Safety and Efficacy of SGLT2 Inhibitors during Ramadan Fasting Salem A Beshyah MBBCh DIC PhD FRCP FACP FACE Consultant Physician Sheikh Khalifa Medical City Abu Dhabi, UAE Delivered in Abu Dhabi 2014 with additional slides

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Safety and Efficacy of SGLT2 inhibitors during Ramadan: Disclosures No potential multiplicity of interests exists.

Safety and Efficacy of SGLT2 inhibitors during Ramadan: Objectives Review potential concerns of SGLT2 inhibitors during Ramadan Discuss the role of SGLT2 inhibitors in management of diabetes aduring Ramadan.

Safety and Efficacy of SGLT2 inhibitors during Ramadan: Outlines A quick recap. Study data. One study only in Ramadan. Physicians perspectives. Opinions of nearly 200 physicians Guidelines/Recommendation: -x3

Safety and Efficacy of SGLT2 inhibitors during Ramadan: Outlines A quick recap. Study data. One study only in Ramadan. Physicians perspectives. Opinions of nearly 200 physicians Guidelines/Recommendation: -x3

Increased urinary glucose excretion SGLT2 inhibitor: An insulin-independent approach to remove excess glucose SGLT2 SGLT2 inhibitor Proximal tubule SGLT2 Glucose SGLT2inhibitor Glucose filtration Increased urinary glucose excretion SGLT2 inhibitors selectively inhibits SGLT2 in the renal proximal tubule1 The maximal reabsorptive capacity of this transport system is otherwise saturated at supraphysiological levels of circulating glucose (>11-14 mmol/l).

Expected clinical effects of SGLT2 inhibition based on the mode of action Reduced glycaemia HbA1c reduction Glucose excretion Weight loss Loss of energy Sodium excretion Blood pressure reduction Reduced sodium load Adapted from: Abdul-Ghani MA, et al. Endocr Rev. 2011;32:515-31. HbA1c, glycated haemoglobin A1c.

SGLT2 inhibitors: Pros and Cons Advantages glucose lowering at all stages of disease potential for combination therapy with a wide range of oral glucose-lowering drugs including insulin weight loss blood pressure lowering low risk of hypoglycaemia Concerns increase in urinary tract infections increase in genital infections potential for volume depletion/electrolyte imbalance Euglycemic ketoacidosis? bone fracture risk? Canagliflozin Summary of Product Characteristics. September 2014. Dapagliflozin Summary of Product Characteristics. May 2015. Empagliflozin Summary of Product Characteristics. February 2015.

Widely Recognized Risks and Concerns of Ramadan Fasting in Diabetes Hypoglycemia Hyperglycemia Diabetic ketoacidosis Dehydration Thrombosis Risk to pregnancy

Concerns about SGLT2 inhibitors in General increase in urinary tract infections increase in genital infections potential for volume depletion/electrolyte imbalance ketoacidosis? bone fracture risk? Canagliflozin Summary of Product Characteristics. September 2014. Dapagliflozin Summary of Product Characteristics. May 2015. Empagliflozin Summary of Product Characteristics. February 2015.

What is in common? Beshyah et al. Use of Sodium-Glucose Co-Transporter 2 Inhibitors during the Fasting of Ramadan: Is There Cause for Concern? Ibnosina Journal of Medicine and Biomedical Sciences 2016;8(3):81-88

Safety and Efficacy of SGLT2 inhibitors during Ramadan: Outlines A quick recap. Study data. One study only in Ramadan. Physicians perspectives. Opinions of nearly 200 physicians Guidelines/Recommendation: -x3

Switching from sulphonylurea to an SGLT2 inhibitor in the fasting month of Ramadan is associated with a reduction in hypoglycaemia WJ W Seman, N Kori, S Rajoo, H Othman, NM Noor, NA Wahab, N Sukor, N Mustafa, NA Kamaruddin. Diabetes, Obesity & Metabolism. Published Online March 2016

WJ W Seman, N Kori, S Rajoo, H Othman, NM Noor, NA Wahab, N Sukor, N Mustafa, NA Kamaruddin. Switching from sulphonylurea to an SGLT2 inhibitor in the fasting month of Ramadan is associated with a reduction in hypoglycaemia. Diabetes, Obesity & Metabolism. Published Online March 2016.

Authors’ Summary Dapaglifozin results in lower rate of both symptomatic and asymptomatic hypoglycaemia during the month of Ramadan compared to sulphonylureas (6.9% vs 28.8%, p=0.002) Dapaglifzin results in an A1c drop of 0.1% cf to 0.2% with sulphonylureas during the month of Ramadan (p=0.029) At the end of Ramadan patients on dapaglifozin lost more weight cf to those on sulphonylureas (3.8 kg vs 1.8 kg, p=0.004) Although increased haematocrit , blood ketones & urine osmolality plus reduced urinary sodium were associated with the use of dapaglifozin in Ramadan, there was no difference in the number of patients who lost more than 1.8% of their daily body weight (pre-sunset minus pre-dawn weight) between the two groups. None of the patients in both groups suffered dehydration that necessitated the breaking of their Ramadan fast.

Safety and Efficacy of SGLT2 inhibitors during Ramadan: Outlines A quick recap. Study data. One study only in Ramadan. Physicians perspectives. Opinions of nearly 200 physicians Guidelines/Recommendation: -x3

SGLT2 inhibitors during Ramadan: Physicians Survey I SGLT2 inhibitors are a new glucose-lowering therapy for type 2 diabetes. There are no recommendations for their use for patients fasting for Ramadan.  We surveyed physicians regarding management of people with type 2 diabetes on SGLT2 inhibitors intending to fast for Ramadan. 

SGLT2 inhibitors during Ramadan: Physicians Survey II Most of the responding 197 physicians had substantial experience with patients who fast for Ramadan. The majority felt that SGLT2 inhibitors were generally appropriate and safe during Ramadan but should be discontinued in selected patients (70.6%).

SGLT2 inhibitors during Ramadan: Physicians Survey III Most respondents (92.2%) would advise taking an SGLT2 inhibitor with the first evening meal (Iftar), but 6.1% advised taking them before the last pre-dawn meal (Suhour). Taking extra clear fluids in the evening of Ramadan was recommended by the majority. 

SGLT2 inhibitors during Ramadan: Physicians Survey IV

SGLT2 inhibitors during Ramadan: Physicians Survey V

SGLT2 inhibitors during Ramadan: Physicians Survey VI

Safety and Efficacy of SGLT2 inhibitors during Ramadan: Outlines A quick recap. Study data. One study only in Ramadan. Physicians perspectives. Opinions of nearly 200 physicians Guidelines/Recommendation: -x3

Any Guidelines/Recommendations

“The low risk of hypoglycaemia and benefits of weight reduction make this new class of glucose lowering agents a potential candidate for use during Ramadan. However, caution must be taken because this class results in glycosuria, and hence induce osmotic diuresis. Therefore, there is a risk of dehydration, particularly in warm countries. Since these agents can also lower blood pressure, during fasting, there is a risk of postural hypotension. To date, there is no available clinical evidence for their use and safety during Ramadan. Therefore, randomized controlled trials for SGLT2 inhibitors in Ramadan are required. Certainly, we would recommend that they are used with caution and patients drink at least 2 L of water a day to reduce the risk of dehydration. In addition, initiating a patient on an SGLT2 inhibitor just prior to Ramadan should be avoided”

REGARDING DKA: In the context of Ramadan fasting, it is not recommended that SGLT2 inhibitors are used in those with Type 1 diabetes, indeed it is not currently licensed for use in this population. In the current climate, it may be pertinent to test for ketones in patients with Type 2 diabetes on SGLT2 inhibitors periodically throughout the fasting period. Furthermore, we would advise, as per FDA recommendations, that patients pay close attention for any signs of ketoacidosis and seek medical attention immediately if they experience symptoms such as difficulty breathing, nausea, vomiting, abdominal pain, confusion, and unusual fatigue or sleepiness.

“The sodium glucose transporter-2 (SGLT-2) inhibitors are the newest class of approved oral antidiabetic agents for the treatment of type 2 diabetes. By increasing glucosuria, SGLT-2 inhibitors are associated with significant improvements of fasting hyperglycemia and HbA1c concentration, and with low risk of hypoglycemia in patients with type 2 diabetes. These agents, however, are associated with increased risk of urinary tract and genital infections, and with a mild increase in the risk of volume contraction and dehydration.”

“The lower rates of hypoglycemia compared with sulfonylurea and insulin treatment make SGLT-2 inhibitors an attractive drug in patients with diabetes during Ramadan. However, the associated volume contraction and risk of dehydration represent a concern during prolonged fasting in warm or hot climates, in particular in elderly patients. Randomized controlled studies are needed to determine the safety and efficacy of SGLT-2 inhibitors during Ramadan, especially after the recent Food and Drug Administration (FDA) warning concerning the possible ketoacidosis.”

“SGLT2 inhibitors have demonstrated effective improvements in glycaemic control and weight loss, and are associated with a low risk of hypoglycaemia. Because of this, it has been proposed that they provide a safe treatment option for patients with T2DM during Ramadan. However, certain safety concerns have been raised, such as an increase in some infections (urinary tract infections and genital mycotic infections) and a risk of ketoacidosis. An increased risk of dehydration in vulnerable patients has also been described, which may be a particularly pertinent issue during Ramadan. Currently, only one study has published data on the effectiveness of SGLT2 inhibitors during Ramadan”

“SGLT2 inhibitors have demonstrated effective improvements in glycaemic control and weight loss, and are associated with a low risk of hypoglycaemia. Because of this, it has been proposed that they provide a safe treatment option for patients with T2DM during Ramadan. However, certain safety concerns have been raised, such as an increase in some infections (urinary tract infections and genital mycotic infections) and a risk of ketoacidosis. An increased risk of dehydration in vulnerable patients has also been described, which may be a particularly pertinent issue during Ramadan. Currently, only one study has published data on the effectiveness of SGLT2 inhibitors during Ramadan”

Conclusions

Safety and Efficacy of SGLT2 inhibitors during Ramadan: Conclusions SGLT2 inhibitors may be potential drugs for management of diabetes during Ramadan on basis of their “No risk of hypoglycemia” being the most feared complication during fasting. This was demonstrated in one study. Limited data exist regarding their potential dehydration and/or hypotension effects. There is increasing body of opinion in favor of their potential use for patients who are not at increased risk but properly conducted studies are still needed.

Safety and Efficacy of SGLT2 inhibitors during Ramadan: Conclusions Prudent precautions on use of SGLT2i in Ramadan; to avoid in the following: On high doses of insulin. Using diuretics (in high doses). Markedly reduced caloric intake. Post surgical care.

Safety and Efficacy of SGLT2 inhibitors during Ramadan: Practical Tips

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