type 2 diabetes mellitus ( t2 dm ) is an increasingly prevalent disease , with an estimated 29.1 million americans , or 9.3% of the us population , having diabetes , including 25.9% of patients 65 years of age and older.1 diabetes was the seventh - leading cause of death in the united states in 2010 and patients with t2 dm have roughly a two- to four - fold greater risk of death caused by cardiovascular disease compared to those without diabetes.1 t2 dm is a progressive , complex disease state with multiple pathophysiologic abnormalities.2 metformin is the recommended first - line pharmacologic therapy for t2dm,3,4 and sulfonylureas have historically been used early in the course of disease . however , these agents are associated with high secondary failure rates,5 and sulfonylurea therapy is associated with hypoglycemia and weight gain . more than 40% of adults with t2 dm in the us have not obtained goal glycemic control.6 patients often require combinations of anti - hyperglycemic agents to maintain glycemic control , because of the progressive nature of t2 dm . thus , combination therapy using drugs with complimentary mechanisms of action should be utilized for appropriate glycemic control.2,3 agents that can improve glycemic control without increasing hypoglycemia , promote weight loss , and improve -cell function are especially desirable . although the sodium - glucose co - transporter 2 ( sglt-2 ) inhibitors have not been shown to be a disease - modifying agent in regards to preserving -cell function , they have been shown to improve blood glucose levels and have a positive effect on body weight and blood pressure.7 sglt-2 inhibitors possess a unique pharmacologic mechanism of action , which is independent of insulin secretion and therefore effective despite the duration of disease . furthermore , the action of sglt-2 inhibitors is additive to that of other diabetes medications . this results in decreased plasma glucose levels , as well as a mild osmotic diuresis and a net caloric loss , thus promoting lower hba1c , weight loss , and systolic blood pressure reduction , all with a minimal risk of hypoglycemia . because of the wide prevalence of t2 dm , drug efficacy and drug safety are important considerations in drug selection for patients with diabetes . the goal of this study was to assess the real - world efficacy and safety of canagliflozin in patients with t2 dm already receiving anti - hyperglycemic therapy . this pre - post observational study assessed the efficacy and tolerability of canagliflozin in type 2 diabetes patients from a private endocrinology practice . the study protocol was approved by the albany college of pharmacy and health sciences institutional review board . a computerized text search of the medication and problem lists of patient electronic medical records ( emr ) was used to identify potential subjects . individual records of identified patients were reviewed to ascertain if all applicable study criteria were met . inclusion criteria were : age between 1895 years , documented diagnosis of type 2 diabetes mellitus , and use of canagliflozin 100 mg or 300 mg for a minimum of 6 months ( unless discontinued due to side effects or cost issues ) . exclusion criteria included : patients with renal impairment ( gfr < 45 ml / min/1.73 m ; 0.75 ml / s/1.73 m ) , patients with type 1 diabetes mellitus , patients with any other change in medication for diabetes ( except insulin ) , hypertension ( except diuretics ) or lipid medication therapy during the evaluation period , and patients receiving prescription medications for weight loss during the evaluation period ( table 1 ) . a data collection form was utilized to collect the following patient information : baseline patient demographic information ( age , gender , and race ) , duration of diabetes , medical history , current medications , laboratory data ( hba1c , cholesterol profile , serum creatinine , blood urea nitrogen ( bun ) , aspartate aminotransferase ( ast ) , and alanine aminotransferase ( alt ) levels ) , blood pressure , height , weight , and reported adverse drug events . drug efficacy was evaluated by a comparison of hba1c levels , weight , blood pressure , and cholesterol profiles of patients on daily canagliflozin . drug safety was evaluated by review of bun and serum creatinine data as well as by review of documented reports of drug side effects . primary study outcomes were changes in hba1c and weight , and percentage of patients reporting adverse effects of therapy . secondary outcomes were differences in the percentage of patients achieving an hba1c level of < 7% ( 53 mmol / mol ) , changes in systolic and diastolic blood pressures , changes in lipid levels ( tc , ldl - c , hdl - c , tgs , and non - hdl - c ) , changes in bun and serum creatinine levels , change in the number of insulin injections per day , and change in the average daily insulin dose . as this was a pre - post observational study , each patient served as his / her own control . statistical analysis was performed using paired t tests , the fisher exact test , and the wilcoxon signed rank test , as appropriate . this pre - post observational study assessed the efficacy and tolerability of canagliflozin in type 2 diabetes patients from a private endocrinology practice . the study protocol was approved by the albany college of pharmacy and health sciences institutional review board . a computerized text search of the medication and problem lists of patient electronic medical records ( emr ) was used to identify potential subjects . individual records of identified patients were reviewed to ascertain if all applicable study criteria were met . inclusion criteria were : age between 1895 years , documented diagnosis of type 2 diabetes mellitus , and use of canagliflozin 100 mg or 300 mg for a minimum of 6 months ( unless discontinued due to side effects or cost issues ) . exclusion criteria included : patients with renal impairment ( gfr < 45 ml / min/1.73 m ; 0.75 ml / s/1.73 m ) , patients with type 1 diabetes mellitus , patients with any other change in medication for diabetes ( except insulin ) , hypertension ( except diuretics ) or lipid medication therapy during the evaluation period , and patients receiving prescription medications for weight loss during the evaluation period ( table 1 ) . a data collection form was utilized to collect the following patient information : baseline patient demographic information ( age , gender , and race ) , duration of diabetes , medical history , current medications , laboratory data ( hba1c , cholesterol profile , serum creatinine , blood urea nitrogen ( bun ) , aspartate aminotransferase ( ast ) , and alanine aminotransferase ( alt ) levels ) , blood pressure , height , weight , and reported adverse drug events . drug efficacy was evaluated by a comparison of hba1c levels , weight , blood pressure , and cholesterol profiles of patients on daily canagliflozin . drug safety was evaluated by review of bun and serum creatinine data as well as by review of documented reports of drug side effects . primary study outcomes were changes in hba1c and weight , and percentage of patients reporting adverse effects of therapy . secondary outcomes were differences in the percentage of patients achieving an hba1c level of < 7% ( 53 mmol / mol ) , changes in systolic and diastolic blood pressures , changes in lipid levels ( tc , ldl - c , hdl - c , tgs , and non - hdl - c ) , changes in bun and serum creatinine levels , change in the number of insulin injections per day , and change in the average daily insulin dose . as this was a pre - post observational study , each patient served as his / her own control . statistical analysis was performed using paired t tests , the fisher exact test , and the wilcoxon signed rank test , as appropriate . , 47 patients were excluded because of a lack of a six - month or later follow - up appointment ( despite receiving therapy for at least six months ) , 77 were excluded as they had received therapy for a duration of less than six months , 13 patients were excluded because of a change in their diabetes medication regimens while receiving canagliflozin , and 8 patients were excluded because of a diagnosis of type 1 diabetes mellitus . overall , this was a middle - aged , morbidly obese , caucasian population , with an average duration of diabetes of 12 years , who were already receiving a median of three diabetes medications . at baseline , three - quarters of patients received metformin therapy , almost two - thirds received insulin , and nearly 60% received glp-1 analog therapy . microvascular complications were documented in 43.2% of the study population , while 26.1% of patients had a history of macrovascular disease . at baseline , 93.7% and 96.4% of patients were receiving lipid lowering ( median of 1 ; mean of 1.4 ) and antihypertensive agents ( median of 2 ; mean of 1.8 ) , respectively . patients received canagliflozin for an average of 9  2 months ( range 612 ) of therapy . two - thirds of patients received a daily canagliflozin dose of 300 mg ; the remaining third of patients received 100 mg daily . during this time , hba1c and weight significantly decreased , by an average of 0.37% and 4.4 kg respectively ( figs . 1 and 2 ) . furthermore , hdl - c levels significantly increased ( 3.5 mg / dl ; 0.091 mol / l ) ( table 3 ) . in addition , 20.7% more patients receiving canagliflozin achieved an hba1c of < 7% ( 53 mmol / mol ) at follow - up ( p < 0.05 ) , compared to baseline , and the mean daily insulin dose significantly decreased by 15 units from an average daily dose of 85 units . there were no significant changes in blood pressure , other lipid levels , bun or creatinine levels , or number of daily insulin injections . the overall rate of drug discontinuation was 27% , with 11.7% ( 13 patients ) discontinuing because of third party payer / cost issues , and 15.3% ( 17 patients ) discontinuing therapy due to adverse effects . other reasons for drug discontinuation included hyperglycemia ( n = 2 ) , polyuria ( 2 ) , urinary tract infection ( 2 ) , stomach upset ( 1 ) , fatigue ( 1 ) , and atrial fibrillation ( 1 ) . there were no reports of hypoglycemic events , hyponatremia , hyperkalemia , or renal insufficiency . an additional four of the 111 patients reported adverse drug events but continued therapy ; one patient developed a urinary tract infection that resolved with ciprofloxacin treatment ; two patients complained of orthostasis from the medication , and one patient developed two yeast infections , which resolved with fluconazole therapy . this is the first reported observational study regarding the real - world safety and efficacy of the sglt-2 inhibitor canagliflozin , in patients with t2 dm concomitantly receiving other classes of anti - hyperglycemic agents . patients in this study demonstrated significantly reduced hba1c and weight and a significant increase in mean hdl - c levels with the addition of canagliflozin . this study reported a modest decrease in mean hba1c level with the use of canagliflozin compared to results from randomized controlled trials . the canagliflozin treatment and trial analysis ( cantata ) trials reported mean reductions in hba1c ranging from 0.731.03% after 26 or 52 weeks of therapy.812 the mean 0.36% reduction demonstrated in this study may be due to the lower average hba1c at initiation of drug therapy compared to that seen in the controlled clinical trials ( 7.5% [ 58.5 mmol / mol ] vs. 8.0% [ 63.9 mmol / mol ] ) . it is well documented that reduction in hba1c is less at lower baseline levels of hba1c versus higher baseline levels.13 in addition , hba1c reduction in this study was achieved despite a 17.6% reduction in mean insulin dose . in addition to improved glycemic profiles , canagliflozin therapy provided statistically significant and clinically relevant weight reductions in t2 dm patients originally managed with other anti - hyperglycemic agents . this study demonstrated a significant mean reduction in body weight of 4.4 kg ( 3.95% ) . this result is consistent with those of the cantata trials , which reported mean weight losses of 2.24.2% in patients in whom canagliflozin was added to a baseline regimen of metformin , sulfonylurea , metformin with pioglitazone , or metformin with sulfonylurea.812 
 figure 2 shows the change in weight over 9 months . as there were only 23 patients with weight data at baseline and 12 months , these results are not presented . ( however , weight in these 23 patients decreased from 123.5  35.4 kg to 117.3  33.3 kg ) . in our patient population , patients receiving insulin were able to decrease their insulin doses by a mean of 15 units per day from an average of 85 units ; this may have contributed to the weight loss . several studies evaluating the addition of sglt-2 inhibitors to insulin therapy have reported similar reductions in insulin doses.812 finally , 59.5% of patients in this study received glp-1 analog therapy at baseline . bell recently published a case report of a patient with a 13.2 kg ( 11.8% ) weight loss over a 4-week period using glp-1 agonist therapy in combination with canagliflozin.14 this study did not demonstrate any significant reduction in mean systolic blood pressure ( sbp ) . in contrast , four of five of the cantata trials reported significant reductions in sbp , ranging from 2.9 to 5.1 mmhg . one explanation for the apparent lack of sbp reducing effect in this study could be the well - controlled sbp at baseline ( 124 mmhg ) . another reason for the apparent lack of sbp reduction in this study could be the fact that diuretic therapy was typically discontinued or the dose reduced by 50% at the initiation of canagliflozin therapy . this was done in an abundance of caution to prevent potential orthostasis from the osmotic diuretic response associated with canagliflozin therapy . comparable to the cantata studies , this study found a significant increase of hdl - c levels ( 3.5 mg / dl ; 0.091 mol / l ) with the treatment of canagliflozin . however , unlike the controlled clinical trials , this study found no changes in other lipid levels . in the cantata studies , canagliflozin use was associated with significant increases in non - hdl - c of 2.15.1 mg / dl ( 0.050.13 mmol / l ) ( 1.53.6% ) from a baseline of 140147 mg / dl ( 3.623.8 mmol / l ) , while ldl - c levels increased by 4.48.2 mg / dl ( 0.1140.212 mmol / l ) ( 4.58% ) , from a baseline of 104110 mg / dl ( 2.72.85 in contrast , baseline lipid levels in our patient population included a mean non - hdl - c of 114 mg / dl ( 2.95 mmol / l ) and ldl - c of 79 mg / dl ( 2.05 mmol / l ) . controlled clinical trials have identified the following as the most common adverse effects associated with canagliflozin use : female and male genital mycotic infections , urinary tract infections , pollakiuria , and thirst . these side effects are consistent with the mechanism of action of the drug . as a standard of practice , patients were typically counseled on appropriate medication administration and possible adverse reactions prior to the initiation of treatment . adverse drug effects were reported by 18.9% of this study population , and canagliflozin was discontinued by 15.3% of patients because of adverse events , with 11 of the 17 discontinuations ( 64.7% ) attributable to the common side effects listed above . one of these patients discontinued medication because of new - onset atrial fibrillation , which occurred within a week of drug initiation . weir et al reported changes in serum electrolytes , including a decrease in serum potassium , associated with the osmotic diuresis resulting from canagliflozin therapy.15 sglt-2 inhibition possesses a unique mechanism of action for the treatment of diabetes , addressing the last of the underlying defects of the ominous octet of t2 dm pathophysiology.2 in healthy individuals with a glomerular filtration rate of greater than 90 ml / min/1.73 m ( 1.5 ml / s/1.73 m ) , approximately 180 l of plasma are filtered through the kidneys each day , which translates to approximately 180 grams of filtered glucose daily . there is a proportional relationship regarding the amount of plasma glucose concentration and filtered glucose . all filtered glucose is reabsorbed until the resorptive capacity of the tubules is reached . in patients without diabetes , the renal threshold ( the blood glucose level at which glycosuria begins ) is approximately 180 mg / dl ( 10 mmol / l ) . in patients with t2 dm , the glucose renal threshold is approximately 240 mg / dl ( 13.3 mmol / l).16 sglt-2 inhibitor therapy resets the renal threshold to approximately 7090 mg / dl ( 3.95 mmol / l ) , and by doing so increases urinary glucose excretion in patients with hyperglycemia . this results in a decrease in plasma glucose , an osmotic diuresis , and a net caloric loss of approximately 400 kcal per day,11 thus promoting weight loss as well as a decrease in hba1c.17 sglt-2 inhibitors reduce fasting and post - prandial glucose levels and their unique pharmacologic mechanism of action is independent of insulin secretion . one would therefore expect it to be effective regardless of the duration of diabetes . because insulin levels are not increased with the use of sglt-2 inhibitors , they have a placebo - like risk of hypoglycemia when used alone or with diabetes medications that do nt cause hypoglycemia . canagliflozin was approved for use by the fda in march of 2013 and represents the first sglt-2 inhibitor approved in the us . first , cause and effect can not be established as this was not a prospective study . for example , this study did not control for diet , exercise , frequency of glucose monitoring , or timing of canagliflozin administration . although food does not affect bioavailability , taking canagliflozin before a meal may delay intestinal glucose absorption,18 thereby reducing postprandial hyperglycemia . ( non - study ) setting , a once - daily oral therapy could lead to less missed doses compared to oral medications or injections with multiple frequencies . fourth , this study consisted of a relative homogenous patient population , a predominately white ( 92.8% ) , middle - aged ( 59  9 years ) population of patients with long - standing ( 12  7 years ) diabetes . it is possible that the results demonstrated here may not be reflective of other , more diverse patient populations . finally , as data were collected by review of emr , only documented adverse effects were captured . in this pre - post observational study , canagliflozin therapy was associated with significant reductions in hba1c and weight , and a significant increase in mean hdl - c levels . canagliflozin was generally well tolerated with an adverse effect profile consistent with that reported in controlled clinical trials . overall , canagliflozin appears to be a useful therapeutic option in patients with t2 dm who are inadequately controlled on other anti - hyperglycemic agents .
objectiveto assess the real - world efficacy and safety of the first sodium - glucose cotransporter-2 inhibitor , canagliflozin , in the treatment of patients with type 2 diabetes mellitus ( t2dm).methodsthis observational study assessed the efficacy and tolerability of canagliflozin in t2 dm patients . 
 primary study outcomes were changes in hba1c and weight , and percentage of patients reporting adverse effects of therapy.resultsthe study criteria were met by 111 patient records . 
 baseline patient characteristics were : average age , 59  9 years ; mean duration of t2 dm , 11.9  7.3 years ; 57.6% of patients were male ; 92.8% were caucasian ; baseline bmi , 38.9  11 kg / m2 ; and mean baseline hba1c , 7.53 ( 58.8 mmol / mol )  1.08% . 
 hba1c and weight were significantly reduced by 0.37% and 4.4 kg , respectively . 
 adverse effects were reported by 21 patients , and 17 ( 15.3% ) discontinued canagliflozin because of adverse reactions.conclusioncanagliflozin was generally well tolerated and significantly reduced hba1c levels and body weight in patients with t2 dm when added to a regimen of other anti - hyperglycemic agents .