Table BEvidence of the comparative effectiveness and safety of diabetes medications as monotherapy and combination therapy on intermediate endpoints, mortality, microvascular outcomes, macrovascular outcomes, and adverse events

OutcomeLevel of Evidence*Conclusions
Key Question 1: In adults age 18 or older with type 2 diabetes mellitus, what is the comparative effectiveness of treatment options for the intermediate outcomes of glycemic control (in terms of HbA1c), weight, or lipids?
HbA1cHighMetformin and second-generation sulfonylureas showed similar changes in HbA1c, with a pooled between-group difference of 0.07% (95% CI −0.12% to 0.26%) for studies lasting longer than 3 months but usually less than 1 year in duration.
HighCombination therapies were better than monotherapy regimens at reducing HbA1c, with an absolute difference of about 1%. In comparisons of metformin versus metformin plus thiazolidinediones, and metformin versus metformin plus sulfonylureas, the combination therapy was favored for HbA1c reduction.
ModerateWhen compared with DPP-4 inhibitors, metformin had a greater reduction in HbA1c, with a pooled between-group difference of −0.4% (95% CI −0.5% to −0.2%).
ModerateComparisons of metformin versus thiazolidinediones, thiazolidinediones versus sulfonylureas, sulfonylureas versus repaglinide, and pioglitazone versus rosiglitazone showed similar reductions in HbA1c, with an absolute reduction in HbA1c of around 1% as compared with baseline values, with trials lasting 1 year or less.
ModerateMetformin plus DPP-4 inhibitor was favored over metformin alone for HbA1c reduction.
ModerateThe combination of metformin plus thiazolidinedione had a similar efficacy in reducing HbA1c as the combination of metformin plus sulfonylurea.
LowThe combination of pioglitazone plus sulfonylurea was minimally favored over metformin plus pioglitazone, by an absolute difference of 0.03%.
LowThe combination of metformin plus a premixed insulin analogue was minimally favored over metformin plus a basal insulin, by an absolute difference of 0.30% to 0.43%.
Body weightHighMetformin maintained or decreased weight to a greater extent than did thiazolidinediones (pooled between-group difference of −2.6 kg, 95% CI −4.1 kg to −1.2 kg), the combination of metformin plus a thiazolidinedione (pooled between-group difference of −2.2 kg, 95% CI −2.6 kg to −1.9 kg), or the combination of metformin plus a sulfonylurea (pooled between-group difference of −2.3 kg, 95% CI −3.3 kg to −1.2 kg). Thiazolidinediones alone or in combination were associated with weight gain.
HighMetformin maintained or decreased weight to a greater extent than did sulfonylureas, with a pooled between-group difference of −2.7 kg (95% CI −3.5 kg to −1.9 kg).
HighSulfonylureas and the meglitinides had similar effects on body weight.
ModerateGLP-1 agonists decreased weight to a greater extent than did sulfonylureas (pooled between-group difference of −2.5 kg, 95% CI −3.8 kg to −1.1 kg).
ModerateMetformin plus sulfonylurea had a more favorable effect on weight than did either the combinations of a thiazolidinedione plus sulfonylurea (pooled between-group difference of −3.2 kg, 95% CI −5.2 kg to −1.1 kg) or metformin plus a thiazolidinedione (pooled between-group difference of −0.9 kg, 95% CI −1.3 kg to −0.4 kg).
ModerateMetformin decreased weight to a greater extent than did DPP-4 inhibitors (pooled between-group difference of −1.4 kg, 95% CI −1.8 kg to −1.0 kg).
ModerateMetformin had no significantly different effect on weight than did the combination of metformin plus DPP-4 inhibitors (pooled between-group difference of −0.2 kg, 95% CI −0.7 kg to 0.2 kg).
LowMetformin plus GLP-1 agonists decreased weight to a greater extent than did several combination therapies (metformin plus sulfonylurea, metformin plus thiazolidinedione, metformin plus basal insulin, or metformin plus DPP-4 inhibitor).
LowMetformin plus DPP-4 inhibitors decreased weight to a greater extent than did two standard combinations, metformin plus thiazolidinedione or metformin plus sulfonylurea.
LDL cholesterolHighMetformin decreased LDL to a greater extent than did sulfonylureas, which generally had little effect on LDL, with a pooled between-group difference of −10.1 mg/dL (95% CI −13.3 mg/dL to −7.0 mg/dL).
HighThe combination of metformin and rosiglitazone decreased LDL to a lesser extent than did metformin monotherapy (pooled between-group difference of 14.5 mg/dL, 95% CI 13.3 mg/dL to 15.7 mg/dL),
ModerateMetformin decreased LDL cholesterol to a greater extent than did pioglitazone, which increased LDL cholesterol, with a pooled between-group difference in LDL of −14.2 mg/dL (95% CI −15.3 mg/dL to −13.1 mg/dL).
ModerateMetformin decreased LDL cholesterol to a greater extent than did rosiglitazone, with a pooled between-group difference in LDL of −12.8 mg/dL (95% CI −24.0 mg/dL to −1.6 mg/dL).
ModerateMetformin decreased LDL to a greater extent than did DPP-4 inhibitors, with a pooled between-group difference of −5.9 mg/dL (95% CI −9.7 mg/dL to −2.0 mg/dL).
ModerateThe combination of metformin and rosiglitazone decreased LDL to a lesser extent than did a combination of metformin and a second-generation sulfonylurea, with a pooled between-group difference in LDL of 13.5 mg/dL (95% CI 9.1 mg/dL to 17.9 mg/dL).
HDL cholesterolHighMetformin increased HDL to a lesser extent than did pioglitazone, with a pooled between group difference of −3.2 mg/dL (95% CI −4.3 mg/dL to −2.1 mg/dL).
HighSulfonylureas were similar to metformin in terms of changes in HDL.
HighThe combination of metformin and rosiglitazone increased HDL to a greater extent than did metformin monotherapy (pooled between-group difference 2.8 mg/dL, 95% CI 2.2 mg/dL to 3.5 mg/dL).
ModerateRosiglitazone increased HDL to a lesser extent than did pioglitazone (pooled between-group difference of −2.3 mg/dL, 95% CI −3.5 mg/dL to −1.2 mg/dL).
ModerateRosiglitazone alone was similar to metformin in terms of changes in HDL.
ModeratePioglitazone increased HDL to a greater extent than did sulfonylureas (pooled between-group difference of 4.3 mg/dL, 95% CI 1.9 mg/dL to 6.6 mg/dL).
ModerateThe combination of metformin and pioglitazone increased HDL by about 5 mg/dL relative to the combination of metformin and a sulfonylurea.
ModerateThe combination of metformin and rosiglitazone increased HDL to a greater extent than did the combination of metformin and a sulfonylurea (pooled between-group difference 2.7 mg/dL, 95% CI 1.4 mg/dL to 4.1 mg/dL).
ModerateThe combination of metformin and DPP-4 inhibitors had similar effect on HDL as did metformin monotherapy (pooled between-group difference was 0.5 mg/dL, 95% CI −1.5 mg/dL to 2.5 mg/dL).
LowThe combination of pioglitazone with another medication was favored for the following comparisons: pioglitazone plus metformin versus metformin monotherapy, metformin plus pioglitazone versus metformin plus sulfonylurea, and pioglitazone plus sulfonylurea versus metformin plus sulfonylurea, with a range of between-group differences from 3.1 mg/dL to 10.5 mg/dL.
TriglyceridesHighPioglitazone decreased TG to a greater extent than did metformin (pooled between-group difference −27.2 mg/dL, 95% CI −30.0 mg/dL to −24.4 mg/dL).
HighMetformin monotherapy decreased TG to a greater extent than did the combination of metformin and rosiglitazone, with a pooled between-group difference in TG of −14.5 mg/dL (95% CI −15.7 mg/dL to −13.3 mg/dL).
ModerateMetformin decreased TG to a greater extent than did rosiglitazone, which increased TG, with a pooled between-group difference of −26.9 mg/dL (95% CI −49.3 mg/dL to −4.5 mg/dL).
ModerateMetformin decreased TG to a greater extent than did sulfonylureas (pooled between-group difference −8.6 mg/dL, 95% CI −15.6 mg/dL to −1.6 mg/dL).
ModerateThe combination of metformin plus rosiglitazone and the combination of metformin plus sulfonylurea had similar effects on TG.
ModerateThe combination of metformin and pioglitazone decreased TG to a greater extent than did the combination of metformin and a sulfonylurea, with between-group differences ranging from −10 mg/dL (p = 0.30) to −24.9 mg/dL (p = 0.045).
ModerateSulfonylureas and meglitinides had similar effects on TG (pooled between-group difference 0.2 mg/dL, 95% CI −3.8 mg/dL to 4.2 mg/dL).
Key Question 2: In adults age 18 or older with type 2 diabetes mellitus, what is the comparative effectiveness of the treatment options in terms of the following long-term clinical outcomes: all-cause mortality, cardiovascular mortality, cardiovascular and cerebrovascular morbidity, retinopathy, nephropathy, and neuropathy?
All-cause mortalityLowCompared to sulfonylureas, metformin was associated with a slightly lower risk of all-cause mortality in observational studies, but the results were inconsistent between trials and observational studies, and all had a moderate risk of bias.
LowMany RCTs were of short duration (less than 1 year) and had few deaths, limiting the precision of the results.
InsufficientNo studies addressed several comparisons, including most DPP-4 inhibitor and GLP-1 agonist comparisons, pioglitazone versus rosiglitazone, comparisons with an insulin preparation, and the majority of combination therapy comparisons.
Cardiovascular disease mortalityLowMetformin was associated with a slightly lower risk of cardiovascular mortality than was a second-generation sulfonylurea, but the results were imprecise and had a moderate risk of bias.
LowThe risk of cardiovascular mortality was similar between metformin and each of the thiazolidinediones as monotherapy, with high imprecision of results, inconsistencies, and a moderate risk of bias.
LowMetformin alone was slightly favored over a combination of metformin and rosiglitazone in terms of lower risk of fatal myocardial infarction, with consistent direction of the results but high imprecision.
InsufficientNo studies addressed several comparisons, including most DPP-4 inhibitor and GLP-1 agonist comparisons, pioglitazone versus rosiglitazone, and the majority of combination therapy comparisons.
Cardiovascular and cerebrovascular morbidity (nonfatal myocardial infarction and stroke)LowA comparison of the risk of cardiovascular morbidity between metformin and thiazolidinedione as monotherapy was inconclusive, with high imprecision and inconsistency in the direction of the findings.
LowMetformin alone was slightly favored over a combination of metformin and rosiglitazone in terms of a lower risk of non-fatal ischemic heart disease, with a consistent direction of the results but high imprecision and a failure to reach statistical significance. The pooled odds ratio (OR) for combined fatal and non-fatal ischemic heart disease events was 0.43, 95% CI 0.17 to 1.10. The range of rates for non-fatal ischemic heart disease for the comparison group, metformin, ranged from 0 to 2.9%.
InsufficientNo studies addressed several comparisons, including most DPP-4 inhibitors and GLP-1 agonist comparisons, pioglitazone versus rosiglitazone, and the majority of combination therapy comparisons.
Microvascular outcomes (retinopathy, nephropathy, neuropathy)ModeratePioglitazone was more effective than metformin in reducing the urinary albumin-to-creatinine ratio (15% and 19% decrease in 2 trials), likely indicating less nephropathy.
LowThree comparisons were included for the outcome of neuropathy, but studies were at high risk for bias, with low sample sizes and poorly defined outcomes.
InsufficientNo studies addressed the outcome of retinopathy.
Key Question 3: In adults age 18 or older with type 2 diabetes mellitus, what is the comparative safety of the treatment options in terms of the adverse events and side effects?
HypoglycemiaHighThe risk of mild to moderate hypoglycemia with sulfonylureas exceeds the risk with metformin, with a pooled OR of 4.6 (95% CI 3.2 to 6.5). The range of rates for mild to moderate hypoglycemia in the metformin group was 0 to 17.7%, with a median rate of 0%.
HighThe risk of mild to moderate hypoglycemia with sulfonylureas exceeds the risk with thiazolidinediones, with a pooled OR of 3.9 (95% CI 3.0 to 4.9). The range of rates for mild to moderate hypoglycemia in the thiazolidinedione group was 0 to 92.1%, with a median rate of 4.4%.
HighThe risk of hypoglycemia with metformin plus sulfonylurea exceeds the risk of metformin plus thiazolidinediones, with a pooled OR of 5.8 (95% CI 4.3 to 7.7). The range of rates for mild to moderate hypoglycemia in the metformin plus thiazolidinediones group ranged from 0 to 9.3%, with a median rate of 1.3%.
ModerateThe risk of hypoglycemia with sulfonylurea exceeds the risk with DPP-4 inhibitors (20 events versus none in a single study).
ModerateThe risk of hypoglycemia was similar between metformin and thiazolidinediones.
ModerateThe risk of hypoglycemia with metformin plus sulfonylurea exceeded the risk with metformin alone, with an OR range of 0.6 to 9.3.
ModerateThe risk of hypoglycemia was modestly higher for meglitinides than for metformin, with an OR of 3.0 (95% CI 1.8 to 5.2). The range of rates for mild to moderate hypoglycemia in the metformin group ranged from 0 to 24%, with a median rate of 3.7%.
ModerateThe risk of hypoglycemia was higher for metformin plus a thiazolidinedione than for metformin alone, with an OR of 1.6 (95% CI 1.0 to 2.4). The range of rates for mild to moderate hypoglycemia in the metformin group ranged from 0 to 9.1%, with a median rate of 1.4%.
ModerateThe combination of metformin and DPP-4 inhibitor had similar risk of hypoglycemia as that of metformin alone.
ModerateThe combination of metformin with a sulfonylurea had a higher risk of hypoglycemia than metformin with GLP-1 agonist.
ModerateMetformin combined with a basal insulin had a modestly lower risk of hypoglycemia when compared to metformin combined with a premixed insulin, with the RR ranging from 0.34 to 0.94 in 5 trials.
Gastrointestinal (GI) side effectsHighMetformin was associated with twice as many GI adverse events, most commonly diarrhea, nausea, and vomiting, as were thiazolidinediones.
HighThe rates of GI adverse effects were similar for thiazolidinediones and sulfonylureas.
ModerateMetformin was associated with more frequent GI adverse events than were DPP-4 inhibitors.
ModerateMetformin was associated with twice as many GI adverse event rates as were second-generation sulfonylureas.
ModerateMetformin monotherapy was associated with more frequent GI adverse events than were either the combination of metformin plus a sulfonylurea or metformin plus a thiazolidinedione, if the metformin component was of a lower dose than in the metformin monotherapy arm.
ModerateThe combination of metformin and sulfonylurea was associated with slightly more frequent GI adverse events than were seen with a combination of a thiazolidinedione and a sulfonylurea.
Congestive heart failureModerateThe risk of CHF was higher for thiazolidinediones than for sulfonylureas (OR 1.68, 95% CI 0.99 to 2.85).
InsufficientNo long-term trials assessed the comparative effects of the DPP-4 inhibitors and GLP-1 agonists on the risk of heart failure
Cholecystitis and pancreatitisLowTwo comparisons were included for the outcome of cholecystitis, and one comparison was included for the outcome of pancreatitis, with unclear conclusions.
Lactic acidosisModerateThe risk of lactic acidosis was similar for metformin and sulfonylurea alone and for the two in combination.
Macula edemaInsufficientOnly one trial reported on macular edema. The evidence was insufficient for all comparisons.
CancerInsufficientFew studies addressed the outcome of cancer.
Liver injuryHighThe risk of liver injury was similar for thiazolidinediones and sulfonylureas.
ModerateThe rates of liver injury were similar between thiazolidinediones and metformin.
FracturesHighThe risk of fracture was higher for thiazolidinediones than for metformin. In one large RCT the RR was 1.57 (95% CI 1.13 to 2.17) and women in the thiazolidinedione arm had a higher fracture risk than men. The fracture rate was 4.1% in the reference (metformin) arm.
HighThe risk of fracture was higher for combination therapy with a thiazolidinedione than for metformin plus sulfonylurea, with higher risk in women than in men. In one large RCT, the RR was 1.57 (95% CI 1.26 to 1.97) for the rosiglitazone combination therapy arm, as compared to the combination of metformin plus sulfonylurea arms. The fracture rate in the reference (metformin + sulfonylurea) arm was 1.6%.

GI = gastrointestinal; HDL = high density lipoprotein; HbA1c = hemoglobin A1c; kg = kilograms; LDL = low density lipoproteins; mg/dL = milligrams per deciliter; RCT = randomized controlled trial; RR = relative risk; TG = triglycerides

*

The strength of the evidence was defined as follows: High = High confidence that the evidence reflects the true effect. Further research is unlikely to change our confidence in the estimate of the effect. Moderate = Moderate confidence that the evidence reflects the true effect. Further research may change our confidence in the estimate of the effect and may change the estimate. Low = Low confidence that the evidence reflects the true effect. Further research is likely to change our confidence in the estimate of the effect and is likely to change the estimate. Insufficient = Evidence is unavailable.

From: Executive Summary

Cover of Oral Diabetes Medications for Adults With Type 2 Diabetes: An Update
Oral Diabetes Medications for Adults With Type 2 Diabetes: An Update [Internet].
Comparative Effectiveness Reviews, No. 27.
Bennett WL, Wilson LM, Bolen S, et al.

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