Journal of Diabetes Mellitus, 2015, 5, 211-226
`Published Online November 2015 in SciRes. http://www.scirp.org/journal/jdm
`http://dx.doi.org/10.4236/jdm.2015.54026
`
`Sulfonylurea Glimepiride: A Proven Cost
`Effective, Safe and Reliable War Horse
`in Combating Hyperglycemia in
`Type 2 Diabetes
`
`Udaya M. Kabadi
`Broadlawns Medical Center, Des Moines, Iowa; Des Moines University, Des Moines, Iowa and University of
`Iowa, Iowa City, Iowa, USA
`Email: ukabadi@gmail.com
`
`Received 19 September 2015; accepted 13 October 2015; published 16 October 2015
`
`Copyright © 2015 by author and Scientific Research Publishing Inc.
`This work is licensed under the Creative Commons Attribution International License (CC BY).
`http://creativecommons.org/licenses/by/4.0/
`
`
`
`
`
`Abstract
`Recently, a debate has been raised regarding the place and the role of sulfonylureas (SU) amongst
`the armamentarium of drugs available for treatment of hyperglycemia in subjects with type 2 di-
`abetes mellitus. With the advent of new drugs, SUs are being relegated and denigrated by some
`authorities contrary to present recommendations by various organizations e.g. American Diabetes
`Association, European Association for the Study of Diabetes and International Diabetes Federation.
`In this article, the advantages of SUs over the new agents in terms of their well established and
`proven better efficacy as well as their short term and long term (over 50 years) safety based on
`extensive literature data are documented. Moreover, lower costs of SUs render them to be far
`more cost effective when compared to new agents and therefore make them affordable in many
`regions of the world. Additionally, SUs are probably the initial drugs of choice in lean subjects with
`prediabetes and type 2 diabetes because they are the most effective secretogogues and major pa-
`thophysiologic mechanism of altered glucose metabolism in lean subjects is the decline in insulin
`secretion and not rising insulin resistance. Furthermore, SUs are also the most cost effective 2nd
`line agents in obese subjects with type 2 diabetes on lapse of glycemic control while receiving
`metformin. Finally, with progression of the disorder, the most cost effective combination of 2 oral
`agents in conjunction with basal insulin remains to be metformin and SUs. Many studies have do-
`cumented a significantly greater extra pancreatic effect of glimepiride in comparison to other SUs
`probably because of its unique property in enhancing insulin sensitivity in conjunction with its
`ability to stimulate both 1st and 2nd phase insulin secretion. These characteristics may contribute
`to its greater efficacy with lesser hypoglycemia when compared with other SUs. Lack of hypogly-
`cemic effect of metabolites of glimepiride may also be responsible for lesser hypoglycaemia. Moreo-
`
`How to cite this paper: Kabadi, U.M. (2015) Sulfonylurea Glimepiride: A Proven Cost Effective, Safe and Reliable War Horse
`in Combating Hyperglycemia in Type 2 Diabetes. Journal of Diabetes Mellitus, 5, 211-226.
`http://dx.doi.org/10.4236/jdm.2015.54026
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`MYLAN - EXHIBIT 1040
`Mylan et al. v. AstraZeneca
`IPR2015-01340
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`

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`U. M. Kabadi
`
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`ver, metabolism of glimepiride performed partially by the liver and partially by the kidneys may
`render it suitable and adaptable to be administered safely in subjects with hepatic or renal dys-
`functional as well as elderly. Finally, the documentation of its pleiotropic effects in lowering of
`cardiovascular surrogate markers, improving thrombotic milleau by reducing platelet aggregation
`factors along with improvement in glycemic control and its preferential binding to SU receptors on
`the pancreatic beta cells rather than myocardium may be responsible for providing better cardi-
`ovascular outcomes in comparison to other SUS and thus make it a better choice amongst SUs in
`subjects with or without presence of cardiovascular disease. Additionally, once daily administra-
`tion because of lasting efficacy for 24 hours based on its half life is likely to enhance compliance on
`the part of patients and assist in attaining and maintaining desirable glycemic control. Therefore,
`SUs still deserve to be major players in management of hyperglycemia in subjects with type 2 di-
`abetes mellitus and glimepiride may be the best choice amongst SUs because of its long term record
`regarding efficacy and safety in diverge population of subjects with type 2 diabetes mellitus.
`
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`Keywords
`Type 2 Diabetes, Sulfonylureas (SU)
`
`
`
`1. Introduction
`“Sulfonylurea” (SU) debate was recently published in Journal “Diabetes Care” [1] [2]. Ganuth [2] affirms that
`newer agents are as effective as SUs although premarketing clinical trials have documented markedly greater
`lowering of A1c from baseline level (25% - 30%) by older drugs, sulfonylureas and metformin in drug naïve
`subjects in comparison to many newer agents (Table 1) as well as SGLT 2 inhibitors (7% - 12%) [3]-[16]. In
`fact in UKPDS [17]-[19]) SUs, glibenclamide and chlorpropamide were more effective in all comers, and obese
`and non-obese subjects when compared with metformin in obese subjects (Table 1). The greater efficacy of
`sulfonylureas in comparison to newer drugs, e.g. DPP4 inhibitors or GLP1 analogs in drug naïve subjects may
`be attributed to their ability to lower both the fasting and postprandial plasma glucose by stimulating both 1st
`and 2nd phase postprandial insulin secretion whereas DPP4 inhibitors and GLP1 analogs stimulate only the 1st
`phase insulin secretion and thus are devoid of much effect on fasting plasma glucose levels [20]-[26]. In fact, the
`major alternative mechanism of lowering post prandial glycemia by DPP4 inhibitors is documented to be via
`decrease in glucagon secretion rather than enhancement of insulin release by beta cells [27]-[40]. Moreover,
`postprandial glycemia is closely correlated to fasting plasma glucose [41]. Therefore, SUs lower post prandial
`glycemia to a greater degree when compared with DPP4 inhibitors and GLP 1 analogs. Furthermore, the decline
`in fasting plasma glucose induced by SUs results in superior efficacy in lowering overall diurnal glycemia with a
`greater reduction in HbA1c as described previously [11]. Finally, Glimepiride induces a rise in both 1st and 2nd
`phase postprandial insulin secretion as well as improvement in insulin sensitivity and therefore appears to be
`more effective than other SUs [11] [26].
`In contrast, an equal or greater lowering of HbA1c by newer agents compared to SUs and even metformin in
`subjects with prolonged duration of diabetes described by Genuth [2] may be attributed to several reasons. Many
`
`Table 1. UKPDS: glycemic control (median HbA1C) and median change (r) in body weight (BWKG) over ten years [17]-
`[19].
`
`Treatment
`
`Chlorpropamide
`
`Glyburide
`
`Insulin
`
`Metformin
`
`Conventional
`
`Median HbA1C
`
`Median r BW
`
`5.1
`
`+4.2
`
`+6.0
`
`+3.0
`
`+2.5
`
`6.7
`
`7.2
`
`7.1
`
`7.4
`
`8.0
`
`212
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`U. M. Kabadi
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`published clinical trials have compared the efficacy of the maximum daily dose of newer agents: DPP4 inhibi-
`tors, GLP1 analogs and SGLT2 inhibitors with either a minimally effective or submaximal recommended daily
`dose of SUs [27]-[40] [42]-[46]. The reason for administration of SUs in a minimally effective or sub maximal
`daily dose, e.g. glimepiride, 1 - 6 mg in these comparative trials may be explained by the selection of subjects
`with average baseline HbA1c between 8% and 8.5% prior to initiation of drugs because the maximal daily dose
`of newer agents is established to lower HbA1c by 10% - 15% whereas the maximum daily dose of glimepiride is
`documented to lower HbA1c by approximately 25% [11] and therefore a much lower than the maximum daily
`dose is adequate to obtain a comparable reduction in HbA1c. Moreover, many of these recent comparative clin-
`ical trials are conducted by using generic SU, e.g. glimepiride probably with variable bioavailability and varia-
`ble efficacy. Also, many of these studies are conducted in “clinical trial mills” with same cadre of subjects in
`their collective databases as recently documented [47] [48]. Thus, recycling of the same subjects hopping from
`one trial to another may have skewed the “real and accurate” comparative efficacy [48]. Finally, reduced effica-
`cy of older drugs in these “comparative efficacy” trials when compared to the efficacy documented in their
`“premarketing” trials may be attributed to “drug receptor interaction”. Previous long term or repeated exposure
`is likely to induce “down regulation” as well as decreased affinity of the receptors of older drugs resulting in de-
`creased efficacy whereas lack of exposure causes “up regulation” and maximal affinity of the receptors for the
`newer agents at their initiation with consequential maximum efficacy. Therefore, the optimal and appropriate
`methodology is the comparative trials in drug naïve subjects with the drugs being used either as monotherapy or
`as a second line agents added to metformin as designed in the ongoing “Grade” trial [49]. Finally, even if the
`similar efficacies of newer agents are factual, as suggested by Ganuth [2], as per his own admission, SUs are
`less expensive, thus rendering them to be distinctly more cost effective than newer agents.
`
`2. Discussion
`Long term safety of SUs especially in terms of cardiovascular outcomes and all cause mortality has been ques-
`tioned in several epidemiologic studies mostly through registry data [50]-[53]. However, all these studies are re-
`trospective in nature. Moreover, the other risk factors such as the degree of glycemic control, lipid profiles, du-
`ration of diabetes, age of the patients and presence of hypertension and other complications including autonomic
`neuropathy and renal dysfunction may have impacted these results and hence conclusions. In contrast, the pros-
`pective clinical trials have established long term safety of SUs regarding cardiovascular outcomes including oc-
`currence of congestive heart failure as well as all cause mortality [54]-[62]. In fact, UKPDS showed that SUs
`specifically glibenclamide and chlorpropamide lowered the rate of both micro and macrovascular complications
`in the original trial as well as during the follow up period of 10 years described as a “Legacy Effect” [17] [18]
`[56]. Moreover, newer SUs, glipizide, glyclazide and glimeperide are documented to be as or more effective and
`safer than glibenclamide in terms of cardiovascular outcomes in several studies with glimeperide being the
`leader [61] [63]-[67]. The superiority of glimeperide over other SUs may be attributed to its ability to improve
`several surrogate cardiovascular qrisk markers [67]-[75]. Unfortunately though, lack of increase or decrease in
`cardiovascular outcomes has become the standard of cardiovascular safety as documented in recent trials with
`newer agents [15] [16] [76]-[84] rather than lowering of these outcomes with improvement in glycemic control
`as was documented in UKPDS and Advance studies [17] [18] [55]-[57]. Moreover, the period of observation for
`safety for newer agents is comparatively markedly shorter when compared with the studies with SUs.
`Other valid concerns regarding SUs are their role in induction of hypoglycemia and weight gain. Severe hy-
`poglycemia as defined by diabetes organizations is documented to be extremely rare with SUs [56] [57] [85]-
`[91]. Non severe hypoglycemia did occur even in metformin treated subjects in UKPDS as well, although the
`occurrence was significantly lower in comparison to subjects receiving SUs [18]. Similarly, in UKPDS, weight
`gain was documented in all groups of subjects over a period of 10 - 15 years including obese subjects treated
`with metformin [17] [18]. Both the occurrences of hypoglycemia and weight gain appeared to be dependent on
`the degree of long term glycemic control and were greater with better glycemic control in both non obese and
`obese subjects treated with SUs in comparison to obese subjects receiving metformin (Table 2); metformin was
`not used in nonobese subjects in this study [17] [18]. Moreover, newer SUs, glipizide, glyclazide and glimepe-
`ride are documented to be safer in terms of hypoglycemia in comparison to glibenclamide used in UKPDS [55]
`[57] [90] [91].
`Thus, newer SUs, glipizide, glyclazide and glimeperide are documented to be as or more effective and safer in
`terms of both hypoglycemia and cardiovascular outcomes in several studies with glimeperide being the leader
`
`
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`Table 2. Comparison of efficacy in drug naïve subjects with type 2 diabetes mellitus [11].
`
`Drug
`
`Glipizide
`
`Glimepiride
`
`Metformin
`
`Avandia
`
`Actos
`
`Prandin
`
`Starlix
`
`GLP1 analogs
`
`Gliptins
`
`Dose mg/day
`
`Pre-RX HbA1C %
`
`Post-RX HbA1C %
`
`r HbA1C %
`
`r% HbA1C
`
`20
`
`8
`
`2550
`
`8
`
`45
`
`12
`
`360
`
`Variable
`
`Variable
`
`8.8
`
`9.1 (13.2)
`
`7.1
`
`6.7 (7.6)
`
`1.7
`
`2.4 (5.6)
`
`19
`
`26 42
`
`8.4
`
`8.5
`
`10.0
`
`8.5
`
`8.3
`
`8.2
`
`8.0
`
`7.0
`
`7.3
`
`8.1
`
`7.8
`
`7.6
`
`6.8
`
`7.2
`
`1.4
`
`1.2
`
`1.9
`
`0.6
`
`0.8
`
`1.4
`
`0.8
`
`16
`
`14
`
`19
`
`7
`
`10
`
`15
`
`10
`
`[61] [63]-[75] [87] [90] [91].
`In contrast, long term efficacy and safety of newer drugs remains to be established. In fact, SGLT 2 inhibitors
`possess much lesser efficacy with far greater costs and undesirable adverse effects when compared to SUs. The
`undesirable adverse effects of SGLT2 inhibitors include dehydration and orthostatic hypotension due to persis-
`tent glycosuria resulting in elevations in serum urea nitrogen, creatinine, potassium with an occasional manife-
`station of severe hypercalcemia and hypernatremia [15] [16] [92]. Moreover, hypercalciuria as well as uricosuria
`accompanying glycosuria in presence of dehydration may facilitate formation of renal calculi [93]. Another re-
`cent report documented increased prevalence of fractures and osteoporosis with use of these agents and attri-
`buted this finding to rise in PTH and FGF 23 [94]. We believe that a simple pathophysiology for increase in os-
`teoporosis and fractures is hypercalciuria and phosphaturia accompanying glycosuria induced by these drugs.
`Additionally high prevalence of genitourinary sepsis secondary to persistent glycosuria should not be acceptable
`because of a consequential decline of quality of life as well as the cost of management of these infections. Fur-
`thermore, glycosuria with resultant polyuria or pollakiuria is likely to induce a decline in quality of life even
`without occurrence of genitourinary infections especially in elderly men with prostatism and postmenopausal
`women with urinary incontinence, the population with the highest prevalence of type 2 Diabetes. In fact, the
`major precipitant in induction of DKA in many of the subjects reported in the recent caution by the U.S Food
`and Drug Administration (FDA) and European Medicine Agency (EMA) was urinary sepsis [95] [96], a fre-
`quent manifestation in subjects with uncontrolled hyperglycemia because of concurrent presence of immunosu-
`pression. The onset of ketoacidosis may also be attributed to increased lipolysis induced by elevated plasma
`glucagon levels required to promote hepatic glucose production to compensate for glycosuria [97]. The rise in
`plasma glucagon is also well established to facilitate lipolysis with onset of ketonemia and consequential keto-
`nuria as documented in several recent clinical trials using these agents [15] [16] [98]. FDA also noted that many
`of these subjects manifested ketoacidosis without hyperglycemia as documented in another recent report [99].
`Serum lipase and amylase concentrations were not determined in these subjects in spite of the presence of
`symptoms, e.g. nausea, vomiting and abdominal pain indicative of acute pancreatitis which has been reported in
`several case studies [100]-[102]. Therefore, it is likely that Euglycemic Ketoacidosis described in these subjects
`[95] [96] [99] may be in fact “Kabadi Syndrome of Pancreatic Ketoacidosis” induced by markedly elevated cir-
`culating lipase concentration [103]-[106] of acute pancreatitis, the diagnosis which was probably missed in these
`subjects [99]. Moreover, a pathophysiologic mechanism is also implicated in occurrence of Ketoacidosis on ad-
`ministration of SGLT2 inhibitors [107]-[109]. However, manufacturers of these drugs refute the significance of
`these reports by FDA and EMA based on the retrospective analysis of pre marketing clinical trials [110] [111].
`The lack of significant occurrence of Ketoacidosis in these trials as compared to the other data may be explained
`by the fact that the participating subjects were healthier because of their selection bias based on several inclusion
`and exclusion criteria when compared with the population of subjects with type 2 Diabetes in clinical practice.
`Moreover, the opinions of investigators conducting these clinical trials require scrutiny [111]. Finally, rise in
`serum LDL and increase in serum viscosity secondary to dehydration is likely to induce a hypercoaggulable
`
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`milleu with increased susceptilibity for macrovascular events, e.g. strokes documented in even short term studies
`with Canagliflozin [15] [16] [112]. Finally, outcomes of the long term exposure of the genitourinary tract to
`hyperglycemic hyperosmolar urine are unkown although the increased prevalence of bladder cancer has been
`reported in early clinical trials using Depagliflozin [113]-[115]. I believe that constant presence of sugar, the
`most efficient fuel for cell growth may have promoted growth of bladder cancer in situ and rendered it to be ma-
`nifested rather than initiating the onset. Therefore, the safety of these agents is questionable in the short term and
`remains to be established in the long term.
`In UKPDS, SUs, glibenclamide and chlorpropamide delayed beta cell failure in more subjects and for a long-
`er period of time in both non obese in comparison to subjects treated with conventional( diet and exercise) pro-
`gram as well as obese subjects in comparison to obese subjects treated with Metformin (Figure 1 and Figure 2)
`[17] [18]. This interesting finding may be attributed to improvement in beta cell function from 50% at diagnosis
`to 80% by the end of 1st year by SUs (Figure 3) [116]. In contrast, beta cell function continued to decline in
`subjects receiving metformin [116]. I believe that progressive beta cell failure is reversible and not universal as
`documented on attaining and maintaining weight loss following long term life style intervention as well as ba-
`riatric procedures [117]-[124]. Moreover, persistent progressive beta cell failure may be secondary to fibrosis of
`islets caused by micrvascular disease analogous to other microvascular complications of diabetes, e.g. retinopa-
`thy, nephropathy and neuropathy [125] [126]. Therefore, sustained, prolonged and permanent preservation of
`desirable glycemic control is likely to delay onset of beta cell failure similar to the other microvascular compli-
`cations as demonstrated in recent “Origin” trial [127] [128]. We have recently documented better efficacy of
`Glimepiride in delaying progression to diabetes for a longer period of time and in fewer lean subjects without
`occurrence of hypoglycemia in comparison to treatment with metformin in obese subjects with prediabetes
`[129]. The efficacy of glimepiride may be attributed to the decline in insulin secretion being the major patho-
`physiologic mechanism in onset of impaired glucose tolerance and type 2 diabetes in lean subjects [130]. In the
`same study, we observed similar improvements in lipid pattern and other cardiovascular surrogate markers with
`no deaths and CV outcomes in both lean and obese groups with prediabetes [67].
`I believe that improvements in lipids and CV surrogate markers by both drugs, glimepiride and metformin
`described in this and several other studies are likely to be induced by improvement in functioning of cells and
`tissues by enhanced entry of glucose, the most effective fuel. In contrast, long term efficacy and safety of newer
`drugs remains to be established.
`
`
`
`
`
`
`Figure 1. Maintenance of A1c < 7% for longer duration in subjects treated with SUs in compar-
`ison to metformin in UKPDS [17] [18].
`
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`
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`Figure 2. More subjects treated with SUs with desirable glycemic goal (7%) in comparison to
`metformin or conventional (diet and exercise) at 9 years [17] [18].
`
`
`Figure 3. Greater beta cell function at 6 years in non obese subjects treated with SUs in compar-
`ison to conventional (diet and exercise) and in obese subjects in comparison to metformin [116].
`
`Finally, therapy with SUs by themselves, especially glimepiride or with metformin when administered con-
`currently with basal insulin has been shown to be more cost effective when compared with combination of basal
`insulin with any other drug e.g. glitazones, DPP4 inhibitors or GLP1 analogs as a single agent. This outcome
`may be attributed to lower cost of SU and metformin as compared to other drugs including glitazones, DPP4 in-
`
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`hibitors and GLP1 analogs [11] as well as the lower daily dose of insulin required to achieve desirable glycemic
`control [85]-[87] [131]-[158]. In fact, adjunctive administration of both glimepiride and metformin is docu-
`mented to lower daily insulin dose, basal type as well NPH or premixed insulins more than when these drugs are
`used alone [134]-[142]. The lower the daily dose, the lesser the number of peaks of insulin, lower is the hypog-
`lycemic events and lesser the weight gain [134]-[144] [157] [158]. Finally a recent study also documented sig-
`nificantly longer delay for requirement of addition of insulin with SUs when compared with DPP4 inhibitors and
`GLP1 analogs [159].
`In the final analysis, SUs have stood the test of time for over 50 years in terms of efficacy and safety whereas
`the long term efficacy and safety of newer drugs remain to be established. Moreover, SUs are thought to provide
`and maintain the better quality of life when compared with newer agents [159] and are distinctly far more cost
`effective than newer agents.
`
`3. Conclusion
`Therefore, SUs must remain as 1st line agents especially in management of non-obese subjects with type 2 di-
`abetes since the dominant pathophysiologic mechanism is the decline in insulin secretion in this population
`[130]. Moreover, SUs remain the 2nd line most cost effective viable oral option in obese subjects on the lapse of
`glycemic control while receiving metformin since the addition of newer drugs is less likely to achieve the desir-
`able glycemic goal of 6.5% - 7.0% due to their documented lesser efficacy in several studies [11]. Finally, in
`many regions of the world with markedly rising prevalence of diabetes e.g. Asia, Africa and South America with
`countries like China and India leading the pack [160], SUs remain the drugs of choice either as a 1st line drug in
`nonobese population and 2nd line agent in obese subjects with type 2 diabetes because of their well established
`efficacy, safety and mainly affordability in these regions and countries.
`
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