An update on sodium-glucose co transporter-2 g pinhibitors for the inhibitors for the treatment of diabetes treatment of diabetes mellitusmellitus

INTRODUCTIONINTRODUCTIONThe unadjusted estimated total The unadjusted estimated total

l f t l f t 2 2 di b t di b t prevalence of type prevalence of type 2 2 diabetes diabetes (diagnosed and undiagnosed) in the (diagnosed and undiagnosed) in the (diagnosed and undiagnosed) in the (diagnosed and undiagnosed) in the USA in USA in 20112011––2012 2012 was was 1414..33% and the % and the estimated prevalence of estimated prevalence of prediabetesprediabeteswas was 3838% demonstrating the severity of % demonstrating the severity of the disease burden which has the disease burden which has the disease burden, which has the disease burden, which has continued to increase over the past continued to increase over the past 30 30 continued to increase over the past continued to increase over the past 30 30 years. years.

Type 2 diabetes is a progressive yp p gdisease typically requiring multiple medications in order to control bl d l l lblood glucose levels.

S di l 2 Sodium-glucose co-transporter-2 (SGLT2) inhibitors are the latest (SGLT2) inhibitors are the latest class of antihyperglycemic agents class of antihyperglycemic agents to receive Food and Drug to receive Food and Drug Administration (FDA) approval.

SGLT2 inhibitors function through a novel mechanism of reducing renal t b l l b ti tubular glucose reabsorption, producing a reduction in blood producing a reduction in blood glucose without stimulating insulin glucose without stimulating insulin release. Other benefits may include release. Other benefits may include favorable effects on blood pressure p(BP) and weight.

The scope of this review will focus on clinical trials published over the past year as well as the new safety concerns that have led to multiple FDA advisories for SGLT2 inhibitors.

PHYSIOLOGY OF SODIUMPHYSIOLOGY OF SODIUM--GLUCOSEGLUCOSECOCO TRANSPORTER INHIBITIONTRANSPORTER INHIBITIONCOCO--TRANSPORTER INHIBITIONTRANSPORTER INHIBITION

GlucosuriaGlucosuria has been studied for over has been studied for over GlucosuriaGlucosuria has been studied for over has been studied for over 150 150 years using the botanical extract, years using the botanical extract, y g ,y g ,phlorizinphlorizin. . PhlorizinPhlorizin was later was later identified as a nonspecific inhibitor identified as a nonspecific inhibitor of SGLT proteins and several types of SGLT proteins and several types of SGLT proteins, and several types of SGLT proteins, and several types of SGLT proteins have since been of SGLT proteins have since been of SGLT proteins have since been of SGLT proteins have since been identified. These proteins function identified. These proteins function ppindependently of insulin.independently of insulin.

Inhibition of these proteins was observed to result in changes that favorably improve carbohydrate metabolism, thus becoming an attractive concept for the treatment of diabete.

SGLT1 proteins are high SGLT1 proteins are high affinity, low capacity y, p ytransporters of glucose. p gThey are expressed in the y psmall intestines as well as the proximal tubule of the kidney.

Inhibition of SGLT1 may lead to gastrointestinal complications, incl ding se ere diarrhea The including severe diarrhea. The SGLT1 proteins in the proximal SGLT1 proteins in the proximal convoluted tubule of the kidneys convoluted tubule of the kidneys are responsible for less than 10% pof filtered glucose reabsorption.

SGLTSGLT2 2 proteins are expressed in the proteins are expressed in the SGLTSGLT2 2 proteins are expressed in the proteins are expressed in the proximal convoluted tubule of the proximal convoluted tubule of the proximal convoluted tubule of the proximal convoluted tubule of the kidneys. These transporters are an kidneys. These transporters are an y py pideal target for the treatment of ideal target for the treatment of diabetes because they are diabetes because they are

ff % f% fresponsible for roughly responsible for roughly 9090% of % of filtered gl cose filtered gl cose reabsorptionreabsorptionfiltered glucose filtered glucose reabsorptionreabsorption..

The normal renal threshold for freabsorption of glucose corresponds

to a serum glucose concentration of to a serum glucose concentration of 180mg/dl. In patients with type 2 180mg/dl. In patients with type 2 diabetes, this threshold can increase and the expression of SGLT2 proteins

b l t d i can be upregulated causing a maladaptive response that worsens maladaptive response that worsens hyperglycemia.yp g y

Selective inhibition of SGLT2 proteins can reduce this threshold to as low as 40 120mg/dl.

Comparatively individuals with the Comparatively, individuals with the rare ‘nondisease’, familial renal rare nondisease , familial renal glucosuria (FRG), have no functional SGLT2 proteins. They

t ith l i i th present with glucosuria in the presence of normoglycemiapresence of normoglycemia.

Individuals with FRG rarely have Individuals with FRG rarely have hypotension or hypoglycemia.yp yp g y

CURRENT SELECTIVE SODIUM-GLUCOSE COTRANSPORTER-2 INHIBITORS:

A handful of SGLTA handful of SGLT2 2 inhibitors have been inhibitors have been approved for the treatment of type approved for the treatment of type 2 2 diabetes diabetes approved for the treatment of type approved for the treatment of type 2 2 diabetes diabetes or are currently undergoing clinical trials. or are currently undergoing clinical trials. Currently, there are three SGLTCurrently, there are three SGLT2 2 selective selective inhibitors approved by the FDA for mono inhibitors approved by the FDA for mono inhibitors approved by the FDA for mono, inhibitors approved by the FDA for mono, dual, and triple therapy: dual, and triple therapy: canagliflozincanagliflozin((I kI k ) ) d lifl id lifl i ((F iF i ) d ) d ((InvokanaInvokana), ), dapagliflozindapagliflozin ((FarxigaFarxiga), and ), and empagliflozinempagliflozin ((JardianceJardiance).).empagliflozinempagliflozin ((JardianceJardiance).).

Of the three FDA approved ppdrugs, empagliflozin has the g , p ggreatest selectivity for SGLT2 g ycompared with SGLT1, whereas canagliflozin is the least selective.

Four combination drugs have also been Four combination drugs have also been Four combination drugs have also been Four combination drugs have also been approved by the FDA:approved by the FDA:approved by the FDA:approved by the FDA:canagliflozincanagliflozin//metforminmetformin ((InvokametInvokamet), ), dapagliflozindapagliflozin/ / metforminmetformin ((XigduoXigduo XRXR), ), empagliflozinempagliflozin//metforminmetformin ((SynjardySynjardy) and ) and empagliflozinempagliflozin//metforminmetformin ((SynjardySynjardy), and ), and empagliflozinempagliflozin//linagliptinlinagliptin ((GlyxambiGlyxambi) as ) as e pag oe pag o // ag ptag pt ((G y a bG y a b ) as) asillustrated in Table illustrated in Table 11..

INDICATIONS FOR THE USE OF INDICATIONS FOR THE USE OF SODIUMGLUCOSE COSODIUMGLUCOSE CO--TRANSPORTERTRANSPORTER--22SODIUMGLUCOSE COSODIUMGLUCOSE CO--TRANSPORTERTRANSPORTER--2 2 INHIBITORSINHIBITORS

SGLT2 inhibitors may be a useful option in obese and hypertensive patients because of their weight loss and antihypertensive benefits.

Patients who are at high risk for at e ts o a e at g s ohypoglycemia may benefit from a y g y ycombination of metformin and an SGLT2 inhibitor because the risk of h l i ith SGLT2 hypoglycemia with SGLT2 inhibitors is small when compared inhibitors is small when compared with insulin and sulfonylureaswith insulin and sulfonylureas.

SGLT2 inhibitors are contraindicated for patients with renal insufficiency [ l l filt ti t (GFR) 45 [glomerular filtration rate (GFR) <45 ml/min/1 73m2] However they may be ml/min/1.73m2]. However, they may be very useful without regard to diabetes y gduration because their action is independent of b cell function and insulin secretioninsulin secretion.

BENEFITS OF SODIUM-GLUCOSE COTRANSPORTER 2 INHIBITORSCOTRANSPORTER 2 INHIBITORS:

Glucose control:Glucose control:In a meta-analysis published in 2014 In a meta-analysis published in 2014, 24-week reduction of HbA1c withSGLT2 inhibitors was greater in trials enrolling patients with a lower mean age shorter duration of mean age, shorter duration of diabetes and a higher baseline BMI diabetes, and a higher baseline BMI, HbA1c, and fasting glucose.

On the basis of recent clinical trials, reduction in HbA1c in comparison with placebo

h it i t reaches its maximum at i t l 6 th d i approximately 6 months and is

i t i d t 1 maintained up to 1 year.

The treatment with SGLT2 inhibitors has been associated with a similar hypoglycemic risk as that of metformin and dipeptidyl peptidase-4 inhibitors.

When compared with other oral antihyperglycemic agents, SGLT2 inhibitors have demonstrated noninferiorityalong with additional metabolic benefits.

As an example, in a randomized, doubleblind study of 1450 patients, HbA1c decreased by – 0.65% with

lifl i 100 d d b canagliflozin 100 mg, decreased by 0 74% with canagliflozin 300 mg 0.74% with canagliflozin 300 mg, and decreased by –0 55% with and decreased by 0.55% with glimepiride 6 or 8mg over a 104-g p gweek period.

Moreover when added to other Moreover, when added to other antihyperglycemic medications antihyperglycemic medications (both oral medications and (both oral medications and insulin) SGLT2 inhibitors have insulin), SGLT2 inhibitors have shown additional improvement shown additional improvement in glucose controlin glucose control.

DapagliflozinDapagliflozin added to patients added to patients DapagliflozinDapagliflozin added to patients added to patients already taking already taking metforminmetformin and and already taking already taking metforminmetformin and and sulfonylurea showed a sulfonylurea showed a sulfonylurea showed a sulfonylurea showed a decrease in HbAdecrease in HbA11c of c of 00..8686% % compared with a decrease in compared with a decrease in ppHbAHbA11c of c of 00..1717% in the placebo % in the placebo ppgroup at group at 24 24 weeks.weeks.

In patients with type In patients with type 2 2 diabetes diabetes inadequately controlled on basal inadequately controlled on basal insulin insulin RosenstockRosenstock et al in a et al in a 7878 week week insulin, insulin, RosenstockRosenstock et al. in a et al. in a 7878--week week randomized, doublerandomized, double--blind, placeboblind, placebo--randomized, doublerandomized, double blind, placeboblind, placebocontrolled trial demonstrated that controlled trial demonstrated that empagliflozin significantly reduced significantly reduced HbAHbA11 ( (00 55++ 00 11% ith % ith 1010 HbAHbA11c (c (00..55+_+_00..11% with % with 1010mg mg andand00 6060++ 11% with % with 25 25 mg both mg both andand00..6060+_.+_.11% with % with 25 25 mg, both mg, both P<P<00..001001).).

Moreover, while the placebo group had to increase its basal insulin dose by -5 5+ 1 6 nits the empagliflo in 10mg 5.5+_1.6 units, the empagliflozin 10mg group lowered its dose by 1 2+ 1 5 group lowered its dose by 1.2+_1.5 units and the 25mg group lowered its g g pdose by 0.5+_1.6 units demonstrating

SGthat SGLT2 inhibitors may reduce insulin dose requirements and mitigate insulin-dose requirements and mitigate insulin-induced weight gain.

OTHER METABOLIC EFFECTS:OTHER METABOLIC EFFECTS:

Weight lossgIn clinical trials of the SGLT2 In clinical trials of the SGLT2

inhibitors as monotherapy or inhibitors as monotherapy or add-on treatment, weight loss , gof approximately 1–4 kg pp y goccurred over 18–104 weeks.

It has been reported that weight loss independen and weight-loss-associated mechanisms contributed to both HbA1c and systolic blood pressure (SBP) lowering with SGLT2 inhibition.

Blood pressure:Blood pressure:To date all studies with SGLT2 To date, all studies with SGLT2

inhibitors have found inhibitors have found significant reductions in BP significant reductions in BP, with greater reductions seen in with greater reductions seen in SBP (1 66–6 9mmHg) than SBP (1.66 6.9mmHg) than diastolic blood pressure (0 88–diastolic blood pressure (0.883.5mmHg).

Interestingly, similar levels of BP Interestingly, similar levels of BP reduction are seen in people p pwith estimated glomerulargfiltration rate of 45 ml/min/ 1.73m2 as those with 85 ml/min/1.73m2, and patients do not develop hyponatremia as many do with diuretics.

The initial reductions in BP are The initial reductions in BP are believed to be due to the believed to be due to the diuretic and volume depletion diuretic and volume depletion effects However longer-term effects. However, longer term effects may be attributable to effects may be attributable to inhibition of the renin–inhibition of the reninangiotensin system and weight angiotensin system and weight loss.

Lipids:Lipids:Although some trials have shown no Although some trials have shown no

h i li id t th h i li id t th change in lipid parameters, others change in lipid parameters, others have shown a modest but statistically have shown a modest but statistically have shown a modest but statistically have shown a modest but statistically significant increase in both highsignificant increase in both high--g gg gdensity lipoprotein (HDL) and lowdensity lipoprotein (HDL) and low--density lipoprotein (LDL) cholesterol density lipoprotein (LDL) cholesterol with no effect on triglycerides or the with no effect on triglycerides or the with no effect on triglycerides or the with no effect on triglycerides or the LDL/HDL ratioLDL/HDL ratioLDL/HDL ratio.LDL/HDL ratio.

CARDIOVASCULAR BENEFITS:CARDIOVASCULAR BENEFITS:One of the most significant trials with reported One of the most significant trials with reported

l h h EMPAl h h EMPA REG REG results over the past year was the EMPAresults over the past year was the EMPA--REG REG OUTCOME study. The randomized doubleOUTCOME study. The randomized double--OUTCOME study. The randomized doubleOUTCOME study. The randomized doubleblind, placeboblind, placebo--controlled study included controlled study included 7020 7020

ti i t ith t bli h d di l ti i t ith t bli h d di l participants with established cardiovascular participants with established cardiovascular disease and demonstrated a disease and demonstrated a 3838% relative risk % relative risk reduction in death from cardiovascular reduction in death from cardiovascular causes in the causes in the empagliflozinempagliflozin group versus the group versus the causes in the causes in the empagliflozinempagliflozin group versus the group versus the placebo group.placebo group.

The precise mechanism of action that The precise mechanism of action that The precise mechanism of action that The precise mechanism of action that resulted in these striking findings are resulted in these striking findings are resulted in these striking findings are resulted in these striking findings are not precisely known at this time, may not precisely known at this time, may include a number of mechanisms, and include a number of mechanisms, and

i f th i ti tii f th i ti tirequire further investigation.require further investigation.Table Table 2 2 ill strates the c rrent ill strates the c rrent Table Table 2 2 illustrates the current illustrates the current

prospective cardiovascular safety prospective cardiovascular safety prospective cardiovascular safety prospective cardiovascular safety trials for SGLTtrials for SGLT2 2 inhibitors.inhibitors.

ADVERSE SIDE-EFFECTS AND WARNINGSWARNINGS:

Th t d idThe most common advers side-ff t t SGLT2 i hibit effect to SGLT2 inhibitors

appears to be genital appears to be genital infections which were infections, which were increased up to four fold in increased up to four-fold in clinical trialsclinical trials.

Detectable concentrations of glucose in the urine can facilitate the onset of mycoticinfections, as observed in patients who experience severe hyperglycemia with glycosuria.

Because of the osmotic diuresisBecause of the osmotic diuresisinduced by glycosuria resulting induced by glycosuria resulting from SGLT2 inhibition volume from SGLT2 inhibition, volume depletion is a possibility This depletion is a possibility. This is usually accompanied by is usually accompanied by increased urinary frequency, increased urinary frequency, thirst, and rarely orthostatic thirst, and rarely orthostatic hypotension.

Risk factors for volume depletion are age above 75 years, GFR less than 60 ml/min/ 1.73m2, and the use of l di ti loop diuretics.

Incidences of genital mycoticinfections, urinary tract infections,

d ti di i l t d and osmotic diuresis-related adverse events were higher in adverse events were higher in clinical trials but were generally clinical trials but were generally mild to moderate in intensity and yled to few discontinuations.

KetoacidosisKetoacidosis and sodiumand sodium--glucose glucose cotransportercotransporter 2 2 inhibitors:inhibitors:cotransportercotransporter-- 2 2 inhibitors:inhibitors:In diabetic ketoacidosis (DKA), d abet c etoac dos s ( ),

absolute insulin deficiency leads to yreduced glucose utilization and enhanced lipolysis; increased free f tt id (FFA ) i th li fatty acids (FFAs) in the liver coupled with high glucagon levels coupled with high glucagon levels promote FFA oxidation and promote FFA oxidation and production of ketone bodies.

DKA presents with hyperglycemia DKA presents with hyperglycemia (glucose>(glucose>250250mg/ dl), mg/ dl), glycosuriaglycosuria, , and and h perketonemiah perketonemia E gl cemicE gl cemicand and hyperketonemiahyperketonemia. . EuglycemicEuglycemicDKA (DKA (euDKAeuDKA) involves a different ) involves a different DKA (DKA (euDKAeuDKA) involves a different ) involves a different mechanism. Full dose SGLTmechanism. Full dose SGLT2 2 mechanism. Full dose SGLTmechanism. Full dose SGLT2 2 inhibition induces a rapid increase inhibition induces a rapid increase ppin urinary glucose excretion, in urinary glucose excretion, ranging from ranging from 5050––100 100 g/ day.g/ day.

Because of the decline in glucose by 20– 25mg/dl, plasma insulin levels also decrease (by 10pmol/l fasting and 60pmol/l postmeal) with a compensatory increase in glucagon levels.

This shift in hormones causes a released inhibition of gluconeogenesis in the liver as g gwell as augmented endogenous glucose production both in the fasting and fed states.

Most importantly, renal glucose clearance (i.e., the ratio of glycosuria to prevailing glycemia) is twice as much with euDKA compared with DKA.

Thus, in SGLT2-treated type 2 Thus, in SGLT2 treated type 2 diabetes patients with euDKA, diabetes patients with euDKA, the lower insulin to- glucagon the lower insulin to glucagon ratio stimulates lipolysisp yaugmenting FFA delivery to the g g yliver and resulting in mild gstimulation of ketogenesis.

If insulin deficiency is more If insulin deficiency is more profound as can happen in profound, as can happen in type 1 diabetes patients or if type 1 diabetes patients, or if carbohydrate availability is carbohydrate availability is drastically restricted, the mild drastically restricted, the mild ketosis would evolve toward ketosis would evolve toward ketoacidosis.

All in all All in all euDKAeuDKA is is All in all, All in all, euDKAeuDKA is is pathophysiologicallypathophysiologically similar to similar to pathophysiologicallypathophysiologically similar to similar to DKA except for the DKA except for the DKA except for the DKA except for the circumstance of SGLTcircumstance of SGLT22--circumstance of SGLTcircumstance of SGLT22induced induced glycosuriaglycosuria that that induced induced glycosuriaglycosuria that that ‘artificially’ lowers plasma ‘artificially’ lowers plasma artificially lowers plasma artificially lowers plasma glucose levels and predisposes glucose levels and predisposes glucose levels and predisposes glucose levels and predisposes to increased to increased ketogenesisketogenesis. .

These lower glucose levels These lower glucose levels make identifying make identifying euDKAeuDKAmore difficult and may lead more difficult and may lead to delayed treatment.to delayed treatment.

Another rare side-effect that has been observed with the use of canagliflozin has been acute pancreatitis.

Two case reports of acute Two case reports of acute pancreatitis associated with pancreatitis associated with DKA in patients with DKA in patients with temporal exposure to temporal exposure to canagliflozin were published canagliflozin were published in 2015 in 2015.

The exact mechanism for the development of pancreatitis and whether there is a similar risk with other drugs in the SGLT2 inhibitor class remains unknown.

In May 2015, the US FDA issued a Drug Safety Communication warning that treatment with SGLT2 inhibitors may increase the risk of ketoacidosis.

From March 2013 to June 6,,2014, 20 cases of acidosis reported , p

as DKA, ketoacidosis, or ketosis in patients treated with SGLT2 i hibi hi h d inhibitors which were reported to the FDA Adverse Events Reporting the FDA Adverse Events Reporting System (FAERS); all of these System (FAERS); all of these patients required emergency patients required emergency treatment or hospitalization.

These FAERS cases were These FAERS cases were These FAERS cases were These FAERS cases were atypical for DKA because most atypical for DKA because most atypical for DKA because most atypical for DKA because most of the patients had type of the patients had type 2 2 of the patients had type of the patients had type 2 2 diabetes and their blood sugar diabetes and their blood sugar diabetes and their blood sugar diabetes and their blood sugar levels were only slightly levels were only slightly levels were only slightly levels were only slightly increased compared with the increased compared with the increased compared with the increased compared with the high blood sugar levels seen in high blood sugar levels seen in high blood sugar levels seen in high blood sugar levels seen in typical cases of DKA.typical cases of DKA.

In June 2015, the European Medicines A d th t f M Agency announced that as of May 2015 a total of 101 cases of DKA 2015 a total of 101 cases of DKA have been reported worldwide pthrough EudraVigilance in type 2 diabetes patients treated with SGLT2 inhibitors with an estimated inhibitors, with an estimated exposure over 0.5 million patient-exposure over 0.5 million patientyears.

Peters et al. identified 13 episodes of SGLT2 pinhibitor-associated euDKA or ketosis in nine individuals seven with type 1 nine individuals, seven with type 1 diabetes and two with type 2 diabetes, from diabetes and two with type 2 diabetes, from various practices across the USA. They reported that the absence of significant hyperglycemia in these patients delayed hyperglycemia in these patients delayed recognition of the emergent nature of the problem by patients and providers.

Th l d d h SGLTTh l d d h SGLT2 2 They concluded that SGLTThey concluded that SGLT2 2 inhibitors seem to be associated inhibitors seem to be associated inhibitors seem to be associated inhibitors seem to be associated with with euDKAeuDKA and ketosis perhaps and ketosis perhaps with with euDKAeuDKA and ketosis, perhaps and ketosis, perhaps as a consequence of their as a consequence of their as a consequence of their as a consequence of their noninsulinnoninsulin--dependent glucose dependent glucose p gp gclearance, clearance, hyperglucagonemiahyperglucagonemia, and , and volume depletion.volume depletion.

In September 2015, the FDA strengthened the warnings related to th i d i k f b f t the increased risk of bone fractures and added new information about and added new information about decreased bone mineral density to ythe labels for canagliflozin(Invokana) and canagliflozin/metformin (Invokamet)canagliflozin/metformin (Invokamet).

In nine pooled clinical trials with a mean In nine pooled clinical trials with a mean duration of exposure to canagliflozinduration of exposure to canagliflozinof 85 weeks, the incidence rates of adjudicated bone fractures were 1.1, 1 4 d 1 5 100 ti t f 1.4, and 1.5 per 100 patient-years of exposure in the comparator (includes exposure in the comparator (includes placebo and active comparators),p p ),canagliflozin 100 mg, and canagliflozin300mg groups, respectively.

Fractures occurred as early as Fractures occurred as early as 12 weeks after treatment 12 weeks after treatment initiation and were more likely initiation and were more likely to be due to low trauma and to be due to low trauma and affect the upper extremities.affect the upper extremities.

A double-blind, placebo-controlled li i l t i l d t d i 714clinical trial was conducted in 714

patients (mean age 64 years patients (mean age 64 years, range 55–80 years) with type 2 range 55 80 years) with type 2 diabetes inadequately controlled d abetes adequate y co t o edon current diabetes therapy as part of an FDA-issued postmarketing requirement.

At 2 years, patients randomized to canagliflozin 100mg and

lifl i 300 h d l b canagliflozin 300mg had placebo corrected declines in BMD at the corrected declines in BMD at the total hip of 0 9 and 1 2% total hip of 0.9 and 1.2%, respectively, and at the lumbar respectively, and at the lumbar spine of 0.3 and 0.7%, prespectively.

In the total hip, a 1.2% decline in BMD translates into a decrease of approximately 0.1 T-score units or 1% of peak bone mass.

In post hoc analysis, change in body weight appeared to explain

b t 40% f th b d about 40% of the observed difference in total hip BMD difference in total hip BMD between the pooled canagliflozinbetween the pooled canagliflozingroup and the placebo group.g p p g p

Clearl more data is needed in Clearly, more data is needed in this area to make definitive this area to make definitive statements and evaluation of statements, and evaluation of the risk of bone fractures with the risk of bone fractures with other drugs in the SGLT2 other drugs in the SGLT2 inhibitor class is ongoinginhibitor class is ongoing.

Furthermore, in December 2015 as a follow-up to the warnings issued in M 2015 th FDA d id d t dd May 2015, the FDA decided to add specific warnings to the labels of all specific warnings to the labels of all SGLT2 inhibitors indicating the risk SGLT2 inhibitors indicating the risk of ketoacidosis and serious urinary of ketoacidosis and serious urinary tract infections.

R i f th FAERS d t b f Review of the FAERS database from March 2013 to May 2015 identified March 2013 to May 2015 identified 73 cases of ketoacidosis in patients 73 cases of ketoacidosis in patients with type 1 or type 2 diabetes yp yptreated with SGLT2 inhibitors [canagliflozin (n=48), dapagliflozin(n=21), and empagliflozin (n=4)] .

Forty-four of the 73 cases Forty-four of the 73 cases occurred in patients with type 2 occurred in patients with type 2 diabete mellitus. Fifteen cases diabete mellitus. Fifteen cases were reported in patients with were reported in patients with type 1 diabetes (SGLT2 type 1 diabetes (SGLT2 inhibitors are not approve for ppuse in this population).

Blood glucose levels were reported in 40 Blood glucose levels were reported in 40 of the 73 cases and ranged from 90 to of the 73 cases and ranged from 90 to 1366 mg/dl (median 211 mg/dl) . The range of time from initiation of an SGLT2 i hibit i i d SGLT2 inhibitor or an increase in dose to the onset of the reported to the onset of the reported ketoacidosis was 1 day–1 year (median y y (43 days).

In the 73 cases of ketoacidosis, potential In the 73 cases of ketoacidosis, potential risk factors for developing ketoacidosis with an SGLT2 inhibitor i l d d i f ti l b h d t included infection, low carbohydrate diet or an overall reduction of caloric diet or an overall reduction of caloric intake, reduction in dose of exogenous , ginsulin or discontinuation of exogenous insulin, discontinuation of an oral insulin secretagogue and an oral insulin secretagogue, and alcohol use.

Finally, 19 cases of urosepsis and pyelonephritis that started as urinary tract infections while t ki SGLT2 i hibit taking an SGLT2 inhibitor [canagliflozin (n=10) and [canagliflozin (n=10) and dapagliflozin (n=9)] were reported dapagliflozin (n 9)] were reported to FAERS from March 2013 through October 2014.

All 19 ti t All 19 patients were h it li d h fhospitalized, whereas fourpatients req ired admission to patients required admission to the ICU and two required the ICU, and two required hemodialysis to treat renal hemodialysis to treat renal failurefailure.

The range of time to onset of The range of time to onset of urosepsisurosepsisThe range of time to onset of The range of time to onset of urosepsisurosepsisor or pyelonephritispyelonephritis was was 22––270 270 days days py ppy p yy(median (median 45 45 days).days).

Eight of the Eight of the 19 19 cases had documented cases had documented blood culture results withblood culture results with Escherichia Escherichia coli coli as the isolated organism and as the isolated organism and coli coli as the isolated organism, and as the isolated organism, and there were no reports of fungal there were no reports of fungal there were no reports of fungal there were no reports of fungal urosepsisurosepsis..

CONCLUSION:CONCLUSION:

SGLT2 inhibitors are the newest class of oral antihyperglycemic agents antihyperglycemic agents available to treat patients available to treat patients with type 2 diabeteswith type 2 diabetes.

Their novel mechanism of action Their novel mechanism of action makes these medications an makes these medications an intriguing option for patients g g p pthroughout the natural history of type 2 diabetes and as a possible

fadjunct therapy for type 1 diabetes ith close s per isiondiabetes with close supervision.

As reported, there have been adverse events related to this class, including recently identified episodes of ketoacidosis related to SGLT2 inhibitor use.

But as reported, euDKA was suggested p , ggto be predictable, detectable and preventable when a heightened awareness of the condition is known awareness of the condition is known. Longer term cardiovascular safety Longer term cardiovascular safety trials are ongoing and will ultimately test the staying power of this class of

di timedications.