Comparative Review of Oral Hypoglycemic Agents in Adults · Page 6 of 37 Since our search focused...

SECTION 18.5

Comparative Review of Oral Hypoglycemic Agents in Adults

Harinder Chahal

For WHO Secretariat

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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

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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

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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), alpha-

glucosidase 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 cost-

comparison. 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.

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Table 1 - New oral hypoglycemic agents for comparison with current EML agents

Comparison # EML Medication Comparison Medication GRADE Table

Comparison 1 Metformin DPP-4 Inhibitors (Sitagliptin) Table 6 Comparison 2 Glitazones (Pioglitazone, Rosiglitazone) Table 7 Comparison 3 Alpha-glucosidase inhibitors (Acarbose) Table 8 Comparison 4 Meglitinides (Repaglinide, Nateglinide) Table 9 Comparison 5 Sulfonylureas DPP-4 Inhibitors (Sitagliptin) None Comparison 6 Glitazones (Pioglitazone, Rosiglitazone) Table 10 Comparison 7 Alpha-glucosidase inhibitors (Acarbose) Table 11 Comparison 8 Meglitinides (Repaglinide, Nateglinide) Table 12 Comparison 9 Pramlintide acetate – Not reviewed None

III. 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 alpha-

glucosidase 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; alpha-

glucosidase 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.

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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:

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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]

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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]


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 double-

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blind, RCT combined GI side-effects were 70% and 47% for metformin and repaglinide,

respectively.[33]


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 side-

effects 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

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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]


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]


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

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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.


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, Lexi-

Comp 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

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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

Strength)

Cost per unit

(USD)

Cost/30

tablets (USD)

Daily Maximum

Dose[17]

Monthly cost based on

maximum dosing (USD)

FDA

Approved

TGA

Approved

Metformin 500mg* 0.0087[16] 0.26 2550mg/day 1.30 Yes Yes Glibenclamide 5mg* 0.0042[16] 0.13 20mg/day 0.52 Yes Yes Prices from Lexi-Comp Online (US based prices) [17]

Metformin 500mg* 0.23 6.50 2550mg/day 26.00 Yes Yes Metformin 1000mg* 0.60 17.99 2550mg/day 44.98 Yes Yes Glibenclamide 5mg* 0.53 15.99 20mg/day 15.99 Yes Yes Sitagliptin 25mg 7.18 215.40 100mg daily 861.60 Yes Yes Sitagliptin 100mg 7.83 234.90 100mg daily 234.90 Yes Yes Rosiglitazone 2mg 3.03 90.90 8mg once or BID 363.60 Yes Yes Rosiglitazone 8mg 8.33 249.99 8mg once or BID 249.99 Yes Yes Pioglitazone 15mg 6.45 193.48 45mg/day 580.44 Yes Yes Pioglitazone 45mg 10.33 310.00 45mg/day 310.00 Yes Yes Acarbose 25mg* 0.84 25.20 100mg TID 302.40 Yes Yes Acarbose 100mg* 0.90 27.00 100mg TID 81.00 Yes Yes Nateglinide 60mg* 1.60 47.99 120mg TID 287.94 Yes No Repaglinide 0.5mg 3.04 91.21 16mg daily 2918.40 Yes Yes Repaglinide 2mg 2.93 87.92 16mg daily 703.20 Yes Yes *Denotes generic price

Table 3: Oral hypoglycemics listed on selected NEMLs

# Country

DPP-4 Inhibitors

(Sitagliptin)

Glitazones

(Pioglitazone and

Rosiglitazone)

Alpha-glucosidase

inhibitors

(Acarbose)

Meglitinides

(Repaglinide and

Nateglinide)

1 Bangladesh No No No No

2 China No No No No

3 Dominican Republic No No No No

4 Ecuador No No No No

5 Fiji No No No No

6 Ghana No No No No

7 India No No No No

8 Iran No Yes (pioglitazone) Yes (acarbose) Yes (repaglinide)

9 Kyrgyzstan No Yes (Rosiglitazone) No No

10 Malta No No Yes (acarbose) Yes (repaglinide)

11 Morocco No No Yes (acarbose) No

12 Malaysia No No No No

13 Namibia No No No No

14 Nigeria No No No No

15 Oman No Yes (rosiglitazone) No No

Total # of surveyed countries with identified

medications on the NEML

0 3 3 2

VI. Summary:

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, alpha-

glucosidase inhibitors and meglitinides – to the EML at this time.

of 37

Appendix:

Table 4: Summary: Comparative efficacy and safety of oral hypoglycemics Comparison HbA1c Weight LDL HDL TG Hypoglycemia Adverse events

(GI)

Relative Cost

(cost for

maximum

monthly dose)

Metformin versus (outcome and strength of evidence) Relative Cost: Metformin Baseline [US$26.00/month for 500mg tablets (strength on EML)]

1 DPP-4 inhibitors

(Sitagliptin,

Saxagliptin)

Favors

Metformin

(Moderate)

Favors

Metformin

(Moderate)

Neither favored

(Low)

Neither favored

(Very Low)

Neither favored

(Low)

Neither favored

(High)

Favors DPP-4-I

(Very Low)

Sitagliptin 100mg:

9x greater than

Metformin

2 Glitazones

(Rosiglitazone,

Pioglitazone)

Neither favored

(Moderate)

Favors

Metformin

(High)

Favors

Metformin

(Moderate)

Neither favored

(Moderate)

Favors

Metformin (Low)

Neither favored

(High)

Favors

Glitazones

(High)

Rosiglitazone 8mg:

9.6x greater

Pioglitazone 45mg:

11.9x greater

3 AGIs (Acarbose,

Miglitol)

Neither favored

(Moderate)

Neither favored

(Low)

Favors Acarbose

(Moderate)

Neither favored

(Moderate)

Neither favored

(Moderate)

Unclear

(Low)

Favors

Metformin

(Moderate)

Acarbose 100mg:

3.11x greater

4 Meglitinides

(Nateglinide,

Repaglinide)

Neither favored

(Moderate)

Neither favored

(Moderate)

Neither favored

(Moderate)

Neither favored

(Moderate)

Neither favored

(Moderate)

Favors

Metformin

(Low)

Favors

Meglitinides

(High)

Nateglinide 60mg:

11x greater

Repaglinide 2mg:

27x greater

Sulfonylureas versus (outcome and strength of evidence) Relative Cost: Glibenclamide Baseline [US$ 15.99/month for 5mg tablets (strength on EML)]

5 DPP-4 inhibitors

(Sitagliptin,

Saxagliptin)

Neither favored

(Low)

Unclear

(Low)

Neither favored

(Low)

Neither favored

(Low)

Neither favored

(Low)

Favors DPP-4-I

(Moderate)

Neither favored

(Moderate)

Sitagliptin 100mg:

14.6x greater than

Glibenclamide

6 Glitazones

(Rosiglitazone,

Pioglitazone)

Neither favored

(Moderate)

Favors SFU

(Low)

Favors SFU

(Low)

Favors Glitazones

(Low)

Unclear

(Low)

Neither favored

(High)

Neither favored

(High)

Rosiglitazone 8mg:

15.6x greater

Pioglitazone 45mg:

19x greater

7 AGIs (Acarbose,

Miglitol)

Neither favored

(Moderate)

Neither favored

(Moderate)

Neither favored

(High)

Neither favored

(High)

Neither favored

(High)

Favors AGI

(High)

Favors SFU

(High)

Acarbose 100mg:

5x greater

8 Meglitinides

(Nateglinide,

Repaglinide)

Neither favored

(High)

Neither favored

(High)

Neither favored

(Low)

Neither favored

(Moderate)

Neither favored

(Low)

Favors

Meglitinides

(Moderate)

Unknown

(n/a)

Nateglinide 60mg:

18x greater

Repaglinide 2mg:

43x greater

of 37

Table 5: Chart of systematic reviews used

Drug Class Drugs Review Period Reviewed

Alpha-glucosidase

inhibitors

1. Acarbose

2. Miglitol

3. Voglibose

Alpha-glucosidase inhibitors for type 2 diabetes mellitus (Van

de Laar FA)[14]

Up to: 29 April 2003

DPP-4 Inhibitors 1. Sitagliptin

2. Saxagliptin

Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes

Mellitus (Richter B)[12]

Up to: 30 January 2008

Meglitinide

Analogues

1. Repaglinide

2. Nateglinide

Meglitinide analogues for type 2 diabetes mellitus (Black C)[8] Up to : 30 October 2006

Biguanides 1. Metformin Metformin monotherapy for type 2 diabetes mellitus (Saenz

A)[13]

Up to: 29 September 2003.

Glitazones 1. Rosiglitazone

Rosiglitazone for type 2 diabetes mellitus (Richter B)[11] Up to: 29 April 2007

1. Pioglitazone Pioglitazone for type 2 diabetes mellitus (Richter B)[10] Up to: 30 August 2006.

All above All above Comparative Effectiveness and Safety of Oral Diabetes

Medications for Adults with Type 2 Diabetes. Comparative

Effectiveness (Bolen et al.)[9]

Up to: January 2006

All above except

Alpha-glucosidase

inhibitors

All above except

Alpha-glucosidase

inhibitors

Oral Diabetes Medications for Adults With Type 2 Diabetes: An

Update (Bennett et al.)[7]

Up to: April 2010

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 Summary of Findings

Participants

(studies)

Follow up

Risk of

bias

Inconsistency Indirectness Imprecision Publication

bias

Overall quality of

evidence

Study event rates

(%)

Relative

effect

(95% CI)

Anticipated absolute effects

With DPP-4

Inhibitors

With

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



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


MODERATE1

due to risk of bias


in weight for metformin vs


control groups was

-0.6 Kg





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


in ldl for metformin vs dpp-

4 inhibitors in the control

groups was

-0.5 mg/dL


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 serious

3 no serious

indirectness

serious3 undetected ⊕⊝⊝⊝

VERY LOW3



in hdl for metformin vs dpp-

4 inhibitors in the control


in hdl for metformin vs dpp-

4 inhibitors in the

of 37

weeks inconsistency,

imprecision

groups was

3.9 mg/dL


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


LOW4


imprecision


in triglycerides for

metformin vs dpp-4

inhibitors in the control

groups was

-3 mg/dL


in triglycerides for metformin

vs dpp-4 inhibitors in the


3.4 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

Cardiovascular mortality for Metformin vs DPP-4 Inhibitor5 (CRITICAL OUTCOME; assessed with: Number of events)

0

(0) See comment - - not

pooled5

See comment See comment

Hypoglycemia for Metformin vs DPP-4 Inhibitor (CRITICAL OUTCOME; assessed with: Number of events)

1050

(1 study)

24 weeks

no serious

risk of

bias6

no serious

inconsistency

no serious

indirectness

no serious

imprecision

undetected ⊕⊕⊕⊕

HIGH6

9/528

(1.7%)

17/522

(3.3%)

RR 1.88

(0 to 0)7

17 per 1000 15 more per 1000

(from 17 fewer to 17 fewer)

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


VERY LOW8


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.

2 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.

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.

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)


Participants

(studies)

Follow up

Risk of

bias


bias

Overall quality of

evidence

Study event rates

(%)

Relative

effect

(95% CI)


With

Glitazones

With

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


MODERATE1,2

due to risk of bias



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


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

risk of

bias

no serious

inconsistency

no serious

indirectness

no serious

imprecision


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


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

risk of

bias

no serious

inconsistency

no serious

indirectness1

serious3 undetected ⊕⊕⊕⊝

MODERATE1,3

due to imprecision


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)

of 37

482

(6 studies)

16 to 52

weeks

serious4 no serious

inconsistency

no serious

indirectness

no serious

imprecision


MODERATE4

due to risk of bias


in hdl for metformin vs.


groups was

3.5 mg/dL

The mean mean

difference in hdl for

metformin vs.

rosiglitazone in the


0.45 lower


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 serious

5 no serious

indirectness


LOW5


inconsistency,

imprecision, large

effect


in tg for metformin vs.


groups was

-4.2 mg/dL

The mean mean

difference in tg for

metformin vs.

rosiglitazone in the


26.86 lower

(49.26 to 4.47 lower)

All-cause mortality for Metformin vs Rosiglitazone (CRITICAL OUTCOME6; assessed with: Number of events)

2910

(1 study6)

4 years

no serious

risk of

bias

no serious

inconsistency

no serious

indirectness

no serious

imprecision6


HIGH6

34/1456

(2.3%)

31/1454

(2.1%)

RR 0.91

(0 to 0)

23 per 1000 2 fewer per 1000


fewer)

Cardiovascular mortality for Metformin vs Rosiglitazone (CRITICAL OUTCOME; assessed with: Number of events)

2910

(1 study7)

4 years

no serious

risk of

bias7

no serious

inconsistency

no serious

indirectness

no serious

imprecision7


HIGH7

2/1456

(0.14%)

2/1454

(0.14%)

RR 1

(0 to 0)

1 per 1000 0 fewer per 1000


Hypoglycemia for Metformin vs Glitazones (CRITICAL OUTCOME; assessed with: Number of events)

2910

(1 study)

4 years

no serious

risk of

bias1,8

no serious

inconsistency

no serious

indirectness

no serious

imprecision


HIGH1,8

141/1456

(9.7%)

167/1454

(11.5%)

RR 0.9

(0.8 to 1)

97 per 1000 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

risk of

bias

no serious

inconsistency

no serious

indirectness

no serious

imprecision


HIGH

22/1456

(1.5%)

19/1454

(1.3%)

RR 0.86

(0 to 0)

15 per 1000 2 fewer per 1000


fewer)

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

risk of

bias

no serious

inconsistency

no serious

indirectness

no serious

imprecision


HIGH

335/1456

(23%)

557/1454

(38.3%)

RR 1.66

(0 to 0)

230 per 1000 152 more per 1000


fewer)1

1 Rating based on documentation by Bennett et al reviewers for 16 studies. No reason for down-grading of evidence was provided.

2 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.

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.


Participants

(studies)

Follow up

Risk of

bias


bias

Overall quality

of evidence

Study event rates

(%)

Relative

effect

(95% CI)


With

Metformin

With

Acarbose

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


HIGH


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


MODERATE2

due to

inconsistency


in hba1c for acarbose vs

metformin in the control

groups was

-0.86


hba1c for acarbose vs

metformin in the intervention

groups was

0.25 lower


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


MODERATE2

due to

inconsistency


in ldl for acarbose vs


groups was

0.05 mg/dL


ldl for acarbose vs metformin


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)

of 37

62

(1 study)

24 weeks

no

serious

risk of

bias

serious2 no serious

indirectness

no serious

imprecision


MODERATE2

due to

inconsistency


in hdl for acarbose vs


groups was

-0.01 mg/dL


hdl for acarbose vs


groups was

0.24 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


MODERATE2

due to

inconsistency


in triglycerides for acarbose

vs metformin in the control

groups was

-0.12 mg/dL


triglycerides for acarbose vs


groups was

0.28 lower


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


in weight for acarbose vs


groups was

-0.5 mg/dL


weight for acarbose vs


groups was

0.30 lower


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


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)

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


LOW6,7

due to

inconsistency,

imprecision

5/29

(17.2%)

3/31

(9.7%)

RR 0.5

(0 to 0)

172 per 1000 86 fewer per 1000


fewer)

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.

2 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."

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.

5 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.

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)


Participants

(studies)

Follow up

Risk of

bias


bias

Overall quality

of evidence

Study event rates

(%)

Relative

effect

(95% CI)


With

Meglitinides

With

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


MODERATE1

due to risk of bias



meglitinides ranged across

control groups from

-0.38 to -0.3 %



meglitinides in the


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


MODERATE3,4

due to risk of bias



meglitinides in the control

groups was

-2.98 Kg



meglitinides in the


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


MODERATE3,4

due to risk of bias




groups was

0.41 SD units



meglitinides in the


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


in hdl for metformin vs


in hdl for metformin vs

of 37

12 weeks inconsistency4 indirectness imprecision due to risk of bias meglitinides in the control

groups was

0.21 SD units

meglitinides in the


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


MODERATE3,4

due to risk of bias


in tg for metformin vs


groups was

1.1 SD units


in tg for metformin vs

meglitinides in the


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

risk of bias

no serious

inconsistency4

no serious

indirectness


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


LOW8,11

due to risk of

bias, imprecision

59/457

(12.9%)

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

risk of bias

no serious

inconsistency4

no serious

indirectness

no serious

imprecision


HIGH4

42/82

(51.2%)

65/83

(78.3%)

RR 1.53

(0 to 0)

512 per 1000 271 more per 1000


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.

2 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.)

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.

7 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.

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)


Participants

(studies)

Follow up

Risk of

bias


bias

Overall quality

of evidence

Study event rates

(%)

Relative

effect

(95% CI)


With SFU With

Glitazones

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


MODERATE1

due to risk of

bias


in hba1c for glitazones vs

sfu in the control groups

was

-0.9 %


in hba1c for glitazones vs

sfu in the intervention

groups was

0.10 lower


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


LOW1,2

due to risk of

bias


difference for glitazones vs


was

1.9 Kg


difference for glitazones vs


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


LOW3

due to risk of

bias


in ldl for pioglitazone vs sfu

in the control groups was

-1.4 mg/dL


in ldl for pioglitazone vs sfu


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


LOW1,4

due to risk of


in hdl for pioglitazone vs



in hdl for pioglitazone vs sfu


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


VERY LOW5

due to risk of

bias, imprecision


in tg for pioglitazone vs sfu


-3.6 mg/dL


in tg for pioglitazone vs sfu


was

31.62 lower

(49.15 to 14.1 lower)

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


HIGH6

32/1441

(2.2%)

34/1456

(2.3%)

RR 1.04

(0 to 0)

22 per 1000 1 more per 1000


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


HIGH6

3/1441

(0.21%)

2/1456

(0.14%)

RR 0.66

(0 to 0)8



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


HIGH10

238/1650

(14.4%)

56/1631

(3.4%)

RR 3.88

(3.05 to

4.94)

144 per 1000 415 more per 1000


more)

Incidence of Heart Failure for Glitazone vs SFU (CRITICAL OUTCOME; assessed with: Number of events)

5323

(4 studies12

)

16-52 weeks

no serious

risk of bias1

no serious

inconsistency

no serious

indirectness


MODERATE1

due to

imprecision

22/2653

(0.83%)

37/2670

(1.4%)

OR 1.68

(0.99 to

2.85)11

8 per 1000 6 more per 1000


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

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


fewer)

Moderate

-




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).

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.


Participants

(studies)

Follow up

Risk of

bias


bias

Overall quality

of evidence

Study event

rates (%)

Relative

effect

(95% CI)


With With

Acarbose

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


HIGH

1442 1389 - The mean mean difference in

hba1c for acarbose vs.

placebo ranged across

control groups from

-1.61 to 1.6 %


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


MODERATE2

due to

inconsistency


hba1c for acarbose vs sfu

ranged across control groups

from

-2.16 to -0.2 %


in hba1c for acarbose vs sfu


was

0.38 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


MODERATE3

due to

inconsistency


difference for acarbose vs sfu


from

-0.59 to 1.84 kg


difference for acarbose vs


groups was

1.90 lower


Mean difference in LDL for Acarbose vs SFU (NOT IMPORTANT OUTCOME; measured with: mg/dL; Better indicated by lower values)

of 37

312

(4 studies)

24 to 30

weeks

no

serious

risk of

bias

no serious

inconsistency

no serious

indirectness

no serious

imprecision


HIGH


ldl for acarbose vs sfu ranged

across control groups from

-0.42 to -0.07 mg/dL


in ldl for acarbose vs sfu in

the intervention groups was

0.10 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


HIGH


hdl for acarbose vs sfu


from

-0.07 to 0.1 mg/dL


in hdl for acarbose vs sfu in

the intervention groups was

0.02 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


HIGH


triglycerides for acarbose vs

sfu ranged across control

groups from

-0.44 to 0.17 mg/dL


in triglycerides for acarbose

vs sfu in the intervention

groups was

0.01 higher


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


MODERATE4,5

due to

imprecision

1/66

(1.5%)

0/67

(0%)

OR 0.32

(0.01 to

8.08)6



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


HIGH7,8

82/302

(27.2%)

161/205

(78.5%)

OR 3.95

(2 to 7.8)

272 per 1000 324 more per 1000


more)

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


HIGH

20/111

(18%)

2/108

(1.9%)

RR 0.1

(0 to 0)

180 per 1000 162 fewer per 1000


fewer)

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


HIGH4,10

24/71

(33.8%)

59/74

(79.7%)

OR 7.70

(3.64 to

16.31)

338 per 1000 459 more per 1000


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.

2 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.

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.


Participants

(studies)

Follow up

Risk of

bias


bias

Overall quality

of evidence

Study event rates

(%)

Relative

effect

(95% CI)


With

Meglitinides

With

SFU

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

risk of bias

no serious

inconsistency

no serious

indirectness

no serious

imprecision


HIGH


in hba1c for sfu vs

repaglinide in the control

groups was

-0.2 %


in hba1c for sfu vs

repaglinide in the


0.07 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

risk of bias

no serious

inconsistency

no serious

indirectness

no serious

imprecision


HIGH


in weight for sfu vs

repaglinide in the control

groups was

-0.1 Kg


in weight for sfu vs

repaglinide in the


0.01 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


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

risk of bias

serious3 no serious

indirectness

no serious

imprecision


MODERATE3

due to


in hdl for sfu vs meglitinides


1.1 mg/dL


in hdl for sfu vs meglitinides


was

of 37

weeks inconsistency 0.67 lower


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


MODERATE4

due to risk of

bias


in triglycerides for sfu vs


groups was

1.0 mg/dL


in triglycerides for sfu vs

meglitinides in the


0.20 higher


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


LOW2,5,6

due to risk of

bias, imprecision

3/362

(0.83%)

1/182

(0.55%)

RR 0.66

(0 to 0)



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


MODERATE7

due to risk of

bias

89/866

(10.3%)

61/521

(11.7%)

OR 0.78

(0.55 to

1.12)

103 per 1000 21 fewer per 1000


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.

2 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.

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