DPP-4 INHIBITORS (GLIPTINS)

DPP-4 inhibitors work by blocking the action of DPP-4, an enzyme which destroys the hormone incretin.

Incretins help the body produce more insulin only when it is needed and reduce the amount of glucose being produced by the liver when it is not needed. These hormones are released throughout the day and levels are increased at meal times. 

Medications in the DPP-4 inhibitor family

Generic or proper name	Brand or trade name
Sitagliptin	Januvia
Sitagliptin + Metformin	Janumet
Vildagliptin	Galvus
Vildagliptin + Metformin	Eucreas
Saxagliptin	Onglyza
Alogliptin	Vipidia
Alogliptin + Metformin	Vipdomet
Linagliptin	Trajenta
Linagliptin + Metformin	Jentadueto
Saxagliptin + Metformin	Kombolyze

Side effects

All medication has side effects and you should check the patient information leaflet (PIL) supplied with your medication to see which side effects you might experience from your particular medication. Remember that you are unlikely to experience all side effects that are listed, and you may not experience any at all. If you do, speak to your doctor as there may be another diabetes medication you could try instead. 

New Type 2 Diabetes Medications

Even if you can manage your diabetes now by just eating well and being active, you may need medication someday.

We've come far since the 1920s, when insulin was first used to treat diabetes. There's no magic pill yet, but you have more options than ever before to help control your blood sugar. And more are coming.

Sodium-Glucose Transporter 2 (SGLT2) Inhibitors

Most type 2 diabetes drugs work by helping your body make insulinor use it better. SGLT2 inhibitors are different because they don't have anything to do with insulin.

Your kidneys try to keep glucose, a kind of sugar your cells use for energy, out of your pee. Proteins called SGLTs make sure the glucose goes back into your body.

But with type 2 diabetes, if your blood sugar level is already creeping up, you don't need the glucose in your body. These pills turn off one of those proteins so that you pee it out instead.

• Canagliflozin (Invokamet, Invokana)
• Dapagliflozin (Farxiga, Xigduo)
• Empagliflozin (Jardiance)

SGLT2 inhibitors have some extra benefits, says John B. Buse, MD, PhD, director of the Diabetes Care Center at the University of North Carolina at Chapel Hill. "You're losing calories through urine, so there is weight loss -- usually about 5 to 10 pounds in 6 to 12 months."

When you take SGLT2 inhibitors, you lose a little bit of salt, too, which can help with your blood pressure.

These drugs aren't perfect, he says. "The downside is that, because there is sugar in your nether regions, women have a higher risk of yeast infections, and uncircumcised men can get foreskin infections."

To avoid the risk of dehydration, Buse says that elderly people withkidney disease and people who are taking diuretics, pills that make you pee out extra water, shouldn't take SGLT2 inhibitors.

Inhaled Insulin

The only inhaled insulin on the market is Afrezza. It's a fast-acting insulin, so you only take it at mealtimes. It comes in 4-unit and 8-unit cartridges that you pop into a small gadget, like the ones people withasthma use.

SGLT2 Inhibitors: A New Treatment Option for Type 2 Diabetes

Introduction
Diabetes mellitus is a chronic disease often requiring complex treatment regimens to prevent long-term complications.¹ In 2010, it was estimated that 18.8 million adults and children in the United States were diagnosed with diabetes and another 7 million went undiagnosed, with the prevalence of diabetes expected to increase significantly by 2050.^2,3 Various classes of medications have been approved by the FDA for the treatment of diabetes; however, few highly effective options are available with minimal adverse effects.¹ Thus, the search continues for improved diabetes therapies.

The FDA recently approved 2 medications from a novel class called sodium- glucose cotransporter 2 (SGLT2) inhibitors. This article will detail the characteristics of these agents, summarize the evidence leading to their approval, describe their current place in therapy, and discuss ongoing research involving this novel class.

SGLT2 Inhibition
Each day, approximately 180 g of glucose are filtered from the glomeruli of a healthy adult, and almost all of the filtered glucose is reabsorbed from the glomerular filtrate and returned to the circulation.⁴ Of the filtered glucose, 90% is reabsorbed in the bloodstream by the SGLT2, located primarily in the luminal membrane of the proximal renal tubules.⁵ The cotransportation of glucose and sodium from the filtrate is driven by the active transport of sodium out of the basolateral cells by the Na/K-ATPase pump.⁴Glucose is also transferred out of the cell with the concentration gradient and subsequently returned to the bloodstream by glucose transporters.

In type 2 diabetes mellitus (T2DM), renal glucose handling and transport is increased, likely due to upregulation of SGLT2. As a result, glucose excretion in the urine occurs only at higher plasma glucose levels, causing conservation of glucose and prolongation of hyperglycemia.⁴ Inhibition of SGLT2 activity reduces reabsorption of filtered glucose and lowers the blood glucose concentration at which glucose is no longer reabsorbed from the proximal tubule but is instead excreted. This concentration is known as the renal threshold for glucose.^6,7

Canagliflozin
On March 29, 2013, canagliflozin became the first SGLT2 inhibitor to be approved by the FDA; it is currently indicated as an adjunct to diet and exercise in adults with T2DM.⁶ Studies have shown glycemic control benefits, weight reduction, and systolic blood pressure lowering with monotherapy as well as in combination with other antihyperglycemic agents.

Online Table 2 summarizes the effects of canagliflozin in several clinical trials, which show that canagliflozin 100 mg and 300 mg once daily significantly reduced glycated hemoglobin (A1C) in T2DM patients who had not achieved adequate control with diet and exercise,⁸ metformin,⁹ sulfonylurea,¹⁰ combination metformin and sulfonylurea,¹¹ combination metformin and pioglitazone,¹² and insulin (at least 30 U daily of basal, bolus, or combination).¹³ Canagliflozin 100 mg and 300 mg have also been shown to significantly decrease fasting plasma glucose (FPG), weight, and systolic blood pressure (SBP) compare with placebo and compared with glimepiride⁹ and sitagliptin.¹⁴ Regarding A1C reduction in T2DM patients inadequately controlled on metformin, canagliflozin 100 mg demonstrated noninferiority to glimepiride9 and sitagliptin,¹⁴ while canagliflozin 300 mg demonstrated statistical superiority to glimepiride⁹ and sitagliptin.¹⁴ Canagliflozin 300 mg also demonstrated superiority to sitagliptin in reducing A1C in patients with T2DM uncontrolled with metformin and sulfonylurea.¹⁵

In clinical trials, adverse effects related to osmotic diuresis (pollakiuria, polyuria) and reduced intravascular volume (postural dizziness, orthostatic hypotension) as well as genital mycotic infections and urinary tract infections (UTIs) were higher with canagliflozin than placebo. Rates of hypoglycemia have been similar to placebo when canagliflozin is used as monotherapy⁸ and when added to combination metformin and pioglitazone.¹² Rates were also similar with canagliflozin compared with sitagliptin when added to metformin¹⁴ and when added to combination metformin and sulfonylurea.¹⁵ Higher rates of hypoglycemia occurred with canagliflozin versus placebo when added to sulfonylurea¹⁰ and combination metformin and sulfonylurea,¹¹ and when added to metformin significantly lower rates of hypoglycemia occurred with canagliflozin versus glimepiride.⁹

In T2DM patients with moderately impaired renal function (GFR ≥30 and <50 mL/min/1.73m²), canagliflozin 100 mg and 300 mg were found to significantly decrease A1C versus placebo (–0.33, –0.44, and –0.03 percentage points respectively); however, the extent of A1C reduction was less than what has been seen in previous canagliflozin studies of patients with normal or mildly impaired renal function.¹⁶In a study with T2DM patients 55 to 80 years of age, greater reductions in A1C were seen with canagliflozin in those <65 years of age (placebo-subtracted mean changes of –0.65 and –0.82 percentage points for 100 mg and 300 mg, respectively) compared with subjects ≥65 years of age (–0.45 and –0.5 percentage points, respectively).¹⁷

Dapagliflozin
A second SGLT2 inhibitor, dapagliflozin, was approved by the FDA on January 8, 2014, as an adjunct to diet and exercise to improve glycemic control in adults with T2DM.⁷ Studies have shown benefits in glycemic control, weight reduction, and SBP reduction with dapagliflozin monotherapy and in combination with other antihyperglycemic medications. Online Table 2 summarizes the results of these trials.

Table 2: Clinical Trial Outcomes for SGLT2 Inhibitors
Clinical Studies Summary – rate (p value)*
Canagliflozin6						Dapagliflozin7
Therapy	A1C (%)	FPG (mmol/L)	Weight (kg)	SBP (mmHg)	Hypoglycemia  (%)	Therapy	A1C (%)	FPG (mmol/L)	Weight (kg)	SBP (mm Hg)	Hypoglycemia (%)
Mono-therapy8 (100 mg and 300 mg, respectively)	-0.77 (p <.001) -1.03 (p <.001)	-1.5 (p <.001) -1.9 (p <.001)	-2.5 (p <.001) -3.4 (p <.001)	-3.3 (p <.001) -5.0 (p <.001)	3.6** 3.0**	Mono-therapy18(2.5 mg, 5 mg, and 10 mg, respectively)	-0.58‡ -0.77 (p = 0.0005) -0.89 (p <.0001)	-0.84‡ -1.34 (p <.001) -1.60 (p <.0001)	-3.3** -2.8** -3.2**	-4.6** -2.3** -3.6**	1.5** 0** 2.9**
Add-on to MET and PIO12 (100 mg and 300 mg, respectively)	-0.89 (p<.001) -1.03 (p <.001)	-1.5 (p <.001) -1.8 (p <.001)	-2.6 (p <.001) -3.7 (p <.001)	-5.3 (p <.01) -4.7 (p <.025)	4.4** 6.1**	Initiated in combo with MET19 (5 mg and 10 mg, respectively)	-2.05 (p<0.0001) -1.98 (p<0.0001)	-3.39 (p<0.0001) -3.35 (p <.0001)	-2.66 (p <.0001) -3.33 (p <.0001)	-2.9** -3.3**	2.6** 3.3**
Add-on to MET & SU11 (100 mg and 300 mg, respectively)	-0.85 (p <.001) -1.06 (p <.001)	-1.0 (p <.001) -1.7 (p <.001)	-2.1%¶ (p <.001) -2.6%¶  (p <.001)	-4.9‡ -4.3‡	33.8** 36.5**	Versus MET19 (5 mg and 10 mg, respectively)	-1.19** -1.45 (non-inferior to metformin)	-2.33** -2.58 (superior to metformin)	-2.61** -2.73 (superior to metformin)	-4.2** -4.0**	0** 0.9**
CAN 300 mg Versus SIT (Add-on to MET +SU)15	-1.03 (superior to SIT)	-1.7 (p <.001)	-2.3 (p <.001)	-5.1 (p <.001)	43.2 ** (40.7 with SIT)	Add-on to MET20 (2.5 mg, 5 mg, and 10 mg, respectively)	-0.67% (p = 0.0002) -0.7% (p <.0001) -0.84% (p<0.0001)	-0.99 (p = 0.0019) -1.19 (p <.0001) -1.30 (p <.0001)	-2.2 (p <.0001) -3.0 (p <.0001) -2.9 (p<0.0001)	-2.1** -4.3** -5.1**	2** 4** 4**
Versus SIT (Add-on to MET)14 (100 mg and 300 mg, respectively)	-0.73 (non-inferior to SIT) -0.88 (superior to SIT)	-1.5 (p <.001 vs. SIT) -2.0 (p <.001 vs. SIT)	-3.3 (p <.001 vs. SIT) -3.7 (p <.001 vs. SIT)	-3.5 (p <.001 vs. SIT) -4.7 (p <.001 vs. SIT)	6.8** 6.8** (4.1 with SIT)	Versus GLIP (Add-on to MET)21(2.5 mg – 10 mg data combined)	-0.52% (non-inferior to glipizide)	-1.24  (from baseline)** -0.20 (vs. glipizide)**	-3.22 (p <.0001 versus glipizide)	-4.3 (from baseline)** -5.0 (vs glipizide)**	3.5 (p <.0001 versus glipizide)
Versus GLIM (Add-on to MET)9 (100 mg and 300 mg, respectively)	-0.82 (non-inferior to GLIM) -0.93 (superior to GLIM)	-1.35** -1.52**	-3.7 (<.0001 vs GLIM) -4.0 (<.0001 vs GLIM)	-3.3** -4.6**	6 (p <.0001 vs. GLIM) 5 (p <.0001 vs. GLIM) (34 with GLIM)	Add-on to GLIM22(2.5 mg, 5 mg, and 10 mg, respectively)	-0.58 (p <.0001) -0.63 (p <.0001) -0.82 (p<0.0001)	-0.93‡ -1.18 (p <.0001) -1.58 (p <.0001)	-1.18 ( p= 0.1410) -1.56 (p = 0.0091) -2.26 (p<0.0001)	-1.1** -1.7** -2.8**	7.1** 6.9** 7.9**
Add-on to Insulin13  (100 mg and 300 mg, respectively)	-0.63 (p <.001) -0.72 (P <.001)	-1.0** -1.4**	-1.8% (p .001) -2.3% (p<0.001)	-5.1 (p <.001) -6.9 (p <.001)	49.3** 48.6**	Add-on to PIO23 (5 mg and 10 mg, respectively)	-0.82 (p = .0007) -0.97% (p <.0001)	-1.38  (p <.0001) -1.64 (p <.0001)	0.09 (p <.0001) -0.14 (p <.0001)	-0.8** -3.4**	2.1** 0**
Add-on to SU10 (100 mg and 300 mg, respectively)	-0.74 (p <.001) -0.83 (p <.001)	-1.4 (p <.001) -2.0 (p <.001)	-1.2 (p = 0.557) -2.4 (p <.025)	-3.5 (p = .975) -5.2 ( = .588)	4.1** 12.5**	Add on to Insulin and MET and/or a TZD24 (10 mg and 20 mg, respectively)	-0.61** -0.69**	-0.13** -0.53**	-4.5** -4.3**	-7.2** -6.1**	29.2** 25.0** (13% with placebo)
						Add on to insulin25 (5 mg and 10 mg, respectively	-0.96 (p <.001) -1.01 (p <.001)	-0.90 (p <.001) -0.94 (p <.001)	-1.00 (p <.001) -1.61 (p <.001)	-4.33** -4.09**	55.7** 53.6** (51.8 with placebo)

FPG = fasting plasma glucose, SBP = systolic blood pressure, MET = metformin, PIO = pioglitazone, SU=sulfonylurea, CAN = canagliflozin, SIT = sitagliptin, GLIM = glimepiride, GLIP = glipizide,
TZD = thiazolidinedione
Outcomes are reported as change from baseline unless otherwise noted.
^*P-values are versus placebo unless otherwise indicated. 
^**P-value not provided
^¶Change in kg was -1.9 for 100mg and -2.5 for 300mg but authors only provided p-value for % change in weight
^‡No significant difference versus placebo
 

In a phase 3 trial of T2DM patients inadequately controlled with diet and exercise, dapagliflozin significantly reduced A1C from baseline compared with placebo. This study included 2 exploratory cohorts, 1 studying evening dosing of dapagliflozin and 1 studying patients with a baseline A1C of 10.1% to 12%. The evening dose cohort saw similar reductions in A1C, FPG, and body weight to the primary cohort, with only 2.8% of patients complaining of nocturia. The high A1C cohort experienced greater reductions in A1C and fasting plasma glucose compared with the primary cohort, indicating that though these patients may present with preexisting glucosuria, dapagliflozin is still able to elicit a considerable improvement in T2DM control.¹⁸

Although it is currently only approved as monotherapy, dapagliflozin has been studied in combination with metformin,^19-21 glimepiride,²² pioglitazone,²³ and insulin (at least 30 U daily of basal, bolus, or both).^24,25 In each trial, dapagliflozin significantly reduced A1C compared with placebo or was found to be noninferior to the active control (metformin or glipizide). Dapagliflozin has also been shown to significantly decrease FPG and weight compared with placebo, metformin, and glipizide. When added to pioglitazone monotherapy, dapagliflozin attenuated pioglitazone-induced weight gain and edema.²³ Dapagliflozin 5 mg and 10 mg, added to insulin therapy with or without other oral antihyperglycemic drugs, decreased total daily insulin doses by 6.28 U/day and 6.82 U/day, respectively. 25 Total body weight decreased by up to 1.61 kg in the dapagliflozin groups compared with a weight gain of 0.43 kg in the placebo group.

In all trials, no clinically meaningful changes in electrolytes, renal function, or fasting lipid profiles were observed. Signs and symptoms suggestive of urogenital infections were more common in patients receiving dapagliflozin. However, these infections tended to be of mild to moderate severity, responded to standard treatments, and rarely led to drug discontinuation. In a long-term study, most urogenital infections occurred during the first year of treatment.²⁶

Current Place in Therapy
The American Association of Clinical Endocrinologists’ (AACE) Comprehensive Diabetes Management Algorithm 2013 Consensus Statement lists SGLT2 inhibitors as a monotherapy option for T2DM patients with A1C <7.5%, or as a dual- or triple-therapy option for patients with baseline A1C ≥7.5% or patients who did not reach their A1C goal after 3 months of noninsulin monotherapy. The consensus statement cites the ability of SGLT2 inhibitors to provide glucose lowering without weight gain or risk of hypoglycemia as justification for their recommendation. In patients where weight loss is a therapeutic goal, the AACE recommends using an SGLT2 inhibitor or a GLP-1 receptor agonist along with metformin and intensive lifestyle management in preference over other therapies that promote weight gain.²⁷ The most recent guidelines published by the American Diabetes Association do not address the use of SGLT2 inhibitors in the treatment of T2DM.¹

Both canagliflozin and dapagliflozin have been shown to increase the risk of genital mycotic infections and should be used with caution in uncircumcised males and patients with a history of infections. Caution should also be used in patients at higher risk of symptomatic hypotension due to intravascular volume depletion, such as those with renal impairment (eGFR <60 mL/min/1.73 m2), the elderly, patients with low SBP, or patients taking antihypertensives. Blood pressure, serum creatinine, and eGFR should be monitored at baseline and periodically throughout treatment.^6,7 Canagliflozin and dapagliflozin can increase hypoglycemia risk when used in combination with insulin or an insulin secretagogue; therefore, it may be necessary to decrease the insulin or insulin secretagogue dose when any of these medications are used in combination with an SGLT2 inhibitor. Increases in low-density lipoprotein (LDL) cholesterol (mean increase of 4.5% to 8% with canagliflozin⁶ and 2.9% with dapagliflozin⁷) have also been shown in studies with SGLT2 inhibitors; therefore, LDL should be monitored at baseline and periodically throughout treatment.^6,7

In addition, serum potassium levels should be monitored periodically after initiating canagliflozin in patients with impaired renal function and in patients predisposed to hyperkalemia. Doserelated increases in serum magnesium and phosphate have also been observed with canagliflozin and should be monitored with treatment as well.⁶

Newly diagnosed bladder cancer occurred more frequently in dapagliflozin patients in clinical trials. The dapagliflozin package insert recommends against its use in patients with active bladder cancer. In patients with prior history of bladder cancer, the unknown risks for cancer recurrence should be weighed against the beneficial effects of dapagliflozin.⁷

Future Directions
SGLT2 inhibitors are a fast-growing class of antidiabetic agents. Ipragliflozin is the first SGLT2 inhibitor approved in Japan. Empagliflozin has recently been approved in Europe and the United States.* Other SGLT2 inhibitors in development include ertugliflozin, currently in phase 3 trials, and remogliflozin, currently in phase 2 trials. There are also studies underway investigating SGLT2 inhibitor use in type 1 diabetes as well as their effects on long-term cardiovascular outcomes. Finally, there is a dual SGLT1/SGLT2 inhibitor currently in development, which theoretically inhibits intestinal absorption of glucose as well.

* Article has been updated since original publication.

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Jennifer L. Simon, PharmD, CPP, is PGY2 ambulatory care specialty resident at UNC Health Care. Sarah Timaeus is a PharmD candidate at the UNC Eshelman School of Pharmacy. Caron Misita, PharmD, BCPS, CDE, CPP, is a clinical pharmacist practitioner at UNC Medical Center Department of Pharmacy and assistant professor of clinical education at UNC Eshelman School of Pharmacy.

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References
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2.     Centers for Disease Control and Prevention. 2011 National Diabetes Fact Sheet. www.cdc.gov/diabetes/pubs/factsheet11.htm. Accessed May 23, 2014.
3.     Boyle JP, Honeycutt AA, Narayan KM, et al. Projection of diabetes burden through 2050: impact of changing demography and disease prevalence in the US. Diabetes Care. 2001;24(11):1936-1940.
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6.     Invokana [package insert]. Gurabo, PR: Janssen Ortho, LLC; 2013.
7.     Farxiga [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2014.
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9.     Cefalu WT, Leiter LA, Yoon KH, et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet. 2013;382(9896):941-950.
10.  Fulcher G, Matthews D, Perkovic V, et al. Canagliflozin in subjects with type 2 diabetes mellitus inadequately controlled on sulfonylurea monotherapy: a CANVAS substudy. Poster presented at the 73rd Scientific Session of the American Diabetes Association; Chicago, IL; June 21-25, 2013,.
11.  Wilding JP, Charpentier G, Hollander P, et al. Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial. Int J Clin Pract. 2013;67(12):1267-1282.
12.  Forst T, Guthrie R, Goldenberg R, et al. Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes on background metformin and pioglitazone. Diabetes Obes Metab. 2014;16(5):467-477.
13.  Matthews D, Fulcher G, Perkovic V, et al. Efficacy and safety of canagliflozin, an inhibitor of sodium glucose co-transporter 2, added on to insulin therapy with or without oral agents in type 2 diabetes. Poster presented at the 48th Annual Meeting of the European Association for the Study of Diabetes; Berlin, Germany; October 1-5, 2012.
14.  Lavalle-González FJ, Januszewicz A, Davidson J, et al. Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial. Diabetologia. 2013;56(12):2582-2592.
15.  Schernthaner G, Gross JL, Rosenstock J, et al. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week randomized trial. Diabetes Care. 2013;36(9):2508-2515.
16.  Yale JF, Bakris G, Cariou B, et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab. 2013;15(5):463-473.
17.  Bode B, Stenlöf K, Sullivan D, Fung A, Usiskin K. Efficacy and safety of canagliflozin treatment in older subjects with type 2 diabetes mellitus: a randomized trial. Hosp Pract. 2013;41(2):72-84.
18.  Ferrannini E, Ramos SJ, Salsali A, Tang W, List JF. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care. 2010;33(10):2217-2224.
19.  Henry RR, Murray AV, Marmolejo MH, et al. Dapagliflozin, metformin XR, or both: initial pharmacotherapy for type 2 diabetes, a randomized controlled trial. Int J Clin Pract. 2012;66(5)446-456.
20.  Bailey CJ, Gross JL, Pieters A, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequately glycemic control with metformin: a randomized, double-blind, placebo-controlled trial. Lancet. 2010;375(9733):2223-2233.
21.  Nauck MA, Del Prato S, Meier JJ, et al. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care. 2011;34(9):2015-2022.
22.  Strojek K, Yoon KH, Hruba V, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycemic control with glimeperide: a randomized, 24-week, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2011;13(10):928-938.
23.  Rosenstock J, Vico M, Wei L, Salsali A, List JF. Effects of dapagliflozin, an SGLT2 inhibitor, on HbA(1c), body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy. Diabetes Care. 2012; 35(7):1473-1478.
24.  Wilding JP, Norwood P, T’joen C, et al. A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin sensitizers: applicability of a novel insulin-independent treatment. Diabetes Care. 2009;32(9):1656-1662.
25.  Wilding JP, Woo V, Soler NG, et al. Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial. Ann Intern Med. 2012;156(6):405-415.
26.  Bailey CJ, Gross JL, Hennicken D, et al. Dapagliflozin add-on to metformin in type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled 102-week trial. BMC Med. 2013;11:43.
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FDA Drug Safety Communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood

Safety :

The U.S. Food and Drug Administration (FDA) is warning that the type 2 diabetes medicines canagliflozin, dapagliflozin, and empagliflozin may lead to ketoacidosis, a serious condition where the body produces high levels of blood acids called ketones that may require hospitalization. We are continuing to investigate this safety issue and will determine whether changes are needed in the prescribing information for this class of drugs, called sodium-glucose cotransporter-2 (SGLT2) inhibitors.

Patients should 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. Do not stop or change your diabetes medicines without first talking to your prescriber. Health care professionals should evaluate for the presence of acidosis, including ketoacidosis, in patients experiencing these signs or symptoms; discontinue SGLT2 inhibitors if acidosis is confirmed; and take appropriate measures to correct the acidosis and monitor sugar levels.

SGLT2 inhibitors are a class of prescription medicines that are FDA-approved for use with diet and exercise to lower blood sugar in adults with type 2 diabetes. When untreated, type 2 diabetes can lead to serious problems, including blindness, nerve and kidney damage, and heart disease. SGLT2 inhibitors lower blood sugar by causing the kidneys to remove sugar from the body through the urine. These medicines are available as single-ingredient products and also in combination with other diabetes medicines such as metformin (see Table 1 below). The safety and efficacy of SGLT2 inhibitors have not been established in patients with type 1 diabetes, and FDA has not approved them for use in these patients.

A search of the FDA Adverse Event Reporting System (FAERS) database identified 20 cases of acidosis reported as diabetic ketoacidosis (DKA), ketoacidosis, or ketosis in patients treated with SGLT2 inhibitors from March 2013 to June 6, 2014 (see Data Summary). All patients required emergency room visits or hospitalization to treat the ketoacidosis. Since June 2014, we have continued to receive additional FAERS reports for DKA and ketoacidosis in patients treated with SGLT2 inhibitors.

DKA, a subset of ketoacidosis or ketosis in diabetic patients, is a type of acidosis that usually develops when insulin levels are too low or during prolonged fasting. DKA most commonly occurs in patients with type 1 diabetes and is usually accompanied by high blood sugar levels. The FAERS cases were not typical for DKA because most of the patients had type 2 diabetes and their blood sugar levels, when reported, were only slightly increased compared to typical cases of DKA. Factors identified in some reports as having potentially triggered the ketoacidosis included major illness, reduced food and fluid intake, and reduced insulin dose.

We urge health care professionals and patients to report side effects involving SGLT2 inhibitors to the FDA MedWatch program, using the information in the “Contact FDA” box at the bottom of the page.

Table 1. List of SGLT2 inhibitors

Brand name	Active ingredient(s)
Invokana	canagliflozin
Invokamet	canagliflozin and metformin
Farxiga	dapagliflozin
Xigduo XR	dapagliflozin and metformin extended-release
Jardiance	empagliflozin
Glyxambi	empagliflozin and linagliptin

SC bars Glenmark from selling copies of Merck diabetes drugs: Sources

The Supreme Court has blocked Glenmark Pharmaceuticals Ltd (GLEN.NS) from selling copies of US drugmaker Merck & Co Inc's (MRK.N) diabetes drugs Januvia and Janumet, sources with knowledge of the matter said after a court hearing on Friday.

The court has, however, allowed Glenmark to continue to sell existing inventory, the sources said.

Merck sued Glenmark in 2013 for infringing a patent it has on sitagliptin, the chemical compound in Januvia and Janumet. Glenmark sells the medicines under the brand names Zita and Zita-met.

(Reuters)

Glenmark gets USFDA approval to sell Rufinamide

Glenmark Pharmaceuticals on Thursday said it has been granted tentative approval by the US health regulator to sell Rufinamide, which is used to treat seizures caused by Lennox-Gastaut syndrome.

Lennox-Gastaut syndrome is a form of childhood-onset epilepsy.

"Glenmark...has been granted tentative approval last week by the United States Food and Drug Administration (USFDA) for its Rufinamide tablets," the company said in a Bombay Stock Exchange (BSE) filing.

The approval has been granted for the tablets in 200 mg and 400 mg strengths. Rufinamide is a therapeutic equivalent of Banzel tablets of Eisai.

Glenmark further said: "Under the terms of a settlement agreement between Glenmark and Eisai, Glenmark will be permitted to market this product in the US on May 30, 2022 or potentially earlier under certain circumstances."

Citing IMS Health sales data, the pharma firm said that "for the 12 month period ending March, the Banzel market achieved annual sales of approximately $ 121.8 million."

Glenmark's current portfolio consists of 96 products authorised for distribution in the US marketplace and 68 ANDAs (Abbreviated New Drug Application) pending approval with the FDA.

"In addition to these internal filings, Glenmark continues to identify and explore external development partnerships to supplement and accelerate the growth of its existing pipeline and portfolio," the company added.

Shares of Glenmark Pharmaceuticals were trading at Rs 902.65 apiece in the morning trade, down 0.48 per cent on the BSE.

Govt plans to provide essential medicines at 60% lower rates

The Centre is planning to provide essential medicines at 40-60 per cent lower rates through its 'Jan-Aushdi' medical stores, Union Minister Ananth Kumar said on Friday.

"In the last one year, more than 300 life saving medicines which are used to treat diseases such as cancer, AIDS and other, the Modi government has brought them under drug price control," the Minister of Chemicals and Fertiliser said.

There are also plans to reduce the prices of medicines, the Minister said. The department of pharmaceuticals comes under his ministry.

"We are planning to increase the total number of Jan-Aushdi stores to 3,000, and at these stores essential medicines will be provided at 40 per cent, 50 per cent and 60 per cent lower rates," Kumar said at an event organised by news channel Aaj Tak.

The minister also said that urea prices have not been increased and there will not be any hike in next four years.

"In the coming four years, there will not be any increase in urea prices. And keeping the prices at Rs 5,360 per tonne, we will increase the domestic production of fertilisers," he said.