ueda2011 incidence of diabetes mellitus in clinical trials of antihypertensive drugs-d.samir

1. Prof. Samir Abd-UlKader (MD, NYAS)Prof. Samir Abd-UlKader (MD, NYAS)
Assiut UniversityAssiut University

2. Background.Background.
Clinical trials.Clinical trials.
Mechanism of protection againstMechanism of protection against
diabetes mellitus.diabetes mellitus.
Limitations of the study.Limitations of the study.
Important points to be undertaken.Important points to be undertaken.

3. The propensity for some antihyper-The propensity for some antihyper-
tensive drugs to lower glucosetensive drugs to lower glucose
tolerance and precipitate diabetes hastolerance and precipitate diabetes has
been known since 1958been known since 1958 (Sheen, 2004).(Sheen, 2004).
Because hypertension is oftenBecause hypertension is often
associated with impaired glucoseassociated with impaired glucose
tolerance, insulin resistance, andtolerance, insulin resistance, and
obesity, many patients withobesity, many patients with
hypertension develop diabetes, evenhypertension develop diabetes, even
when treated with placebowhen treated with placebo (Taglor(Taglor etet
al.al., 2006)., 2006).

4. Some long-term clinical trails ofSome long-term clinical trails of
antihypertensive agents haveantihypertensive agents have
shown significant differences in theshown significant differences in the
rates of new cases of diabetesrates of new cases of diabetes
(Padwal(Padwal et al.,et al., 2005).2005).
Network meta-analysis is a fairlyNetwork meta-analysis is a fairly
new statistical technique thatnew statistical technique that
allows both direct and indirectallows both direct and indirect
comparisons of different drugs.comparisons of different drugs.

5. This type of analysis canThis type of analysis can
summarize randomized clinicalsummarize randomized clinical
trails (RCTs) of several differenttrails (RCTs) of several different
treatment strategies, and providetreatment strategies, and provide
point estimates (and 95% Cl) forpoint estimates (and 95% Cl) for
their association with a giventheir association with a given
endpoint, as well as an estimateendpoint, as well as an estimate
of incoherence.of incoherence.

6. Network meta-analysis techniqueNetwork meta-analysis technique
allow estimation of the relativeallow estimation of the relative
odds of developing diabetes duringodds of developing diabetes during
long-term treatmentlong-term treatment with an initialwith an initial
class of antihypertensive drug, onclass of antihypertensive drug, on
the basis of the reported numbersthe basis of the reported numbers
of participants with, or at risk of,of participants with, or at risk of,
incident diabetes in RCTsincident diabetes in RCTs (Elliott(Elliott
and Meyer, 2007).and Meyer, 2007).

7. Summary of clinical trials of antihypertensive drugs thatSummary of clinical trials of antihypertensive drugs that
reported new cases of diabetes.reported new cases of diabetes.
Year
Duration
(years)
Drug 1
New cases of
diabetes/total
Drug 2
New cases of
diabetes/total
Drug 3
New cases of
diabetes/total
AASK26
2006 3.8 ACE inhibitor 42/410 β blocker 70/405 CCB 32/202
ALLHAT26
2002 4.0 ACE inhibitor 119/4096 CCB 154/3954 Diuretic 302/6766
ALPINE27
2003 1.0 ARB 1/196 Diuretic 8/196 - -
ANBP-218
2005 4.1 ACE inhibitor 138/2800 Diuretic 200/2826 - -
ASCOT28
2005 5.5 β blocker 799/7040 CCB 56/7072 - -
CAPPP29
1999 6.1 ACE inhibitor 337/5183 β blocker 380/5230 - -
CHARM30
2003 ~3.1 ARB 163/2715 Placebo 202/2721 - -
DREAM31
2006 ~3.0 ACE inhibitor 449/2623 Placebo 489/2646 - -
EWPHE32
1991 4.7 Diuretic 29/416 Placebo 20/424 - -
FEVER20
2005 3.3 CCB 177/4841 Placebo 154/4870 - -
HAPPHY33
1987 3.8 β blocker 86/3297 Diuretic 75/3272 - -
HOPE34
2001 4.5 ACE inhibitor 102/2837 Placebo 155/2883 - -
INSIGHT35
2000 3.0 CCB 136/2508 Diuretic 176/2511 - -
INVEST36
2003 4.0 β blocker 665/8078 CCB 569/8098 - -
LIFE37
2002 4.8 ARB 242/4020 β blocker 320/3979 - -
MRC-E38
1992 5.8 β blocker 37/1102 Diuretic 43/1081 Placebo 34/2213
NORDIL39
2000 4.5 β blocker or diuretic 251/5059 CCB 216/5095 - -
PEACE40
2004 4.8 ACE inhibitor 335/3432 Placebo 339/3472 - -
SCOPE41
2003 3.7 ARB 93/2167 Placebo 115/2175 - -
SHEP42
1998 3.0 Diuretic 140/1631 Placebo 118/1578 - -
STOP-243
1999 4.0 ACE inhibitor 93/1970 β blocker or diuretic 97/1960 CCB 95/1965
VALUE44
2004 4.2 ARB 690/5087 CCB 845/5074 - -

8. Network of clinical trials of antihypertensiveNetwork of clinical trials of antihypertensive
drugs in which incident diabetes was reported.drugs in which incident diabetes was reported.
Arrow head points to class of drugs with lowerArrow head points to class of drugs with lower
risk of incident diabetes.risk of incident diabetes.

9. Results of network meta-analysis of 22Results of network meta-analysis of 22
clinical trials.clinical trials.
ARB
ACE inhibitor
CCB
Placebo
blocker
Diuretic
0.57 (0.46-0.72) p< 0.0001
0.67 (0.56-0.80) p< 0.0001
0.75 (0.62-0.90) p= 0.002
0.77 (0.63-0.94) p= 0.009
0.90 (0.75-1.09) p= 0.30
Referent
0.50 0.70 0.90 1.26
Odds ratio of incident diabetes Incoherence = 0.000017
β 





10. According to these data, anAccording to these data, an
initial ARB, ACE inhibitors,initial ARB, ACE inhibitors,
CCB, or placebo is eachCCB, or placebo is each
associated with significantlyassociated with significantly
fewer new cases of diabetesfewer new cases of diabetes
than an initial diuretic.than an initial diuretic.

11. 1) Improved Muscle Blow Flow:1) Improved Muscle Blow Flow:
Leads to increase in glucose utilizationLeads to increase in glucose utilization
and insulin delivery to insulin-sensitiveand insulin delivery to insulin-sensitive
tissues and cause an increase intissues and cause an increase in
glucose utilizationglucose utilization (Kodama(Kodama et alet al., 1990).., 1990).
Increased bradykinin-mediated NOIncreased bradykinin-mediated NO
production increases insulin mediatedproduction increases insulin mediated
glucose uptake by increase blood flowglucose uptake by increase blood flow
(Henriksen(Henriksen et al.,et al., 1999).1999).
Mechanism of ProtectionMechanism of Protection
Against Type 2 DiabetesAgainst Type 2 Diabetes

12. 2) Decreased Sympathetic2) Decreased Sympathetic
ActivityActivity
ACE inhibitors increase glucoseACE inhibitors increase glucose
uptake and reduce plasmauptake and reduce plasma
norepinephrine and epinephrinenorepinephrine and epinephrine
levelslevels (Dimattia(Dimattia et alet al., 1996).., 1996).
ARBS may improve insulinARBS may improve insulin
sensitivity possibly by asensitivity possibly by a
sympatholytic effectsympatholytic effect (Moan(Moan et alet al.,.,
1994).1994).

13. 3) Ionic changes3) Ionic changes
Potassium appears to play aPotassium appears to play a
greater role in insulin secretiongreater role in insulin secretion
than in insulin action.than in insulin action.
Serum magnesium and calciumSerum magnesium and calcium
may play an indefinite roles inmay play an indefinite roles in
glucose metabolismglucose metabolism (Hachni(Hachni etet
al.al., 1997)., 1997).

14. 4) Enhanced Insulin Signaling4) Enhanced Insulin Signaling
Inhibition of AT1 receptors preventsInhibition of AT1 receptors prevents
decline of glucose transporter-4decline of glucose transporter-4
(GLUT-4) in diabetics.(GLUT-4) in diabetics.
Chronic administration of ACEIs orChronic administration of ACEIs or
ARBs can increase protein expressionARBs can increase protein expression
of GLUT-4 in skeletal muscles andof GLUT-4 in skeletal muscles and
myocardiummyocardium (Henriksen and Jacop,(Henriksen and Jacop,
2003).2003).
Accumulated bradykinin followingAccumulated bradykinin following
ACEI increases glucose uptake inACEI increases glucose uptake in
skeletal muscle.skeletal muscle.

15. 5) Effects on Free Fatty Acids5) Effects on Free Fatty Acids
and Adipose Tissueand Adipose Tissue
• ACEIs reduce FFA levels andACEIs reduce FFA levels and
ameliorate FFA-induced inhibition ofameliorate FFA-induced inhibition of
glucose consumption.glucose consumption.
• ACEI and ARB (candesartan)ACEI and ARB (candesartan)
significantly increase insulin-significantly increase insulin-
mediated glucose disposal andmediated glucose disposal and
plasma adiponectin concentrationsplasma adiponectin concentrations
(Chandran(Chandran et alet al., 2003).., 2003).

16. RAS blockade may prevent diabetes byRAS blockade may prevent diabetes by
promoting the recruitment andpromoting the recruitment and
differentiation of pre-adipocytes todifferentiation of pre-adipocytes to
mature adipocytes which serve as amature adipocytes which serve as a
sump or drain for fatsump or drain for fat (Lewis(Lewis et alet al., 2002).., 2002).
They also counteract the ectopicThey also counteract the ectopic
deposition of lipids in other tissuesdeposition of lipids in other tissues
(muscle, liver, pancreas), thereby(muscle, liver, pancreas), thereby
improving insulin sensitivity andimproving insulin sensitivity and
preventing the development of type 2preventing the development of type 2
diabetes.diabetes.

17. Partial PPAR-Gamma Activity ofPartial PPAR-Gamma Activity of
Some ARBsSome ARBs
PPAR-PPAR-γγ plays an important role in theplays an important role in the
regulation of insulin sensitivity,regulation of insulin sensitivity,
especially in the adipose tissue andespecially in the adipose tissue and
subsequently in skeletal muscles.subsequently in skeletal muscles.
ARBs induces PPAR-ARBs induces PPAR-γγ activity byactivity by
interaction with the PPAR-interaction with the PPAR-γγ ligandligand
binding domain, thereby promotingbinding domain, thereby promoting
PPAR-PPAR-γγ dependent differentiation independent differentiation in
adipocytesadipocytes (Schubb(Schubb et alet al., 2004).., 2004).

18. 6) Effect on Muscle Fibre6) Effect on Muscle Fibre
CompositionComposition
 By its vasodilatory effect, ACEI mayBy its vasodilatory effect, ACEI may
modulate muscle fibre compositionmodulate muscle fibre composition
especially type I fibres which have theespecially type I fibres which have the
greatest oxidative metabolism.greatest oxidative metabolism.
 This may contribute to improvedThis may contribute to improved
glucose uptake by the skeletalglucose uptake by the skeletal
muscles and thus increase insulinmuscles and thus increase insulin
sensitivitysensitivity (Ura(Ura et alet al., 1999).., 1999).

19. 7) Effect of RAS Inhibition on7) Effect of RAS Inhibition on
Insulin SecretionInsulin Secretion
RAS inhibition increases insulinRAS inhibition increases insulin
secretion by improving ionicsecretion by improving ionic
balance (potassium andbalance (potassium and
magnesium) and enhancesmagnesium) and enhances
microcirculation in the islets ofmicrocirculation in the islets of
Langerhans in the pancreasLangerhans in the pancreas (Khan,(Khan,
2003).2003).

20. 8) Improved Ionic Balance8) Improved Ionic Balance
When potassium is added to thiazides, theWhen potassium is added to thiazides, the
induced glucose intolerance and insulininduced glucose intolerance and insulin
hyposecretion are fully prevented.hyposecretion are fully prevented.
ACEIs or ARBs lower aldoesteroneACEIs or ARBs lower aldoesterone
secretion and renal potassium wasting,secretion and renal potassium wasting,
which could preserve beta-cellwhich could preserve beta-cell
responsivenessresponsiveness (Ferrannini(Ferrannini et alet al., 1994).., 1994).
Positive magnesium balance resultingPositive magnesium balance resulting
from RAS inhibition and aldosteronefrom RAS inhibition and aldosterone
blockade might favour insulin secretionblockade might favour insulin secretion
and thus contribute to delay type 2and thus contribute to delay type 2
diabetes in hypertensive patients.diabetes in hypertensive patients.

21. 9) Improved Islet Blood Flow9) Improved Islet Blood Flow
ACEIs and ARBs may increaseACEIs and ARBs may increase
islet blood flow and pancreaticislet blood flow and pancreatic
beta-cell perfusion by reducingbeta-cell perfusion by reducing
ATII-mediated vasoconstriction inATII-mediated vasoconstriction in
the pancreas. These effectsthe pancreas. These effects
potentially slow or reverse thepotentially slow or reverse the
decline in beta-cell functiondecline in beta-cell function
(Leung(Leung et alet al., 2001).., 2001).

22. 1)1) some trials were double-blind,some trials were double-blind,
whereas the others used thewhereas the others used the
prospective randomized open-prospective randomized open-
blinded end point designblinded end point design (Elliott(Elliott
and Mayer, 2007).and Mayer, 2007).
Limitations of the TrialsLimitations of the TrialsLimitations of the TrialsLimitations of the Trials

23. 2)2) The definition of diabetes differed amongThe definition of diabetes differed among
the trials. The diagnostic criteria forthe trials. The diagnostic criteria for
diabetes mellitus changed in 1999, sodiabetes mellitus changed in 1999, so
studies done or reported before, used thestudies done or reported before, used the
older criteria (older criteria (≥≥7.8 mmol/L); while, most7.8 mmol/L); while, most
studies have used the current threshold ofstudies have used the current threshold of
≥≥7.0 mmol/L7.0 mmol/L (American Diabetes(American Diabetes
Association, 2004).Association, 2004).
3)3) In meta-analyses of clinical trails,In meta-analyses of clinical trails,
observations are grouped by the initialobservations are grouped by the initial
randomized drug, but differences mightrandomized drug, but differences might
exist between drugs in the same classexist between drugs in the same class
(Bakris et al., 2004).(Bakris et al., 2004).

24. Additional trails may be needed toAdditional trails may be needed to
confirm the role of ACE inhibitorsconfirm the role of ACE inhibitors
and ARBs in diabetes prevention,and ARBs in diabetes prevention,
and no pharmacologic agent isand no pharmacologic agent is
currently approved for thiscurrently approved for this
particular indication. Prospectiveparticular indication. Prospective
trials that specifically address thistrials that specifically address this
issue are underway.issue are underway.

25. 1)1) Concern about the risk of diabetes shouldConcern about the risk of diabetes should
not discourage physicians fromnot discourage physicians from
prescribing thiazide diuretics toprescribing thiazide diuretics to
nondiabetic adults who havenondiabetic adults who have
hypertension.hypertension.
2)2) The use of beta-blockers appears toThe use of beta-blockers appears to
increase the risk of diabetes, but thisincrease the risk of diabetes, but this
adverse effect must be weighed againstadverse effect must be weighed against
the proven benefits of beta-blockers inthe proven benefits of beta-blockers in
reducing the risk of cardiovascular eventsreducing the risk of cardiovascular events
(Gress(Gress et alet al., 2000).., 2000).
Important Points to be UndertakenImportant Points to be UndertakenImportant Points to be UndertakenImportant Points to be Undertaken