European Association for the Study of Diabetes — 49th Annual Meeting

September 22-27, 2013; Barcelona, Spain — SGLT-2 Inhibitors – Draft

Executive Highlights

EASD 2013 featured slightly more new data and discussion on SGLT-2 inhibitors (and SGLT-1/SGLT-2 dual inhibitors) than 2012’s meeting – as at ADA 2013, EASD 2013 had less focus on primary efficacy data and more focus on the drugs’ side effect and safety profiles and their use in special populations. An ADA poster on the use of BI/Lilly’s empagliflozin in type 1 diabetes was presented as an oral at EASD 2013: after eight weeks, patients experienced a 0.4% drop in A1c from an 8.0% baseline, 20% reduced their daily insulin requirement, and 33% saw reduced rates of symptomatic hypoglycemia. Lexicon Pharmaceuticals’ Chief Medical Officer Dr. Pablo Lapuerta presented an oral on the robust gastrointestinal and genitourinary safety profile of Lexicon’s SGLT-1/SGLT-2 dual inhibitor LX4211 – while many KOLs have noted that SGLT-1 inhibition causes GI side effects, LX4211 therapy did not lead to an excess of GI side effects (nausea, diarrhea). Participants on LX4211 saw similar rates of UTIs compared to placebo, as well as a low incidence of vaginal infections that did not lead to treatment discontinuation. EASD also featured a poster (#953) on the use of canagliflozin (J&J’s Invokana) in people with stage 3 chronic kidney disease – as expected, canagliflozin was shown to be more effective in those with less severe kidney disease. We were pleased to see new data from lesser-known SGLT-2 inhibitor candidates, including Taisho’s luseogliflozin and Roche/Chugai’s recently discontinued tofogliflozin.

With CVOTs at the forefront of everyone’s minds at EASD, we heard murmurs throughout the conference of hope that SGLT-2 inhibitors might ultimately be cardioprotective due to their favorable effects on weight and blood pressure (as a reminder, they also cause an increase in LDL cholesterol levels). We attended an oral presentation by Dr. David Sjöström (Global Brand Physician, AstraZeneca, Molndal, Sweden) that concluded that dapagliflozin-induced weight loss was a critical factor in much of the improvement in A1c and blood pressure seen with the candidate. While we will, of course, need to wait until SGLT-2 inhibitor CVOTs report results to draw firm conclusions, some characterized it as interesting that researchers have not lost hope that a diabetes therapy could prove CV-protective after SAVOR and EXAMINE’s neutral results. While discussing the evaluation of SGLT-2 inhibitor safety, Dr. Sanjay Kaul (Cedars-Sinai Medical Center, Los Angeles, CA) provided a truly valuable synthesis and overview on CVOTs, FDA policy, clinical trial design, and data interpretation. The clear theme of Dr. Kaul’s presentation was uncertainty – he emphasized a vast array of unanswered questions for the drug class, including cardiovascular and renal safety, bone health, risks of malignancy, and volume depletion.

Excitingly, SGLT-2 inhibitors were part of the combination therapy discussion this year — notably, Dr. Julio Rosenstock (University of Texas Southwest Medical Center, Dallas, TX) forecasted the combination of SGLT-2 inhibitors with either incretin therapies (as an early treatment option) or basal insulin (as a later-stage option). During a panel discussion during a BMS/AZ corporate symposium on GLP-1 agonists and SGLT-2 inhibitors, Dr. Tina Vilsbøll (University of Copenhagen, Copenhagen, Denmark) noted that triple-therapy fixed-dose combinations of DPP-4 inhibitors, metformin, and SGLT-2 inhibitors are being developed and studied. In our report below, talks highlighted in yellow are on our list of our ten favorite talks of the entire conference, while those highlighted in blue are new additions to the report that were not included in our daily updates from Barcelona.


Table of Contents 


SGLT-2 Inhibitors

Oral Presentations: Glucose Down The Drain


Bruce Perkins, MD (Toronto General Research Institute, Ontario, Canada)

This single-arm, open-label, proof of concept, eight-week study explored use of BI/Lilly’s SGLT-2 inhibitor empagliflozin in 42 patients with type 1 diabetes (mean age: 24 years; mean BMI: 25 kg/m2). We first covered results of this study in a poster in our ADA 2013 Full Report; see page 139 at Results of the treatment period were compared to a two-week placebo run-in period. Mean A1c levels decreased by 0.4% from an 8% baseline, and a stratified analysis found a more pronounced decline in those with the highest baseline A1c (>8.0%). Frequency of symptomatic hypoglycemia was reduced by 33% (0.12 to 0.04 events/day) A range of non-hypoglycemia adverse events were reported by the sample, including two cases of diabetes ketoacidosis that forced the two participants to drop out of the study (though Dr. Perkins attributed these occurrences to the effect of aggressive insulin reductions and not empagliflozin itself – a reminder that more defined insulin protocols may be needed in future studies). Two interesting and currently inexplicable findings are: 1) the 20% drop in total daily insulin needs was explained primarily by reductions in basal insulin (not bolus as might be expected); and 2) the amount of carbohydrate intake in subjects increased dramatically, shooting up from 177 grams per day at baseline to 229 grams per day at week eight (we would guess this has to do with patients’ feeling more freedom to eat less strictly). CGM parameters were also measured but are still undergoing analysis and will be presented at a later date. The data on SGLT-2s continues to look encouraging in type 1 diabetes, and we hope companies aggressively move this class into trials for type 1 diabetes. 

Questions and Answers

Q: With regards to the increased intake of carbohydrates, was this suggested by doctors or done spontaneously by patients?

A: There is no question that this was a spontaneous compensation to this therapy. It was a substantial increase. Unfortunately, we didn't expect this and don't have a way to reveal the mechanism. Of course, there substantial glycemic mass is lost through the mechanism of action of this drug.

Q: Could the altered renal dynamic change the excretion of ketones?

A: I do not know, but further studies are going to have to look at blood and urinary ketones, although I do not see a mechanism for their loss.



Gisle Langslet, MD (Oslo University Hospital, Oslo, Norway)

Dr. Gisle Langslet presented the results of a 104-week study of the efficacy and safety of J&J’s SGLT-2 inhibitor Invokana (canagliflozin). According to the abstract, these results represented the longest follow-up of canagliflozin treatment presented to date. People (n=1,450) on stable background metformin were randomized them to one of three therapy groups: canagliflozin 100 mg, canagliflozin 300 mg, or the sulfonylurea glimepiride. Both canagliflozin doses led to a significantly greater reduction in A1c (from an average of 7.8%) than glimepiride (-0.74% with canagliflozin 300 mg, -0.65% with canagliflozin 100 mg, -0.55% with glimepiride, p=0.04). Furthermore, the glycemic improvement seen in both canagliflozin groups was significantly more durable over 104 weeks than that seen with glimepiride Regarding safety, the incidence of adverse events (AEs) was similar across all groups, with more serious AEs seen with glimepiride. Most serious AEs were severe hypoglycemic events, which were more common with glimepiride (41% incidence with glimepiride compared to 7% and 8% in the canagliflozin 100 mg and 300 mg doses, respectively). Genitourinary infections were seen more frequently with both doses of canagliflozin (15% of female canagliflozin patients experienced them), but these effects were generally mild and few led to discontinuation of treatment. Although previous studies have demonstrated the safety and efficacy of canagliflozin, this study was valuable in that it demonstrated the durability of earlier results over nearly two years. 

  • The double-blind, phase 3 trial (n=1,450 people on stable background metformin) randomized people to one of three therapy groups: canagliflozin 100 mg, canagliflozin 300 mg, or the sulfonylurea glimepiride (dose titrated as needed up to 8 mg; mean dose 5.6 mg).
  • At baseline, patients had an average age of 56 years, average A1c of 7.8%, average BMI of 31, and average disease duration of 6.6 years.
  • Fasting plasma glucose, body weight, and systolic blood pressure were also significantly decreased in both canagliflozin cohorts compared to the glimepiride group. Both canagliflozin doses led to a 10% increase in HDL cholesterol, and the 300 mg canagliflozin group saw a 14% increase in LDL cholesterol (11% increase for 100 mg dose) — these changes occurred during the first 26 weeks, and were stable from then until the end of the trial.

Questions and Answers

Q: It seems that the difference in fasting plasma glucose was greater than the difference in A1c — is that correct?

A: Yes, at the end of the 104-week period, that is what we saw.

Q: It has been suggested that the changes in cholesterol may be a measure of hemoconcentration. Do you have any data on this from earlier in the therapy?

A: I don’t think we have lipid measurements from early in the study. These changes in cholesterol are seen with most SGLT-2 inhibitors.

Comment: Regarding the LDL rise, which was seen only in the first 26 weeks, the question is whether it is a direct or indirect effect. The fact that this increase is not seen in patients with renal impairment, for whom the drug is less effective, tells me that it is a direct effect.

Q: What is nice about this protocol is that glimepiride could be titrated; this is more clinically realistic. My question is, did you see that the glimepiride dose was increased during the study?

A: During our study, glimepiride could be up and down titrated, and as I said, the mean maximum dose of glimepiride was 5.6 mg.



David Sjöström, MD, PhD (Global Brand Physician, AstraZeneca, Molndal, Sweden)

Dr. David Sjöström presented an analysis to determine how much of the A1c and blood pressure improvements dapagliflozin was associated with in a 24-week study were due to the concomitant weight loss. He framed this research question by explaining that it is not clear whether relatively small amounts of weight loss (<5%) lead to significant improvements in CV risk factors like A1c and blood pressure. The baseline characteristics of the study cohort mirror the populations of the six phase 3 studies from which data for this analysis were pooled. The average baseline BMI was ~32 kg/m2 and the mean A1c was 8.3%. In total, 1,066 patients were randomized to receive either 10 mg dapagliflozin or placebo. Treatment with dapagliflozin resulted in significantly greater reductions in A1c, weight, and blood pressure than placebo. Estimating the contribution of dapagliflozin-induced weight loss to the improvements observed in A1c, SBP, and DBP found a significant association between change in body weight and the three dependent variables. Each kilogram of body weight lost was associated with a 0.028 percentage point reduction in A1c, a 0.606 mmHg reduction in SBP, and a 0.253 mmHg drop in DBP. The researchers found that, in a dapagliflozin treated patient, 3 kg of weight loss drove an 8% relative decline in A1c from baseline, a 37% decline in SBP, and a 32% reduction in DBP. Purifying the effect of weight loss independent of dapagliflozin treatment demonstrated that the modest reductions in body weight achievable through SGLT-2 inhibition produce notable improvements in CV risk factors.

Questions and Answers

Q: Why don’t patients disappear if they are continuously excreting calories?

A: The large majority of patients do lose weight on dapa. However, the response is variable. You have a number of different regulatory layers, such as appetite, which would be more individualized, giving us a more varied response. However, overall there does consistently seem to be weight loss of some magnitude. The reason people do not disappear when they keep excreting calories – say you lose approximately 240 calories/day via urine, and if you have a typical intake of 2,400 calories, you are losing 10% of your calories. If you retain the same intake over time, you would lose the part of your body weight that needed the 10% of calories you excreted to be supported. If you put that into thermodynamic equations, it would take one-to-two years to equalize. However, what we have noticed is that patients have a propensity to increase their food intake. There is no threat of disappearing from use of SGLT-2 inhibitors.

Q: Don’t you think that it is difficult to fully disentangle weight loss and changes in blood pressure? How do you differentiate between glucose loss and sodium loss? 

A: In our studies, we saw a transient increase in sodium excretion, but over time there was no change in sodium levels. I agree there are some aspects this presentation could not fully answer.

Q: What do you think about SGLT-2 in type 1 diabetes patients?

A: I think that the other speaker in this session will have a nice presentation on this topic.



Nobuya Inagaki, MD, PhD (Kyoto Graduate School of Medicine, Kyoto, Japan)

Luseogliflozin is an SGLT-2 inhibitor being developed in Japan by Taisho Pharmaceuticals. It is reported to be more specific for SGLT-2 (over SGLT-1) compared to dapagliflozin or canagliflozin. This phase 3 study assessed the performance of luseogliflozin 2.5 mg versus placebo on top of stable glimepiride (GLIM) in 221 patients over 24 weeks and then with an open label extension for all patients to 52 weeks (during which dose could be increased to 5 mg). A1c reduction was 0.5% from the baseline (8.1%) and 0.9% with respect to placebo at 24 weeks, and was maintained to a 0.6% reduction out to 52 weeks. Weight reduction for luseogliflozin was 2.2 kg from baseline at 52 weeks, and 1.5 kg at 24 weeks relative to the placebo group. As expected, there was an excess of genitourinary adverse events in the luseogliflozin group (2.7%) but no resultant discontinuations, and there was also double the hypoglycemia in the luseogliflozin group, which Dr. Inagaki implied was because glimepiride doses were not decreased when luseogliflozin was added.

  • Luseogliflozin is a phase 3 SGLT-2 inhibitor being developed by Taisho Pharmaceutical that is highly selective for SGLT-2 (versus SGLT-1). This study assessed the efficacy and safety of luseogliflozin added to glimepiride (GLIM) over 52 weeks, since sulfonylureas represent the majority treatment in Japan.

  • The study was a double blind randomized controlled trial of luseogliflozin 2.5 mg versus placebo on top of GLIM for 24 weeks in 221 patients. There was an open label extension to 52 weeks, in which all patients took luseogliflozin, but those with insufficient control could increase the dose to 5 mg. Baseline A1c was 8.1%, participants were 75% male, average BMI was 25 kg/m2 and average diabetes duration was about 7 years.

  • At week 24, the luseogliflozin arm exhibited an A1c reduction of 0.5% from the baseline (8.1%) and 0.9% with respect to the placebo arm. This was maintained out to 52 weeks with a 0.6% reduction from baseline. Weight reduction for luseogliflozin was 2.2 kg from baseline at 52 weeks, and 1.5 kg at 24 weeks relative to the placebo group. Fasting glucose in the luseogliflozin group was 34 mg/dl lower than the placebo arm at 24 weeks. Other parameters showed slight improvement, including insulin resistance, blood pressure and lipids.

  • As might have been expected, there was an excess of genitourinary adverse events in the luseogliflozin group (2.7%) but no resultant withdrawals. There was also 8.7% hypoglycemia in the luseogliflozin group, compared to 4.2% in the placebo arm. It seems that glimepiride doses were not decreased when luseogliflozin was added, leading to the excess hypoglycemia.

Questions and Answers

Q: Are there any differences with luseogliflozin compared to dapagliflozin or canagliflozin?

A: This drug has a very high affinity for SGLT-2 and so the dose is very small compared to other drugs. This drug is metabolized in the liver via several pathways, which may lead to differences to the other drugs.



Yukio Tanizawa, MD, PhD (Yamaguchi University, Yamaguchi Prefecture, Japan)

Dr. Yukio Tanizawa presented data on the use of tofogliflozin (Chugai’s SGLT-2 inhibitor) as a monotherapy and in combination with other oral therapies for 52 weeks. Dr. Tanizawa concluded that tofogliflozin positively reduced A1c (~0.7-0.9%) and body weight in both mono- and combination therapy. In monotherapy, participants were randomized to either 20 mg (n=63) or 40 mg (n=127) of tofogliflozin, and in the combination therapy, participants were randomized to use of either sulfonylureas (n=171), glinide (n=22), “BG” (n=105; this was not defined), TZD (n=102), α-glucosidase inhibitor (n=99), and DPP-4 inhibitor (n=103), with either a 20 mg (n=178) or 40 mg (n=424) dose of tofogliflozin. In the monotherapy group, A1c levels dropped 0.7% (baseline of 7.8%) and body weight dropped 3.0 and 3.4 kg for 20 mg and 40 mg of tofogliflozin, respectively. A1c dropped an average of 0.8% for all combination therapies for 20 mg tofogliflozin, and dropped 0.9% for 40 mg of tofogliflozin (baseline range from 7.7% to 8.4%). Body weight dropped an average of 2.5 kg for all combination therapies with 20 mg tofogliflozin, and 3 kg with 40 mg of tofogliflozin. Interestingly, Dr. Tanizawa remarked that tofogliflozin in addition to “BG” and an α-glucosidase inhibitor increased weight loss to 3.9 kg on average, but only when used with 40 mg of tofogliflozin. Dr. Tanizawa highlighted that the use of tofogliflozin as a monotherapy may significantly reduce waist circumference, adiponectin, blood pressure, and HDL and LDL, relative to baseline.

  • Both the monotherapy and combination studies were 52-week randomized, open-label, parallel-group comparison. There were 194 participants in the monotherapy trial and 602 in the combination therapy trial.

  • The baseline A1c for patients on monotherapy was 7.8%, and patients had an average BMI of 25-26 kg/m2. Additionally, the average age was 58-59 years in the tofogliflozin groups. For patients on combination therapy, the baseline A1c ranged from 7.7-8.4% and BMI ranged from 24-28 kg/m2. The average age of patients ranged from 56 years to 60 years for both doses.

  • Patients in monotherapy experienced a significant decrease in weight circumference (p <0.001), adiponectin (p <0.001), blood pressure (SBP: p <0.01 and p <0.05, 20 mg and 40 mg, respectively), and HDL (p <0.01 and p <0.001, 20 mg and 40 mg, respectively) for both the 20 mg and 40 mg groups. Additionally, patients taking 40 mg of tofogliflozin had a significant reduction in triglyceride levels (p <0.01). Surprisingly, Dr. Tanizawa noted, patients on 20 mg, but not 40 mg, of tofogliflozin experienced significant reductions in both DBP (p <0.01) and LDL (p<0.05) levels.

  • There were low levels of cystitis, urinary tract infection, genital infection, and hypoglycemia reported across all groups. There was a particularly low rate of urinary and genital infections – 1-3% in those on tofogliflozin – prompting someone in Q&A to suggest cultural biases. There was no significant difference between groups, and no more than 5% of patients in any group experienced any one adverse events (except for 6% of participants taking a 20 mg dose experiencing mild hypoglycemia). Dr. Tanizawa noted that the three moderate hypoglycemic events all occurred when tofogliflozin was used in conjunction with sulfonylureas.

  • Nasopharyngitis and upper respiratory tract infection were the most common adverse event. Dr. Tanizawa noted that 70% of patients experienced an adverse event, however, these were likely not due to the medications. There were other changes in safety parameters in the monotherapy group, such as an increase in uric acid levels.

Questions and Answers

Q: This was an interesting presentation, thank you. I am wondering why you are doing this open label? Is it ok for regulations to do this without a placebo control? I am also surprised that there were close to zero genital infections. Could it be that something else is going on? Maybe it is just cultural for women not to complain?

A: We had done a separate, placebo, double-blinded trial.

Q: Do you think it is conceivable that there are cultural differences that cause women not to report their genital infections?

A: I don’t know if this is cultural difference. In fact, genital infections are very rare in Japanese populations.

Comment: If that is the case, then maybe we will start to have country-specific drugs.

Q: Are you examining triple therapy?

A: No, not at this moment.



Pablo Lapuerta, MD (Chief Medical Officer,  Lexicon Pharmaceuticals, The Woodlands, TX)

LX4211 is Lexicon Pharmaceutical’s dual SGLT-1/SGLT-2 inhibitor. SGLT-2 is the major glucose transporter in the kidney, and SGLT-1 primarily influences glucose and galactose absorption in the gut, although it has a lesser role in the kidney. In this phase 2b 12-week study of 299 patients on top of metformin, LX4211 didn’t show an excess of GI side effects (nausea, diarrhea) or urinary tract infections over placebo. Vaginal infections were only seen with LX4211, but their incidence was reasonably low and no patients discontinued as a result.

  • LX4211 is an interesting dual SGLT-1/SGLT-2 inhibitor under development by Lexicon Pharmaceuticals and is currently undergoing phase 2b studies. SGLT-1 is the primary glucose and galactose transporter in the gastrointestinal tract, although it has a minor role in the kidney, where SGLT-2 is the primary transporter. SGLT-2 inhibition has been associated with an increase in genitourinary infections, and it is thought that the incidence may relate to the degree of glycosuria. Lexicon believes that the SGLT-1 inhibition of LX4211 might lead to lower glycosuria and therefore a better safety profile. On the other hand, SGLT-1 inhibition is often linked with GI side effects such as diarrhea, although studies of people with natural SGLT-1 mutations do not support this.
  • Accordingly, this study seeks to investigate the safety profile of LX4211 added to metformin, over a 12-week period. At baseline, 299 subjects inadequately controlled on metformin were randomized to four doses (from 75 mg to 400 mg) and placebo. BMI was 33 kg/m2 and baseline A1c was 8.0%.
  • After 12 weeks, the highest dose of LX4211 (400 mg) showed a 0.9% A1c reduction from baseline, and the lowest dose (75 mg) reached 0.5% reduction. There was a nice dose response effect. However, higher doses of LX4211 didn’t increase glucose excretion in the urine above that of the 200 mg dose
  • Genital tract infections were observed in 7%-10% of women at the three higher doses, with none occurring in men or in the placebo group. There wasn’t a strong trend with dose, and there were no discontinuations as a result. Urinary tract infections were the same as placebo. Diarrhea ranged from 4%-10%, compared to 7% in the placebo group. Nausea, vomiting and constipation were also comparable with placebo. LX4211 also exhibited no changes in hypoglycemia, orthostatic blood pressure, LDL or urine electrolytes.
  • Dr. Lapuerta concluded that the favorable GI profile of LX4211 suggests that there is a therapeutic window for SGLT-1 inhibition, and that the dual inhibition approach is promising. Longer duration studies will be forthcoming.

Questions and Answers

Q: Is there an increase in GLP-1?

A: We didn’t measure it in this study, but we have documented sustained GLP-1 elevation for several hours in other studies.

Q: What was the impact on body weight?

A: There was an approximately 2% reduction in body weight. So we see similar weight loss to other members of the class despite less glycosuria.

Q: What was the change in blood pressure?

A: There was a 6mm Hg decline in systolic blood pressure.

Q: Isn’t SGLT-2 blocking better, because of SGLT-1’s effect on the kidney?

A: Looking at the pharmacokinetic profile, we don’t think systemic SGLT-1 inhibition is likely. If it was, there would be more glycosuria. We believe that the inhibition is in the GI tract.

Q: How much was water weight loss? Did you check serum electrolytes?

A: There was no change in serum sodium and potassium. We didn’t check weight loss via DEXA or waist circumference. But the weight change was gradual and did not plateau. A diuretic effect would have been more dramatic, and we didn’t observe this.




Vincent Woo, Melanie Davies, Dick de Zeeuw, George Bakris, Vlado Perkovic, Cristiana Mayer, Ujwala Vijapurkar, Keith Usiskin, and Gary Meininger

Treatment with antihyperglycemic agents is often contraindicated in patients with type 2 diabetes and compromised renal function. The present poster detailed the results of an analysis assessing the efficacy and safety of the SGLT-2 inhibitor canagliflozin (CANA) compared to placebo in patients with suboptimal type 2 diabetes control and stage 3 chronic kidney disease (CKD). This analysis pooled data from subjects (n=1,085) enrolled in four randomized, double-blind, placebo-controlled, phase 3 studies. The total study sample (eGFR ³30 and <60 ml/min/1.73 m2) was further divided into two eGFR subgroups of subjects with: 1) eGFR ³45 and <60 ml/min/1.73 m2 (n=721), and 2) eGFR ≥30 and <45 ml/min/1.73 m2 (n=364). CANA 100 mg and CANA 300 mg lowered A1c an average 0.52% and 0.62%, respectively, from baseline compared to an average 0.14% decrease with placebo. Furthermore, treatment with CANA resulted in significantly more body weight loss than placebo (2.0 kg [4.4 lbs] and 2.4 kg [5.3 lbs] with CANA 100 and 300, respectively, vs. 0.5 kg [1.1 lbs] with placebo). Comparing the two subgroups, reductions in A1c and body weight with CANA were more pronounced in patients with eGFR ³45 ml/min/1.73m2 than in patients with eGFR <45 mL/min/1.73 m2. For the overall population, the two CANA doses were significantly more effective than placebo in lowering systolic blood pressure (CANA 100: 4.4 mmHg; CANA 300: 6.0 mmHg; placebo: 1.6 mmHg), which was a trend observed in both eGFR subgroups. Most importantly, CANA was well tolerated among patients with CKD, with the incidence of overall adverse events being only marginally higher in treatment groups. These positive results attesting to the tolerability and efficacy of CANA in patients with renal impairment are much welcomed, especially given hesitations regarding the safety of this class of agents in high-risk populations. 

  • Baseline characteristics for the overall population included a mean age of 67.1 years, BMI of 32.5 kg/m2, A1c of 8.1%, and duration of diabetes of 15.1 years. The study was primarily comprised of white males.
  • In terms of the safety of CANA in the overall population, the incidence of overall adverse events was slightly higher in the CANA 100 and 300 mg groups than in the control arm (74% and 75.3%, respectively, vs. 70.4% in placebo). Serious adverse events, however, were more commonly reported with placebo group than with CANA (13.3% and 14.8% in the CANA 100 and 300 mg groups, respectively, vs. 19.6% in placebo). Treatment with CANA was associated with a higher rate of adverse events related to reduced intravascular volume and renal function. Furthermore, among the 88.2% of subjects on background insulin or a sulfonylurea, the proportion that had documented episodes of hypoglycemia was higher in the CANA 100 and 300 mg-treated arms (41.9% and 43.8%, respectively) than in placebo (29.2%). In subjects not on insulin or a sulfonylurea, the reported rates of hypoglycemia were low across all groups, with no incidences of severe hypoglycemia.


Symposium: Risks and Benefits of Drugs


Sanjay Kaul, MD (Cedars-Sinai Medical Center, Los Angeles, CA)

Dr. Sanjay Kaul gave a truly outstanding, opinion-filled talk on SGLT-2 inhibitors, cardiovascular outcomes trials, FDA policy, clinical trial design, and data interpretation. Regarding SGLT-2s, the clear theme of Dr. Kaul’s presentation was uncertainty – he emphasized a vast array of unanswered questions for the drug class, including cardiovascular and renal safety, bone health, risks of malignancy, and volume depletion. He specifically reviewed the cardiovascular profiles of dapagliflozin and canagliflozin, outlining more concerns with canagliflozin based on the data. As he did at the canagliflozin advisory committee, Dr. Kaul came out against the release of interim CVOT data, though he also proposed a number of valuable ways to ensure trial integrity. Speaking more broadly, Dr. Kaul commented that the 2008 cardiovascular risk assessment guidance has hardly stifled innovation, a comment we found reasonable when he compared it to blood pressure medications – but not in diabetes, our major concern. Dr. Kaul spoke out against the FDA’s use of fixed hazard ratios for cardiovascular safety (1.8 and 1.3) – instead, he advocated for flexible assessments based on risk/benefit profiles (i.e., to accept a higher level of risk for a higher level of benefit). This was great to hear from a patient perspective. We appreciated his discussion of rosiglitazone as well, a drug that, in his view, still has insufficient high-quality evidence to incriminate or exonerate it on the cardiovascular safety front. Dr. Kaul highlighted the scary duality implicit in that drug’s story: it became a blockbuster without an established outcome benefit though was virtually killed on insufficient evidence and entrenched opinions. We thought this was one of the best talks at EASD 2013 – more of Dr. Kaul’s opinions and nuanced discussion is below.

  • Regarding rosiglitazone, the catalyst for the development of 2008 cardiovascular guidance for drug development, Dr. Kaul noted that a lingering uncertainty remains regarding its safety. In his opinion, there is insufficient high-quality evidence to incriminate or exonerate the drug’s effect on cardiovascular safety. The fact that the drug became a blockbuster without an established outcome benefit does not reflect well on drug development; however, it is equally lamentable that the drug was virtually killed on insufficient evidence and entrenched opinions.

    • Dr. Kaul commented that he thought the 2008 cardiovascular risk assessment guidance has hardly stifled innovation, noting that there are 15 cardiovascular outcomes trials, with two completed (SAVOR and EXAMINE) and many underway. He said there is “quite a rich landscape” in diabetes drug development right now; for comparison, only one new blood pressure medication has been approved by the FDA in the last 15 years.

  • Dr. Kaul summarized the current benefits of SGLT-2 inhibitors. He noted that SGLT-2 inhibitors have been shown to have “modest” glycemic control (an ~0.7% reduction from a baseline of ~8%), relatively low frequency of hypoglycemia, “modest” weight loss (~1.8 kg [4.0 lbs]), and a blood-pressure-lowering effect on the order of approximately 4.5 mmHg, which could potentially be clinically beneficial. To this regard, he commented that we don’t know whether non-physiologic reductions in blood pressure yield cardioprotective effects.

  • He also addressed risks of the class: mycotic genital infection (odds ratio=5.0); urinary tract infections (odds ratio=1.4), but not pyelonephritis; polyuria, nocturia, and dysuria; volume depletion, thirst, and increased hematocrit; and increased LDL (benefits and risks were adapted from Vasilakou et al., Ann Intern Med 2013). Dr. Kaul commented that he did not know what the clinical relevance of increased LDL observed with SGLT-2 inhibitor treatment might be.
  • Dr. Kaul noted that in terms of cardiovascular safety, canagliflozin had an imbalance in stroke as well as uncertainty around an early increase in MACE. Additionally, an increased LDL was observed with canagliflozin and empagliflozin.
  • In Dr. Kaul’s opinion, the issue of volume depletion with SGLT-2 inhibitors is likely underestimated, noting that in CANVAS’ study protocol design, the earliest assessments of volume depletion were conducted at six weeks. He emphasized that the potential effects of volume depletion on the RAAS system activation should be explored, since the CETP inhibitor torcetrapib (a lipid drug to increase HDL) that increased aldosterone was also associated with a significant increase in cardiovascular events.
  • Dr. Kaul commented that we have no idea what the effects of SGLT-2 inhibitors are on bone health, given that at present, most evaluations have only been conducted out to one or two years at most. As for malignancy, it remains uncertain what the implications the observed imbalances in bladder and breast cancer with dapagliflozin treatment are. He did not think tumor induction was the likely mechanism, but tumor promotion might be (though, to date, little is known about tumor-promoting agents). During Q&A, Dr. Kaul commented that he believed the imbalances were likely due to detection/ascertainment bias.
  • In Dr. Kaul’s review of the cardiovascular profiles of SGLT-2 inhibitors, he expressed more comfort with dapagliflozin’s profile than with canagliflozin’s profile. He noted that in the meta-analysis of cardiovascular risk with dapagliflozin treatment: 1) the observed population in trials for dapagliflozin were representative of the intended treatment population; 2) excess cardiovascular risk (HR of 1.8) was ruled out; and 3) numerical imbalances in cardiovascular endpoints consistently favored dapagliflozin versus control. As for canagliflozin, Dr. Kaul pointed out a number of concerns he had with the conducted meta-analysis, including that: 1) there was an early increased MACE risk (whether it is a true risk or a “random high” remains uncertain); 2) the sponsors’ claim of a “lack of association with volume depletion-related AEs” might not have painted the whole picture, since early (less than six week) volume and blood pressure changes were not captured due to protocol; 3) there was limited patient exposure (~1.1 years), that is, the number of events was driven by a high number of patients as opposed to duration of exposure; 4) the impact of imbalance in rescue therapy use remains unclear; and 5) the public release of interim results may have compromised trial integrity.
  • With the public release of interim results for the cardiovascular outcomes trial for canagliflozin (CANVAS) in mind, Dr. Kaul emphasized that partial unblinding threatens trial integrity and reliability, and proposed a solution to the issue. He noted that disclosure of interim analyses slows enrollment; reduces adherence in the experimental arm (for HR >1.2); encourages cross-ins in the control arm (HR <0.8); and minimizes retention. To use interim analysis results and maintain trial integrity, Dr. Kaul suggested that data access be restricted to an unblinded “firewalled group” formed with input from the regulator, DMC, and steering committee; discussions should occur in a “closed” session to preserve data integrity; and regulators should only disclose publicly if a hazard ratio of 1.8 has been ruled out (implying a point estimate of <1.26 without loss of equipoise).
  • There are a number of remaining unanswered questions about SGLT-2 inhibitors. Regarding durability, it remains to be seen whether the efficacy of drugs in the class will wane with normalized glucose levels. As for safety and tolerability, SGLT-2 inhibitors have unproven long-term safety (especially in the elderly [>75 years], those with renal impairment [GFR <45-60 ml/min/1.73 m2], and those on loop diuretics). He emphasized that the use of SGLT-2 inhibitors should be further investigated in patients with renal impairment, in particular with regards to nephropathy and increased volume depletion. Finally, he also commented that SGLT-2 inhibitors have not been substantially evaluated in minority populations.
  • Reflecting on cardiovascular safety assessments performed to date and their limitations, Dr. Kaul proposed a number of ways to enhance the integrity of non-inferiority safety trials. Dr. Kaul emphasized the need for such trials to: reduce the ineligibility rate; optimize adherence in the experimental arm (to decrease bias to the null); avoid cross-ins in the control arm (to decrease bias to the null); maximize retention and avoid protocol deviation and drop out (to decrease bias to the null); enroll, capture data, and adjudicate events in a timely manner; minimize exposure of the control arm to treatments that increase cardiovascular risk (to decrease bias to the null); restrict the primary endpoint to stringent MACE – cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (to decrease ascertainment error and misclassification); adjust for multiplicity if interim data is used for the final analysis (to reduce type 1 error); not publicly disclose results of interim analyses (to increase trial integrity). Dr. Kaul also noted that placebo-controlled trials should be preferred over active-controlled trials (as one would not necessarily know the safety profile of the active comparator). In addition, extension phases of trials add noise (given that they are often unblinded); as such Dr. Kaul advocated for extensions to be blinded.
  • Dr. Kaul questioned whether we should continue to allow disease-oriented surrogate endpoints to be the standard for regulatory approval, or demand patient-oriented health outcomes benefit for both microvascular and macrovascular complications. He commented that he is not persuaded by the statement that microvascular benefits are unequivocally demonstrated with oral agents for type 2 diabetes, deeming laserphotocoagulation and reduced albuminuria as examples of unvalidated surrogate endpoints. Instead, he would like to see studies with concrete patient outcome benefits – for example, in renal failure, amputations, and blindness.
  • Dr. Kaul argued against the FDA’s use of fixed hazard ratios (1.8 and 1.3) with regards to cardiovascular safety. Instead of fixed margins, Dr. Kaul proposed that allowable risk should be determined based on the amount of benefit, as opposed to trial feasibility. For example, he would be willing to accept a greater potential increase in harm for a therapy that lowered A1c by 1.5-2.0%, whereas for a therapy that lowered A1c by 0.5%, he might not even be willing to accept a hazard ratio of 1.3. Furthermore, he advocated for benefit/risk assessment to incorporate the patient’s view of acceptable or tolerable risk, and for it to evolve from the mindset to “ensure drug safety” to ensure “favorable risk/benefit.” Finally, he emphasized the need to develop more tools for communication of benefit/risk not only to patients, but also to the scientific community, academia, and regulators. 
  • Dr. Kaul explained that an asymmetry exists in how drug efficacy and safety are evaluated – RCTs vs. non-clinical data/PK-PD studies/retrospective review. Efficacy is assessed in randomized controlled trials, in which endpoints are anticipated and prespecified. These trials are designed with adequate power to assess the endpoint, and the endpoints have clear adjudication, and are precisely measured/quantified. In contrast, safety is typically assessed using a combination of non-clinical data, pharmacokinetic/pharmacodynamic studies, meta-analyses, observation databases, and monitoring programs (e.g., FDA AERS and Sentinel). This stems from a major limitation in randomized controlled trials: there is limited exposure to treatment and narrow study populations, so safety issues cannot be fully captured. In contrast to efficacy assessments, safety issues are often unanticipated, and as such are not prespecified for measurement, or adjudicated proactively (O’Neill, Drug Information Journal 2008).

Questions and Answers

Q: Surely when we prescribe to patients, they are exposed to risks other than cardiovascular risk. What do you think of things like bladder cancer or breast cancer?

A: As I mentioned fleetingly, there was an imbalance in one of the drugs. I believe it’s probably related to ascertainment bias. In order for sponsors to clearly adjudicate this uncertainty, it would require a 30,000-patient trial, which in my opinion, and probably the majority of yours, is not possible to do pre-approval. That should be evaluated in a post-approval, phase 4 type of study.


Corporate Symposium: What is Important in T2D Management — Experts’ Perspectives (Sponsored by Lilly)


Bernard Zinman, MD (Leadership Sinai Centre for Diabetes, Toronto, Canada)

Dr. Bernard Zinman delivered a comprehensive talk on Lilly/BI’s SGLT-2 inhibitor candidate empagliflozin, which is currently under regulatory review in the US and EU — read our coverage of the drug’s submission at Dr. Zinman began by comparing pooled phase 3 data on empagliflozin, J&J’s Invokana (canagliflozin) and BMS/AZ’s Forxiga (dapagliflozin). Empagliflozin appears to be slightly more effective than dapagliflozin in terms of A1c reduction, but slightly less effective than canagliflozin. Of course, it is important to keep in mind that these comparisons are not drawn from head-to-head studies. Dr. Zinman next discussed a 78-week phase 3 study comparing empagliflozin to placebo in patients on basal insulin, in which empagliflozin demonstrated a 0.6% placebo-adjusted A1c reduction from a baseline of 8.2%. Additionally, empagliflozin led to an average of 4 lbs of weight loss and a reduction in patients’ daily insulin needs by six units (although no difference in hypoglycemia was seen despite this reduction). Another phase 3 study showed that the drug’s A1c-lowering efficacy and weight loss benefits were largely preserved in patients with mild renal impairment; a less robust but still clinically meaningful change in A1c and weight loss was seen in patients with moderate renal impairment. With regard to the increase in genitourinary infections seen in the trials, Dr. Zinman noted that patients with a past history of such infections were overrepresented in empagliflozin’s phase 3 program.

  • Dr. Zinman shared pooled data from pivotal phase 3 trials of empagliflozin, canagliflozin, and dapagliflozin. On average, empagliflozin demonstrated a 0.6% A1c reduction. Dapagliflozin demonstrated slightly lower efficacy, while results with canagliflozin appeared stronger than either dapagliflozin or empagliflozin. However, Dr. Zinman pointed out, canagliflozin’s efficacy is substantially diminished in patients with renal impairment.
  •  The beauty of the SGLT-2 inhibitor class, Dr. Zinman stated, is that the A1c reductions seen with SGLT-2 inhibitors do not seem to depend on background therapy, due in large part to the class’ insulin-independent mechanism of action. With this in mind, it will be interesting to see how SGLT-2 inhibitors are incorporated into the treatment algorithm in the coming years – Will they emerge as the most common third line option after metformin and DPP-4 inhibitors? Will they increase the time before patients go on injectable therapy? 
  • Dr. Zinman discussed the results of a 78-week, phase 3 trial comparing empagliflozin 10 and 25 mg vs. placebo as an add-on to basal insulin in type 2 diabetes patients (n=494). The data was first presented at this year’s ADA. At week 78, the higher dose of empagliflozin led to a 0.6% placebo-adjusted reduction in A1c from a baseline of 8.3%, a six-unit reduction in patients’ daily insulin requirements, and 2 kg (~4 lbs) average weight loss. There was no significant difference in hypoglycemia (despite the reduction in insulin dose), and a slight increase in drug-related adverse events with empagliflozin (largely attributable to genitourinary infections).
  • Dr. Zinman also discussed the findings of a phase 3 trial investigating empagliflozin in patients with stage 2-4 renal disease. The study (also first presented at ADA) ran for 52 weeks and enrolled 741 patients with mild and moderate renal impairment (eGFRs from 60-90 and 30-60 ml/min/1.73 m2, respectively). Empagliflozin 25 mg led to an average A1c reduction of approximately 0.6% vs. placebo at 52 weeks in patients with mild renal impairment from a baseline of 8.0% – the improvement was similar in magnitude to the reduction seen in patients with normal renal function. Reductions in weight (~5 lbs or 2 kg) and systolic blood pressure (~5 mmHg) were also largely preserved in patients with mild renal impairment. The sustained A1c reduction in those with moderate renal impairment (0.4% from a baseline of 8.0%) was slightly less robust though still clinically meaningful. Dr. Zinman noted that empagliflozin seemed to temporarily reduce eGFR slightly, but that deficit recovered almost immediately once the medicine was stopped, indicating that the change was likely due to hemodynamics rather than tissue changes.
  • A tolerability analysis of empagliflozin shows that the candidate led to an increase in the incidence of genitourinary infections. This is not altogether surprising, as the same side effect has been seen with other SGLT-2 inhibitors. However, Dr. Zinman noted that patients with a past history of genitourinary effects were overrepresented in empagliflozin’s phase 3 study pool, and that infections were generally mild and rarely led to a discontinuation of treatment.
  • For Dr. Sanjay Kaul’s outstanding review of the SGLT-2 inhibitor class and outstanding safety concerns, please see pages three through six of our EASD report at


Corporate Symposium: New Options and Opportunities in the Era of Individualized Therapy (Sponsored by Janssen Cilag)


Julio Rosenstock, MD (University of Texas Southwestern Medical Center, Dallas, TX)

Dr. Julio Rosenstock reviewed clinical data for SGLT-2 inhibitors (specifically dapagliflozin, canagliflozin, and empagliflozin), highlighting their: 1) ability to lower A1c consistently across various therapy regimens (by ~0.6-0.9% from a baseline of 8%); 2) consistent and persistent ~2 kg (4 lb) weight loss; 3) low risk of hypoglycemia; 4) ability to lower and sustain a loss of ~5 mmHg in systolic blood pressure; and 5) elevated risk of urinary tract and genital infections. Regarding canagliflozin, Dr. Rosenstock noted that when added on to metformin, canagliflozin 300 mg provided slightly greater A1c reduction than sitagliptin, and brought about significantly greater weight loss (Diabetologia 2013). He also commented that he thinks SGLT-2 inhibitor in combination with insulin is an important combination, given the difficult nature of control for many on insulin. Dr. Rosenstock commented that he sees metformin in combination with a DPP-4 inhibitor or GLP-1 agonist as an early combination treatment on the horizon, followed by the addition of an SGLT-2 inhibitor or basal insulin (assuming patients can afford and tolerate such therapies). 

  • Dr. Rosenstock listed the potential benefits of SGLT-2 inhibitors: once-daily dosing; their ability to reduce both fasting and postprandial glucose; their ability to lower A1c in a predictable and consistent manner; blood-pressure-lowering effects; a mechanism independent from insulin secretion; their ability to complement any other drug; and their potential for use in type 1 diabetes.
  • Subsequently, he commented on a number of concerns that have arisen with the class. Dr. Rosenstock does not believe that weight loss with SGLT-2 inhibitors will wane over time (they’ve been shown to have a persistent effect out to two years). He believes the effects are minimal regarding polyuria, that electrolyte disturbances aren’t really an issue, and that there isn’t currently enough data to comment on the potential of hypotension/dehydration. Although there is indeed an increased risk of urinary tract infections with SGLT-2 inhibitors, Dr. Rosenstock pointed out that, reassuringly, there was no increased risk of pyelonephritis. As fungal genital infections are a real concern of these drugs, Dr. Rosenstock explained that those who have recurrent episodes should not be on the medications. In addition, he pointed out that SGLT-2 inhibitors are indeed less effective in patients with renal impairment. Meanwhile, the jury remains out on unexpected side effects and long-term safety.



David Matthews, PhD (University of Oxford, Oxford, United Kingdom)

Dr. David Matthews argued that individualizing treatment approaches for patients is imperative, delineating mathematical, statistical, and pragmatic considerations. In terms of mathematics, Dr. Matthews noted with 12 drug classes now available for type 2 diabetes, the number of permutations of therapies (as monotherapy or in combination) that could be used would be in the millions, so it would be nearly impossible to have an evidence base for every combination therapy before trying them. Regarding statistics, Dr. Matthews explained that even though one drug may on average be more effective than another, each has a distribution of efficacy; that is, even though a drug may be worse on average, some individuals still benefit. In terms of practical considerations, healthcare providers must consider factors such as resources, patient engagement, needle phobia, and work imperatives, to name a few, when individualizing therapy. He commented that obviously, treatment individualization should take into account what the best option would be for the patient, and that it should aim to be minimally disruptive. Given the fact that the evidence base will never come close to completely characterizing all possible therapy regimens, Dr. Matthews proposed for doctors to conduct “trials of one” with their patients – to test out one drug for a period, see how they’re responding, and then consider switching to a different medication if appropriate. To further engage patients in tailoring treatment for their diabetes, Dr. Matthews suggested the use of topic cards, getting patient involvement in research, and advocacy as several options. In conclusion, Dr. Matthews quoted William Osler, who stated, “Medicine is a science of uncertainty and an art of probability.”



Manuel Puig Domingo, MD (Universitat Autònoma de Barcelona, Barcelona, Spain); David Matthews, DPhil (Oxford, England, UK); Julio Rosenstock, MD (Dallas Diabetes and Endocrine Center, Dallas, TX); Guntram Schernthaner, MD (University of Vienna, Vienna, Austria); John Wilding, MD (University of Liverpool, Liverpool, UK)

Dr. Schernthaner: Can SGLT-2 inhibitors be used in patients with type 1 diabetes?

Dr. Wilding: It is certainly an area to watch for in the future, though it would always be complimentary to insulin.

Dr. Schernthaner: I have some friends who are doctors and also have type 1 diabetes. They have taken SGLT-2 inhibitors and have had an enormous decrease in postprandial glucose levels and far fewer hypoglycemic events. They are experts and have been using insulin for 30 years, so in some cases it could be helpful. Some of the doctors were obese and lost weight, but many people with type 1 are slim and further weight reduction would not be a good option. There was a paper that showed change in intestinal absorption of glucose. What is your comment on this observation?

Dr. Wilding: Canagliflozin is selective for SGLT-2, but it will have a small and transient effect to inhibit SGLT-1. In that situation, what it may be doing at the initial dose is delaying the absorption of glucose from the gut, reducing post-prandial glucose levels. The mechanism is speculative, and it’s still very clear that about 90% of canagliflozin’s effect is due to its effect on the kidney, though the modest gut effect is scientifically interesting and may contribute in a small way to the therapeutic effect of canagliflozin.

Dr. Schernthaner: The comparison with sitagliptin is not the best. If canagliflozin was compared to something more potent, would it show similar results?

Dr. Matthews: You need to do the trial, so I don't know. All of the head-to-head trials are quite interesting, but drug companies tend to select something they think they will win against. Traditionally, if you have something that works weakly, you try against placebo because you’re sure you’ll win against that. They try against the worst agent around. The industry is skewing what you’re going to get out of trials, so take them with a pinch of salt. They’ve been chosen to give some sort of gloss. Having said that, the reality is that all these data, because drug companies have so many people involved, are absolutely correct. The realty is that pharmaceutical companies give you truth, but only the truth about what it is they have done. Why haven’t we done another trial with metformin? Nobody is doing trials on metformin now to see if it has CVD protection because no one will fund that stuff! With trials, you can come up with any question, and all I would say is, go and talk to Novartis and I’m sure you could persuade them to do the trial.

Dr. Wilding: Everyone has a good response to glimepiride initially – how long do you have to go for before you know who the right people are?

Dr. Matthews: Once you start on the principle of individualized treatments, then it behooves us to think about pharmacokinetics and indicators. Rob Ratner has done some interesting work looking at who did well in what trials. There are huge problems with doing that. If you’re not careful, you will get some chance findings, but at least you can start thinking about whether those people had certain characteristics. As soon as we start to focus on that, we’ll get more useful information on to whom to administer the drug.

Dr. Schernthaner: There is a weight loss of 3 kg [6.6 lbs.] associated with the use of SGLT-2 inhibitors. Patients are not shrinking. What is the stabilizing mechanism so that weight is not continuously going down with SGLT-2 inhibitors?

Dr. Domingo: We have some mechanistic explanations. They lose calories and water, but the initial effects are overcome by adaptive mechanisms that might tend to avoid or prevent additional weight loss. We are focusing on this particular new treatment, but if you look at any treatments currently available, all show this stabilizing effect. This is case with GLP-1 related treatments, as well. They lose weight but at the end they tend to stabilize and not lose additional weight. Patients treated with bariatric surgery lose weight, and after 1-2 years it is maintained, or recovered, but in most cases it is stabilized. We think an adaptive mechanism is playing a huge role.

Dr. Matthews: You’re going to defend your weight. This is central to the whole of your genetic makeup – the whole of your genome is designed to do that. You can’t just say why didn’t you lose weight? This doesn’t work. You do defend your weight in all sorts of ways, and that is built directly into homeostatic mechanisms. You’ll defend your body size.

Dr. Wilding: As your weight falls, your metabolic rate falls. That’s why all weight interventions result in a plateau. In dapagliflozin and canagliflozin, if you look at what type of tissue if being lost, two-thirds is fat and one-third is lean tissue. It’s about the same proportion if you go on diet or take canagliflozin. The majority is fat, and that’s an important thing to make clear.

Q: Can you comment on the CANVAS trials?

Dr. Matthews: CVOTs are always complex. You need to take patients and study them for a long time for cardiovascular effects to be apparent. Rosiglitazone is a classic example. Pharmaceuticals get completely locked into the 1.3 upper limit of confidence intervals for CV protection. CVOTs are expensive things to do. If you look at EXAMINE and SAVOR, they saw zero changes, which satisfies regulators, and the 1.3 margin hasn’t been exceeded. CANVAS trials are an absolute nightmare, with J&J and investigators of CANVAS trials trying to defend it from people trying to look into it too early. You have to give stuff to regulators to get canagliflozin on books, so they can start to make return on investments, and then you can start a longer CVOT. The reason UKPDS chose what it chose is that it ran for 10 years. Robert Turner thought the whole thing would be over in three years, and at 10 years we finally produced results. It’s tough to do those things, but if you take the right people for long enough, then you get effects and you can bank that. With CANVAS, we hope to get results that are we are proud to show you.

Dr. Schernthaner: Julio, are there any differences between SGLT-2 inhibitors? What proportion of canagliflozin’s action is due to SGLT-1 inhibition?

Dr. Rosenstock: There is a little bit of SGLT-1 inhibition. There is a nice study that shows a reduction in GI absorption with canagliflozin. I’m not sure if the SGLT-1 effect is that important.

Dr. Schernthaner: We have experienced dapagliflozin in a number of different countries. We also have full reimbursement. But we don’t have any experience with canagliflozin, so how is the situation in the States with that?

Dr. Rosenstock: It’s hard to tell, but from what we hear from the sponsor, they say take-up is going very well, especially with general practitioners. There were concerns because the class is counterintuitive – all of a sudden we’re telling them glycosuria is a good thing – but they say uptake is good. I’m told in Germany dapagliflozin is doing very well. The thing is with this type of drug is that you can tell from day one that it works. It’s predictable and consistent.

Dr. Schernthaner: When will SGLT-2 inhibitors officially be added to ADA/EASD guidelines?

Dr. Matthews: We said in the position statement last year that we would think about revising this in three years. The EASD will probably set up a process next year. We did write it with the idea that it is a flexible document. That’s why we didn’t call it “guidelines”– it's a position statement. I think SGLT-2 will be another box on the options you get. There’s no plan to reconvene at the moment. The process is you get together a collection of people appointed by EASD and ADA and get lots of reviewers before it reaches the public domain. It requires multiple stages, rather than algorithmic guidelines that no one reads.

Dr. Rosenstock: The class look good, but I have concerns about the elderly, about the frail, about the people on diuretics, about the people with good blood pressures of 110/70 who might have hypotensive episodes. Those things need to be discussed. I still have concerns about people with borderline compromised renal function, though there doesn't seem to be an indication with that. The jury is still out about the long-term safety of these compounds. 

Dr. Schernthaner: I’m always really concerned about new compounds. In my opinion, no drug is the drug for anyone. Individual use if very important.

Dr. Wilding: In the UK, dapagliflozin has been positioned in same way as DPP-inhibitors; it is also reimbursed. You are then down to having an individual discussion with the patient to see which is the most appropriate option for that patient. For a patient who is obese and on insulin and metformin, I would recommend a SGLT-2 because there is good chance that they would lose weight and see an improvement in control. But if they have problems with genital infections, that might push me to recommend a DPP-4 inhibitors. You have to take into account the individual patient.

Dr. Rosenstock: Both are valid options. You have to take everything into consideration. The advantage with SGLT-2 inhibitors is that you get an immediate effect. The patient can feel it, whereas DPP-4 inhibitors are not satisfying expectations for a sustained effect.


-- by Adam Brown, Poonam Daryani, Hannah Deming, Jessica Dong, Hannah Martin, Manu Venkat, Vincent Wu, and Kelly Close