to insulin. Placebo-subtracted HbA1c (−0.62 and −0.73%; P < 0.001) and weight reduction (−1.9 and −2.4%, P < 0.001) was significantly higher with canagliflozin 100 and 300 mg, respectively, at week 18. Similarly HbA1c was lower with canagliflozin 100 and 300 mg at week 52, respectively (−0.58 and −0.73%), although P value was not reported. Moreover, 13.3% and 18.7% of patients achieved the HbA1c target of <7% with canagliflozin 100 and 300 mg at week 52, respectively. In addition, canagliflozin showed a dose-dependent reduction of SBP compared to placebo at both time points, although P value not reported. No difference in hypoglycemia observed versus placebo arm. Hypotension was higher in canagliflozin arm. While UTI rates were similar in all arms, the GTI rates were 5-times higher in canagliflozin 100 and 300 mg (26% and 25%, respectively), compared to placebo (5%). Nevertheless, GTI were managed with topical or oral antifungal medications. [43] Empagliflozin plus insulin Rosenstock et al., in a randomized, placebo-controlled, parallel group, two-point (week 18 and 52) outcome study (n = 563), studied the effect of empagliflozin 10 mg and 25 mg to placebo, as an add-on to multiple daily injections of insulin. Insulin dose was kept stable for first 18-week, then titrated to meet target from weeks 19 to 40, followed by further stable dose from weeks 41 to 52. Study found significant reduction in HbA1c with empagliflozin 10 mg (∆ −0.44, P < 0.001) and 25 mg (∆ −0.52, P < 0.001) at week 18, respectively, versus placebo. Similarly, HbA1c significantly reduced with empagliflozin 10 mg (∆ −0.38, P < 0.001) and 25 mg (∆ −0.46, P < 0.001) at week 52, versus placebo. The daily total insulin dose were significantly lower in empagliflozin 10 mg (∆ −8.8 IU/day, P = 0.004) and 25 mg (∆ −11.2, P < 0.001), versus placebo at week 52. Moreover, there was a significant reduction in body weight (∆ −1.6 kg and ∆ −2.2 kg, both P < 0.001) with empagliflozin 10 and 25 mg, respectively, versus placebo. Furthermore, empagliflozin 10 mg reduced SBP significantly (∆ −2.4 mm Hg, P = 0.03) at week 18 versus placebo, although this reduction were not statistically significant at week 52 with any dose of empagliflozin. Hypoglycemia was similar in all arms at both point of time. While UTI were similar in all arms, GTI was 2-to 6-times higher in empagliflozin arm, at week 52. [44] In a two-point (week 18 and 76) outcome study (n = 494), Rosenstock et al. evaluated the addition of empagliflozin 10 mg and 25 mg to basal insulin versus placebo. Insulin dose was kept constant for the first 18-week, then was allowed to be up-or down-titrated for next 60-weeks. HbA1c reduction was significantly lower with empagliflozin 10 mg and 25 mg at week 18 (∆ −0.6 and −0.7%, all P < 0.001) and at week 78 (−0.50 and −0.60%; all P < 0.001) respectively versus placebo. Moreover, higher proportion of patients could achieve the target HbA1c of <7% in empagliflozin 10 and 25 mg week 18 (18 and 19% vs. 5%; both P < 0.001), compared to placebo. However, only empagliflozin 25 mg could achieve significant proportion of patient reaching HbA1c target of <7% (27%, P = 0.002) at week 78, versus placebo. The rate of hypoglycemic episodes appeared higher during the first 18-weeks with a fixed insulin dose regime, especially with empagliflozin 25 mg; however, it was similar to placebo at week 78. While both UTI and GTI were 1.5-to 4-times higher in empagliflozin arm, these events were higher in women, generally mild and managed easily with standard care of therapy. [45] Comparative placebo-subtracted HbA1c lowering with DPP-4I or SGLT-2I as an add-on to insulin therapy has been depicted in Figure 1. The proportion of patients achieving target HbA1c of <7% with SGLT-2I and DPP4-I, as an add-on to insulin therapy has been summarized in Figures 2 and 3, respectively. A comparative placebo-subtracted change in body weight with SGLT-2I and DPP-4I as an add-on to insulin has been depicted in Figure 4. cOnclusiOn Metformin being insulin sensitizers undoubtedly remains the best partner to insulin therapy. Moreover, it can potentially counter the insulin-induced weight gain and do not augment hypoglycemia. Indeed, metformin should be used in all T2DM patients, unless it is not tolerated or contraindicated. Pioglitazone is even more effective insulin sensitizer; however as an add-on agent to insulin therapy does carry the potential of weight gain, fluid retention, and precipitation of heart failure.
While the addition of SU to basal insulin therapy is a logical choice considering its cost, time-tested use, ability to reduce post-prandial plasma glucose, and, therefore, overall glycemic control, however, augmentation of hypoglycemia and weight gain is a potential concern. Moreover, SU would be preferably discontinued, once prandial or premix insulin is commenced. GLP-1 RA as an add-on to insulin therapy is an effective combination and has the potential to counter the insulin-induced weight gain without potentiating hypoglycemia. However, this regime incurs additional injection and cost. DPP-4I, as an add-on to insulin therapy, have shown a significant reduction in HbA1c, without any apparent increase in hypoglycemia and body weight. In addition, DPP-4I with insulin required ~10-20% reduction in total daily dose of insulin and significantly higher proportion of patients achieved the target HbA1c of <7%. Similarly, SGLT-2I as an add-on to insulin therapy have shown a significant reduction in HbA1c and body weight, without any apparent increase in hypoglycemia. Furthermore, the   addition of SGLT-2I required ~10% reduction in total daily dose of insulin and significant higher proportion of patients achieved the target HbA1c of <7%. It should be noted that gross reduction in insulin dosage with concomitant SGLT-2I therapy has been reported to be associated with EuDKA.
Taken together, DPP-4I or SGLT-2I both appears as a near-ideal partner to insulin. Both DPP-4I and SGLT-2I have an advantage of oral route, in contrast to GLP-1 RA. However, significant weight loss with all SGLT-2I consistently seen across the studies, and CV benefits observed with empagliflozin; SGLT-2I appears as an ideal partner to insulin in renal uncompromised T2DM, in authors' opinion. Nevertheless, DPP-4I would be preferred choice as an add-on to insulin in elderly and renal compromised T2DM patient. In addition, reduction in insulin dose while on concomitant SGLT-2I therapy should carefully be done to avoid EuDKA, especially in insulinopenic T2DM. Future studies would be even more interesting to find the outcomes of DPP-4I plus SGLT-2I combination as an add-on to insulin therapy.

Acknowledgment
Authors would like to thank Dr. Kalpesh Prakashchandra Jain and Dr. Jaydeep Mazumdar in collecting data while preparing this manuscript.

Financial support and sponsorship
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Conflicts of interest
There are no conflicts of interest.