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αグルコシダーゼ阻害剤は、SGLT2阻害剤との相性がよい薬剤である。(ASSD, p0072, 2015)

Alpha-glucosidase inhibitor is suitable as combination therapy of SGLT2 inhibitor in Japanese patients with type 2 diabetes: (ASSD, p0072, Hong Kong,2015)

 

According to open-label study of dapagliflozin (1), three drugs reduced HbA1c than other oral hypoglycemic agents or GLP1 injection therapies.One is alpha-glucosedase inhibitor (aGI), the other is glinide, and the third is pioglitazone.

 

 

The reason why alpha-GI(aGI) is so effective has not been clarified.SGLT2i is characterized as having effect of lowing and stabilizing fasting blood glucose. However, patients are likely to have compensatory over-eating (COE) (2). Therefore, we speculate thatpostprandial hyperglycemia in the morning is emphasized.

According to the phase III study of luseogliflozin (3) even though blood glucose curve of SGLT2i after eating meal is lower than that of placebo curve, hyperinsulinemia remains.Therefore, when miglitol is added, we hypothesize that the hyperinsulinemic state will be alleviated to normal state, thereby leading to normal insulin secretion curve and helping to reduce insulin resistance.

In addition, aGI, especially, miglitol, has more beneficial effect practically. It has a potential effect to induce mild diarrhea for some persons. SGLT2i, especially the product which has high selectivity to SGLT2 but not SGLT1, has potential effect to have constipation. Therefore, miglitol theoretically alleviates the tendency of constipation of high selective SGLT2i.

 

 

 

Furthermore at our clinic, the complaints of gas, which is the side effect of aGI, seems to be reduced.

We hypothesized that, because patients who received SGLT2i therapy are likely to go toilet frequently due to polyuria, they can fart in the toilet at the same time.

This time synergistic effect can let the patients not to suffer from the social trouble of fart, thereby making this adverse effect to be felt not so severe troublesome.Thus, after SGLT2i treatment, miglitol has gained more attractive effect, by having the synergistic effect to suppress the postprandial hyperglycemia in the morning and by alleviating the constipation, with less worry about the trouble of fart.

 

References

1.    Kaku K, et al. Dapagliflozin as monotherapy or combination therapy in Japanese patients with type 2 diabetes: an open-label study. Diabetes Ther. 5:415-33, 2014

2.  Suzuki Y.  Compensatory overeating (COE) could be a problem of diabetes diet education after sodium-glucose co-transporter 2 inhibitor treatment. The 6th international conf. on fixed combination of hypertension, dyslipidemia and diabetes, p18, 2015

3.    Seino Y et al. Efficacy and safety of luseogliflozin as monotherapy in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled, phase 3 study. Curr Med Res Opin. 30:1245-55. 2014

 

PS.

SGLT2阻害剤を服用すると頻尿になり、トイレにいく回数が増える。トイレにいけば、αグルコシダーゼ阻害剤の放屁が気にならなくなってしまう。

 

SGLT2阻害剤を服用すると、QOL(生活の質)は、著しく向上する。(ASSD, p0041, 2015)

Objectives: To know the QOL change and adverse effect after the SGLT2i treatment, we examined the questionnaire in Japanese.

Method: 188 patients  who had taken SGLT2i treatment and 369 patients who had not taken the treatment were subjected. They were examined by questionnaire regarding QOL and adverse effect. This study was conducted during November to December of 2014 in Tokyo.

Result: Between the two groups, there were not significant differences of frequency in the improved QOL items such as, intimacy in the family (3.2% vs.2.4%), performance of work (6.4% vs. 3.5%), social activity(1.1% vs. 1.4%), physical wellness(11.2% vs. 6.8%), everyday activities(6.9% vs. 4.9%), and exchanges with friends(3.2% vs. 2.2%). However, in SGLT2i-treated groups, frequencies of self-esteem(3.2% vs. 0.6%) and emotional wellness(4.3% vs. 1.1%) were significantly higher than SGLT2i non-treated group (p<0.05).

 

 

As for eating habit, compensatory overeating (COE) was significantly higher in SGLT2i-treated group (19.7%) than SGLT2i non-treated group (10%, p<0.05).

 

 

Negligence state was significantly higher in SGLT2i group (30.3%) than in SGLT2i non-treated group(16.5%). As for adverse effect,

Dry mouth (4.8% vs. 0.8%) and frequent urination(8% vs. 3.8%)were significantly higher in SGLT2i group than SGLT2i non-treated group.

 


Conclusion: SGLT2i treatment has an enough advantage for improving the QOL of diabetes patients, especially in self-esteem and emotional wellness.

Also, frequency of COE together with Negligence state is highly found in the group under SGLT2i therapy, which possibly leads to weight stability.

The patients of diabetes are likely to be satisfied with this SGLT2i treatment, because they can eat more than before as they like, even sometime they become negligent. This change of life style leads to the improvement of self esteem and emotional wellness.

 

In Conclusion;despite that this therapy of SGLT2i has some adverse effect like dry mouth and frequent urination, the improvement of QOL is more valuable for the patients’ long-term way of life.

 

SGLT2阻害剤の夜間頻尿を抑えるには、ベタニスを追加処方が、著効する。(ASSD, p0040, 2015)

 The efficacy of combined treatment with standard doses of tofogliflozin and mirabegron for old diabetes men with nocturia.

 

The sodium-glucose co-transporter 2 (SGLT2) inhibitors represent novel therapeutic approaches in the management of type 2 diabetes mellitus. Several compounds are already available in many countries (dapagliflozin, canagliflozin, empagliflozin, ipragliflozin, luseogliflozin and tofogliflozin) . Among them, plasma half-life of tofogliflozin is shorter. The half-life (t1/2) of tofogliflozin is 5.4 hour, while that of other SGLT2 inhibitors are over 10 hours. The short half-life of tofogliflozin may provide clinical benefits compared to other SGLT2 inhibitors from the viewpoint of risk reduction of nocturnal hypoglycemia,nocturnal increase of urine volume, and frequency of nocturnal urination (1,2)

The drugs (solifenacin, isoproterenol and mirabegron) have urinary bladder contraction effect. Mirabegron is used for the treatment of symptoms associated with overactive bladder syndrome. It selectively stimulates the β3 -adrenoreceptor, which relaxes the detrusor muscle. This improves urine storage by distension of the bladder body.One of side effects of SGLT2 inhibitors is dry mouth. In addition, common side-effects of solifenacin were dry mouth and constipation. Due to this reason, mirabegron is better treatment for diabetic patients under SGLT2 inhibitors treatment than solifenacin.

Therefore, to suppress frequency of nocturnal urination caused by SGLT2 inhibitors treatment, we examined the efficacy of combined treatment with standard doses of tofogliflozin and mirabegron. In result, two cases provided satisfactory therapeutic effect and improved nocturia. 

 

Case 1:

 72 y/o man. Height was 175cm, and weight was 70 kg. Duration of diabetes was 11 years.

After taking tofogliflozin 20 mg, and after taking mirabegron 50 mg, his nocturia relieved promptly.

 

Case 2:

73 y/o man. Height was 183 cm, and weight was 69 kg. Duration was 9 years.

After taking tofogliflozin 20 mg, and after taking mirabegron 50 mg, his nocturia relieved promptly.

 

These two cases suggested a solution that diabetic patients under SGLT2 inhibitor treatment can safely receive the merit without worrying about the increase of frequency of nocturnal urination. To our knowledge, the efficacy of combined treatment with standard doses of tofogliflozin and mirabegron is a new finding in the treatment of SGLT2 inhibitor treatment for old men who are suffering from overactive bladder and/or nocturia.

 

References

1) Life Style Medicine vol.9 no.1 2015(in Japanese)

2) Sanofi, Aleway 20mg Tablet (Tofogliflozin Hydrate), CTD, March, 2014:Phase Ⅰstudy, CSG010JP study, in Japanese   Online: Available from URL:http://www.pmda.go.jp/drugs/2014/P201400036/index.html

 

 

SGLT2阻害剤ではHbA1cか、体重かの、どちらかが改善する。(ASSD, p0043, 2015)

 Retrospective postmarket result of Sodium Glucose Transporter 2 inhibitor (SGLT2i) therapy in Japanese, targeting HbA1c improvement and Weight reduction

 

Objectives

Premarket clinical trial of dapagliflozin suggested that dapagliflozin has attained the improvement of HbA1c and/or weight with high percentage in Japanese.

We aimed to confirm the effect of SGLT2i therapy at the postmarket diabetes department.

Method

Among the diabetes patients at our clinic, we examined retrospectively the result of HbA1c and weight loss towards the patients who had continued the treatment of SGLT2i therapy for over six months.

Result

In result, 136 patients of diabetes were subjected. After three months of SGLT2i therapy (by ipragliflozin, luseogliflozin, dapagliflozin or tohogliflozin ) , HbA1c improved by 0.7% and weight reduced by 2.4kg on average. Percentage of the group who had both reduced HbA1c and reduced weight was 70.6%. Percentage of the group who had reduced HbA1c but not reduced weight was 7.4%. Percentage of the group who had reduced weight but not reduced HbA1c was 20% . Percentage of no reduction of weight and HbA1c was 2.2%. Hence, 97.8% improved the improvement of HbA1c and/or weight.

 

After six months of SGLT2i therapy, HbA1c improved by 0.8% and weight reduced by 3.0kg on average. Percentage of the group who had both reduced HbA1c and reduced weight was 53.7%. Percentage of the group who had reduced HbA1c but not reduced weight was 10.3%. Percentage of the group who had reduced weight but not reduced HbA1c was 31.6%. Percentage of no reduction of weight and HbA1c was 4.4%. Hence, 95.6% improved the improvement of HbA1c and/or weight.

 

Conclusion

This study confirmed the premarket data of dapagliflozin trial are right in terms of that SGLT2i therapy promises the improvement of HbA1c or weight reduction with the hope over 95%. Also the difference of three months data and six months data suggests that weight reduction is more sustainable than the improvement of HbA1c. The both improvement of HbA1c and weight reduction is likely to go weak with time. Therefore, SGLT2i treatment has more promising future effect on weight reduction rather than HbA1c reduction. As for the mechanism, we previously reported that SGLT2i treatment is likely to induce compensatory overeating (COE), which hampers the reduction of extreme weight loss as well as the improvement of HbA1c. We speculate that COE might trigger the worsening of HbA1c, thereby reducing the percentage of patients who maintained the improvement of HbA1c.

 

" Set Point Change " Hypothesis を世界で最初に提言。(ASSD, p0061, 2015)

 Compensative Hyper-Insulinemia caused by Chronic Treatment of SGLT2 inhibitor:.A proposal of “ Set Point Change” Hypothesis.

 

We previously reported that Compensative overeating (COE) could be a trouble to counteract the weight-loss caused by sodium glucose co-transporter 2 inhibitor (SGLT2i) (1). Thereafter, we added that predisposition of food shifted mainly to carbohydrate.

 However, not all the patients do not have COE. Therefore, we should consider other different mechanism to solve the question why the weight of patients gets stable after chronic treatment of SGLT2i.  In literature, 4-weeks trial of empagliflozin indicated that after meal ingestion, glucose and insulin AUC decreased, whereas the glucagon response increased. Insulin sensitivity was improved. In the article, the authors (Ele Ferrannini, et al.) defined that the 4 weeks observation is “chronic” observation (2).

  However, in Japanese, looking back to the result of clinical trial with luseogliflozin, there were no differences in AUC of plasma insulin concentration between baseline and 24 weeks (3). Glucose AUC decreased, but insulin AUC did not decreased. Insulin AUC was almost the same as baseline. This is in contrast to that of 4-weeks observation.

Therefore, these facts suggest that, in Japanese, COE and/or compensatory hyperinsulinemia mainly to carbohydrate must have occurred during 6 months chronic trial period.

  Theoretically, compensatory overeating can induce insulin secretion from pancreas, leading to hyperinsulinemia. The hyperinsulinemia suppresses the hyperglycemia, leading to glycemic control. This is in contrast to the hyperinsulinemia based on the insulin resistance of obese type 2 diabetes.

 We hence hypothesize that seemingly similar two hyperinsulinemias are different in the meaning of the phenomena based on insulin resistance or the phenomena based on COE and/or carbohydrate predispositional food change after SGLT2i treatment.

   And compensatory postprandial temporary hyperinsulinemia on chronic phase of SGLT2 treatment might be an essential effect to keep body weight balance stable, despite the chronic constant loss of energy in urine.

We propose this new idea to be called as "Set Point Change” Hypothesis.

 

 

1.Suzuki Y. Compensatory Overeating (COE) could be a Problem of Diabetes Diet Education after Sodium-Glucose Co-Transporter 2 Inhibitor Treatment. The 6th International Conference on Fixed Combination in the Treatment of Hypertension, Dyslipidemia and Diabetes Mellitus, Berlin, Germany : P 18 、2015. 

2.Ele Ferrannini, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. The Journal of clinical investigation 124: 499- 508 , 2-14

3. Seino Y, et al. Efficacy and safety of luseogliflozin as monotherapy in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled, phase 3 study.Curr Med Res Opin. 30:1245-55, 2014

 

手根管症候群はSGLT2阻害剤で改善し、秋になって悪化した事象。(ASSD, p0081, 2015)

 

 A Case of Type 2 Diabetes whose symptoms of carpal tunnel syndrome improved after taking SGLT2 inhibitors during Spring and Summer, but the symptom recurred in Autumn.

 

Carpal tunnel syndrome (CTS) is known to be more prevalent in diabetic patients than in non-diabetic population 1). Sodium-glucose co-transporter 2 inhibitor (SGLT2i) is a medication for glycemic control. We experienced a patient of type 2 diabetes,who had an interesting episode of seasonal variation for the efficacy of SGLT2i on CTS symptoms. Her symptoms of CTS improved dramatically after SGLT2i treatment during spring and end of summer (from Apr 2014 till Nov 2014), while they recurred in autumn (from Nov 2014). 

Sixty-five years of old, female, 154.4cm height, 57.4kg body weight (BMI: 24.2),was diagnosed to have type 2 diabetes at age 55.

She had been treated with sitagliptin 100mg/day with moderate glycemic control. HbA1c was around 6.7% before SGLT2i treatment.  Definite diagnosis of CTS was made two years ago by her manifestation of Tinel's sign, Phalen maneuver, hand pain, tingling, numbness and sleep disturbances. Because the symptoms were not relieved for long time, she was recommended surgical intervention for her hands.

However, after SGLT2i medication(either of ipragliflozin 50mg/day, luseogliflozin 2.5mg/day, tohogliflozin 20 mg/day, or dapagliflozin 5 mg/day) during from spring to end of summer (from 23th Apr 2014 till 15th Nov 2014), symptoms of CTS (such as pain and numbness) in both hands and sleep disturbance have improved dramatically and disappeared.

During the period of SGLT2i treatment, HbA1c became 6.3% and sustained its good glycemic level thereafter. However, after Nov 2014, the symptoms of CTS recurred.  As for the mechanism, we speculate that SGLT2i has a beneficial effect by reducing the body fluid volume 2), thereby releasing the pressure on the strangulated nerves to alleviate the CTS symptoms.

The same pathogenetic mechanism was already recognized by that diuretics is effective as conservative treatment of CTS 3).

Alternatively, the improved glycemic control might have contributed to the improvement of peripheral nerve diabetic neuropathy, leading to the alleviation of CTS symptoms.

Interestingly, the recurrence in the autumn strongly supports the former speculation, since it occurred under the treatment of SGLT2i treatment with good glycemic control.In summer, body fluid volume tends to decrease under STLT2i treatment and in part due to much sweating.

 In contrast, when the weather becomes cold in autumn, body fluid volume should be likely to increase.

In summer, body fluid volume tends to decrease under STLT2i treatment and in part due to much sweating. In contrast, when the weather becomes cold in autumn, body fluid volume should be likely to increase. The worsening of CTS symptoms may therefore be explained by the increased body fluid volume, which increased the pressure on the strangulated nerves.Thus, the above episode supports a hypothesis that body fluid volume effect of SGLT2i and seasonal variation of temperature are associated with the changing pressure on the strangulated peripheral nerves in diabetes and the wane and waxing of CTS symptoms.So far, similar case has not been reported in the literature.

 In conclusion, we propose that SGLT2i can be one of the choices for the oral conservative treatment of CTS with diabetes. Although other conservative treatment of CTS, such as steroids 4) or diuretics produce side-effects like induction of hyperglycemia, SGLT2i with diuretic properties has a big advantage without side effect to glycemic control 5).

 

 

References

1)Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM, Wilson DM, O'Brien PC, Melton LJ 3rd, Service FJ.The prevalence of staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study. Neurology 43:817-824, 1993

2) Rosenstock JVico MWei LSalsali AList JF. Effects of dapagliflozin, an SGLT2 inhibitor, on HbA1c, body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy. Diabetes Care. 35:1473-8, 2012

3) Piazzini DB et al. A systematic review of conservative treatment of carpal tunnel syndrome. Clin Rehabil. 21:299-314, 2007

4) Ashworth NL, et al. Effectiveness of second corticosteroid injections for carpal tunnel syndrome. Muscle Nerve. 48:122-6, 2013

5) Lambers Heerspink HJ, et al. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab 15:853-62, 2013

 

SGLT2阻害剤が惹起する皮膚障害に対する一考察。(ASSD, p0057, 2015)

A consideration of skin complication caused by treatment of SGLT2 inhibitor in Japanese

In Japan, skin disorders of SGLT2 inhibitors (SGLT2i) have been reported so many in the spring of 2014. We previously reported skin disorders in 17 cases (12%) among 142 cases 1). It became uproar, because the disorders such as eruptions occur in a short period of time after oral administration.

Several coincidences give us hints to solve the mechanism.

First; SGLT2i was released first from ipragliflozin  which is prone to cause skin disorders than other SGLT2i products. Recent study revealed that ipragliflozin remains in the skin with high concentration than other SGLT2i such as dapagliflozin,tofogliflozin and leseogliflozin 2).

Second; Drug eruption that occurs from the first day of oral one tablet suggests that allergic predisposition due to other certain environmental causes might have been potentially existed. SGLT2i might only became a trigger which makes the potential type I skin allergy apparent.

 

Third; According to the reports from pharmaceutical companies, skin disorder incidence after SGLT2i prescription has decreased over the autumn and winter from the summer, suggesting that the SGLT2i associated skin disorder has seasonal variation in Japan.

 

 

 Interestingly, cypress dermatitis occurs during the spring season and PM2.5 dermatitis occurs from spring season to summer.

Hence, we speculate that the coincidences of the below elements induced the uproar. The first release of ipragliflozin possibly makes skin disorder apparent socially.

Cypress dermatitis by and PM2.5 dermatitis overlapped during the released season of SGLT2i products, thereby making this accidence severe socially.

In 2015, skin disorder from spring to summer has not become uproar unlike 2014. However, at our clinic, skin disorder matched the timing of cypress dermatitis and PM2.5 dermatitis period. These facts confirm us that, when we discuss about the skin disorder of SGLT2i, we should consider the timing of cypress dermatitis and PM2.5 dermatitis.

In conclusion, as Asian dust problem, PM2.5 has been recently reported about the correlation between the type I skin allergy, which become a social problem.

 It is hence easy and logically assumed that the PM2.5 causes health damage from 2013. This will help us to understand why the skin disorder by SGLT2i is so specifically seen in Japanese at 2014, compared with Caucasians.

 

 

Ref

1)Diab.Res.Clic. Prac. 106, sup1:272, 2014
2)Japan Diabetes Society, Scientific meeting, yamaguchi, 2015: poster I-P-43

    (in Japanese; SGLT2阻害剤のラット皮膚組織移行性の比較:糖尿病,  

    58(S1), S173, 2015 )

 

 

ピオグリタゾンによる下腿静脈欝滞性皮膚炎にSGLT2阻害剤が著効した症例。(ASSD, p0144, 2015)

A Case of Type 2 Diabetes who improved severe leg edema and skin complication by treatment of SGLT2 inhibitors.

 

In the treatment of diabetes, by oral administration of pioglitazone, lower leg edema is observed frequently. Women are likely to complicate the leg edema.

We experienced a patient who had a lesion that showed festering skin and the stagnant vein depression phenomenon, complicated by dermatitis.

78-year-old woman. Duration of diabetes was 24 years. She has been under insulin therapy with pioglitazone. With pioglitazone, her HbA1c had dramatically improved. The best level of recent HbA1c was 5.8%. However, leg edema occurred not only due to pioglitazone, but also due to sleep apnea syndrome. The leg edema was also resistant to diuretics. Lower leg edema did not improve by furosemide 40mg and by mix of hydrochlorothiazide 12.5mg and losartan potassium 50mg.

 

Fig.1

Surprisingly, after administration of ipragliflozin 50mg, one of SGLT2 (sodium glucose co-transporter 2) inhibitors, leg edema disappeared in two weeks.

Dermatitis improved, and purulent lesions also improved. Several other SGLT2 inhibitors such as depagliflozin have same effect on the improvement of dermatitis.

 

Fig.2

Conclusion

Although a single case report is insufficient to determine pathogenesis, the present case does suggest the beneficial effect of SGLT2 inhibitor, on skin complication caused by leg edema due to pioglitazone and/or sleep apnea syndrome.

 

References:

1.Mudaliar S, et al. : Thiazolidinediones, peripheral edema, and type 2 diabetes: incidence, pathophysiology, and clinical implications. Endocr Pract. 9:406-16, 2003

2. Abbade LP et al. : Venous ulcer: clinical characteristics and risk factors. Int J Dermatol. 50:405-11, 2011

3. Ely JW et al. : Approach to leg edema of unclear etiology. J Am Board Fam Med. 19:148-60, 2006

 

 

ダパグリフロジンとカナグリフロジンとの間において第3相試験の比較結果 (ASSD, p0121, 2015)

 

Results of Phase III trials suggest the difference of SGLT2/ SGLT1 inhibition between Dapagliflozin and Canagliflozin in Japanese Type 2 diabetes patients

 

 A phase III trial of dapagliflozin (52weeks) in Japanese Type 2 diabetes (T2DM) patients indicates a significant decrease of HbA1c in combination with alpha-glucosidase (a-GI), thiazolidinedione (TZD), or glinide (GLD). The reduction was -0.81% with a-GI, -0.86% with TZD, and -0.76% with GLD.

The data suggest that dapagliflozin has synergistic effect with post prandial glucose regulator like a-GI and GLD, and with insulin sensitizer like TZD (1).

 A phase III trial of canagliflozin (52weeks) in Japanese T2DM patients indicates a significant reduction of HbA1c in combination with DPP-4 inhibitor (DPP-4i), TZD, or GLD. The reduction was -1.04% with DPP-4i and TZD, and -1.06% with GLD. Compared with dapagliflozin, canagliflozin seems to have more synergistic effect with DPP4i than with a-GI in reducing HbA1c (2).

 Canagliflozin has a suppressive effect against postprandial glucose, compared with dapagliflozin (3). Theoretically, in the case of canagliflozin, because of low-potency SGLT1 inhibition, the non-renal (intestinal) effect may also be considered, which may contribute to better control of postprandial hyperglycaemia.

In literature, so far, this contribution remains to be better analyzed in humans. However, when we look at the results of phase III trials in Japanese T2DM patients, the difference seems to be apparent.

 Namely, because of low-potency SGLT1 inhibition, canagliflozin has an effect to increase plasma active GLP-1 concentration (4). As for GLP-1, miglitol is well known to enhance GLP-1 secretion by delaying the absorption of glucose in upper intestine (5). Therefore, canagliflozin has both SGLT2i effect plus non-renal (intestinal) effect like miglitol, which can induce the anorectic effects (similarly to incretin-based therapies), leading to better glycemic control. As is shown in a phase III trial of canagliflozin, the beneficial synergistic effect with DPP4i suggests that canagliflozin has a-GI-like anorectic effects similarly to miglitol. In addition, the less reduction of HbA1c by canagliflozin when administered with a-GI suggests that the intestinal effect of calagliflozin offsets the synergistic effect of a-GI.

 In conclusion, phase III trials of dapagliflozin and canagliflozin suggest the importance of their difference of SGLT2/SGLT1 inhibition in humans. The difference is obviously indicated as we compare the synergistic and offset effect when they are administered with a-GI and with DPP4i.

 

References

1. Diabetes Ther 5:415-33, 2014

2. J Diabetes Investig 6:210-8, 2015

3. Diabetes Obes Metab 17:188-97, 2015

4. J Pharmacol Sci 127:456-61, 2015

5. Diabet Med 26:187-8, 2009