Insulin Monotherapy Versus Insulin Combined with Other Glucose-Lowering Agents in Type 2 Diabetes: A Narrative Review

authors:

avatar Hengameh Abdi 1 , avatar Fereidoun Azizi ORCID 1 , * , avatar Atieh Amouzegar 1

Endocrine Research Centre, Research Institute for Endocrine Science, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran
International Journal of Endocrinology and Metabolism: Vol.16, issue 2; e65600
published online: April 21, 2018
article type: Review Article
received: December 27, 2017
revised: April 4, 2018
accepted: April 4, 2018
DOI: https://doi.org/10.5812/ijem.65600

how to cite: Abdi H, Azizi F, Amouzegar A. Insulin Monotherapy Versus Insulin Combined with Other Glucose-Lowering Agents in Type 2 Diabetes: A Narrative Review. Int J Endocrinol Metab. 2018;16(2):e65600. https://doi.org/10.5812/ijem.65600.

Abstract

Context:

Insulin can be prescribed as a monotherapy or a combined therapy with other anti-diabetic medications. In this narrative review, the authors aimed to gather data related to comparison of insulin monotherapy versus combination of insulin and other anti-diabetic treatments with regards to different outcome measures in type 2 diabetes.

Evidence Acquisition:

This study searched and focused on the most recently published systematic reviews and their references investigating issues related to the primary aim.

Results:

The current data available on this topic is heterogeneous and suffers from low quality with respect to most combination treatments. Considering the efficacy and safety of combination therapy of insulin with older hypoglycemic agents, in general metformin and pioglitazone have the best and worst profiles, respectively. Compared to insulin monotherapy, combination of insulin and metformin is associated with better glycemic control, reduced daily insulin dose, less hypoglycemia, and weight gain; combination of insulin and pioglitazone results in greater hypoglycemia and weight gain and is associated with increased risk of edema and heart failure. Regarding sulphonylurea, there is some concern regarding hypoglycemia and weight gain. Addition of dipeptidyl peptidase-4 inhibitors to insulin seems to be beneficial with respect to glycemic control without any significant adverse effects. New drugs, including glucagon-like peptide-1 agonists and sodium glucose co-transporter 2 inhibitors, have acceptable profiles with significant benefits regarding weight reduction when added on insulin therapy.

Conclusions:

Considering the quality and longevity of evidence, compared to insulin monotherapy, insulin combined with metformin and pioglitazone has the best and worst profiles, respectively. New anti-diabetic medications have acceptable profiles yet are expensive. It is important for clinicians to meticulously weigh the advantages of combination therapy against the possible adverse effects with each drug class in every patient, individually.

1. Context

Type 2 diabetes mellitus (T2DM) is a progressive disease characterized by worsening pathophysiology. With currently available anti-diabetic therapies, most of them not being disease modifying, pancreatic β-cell mass and function decrease over time (1), and the usual course of therapeutic approach for patients with T2DM is sequential addition of hypoglycemic agents with different mechanisms of action followed by insulin therapy (2).

Insulin can be prescribed as a monotherapy or a combined therapy with other anti-diabetic medications. A desired diabetes treatment protocol includes use of medications that in parallel with optimal glycemic control, do not have significant adverse effects; two of these adverse effects, hypoglycemia and weight gain, are amongst important barriers of insulin initiation or intensification (3). Moreover, consideration of patient-important outcomes resulting from vascular complications of DM has been emphasized to be incorporated in diabetes care protocols (4) and should be acknowledged in management strategies of patients with diabetes.

Until now, two Cochrane systematic reviews regarding comparison of insulin monotherapy versus insulin combined with oral hypoglycemic agents have been conducted on patients, who were insulin-naive (5) and those, who were already on insulin therapy (6). Based on their date of publication and protocol, these comprehensive and sophisticated systematic reviews did not include new anti-diabetic therapies, including Sodium glucose co-transporter 2 (SGLT2) inhibitors and injectable hypoglycemic agents other than insulin, i.e. glucagon like peptide 1 (GLP-1) agonists.

In this narrative review, the authors aimed to gather data related to comparison of insulin monotherapy versus combinations of insulin and other anti-diabetes treatments with regards to different outcome measures, including a) glycemic control, b) required daily insulin dose, c) adverse events, d) diabetes-related morbidity, e) health-related quality of life and patient satisfaction, and f) mortality.

2. Evidence Acquisition

The terms (insulin) AND (hypoglycemic) OR (antidiabetic) OR “glucose-lowering” OR (sulphonylurea) OR (metformin) OR (pioglitazone) OR “DPP-4 inhibitor” OR “DPP4 inhibitor” OR “GLP-1 agonist” OR “GLP-1 receptor agonist” OR “SGLT2 inhibitor” were used to search review articles in Pubmed, Scopus, and Cochrane library up to 01 September 2017. The researchers focused on the most recently published systematic reviews and their references investigating issues related to the primary aim. With regards to the scarse data available on the comparison of insulin monotherapy versus combinations of insulin with new medication classes, addition of these drugs to any insulin-based therapies has been considered.

3. Results

3.1. Insulin Monotherapy Versus Insulin Plus Sulphonylurea

In the 2004 Cochrane systematic review (5), Goudswaard et al. included 20 randomized controlled trials (RCTs) (7-15) (16-25) with follow-up durations of 2 months to 3 years (mean 10 months). Primary outcomes were any diabetes-related morbidity and glycemic control. Secondary outcomes included quality of life, patient satisfaction, insulin requirement, and adverse effects. Methodological quality of studies was low. Not all, but most trials included studies comparing insulin monotherapy regimens with combinations of insulin and sulphonylurea with or without metformin. Only one study used an insulin analogue, lispro insulin (25). Regarding glycemic control, meta-analysis of 5 studies with low heterogeneity (16%) showed that bedtime neutral protamine Hagedorn (NPH) insulin plus sulphonylurea was associated with lower HbA1c compared with once daily NPH insulin alone (mean difference: 0.33% [95% CI 0.03, 0.62]); when the comparison included twice-daily insulin monotherapy regimens, this difference abated. With respect to other outcomes, insulin-sulphonylurea (± metformin) combination therapy versus insulin monotherapy in insulin-naive patients resulted in 43% relative reduction in total daily insulin requirement; no significant difference in the frequency of symptomatic or biochemical hypoglycemia and weight gain was detected. Quality of life was assessed in 4 studies (16, 21-23) and no significant differences were reported between groups. None of the mentioned studies investigated diabetes-related morbidity or mortality.

Recently, the Cochrane group published a systematic review with the aim of assessing the effects of addition of oral hypoglycemic agents to insulin monotherapy (6). The main difference between this review protocol and older ones was the manner, according to which they included trials with patients already on insulin therapy. Primary outcomes included all-cause mortality, diabetes-related morbidity, and adverse events. With regards to different sulphonylureas, including glibenclamide, glipizide, tolazamide, gliclazide, and glimepiride, 17 trials (26-41) had low quality evidence, and compared combination therapy with insulin monotherapy; mortality and morbidity were not evaluated in any trials. Regarding patient satisfaction, results of the Switch pilot study showed no differences between insulin-glimepiride therapy and insulin monotherapy (31). The main findings of analyses related to other outcomes have been depicted in Table 1.

Table 1.

Pooled Effects of Addition of Sulphonylurea to Insulin Versus Insulin Monotherapya

OutcomeInsulin MonotherapyInsulin-Sulphonylure
Mean difference in HbA1c, %--1 (95% CI: -1.6 to -0.5)
Mild hypoglycemic episodes per participant2.0 to 2.62.2 to 6.1
Additional weight gain, kg-0.4 to 1.9

Abbreviations: CI: confidence interval; HbA1c, glycosylated hemoglobin.

aData derived from reference 6.

Taken together, findings of 2 Cochrane systematic reviews mentioned above indicate that the additional effect of the combination of insulin with sulphonylurea on glycemic control in insulin-naive patients seems to be small; regarding the effectiveness of sulphonylurea-insulin combination compared to insulin monotherapy, it is important to note whether patients are insulin-naive or already on insulin therapy.

3.2. Insulin Monotherapy Versus Insulin Plus Metformin

In 2012, Hemmingsen et al. reported results of a meta-analysis on 23 RCTs (24, 42-52) (53-67) with 2,117 participants, investigating the efficacy and safety of metformin and insulin versus insulin therapy alone (68). Primary outcomes were all cause mortality and cardiovascular mortality. Secondary outcomes were macrovascular and microvascular diseases, adverse events, cancer, quality of life, costs, insulin dose, glycemic control, weight, and blood pressure. Based on bias risk assessment of this review, all trials had high risk of bias. Duration of studies was between 3 to 24 months. Regarding the random effects model, combined insulin-metformin therapy resulted in greater HbA1c reduction (mean difference: -0.6% [95% CI -0.89 to -0.31]) accompanied with reduced insulin dose (mean difference: -18.65 units/day [95% CI -22.7 to -14.61]) and less weight gain (mean difference: -1.68 kg [95% CI -2.22 to -1.13]), compared to insulin alone. There was no significant difference in the frequency of severe or mild hypoglycemia or other adverse events. Data regarding primary outcomes was sparse and combination therapy did not significantly affect all-cause mortality (5 trials (24, 58, 62, 63, 67), relative risk 1.30, 95% CI 0.57 to 2.99) or cardiovascular mortality (3 trials (58, 62, 63), relative risk 1.70, 0.35 to 8.30). Based on 3 trials, macrovascular complications were similar; only one trial reported data for composite microvascular outcome, which was not different (63). For quality of life, only 3 trials were found, all of which reported no significant difference between the 2 treatment groups (56, 59). Trial sequential analysis revealed sufficient evidence for HbA1c reduction of 0.5%, lower weight gain of 1 kg, and lower insulin dose of 5 units/day for combined insulin and metformin therapy versus insulin therapy alone. Findings of a recent Cochrane systematic review (6) regarding insulin-metformin therapy versus insulin monotherapy were in agreement with those of Hemmingsen et al.’s systematic review, except regarding Gastrointestinal (GI) adverse effects. Vos et al. reported higher GI complaints with combination therapy (7% to 67%) compared to insulin monotherapy (5% to 16%) (6).

3.3. Insulin Monotherapy Versus Insulin Plus Pioglitazone

According to Vos et al.’s systematic review (6), data for comparison of the efficacy and safety of combined insulin-pioglitazone therapy with insulin monotherapy, from 3 trials (69-71), was rated as low-quality evidence. Regarding glycemic control, it was not possible to run a meta-analysis. Overall glycemic control was comparable in the 2 groups. Insulin plus pioglitazone therapy was associated with both increase in mild to moderate hypoglycemic episodes and weight gain (3.8 kg [95% CI 3.0 to 4.6]) and a small reduction in total daily insulin requirement compared to insulin alone; more cases of dose-dependent edema (69, 70) and heart failure (69) were also observed.

3.4. Insulin Monotherapy Versus Insulin Plus Dipeptidyl Peptidase-4 (DPP-4) Inhibitors

Based on a recent Cochrane review (6), low-quality evidence from 3 trials using vildagliptin (72), sitagliptin (73), and saxagliptin (74) documented slightly better glycemic control in the insulin-DPP4 inhibitor group (mean difference in HbA1c: -0.4% (-0.5 to -0.4)) associated with no significant difference in total daily insulin requirement and weight gain. Heterogeneous data regarding hypoglycemic episodes was in favor of lower rates of these episodes in the combination therapy group.

3.5. Insulin Plus SGLT2 Inhibitors

Efficacy and safety of adding SGLT2 inhibitors, as the most recently developed oral anti-diabetic agents, on insulin therapy have been investigated by several studies, none of which compared the combination therapy with a placebo group receiving insulin monotherapy. Summarizing data derived from these studies with durations ranging from 12 to 104 weeks considered in a recent review (75), yielded the following results: SGLT2 inhibitors when added on insulin could result in improved glycemic control (range of HbA1c difference: -0.4 to -1.1%) associated with reduced daily insulin requirement and weight reduction (1.2 to 4.5 kg). It should be noted that in some studies, this combination resulted in elevated incidence of hypoglycemia.

3.6. Insulin Plus GLP-1 Agonists

Findings of a meta-analysis of 15 RCTs with 4,348 participants (76-90) assessing different outcomes of basal insulin-GLP-1 agonist combination therapy compared to other hypoglycemic agents (91) demonstrated that combined treatment results the followings: 1) greater reduction in HbA1c (0.44% [95% CI 0.29 - 0.6]); 2) greater proportion of participants achieving HbA1c ≤ 7%; 3) no increased relative risk of hypoglycemia (0.99; 95% CI 0.76 to 1.29); and 4) higher weight reduction (mean difference: -3.22 kg [95% CI -4.90 to -1.54]). Compared to basal-bolus insulin regimens, the combination of GLP-1 agonist and basal insulin leads to slightly better glycemic control (mean difference in HbA1c: -0.1% [-0.17 to -0.02]), yet no benefit regarding proportion of participants achieving HbA1c ≤ 7%; regarding this comparison, insulin plus GLP-1 agonists resulted in lower risk of hypoglycemia (RR 0.67, 95% CI 0.56 to 0.80) and greater weight reduction (-5.66 kg; 95% CI -9.8 to -1.51).

Recently, Maiorino et al. compared GLP-1 agonists alone or as titratable fixed-ratio plus basal insulin with other injectable treatments (92); 26 RCTs (76-84) (86-88, 93-106), lasting 12 to 52 weeks and involving 11,425 patients were included in this meta-analysis, yet the results had high heterogeneity and a significant publication bias. Insulin plus GLP-1 agonists versus other injectable therapies resulted in greater reduction of HbA1c (mean difference: -0.47%, 95% CI -0.59 to -0.35), more patients at HbA1c target (RR: 1.65, 95% CI 1.44 - 1.88), similar hypoglycemic events (RR: 1.14, 95% CI 0.93 - 1.39), and greater weight reduction (mean difference: -2.5 kg, 95% CI -3.3 to -1.7). Compared with basal-bolus insulin regimens, insulin plus GLP-1 agonists produced comparable glycemic control, less hypoglycemia (RR: 0.66, 95% CI 0.46 to 0.93), and greater weight reduction (mean difference: -4.7 kg, 95% CI -6.9 to -2.4).

4. Conclusions

Current data available on this topic is heterogeneous and suffers from low quality with respect to most combination treatments. Based on the findings presented in Table 2, considering the efficacy and safety of combination therapy of insulin with older hypoglycemic agents, generally, metformin and pioglitazone have the best and worst profiles, respectively. Compared with insulin monotherapy, combination of insulin and metformin is associated with better glycemic control, reduced daily insulin dose, less hypoglycemia, and weight gain; combination of insulin and pioglitazone results in greater hypoglycemia and weight gain and has increased risk of edema and heart failure. Regarding sulphonylurea, there is some concern about hypoglycemia and weight gain. Addition of dipeptidyl peptidase inhibitors to insulin seems to be beneficial with respect to glycemic control without any significant adverse effects. New drugs, including glucagon like peptide-1 agonists and sodium glucose co-transporter 2 inhibitors, have acceptable profiles with significant benefits regarding weight reduction when added on insulin therapy.

Table 2.

Effects of Addition of Different Glucose Lowering Agents to Insulin Regimens

Outcome MeasuresMonthly Cost
Anti-Diabetic AgentGlycemic ControlRequired Daily InsulinHypoglycemiaWeight GainOther Adverse EffectsUS, $a,bIran, Tomansa
Sulphonylurea+ or ND+- or ND- or NDNone936,000
Metformin++++Gastrointestinal8410,800
PioglitazoneND+--Edema, Heart failure34814,400
DPP-4 inhibitors+ND+ or NDNDNone47760,000
SGLT2 inhibitors++- or ND+None517Not available
GLP-1 agonists+ or ND+++None968840,000

Abbreviations: DPP-4, Dipeptidyl peptidase-4; GLP-1, Glucagon like peptide-1; ND, no difference; SGLT2, sodium glucose co-transporter 2; +, in favor of benefit of combination therapy; -, in favor of monotherapy.

aEstimated cost of maximum approved daily dose.

bData derived from American diabetes association standards of medical care in diabetes-2018.

It should be noted that this research did not undertake a systematic search on this subject. Although qualified systematic reviews included in the review covered most related evidence, there is certainly concern regarding missing available evidence related to the topic.

In conclusion, when considering a patient receiving insulin or scheduled for initiation of insulin therapy, decision-making about concomitant use of other hypoglycemic medications needs attention and must be based on different patient characteristics and his/her disease status. It is important for clinicians to meticulously weigh the advantages of combination therapy against possible negative effects in every patient on an individual basis. Data available on the efficacy and safety of insulin plus other anti-diabetic agents have low quality and some outcomes, including microvascular complications of DM, cardiovascular morbidity and mortality, and patient-reported outcomes, have not been assessed and should be considered in future research studies.

Acknowledgements

References

  • 1.

    Nolan CJ, Damm P, Prentki M. Type 2 diabetes across generations: from pathophysiology to prevention and management. Lancet. 2011;378(9786):169-81. [PubMed ID: 21705072]. https://doi.org/10.1016/S0140-6736(11)60614-4.

  • 2.

    Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1):140-9. [PubMed ID: 25538310]. https://doi.org/10.2337/dc14-2441.

  • 3.

    Nakar S, Yitzhaki G, Rosenberg R, Vinker S. Transition to insulin in Type 2 diabetes: family physicians' misconception of patients' fears contributes to existing barriers. J Diabetes Complications. 2007;21(4):220-6. [PubMed ID: 17616351]. https://doi.org/10.1016/j.jdiacomp.2006.02.004.

  • 4.

    Rodriguez-Gutierrez R, Montori VM. Glycemic Control for Patients With Type 2 Diabetes Mellitus: Our Evolving Faith in the Face of Evidence. Circ Cardiovasc Qual Outcomes. 2016;9(5):504-12. [PubMed ID: 27553599]. https://doi.org/10.1161/CIRCOUTCOMES.116.002901.

  • 5.

    Goudswaard AN, Furlong NJ, Rutten GE, Stolk RP, Valk GD. Insulin monotherapy versus combinations of insulin with oral hypoglycaemic agents in patients with type 2 diabetes mellitus. Cochrane Database Syst Rev. 2004;(4). CD003418. [PubMed ID: 15495054]. https://doi.org/10.1002/14651858.CD003418.pub2.

  • 6.

    Vos RC, van Avendonk MJ, Jansen H, Goudswaard AN, van den Donk M, Gorter K, et al. Insulin monotherapy compared with the addition of oral glucose-lowering agents to insulin for people with type 2 diabetes already on insulin therapy and inadequate glycaemic control. Cochrane Database Syst Rev. 2016;9. CD006992. [PubMed ID: 27640062]. https://doi.org/10.1002/14651858.CD006992.pub2.

  • 7.

    Holman RR, Steemson J, Turner RC. Sulphonylurea failure in type 2 diabetes: treatment with a basal insulin supplement. Diabet Med. 1987;4(5):457-62. [PubMed ID: 2959438].

  • 8.

    Lundershausen R, Orban S, Pissarek D, Panzram G. [Long-term effect of combination glibenclamide-insulin treatment in the secondary failure of sulfonylurea therapy--results of a one-year double blind study]. Wien Klin Wochenschr. 1987;99(17):603-8. [PubMed ID: 3118579].

  • 9.

    Pontiroli AE, Dino G, Capra F, Pozza G. Combined therapy with glibenclamide and ultralente insulin in lean patients with NIDDM with secondary failure of sulfonylureas. Follow up at two years. Diabete Metab. 1990;16(4):323-7. [PubMed ID: 2125014].

  • 10.

    Riddle MC, Hart JS, Bouma DJ, Phillipson BE, Youker G. Efficacy of bedtime NPH insulin with daytime sulfonylurea for subpopulation of type II diabetic subjects. Diabetes Care. 1989;12(9):623-9. [PubMed ID: 2507265].

  • 11.

    Riddle M, Hart J, Bingham P, Garrison C, McDaniel P. Combined therapy for obese type 2 diabetes: suppertime mixed insulin with daytime sulfonylurea. Am J Med Sci. 1992;303(3):151-6. [PubMed ID: 1595776].

  • 12.

    Riddle MC, Schneider J. Beginning insulin treatment of obese patients with evening 70/30 insulin plus glimepiride versus insulin alone. Glimepiride Combination Group. Diabetes Care. 1998;21(7):1052-7. [PubMed ID: 9653594].

  • 13.

    Shank ML, Del Prato S, DeFronzo RA. Bedtime insulin/daytime glipizide. Effective therapy for sulfonylurea failures in NIDDM. Diabetes. 1995;44(2):165-72. [PubMed ID: 7859936].

  • 14.

    Sun Y, Xiong Y, Yang J. The effectiveness of combined insulin and sulfonylurea in treating non-insulin dependent diabetic patients. Zhonghua Nei Ke Za Zhi. 1995;34(4):246-9. [PubMed ID: 7587604].

  • 15.

    Bachmann W, Lotz N, Mehnert H, Rosak C, Schoffling K. Effectiveness of combined treatment with glibenclamide and insulin in secondary sulfonylurea failure. A controlled multicenter double-blind clinical trial. Dtsch Med Wochenschr. 1988;113(16):631-6. [PubMed ID: 3129273]. https://doi.org/10.1055/s-2008-1067696.

  • 16.

    Chow CC, Tsang LW, Sorensen JP, Cockram CS. Comparison of insulin with or without continuation of oral hypoglycemic agents in the treatment of secondary failure in NIDDM patients. Diabetes Care. 1995;18(3):307-14. [PubMed ID: 7555472].

  • 17.

    Fovenyi J, Grosz A, Thaisz E. Daytime sulfonyluyrea—bedtime insulin combination therapy in type 2 diabetes. Hungarian Arch Intern Med. 1997;50:607-13.

  • 18.

    Gutniak M, Karlander SG, Efendic S. Glyburide decreases insulin requirement, increases beta-cell response to mixed meal, and does not affect insulin sensitivity: effects of short- and long-term combined treatment in secondary failure to sulfonylurea. Diabetes Care. 1987;10(5):545-54. [PubMed ID: 2890501].

  • 19.

    Lotz N, Bachmann W, Ladik T, Mehnert H. Combination therapy with insulin/sulfonylurea in the long-term therapy of type II diabetes following "secondary failure". Klin Wochenschr. 1988;66(21):1079-84. [PubMed ID: 3148787].

  • 20.

    Ravnik-Oblak M, Mrevlje F. Insulin versus a combination of insulin and sulfonylurea in the treatment of NIDDM patients with secondary oral failure. Diabetes Res Clin Pract. 1995;30(1):27-35. [PubMed ID: 8745203].

  • 21.

    Wolffenbuttel BH, Rondas-Colbers GJ, Menheere PP, Sels JP, Nieuwenhuijzen Kruseman AC. The effects of insulin combined with glibenclamide on glucose and lipid metabolism in patients with Type II diabetes mellitus. Ned Tijdschr Geneeskd. 1991;135(24):1080-4. [PubMed ID: 1906584].

  • 22.

    Wolffenbuttel BH, Sels JP, Rondas-Colbers GJ, Menheere PP, Nieuwenhuijzen Kruseman AC. Comparison of different insulin regimens in elderly patients with NIDDM. Diabetes Care. 1996;19(12):1326-32. [PubMed ID: 8941458].

  • 23.

    Yki-Jarvinen H, Kauppila M, Kujansuu E, Lahti J, Marjanen T, Niskanen L, et al. Comparison of insulin regimens in patients with non-insulin-dependent diabetes mellitus. N Engl J Med. 1992;327(20):1426-33. [PubMed ID: 1406860]. https://doi.org/10.1056/NEJM199211123272005.

  • 24.

    Yki-Jarvinen H, Ryysy L, Nikkila K, Tulokas T, Vanamo R, Heikkila M. Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus. A randomized, controlled trial. Ann Intern Med. 1999;130(5):389-96. [PubMed ID: 10068412].

  • 25.

    Bastyr EJ 3rd, Johnson ME, Trautmann ME, Anderson JH jr, Vignati L. Insulin lispro in the treatment of patients with type 2 diabetes mellitus after oral agent failure. Clin Ther. 1999;21(10):1703-14. [PubMed ID: 10566566].

  • 26.

    Casner PR. Insulin-glyburide combination therapy for non-insulin-dependent diabetes mellitus: A long-term double-blind, placebo-controlled trial. Clin Pharmacol Ther. 1988;44(5):594-603. https://doi.org/10.1038/clpt.1988.199.

  • 27.

    Feinglos MN, Thacker CR, Lobaugh B, DeAtkine DD, McNeill DB, English JS, et al. Combination insulin and sulfonylurea therapy in insulin-requiring type 2 diabetes mellitus. Diabetes Res Clin Pract. 1998;39(3):193-9. [PubMed ID: 9649951].

  • 28.

    Mauerhoff T, Ketelslegers JM, Lambert AE. Effect of glibenclamide in insulin-treated diabetic patients with a residual insulin secretion. Diabete Metab. 1986;12(1):34-8. [PubMed ID: 3084315].

  • 29.

    Reich A, Abraira C, Lawrence AM. Combined glyburide and insulin therapy in type II diabetes. Diabetes Res. 1987;6(2):99-104. [PubMed ID: 3123116].

  • 30.

    Schade DS, Mitchell WJ, Griego G. Addition of sulfonylurea to insulin treatment in poorly controlled type II diabetes. A double-blind, randomized clinical trial. JAMA. 1987;257(18):2441-5. [PubMed ID: 3106656].

  • 31.

    Schiel R, Muller UA. Efficacy and treatment satisfaction of once-daily insulin glargine plus one or two oral antidiabetic agents versus continuing premixed human insulin in patients with type 2 diabetes previously on long-term conventional insulin therapy: the Switch pilot study. Exp Clin Endocrinol Diabetes. 2007;115(10):627-33. [PubMed ID: 18058596]. https://doi.org/10.1055/s-2007-984445.

  • 32.

    Simpson HC, Sturley R, Stirling CA, Reckless JP. Combination of insulin with glipizide increases peripheral glucose disposal in secondary failure type 2 diabetic patients. Diabet Med. 1990;7(2):143-7. [PubMed ID: 2137755].

  • 33.

    Stenman S, Groop PH, Saloranta C, Totterman KJ, Fyhrqvist F, Groop L. Effects of the combination of insulin and glibenclamide in type 2 (non-insulin-dependent) diabetic patients with secondary failure to oral hypoglycaemic agents. Diabetologia. 1988;31(4):206-13. [PubMed ID: 3133266].

  • 34.

    Kyllastinen M, Groop L. Combination of insulin and glibenclamide in the treatment of elderly non-insulin dependent (type 2) diabetic patients. Ann Clin Res. 1985;17(3):100-4. [PubMed ID: 3931537].

  • 35.

    Lindstrom T, Nystrom FH, Olsson AG, Ottosson AM, Arnqvist HJ. The lipoprotein profile differs during insulin treatment alone and combination therapy with insulin and sulphonylureas in patients with Type 2 diabetes mellitus. Diabet Med. 1999;16(10):820-6. [PubMed ID: 10547208].

  • 36.

    Kitabchi AE, Soria AG, Radparvar A, Lawson-Grant V. Combined therapy of insulin and tolazamide decreases insulin requirement and serum triglycerides in obese patients with noninsulin-dependent diabetes mellitus. Am J Med Sci. 1987;294(1):10-4. [PubMed ID: 3605188].

  • 37.

    Longnecker MP, Elsenhans VD, Leiman SM, Owen OE, Boden G. Insulin and a sulfonylurea agent in non-insulin-dependent diabetes mellitus. Arch Intern Med. 1986;146(4):673-6. [PubMed ID: 3516096].

  • 38.

    Quatraro A, Consoli G, Ceriello A, Giugliano D. Combined insulin and sulfonylurea therapy in non-insulin-dependent diabetics with secondary failure to oral drugs: a one year follow-up. Diabete Metab. 1986;12(6):315-8. [PubMed ID: 3545931].

  • 39.

    Groop L, Harno K, Nikkila EA, Pelkonen R, Tolppanen EM. Transient effect of the combination of insulin and sulfonylurea (glibenclamide) on glycemic control in non-insulin dependent diabetics poorly controlled with insulin alone. Acta Med Scand. 1985;217(1):33-9. [PubMed ID: 3919531].

  • 40.

    Osei K, O'Dorisio TM, Falko JM. Concomitant insulin and sulfonylurea therapy in patients with type II diabetes. Effects on glucoregulation and lipid metabolism. Am J Med. 1984;77(6):1002-9. [PubMed ID: 6439036].

  • 41.

    Lewitt MS, Yu VK, Rennie GC, Carter JN, Marel GM, Yue DK, et al. Effects of combined insulin-sulfonylurea therapy in type II patients. Diabetes Care. 1989;12(6):379-83. [PubMed ID: 2499443].

  • 42.

    Giugliano D, Quatraro A, Consoli G, Minei A, Ceriello A, De Rosa N, et al. Metformin for obese, insulin-treated diabetic patients: improvement in glycaemic control and reduction of metabolic risk factors. Eur J Clin Pharmacol. 1993;44(2):107-12. [PubMed ID: 8453955].

  • 43.

    Van Der Wal PS, Scheen A, Van Gaal L, Schmitt H, Heine RJ. Efficacy of bedtime NPH insulin alone, as compared to combination with metformin and/or glipizide in NIDDM patients with secondary failure to oral hypoglycemic agents. Diabetes. 1996;45(2S):286A.

  • 44.

    van der Wal PS, Scheen A, Van Gaal L, Schmitt H, Heine RJ. Predictors of glycaemic efficacy of four treatment strategies in NIDDM patients with secondary failure to oral hypoglycaemic agents. Netherlands J Med. 1996;4(48). A49.

  • 45.

    Schnack C, Biesenbach G, Kacerovsky G, Mihaljevic R, Pecnik I, Pieber T, et al. Evaluation of optimal therapy in type-2 diabetic patients insufficiently treated with sulfonylureas: The Austrian insulin intervention study. New York: Springer; 1996.

  • 46.

    Relimpio F, Pumar A, Losada F, Mangas MA, Acosta D, Astorga R. Adding metformin versus insulin dose increase in insulin-treated but poorly controlled Type 2 diabetes mellitus: an open-label randomized trial. Diabet Med. 1998;15(12):997-1002. [PubMed ID: 9868971]. https://doi.org/10.1002/(SICI)1096-9136(1998120)15:12<997::AID-DIA716>3.0.CO;2-B.

  • 47.

    Robinson AC, Burke J, Robinson S, Johnston DG, Elkeles RS. The effects of metformin on glycemic control and serum lipids in insulin-treated NIDDM patients with suboptimal metabolic control. Diabetes Care. 1998;21(5):701-5. [PubMed ID: 9589227].

  • 48.

    Hirsch IB. Metformin added to insulin therapy in poorly controlled type 2 diabetes. Diabetes Care. 1999;22(5):854. [PubMed ID: 10332695].

  • 49.

    Aviles-Santa L, Sinding J, Raskin P. Effects of metformin in patients with poorly controlled, insulin-treated type 2 diabetes mellitus. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1999;131(3):182-8. [PubMed ID: 10428734].

  • 50.

    Ponssen HH, Elte JW, Lehert P, Schouten JP, Bets D. Combined metformin and insulin therapy for patients with type 2 diabetes mellitus. Clin Ther. 2000;22(6):709-18. [PubMed ID: 10929918]. https://doi.org/10.1016/S0149-2918(00)90005-5.

  • 51.

    Hermann LS, Kalen J, Katzman P, Lager I, Nilsson A, Norrhamn O, et al. Long-term glycaemic improvement after addition of metformin to insulin in insulin-treated obese type 2 diabetes patients. Diabetes Obes Metab. 2001;3(6):428-34. [PubMed ID: 11903415].

  • 52.

    Wulffele MG, Kooy A, Lehert P, Bets D, Ogterop JC, Borger van der Burg B, et al. Combination of insulin and metformin in the treatment of type 2 diabetes. Diabetes Care. 2002;25(12):2133-40. [PubMed ID: 12453950].

  • 53.

    Strowig SM, Aviles-Santa ML, Raskin P. Comparison of insulin monotherapy and combination therapy with insulin and metformin or insulin and troglitazone in type 2 diabetes. Diabetes Care. 2002;25(10):1691-8. [PubMed ID: 12351463].

  • 54.

    Altuntas Y, Ozen B, Ozturk B, Sengul A, Ucak S, Ersoy O, et al. Comparison of additional metformin or NPH insulin to mealtime insulin lispro therapy with mealtime human insulin therapy in secondary OAD failure. Diabetes Obes Metab. 2003;5(6):371-8. [PubMed ID: 14617222].

  • 55.

    Kokic S, Bukovic D, Radman M, Capkun V, Gabric N, Lesko V, et al. Lispro insulin and metformin versus other combination in the diabetes mellitus type 2 management after secondary oral antidiabetic drug failure. Coll Antropol. 2003;27(1):181-7. [PubMed ID: 12974145].

  • 56.

    Douek IF, Allen SE, Ewings P, Gale EA, Bingley PJ; Metformin Trial Group. Continuing metformin when starting insulin in patients with Type 2 diabetes: a double-blind randomized placebo-controlled trial. Diabet Med. 2005;22(5):634-40. [PubMed ID: 15842521]. https://doi.org/10.1111/j.1464-5491.2005.01475.x.

  • 57.

    Kabadi UM, Kabadi M. Comparative efficacy of glimepiride and/or metformin with insulin in type 2 diabetes. Diabetes Res Clin Pract. 2006;72(3):265-70. [PubMed ID: 16406190]. https://doi.org/10.1016/j.diabres.2005.10.024.

  • 58.

    Kvapil M, Swatko A, Hilberg C, Shestakova M. Biphasic insulin aspart 30 plus metformin: an effective combination in type 2 diabetes. Diabetes Obes Metab. 2006;8(1):39-48. [PubMed ID: 16367881]. https://doi.org/10.1111/j.1463-1326.2005.00492.x.

  • 59.

    Ushakova O, Sokolovskaya V, Morozova A, Valeeva F, Zanozina O, Sazonova O, et al. Comparison of biphasic insulin aspart 30 given three times daily or twice daily in combination with metformin versus oral antidiabetic drugs alone in patients with poorly controlled type 2 diabetes: a 16-week, randomized, open-label, parallel-group trial conducted in russia. Clin Ther. 2007;29(11):2374-84. [PubMed ID: 18158078]. https://doi.org/10.1016/j.clinthera.2007.11.017.

  • 60.

    Vahatalo M, Ronnemaa T, Viikari J. Recognition of fasting or overall hyperglycaemia when starting insulin treatment in patients with type 2 diabetes in general practice. Scand J Prim Health Care. 2007;25(3):147-53. [PubMed ID: 17846932]. https://doi.org/10.1080/02813430701507719.

  • 61.

    Yilmaz H, Gursoy A, Sahin M, Guvener Demirag N. Comparison of insulin monotherapy and combination therapy with insulin and metformin or insulin and rosiglitazone or insulin and acarbose in type 2 diabetes. Acta Diabetol. 2007;44(4):187-92. [PubMed ID: 17726570]. https://doi.org/10.1007/s00592-007-0004-9.

  • 62.

    Civera M, Merchante A, Salvador M, Sanz J, Martinez I. Safety and efficacy of repaglinide in combination with metformin and bedtime NPH insulin as an insulin treatment regimen in type 2 diabetes. Diabetes Res Clin Pract. 2008;79(1):42-7. [PubMed ID: 17714824]. https://doi.org/10.1016/j.diabres.2007.07.001.

  • 63.

    Kooy A, De Jager J, Lehert P, Bets D, Wulffele MG, Donker AJ, et al. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med. 2009;169(6):616-25. [PubMed ID: 19307526]. https://doi.org/10.1001/archinternmed.2009.20.

  • 64.

    Kokic S, Kokic V, Krnic M, Miric L, Jovanovic Z, Orlic-Crncevic Z. Advantage of prandial insulin as a therapeutic approach in initial secondary pancreatic beta-cell exhaustion in type 2 diabetic patients. Diabetologia Croatica. 2010;39(1):37-42.

  • 65.

    Onuchin SG, Elsukova OS, Solov'ev OV, Onuchina EL. Capabilities of hypoglycemic therapy in women with decompensated type 2 diabetes mellitus. Ter Arkh. 2010;82(8):34-41. [PubMed ID: 20873243].

  • 66.

    Galani V. Comparison of Metformin and Insulin Monotherapy with Combined Metformin and Insulin Therapy in Patients of Type 2 Diabetes with HbA1c> 7%. Int J Pharm Biol Arch. 2011;2(1).

  • 67.

    Gram J, Henriksen JE, Grodum E, Juhl H, Hansen TB, Christiansen C, et al. Pharmacological treatment of the pathogenetic defects in type 2 diabetes: the randomized multicenter South Danish Diabetes Study. Diabetes Care. 2011;34(1):27-33. [PubMed ID: 20929990]. https://doi.org/10.2337/dc10-0531.

  • 68.

    Hemmingsen B, Christensen LL, Wetterslev J, Vaag A, Gluud C, Lund SS, et al. Comparison of metformin and insulin versus insulin alone for type 2 diabetes: systematic review of randomised clinical trials with meta-analyses and trial sequential analyses. BMJ. 2012;344. e1771. [PubMed ID: 22517929]. https://doi.org/10.1136/bmj.e1771.

  • 69.

    Rosenstock J, Einhorn D, Hershon K, Glazer NB, Yu S, Pioglitazone 014 Study G. Efficacy and safety of pioglitazone in type 2 diabetes: a randomised, placebo-controlled study in patients receiving stable insulin therapy. Int J Clin Pract. 2002;56(4):251-7. [PubMed ID: 12074206].

  • 70.

    Mattoo V, Eckland D, Widel M, Duran S, Fajardo C, Strand J, et al. Metabolic effects of pioglitazone in combination with insulin in patients with type 2 diabetes mellitus whose disease is not adequately controlled with insulin therapy: results of a six-month, randomized, double-blind, prospective, multicenter, parallel-group study. Clin Ther. 2005;27(5):554-67. [PubMed ID: 15978304]. https://doi.org/10.1016/j.clinthera.2005.05.005.

  • 71.

    Mudaliar S, Chang AR, Aroda VR, Chao E, Burke P, Baxi S, et al. Effects of intensive insulin therapy alone and with added pioglitazone on renal salt/water balance and fluid compartment shifts in type 2 diabetes. Diabetes Obes Metab. 2010;12(2):133-8. [PubMed ID: 19889003]. https://doi.org/10.1111/j.1463-1326.2009.01126.x.

  • 72.

    Fonseca V, Schweizer A, Albrecht D, Baron MA, Chang I, Dejager S. Addition of vildagliptin to insulin improves glycaemic control in type 2 diabetes. Diabetologia. 2007;50(6):1148-55. [PubMed ID: 17387446]. https://doi.org/10.1007/s00125-007-0633-0.

  • 73.

    Hong ES, Khang AR, Yoon JW, Kang SM, Choi SH, Park KS, et al. Comparison between sitagliptin as add-on therapy to insulin and insulin dose-increase therapy in uncontrolled Korean type 2 diabetes: CSI study. Diabetes Obes Metab. 2012;14(9):795-802. [PubMed ID: 22443183]. https://doi.org/10.1111/j.1463-1326.2012.01600.x.

  • 74.

    Barnett AH, Charbonnel B, Li J, Donovan M, Fleming D, Iqbal N. Saxagliptin add-on therapy to insulin with or without metformin for type 2 diabetes mellitus: 52-week safety and efficacy. Clin Drug Investig. 2013;33(10):707-17. [PubMed ID: 23949898]. https://doi.org/10.1007/s40261-013-0107-8.

  • 75.

    Woo VC, Berard LD, Bajaj HS, Ekoe JM, Senior PA. Considerations for Initiating a Sodium-Glucose Co-Transporter 2 Inhibitor in Adults With Type 2 Diabetes Using Insulin. Can J Diabetes. 2018;42(1):88-93. [PubMed ID: 28579198]. https://doi.org/10.1016/j.jcjd.2017.01.009.

  • 76.

    Buse JB, Bergenstal RM, Glass LC, Heilmann CR, Lewis MS, Kwan AY, et al. Use of twice-daily exenatide in Basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial. Ann Intern Med. 2011;154(2):103-12. [PubMed ID: 21138825]. https://doi.org/10.7326/0003-4819-154-2-201101180-00300.

  • 77.

    DeVries JH, Bain SC, Rodbard HW, Seufert J, D'Alessio D, Thomsen AB, et al. Sequential intensification of metformin treatment in type 2 diabetes with liraglutide followed by randomized addition of basal insulin prompted by A1C targets. Diabetes Care. 2012;35(7):1446-54. [PubMed ID: 22584132]. https://doi.org/10.2337/dc11-1928.

  • 78.

    Li CJ, Li J, Zhang QM, Lv L, Chen R, Lv CF, et al. Efficacy and safety comparison between liraglutide as add-on therapy to insulin and insulin dose-increase in Chinese subjects with poorly controlled type 2 diabetes and abdominal obesity. Cardiovasc Diabetol. 2012;11:142. [PubMed ID: 23153177]. https://doi.org/10.1186/1475-2840-11-142.

  • 79.

    Seino Y, Min KW, Niemoeller E, Takami A, Efc Getgoal- L. Asia Study Investigators. Randomized, double-blind, placebo-controlled trial of the once-daily GLP-1 receptor agonist lixisenatide in Asian patients with type 2 diabetes insufficiently controlled on basal insulin with or without a sulfonylurea (GetGoal-L-Asia). Diabetes Obes Metab. 2012;14(10):910-7. [PubMed ID: 22564709]. https://doi.org/10.1111/j.1463-1326.2012.01618.x.

  • 80.

    Riddle MC, Forst T, Aronson R, Sauque-Reyna L, Souhami E, Silvestre L. Adding once-daily lixisenatide for type 2 diabetes inadequately controlled with newly initiated and continuously titrated basal insulin glargine. Diabetes Care. 2013;36(9):2497-503. https://doi.org/10.2337/dc12-2462.

  • 81.

    Riddle MC, Aronson R, Home P, Marre M, Niemoeller E, Miossec P, et al. Adding once-daily lixisenatide for type 2 diabetes inadequately controlled by established basal insulin: a 24-week, randomized, placebo-controlled comparison (GetGoal-L). Diabetes Care. 2013;36(9):2489-96. [PubMed ID: 23628617]. https://doi.org/10.2337/dc12-2454.

  • 82.

    Diamant M, Nauck MA, Shaginian R, Malone JK, Cleall S, Reaney M, et al. Glucagon-like peptide 1 receptor agonist or bolus insulin with optimized basal insulin in type 2 diabetes. Diabetes Care. 2014;37(10):2763-73. [PubMed ID: 25011946]. https://doi.org/10.2337/dc14-0876.

  • 83.

    Lane W, Weinrib S, Rappaport J, Hale C. The effect of addition of liraglutide to high-dose intensive insulin therapy: a randomized prospective trial. Diabetes Obes Metab. 2014;16(9):827-32. [PubMed ID: 24589127]. https://doi.org/10.1111/dom.12286.

  • 84.

    Mathieu C, Rodbard HW, Cariou B, Handelsman Y, Philis-Tsimikas A, Ocampo Francisco AM, et al. A comparison of adding liraglutide versus a single daily dose of insulin aspart to insulin degludec in subjects with type 2 diabetes (BEGIN: VICTOZA ADD-ON). Diabetes Obes Metab. 2014;16(7):636-44. [PubMed ID: 24443830]. https://doi.org/10.1111/dom.12262.

  • 85.

    Rosenstock J, Fonseca VA, Gross JL, Ratner RE, Ahren B, Chow FC, et al. Advancing basal insulin replacement in type 2 diabetes inadequately controlled with insulin glargine plus oral agents: a comparison of adding albiglutide, a weekly GLP-1 receptor agonist, versus thrice-daily prandial insulin lispro. Diabetes Care. 2014;37(8):2317-25. [PubMed ID: 24898300]. https://doi.org/10.2337/dc14-0001.

  • 86.

    Shao N, Kuang HY, Hao M, Gao XY, Lin WJ, Zou W. Benefits of exenatide on obesity and non-alcoholic fatty liver disease with elevated liver enzymes in patients with type 2 diabetes. Diabetes Metab Res Rev. 2014;30(6):521-9. [PubMed ID: 24823873]. https://doi.org/10.1002/dmrr.2561.

  • 87.

    De Wit HM, Vervoort GM, Jansen HJ, De Grauw WJ, De Galan BE, Tack CJ. Liraglutide reverses pronounced insulin-associated weight gain, improves glycaemic control and decreases insulin dose in patients with type 2 diabetes: a 26 week, randomised clinical trial (ELEGANT). Diabetologia. 2014;57(9):1812-9. [PubMed ID: 24947583]. https://doi.org/10.1007/s00125-014-3302-0.

  • 88.

    Rosenstock J, Diamant M, Silvestre L, Souhami E, Zhou T, Fonseca V. Benefits of a fixed-ratio formulation of once-daily insulin glargine/lixisenatide (LixiLan) vs. glargine in type 2 diabetes (T2DM) inadequately controlled on metformin. USA: Amer Diabetes Assoc; 2014.

  • 89.

    Seino Y, Kaneko S, Fukuda S, Osonoi T, Shiraiwa T, Wang F, et al. Op72 combination therapy with liraglutide and insulin in japanese subjects with type 2 diabetes: The lira-add2insulin japan trial. Diabetes Res Clin Pract. 2014;106. S37.

  • 90.

    Conway JR, Ahmann A, Rodbard HW, Rosenstock J, Lahtela JT, Loredo L, et al. Efficacy and Safety of Liraglutide vs. Placebo When Added to Basal Insulin Analogues in Subjects with Type 2 Diabetes (LIRA-ADD2BASAL): A Randomized, Placebo-Controlled Trial. Can J Diabetes. 2014;38(5). S7. https://doi.org/10.1016/j.jcjd.2014.07.017.

  • 91.

    Eng C, Kramer CK, Zinman B, Retnakaran R. Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and meta-analysis. Lancet. 2014;384(9961):2228-34. [PubMed ID: 25220191]. https://doi.org/10.1016/S0140-6736(14)61335-0.

  • 92.

    Maiorino MI, Chiodini P, Bellastella G, Capuano A, Esposito K, Giugliano D. Insulin and Glucagon-Like Peptide 1 Receptor Agonist Combination Therapy in Type 2 Diabetes: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Diabetes Care. 2017;40(4):614-24. [PubMed ID: 28325801]. https://doi.org/10.2337/dc16-1957.

  • 93.

    Aroda VR, Bailey TS, Cariou B, Kumar S, Leiter LA, Raskin P, et al. Effect of adding insulin degludec to treatment in patients with type 2 diabetes inadequately controlled with metformin and liraglutide: a double-blind randomized controlled trial (BEGIN: ADD TO GLP-1 Study). Diabetes Obes Metab. 2016;18(7):663-70. [PubMed ID: 26990378]. https://doi.org/10.1111/dom.12661.

  • 94.

    Seino Y, Kaneko S, Fukuda S, Osonoi T, Shiraiwa T, Nishijima K, et al. Combination therapy with liraglutide and insulin in Japanese patients with type 2 diabetes: A 36-week, randomized, double-blind, parallel-group trial. J Diabetes Investig. 2016;7(4):565-73. [PubMed ID: 27182042]. https://doi.org/10.1111/jdi.12457.

  • 95.

    Vanderheiden A, Harrison L, Warshauer J, Li X, Adams-Huet B, Lingvay I. Effect of Adding Liraglutide vs Placebo to a High-Dose lnsulin Regimen in Patients With Type 2 Diabetes: A Randomized Clinical Trial. JAMA Intern Med. 2016;176(7):939-47. [PubMed ID: 27273731]. https://doi.org/10.1001/jamainternmed.2016.1540.

  • 96.

    Rosenstock J, Guerci B, Hanefeld M, Gentile S, Aronson R, Tinahones FJ, et al. Prandial Options to Advance Basal Insulin Glargine Therapy: Testing Lixisenatide Plus Basal Insulin Versus Insulin Glulisine Either as Basal-Plus or Basal-Bolus in Type 2 Diabetes: The GetGoal Duo-2 Trial. Diabetes Care. 2016;39(8):1318-28. [PubMed ID: 27222510]. https://doi.org/10.2337/dc16-0014.

  • 97.

    Flat-Sugar Trial Investigators. Glucose Variability in a 26-Week Randomized Comparison of Mealtime Treatment With Rapid-Acting Insulin Versus GLP-1 Agonist in Participants With Type 2 Diabetes at High Cardiovascular Risk. Diabetes Care. 2016;39(6):973-81. [PubMed ID: 27208320]. https://doi.org/10.2337/dc15-2782.

  • 98.

    Lingvay I, Perez Manghi F, Garcia-Hernandez P, Norwood P, Lehmann L, Tarp-Johansen MJ, et al. Effect of Insulin Glargine Up-titration vs Insulin Degludec/Liraglutide on Glycated Hemoglobin Levels in Patients With Uncontrolled Type 2 Diabetes: The DUAL V Randomized Clinical Trial. JAMA. 2016;315(9):898-907. [PubMed ID: 26934259]. https://doi.org/10.1001/jama.2016.1252.

  • 99.

    Aroda VR, Rosenstock J, Wysham C, Unger J, Bellido D, Gonzalez-Galvez G, et al. Efficacy and Safety of LixiLan, a Titratable Fixed-Ratio Combination of Insulin Glargine Plus Lixisenatide in Type 2 Diabetes Inadequately Controlled on Basal Insulin and Metformin: The LixiLan-L Randomized Trial. Diabetes Care. 2016;39(11):1972-80. [PubMed ID: 27650977]. https://doi.org/10.2337/dc16-1495.

  • 100.

    Rosenstock J, Diamant M, Aroda VR, Silvestre L, Souhami E, Zhou T, et al. Efficacy and Safety of LixiLan, a Titratable Fixed-Ratio Combination of Lixisenatide and Insulin Glargine, Versus Insulin Glargine in Type 2 Diabetes Inadequately Controlled on Metformin Monotherapy: The LixiLan Proof-of-Concept Randomized Trial. Diabetes Care. 2016;39(9):1579-86. [PubMed ID: 27284114]. https://doi.org/10.2337/dc16-0046.

  • 101.

    Rosenstock J, Aronson R, Grunberger G, Hanefeld M, Piatti P, Serusclat P, et al. Benefits of LixiLan, a Titratable Fixed-Ratio Combination of Insulin Glargine Plus Lixisenatide, Versus Insulin Glargine and Lixisenatide Monocomponents in Type 2 Diabetes Inadequately Controlled on Oral Agents: The LixiLan-O Randomized Trial. Diabetes Care. 2016;39(11):2026-35. [PubMed ID: 27527848]. https://doi.org/10.2337/dc16-0917.

  • 102.

    Ahmann A, Rodbard HW, Rosenstock J, Lahtela JT, de Loredo L, Tornoe K, et al. Efficacy and safety of liraglutide versus placebo added to basal insulin analogues (with or without metformin) in patients with type 2 diabetes: a randomized, placebo-controlled trial. Diabetes Obes Metab. 2015;17(11):1056-64. [PubMed ID: 26179619]. https://doi.org/10.1111/dom.12539.

  • 103.

    Buse JB, Vilsboll T, Thurman J, Blevins TC, Langbakke IH, Bottcher SG, et al. Contribution of liraglutide in the fixed-ratio combination of insulin degludec and liraglutide (IDegLira). Diabetes Care. 2014;37(11):2926-33. [PubMed ID: 25114296]. https://doi.org/10.2337/dc14-0785.

  • 104.

    Gough SC, Bode B, Woo V, Rodbard HW, Linjawi S, Poulsen P, et al. Efficacy and safety of a fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with its components given alone: results of a phase 3, open-label, randomised, 26-week, treat-to-target trial in insulin-naive patients with type 2 diabetes. Lancet Diabetes Endocrinol. 2014;2(11):885-93. [PubMed ID: 25190523]. https://doi.org/10.1016/S2213-8587(14)70174-3.

  • 105.

    Lind M, Hirsch IB, Tuomilehto J, Dahlqvist S, Ahren B, Torffvit O, et al. Liraglutide in people treated for type 2 diabetes with multiple daily insulin injections: randomised clinical trial (MDI Liraglutide trial). BMJ. 2015;351. h5364. [PubMed ID: 26512041]. https://doi.org/10.1136/bmj.h5364.

  • 106.

    Blonde L, Jendle J, Gross J, Woo V, Jiang H, Fahrbach JL, et al. Once-weekly dulaglutide versus bedtime insulin glargine, both in combination with prandial insulin lispro, in patients with type 2 diabetes (AWARD-4): a randomised, open-label, phase 3, non-inferiority study. Lancet. 2015;385(9982):2057-66. [PubMed ID: 26009229]. https://doi.org/10.1016/S0140-6736(15)60936-9.