Safety of Dipeptidylpeptidase-4 Inhibitors in Older Adults with Type 2 Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

doi:10.21203/rs.3.rs-524787/v1

Background

We aim to assess the safety of dipeptidylpeptidase-4 inhibitors (DPP4s) in older type 2 diabetes patients with inadequate glycaemic control.

Methods

We included RCTs in older (≥65 years) patients with type 2 diabetes. The intervention group was treated with any DPP4. A systematic search in MEDLINE and EMBASE was performed in December 2020. For assessing risk of bias, the RoB 2 tool was applied. The quality of evidence was assessed using GRADE. We pooled outcomes using random-effects meta-analyses.

Results

We identified 16 RCTs that included 19,317 patients with a mean age >70 years. The mean HbA1c ranged between 7.1g/dl and 10.0g/dl.

Adding DPP4s to standard alone care may increase mortality slightly (RR 1.04; 0.89-1.21). Adding DPP4s to standard care increases the risk for hypoglycaemia (RR 1.08; 95%CI 1.01-1.16), but difference in overall adverse events is negligible.

DPP4s added to standard care likely reduce mortality compared to sulfonylureas (RR 0.88; 0.75-1.04). DPP4s probably reduce the risk for hypoglycaemia compared to sulfonylureas (magnitude of effect not quantifiable because of heterogeneity) but difference in overall adverse events is negligible.

There is insufficient evidence on hospitalizations, falls, fractures, renal impairment, and pancreatitis.

Conclusion

There is no evidence that DPP4s in addition to standard care decrease mortality but DPP4s increase hypoglycaemia risk. Second-line therapy in older patients should be considered cautiously because even in drugs with a good safety profile like DPP4s.

In the case second-line treatment is necessary, DPP4s appear to be superior to sulfonylureas.

Registration

PROSPERO: CRD42020210645

Geriatrics & Gerontology

Older people

dipeptidylpeptidase-4 inhibitors (DPP4s)

systematic review

meta-analyses

In clinical practice a large share of patients with type 2 diabetes are older adults and it can be expected that they will make up the most of diabetic patients in western countries in the future [1–3]. Older adults are at higher risk for adverse drug-related effects and often experience more serious consequences from such reactions (e.g., hospitalization and death) [4, 5]. Moreover, older adults have a higher risk to experience adverse reactions mimicking typical geriatric symptoms such as falls and delirium [6]. Therefore, it could be questioned whether the benefits of strict glycaemic control outweigh the harms in older adults [7]. To our knowledge, there is no high-quality evidence specifically for older adults that supports this assumption.

In clinical practice guidelines dipeptidylpeptidase-4 (DPP4) inhibitors are primarily recommended for second-line treatment as an alternative to other antidiabetics, especially when aiming to reduce risk for hypoglycaemia [8, 9]. Likewise, guidelines for older adults assume that DPP4 inhibitors may reduce the risk for hypoglycaemia and therefore are considered as a preferred treatment in older patients [10].

Previous systematic reviews showed that DPP4 inhibitors added to standard diabetic treatment, which usually consists of metformin and lifestyle interventions, is effective regarding glycaemic control and safe [11, 12]. A systematic review on studies in older adults found that DPP4 inhibitors may reduce hypoglycaemia but results were uncertain regarding other safety outcomes [13]. In the view of the narrow ridge between over- and under-treatment and the relevance of adverse events in older adults, reliable data on safety are of major importance to allow sufficient balancing of benefit and risks in treatment decisions. Robust evidence is of particular interest because costs for DPP4 inhibitors are much higher than costs of alternative treatments [14].

The objective of our systematic review is two-fold. First, we aim to assess the safety of DPP4 inhibitors as add-on therapy compared to no additional treatment in older adults with inadequate glycaemic control. Second, we aim to assess the safety of DPP4 inhibitors compared to alternative treatments in older adults with inadequate glycaemic control.

We registered this review in PROSPERO: CRD42020210645.There were no changes to the protocol.

This systematic review follows the reporting recommendations of the updated Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement[15].

Eligibility criteria

Participants

We only included studies on older type 2 diabetes patients. We operationalized the age criterion as follows:

• ≥80% of the total study population aged ≥65 years.

• subgroup analysis reports on participants aged ≥65 years.

Intervention

The intervention group must be treated with any type of DPP4 inhibitor. Any dose or regimen were eligible. Trials on DPP4 inhibitors not approved in the European Union before 2020 were excluded.

As comparator we accepted any active control, including standard care and no treatment or placebo. In studies of additional DPP4 inhibitor treatment in combined regimens (e.g., metformin), the non-DPP4-treatment must be the same in all groups, so that the groups only differ regarding DPP4 inhibitors.

Outcomes

We prioritized all-cause mortality, overall adverse events, and hypoglycaemia as primary outcomes (critical outcomes in GRADE). Secondary outcomes were hospitalization, discontinuation due to adverse events, falls, fractures, delirium, and pancreatitis (important outcomes).

We anticipated that the effectiveness of DPP4 inhibitors regarding glycaemic control is constant across different age subgroups and consequently would not have a shifting effect on the benefit-risk ratio[13, 16, 17]. Moreover, glycaemic control is a surrogate endpoint. Although it may be important in older patients, a greater reduction in morbidity and mortality may rather result from control of other cardiovascular risk factors than from tight glycaemic control alone. Thus, a benefit for patients cannot be directly assumed when glycaemic targets are met[10].

Types of studies

Only RCTs or subgroup analyses of RCTs on the relevant age group were eligible.

Information sources

First, we screened the title/abstracts of the references of all systematic reviews included in a systematic review previously performed by the research group of one member of our review team[13].

Second, we updated the electronic literature searches of the previous systematic review. For this purpose, we searched MEDLINE, MEDLINE in Process, and Embase (all via Embase) for studies published from 1st December 2015 onwards. We last run the search on 11 December 2020.

In addition, we searched the references lists of all included RCTs and systematic reviews on the same topic.

Search strategy

The search strategy was prepared by an experienced information specialist in collaboration with the clinical experts. The full search is presented in supplement I. The searches were limited to English and German. In addition, we limited the search to articles and reviews and excluded case reports, in vitro studies, and animal experiments. The search strategy included a search filter for RCTs, a search filter for older patients and a generic search filter (modified and with additional specific terms) for adverse events[18-20]. The search strategy was reviewed by a second person using the PRESS checklist and validated by checking whether clearly eligible RCTs already known would have been identified[21].

Selection process

Two reviewers independently screened the titles and abstracts of all records identified by the literature search. Next, full-text articles of potentially relevant reports were retrieved and assessed for compliance with the eligibility criteria by two reviewers independently. Disagreements between reviewers were resolved by discussion until consensus.

Multiple reports of the same RCT were merged, so that each trial is the unit of analysis. Title/Abstract screening of the update search was performed in Rayyan[22].

Data collection process

Descriptive data were extracted by one reviewer and checked by a second reviewer for accuracy. Relevant outcome data were identified by two reviewers independently by marking the section in the relevant report. Subsequently, one reviewer extracted the data and a second reviewer checked the correctness. All disagreements were resolved in discussions until consensus.

Data items

Supplement II lists all items for which we extracted data.

We extracted data on outcomes for the last available follow-up, i.e., the longest observation period.

Study risk of bias assessment

We assessed the risk of bias with the revised Cochrane risk-of-bias tool for RCTs (RoB 2 tool)[23]. The RoB 2 tool provides a framework for assessing the risk of bias in five distinct domains on one particular outcome, i.e. for each outcome separately.

In the first domain we considered if the subgroup consideration raised a problem in the randomization process (e.g., unbalanced confounders) in addition.

One of the three levels of risk of bias was assigned to each domain:

• Low risk of bias

• Some concerns

• High risk of bias

Effect measures

All considered outcomes were dichotomous. We extracted raw data on events and number of participants for each group and calculated relative risks for all outcomes.

Synthesis methods

Statistical synthesis method

We pooled data only if RCTs were sufficiently clinically and methodologically homogenous and the p-value of the statistical test for heterogeneity was >0.05. To describe statistical heterogeneity, we calculated prediction intervals and I-square.

We pooled adverse event data separately for each comparator (placebo, no treatment, active control, standard care).

We performed an inverse variance random effects meta-analysis using the Hartung-Knapp method and the Paule-Mandel heterogeneity variance estimator[24, 25]. For outcomes for which only sparse data were available (event rate <5%, zero event studies, less than four RCTs in meta-analysis), we additionally pooled the results using beta-binomial regression models for sensitivity analysis[26, 27].

We used the R-Package Meta for the meta-analysis and SAS 9.4 for estimating the beta-binomial models[28]. In case of heterogeneity, we synthesized results across RCTs presenting range of effects of the point estimate of the relative risk ratio.

Sensitivity analyses

We performed a sensitivity analysis according to risk of bias. More precisely, we excluded RCTs at high risk of bias.

Reporting bias assessment

We planned to assess publication bias by visual inspection of funnel plots for asymmetry, if at least 10 trials for each outcome would had been available.

Bias in selection of the reported results within one trial is a domain of the RoB 2 tool (see above). For RoB 2 assessment, we compared the list of outcomes reported in the protocols or methods section with the outcomes reported in the published paper.

Certainty of evidence assessment

We rated the certainty of the body of evidence using the GRADE approach (Grading of Recommendations Assessment, Development and Evaluation). In the GRADE system, evidence from RCTs starts as “high-certainty” and the following criteria are applied for downgrading the certainty of evidence by one or two levels[29]:

• Risk of bias

• Imprecision

• Inconsistency

• Indirectness

• Publication bias

The rating of these criteria leads to four levels of the certainty of evidence for each of the prioritized outcomes[30]:

• High-certainty evidence: the review authors have a lot of confidence that the true effect is similar to the estimated effect.

• Moderate-certainty evidence: the review authors believe that the true effect is probably close to the estimated effect.

• Low-certainty evidence: the review authors believe that the true effect might be markedly different from the estimated effect.

• Very low-certainty evidence: the review authors believe that the true effect is probably markedly different from the estimated effect.

One reviewer judged the certainty of the evidence and a second reviewer verified the assessment. Disagreements were resolved by discussion until consensus.

The certainty of evidence and results are presented in the 'Summary of Findings' (SoF) tables[31]. The SoF tables were prepared using GRADEpro GDT[32]. For estimating the absolute effect, we used absolute risks of the comparator group of included RCTs.

To report the findings in consideration of the certainty of evidence, we used the standardized informative statements suggested by the GRADE working group[33].

The certainty of evidence is expressed with the following statements:

• High-certainty: reduces/increases in outcome

• Moderate-certainty: likely/probably reduces/increases in outcome

• Low-certainty: may reduce/increase in outcome

• Very low-certainty: the evidence is uncertain in outcome

Study selection

The initial screening of publications included in the previously published systematic review [13] identified 18 potentially relevant reports. The electronic search provided a total of 259 citations after duplicate removal. Reference screening revealed further four potentially relevant publications. Title/abstracts of these were screened and 52 potentially eligible publications remained. The screening of full-text publications resulted in 16 RCTs (21 publications) which met all eligibility criteria [34-54]. Supplemental figure 1 shows the study selection according to the updated Preferred Re-porting Items for Systematic Reviews and Meta-analyses (PRISMA) statement 2020 [15]. A list of excluded studies with primary reason for exclusion is provided in Supplement III.

Study characteristics

Table 1 shows the study characteristics (for detailed characteristics see Supplement IV).

Table 1

Characteristics of included studies

Study

Age [years] mean IG/CG

Female n(%) IG/CG

HbA1c [%] mean IG/CG

BMI [kg/m²] mean IG/CG

Renal function

IG/CG

Intervention/

comparison

Outcomes

Add-on placebo comparison

Barnett 2013

74.9/ 74.9

46(28.4)/ 30(38.0)

7.8/ 7.7

29.6/29.8

eGFR [ml/min/1.73m², according to MDRD] n(%)

Normal (≥90) 36(22.2)/15(19.0)

Mild impairment (60 to <90) 83(51.2)/42(53.2)

Moderate impairment (30 to <60) 41(25.3)/21(26.6)

Severe impairment (<30) 2(1.2)/1(1.3)

Intervention

Linagliptin, once-daily 5 mg

Comparison

Placebo, once-daily 5mg

Any AE

Discontinuation*

Falls

Fractures

Hospitalisation

Hypoglycaemia

Mortality

Pancreatitis

Bethel 2017

78.3/78.4

288(29.7)/

360(34.8)

7.19/7.17

29.0/28.9

eGFR[ml/min/1.73m²] mean

65.3/65.7

Intervention

Sitagliptin, once-daily 100mg (or 50mg, if the baseline eGFR was ≥30 and <50ml/min/1.73m²)

Comparison

Placebo, once-daily

Fractures

Hospitalisation

Mortality

Pancreatitis

Cooper 2020

72.2/72.0

852(42.0)/ 747(37.7)

7.9/7.8

31.0/31.0

eGFR[ml/min/1.73m²] mean

49.5/49.1

Intervention

Linagliptin, once-daily 5 mg, added to usual care

Comparison

Placebo, one-daily, 5 mg

Any AE

Discontinuation

Hypoglycaemia

Pancreatitis

Renal Impairment

Kadowaki 2014**

58.4/60.3

34(35.4)/

32(32.7)

8.4/8.4

24.9/24.6

NR

Intervention

Teneligliptin 20mg + glimepiride
Comparison

Placebo

Hypoglycaemia

Ledesma 2019

72.3/72.5

59(39.1)/

60(39.7)

8.2/8.1

28.3/27.9

eGFR (MDRD) [ml/min/1.73 m²] mean

65.9/70.3

Intervention

Linagliptin, once-daily, 5 mg

Comparison

Placebo, 5 mg

Falls

Fractures

Hospitalisation

Hypoglycaemia

Mortality

Pancreatitis

Leiter 2015

71.6/71.6

1542(35.9)/

1527(35.8)

7.5/7.4***

30.6/30.7

eGFR [ml/min/1.73m²] mean

66.6/66.5

Intervention

Saxagliptin, once-daily, 5 mg (normal renal function/mild impaired renal function (eGFR >50 ml/ min/1.73m2) or 2.5 mg daily if they had an eGFR of ≤ 50 ml/min/1.73m²
Control

Placebo

Any AE

Discontinuation

Hypoglycaemia

Mortality

Schweizer 2013

78.0/78.3

24(48.0)/

25(45.5)

7.8/7.8

31.0/30.0

eGFR (MDRD) [ml/min/1.73m²] mean

35.5/35.1

Intervention

Vildagliptin, once-daily, 50 mg

Comparison

Placebo

Any AE

Discontinuation

Hypoglycaemia

Mortality

Strain 2013

75.1/74.4

66(47.5)/

86(61.9)

7.9/7.9

29.1/30.5

GFR (MDRD) [ml/min/1.73m²] n(%)

Normal (>80): 34(24.5)/31(22.3)

Mild (≥50 to ≤80): 86(61.9)/87(62.6)

Moderate (≥30 to <50): 19(13.7)/21(15.1)

Intervention

Vildagliptin, twice daily (if drug-naïve and other background OAD) or once-daily (if sulphonylurea monotherapy), 50 mg

Comparison

Placebo, twice daily, 50mg

Any AE

Discontinuation

Hypoglycaemia

Mortality

Pancreatitis

Open-label comparison

Chien 2011

73.5/72.5

31(63.3)/

25(52.1

9.5/10.0

26.2/26.0

NR

Intervention

Sitagliptin 100 mg, once-daily
Comparison

Only OAD

Any AE

Discontinuation

Hypoglycaemia

Sulfonylurea comparison

Espeland 2020

72.0/72.0

597(40.7)/ 633(42.0)

7.1/7.1

29.4/29.1

eGFR [ml/min/1.73m²] mean

70.2/70.9

Intervention

Linagliptin, once-daily 5 mg

Comparison

Glimepiride, once-daily,

1-4 mg

Any AE

Discontinuation

Falls

Fractures

Hospitalisation

Hypoglycaemia

Mortality

Pancreatitis

Hartley 2015

70.6/70.8

104(52.8)/

114(59.7)

7.8/7.8

29.7/29.7

NR

Intervention

Sitagliptin, once-daily 100 mg (if eGFR ≥50 ml/min/1.73m²)

50 mg (if eGFR ≥ 35 and <50 ml/min/1.73m²)

Comparison

Glimepiride has started 1 mg once daily and could be up-titrated to a maximum dose of 6 mg/day over the first 18 weeks

Any AE

Discontinuation

Hypoglycaemia

Mortality

Pancreatitis

Matthews 2010**

57.5/57.5

733(46.9)/

718(46.1)

7.3/7.3

31.9/31.7

Mild renal impairment**** n(%)

482(30.9)/485(31.2)

Intervention

Vildagliptin, twice daily 50 mg
Comparison

Glimepiride up to 6 mg/day

Hypoglycaemia

Rosenstock 2013

70.1/69.8

120(54.1)/

123(56.2)

7.5/7.5

29.6/30.0

eGFR (MDRD) [ml/min/1.73m²] mean

73.6/72.9

Intervention

Alogliptin, once-daily 25 mg
Comparison

Glipizide, once-daily 5 mg titrated for inadequate control to 10 mg, as needed

Any AE

Discontinuation

Falls

Fractures

Hypoglycaemia

Mortality

Pancreatitis

Schern-thaner 2015

72.5/72.7

143(39.7)/

132(36.7)

7.58/7.62

BMI category(%)

<25 kg/m² 14.2/18.3

≥25 and <30 kg/m² 40.8/38.1

≥30 kg/m² 44.7/43.3

NR

Intervention

Saxagliptin, once-daily 5 mg
Comparison

Glimepiride, once-daily

1-6 mg (uptitrated every 3 weeks in 1- or 2-mg/day increments to the optimum dose (FPG≤6.1mmol/l), up to 6mg/day)

Any AE

Discontinuation

Fractures

Hypoglycaemia

Mortality

Pancreatitis

Placebo comparison

Barzilai 2011

71.6/72.1

54(53)/55(53)

7.8/7.8

30.8/ 31.1

Creatinine clearance estimated via Cockcroft–Gault [ml/min] mean

70/72

Intervention

Sitagliptin, once-daily 50-100mg (based on creatinine clearance)

Comparison

Placebo

Any AE

Discontinuation

Fractures

Hypoglycaemia

Mortality

Renal impairment

Metformin comparison

Schweizer 2009

71.6/70.2

94(55.6)/

78(47.0)

7.8/7.7

29.8/29.4

GFR (MDRD) [ml/min/1.73 m²] n(%)

>80 (normal)

65(38.5)/72(43.4)

≥50 to ≤80 (mild impairment) 102(60.4)/90(54.2)

≤30 to <50 (moderate impairment)

2(1.2)/4(2.4)

Intervention

Vildagliptin, once-daily

100 mg
Control

Metformin, daily 1500 mg

Any AE

Discontinuation

Hypoglycaemia

Mortality

Abbreviations: AE: adverse event; BMI: body mass index; CG: control group; eGFR: estimated glomerular filtration rate; FPG: fasting plasma glucose; IG: intervention group; MDRD: Modification of Diet in Renal Disease equation; n: number; NR: not reported; OAD: oral antidiabetic agents

*due to AEs

**According to the overall study population (characteristics of patients ≥ 65y years were not reported separately)

***median

****GFR=50–80 ml/min per 1.73 m².

The 16 RCTs included 19,317 older patients. The mean age of the population included in the analysis was >70 years in each RCT. In most studies, the study population comprised more men than women. The mean HbA1c at baseline ranged between 7.1 g/dl and 10.0 g/dl. In all studies, the mean BMI was above normal and there were participants who had reduced renal function. Background treatment for type 2 diabetes and other co-medications were well-balanced between groups in almost all RCTs.

Nine RCTs compared DPP4 inhibitors as second-line treatment in patients inadequately controlled with standard care against no-treatment or placebo [34, 36, 37, 39, 41, 42, 47-49] and five RCTs compared DPP4 inhibitor second-line treatment with sulfonylureas [38, 40, 43-45]. Barzilai et al. 2011 [35] and Schweizer et al. 2009 [46] compared DPP4 inhibitor first-line monotherapy with placebo and metformin, respectively.

Of the 16 included studies, 15 were funded by the pharmaceutical industry. For one RCT, we could not find any information on funding sources [36].

Risk of bias of included RCTs

The risk of bias assessment for each study is presented in table 2.

Results are presented on study level (not outcome level) because in none of the RCTs the risk of bias differed for different outcomes (e.g., adverse events and hypoglycaemia). We rated 5 RCTs to be at low risk of bias [37-39, 48, 49]. We had some concerns regarding risk of bias for ten RCTs [34, 35, 40-47] and assessed one RCT to be at high risk of bias [36]. The main reason for concerns arose in the randomisation domain because allocation concealment was not clear.

Noticeably, no outcome was rated down for risk of bias in the GRADE assessment because those RCTs potentially suffering bias had smaller overall weight in the meta-analyses than the RCTs at low risk of bias. Furthermore, results did not appear to be systematically different.

Reporting bias

We could not assess reporting bias because in none of the meta-analyses 10 RCTs or more were included.

Effects of DPP4 inhibitors on older patients

DPP4 inhibitors as add-on to standard care alone compared to no add-on treatment

The summary of findings table (table 3) shows the results of the synthesis, and the certainty of evidence assessment for DPP4 inhibitors compared to no further treatment or placebo treatment in addition to standard care alone. Results of meta-analyses and individual RCTs are presented in the forest plots (figure 1-3 and supplemental figures 2-7).

Table 3

GRADE summary of findings table DPP4-inhibitors compared to no-treatment/placebo

	Anticipated absolute effects^* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with standard care	Risk with Dipeptidyl Peptidase-4 (DPP-4) Inhibitors as add-on	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
All-cause mortality follow up: range 24 weeks to 5.7 years	67 per 1.000	70 per 1.000 (60 to 81)	RR 1.04 (0.89 to 1.21)	11697 (6 RCTs)	⨁⨁◯◯ LOW	Rated down for: Imprecision (two levels)
Any adverse events follow up: range 24 weeks to 2.9 years	755 per 1.000	762 per 1.000 (740 to 778)	RR 1.01 (0.98 to 1.03)	13595 (7 RCTs)	⨁⨁⨁⨁ HIGH
Discontinuation due to adverse events follow up: range 24 weeks to 2.9 years	80 per 1.000	77 per 1.000 (67 to 89)	RR 0.97 (0.84 to 1.12)	13294 (6 RCTs)	⨁⨁◯◯ LOW	Rated down for: Imprecision (two levels)
Hypoglycemia follow up: range 12 weeks to 2.9 years	188 per 1.000	203 per 1.000 (190 to 218)	RR 1.08 (1.01 to 1.16)	13522 (8 RCTs)	⨁⨁⨁⨁ HIGH
Hospitalization follow up: range 24 weeks to 5.7 years	44 per 1.000	43 per 1.000 (22 to 84)	RR 0.99 (0.50 to 1.94)	2547 (3 RCTs)	⨁◯◯◯ VERY LOW	Rated down for: Imprecision (two levels), and inconsistency (one level)
Falls follow up: 24 weeks	13 per 1.000	16 per 1.000 (0 to 1.000)	RR 1.25 (0.00 to 4320.00)	543 (2 RCTs)	⨁◯◯◯ VERY LOW	Rated down for: Imprecision (two levels), and inconsistency (one level)
Fractures follow up: range 24 weeks to 5.7 years	36 per 1.000	41 per 1.000 (19 to 91)	RR 1.15 (0.52 to 2.53)	2566 (4 RCTs)	⨁◯◯◯ VERY LOW	Rated down for: Imprecision (two levels), and inconsistency (one level)
Pancreatitis follow up: range 24 weeks to 5.7 years	2 per 1.000	3 per 1.000 (1 to 8)	RR 1.39 (0.47 to 4.06)	15397 (6 RCTs)	⨁⨁◯◯ LOW	Rated down for: Imprecision (two levels)
Renal impairment follow up: range 24 weeks to 2.9 years	98 per 1.000	89 per 1.000 (72 to 113)	RR 0.91 (0.73 to 1.15)	12572 (3 RCTs)	⨁⨁◯◯ LOW	Rated down for: Imprecision (two levels)
Delirium	No evidence for this outcome			(0 studies)	-
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Adding DPP4 inhibitors to standard care may increase mortality slightly in older type 2 diabetes patients with inadequate glycaemic control [34, 39, 42, 47-49]. DPP4 inhibitors increase the risk for hypoglycaemia [34, 36, 37, 41, 42, 47-49]. Differences in overall adverse events [34, 36, 37, 42, 47-49] and discontinuation due to adverse events [34, 36, 37, 47-49] are negligible. DPP4 inhibitors may increase the risk for pancreatitis [34, 36, 37, 47-49] but may reduce the risk for renal impairment [37, 48] slightly. It is unclear whether DPP4 inhibitors have an impact on hospitalization [34, 39, 42], falls, [34, 42] fractures, [34, 39, 42] and delirium (no RCT) compared to no add-on treatment because either no study assessed these pre-defined outcomes or the quality of evidence was very low.

Excluding the RCT at high risk of bias in the sensitivity analyses on primary outcomes does not change the results.

DPP4 inhibitors as add-on to standard care compared to sulfonylureas as add-on to standard care

The summary of findings table (table 4) shows the results of the synthesis and the certainty of evidence assessment for DPP4 inhibitors added to standard care compared to sulfonylureas added to standard care. Results of the meta-analyses and individual RCTs are presented in the forest-plots (figure 4-6 and supplemental figures 8-11) and supplement V. Results for the RCTs which were not included in any meta-analyses because there was only one RCT on the outcome are presented in supplemental table VI.

Table 4

the results of the synthesis and the certainty of evidence assessment for DPP4 inhibitors added to standard care compared to sulfonylureas added to standard care

	Anticipated absolute effects^* (95% CI)				Relative effect (95% CI)		№ of participants (studies)		Certainty of the evidence (GRADE)	Comments
	Risk with standard care		Risk with Dipeptidyl Peptidase-4 (DPP-4) Inhibitors as add-on		Relative effect (95% CI)		№ of participants (studies)		Certainty of the evidence (GRADE)	Comments
All-cause mortality follow up: range 52 weeks to 6 years	109 per 1.000	96 per 1.000 (82 to 113)		RR 0.88 (0.75 to 1.04)		4611 (4 RCTs)		⨁⨁◯◯ LOW			Rated down for: Imprecision (tow levels); results mainly based on one study and 95%CIs of the beta-binomial model were very wide.
Any adverse events follow up: range 24 weeks to 6 years	826 per 1.000	818 per 1.000 (809 to 834)		RR 0.99 (0.98 to 1.01)		4611 (4 RCTs)		⨁⨁⨁⨁ HIGH
Discontinuation due to adverse events follow up: range 24 weeks to 6 years	136 per 1.000	128 per 1.000 (103 to 158)		RR 0.94 (0.76 to 1.16)		5041 (4 RCTs)		⨁⨁◯◯ LOW			Rated down for: Imprecision (one level) Inconsistency (one level)
Hypoglycemia follow up: range 24 weeks to 6 years	434 per 1.000	69 per 1.000 (39 to 399)		RR ranged from 0.09 to 0.92		5567 (5 RCTs)		⨁⨁⨁◯ MODERATE			Rated down for: Inconsistency (one level)
Hospitalization follow up: median 6 years	476 per 1.000	453 per 1.000 (415 to 491)		RR 0.95 (0.87 to 1.03)		2975 (1 RCT)		⨁⨁◯◯ LOW			Rated down for: Imprecision (two levels)
Falls follow up: range 52 weeks to 6.1 years	86 per 1.000	89 per 1.000 (0 to 1.000)		RR 1.03 (0.00 to 2830.00)		3416 (2 RCTs)		⨁◯◯◯ VERY LOW			Rated down for: Imprecision (two levels) Inconsistency (two levels)
Fractures follow up: range 52 weeks to 6 years	142 per 1.000	149 per 1.000 (41 to 551)		RR 1.05 (0.29 to 3.89)		4611 (3 RCTs)		⨁◯◯◯ VERY LOW			Rated down for: Imprecision (two levels) Inconsistency (two levels)
Pancreatitis follow up: range 52 weeks to 6 years	4 per 1.000	4 per 1.000 (0 to 90)		RR 0.97 (0.05 to 20.85)		4611 (4 RCTs)		⨁⨁◯◯ LOW			Rated down for: Imprecision (two levels)
Renal impairment	No evidence for this outcome (one RCT with no events)					441 (1 RCT)		-
Delirium	No evidence for this outcome (only one study with one event)					(0 studies)		-
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

DPP4 inhibitors added to standard care likely reduce mortality compared to sulfonylureas added to standard care in older type 2 diabetes patients with inadequate glycaemic control [38, 40, 44, 45]. DPP4 inhibitors probably reduce hypoglycaemia compared to sulfonylureas, but the magnitude of the reduction cannot be reliably quantified because of heterogeneity in effect sizes between studies [38, 40, 43-45]. DPP4 inhibitors have no impact on overall adverse events [38, 40, 44, 45] but may reduce discontinuation due to adverse events [38, 40, 44, 45] slightly. DPP4 inhibitors may reduce hospitalizations [38]. Pancreatitis was very rare and occurred similarly often in both groups [38, 40, 44, 45]. It is unclear whether DPP4 inhibitors have an impact on falls [38, 44], fractures [38, 44, 45], renal impairment [44], and delirium (no RCT) compared to sulfonylureas as add-on treatment to standard care because no study assessed these pre-defined outcomes or the quality of evidence was very low.

Other comparisons

The results for the RCTs that were not included in any meta-analysis because there was only one study on this comparison are shown in supplement VII.

Barzilai et al. 2011 [35] found numerically fewer overall adverse events (RR 0.87; 95%CI 0.66 to 1.15) but much more adverse events leading to discontinuation (RR 1.70; 95%CI 0.42 to 6.93) in the DPP4 inhibitor group compared to the placebo group but statistical uncertainty was high for both outcomes. Evidence for mortality, hypoglycaemia, fractures, and renal impairment was insufficient because there were no events at all or only very few events in one study arm.

Schweizer et al. 2009 [46] found numerically fewer adverse events (RR 0.88; 95%CI 0.70 to 1.11) and much less discontinuations due to adverse events (RR 0.53; 95%CI 0.22 to 1.30) when taking DPP4 inhibitors compared to metformin; but again statistical uncertainty was high for both outcomes. Evidence on hypoglycaemia was inconclusive in this RCT because only two adverse events were observed in the metformin group.

Main findings and comparison with other evidence

We found that in older patients with “inadequate” glycaemic control the addition of DPP4 inhibitors may increase mortality and increases the risk of experiencing hypoglycaemia compared to standard care. Our results are in agreement with a previous systematic review that included RCTs and observational studies and which showed higher cardiovascular morbidity when using DPP4 inhibitors compared to standard care [55]. DPP4 inhibitors are considered to be among the preferable drugs for treating older patients with type 2 diabetes because of their low risk of hypoglycaemia [10, 56]. However, our findings point out that it may be questioned whether the cardiovascular benefits from reaching strict glycaemic targets outweigh the disadvantages arising from unintended effects in older patients even when treated with DPP4 inhibitors. Similar concerns and the call for more individualization of antidiabetic therapy, in particular in frail older adults have already been raised in the literature [13, 57]. However, as far as we know until now, no high-quality evidence exists that underpins this clinical judgement.

All RCTs that compared DPP4 inhibitors to an active control as add-on therapy used sulfonylureas. We found that DPP4 inhibitors likely reduce the risk for mortality, hospitalization, hypoglycaemia, and adverse events leading to discontinuation and may have little impact on pancreatitis suggesting that DPP4 inhibitors have a better benefit-risk ratio than sulfonylureas in older patients. Likewise, recent systematic reviews on the safety of DPP4 inhibitors showed that DPP4 inhibitors are safer compared to other oral antidiabetic drugs [12] and that DPP4 inhibitor use may not be associated with a higher risk for pancreatitis than other antidiabetic drugs [58]. Our analyses suggest that the main benefit of DPP4 inhibitors arises from the avoidance of severe adverse events and reduction of risks particularly relevant for older patients (e.g., falls). The safety profile appears to be even better in older compared to younger patients [11], which is in particular an important finding because adverse events often have more severe consequences in older patients (e.g., falls and hospitalization because of hypoglycaemia). In agreement with expert-based guideline recommendations on treating older patients with type 2 diabetes, the generated evidence supports the judgement that safety considerations are of major importance when treating older patients [59]. However, the high costs might be a limiting factor for prescribing DPP4 inhibitors in many countries [14].

Quality of evidence and applicability of findings

The quality of the evidence was low for some outcomes. The main reason was imprecision because events were rare (e.g., pancreatitis). Moreover, we had moderate concerns regarding risk of bias in about half of the RCTs because of problems in the randomisation domain.

Almost all studies had quite broad inclusion criteria and only few exclusion criteria (e.g., patients with end-stage renal disease) and the population appeared to be similar to real-world patients [60, 61]. Therefore, none of the studies was rated down because of applicability concerns. Most RCTs were performed in Western countries. Therefore, the applicability of findings to other countries might be limited.

Limitations

A limitation of this systematic review is the literature search. We decided to use the evidence from existing systematic reviews to speed up the review process. Although this could be a limitation, we anticipated that it is a reasonable shortcut considering the very huge number of systematic reviews on DPP4 inhibitors and therefore low risk of missing relevant literature when relying on pervious systematic literature searches.

Implications for research

Older patients will probably make-up most patients with type 2 diabetes in the near future [1, 2]. Nevertheless, there is an important research gap in the existing evidence from RCTs regarding relevant outcomes for older patients such as falls, fractures, or delirium. Future studies should assess these outcomes because without evidence on these the information for judging the benefits and harms of diabetic treatment in older patients will remain incomplete.

In addition, there is a lack of RCTs comparing DPP4 inhibitors to other antidiabetic drugs with a presumably better safety profile than sulfonylureas (e.g., SGLT2-inhibitors) in older patients.

Implications for practice

There is no evidence from RCTs that DPP4 inhibitors when added to standard care decrease mortality or hospitalization in older patients. These findings indicate that initiating second-line therapy in older patients should be considered cautiously because even in drugs with a good safety profile, such as DPP4 inhibitors, the supposed benefits of glycaemic control, appear not to outweigh the consequences from adverse events Individualizing glycaemic targets under consideration of comorbidity, co-medications and alternative measures, which could reduce the cardiovascular risk might be a more suitable approach for treating older patients with diabetes 2 [10].

In case second-line treatment is necessary, DPP4 inhibitors appear to be superior to sulfonylureas, in particular because of the reduction of hypoglycaemia and its associated consequences, such as hospitalization.

DPP4s	Dipeptidylpeptidase-4 inhibitors
RCT	Randomised controlled trial

Funding

This work was part of the project “Updating the PRISCUS list of potentially inappropriate medications for the elderly” funded by the German Federal Ministry of Education and Research (Grant Number: 01KX1812). The funder was not involved in the study.

Conflicts of interest/Competing interests

Not applicable.

Availability of data and materials

All data generated or analysed in this study are included in this published article [and its supplementary information files]

Authors' contributions

KD: study selection, data extraction, interpretation of results, writing of manuscript, revision of manuscript

SB: data extraction, interpretation of results, revision of manuscript

AW: study selection, data extraction, interpretation of results, revision of manuscript

NKM: interpretation of results, writing of manuscript

SH: design and conduct of electronic searches

AS: development of study concept, interpretation of results, revision of manuscript

DP: development of study concept, interpretation of results, revision of manuscript

PAT: development of study concept, interpretation of results, revision of manuscript

TM: development of study concept, study selection, data extraction, statistical analysis, interpretation of results, writing of manuscript

All authors have read and approved the manuscript.

Ethics approval and consent to participate

Not applicable (secondary data).

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Acknowledgements

Not applicable.

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Due to technical limitations, table 2 is only available as a download in the Supplemental Files section.

No competing interests reported.

Supplementfinal.docx
Table2.png
Table 2: risk of bias of included studies

Safety of Dipeptidylpeptidase-4 Inhibitors in Older Adults with Type 2 Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Status:

Version 1

Abstract

Figures

Background

Methods

Eligibility criteria

Participants

Intervention

Outcomes

Types of studies

Information sources

Search strategy

Selection process

Data collection process

Data items

Study risk of bias assessment

Effect measures

Synthesis methods

Statistical synthesis method

Sensitivity analyses

Reporting bias assessment

Certainty of evidence assessment

Results

Study selection

Study characteristics

Risk of bias of included RCTs

Reporting bias

Effects of DPP4 inhibitors on older patients

DPP4 inhibitors as add-on to standard care compared to sulfonylureas as add-on to standard care

Other comparisons

Discussion

Main findings and comparison with other evidence

Quality of evidence and applicability of findings

Limitations

Conclusion

Implications for research

Implications for practice

Abbreviations

Declarations

Funding

Conflicts of interest/Competing interests

Availability of data and materials

Authors' contributions

Ethics approval and consent to participate

Consent to participate

Consent for publication

Acknowledgements

References

Table

Additional Declarations

Supplementary Files

Status:

Version 1