SECTION 18.5
Comparative Review of Oral Hypoglycemic Agents in Adults
Harinder Chahal
For WHO Secretariat
Table of Contents
Acronyms: ............................................................................................................................................................................... 3
I.
Background and Rationale for the review: ....................................................................................................................... 4
II. Medications under comparative review: ......................................................................................................................... 4
Table 1 - New oral hypoglycemic agents for comparison with current EML agents .......................................................... 5
III. Literature searches and methodology: ............................................................................................................................ 5
1.
Title Search Results: .................................................................................................................................................... 6
2.
Statement about quality of evidence: ........................................................................................................................ 6
IV. Clinical efficacy and safety evaluation: ............................................................................................................................ 6
1.
DPP-4 Inhibitors (Sitagliptin, Saxagliptin) and Metformin: ......................................................................................... 6
2.
Glitazones (Rosiglitazone, Pioglitazone) and Metformin: ........................................................................................... 7
3.
Alpha-glucosidase inhibitors (AGIs – Acarbose, Miglitol) and Metformin:................................................................. 8
4.
Meglitinides (Repaglinide, Nateglinide) and Metformin: ........................................................................................... 8
5.
DPP-4 Inhibitors (Sitagliptin, Saxagliptin) and Sulfonylureas:..................................................................................... 9
6.
Glitazones (Rosiglitazone, Pioglitazone) and Sulfonylureas: ...................................................................................... 9
7.
Alpha-glucosidase inhibitors (AGIs – Acarbose, Miglitol) and Sulfonylureas: .......................................................... 10
8.
Meglitinides (Repaglinide, Nateglinide) and Sulfonylureas: .................................................................................... 10
9.
Statement on Amylin Analogues – Pramlintide: ....................................................................................................... 11
V. Cost, Regulatory and Current NEML Availability Evaluation: ......................................................................................... 11
Table 2: Comparative Cost Chart and Drug Approval by US and Australian Regulatory Agencies ................................... 12
Table 3: Oral hypoglycemics listed on selected NEMLs .................................................................................................... 12
VI. Summary: ....................................................................................................................................................................... 12
Appendix: .............................................................................................................................................................................. 14
Table 4: Summary: Comparative efficacy and safety of oral hypoglycemics.................................................................... 14
Table 5: Chart of systematic reviews used ....................................................................................................................... 15
Table 6: Question: Should Metformin vs DPP-4 Inhibitors be used for Diabetes Mellitus, Type 2? ................................ 16
Table 7: Question: Should Metformin vs Glitazones be used for Diabetes Mellitus Type 2? .......................................... 19
Table 8: Question: Should Acarbose vs Metformin be used for Diabetes Mellitus, Type 2? ........................................... 22
Table 9: Question: Should Metformin vs meglitinides be used for Diabetes Mellitus, Type 2?....................................... 25
Table 10: Question: Should Glitazones vs SFU be used for Diabetes Mellitus, Type 2? ................................................... 28
Table 11: Question: Should Acarbose vs be used in SFU? ................................................................................................ 31
Table 12: Question: Should SFU vs meglitinides be used for Diabetes Mellitus, Type 2? ................................................ 34
References: ........................................................................................................................................................................... 36
Page 2 of 37
Acronyms:
AGI - Alpha-glucosidase inhibitor
AHRQ – Agency for Healthcare Research and Quality
CHF – Congestive heart failure
CI – Confidence interval
CV – Cardiovascular
DM – Diabetes Mellitus
DPP-4 inhibitors – dipeptidylpeptidase-4 inhibitors
EC – Expert Committee
EML – Essential Medicines List
FDA – Food and Drug Administration
GRADE – Grading of Recommendations Assessment, Development and Evaluation
HbA1c – Glycosylated hemoglobin
HDL – High density lipoprotein-cholesterol
LDL – Low density lipoprotein-cholesterol
LMICs - Low- and Middle-Income Countries
MSH – Management Sciences for Health
NEML – National Essential Medicines List
RCT – Randomized controlled trial
SFU – Sulfonylureas
TG – Triglycerides
TGA – Therapeutics Goods Administration
US – United States of America
USD – United States dollar
WHO – World Health Organization
Page 3 of 37
I.
Background and Rationale for the review:
Diabetes mellitus is a chronic disease that requires life-long pharmacological and non-pharmacological
management to prevent complications such as cardiovascular disease, retinopathy, nephropathy, and
neuropathy.[1, 2] While type 2 diabetes mellitus is the most common form of diabetes comprising of
90% to 95% of all diabetes cases.[2] An estimated 346 million people worldwide live with diabetes,
resulting in 3.4 million deaths in 2004, with more than 80% of these deaths occurring in low- and middle
income countries.[3] It is projected that the death burden from diabetes will double by the year 2030.[3]
According to the 2010 WHO report on NCDs, the estimated prevalence of diabetes in 2008 was about
8% for men and women in low-income countries and 10% for both sexes in upper-middle-income
countries with the highest global prevalence of diabetes in Eastern Mediterranean Region and Region of
the Americas.[4] The high prevalence rate is of concern since diabetes in the leading cause of renal
failure, visual impairment and blindness and increases the risk of lower limb amputation by at least 10
times.[4] Additionally, patients living with diabetes may need 2 to 3 three times the health-care
resources compared to people without diabetes and diabetes care may require allocation of up to 15% of
national health care budgets.[4] Furthermore, given the close link between poverty and NCDs, the NCDs
impose a disproportionate burden on low and middle income countries.[4]
In the United States, 11 classes of medications are approved for management of DM; these include 8
oral agents such as – biguanides, sulfonylureas, meglitinides, thiazolidinediones (glitazones), alphaglucosidase inhibitors, DPP-4 inhibitors, bile acid sequestrants, dopamine-2 agonists, and 3 injectable
agents such as – GLP-1 receptor agonists (incretins), amylin analogues and insulin.[1, 5] The 18th WHO
expert committee on the selection and use of essential medicines in 2011 requested a review of the
current oral hypoglycemic medicines for use in adult to determine if updates to the EML are needed. [6]
Currently, the EML contains two oral hypoglycemics, glibenclamide (sulfonylurea) and metformin. This
document will conduct comparative analysis of four oral hypoglycemic agents – glitazones
(thiazolidinediones), DPP-4 inhibitors, alpha-glucosidase inhibitors and meglitinides versus
sulfonylureas (SFU) and metformin to determine their efficacy and safety, as well as conduct a costcomparison. This review will also provide an overview of the current availability of the four agents in
questions in LMICs by surveying NEMLs of 15 nations at random; as well as provide information on
regulatory status of these agents in the US and Australia. The regulatory status in US and Australia was
selected as an initial reference point given the stringent review and approval process required for
therapeutic approval by these agencies and due to the availability of the databases in English.
II.
Medications under comparative review:
Table 1 lists the medications reviewed by this document and the comparisons made. The 18th EC on the
Selection and Use of Essential Medicines had also requested a review on pramlintide – this medication
was not reviewed; a statement regarding this therapeutic peptide is made in section IV-9.
Page 4 of 37
Table 1 - New oral hypoglycemic agents for comparison with current EML agents
Comparison #
Comparison 1
Comparison 2
Comparison 3
Comparison 4
EML Medication
Metformin
Comparison 5
Comparison 6
Comparison 7
Comparison 8
Comparison 9
Sulfonylureas
III.
Comparison Medication
DPP-4 Inhibitors (Sitagliptin)
Glitazones (Pioglitazone, Rosiglitazone)
Alpha-glucosidase inhibitors (Acarbose)
Meglitinides (Repaglinide, Nateglinide)
DPP-4 Inhibitors (Sitagliptin)
Glitazones (Pioglitazone, Rosiglitazone)
Alpha-glucosidase inhibitors (Acarbose)
Meglitinides (Repaglinide, Nateglinide)
Pramlintide acetate – Not reviewed
GRADE Table
Table 6
Table 7
Table 8
Table 9
None
Table 10
Table 11
Table 12
None
Literature searches and methodology:
The purpose of this review is to present evidence for safety, efficacy and cost for DPP-4 inhibitors,
glitazones, alpha-glucosidase inhibitors and meglitinides as compared to the current EML oral
hypoglycemics, metformin (biguanide) and glibenclamide (sulfonylurea). Literature search was focused
to answer this question.
The Cochrane library and PubMed databases were searched for existing systematic reviews on
hypoglycemic medications up to July 2012 using the following terms: sitagliptin, saxagliptin, DPP-4
inhibitors, dipeptidylpeptidase-4 inhibitors; alpha-glucosidase inhibitors, acarbose; sulfonylureas,
glibenclamide, glyburide, glimepiride, gliclazide; thiazolidinediones, glitazones, pioglitazone,
rosiglitazone; biguanides, metformin; meglitinides, nateglinide, repaglinide, mitiglinide.
Eight (8) reviews were identified relevant to topic of this review (Table 4); 6 reviews from Cochrane
and 2 from AHRQ.[7-14] The primary reviews used for this report were by Bennett et al and Bolen et al
due to their most recent publication dates and review of medications of interest.[7, 9] However, other
reviews as shown in Table 4, were used and referenced as needed to clarify and to add to the body of
evidence. Bennett et al reviewed literature up to April 2010 on all anti-diabetic medications except
alpha-glucosidase inhibitors.[7] Bolen et al reviewed literature up to January 2006 on all anti-diabetic
medications of interest.[9]
New, English-language literature beyond the periods covered by the systematic reviews was searched
using Cochrane Central Register for Controlled Trials for titles addressing comparative safety and
efficacy of monotherapy with medications for whom a paucity of data was determined. For alphaglucosidase inhibitors the databases for searched from February 2006 up to July 2012. For meglitinides
and DPP-4 inhibitors the databases were searched from June 2010 up to July 2012. The following search
terms were used: sitagliptin, saxagliptin, DPP-4 inhibitors, dipeptidylpeptidase-4 inhibitors; alphaglucosidase inhibitors, acarbose; sulfonylureas, glibenclamide, glyburide, glimepiride, gliclazide,
glipizide; biguanides, metformin; meglitinides, nateglinide, repaglinide, mitiglinide. No additional
search was conducted on glitazones or DPP-4 inhibitors versus metformin because it was determined the
evidence available in the systematic reviews used on these comparisons was sufficient for review of
efficacy and safety. The results of these searches are provided under section III-1 – Title Search Results.
Page 5 of 37
Since our search focused on comparative literature for the classes of medications in question, this review
does not include many of the placebo-controlled studies conducted for safety and efficacy of these
agents.
The WHO Essential Medicines website was used to reference NEMLs of 15 nations at random to
determine how many of the surveyed nations had four classes of drugs in question on their NEML.[15]
(Table 3)
MSH 2010 International Drug Price Indicator Guide was referenced first to obtain median buyer price
per unit.[16] However, for majority of the medications of interest, prices were not available in MSH
2010 guide, Lexi-Comp online database was used for price and maximum daily dose of all medications
as a reference source for pricing.[17]
1. Title Search Results:
a. DPP-4 Inhibitors versus SFU: 80 trials resulted in the search; 6 studies were identified as
relevant to the question from title review. Two were duplicates from the Bennett et al review.
None of the 4 new studies identified compared DPP-4 monotherapy with SFU
monotherapy.[18-21] These studies were included in this review due to their relevance to
efficacy and safety outcomes.
b. Meglitinides versus Metformin: The search resulted in 3 trials. The trials did not address the
question of comparative efficacy and safety of these agents. No new trials of interest were
identified.
c. Meglitinides versus SFU: The search resulted in 38 trials. 2 new trials of interest were
identified. These trials did not address all outcomes of interest; however, they were included
in this review due to their relevance to the safety outcome data.[22, 23]
d. Alpha-glucosidase inhibitors versus metformin: The search resulted in 17 trials. The trials did
not address the question of comparative efficacy and safety of these agents. No new trials of
interest were identified.
e. Alpha-glucosidase inhibitors versus SFU: The search resulted in 11 trials. The trials did not
address the question of comparative efficacy and safety of these agents. No new trials of
interest were identified.
2. Statement about quality of evidence:
The quality evidence presented in the systematic reviews and other clinical trials used in this review
were evaluated using the GRADE methodology. GRADE tables were prepared for efficacy and
safety outcomes, whenever possible, based on the evidence presented in the referenced reviews;
other GRADE assessments were at the judgment of the author of this review. When necessary, the
primary publication was referenced to determine GRADE rating. The strength of evidence
evaluations are presented in Tables 6 through 12 in the appendix.
IV.
Clinical efficacy and safety evaluation:
1. DPP-4 Inhibitors (Sitagliptin, Saxagliptin) and Metformin:
Page 6 of 37
Efficacy: Bennett et al reviewed three RCTs that compared metformin with DPP-4 inhibitors, and found
greater reductions in HbA1c with metformin.[7] The between-group difference of -0.4 percent (95
percent CI -0.5 percent to -0.2 percent) were observed, favoring metformin.[7] For weight loss, 3 short
duration RCTs comparing these 2 agents found greater reduction in weight with metformin.[7] Although
evidence favors a greater reduction in LDL and a greater increase in HDL with metformin compared to
DPP-4 inhibitors, no statistical significance is seen.[7] While a greater reduction in triglycerides is seen
with DPP-4 inhibitors, these results are also not statistically significant.[7] Bennett et al, found
insufficient data to make a determination regarding all-cause mortality and cardiovascular mortality
benefits between DPP-4 inhibitors and metformin.[7]
Safety: DPP-4 inhibitors have a better safety profile in terms of mild to moderate hypoglycemia
symptoms and gastrointestinal side effects.[7] In one 24-week RCT mild to moderate hypoglycemic
symptoms were observed at a rate of 3.3% for metformin and 1.7% with DPP-4 inhibitors, however, the
results were not statistically significant (p=0.12).[7, 24] One RCT showed an occurrence of adverse GI
events (nausea/vomiting/diarrhea/abdominal discomfort) in metformin group at a rate of 20.7% and
11.5% in DPP-4 inhibitor group, in which diarrhea accounted for majority of the difference at 10.9%
with metformin and 3.6% for sitagliptin.[7] The high incidence of diarrhea with metformin is consistent
with published literature as a common side-effect of therapy and usually subsides with continued
therapy.[25]
GRADE evidence is summarized in Table 6.
2. Glitazones (Rosiglitazone, Pioglitazone) and Metformin:
Efficacy: From the 14 RCTs comparing glitazones and metformin reviewed by Bennett et al, no
between-group differences in reduction of HbA1c was observed.[7] A review of 8 RCTs comparing
weight loss between therapy with metformin and glitazones, found weight loss with metformin and mild
increases in weight with glitazone treatment.[7] A four-year RCT observed a between-group reduction
in weight of 6.9kg favoring metformin over rosiglitazone.[7, 26] A review of 6 RCTs favors metformin
for reduction in LDL and TG over rosiglitazone, with pooled between-group difference of -12.8mg/dL
for LDL and -26.9mg/dL for TG.[7] However, an evaluation of 6 RCTs found no HDL benefit with
either metformin or rosiglitazone.[7] There was no all-cause mortality or cardiovascular mortality
benefit with either treatment.[7, 26]
Safety: A large 4-year double-blind RCT (ADOPT) with over 1400 participants in each arm found no
significant differences in the occurrence of self-reported hypoglycemic events in patient assigned to the
rosiglitazone or the metformin group, with one serious hypoglycemic event in each group.[7, 26]
Bennett et al notes conflicting evidence for rate of CHF with metformin and glitazones.[7] Three RCTs
and four observational studies provide a low grade evidence for increased risk of CHF with
glitazones.[7] However, the ADOPT study notes no difference in CHF adverse events between either
treatment group.[7, 26] It is important note that the FDA has placed a boxed warning for all
thiazolidinedione agents, including rosiglitazone and pioglitazone for risk of congestive heart
failure.[27-29] Metformin has been consistently shown to have a greater occurrence of GI adverse
events over glitazones.[7]
Page 7 of 37
GRADE evidence is summarized in Table 7.
3. Alpha-glucosidase inhibitors (AGIs – Acarbose, Miglitol) and Metformin:
Efficacy: Van de Laar et al. and Bolen et al. reviewed 2 RCTs comparing submaximal dosed metformin
and maximally dosed acarbose showing no significant differences in HbA1c reduction between the two
treatment groups.[9, 14] No statistically significant differences were observed for weight reduction with
either AGIs or metformin.[9, 14] Reviews by Van de Laar et al and Bolen et al, found no benefits to
HDL or TG with either therapy. [9, 14] One study, using submaximal doses of metformin and maximum
doses of acarbose showed a reduction in LDL favoring acarbose.[14] No evidence is available to
determine all-cause or CV mortality benefits with either treatment.
Safety: One RCT reported a low incidence of hypoglycemia risk with both agents, however, provided no
statistical analysis.[30] Van de Laar et al and Bolen et al reviews based on two trials, report higher rate
of side effects for acarbose, favoring metformin.[9, 14] For total adverse events, one study reported an
odds ratio of 15 in favor of metformin.[14] Van de Laar et al, reviewed one RCT comparing miglitol
(AGI) and metformin, in which no statistically significant differences in GI adverse events were
observed.[14] Another study reports the incidence of withdrawal from the study due to GI adverse
effects was 58% for acarbose arm and 14.8% for metformin.[9, 30]
GRADE evidence is summarized in Table 8.
4. Meglitinides (Repaglinide, Nateglinide) and Metformin:
Efficacy: Bennett et al reviewed 3 RCTs comparing metformin with meglitinides, which found similar
effects on HbA1c with both treatments.[7] Two studies compared metformin and repaglinide at
comparable doses showing non-significant HbA1c differences between treatment groups.[7] Evidence
regarding benefits of weight reduction with meglitinides or metformin is low, however, indicates
generally non-significant weight differences, with a slight trend that may favor metformin.[7] Similarly,
evidence suggests a reduction in LDL and TG that may favor metformin over meglitinides, however is
non-significant.[7] For HDL, their maybe a benefit with repaglinide over metformin, however the results
are non-significant.[7] Overall, the evidence for benefits to lipid profile with meglitinides versus
metformin is low.[7] There is low level of evidence to determine all-cause mortality or CV mortality
benefits, however, one 24-week trial found one death in the metformin group and no deaths in the
nateglinide treatment group.[7, 31] The one death in the metformin group was judged by investigators to
be unlikely to be associated with therapy.[31] A recent nationwide study of over 100,000 Danish
residents >20years of age, determined no statistical difference in all-cause mortality between patients
taking repaglinide versus metformin.[32]
Safety: In Bennett et al review, 5 RCTs determined a favorable side effect profile for mild or moderate
hypoglycemic events for metformin over meglitinides with an OR of 3.01.[7] Comparatively,
meglitinides present with a favorable GI adverse effect profile over metformin.[7, 33] In one doublePage 8 of 37
blind, RCT combined GI side-effects were 70% and 47% for metformin and repaglinide,
respectively.[33]
GRADE evidence is summarized in Table 9.
5. DPP-4 Inhibitors (Sitagliptin, Saxagliptin) and Sulfonylureas:
Efficacy: Bennett et al reviewed one 12-week moderately-sized double-blind RCT compared high dose
sitagliptin with maximum dose glipizide and found similar reductions in HbA1c, -0.77% versus -1.00%,
for DPP-4 inhibitor and SFU, respectively.[7] Additional studies comparing DPP-4 inhibitor or SFU
add-on therapy to metformin have shown similar results for reduction of HbA1c, not favoring either
agent.[7, 19, 20, 34] Evidence indicates a benefit for weight reduction with a DPP-4 inhibitor over SFU,
either as monotherapy and as combination therapy with metformin.[7, 19, 20, 34] However, due to lack
of direct monotherapy comparative data, unable to determine true effect. Bennett et al review of lipid
profile indicated an increase in LDL and HDL with sitagliptin over SFU, while the increase in TG with
sitagliptin was less than the increase with SFU (3.6% versus 7.0%).[7] However, in all lipid measures
reviewers found an overlapping CI after placebo-subtracted change from baseline in each group.[7]
There is insufficient data to determine all-cause mortality benefits for this comparison.[7]
Safety: Sitagliptin consistently has a better hypoglycemic profile compared to SFUs as monotherapy and
as combination therapy with metformin.[7, 18-20] Additionally, reduced incidence of hypoglycemia
with sitagliptin versus glipizide or glimepiride was observed during Ramadan in a multi-center
study.[18] This is a specialized patient population since observers of Ramadan abstain from food or
water from dawn until dusk for the duration of the month of Ramadan.[18] No differences in GI sideeffects have been observed with DPP-4 inhibitors and SFU as monotherapy or combination therapy.[7,
20, 35]
GRADE evidence: For all outcomes, the evidence strength for DPP-4 inhibitor comparison with SFUs is
Low, with the exception of hypoglycemia and GI adverse events, for which the evidence strength is
Moderate. One short term RCT evaluating direct comparison of DPP-4 inhibitor with SFU was
identified [35]; this trial is reviewed in Bennett et al.[7] Low risk of bias is detected, the outcomes
observed were direct, however, it is not possible to determine consistency (due to only one study) and
there is concern for precision since the trial moderately sized and no statistical analysis was provided for
some outcomes (such as GI side effects), and differing doses on sitagliptin and glipizide (based on
titration protocol) were compared leading to uncertainty in results.
6. Glitazones (Rosiglitazone, Pioglitazone) and Sulfonylureas:
Efficacy: Bennett et al reviewed 13 RCTs comparing glitazones or thiazolidinediones (TZDs)
(pioglitazone and rosiglitazone) and second-generation sulfonylureas (glibenclamide, glimepiride, and
glyburide). The review found both treatments had similar effects on HbA1c.[7] Five RCTs with up to 1
year or less in duration, compared glitazones and a SFU, showing greater weight gain with glitazones,
favoring SFUs.[7] Five RCTs compared rosiglitazone or pioglitazone with a SFU, indicating a greater
increase in LDL with glitazones relative to a SFU.[7] Eight RCTs compared rosiglitazone or
Page 9 of 37
pioglitazone with a SFU, indicating a favorable increase in HDL with glitazones relative to a SFU.[7]
Pioglitazone is favored for a greater decrease in TG over SFUs in 6 RCTs.[7] However, when
comparing rosiglitazone and SFUs, Bennett et al found conflicting evidence for benefits of TG lowering.
In one RCT, while both rosiglitazone (at 8mg dose) and a SFU were associated with a decrease in TG,
the differences were non-significant; in another RCT a lower dose (4mg) of rosiglitazone lowered TG
relative to a SFU, however, at a dose of 8mg, rosiglitazone increased TG relative to SFU with no
statistical significance reported.[7] The ADOPT study showed all-cause mortality and cardiovascular
mortality to be similar for rosiglitazone and glyburide at 2.3% and 2.2%, respectively.[7, 26] As above,
it should be noted that the FDA has placed a boxed warning for all thiazolidinedione agents, including
rosiglitazone and pioglitazone for risk of congestive heart failure.[27-29]
Safety: Five RCTs determined a greater risk of mild to moderate hypoglycemia with SFUs over
glitazones with an OR of 3.9.[7] Although the ADOPT study with over 1300 participants in each arm
reported no statistical significance for outcome of hypoglycemia between rosiglitazone and glyburide.[7]
Bennett et al reviewed 4 RCTs looking at outcome of CHF with glitazones versus SFU and found an
increase of CHF incidence with glitazones over SFUs with an OR of 1.68.[7] While the review did not
show statistical significance, clinical significance could not be ruled out.[7] Three RCTs did not show a
consistent difference in the occurrence of diarrhea between groups treated with pioglitazone or
rosiglitazone and glyburide.[7]
GRADE evidence is summarized in Table 10.
7. Alpha-glucosidase inhibitors (AGIs – Acarbose, Miglitol) and Sulfonylureas:
Efficacy: Van de Laar et al reviewed 8 RCTs comparing SFU and acarbose showing a non-significant
trend for reduction in HbA1c in favor of SFU.[14] However, for most comparisons the review found that
the SFU was dosed sub-maximally.[14] Van de Laar et al review found no statistically significant
differences in weight between AGIs and SU.[14] Five RCTs show Reviews of RCTs by Van de Laar et
al and Bolen et al, found no benefit for lipid profile (LDL, HDL or TG) when comparing acarbose
versus a SFU.[9, 14] All-cause mortality and cardiovascular mortality evidence is limited to allow for
determination of mortality benefit between SFU and acarbose.[9] One small RCT comparing acarbose
and tolbutamide showed no statistical difference in mortality benefit between the two treatments.[9, 14]
Safety: SFUs are favored for their overall and GI side effect profile. One RCT favors SFU over acarbose
for GI side effects with an OR of 7.70.[14] However, in contrast, in terms hypoglycemic risks acarbose
is favored over SFU.[9, 36]
GRADE evidence is summarized in Table 11.
8. Meglitinides (Repaglinide, Nateglinide) and Sulfonylureas:
Efficacy: Bennett et al reviewed 7 RCTs comparing a second-generation sulfonylurea with repaglinide,
showing a pooled between-group difference of 0.1 percent (95 percent CI -0.2 percent to 0.3 percent)
slightly favoring meglitinides.[7] However, when only studies using comparable doses of the two agents
Page 10 of 37
were evaluated (3 out 7 studies), no differences in HbA1c reduction were observed.[7] The review found
that no single study significantly influenced the results.[7] A review of 6 RCTs comparing meglitinides
with SFUs showed no benefit for reduction in weight.[7] No statistically significant differences have
been observed for improvement of lipid profile (LDL, HDL, TG) when comparing SFUs and
meglitinides.[7] Evidence is limited to for mortality benefits when comparing these two classes of drugs.
Bennett et al reviewed one, 1-year long RCT that looked at the all-cause mortality between repaglinide
and glyburide and observed 3 deaths out of 362 participants in the repaglinide group and 1 death out of
182 participants in the glyburide group.[7] Each treatment group had one CV related death.[7] To note,
the reviewers identified the strength of the evidence for all-cause mortality and CV mortality outcomes
as low.[7]
Safety: Six studies reviewed by Bennett et al showed a lower incidence of hypoglycemia with
meglitinides when compared with a SFU, however, the pooled results were not statistically
significant.[7] The lower incidence of hypoglycemia is supported by 2 RCTs since the Bennett
review.[22, 32] Additionally, a high-quality trial comparing repaglinide versus glibenclamide in patients
observing Ramadan, showed statistically significant lower incidence of hypoglycemia with repaglinide
than with glibenclamide (p<0.001).[7, 37] As mentioned above, Ramadan is a period during which the
practitioners do not drink or eat from sunrise to sunset, so this study applies to a specific subset of
patient population.[18, 37] The same study and two others have found that apart from incidence of
hypoglycemia, both treatments were equally well tolerated.[37-39] However, there is paucity of data for
evaluation of comparative GI side-effects between these agents.
GRADE evidence is summarized in Table 12.
9. Statement on Amylin Analogues – Pramlintide:
The 18th EC on Essential Medicines had also requested a comparative review of pramlintide, an amylin
analogue.[6] However, a detailed review on this medication was not prepared because it was determined
to be not appropriate for a comparison with oral hypoglycemics, the primary focus of this review.
Pramlintide is a subcutaneous injectable synthetic analog of the human amylin peptide, a hormone
produced by the pancreas for glycemic control during postprandial period.[40] Pramlintide works by
delaying gastric emptying to reduce the initial postprandial increase in glucose, preventing a rise in
plasma glucagon during postprandial period and causes satiety to decrease caloric intake.[40]
Pramlintide is indicated for use prior to meals as an adjunct to insulin with or without SFU or
metformin.[40]
V.
Cost, Regulatory and Current NEML Availability Evaluation:
Table 2 provides an overview of the cost per unit, per 30 units and estimated monthly cost of treatment
with medications under review in US dollars. Metformin and glibenclamide prices are from MSH and
Lexi-Comp online; however, the cost of other agents was not available from MSH, therefore, LexiComp online was used to evaluation – this provides costs of medications as they pertain to US
markets.[16, 17] Regulatory status of medications in the US (FDA) and Australia (TGA) is also
Page 11 of 37
shown.[27, 41] As mentioned above, the regulatory status in US and Australia was selected as an initial
reference point given the stringent review and approval process required for therapeutic approval by
these agencies and due to the availability of the databases in English.
Table 3 evaluates the availability of DPP-4 inhibitors, glitazones, acarbose and meglitinides across 15
low and middle-income countries based on the NEML for each nation. The countries for this review
were selected at random from the WHO website hosting NEMLs.[15]
Table 2: Comparative Cost Chart and Drug Approval by US and Australian Regulatory Agencies
Medication (Name and
Cost per unit
Cost/30
Strength)
(USD)
tablets (USD)
0.0087[16]
0.26
Metformin 500mg*
0.0042[16]
0.13
Glibenclamide 5mg*
Prices from Lexi-Comp Online (US based prices) [17]
0.23
6.50
Metformin 500mg*
0.60
17.99
Metformin 1000mg*
0.53
15.99
Glibenclamide 5mg*
7.18
215.40
Sitagliptin 25mg
7.83
234.90
Sitagliptin 100mg
3.03
90.90
Rosiglitazone 2mg
8.33
249.99
Rosiglitazone 8mg
6.45
193.48
Pioglitazone 15mg
10.33
310.00
Pioglitazone 45mg
0.84
25.20
Acarbose 25mg*
0.90
27.00
Acarbose 100mg*
1.60
47.99
Nateglinide 60mg*
3.04
91.21
Repaglinide 0.5mg
2.93
87.92
Repaglinide 2mg
*Denotes generic price
Daily Maximum
Dose[17]
2550mg/day
20mg/day
Monthly cost based on
maximum dosing (USD)
1.30
0.52
FDA
Approved
Yes
Yes
TGA
Approved
Yes
Yes
2550mg/day
2550mg/day
20mg/day
100mg daily
100mg daily
8mg once or BID
8mg once or BID
45mg/day
45mg/day
100mg TID
100mg TID
120mg TID
16mg daily
16mg daily
26.00
44.98
15.99
861.60
234.90
363.60
249.99
580.44
310.00
302.40
81.00
287.94
2918.40
703.20
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
Yes
Table 3: Oral hypoglycemics listed on selected NEMLs
#
Country
Bangladesh
1
China
2
Dominican Republic
3
Ecuador
4
Fiji
5
Ghana
6
India
7
Iran
8
Kyrgyzstan
9
10 Malta
11 Morocco
12 Malaysia
13 Namibia
14 Nigeria
15 Oman
Total # of surveyed countries with identified
medications on the NEML
VI.
DPP-4 Inhibitors
(Sitagliptin)
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
0
Glitazones
(Pioglitazone and
Rosiglitazone)
No
No
No
No
No
No
No
Yes (pioglitazone)
Yes (Rosiglitazone)
No
No
No
No
No
Yes (rosiglitazone)
3
Alpha-glucosidase
inhibitors
(Acarbose)
No
No
No
No
No
No
No
Yes (acarbose)
No
Yes (acarbose)
Yes (acarbose)
No
No
No
No
3
Meglitinides
(Repaglinide and
Nateglinide)
No
No
No
No
No
No
No
Yes (repaglinide)
No
Yes (repaglinide)
No
No
No
No
No
2
Summary:
Page 12 of 37
This document provides a comprehensive comparative efficacy, safety and cost profile of four classes of
oral hypoglycemic agents – glitazones, DPP-4 inhibitors, alpha-glucosidase inhibitors and meglitinides
versus sulfonylureas and metformin using GRADE methodology in Section IV and in Tables 6 through
12. Table 4 provides a summary of the key efficacy and safety outcomes alongside the strength of
evidence. The summary table also provides a relative comparison of cost for the agents in review
compared to metformin and glibenclamide as baseline agents. The cost comparison is based on US
market as referenced from Lexi-Comp online database for the recommended maximum daily dose. Costs
for metformin 500mg strength and glibenclamide 5mg strength was used as these dosage strengths are
on the EML and compared to maximum available strength for the comparative agents. Additionally this
review has shown the limited availability of these agents on NEMLs from a survey of 15 LMICs in
Table 3 and provided information on regulatory status of these agents in the US and Australia in Table
2.
Evidence on efficacy, safety, cost and availability on selected NEMLs does not support the addition of
any agent from the four classes of oral hypoglycemics reviewed – glitazones, DPP-4 inhibitors, alphaglucosidase inhibitors and meglitinides – to the EML at this time.
Page 13 of 37
Appendix:
Table 4: Summary: Comparative efficacy and safety of oral hypoglycemics
Comparison
HbA1c
Weight
LDL
HDL
TG
Hypoglycemia
Adverse events
(GI)
Metformin versus (outcome and strength of evidence) Relative Cost: Metformin Baseline [US$26.00/month for 500mg tablets (strength on EML)]
Favors
Favors
Neither favored
Neither favored
Neither favored
Neither favored Favors DPP-4-I
1 DPP-4 inhibitors
(Sitagliptin,
Metformin
Metformin
(Low)
(Very Low)
(Low)
(High)
(Very Low)
Saxagliptin)
(Moderate)
(Moderate)
Neither favored
Favors
Favors
Neither favored
Favors
Neither favored Favors
2 Glitazones
(Rosiglitazone,
(Moderate)
Metformin
Metformin
(Moderate)
Metformin (Low) (High)
Glitazones
Pioglitazone)
(High)
(Moderate)
(High)
3
AGIs (Acarbose,
Miglitol)
Neither favored
(Moderate)
Neither favored
(Low)
Favors Acarbose
(Moderate)
Neither favored
(Moderate)
Neither favored
(Moderate)
Unclear
(Low)
4
Meglitinides
(Nateglinide,
Repaglinide)
Neither favored
(Moderate)
Neither favored
(Moderate)
Neither favored
(Moderate)
Neither favored
(Moderate)
Neither favored
(Moderate)
Favors
Metformin
(Low)
Favors
Metformin
(Moderate)
Favors
Meglitinides
(High)
Sulfonylureas versus (outcome and strength of evidence) Relative Cost: Glibenclamide Baseline [US$ 15.99/month for 5mg tablets (strength on EML)]
Neither favored
Unclear
Neither favored
Neither favored
Neither favored
Favors DPP-4-I Neither favored
5 DPP-4 inhibitors
(Sitagliptin,
(Low)
(Low)
(Low)
(Low)
(Low)
(Moderate)
(Moderate)
Saxagliptin)
Neither favored
Favors SFU
Favors SFU
Favors Glitazones Unclear
Neither favored Neither favored
6 Glitazones
(Rosiglitazone,
(Moderate)
(Low)
(Low)
(Low)
(Low)
(High)
(High)
Pioglitazone)
7
8
AGIs (Acarbose,
Miglitol)
Meglitinides
(Nateglinide,
Repaglinide)
Neither favored
(Moderate)
Neither favored
(High)
Neither favored
(Moderate)
Neither favored
(High)
Neither favored
(High)
Neither favored
(Low)
Neither favored
(High)
Neither favored
(Moderate)
Neither favored
(High)
Neither favored
(Low)
Favors AGI
(High)
Favors
Meglitinides
(Moderate)
Favors SFU
(High)
Unknown
(n/a)
Relative Cost
(cost for
maximum
monthly dose)
Sitagliptin 100mg:
9x greater than
Metformin
Rosiglitazone 8mg:
9.6x greater
Pioglitazone 45mg:
11.9x greater
Acarbose 100mg:
3.11x greater
Nateglinide 60mg:
11x greater
Repaglinide 2mg:
27x greater
Sitagliptin 100mg:
14.6x greater than
Glibenclamide
Rosiglitazone 8mg:
15.6x greater
Pioglitazone 45mg:
19x greater
Acarbose 100mg:
5x greater
Nateglinide 60mg:
18x greater
Repaglinide 2mg:
43x greater
Page 14 of 37
Table 5: Chart of systematic reviews used
Drug Class
Drugs
Alpha-glucosidase
1. Acarbose
inhibitors
2. Miglitol
3. Voglibose
DPP-4 Inhibitors
1. Sitagliptin
2. Saxagliptin
Meglitinide
1. Repaglinide
Analogues
2. Nateglinide
Biguanides
1. Metformin
Glitazones
1. Rosiglitazone
All above
1. Pioglitazone
All above
All above except
Alpha-glucosidase
inhibitors
All above except
Alpha-glucosidase
inhibitors
Review
Alpha-glucosidase inhibitors for type 2 diabetes mellitus (Van
de Laar FA)[14]
Period Reviewed
Up to: 29 April 2003
Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes
Mellitus (Richter B)[12]
Meglitinide analogues for type 2 diabetes mellitus (Black C)[8]
Up to: 30 January 2008
Metformin monotherapy for type 2 diabetes mellitus (Saenz
A)[13]
Rosiglitazone for type 2 diabetes mellitus (Richter B)[11]
Up to: 29 September 2003.
Pioglitazone for type 2 diabetes mellitus (Richter B)[10]
Comparative Effectiveness and Safety of Oral Diabetes
Medications for Adults with Type 2 Diabetes. Comparative
Effectiveness (Bolen et al.)[9]
Oral Diabetes Medications for Adults With Type 2 Diabetes: An
Update (Bennett et al.)[7]
Up to: 30 August 2006.
Up to: January 2006
Up to : 30 October 2006
Up to: 29 April 2007
Up to: April 2010
Page 15 of 37
Table 6: Question: Should Metformin vs DPP-4 Inhibitors be used for Diabetes Mellitus, Type 2?
Bibliography: Oral diabetes medications for adults with type 2 diabetes: An update. Bennett W. et al.
Quality assessment
Participants Risk of
(studies)
bias
Follow up
Inconsistency
Indirectness
Imprecision
Summary of Findings
Publication Overall quality of
bias
evidence
Study event rates
(%)
Relative Anticipated absolute effects
effect
(95% CI)
With DPP-4 With
Inhibitors Metformin
Risk with DPP-4 Inhibitors
Risk difference with Metformin
(95% CI)
Mean difference in HbA1c for Metformin vs DPP-4 Inhibitors (CRITICAL OUTCOME; measured with: %; Better indicated by lower values)
1921
(3 studies)
24 weeks
serious1
no serious
inconsistency
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊝
MODERATE1
due to risk of bias
972
949
-
The mean mean difference
in hba1c for metformin vs
dpp-4 inhibitors in the
control groups was
-0.7 %
The mean mean difference
in hba1c for metformin vs
dpp-4 inhibitors in the
intervention groups was
0.37 lower
(0.54 to 0.2 lower)
Mean difference in weight for Metformin vs DPP-4 Inhibitors (NOT IMPORTANT OUTCOME; measured with: Kg; Better indicated by lower values)
1918
(3 studies)
24 to 54
weeks
serious1
no serious
inconsistency
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊝
MODERATE1
due to risk of bias
969
949
-
The mean mean difference
in weight for metformin vs
dpp-4 inhibitors in the
control groups was
-0.6 Kg
The mean mean difference
in weight for metformin vs
dpp-4 inhibitors in the
intervention groups was
1.40 lower
(1.8 to 1 lower)
Mean difference in LDL for Metformin vs DPP-4 Inhibitors (NOT IMPORTANT OUTCOME; measured with: mg/dL; Better indicated by lower values)
1918
(3 studies)
24 to 54
weeks
serious2
no serious
inconsistency
no serious
indirectness
serious2
undetected
⊕⊕⊝⊝
LOW2
due to risk of bias,
imprecision
969
949
-
The mean mean difference
in ldl for metformin vs dpp4 inhibitors in the control
groups was
-0.5 mg/dL
The mean mean difference
in ldl for metformin vs dpp-4
inhibitors in the intervention
groups was
5.85 lower
(9.65 to 2.05 lower)
Mean difference in HDL for Metformin vs DPP-4 Inhibitors (NOT IMPORTANT OUTCOME; measured with: mg/dL; Better indicated by higher values)
1918
(3 studies)
24 to 54
serious3
serious3
no serious
indirectness
serious3
undetected
⊕⊝⊝⊝
VERY LOW3
due to risk of bias,
969
949
-
The mean mean difference The mean mean difference
in hdl for metformin vs dpp- in hdl for metformin vs dpp4 inhibitors in the control
4 inhibitors in the
Page 16 of 37
weeks
inconsistency,
imprecision
groups was
3.9 mg/dL
intervention groups was
2.30 higher
(0.28 lower to 4.88 higher)
Mean difference in triglycerides for Metformin vs DPP-4 Inhibitors (NOT IMPORTANT OUTCOME; measured with: mg/dL; Better indicated by lower values)
1918
(3 studies)
24 to 54
weeks
serious4
no serious
inconsistency
no serious
indirectness
serious4
undetected
⊕⊕⊝⊝
LOW4
due to risk of bias,
imprecision
969
949
-
The mean mean difference
in triglycerides for
metformin vs dpp-4
inhibitors in the control
groups was
-3 mg/dL
The mean mean difference
in triglycerides for metformin
vs dpp-4 inhibitors in the
intervention groups was
3.4 higher
(0.39 lower to 7.19 higher)
All-cause mortality for Metformin vs DPP-4 Inhibitor5 (CRITICAL OUTCOME; measured with: Number of events; Better indicated by lower values)
0
(0)
See comment
-
0
-5
See comment
See comment
not
pooled5
See comment
See comment
RR 1.88
(0 to 0)7
17 per 1000
15 more per 1000
(from 17 fewer to 17 fewer)
Cardiovascular mortality for Metformin vs DPP-4 Inhibitor5 (CRITICAL OUTCOME; assessed with: Number of events)
0
(0)
See comment
-
-
Hypoglycemia for Metformin vs DPP-4 Inhibitor (CRITICAL OUTCOME; assessed with: Number of events)
1050
(1 study)
24 weeks
no serious no serious
risk of
inconsistency
bias6
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊕
HIGH6
9/528
(1.7%)
17/522
(3.3%)
Combined GI adverse effects for Metformin vs DPP-4 Inhibitor (Nausea/Vomiting/Diarrhea/Abdominal discomfort) (IMPORTANT OUTCOME;
assessed with: Number of events)
1155
(2 studies)
24 weeks
very
serious8
no serious
inconsistency8
no serious
indirectness
serious8
undetected
⊕⊝⊝⊝
VERY LOW8
due to risk of bias,
imprecision
88/534
(16.5%)
146/621
(23.5%)
RR 1.42
(0 to 0)
165 per 1000
69 more per 1000
(from 165 fewer to 165
fewer)
1
Bennett et al reviewers rated 3 RCTs as Moderate due to medium risk of bias. No identification for the source of bias was provided.
Bennett et al reviewers rated 3 RCTs as Moderate due to medium risk of bias and imprecision. No identification for the source of bias was provided. Possible reason for the rating of imprecision may be
the MD of -5.85mg/dL with a somewhat wide CI [-9.65, -2,.05]. However, using the GRADE criteria, the rating for this evidence has been decreased to Low.
3
Bennett et al reviewers rated 3 RCTs as Low due to medium risk of bias, inconsistency and imprecision. No identification for the source of bias was provided. Possible reason for the rating of imprecision
may be the MD of 2.30mg/dL with a CI [-0.28, 4.88] that cross the line of no difference. A possible reason for inconsistency may be due to the I-squared value of 49%. However, using the GRADE criteria,
the rating for this evidence has been decreased to Very Low.
2
Page 17 of 37
4
Bennett et al reviewers rated 3 RCTs as Low due to medium risk of bias and imprecision. No identification for the source of bias was provided. Possible reason for the rating of imprecision may be the
MD of 3.40mg/dL with a relatively wide CI [-0.39, 7.19] that crosses the line of no difference.
5
Insufficient data
6
Bennett et al reviewers rated 3 RCTs as High with medium risk of bias. No identification for the source of bias was provided. This table is based on 1 double-blind, multi-center RCT with over 500
participants in each treatmentment group. No points were deducted for bias. The overall rating of the evidence remains consistent with that of the reveiwers as High.
7
No statistically significant (p=0.12)
8
Bennett et al reviewers rated 2 RCTs as Low due to high risk of bias, unknown inconsistency and imprecision. No source of bias was identified. The review did not provide a meta-analysis of these trial,
therefore, the reveiwers determination of bias and imprecision is accepted, however, the no points will be deducted for inconsistency. Further, using the GRADE criteria, the rating for this evidence has
been decreased to Very Low.
Page 18 of 37
Table 7: Question: Should Metformin vs Glitazones be used for Diabetes Mellitus Type 2?
Bibliography: Oral Diabetes Medications for Adults With Type 2 Diabetes: An Update (Bennett et al)
Quality assessment
Participants Risk of
(studies)
bias
Follow up
Inconsistency
Indirectness
Imprecision
Summary of Findings
Publication Overall quality of
bias
evidence
Study event rates
(%)
Relative Anticipated absolute effects
effect
(95% CI)
With
With
Glitazones Metformin
Risk with Glitazones
Risk difference with
Metformin (95% CI)
Mean difference in HbA1c for Metformin vs Glitazones (CRITICAL OUTCOME; measured with: %; Better indicated by lower values)
2662
(14 studies)
12 to 52
weeks
serious1
no serious
inconsistency2
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊝
MODERATE1,2
due to risk of bias
1334
1328
-
The mean mean difference
in hba1c for metformin vs
glitazones ranged across
control groups from
-2.6 to -0.3 %
The mean mean
difference in hba1c for
metformin vs glitazones in
the intervention groups
was
0.07 lower
(0.18 lower to 0.04 higher)
Mean weight difference for Metformin vs Glitazones (NOT IMPORTANT OUTCOME; measured with: Kg; Better indicated by lower values)
1914
(8 studies)
16 to 52
weeks
no serious no serious
risk of
inconsistency
bias
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊕
HIGH
972
942
-
The mean mean weight
difference for metformin vs
glitazones in the control
groups was
-0.3 Kg
The mean mean weight
difference for metformin
vs glitazones in the
intervention groups was
2.61 lower
(4.06 to 1.16 lower)
Mean difference in LDL for Metformin vs Rosiglitazone (NOT IMPORTANT OUTCOME; measured with: mg/dL; Better indicated by lower values)
482
(6 studies)
16 to 52
weeks
no serious no serious
risk of
inconsistency
bias
no serious
indirectness1
serious3
undetected
⊕⊕⊕⊝
MODERATE1,3
due to imprecision
246
236
-
The mean mean difference
in ldl for metformin vs
rosiglitazone in the control
groups was
5.1 mg/dL
The mean mean
difference in ldl for
metformin vs rosiglitazone
in the intervention groups
was
12.76 lower
(23.96 to 1.56 lower)
Mean difference in HDL for Metformin vs. Rosiglitazone (NOT IMPORTANT OUTCOME; measured with: mg/dL; Better indicated by higher values)
Page 19 of 37
482
(6 studies)
16 to 52
weeks
serious4
no serious
inconsistency
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊝
MODERATE4
due to risk of bias
246
236
-
The mean mean difference
in hdl for metformin vs.
rosiglitazone in the control
groups was
3.5 mg/dL
The mean mean
difference in hdl for
metformin vs.
rosiglitazone in the
intervention groups was
0.45 lower
(2.34 lower to 1.43 higher)
Mean difference in TG for Metformin vs. Rosiglitazone (NOT IMPORTANT OUTCOME; measured with: mg/dL; Better indicated by lower values)
482
(6 studies)
16 to 52
weeks
serious5
serious5
no serious
indirectness
serious5
undetected
⊕⊕⊝⊝
LOW5
due to risk of bias,
inconsistency,
imprecision, large
effect
246
236
-
The mean mean difference
in tg for metformin vs.
rosiglitazone in the control
groups was
-4.2 mg/dL
The mean mean
difference in tg for
metformin vs.
rosiglitazone in the
intervention groups was
26.86 lower
(49.26 to 4.47 lower)
RR 0.91
(0 to 0)
23 per 1000
2 fewer per 1000
(from 23 fewer to 23
fewer)
1 per 1000
0 fewer per 1000
(from 1 fewer to 1 fewer)
All-cause mortality for Metformin vs Rosiglitazone (CRITICAL OUTCOME6; assessed with: Number of events)
2910
(1 study6)
4 years
no serious no serious
risk of
inconsistency
bias
no serious
indirectness
no serious
imprecision6
undetected
⊕⊕⊕⊕
HIGH6
34/1456
(2.3%)
31/1454
(2.1%)
Cardiovascular mortality for Metformin vs Rosiglitazone (CRITICAL OUTCOME; assessed with: Number of events)
2910
(1 study7)
4 years
no serious no serious
risk of
inconsistency
bias7
no serious
indirectness
no serious
imprecision7
undetected
⊕⊕⊕⊕
HIGH7
2/1456
(0.14%)
2/1454
(0.14%)
RR 1
(0 to 0)
Hypoglycemia for Metformin vs Glitazones (CRITICAL OUTCOME; assessed with: Number of events)
2910
(1 study)
4 years
no serious no serious
risk of
inconsistency
bias1,8
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊕
HIGH1,8
97 per 1000
141/1456 167/1454 RR 0.9
(9.7%)
(11.5%)
(0.8 to 1)
10 fewer per 1000
(from 19 fewer to 0 more)
Incidence of Heart Failure for Metformin vs Rosiglitazone (IMPORTANT OUTCOME; assessed with: Number of events)
2910
(1 study9)
4 years
no serious no serious
risk of
inconsistency
bias
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊕
HIGH
22/1456
(1.5%)
19/1454
(1.3%)
RR 0.86
(0 to 0)
15 per 1000
2 fewer per 1000
(from 15 fewer to 15
fewer)
Page 20 of 37
Combined GI adverse effects for Metformin vs Rosiglitazone (Nausea/Vomiting/Diarrhea/Abdominal discomfort) (IMPORTANT OUTCOME; assessed
with: Number of events)
2910
(1 study10)
4 years
no serious no serious
risk of
inconsistency
bias
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊕
HIGH
335/1456 557/1454 RR 1.66
(23%)
(38.3%)
(0 to 0)
230 per 1000
152 more per 1000
(from 230 fewer to 230
fewer)1
1
Rating based on documentation by Bennett et al reviewers for 16 studies. No reason for down-grading of evidence was provided.
Rating based on documentation by Bennett et al reviewers for 16 studies. Consistent for short-duration studies. One long-term study inconsistent. No points were deducted.
3
Rating based on documentation by Bennett et al reviewers for 7 studies. No reason for down-grading of evidence was provided. However, a MD of -12.76 is reported with a wide CI [-23.96, -1.56], which
may account for imprecision of evidence.
4
Rating based on documentation by Bennett et al reviewers for 6 studies. No reason for down-grading of evidence was provided. However, a modest MD of -0.45 is reported with a CI crossing the line of
no difference [-2.34, 1.43], which may account for imprecision of evidence.
5
Rating based on documentation by Bennett et al reviewers for 7 studies. No reason for down-grading of evidence was provided. An I-squared value of 70% is reported, which could account for the
imprecision rating. A wide CI [-49.26, -4.47] with a mean difference of -26.86mg/dL favoring metformin is reported, which could account for the inconsistency rating. The median change for rosiglitazone
was -4.2mg/dL versus -26.86mg/dL for metformin, which could account for the large effect reported by the authors.
6
Bennett et al reviewers report Low strength of evidence based of 4 RCTs for all-cause mortality due to imprecision, however, no further explanation was provided. The all-cause mortality outcome on this
table is based on the ADOPT study, a large double-blind, RCT; the strength of this evidence is ranked as High.
7
Bennett et al reviewers report Low strength of evidence based of 2 RCTs for CV mortality due to imprecision and moderate level of bias, however, no further explanation was provided. The CV mortality
outcome on this table is based on the ADOPT study, a large double-blind RCT; the strength of this evidence is ranked as High.
8
Bennett et al reviewers report Moderate strength of evidence based on ADOPT study for hypoglycemia due to moderate level of bias and unknown consistency, however, no further explanation was
provided. Given only 1 RCT, the consistency of this evidence can be classified as unknown. The hypoglycemia outcome on this table is based on the ADOPT study, a large double-blind RCT; we are
classifying the strength of this evidence as High.
9
Bennett et al reviewers report Moderate strength of evidence based of 3 RCTs and 4 observational studies for CHF due to moderate level of bias, inconsistency and imprecision, however, no further
explanation was provided. The reviewers note low-grade evidence showing increased risk of HF with glitazones, which could explain the Moderate strength of evidence. The CHF outcome on this table is
based on the ADOPT study, a large double-blind, RCT; the strength of this evidence is ranked as High.
10
Bennett et al reviewers report High strength of evidence based of 5 RCTs for GI side-effects. The GI side-effects outcome on this table is based on the ADOPT study, a large double-blind RCT; the
strength of this evidence is ranked as High.
2
Page 21 of 37
Table 8: Question: Should Acarbose vs Metformin be used for Diabetes Mellitus, Type 2?
Bibliography: 1. Alpha-glucosidase inhibitors for type 2 diabetes mellitus. Van de Laar FA, et al. 2. Comparative Effectiveness and Safety of Oral Diabetes Medications for Adults with Type 2 Diabetes.
Bolen, et al. 3. Comparison of acarbose and metformin in patients with Type 2 diabetes mellitus insufficiently controlled with diet and sulphonylureas: a randomized, placebo-controlled study. Willms B. et
al.
Quality assessment
Participants Risk of
(studies)
bias
Follow up
Inconsistency
Indirectness
Imprecision
Summary of Findings
Publication
bias
Overall quality
of evidence
Study event rates
(%)
Relative
effect
(95% CI)
With
With
Metformin Acarbose
Anticipated absolute effects
Risk with Metformin
Risk difference with Acarbose
(95% CI)
Mean difference in HbA1c for Acarbose vs. Placebo (IMPORTANT OUTCOME; measured with: %; Better indicated by lower values)
2831
(28 studies1)
16 to 52
weeks
no
serious
risk of
bias
no serious
inconsistency
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊕
HIGH
1442
1389
-
The mean mean difference
in hba1c for acarbose vs.
placebo ranged across
control groups from
-1.61 to 1.6 %
The mean mean difference in
hba1c for acarbose vs.
placebo in the intervention
groups was
0.77 lower
(0.9 to 0.64 lower)
Mean difference in HbA1c for Acarbose vs Metformin (CRITICAL OUTCOME; measured with: %; Better indicated by lower values)
62
(1 study3)
24 weeks
no
serious
risk of
bias
serious2
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊝
MODERATE2
due to
inconsistency
31
31
-
The mean mean difference
in hba1c for acarbose vs
metformin in the control
groups was
-0.86
The mean mean difference in
hba1c for acarbose vs
metformin in the intervention
groups was
0.25 lower
(0.61 lower to 0.11 higher)
Mean difference in LDL for Acarbose vs Metformin (NOT IMPORTANT OUTCOME; measured with: mg/dL; Better indicated by lower values)
62
(1 study)
24 weeks
no
serious
risk of
bias
serious2
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊝
MODERATE2
due to
inconsistency
31
31
-
The mean mean difference
in ldl for acarbose vs
metformin in the control
groups was
0.05 mg/dL
The mean mean difference in
ldl for acarbose vs metformin
in the intervention groups
was
0.94 lower
(1.52 to 0.36 lower)
Mean difference in HDL for Acarbose vs Metformin (NOT IMPORTANT OUTCOME; measured with: mg/dL; Better indicated by higher values)
Page 22 of 37
62
(1 study)
24 weeks
no
serious
risk of
bias
serious2
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊝
MODERATE2
due to
inconsistency
31
31
-
The mean mean difference
in hdl for acarbose vs
metformin in the control
groups was
-0.01 mg/dL
The mean mean difference in
hdl for acarbose vs
metformin in the intervention
groups was
0.24 higher
(0.02 lower to 0.5 higher)
Mean difference in triglycerides for Acarbose vs Metformin (measured with: mg/dL; Better indicated by lower values)
62
(1 study)
24 weeks
no
serious
risk of
bias
serious2
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊝
MODERATE2
due to
inconsistency
31
31
-
The mean mean difference
in triglycerides for acarbose
vs metformin in the control
groups was
-0.12 mg/dL
The mean mean difference in
triglycerides for acarbose vs
metformin in the intervention
groups was
0.28 lower
(0.8 lower to 0.24 higher)
Mean difference in weight for Acarbose vs Metformin (NOT IMPORTANT OUTCOME; measured with: Kg; Better indicated by lower values)
62
(1 study)
24 weeks
no
serious
risk of
bias
serious2
no serious
indirectness
serious2,4
undetected
⊕⊕⊝⊝
LOW2,4
due to
inconsistency,
imprecision
31
31
-
The mean mean difference
in weight for acarbose vs
metformin in the control
groups was
-0.5 mg/dL
The mean mean difference in
weight for acarbose vs
metformin in the intervention
groups was
0.30 lower
(5.45 lower to 4.85 higher)
Adverse effects for Acarbose vs Metformin (Total) (IMPORTANT OUTCOME; assessed with: Number of events)
64
(1 study)
24 weeks
no
serious
risk of
bias
serious2
no serious
indirectness
serious5
undetected
⊕⊕⊝⊝
LOW2,5
due to
inconsistency,
imprecision
2/32
(6.3%)
16/32
(50%)
OR 15
(3.06 to
73.58)
62 per 1000
438 more per 1000
(from 107 more to 768 more)
3/31
(9.7%)
RR 0.5
(0 to 0)
172 per 1000
86 fewer per 1000
(from 172 fewer to 172
fewer)
Hypoglycemia Acarbose vs Metformin (CRITICAL OUTCOME; assessed with: Number of events)
60
(1 study8)
12 weeks
no
serious
risk of
bias
serious6
no serious
indirectness
serious7
undetected
⊕⊕⊝⊝
LOW6,7
due to
inconsistency,
imprecision
5/29
(17.2%)
1
Bases on the review by Van De Laar, et al. Review by Bolen et al. found 4 additional trials comparing alpha-glucosidase inhibitors with placebo that showed similar results.
The trial compared maximal doses of acarbose with submaximal doses of metformin.
3
Bases on the review by Van De Laar, et al. Review by Bolen et al. found 1 additional review that "compared submaximal doses of metformin to maximal doses of acarbose and showed no meaningful or
consistent effects on HbA1c."
2
Page 23 of 37
4
Mean difference of -0,30Kg is reported with a wide CI [-5.45, 4.85]. May include benefit for treatment with either treatment group.
An OR of 15.00 is reported in favor of metformin, however, with a wide CI [3.06, 73.58]. Given one study with small N and wide CI, unable to determine true effect.
6
Maximum dose of acarbose was compared with sub-maximal doses of metformin. A point for inconsistency was deducted.
7
No definition of hypoglycemia or criteria of evaluation for hypoglycemia was provided. Absolute number of events for hypoglycemia were reported with no stastical significance. A point was deducted for
imprecision.
8
Data from: Comparison of acarbose and metformin in patients with Type 2 diabetes mellitus insufficiently controlled with diet and sulphonylureas: a randomized, placebo-controlled study. Willms B. et al.
5
Page 24 of 37
Table 9: Question: Should Metformin vs meglitinides be used for Diabetes Mellitus, Type 2?
Bibliography: 1. Metformin monotherapy for type 2 diabetes mellitus (Review). (Saenz A. et al) 2. Oral diabetes medications for adults with type 2 diabetes: An update. (Bennett W. et al) 3. Comparative
Effectiveness and Safety of Oral Diabetes Medications for Adults with Type 2 Diabetes. Comparative Effectiveness Review No. 8. 2007. (Bolen S. et al)
Quality assessment
Participants Risk of
(studies)
bias
Follow up
Inconsistency
Indirectness
Imprecision
Summary of Findings
Publication Overall quality
bias
of evidence
Study event rates
(%)
Relative Anticipated absolute effects
effect
(95% CI)
With
With
Meglitinides Metformin
Risk with Meglitinides
Risk difference with Metformin
(95% CI)
Mean difference in HbA1c for Metformin vs Meglitinides (CRITICAL OUTCOME; measured with: %; Better indicated by lower values)
413
(2 studies2)
12 to 24
weeks
serious1
no serious
inconsistency
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊝
208
MODERATE1
due to risk of bias
205
-
The mean mean difference
in hba1c for metformin vs
meglitinides ranged across
control groups from
-0.38 to -0.3 %
The mean mean difference
in hba1c for metformin vs
meglitinides in the
intervention groups was
0.16 lower
(0.36 lower to 0.03 higher)2
Mean difference in weight for Metformin vs Meglitinides (NOT IMPORTANT OUTCOME; measured with: Kg; Better indicated by lower values)
56
(1 study)
12 weeks
serious3
no serious
inconsistency4
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊝
29
MODERATE3,4
due to risk of bias
27
-
The mean mean difference
in weight for metformin vs
meglitinides in the control
groups was
-2.98 Kg
The mean mean difference
in weight for metformin vs
meglitinides in the
intervention groups was
0.41 higher
(0.12 lower to 0.94 higher)5
Mean difference in LDL for Metformin vs Meglitinides (NOT IMPORTANT OUTCOME; measured with: SD units; Better indicated by lower values)
56
(1 study)
12 weeks
serious3
no serious
inconsistency4
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊝
29
MODERATE3,4
due to risk of bias
27
-
The mean mean difference
in ldl for metformin vs
meglitinides in the control
groups was
0.41 SD units
The mean mean difference
in ldl for metformin vs
meglitinides in the
intervention groups was
0.43 lower
(0.96 lower to 0.1 higher)6,7
Mean difference in HDL for Metformin vs Meglitinides (NOT IMPORTANT OUTCOME; measured with: SD units; Better indicated by higher values)
56
(1 study)
serious3
no serious
no serious
no serious
undetected
⊕⊕⊕⊝
MODERATE3,4
29
27
-
The mean mean difference
in hdl for metformin vs
The mean mean difference
in hdl for metformin vs
Page 25 of 37
inconsistency4
12 weeks
indirectness
imprecision
due to risk of bias
meglitinides in the control
groups was
0.21 SD units
meglitinides in the
intervention groups was
0.45 lower
(0.95 lower to 0.06
higher)6,7
Mean difference in TG for Metformin vs Meglitinides (NOT IMPORTANT OUTCOME; measured with: SD units; Better indicated by lower values)
56
(1 study)
12 weeks
serious3
no serious
inconsistency4
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊝
29
MODERATE3,4
due to risk of bias
27
-
The mean mean difference
in tg for metformin vs
meglitinides in the control
groups was
1.1 SD units
The mean mean difference
in tg for metformin vs
meglitinides in the
intervention groups was
0.24 lower
(0.76 lower to 0.29
higher)6,7
All-cause mortality for Metformin vs. Meglitinides (CRITICAL OUTCOME; assessed with: Number of events)
357
(1 study)
24 weeks
no serious no serious
risk of bias inconsistency4
no serious
indirectness
serious8
undetected
⊕⊕⊕⊝
MODERATE4,8
due to
imprecision
0/179
(0%)
1/178
(0.56%)9
-
-
Hypoglycemia for Metformin vs Meglitinides (CRITICAL OUTCOME10; assessed with: Number of events)
915
(5 studies)
16 to 52
weeks
serious11
no serious
inconsistency
no serious
indirectness
serious8
undetected
⊕⊕⊝⊝
59/457
(12.9%)
LOW8,11
due to risk of
bias, imprecision
25/458
(5.5%)
OR 3.01
(1.76 to
5.15)
129 per 1000
179 more per 1000
(from 78 more to 304
more)
Combined GI adverse effects for Metformin vs Meglitinides (Nausea/Vomiting/Diarrhea/Abdominal discomfort) (IMPORTANT OUTCOME12; assessed
with: Number of events)
165
(1 study)
8 months
no serious no serious
risk of bias inconsistency4
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊕
HIGH4
42/82
(51.2%)
65/83
(78.3%)
RR 1.53
(0 to 0)
512 per 1000
271 more per 1000
(from 512 fewer to 512
fewer)
1
For one of the studies in the analysis (Moses 1999), the allocation concealment is unclear; the weight of this study in the analysis is high (44.7%), resulting in deduction of a point.
Based on Saenz A. et al Cochrane review. Bennett et al identified another study that did not show meaningful between-group differences. (Derosa G, Mugellini A, Ciccarelli L, et al. Comparison of
glycaemic control and cardiovascular risk profile in patients with type 2 diabetes during treatment with either repaglinide or metformin. Diabetes Res Clin Pract 2003;60(3):161-169. )
3
The allocation concealment in Moses 1999 study unclear, resulting in deduction of a point.
4
Given only one study, inconsistency is unknown. No points are deducted.
5
Based on Saenz A. et al Cochrane review. Bennett et al identified a study indicating weight differences as non-significant. (Derosa G, Mugellini A, Ciccarelli L, et al. Comparison of glycaemic control and
cardiovascular risk profile in patients with type 2 diabetes during treatment with either repaglinide or metformin. Diabetes Res Clin Pract 2003;60(3):161-169.)
2
Page 26 of 37
6
Based on review by Saenz A. et al. Bennett et al, identified an RCT, indicating similar findings that between-group differences in LDL, HDL and TG were not statistically significant.
Not statistically significant.
8
Bennett et al reviewers classified the evidence as Low due to unknown consistency and imprecision, with no source of imprecision was identified. However, imprecision may stem from this outcome
being based on 1 small, short-term RCT with no clear conclusion on mortality benefit with either treatment. A point for imprecision was deducted. However, with GRADE assessment the the level of
evidence is classified as Moderate.
9
The relationship of the death was judged to be unlikely to be due to therapy.
10
This outcome based on review by Bennett et al.
11
Bennett et al reviewers classified the evidence as Moderate due to medium level of bias and imprecision, with no source of bias or imprecision identified. However, imprecision may stem for this
outcome based on wide 95% CI for 3 out of the 5 individual studies in this analysis. A point for imprecision and bias was deducted. However, with GRADE assessment the the level of evidence is
classified as Low.
12
The RCT for this outcome is discussed in Bennett et al, however, GRADE evidence outcome and GI effect incidence rate determined directly from the study. Lund, S.S., et al., Targeting hyperglycaemia
with either metformin or repaglinide in non-obese patients with type 2 diabetes: results from a randomized crossover trial. Diabetes Obes Metab, 2007. 9(3): p. 394-407.
7
Page 27 of 37
Table 10: Question: Should Glitazones vs SFU be used for Diabetes Mellitus, Type 2?
Bibliography: Oral Diabetes Medications for Adults With Type 2 Diabetes: An Update (Bennett et al)
Quality assessment
Participants Risk of
(studies)
bias
Follow up
Inconsistency
Indirectness
Imprecision
Summary of Findings
Publication
bias
Overall quality
of evidence
Study event rates
(%)
With SFU
Relative
effect
(95% CI)
With
Glitazones
Anticipated absolute effects
Risk with SFU
Risk difference with Glitazones
(95% CI)
Mean difference in HbA1c for Glitazones vs SFU (CRITICAL OUTCOME; measured with: %; Better indicated by lower values)
2170
(13 studies)
12 to 52
weeks
serious1
no serious
inconsistency
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊝
MODERATE1
due to risk of
bias
1003
1167
-
The mean mean difference
in hba1c for glitazones vs
sfu in the control groups
was
-0.9 %
The mean mean difference
in hba1c for glitazones vs
sfu in the intervention
groups was
0.10 lower
(0.22 lower to 0.01 higher)
Mean weight difference for Glitazones vs SFU (NOT IMPORTANT OUTCOME; measured with: Kg; Better indicated by lower values)
1533
(5 studies)
14 to 52
weeks
very
serious1,2
no serious
inconsistency
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊝⊝
LOW1,2
due to risk of
bias
680
853
-
The mean mean weight
difference for glitazones vs
sfu in the control groups
was
1.9 Kg
The mean mean weight
difference for glitazones vs
sfu in the intervention
groups was
1.24 higher
(0.63 to 1.85 higher)
Mean difference in LDL for Pioglitazone vs SFU (NOT IMPORTANT OUTCOME; measured with: mg/dL; Better indicated by lower values)
465
(3 studies)
24 to 52
weeks
very
serious3
no serious
inconsistency
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊝⊝
LOW3
due to risk of
bias
239
226
-
The mean mean difference
in ldl for pioglitazone vs sfu
in the control groups was
-1.4 mg/dL
The mean mean difference
in ldl for pioglitazone vs sfu
in the intervention groups
was
7.12 higher
(5.26 to 8.98 higher)
Mean difference in HDL for Pioglitazone vs SFU (NOT IMPORTANT OUTCOME; measured with: mg/dL; Better indicated by higher values)
616
(6 studies)
14 to 52
serious1
no serious
inconsistency
no serious
indirectness1
serious4
undetected
⊕⊕⊝⊝
LOW1,4
due to risk of
312
304
-
The mean mean difference The mean mean difference
in hdl for pioglitazone vs
in hdl for pioglitazone vs sfu
sfu in the control groups
in the intervention groups
Page 28 of 37
weeks
bias, imprecision
was
0.5 mg/dL
was
4.27 higher
(1.93 to 6.61 higher)
Mean difference in TG for Pioglitazone vs SFU (NOT IMPORTANT OUTCOME; measured with: mg/dL; Better indicated by lower values)
616
(6 studies)
14 to 52
weeks
very
serious5
no serious
inconsistency
no serious
indirectness
serious5
undetected
⊕⊝⊝⊝
312
VERY LOW5
due to risk of
bias, imprecision
-
The mean mean difference
in tg for pioglitazone vs sfu
in the control groups was
-3.6 mg/dL
The mean mean difference
in tg for pioglitazone vs sfu
in the intervention groups
was
31.62 lower
(49.15 to 14.1 lower)
RR 1.04
(0 to 0)
22 per 1000
1 more per 1000
(from 22 fewer to 22 fewer)
2/1456
(0.14%)
RR 0.66
(0 to 0)8
2 per 1000
1 fewer per 1000
(from 2 fewer to 2 fewer)
238/1650 56/1631
(14.4%) (3.4%)
RR 3.88
(3.05 to
4.94)
144 per 1000
415 more per 1000
(from 296 more to 568
more)
OR 1.68
(0.99 to
2.85)11
8 per 1000
6 more per 1000
(from 0 fewer to 15 more)
304
All-cause mortality for Rosilitazones vs SFU (CRITICAL OUTCOME; assessed with: Number of events)
2897
(1 study7)
4 years
no serious
risk of bias
no serious
inconsistency6
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊕
HIGH6
32/1441
(2.2%)
34/1456
(2.3%)
Cardiovascular mortality for SFU vs Rosiglitazone (CRITICAL OUTCOME; assessed with: Number of events)
2897
(1 study9)
4 years
no serious
risk of bias
no serious
inconsistency6
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊕
HIGH6
3/1441
(0.21%)
Hypoglycemia for Glitazones vs SFU (CRITICAL OUTCOME; assessed with: Number of events)
3281
(5 studies10)
1-3 years
no serious
risk of
bias10
no serious
inconsistency
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊕
HIGH10
Incidence of Heart Failure for Glitazone vs SFU (CRITICAL OUTCOME; assessed with: Number of events)
5323
no serious no serious
(4 studies12) risk of bias1 inconsistency
16-52 weeks
no serious
indirectness
serious1
undetected
⊕⊕⊕⊝
MODERATE1
due to
imprecision
22/2653
(0.83%)
37/2670
(1.4%)
Combined GI adverse effects for Rosiglitazone vs SFU (Nausea/Vomiting/Diarrhea/Abdominal discomfort) (IMPORTANT OUTCOME; assessed with:
Number of events)
2897
no serious
no serious
no serious
no serious
undetected
⊕⊕⊕⊕
316/1441 335/1456 RR 1.05
Study population
Page 29 of 37
(1 study13)
4 years
risk of bias
inconsistency
indirectness
imprecision
HIGH
(21.9%)
(23%)
(0 to 0)
219 per 1000
11 more per 1000
(from 219 fewer to 219
fewer)
Moderate
1
Rating based on documentation by Bennett et al reviewers for 14 studies. No reason for down-grading of evidence was provided.
Rating based on documentation by Bennett et al reviewers for 7 studies. No reason for down-grading of evidence was provided.
3
Rating based on documentation by Bennett et al reviewers for 3 studies. No reason for down-grading of evidence was provided.
4
Rating based on documentation by Bennett et al reviewers for 5 studies. No reason for down-grading of evidence was provided. However, the I-squared stastic 99% and the meand difference between
the studies ranges from -1.17 to 8.0, which could account for the down-grading of the evidence due to imprecision.
5
Rating based on documentation by Bennett et al reviewers for 6 studies. No reason for down-grading of evidence was provided. However, down-grading due to imprecision maybe accounted by large
mean difference variation between studies ranging from -65mg/dL to -6mg/dL, with overall MD of -31.62, CI [-49.15, -14.10].
6
Given only 1 study, inconsistency is unknown.
7
Bennett et al reviewers report Low strength of evidence based of 3 RCTs for all-cause mortality due to imprecision, however, no further explanation was provided. The all-cause mortality outcome on this
table is based on the ADOPT study, a large double-blind, RCT; the strength of this evidence is ranked as High.
8
No stastical significance tests were provided by the trial.
9
Bennett et al reviewers report Low strength of evidence based of 1 RCTs for all-cause mortality due to imprecision, however, no further explanation was provided. The all-cause mortality outcome on this
table is based on the ADOPT study, a large double-blind, RCT; the strength of this evidence is ranked as High.
10
Bennett et al reviewers rated 8 RCTs and 1 observational study as High with medium risk of bias; no explanation for rating of bias was provided. However, the rating of medium bias may be due to the
inclusion of the observation study. This table only evaluated 5 RCTs, therefore no points are deducted for bias, and the evidence rating remains consistent with the reviewers' as High.
11
Not statistically significant, however, clinical significance in unknown given CHF RR of 1.68 CI [0.99, 2.85] associated with glitazones.
12
Bennett et al reviewers rated 4 RCTs and 5 observational studies as Moderate with medium risk of bias and imprecision; no explanation for rating of bias was provided. However, the rating of medium
bias and imprecision may be due to the inclusion of the observation studies. This table only evaluated 4 RCTs, therefore no points are deducted for bias; point for imprecision was deducted based
variability of OR in 4 RCTs ranging from 1.0 to 67.06. and the evidence rating remains consistent with the reviewers' as Moderate.
13
Bennett et al reviewers rated 4 RCTs High. This table is based on 1 large, double-blind, RCT (ADOPT).
2
Page 30 of 37
Table 11: Question: Should Acarbose vs be used in SFU?
Bibliography: 1. Alpha-glucosidase inhibitors for type 2 diabetes mellitus. Van de Laar FA, et al. 2. Comparative Effectiveness and Safety of Oral Diabetes Medications for Adults with Type 2 Diabetes.
Bolen, et al. 3. Prospective multicentre trial comparing the efficacy of, and compliance with, glimepiride or acarbose treatment in patients with type 2 diabetes not controlled with diet alone. Feinbock C. et
al.
Quality assessment
Participants Risk of
(studies)
bias
Follow up
Inconsistency
Indirectness
Imprecision
Summary of Findings
Publication
bias
Overall quality
of evidence
Study event
rates (%)
With
Relative
effect
(95% CI)
With
Acarbose
Anticipated absolute effects
Risk with
Risk difference with Acarbose
(95% CI)
Mean difference in HbA1c for Acarbose vs. Placebo (IMPORTANT OUTCOME; measured with: %; Better indicated by lower values)
2831
(28 studies1)
16 to 52
weeks
no
serious
risk of
bias
no serious
inconsistency
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊕
HIGH
1442
1389
-
The mean mean difference in
hba1c for acarbose vs.
placebo ranged across
control groups from
-1.61 to 1.6 %
The mean mean difference
in hba1c for acarbose vs.
placebo in the intervention
groups was
0.77 lower
(0.9 to 0.64 lower)
Mean difference in HbA1c for Acarbose vs SFU (CRITICAL OUTCOME; measured with: %; Better indicated by lower values)
596
(8 studies)
16 to 30
weeks
no
serious
risk of
bias
serious2
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊝
MODERATE2
due to
inconsistency
304
292
-
The mean mean difference in
hba1c for acarbose vs sfu
ranged across control groups
from
-2.16 to -0.2 %
The mean mean difference
in hba1c for acarbose vs sfu
in the intervention groups
was
0.38 higher
(0.02 lower to 0.77 higher)
Mean weight difference for Acarbose vs SFU (NOT IMPORTANT OUTCOME; measured with: Kg; Better indicated by lower values)
397
(5 studies)
16 to 24
weeks
no
serious
risk of
bias
serious3
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊝
MODERATE3
due to
inconsistency
200
197
-
The mean mean weight
difference for acarbose vs sfu
ranged across control groups
from
-0.59 to 1.84 kg
The mean mean weight
difference for acarbose vs
sfu in the intervention
groups was
1.90 lower
(4.01 lower to 0.21 higher)
Mean difference in LDL for Acarbose vs SFU (NOT IMPORTANT OUTCOME; measured with: mg/dL; Better indicated by lower values)
Page 31 of 37
312
(4 studies)
24 to 30
weeks
no
serious
risk of
bias
no serious
inconsistency
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊕
HIGH
162
150
-
The mean mean difference in
ldl for acarbose vs sfu ranged
across control groups from
-0.42 to -0.07 mg/dL
The mean mean difference
in ldl for acarbose vs sfu in
the intervention groups was
0.10 higher
(0.07 lower to 0.27 higher)
Mean difference in HDL for Acarbose vs SFU (NOT IMPORTANT OUTCOME; measured with: mg/dL; Better indicated by higher values)
485
(7 studies)
16 to 30
weeks
no
serious
risk of
bias
no serious
inconsistency
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊕
HIGH
246
239
-
The mean mean difference in
hdl for acarbose vs sfu
ranged across control groups
from
-0.07 to 0.1 mg/dL
The mean mean difference
in hdl for acarbose vs sfu in
the intervention groups was
0.02 higher
(0.02 lower to 0.06 higher)
Mean difference in triglycerides for Acarbose vs SFU (NOT IMPORTANT OUTCOME; measured with: mg/dL; Better indicated by lower values)
591
(8 studies)
16 to 30
weeks
no
serious
risk of
bias
no serious
inconsistency
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊕
HIGH
-
The mean mean difference in
triglycerides for acarbose vs
sfu ranged across control
groups from
-0.44 to 0.17 mg/dL
The mean mean difference
in triglycerides for acarbose
vs sfu in the intervention
groups was
0.01 higher
(0.18 lower to 0.2 higher)
OR 0.32
(0.01 to
8.08)6
2 per 100
1 fewer per 100
(from 1 fewer to 10 more)
82/302 161/205
(27.2%) (78.5%)
OR 3.95
(2 to 7.8)
272 per 1000
324 more per 1000
(from 156 more to 473
more)
20/111
(18%)
RR 0.1
(0 to 0)
180 per 1000
162 fewer per 1000
(from 180 fewer to 180
fewer)
300
291
Disease Related Deaths for Acarbose vs. SFU (CRITICAL OUTCOME; assessed with: Number of events)
133
(1 study)
24 weeks
no
serious
risk of
bias
no serious
inconsistency4
no serious
indirectness
serious5
undetected
⊕⊕⊕⊝
MODERATE4,5
due to
imprecision
1/66
(1.5%)
0/67
(0%)
Adverse effects for Acarbose vs SFU (Total) (IMPORTANT OUTCOME; assessed with: Number of events)
507
(7 studies)
24 weeks
no
serious
risk of
bias
no serious
inconsistency7
no serious
indirectness
no serious
imprecision8
undetected
⊕⊕⊕⊕
HIGH7,8
Hypoglycemia Acarbose vs SFU (CRITICAL OUTCOME; assessed with: Number of events)
219
(1 study9)
26 weeks
no
serious
risk of
bias
no serious
inconsistency
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊕
HIGH
2/108
(1.9%)
Page 32 of 37
Adverse effects (Gastrointestinal) Acarbose vs SFU (IMPORTANT OUTCOME; assessed with: Number of events)
145
(1 study)
24 weeks
no
serious
risk of
bias
no serious
inconsistency4
no serious
indirectness
no serious
imprecision10
undetected
⊕⊕⊕⊕
HIGH4,10
24/71
59/74
(33.8%) (79.7%)
OR 7.70
(3.64 to
16.31)
338 per 1000
459 more per 1000
(from 312 more to 555
more)
1
Bases on the review by Van De Laar, et al. Review by Bolen et al. found 4 additional trials comparing alpha-glucosidase inhibitors with placebo that showed similar results.
In majority of the trials in the analysis, the dosing for second-generation SFUs was submaximal.
3
I-squared value of 82% is reported with a mean difference ranging from -3.26 to -0.55 Kg between studies.
4
Given that there is only one study for this outcome, inconsistency in unknown.
5
Study has small N, with low number of outcomes and wide CI -- OR 0.32 [0.01, 8.08].
6
Determined to be not statistically or clinically significant.
7
I-squared value of 63% is reported with an OR ranging from 1.20 up to 19.46. However, after excluding one study the OR ranges from 1.20 to 6.72. Majority of the studies favor SFUs, therefore, no
points were deducted for inconsistency.
8
A mean effect of OR 3.95 is reported with a wide CI [2.00, 7.80]. Since most of the studies included in the analysis favor SFUs over acarbose and is consistent with the OR, no points were deducted.
9
Data from: Prospective multicentre trial comparing the efficacy of, and compliance with, glimepiride or acarbose treatment in patients with type 2 diabetes not controlled with diet alone. Feinbock C. et al.
10
The CI is wide [3.64, 16.31] with an OR of 7.70; however, this is supported by the overall adverse effect profile, therefore, no points were deducted.
2
Page 33 of 37
Table 12: Question: Should SFU vs meglitinides be used for Diabetes Mellitus, Type 2?
Bibliography: Oral diabetes medications for adults with type 2 diabetes: An update. Bennett W. et al.
Quality assessment
Participants Risk of
(studies)
bias
Follow up
Inconsistency
Indirectness
Imprecision
Summary of Findings
Publication
bias
Overall quality
of evidence
Study event rates
(%)
Relative
effect
(95% CI)
With
With
Meglitinides SFU
Anticipated absolute effects
Risk with Meglitinides
Risk difference with SFU (95%
CI)
Mean difference in HbA1c for SFU vs Repaglinide (CRITICAL OUTCOME; measured with: %; Better indicated by lower values)
1687
(7 studies)
12 to 52
weeks
no serious no serious
risk of bias inconsistency
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊕
HIGH
1058
629
-
The mean mean difference
in hba1c for sfu vs
repaglinide in the control
groups was
-0.2 %
The mean mean difference
in hba1c for sfu vs
repaglinide in the
intervention groups was
0.07 higher
(0.15 lower to 0.29 higher)
Mean difference in weight for SFU vs Repaglinide (NOT IMPORTANT OUTCOME; measured with: Kg; Better indicated by lower values)
1431
(6 studies)
12 to 52
weeks
no serious no serious
risk of bias inconsistency
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊕
HIGH
883
548
-
The mean mean difference
in weight for sfu vs
repaglinide in the control
groups was
-0.1 Kg
The mean mean difference
in weight for sfu vs
repaglinide in the
intervention groups was
0.01 higher
(0.97 lower to 0.99 higher)
Mean difference in LDL for SFU vs Meglitinides1 (NOT IMPORTANT OUTCOME; measured with: mg/dL; Better indicated by lower values)
0
(2 studies)
12 months
serious2
no serious
inconsistency
no serious
indirectness
serious2
undetected
⊕⊕⊝⊝
LOW2
due to risk of
bias, imprecision
0
-1
See comment
See comment
Mean difference in HDL for SFU vs Meglitinides (NOT IMPORTANT OUTCOME; measured with: mg/dL; Better indicated by higher values)
1577
(6 studies)
12 to 52
no serious serious3
risk of bias
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊝
MODERATE3
due to
995
582
-
The mean mean difference
in hdl for sfu vs meglitinides
in the control groups was
1.1 mg/dL
The mean mean difference
in hdl for sfu vs meglitinides
in the intervention groups
was
Page 34 of 37
weeks
0.67 lower
(2.07 lower to 0.74 higher)
inconsistency
Mean difference in triglycerides for SFU vs Meglitinides (NOT IMPORTANT OUTCOME; measured with: mg/dL; Better indicated by lower values)
958
(4 studies)
12 to 52
weeks
serious4
no serious
inconsistency
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊝
MODERATE4
due to risk of
bias
615
343
-
The mean mean difference
in triglycerides for sfu vs
meglitinides in the control
groups was
1.0 mg/dL
The mean mean difference
in triglycerides for sfu vs
meglitinides in the
intervention groups was
0.20 higher
(3.83 lower to 6.57 higher)
RR 0.66
1/182
(0.55%) (0 to 0)
1 per 100
0 fewer per 100
(from 1 fewer to 1 fewer)
61/521 OR 0.78
(11.7%) (0.55 to
1.12)
103 per 1000
21 fewer per 1000
(from 44 fewer to 11 more)
All-cause mortality for SFU vs. Meglitinides (CRITICAL OUTCOME; assessed with: Number of events)
544
(1 study)
1 years
serious5
no serious
inconsistency6
no serious
indirectness
serious2
undetected
⊕⊕⊝⊝
3/362
LOW2,5,6
(0.83%)
due to risk of
bias, imprecision
Hypoglycemia for SFU vs Meglitinides (CRITICAL OUTCOME; assessed with: Number of events)
1387
(6 studies)
12 to 52
weeks
serious7
no serious
inconsistency
no serious
indirectness
no serious
imprecision
undetected
⊕⊕⊕⊝
MODERATE7
due to risk of
bias
89/866
(10.3%)
1
Per two RCTs comparing SFUs with repaglinide, the between-group differences were non-significant with a range from -1.5mg/dL to 1mg/dL.
Bennett et al reviewers rated 2 RCTs as Low due to medium risk of bias and imprecision. No source of bias or imprecision was identified. No meta-analysis or Forest plot is included for this outcome.
Two points were deducted for bias and imprecision.
3
I-squared stastic is 95%. However, inconsistency is not identified by Bennett et al. A point was deducted for iconsistency. With GRADE, the strength of evidence is reduced to Moderate from High, as
identified by Bennett et al.
4
Bennett et al reviewers rated 6 RCTs as Moderate due to medium risk of bias. No source of bias was identified.A point was deducted for bias.
5
Bennett et al reviewers rated 1 RCT as Low due to medium risk of bias and imprecision. No source of bias or imprecision was identified. The imprecision may stem from this outcome being based on 1
RCT with limited outcomes. The review did not provide a meta-analysis of these trial, therefore, the reveiwers determination of bias and imprecision is accepted,
6
Given only 1 RCT, consistency is unknown. No points deducted.
7
Bennett et al reviewers rated 8 RCTs as Low due to medium risk of bias. No source of bias was identified. A point was deducted for bias. Using GRADE, the strength of evidence was increased to
Moderate from Low.
2
Page 35 of 37
References:
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
ADA, Standards of medical care in diabetes--2012, American Diabetes Association. Diabetes Care, 2012. 35 Suppl
1: p. S11-63.
Qaseem, A., et al., Oral pharmacologic treatment of type 2 diabetes mellitus: a clinical practice guideline from
the American College of Physicians. Ann Intern Med, 2012. 156(3): p. 218-31.
WHO. WHO Diabetes Fact Sheet, August 2011. 2011 July 21, 2012]; Available from:
http://www.who.int/mediacentre/factsheets/fs312/en/index.html.
WHO, Global status report on noncommunicable disease 2010. 2010.
Alexander, G.C., et al., National trends in treatment of type 2 diabetes mellitus, 1994-2007. Arch Intern Med,
2008. 168(19): p. 2088-94.
WHO, The Selection and Use of Essential Medicines - Report of the WHO Expert Committee, 2011. 2011.
Bennett, W.L., et al., Oral Diabetes Medications for Adults With Type 2 Diabetes: An Update, 2011: Rockville
(MD).
Black, C., et al., Meglitinide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev, 2007(2): p.
CD004654.
Bolen, S., et al., Comparative Effectiveness and Safety of Oral Diabetes Medications for Adults With Type 2
Diabetes, 2007: Rockville (MD).
Richter, B., et al., Pioglitazone for type 2 diabetes mellitus. Cochrane Database Syst Rev, 2006(4): p. CD006060.
Richter, B., et al., Rosiglitazone for type 2 diabetes mellitus. Cochrane Database Syst Rev, 2007(3): p. CD006063.
Richter, B., et al., Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus. Cochrane Database Syst
Rev, 2008(2): p. CD006739.
Saenz, A., et al., Metformin monotherapy for type 2 diabetes mellitus. Cochrane Database Syst Rev, 2005(3): p.
CD002966.
Van de Laar, F.A., et al., Alpha-glucosidase inhibitors for type 2 diabetes mellitus. Cochrane Database Syst Rev,
2005(2): p. CD003639.
WHO. National Medicines List/Formulary/Standard Treatment Guidelines. 2012 July 7th, 2012]; Available from:
http://www.who.int/selection_medicines/country_lists/en/index.html.
(MSH), M.S.f.H., International Drug Price Indicator Guide. 2010.
Lexicomp, Lexicomp online database, 2012.
Al Sifri, S., et al., The incidence of hypoglycaemia in Muslim patients with type 2 diabetes treated with sitagliptin
or a sulphonylurea during Ramadan: a randomised trial. Int J Clin Pract, 2011. 65(11): p. 1132-40.
Arechavaleta, R., et al., Efficacy and safety of treatment with sitagliptin or glimepiride in patients with type 2
diabetes inadequately controlled on metformin monotherapy: a randomized, double-blind, non-inferiority trial.
Diabetes Obes Metab, 2011. 13(2): p. 160-8.
Goke, B., et al., Saxagliptin is non-inferior to glipizide in patients with type 2 diabetes mellitus inadequately
controlled on metformin alone: a 52-week randomised controlled trial. Int J Clin Pract, 2010. 64(12): p. 1619-31.
Nowicki, M., et al., Long-term treatment with the dipeptidyl peptidase-4 inhibitor saxagliptin in patients with
type 2 diabetes mellitus and renal impairment: a randomised controlled 52-week efficacy and safety study. Int J
Clin Pract, 2011. 65(12): p. 1230-9.
Bellomo Damato, A., et al., Nateglinide provides tighter glycaemic control than glyburide in patients with Type 2
diabetes with prevalent postprandial hyperglycaemia. Diabet Med, 2011. 28(5): p. 560-6.
Zhang, H., et al., Effect of repaglinide and gliclazide on glycaemic control, early-phase insulin secretion and lipid
profiles in newly diagnosed type 2 diabetics. Chin Med J (Engl), 2011. 124(2): p. 172-6.
Aschner, P., et al., Efficacy and safety of monotherapy of sitagliptin compared with metformin in patients with
type 2 diabetes. Diabetes Obes Metab, 2010. 12(3): p. 252-61.
Okayasu, S., et al., The evaluation of risk factors associated with adverse drug reactions by metformin in type 2
diabetes mellitus. Biol Pharm Bull, 2012. 35(6): p. 933-7.
Kahn, S.E., et al., Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med, 2006.
355(23): p. 2427-43.
Page 36 of 37
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
(FDA), F.a.D.A. Food and Drug Administration (FDA). 2012 July 18th, 2012]; Available from: www.fda.gov.
GlaxoSmithKline, Prescribing Information and Medication Guide, 2011.
Takeda Pharmaceuticals America, I., Pioglitazone prescribing information and medication guide, 2012.
Willms, B. and D. Ruge, Comparison of acarbose and metformin in patients with Type 2 diabetes mellitus
insufficiently controlled with diet and sulphonylureas: a randomized, placebo-controlled study. Diabet Med,
1999. 16(9): p. 755-61.
Horton, E.S., et al., Nateglinide alone and in combination with metformin improves glycemic control by reducing
mealtime glucose levels in type 2 diabetes. Diabetes Care, 2000. 23(11): p. 1660-5.
Schramm, T.K., et al., Mortality and cardiovascular risk associated with different insulin secretagogues compared
with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study. Eur
Heart J, 2011. 32(15): p. 1900-8.
Lund, S.S., et al., Targeting hyperglycaemia with either metformin or repaglinide in non-obese patients with type
2 diabetes: results from a randomized crossover trial. Diabetes Obes Metab, 2007. 9(3): p. 394-407.
Seck, T., et al., Safety and efficacy of treatment with sitagliptin or glipizide in patients with type 2 diabetes
inadequately controlled on metformin: a 2-year study. Int J Clin Pract, 2010. 64(5): p. 562-76.
Scott, R., et al., Efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy over 12
weeks in patients with type 2 diabetes. Int J Clin Pract, 2007. 61(1): p. 171-80.
Feinbock, C., et al., Prospective multicentre trial comparing the efficacy of, and compliance with, glimepiride or
acarbose treatment in patients with type 2 diabetes not controlled with diet alone. Diabetes Nutr Metab, 2003.
16(4): p. 214-21.
Mafauzy, M., Repaglinide versus glibenclamide treatment of Type 2 diabetes during Ramadan fasting. Diabetes
Res Clin Pract, 2002. 58(1): p. 45-53.
Madsbad, S., et al., Comparison between repaglinide and glipizide in Type 2 diabetes mellitus: a 1-year
multicentre study. Diabet Med, 2001. 18(5): p. 395-401.
Marbury, T., et al., Repaglinide versus glyburide: a one-year comparison trial. Diabetes Res Clin Pract, 1999.
43(3): p. 155-66.
Amylin Pharmaceuticals, I., Symlin Prescribing Information, 2008.
(TGA), T.G.A. Therapeutic Goods Administration (TGA). 2012 July 18th, 2012]; Available from: www.tga.gov.au.
Page 37 of 37