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Pragmatic use of combination treatments in type 2 diabetes care

Exploring fixed-dose and fixed-ratio combinations therapies

18-03-2021 | Medications | View from the clinic | Article


Sanjay Kalra

The number of glucose-lowering drug classes, molecules, and combinations at our disposal has increased dramatically over the past few decades. For some, the wider range of treatment options has increased the complexity of clinical decision making.

In some respects, the development of fixed-dose and fixed-ratio combinations of newer agents has been driven by the need to simplify matters. However, appropriate use of these agents requires in-depth knowledge of both pathophysiology and pharmacology, along with clinical aspects of diabetology.

This series of articles presents my insights on the pragmatic use of glucose-lowering drug combinations, and aims to assist diabetes-care practitioners in identifying the most appropriate patient profiles when considering their use.

DPP-4 inhibitor + SGLT2 inhibitor fixed-dose combination

Pragmatic use of DPP-4 inhibitor + SGLT2 inhibitor fixed-dose combination

The management of type 2 diabetes has become increasingly complex due to an increasing array of drug treatment options, and the associated issues of comorbidities [1]. Treatment with a single glucose-lowering agent can only address limited pathophysiologic targets, and usually does not provide adequate glycemic control. Consequently, most people with type 2 diabetes eventually require treatment with multiple glucose-lowering medications.

Fixed-dose combinations offer convenience of administration, and a reduction in the medication burden [2]. Linagliptin + empagliflozin is an effective fixed-dose combination for patient-friendly initiation or intensification of therapy in type 2 diabetes [3,4]. This article explores the usage of this combination in clinical practice.


The striking feature of this novel combination lies in the fact that both linagliptin + empagliflozin have proven safety in their respective cardiovascular outcome trials (CVOTs), with additional protection demonstrated by empagliflozin in heart disease [5,6].

Also, both these agents are effective at lowering blood glucose levels, each through a different mechanism of action. This ensures that a single fixed-dose combination is able to offer both efficacy and proven safety in diabetes management.

Thus, with unique applicability across a broad spectrum of type 2 diabetes patient populations, this fixed-dose combination is of distinct benefit in patients with or without associated heart and kidney impairment. It can also be safely combined with any of the existing anti-diabetic agents, with the exception of GLP‑1 receptor agonists [7].

Caveats, contraindications, and confident indications

The use of linagliptin + empagliflozin should be restricted in women contemplating pregnancy/breastfeeding, and in patients with severe kidney impairment (eGFR <45 mL/min per 1.73 m2). The safety profile of the fixed-dose combination is the same as that of the individual agents, and all contraindications to the individual agents also apply to the linagliptin + empagliflozin combination [7].

With the multi-pronged benefit of this drug combination, it seems prudent to look into the advantages that this fixed-dose combination has to offer. Table 1 illustrates the mnemonic “GRACE” outlining the characteristics of a linagliptin/empagliflozin fixed-dose combination:

Table 1. Advantages of linagliptin + empagliflozin fixed-dose combination

Glucose lowering

  • Reduction in HbA1cWith additional reduction in weight

Renal benefits

  • Reduction of progression of albuminuria
  • No adverse effect on eGFR


  • Single tablet with convenient timing of administration
  • Allows titration of concomitant anti-diabetic medications

Cardiac benefits

  • Reduction in cardiovascular mortality
  • Reduction in blood pressure

Error free

  • Lesser side effects
  • Fewer drug–drug interactions

The “GRACE”-ful advantages of this combination, listed above, facilitate understanding of its indications.

Table 2 lists the indications of this fixed-dose combination in various patient profiles, which correspond to the clinical viewpoint of practicing physicians.

Table 2. Indications for linagliptin + empagliflozin fixed-dose combination

Glycemia based

  • As intensification in patients who are not responding to other drugs, if HbA1c >8.5% (69 mmol/mol)
  • As initiation therapy, along with metformin, if HbA1c >9.0% (75 mmol/mol)

Vascular health based

  • In patients with/at high risk of atherosclerotic cardiovascular disease (ASCVD)
  • In patients with mild/moderate renal impairment
    • eGFR (eGFR >45 to <90 mL/min per 1.73 m2)
    • Albuminuria (UACR >30 to <300 mg/g)

Risk profile based

  • In patients at high risk of hypoglycemia/with hypoglycemia unawareness
  • In patients where weight gain is a concern

Concomitant medication based

  • In patients who are unable to tolerate standard doses of metformin or who need repeated titration of metformin doses
  • In patients not well controlled on higher doses of insulin


  • In patients who request a minimum number of tablets
  • In patients who may not be able to persist with complex regimens

My personal experience

A distinct characteristic of this patient-friendly, fixed-dose combination is that it can be used in patients with established heart disease: those with renal impairment; patients not controlled on higher doses of insulin or metformin; and also in patients in whom hypoglycemia and/or weight gain is a concern. Especially, in patients with certain gastrointestinal intolerance to metformin, this fixed-dose combination allows us to titrate the doses of concomitant metformin, exemplifying the patient-friendly uniqueness of this fixed-dose combination.


  1. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes—2019. Diabetes Care. 2019; 42(Supplement 1): S90–S102.
  2. Mooradian A, Chehade JM, Mooradian AD. Advantages and pitfalls of antihyperglycemic combination pills as first-line therapy in the management of type 2 diabetes. Am J Ther 2016; 23: e1857–e1866.
  3. DeFronzo RA, Lewin A, Patel S, et al. Combination of empagliflozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin. Diabetes Care. 2015; 38:384–393.
  4. Lewin A, DeFronzo RA, Patel S, et al. Initial combination of empagliflozin and linagliptin in subjects with type 2 diabetes. Diabetes Care. 2015; 38:394–402.
  5. Rosenstock J, Perkovic V, Johansen OE, et al. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial. JAMA 2019; 321: 69–79.
  6. Zinman B, Wanner C, Lachin JM. Glucose-lowering agent shows CV benefit in outcome trial, for the first time. N Engl J Med. 2015; 373: 2117–2128.
  7. Scheen AJ. DPP-4 inhibitor plus SGLT-2 inhibitor as combination therapy for type 2 diabetes: from rationale to clinical aspects. Expert Opin Drug Metab Toxicol 2016; 12: 1407–1417.

GLP-1 receptor agonist + basal insulin co-formulation

Pragmatic use of GLP-1 receptor agonist + basal insulin co-formulation

Injectable therapies for diabetes mellitus have evolved significantly since the discovery of insulin. Modern guidelines support the use of GLP-1 receptor agonists (GLP-1RAs) as a first-line injectable therapy, as opposed to insulin, in metformin inadequacy [1]. GLP‑1RA addition is also suggested as a preferred means of intensifying basal insulin therapy, in cases of basal insulin inadequacy [1]. Current thinking encourages the initiation of combination therapy in people with high HbA1c levels at presentation; GLP‑1RA and insulin can also be initiated as a combination injectable therapy [2]. 

This part of the article briefly explores the utility of GLP‑1RA and insulin combinations currently available as co-formulations, including LixiLan (lixisenatide + insulin glargine) and IDegLira (liraglutide + insulin degludec). While each LixiLan unit contains 0.001 mg of lixisenatide and 2 U of glargine, IDegLira is formulated in a concentration of 0.036 mg liraglutide and 1 U degludec per unit.


Injectable co-formulations of GLP‑1RA and insulin are backed by rationale and evidence. While insulin serves to supplement inadequate endogenous secretion, GLP‑1RA works through multiple mechanisms to enhance insulin secretion, reduce insulin resistance, restrict calories, and work as a calorie restriction mimetic. Prescribing a combination allows lower doses of both agents to be used, thus improving tolerability and facilitating consistent medication taking [3,4].

Rates of hypoglycemia, weight gain, and gastrointestinal disturbance are lower with co-formulations, as relatively low doses can be prescribed. This is in contrast to the higher doses that are required when individual drugs are used. Consistent medication taking is also promoted by the convenience of using a single injection, and flexibility of timing of administration [5].

Table 1 lists some advantages of using a GLP‑1RA + insulin co-formulation. Table 2 lists patient characteristics where GLP‑1RA + insulin combination can be used.

Table 1. Advantages of GLP‑1RA + insulin co-formulation

  • Strength of glucose lowering
  • Sustainability of action
  • Safety: low risk of hypoglycemia, weight gain, gastrointestinal side effects
  • Sparing of insulin
  • Simplicity of use: technique and titration
  • Spectrum of use: wide applicability

Table 2. Indications of GLP‑1RA + insulin co-formulation

All type 2 diabetes patients, except children <18 years. women planning conception, antenatal women, and breastfeeding women

  • Inadequate control on:
    • metformin
    • dual/triple oral therapy
    • basal insulin
  • Intolerance of high doses of:
    • insulin, eg, hypoglycemia, weight gain
    • GLP‑1RA, eg, gastrointestinal disturbance
  • Inconvenience of multiple injections with:
    • basal insulin+ GLP‑1RA, at separate times
    • premixed insulin + GLP‑1RA, at separate times
  • Intensification for cardiovascular benefit/safety in people receiving:
    • basal insulin
    • other therapy

My personal experience

GLP‑1RA + insulin co-formulation is an easy and effective way of initiating injectable therapy in people with diabetes who fear multiple injections, hypoglycemia, and intrusion into their preferred lifestyle. The co-formulation provides multiple extra-glycemic benefits, including cardiovascular safety and mitigation of weight gain.

These co-formulations are also a preferred means of intensifying therapy in persons who do not respond to basal insulin monotherapy or to GLP‑1RA therapy.

While adding insulin to pre-existing GLP‑1RA therapy, one must remember to reduce the dose of sulfonylureas, as necessary. Similarly, addition of GLP‑1RA to insulin should prompt discontinuation of gliptin therapy.


  1. Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2018; 61: 2461–2498.
  2. AACE/ACE Comprehensive Type 2 Diabetes Management Algorithm. Available at: Last accessed on 25 June 2019
  3. Kalra S, Gupta Y. Injectable coformulations in diabetology. Diabetes Therapy 2015; 6: 101–111.
  4. Holst JJ, Vilsbøll T. Combining GLP‐1 receptor agonists with insulin: therapeutic rationales and clinical findings.  Diabetes Obes Metab 2013; 15: 3–1.
  5. Kalra S, Gupta Y, Unnikrishnan AG. Flexibility in insulin prescription. Indian J Endocrinol Metab 2016; 20: 408–411.

Fixed-dose metformin + DPP-4 inhibitor combination

Pragmatic use of a fixed-dose metformin + DPP-4 inhibitor combination


Fixed-dose metformin + dipeptidyl peptidase-4 (DPP-4) inhibitor combinations are used to treat type 2 diabetes. Individually, both agents have a distinct blood glucose-lowering mechanism of action, and thus complement each other as a combination.

Metformin has been in use for over 60 years and, in this time, has established itself as a safe and effective medication, as well as the primary agent of choice for type 2 diabetes across the majority of global guidelines. On the other hand, DPP‑4 inhibitors are one of the safest glucose-lowering agents with proven cardiac and renal safety.

The versatile applicability of metformin and DPP‑4 inhibitors makes their combination a valuable tool for the treatment of type 2 diabetes. This article discusses the indications, advantages, and limitations of this combination.


For the majority of people with type 2 diabetes, metformin is the recommended first-line pharmacotherapy [1]. However, most patients will ultimately require additional therapies to help sustain glycemic control as their condition advances.

Ensuring intensive glucose control early on in the disease process is imperative, and may eventually lead to benefits that continue beyond the period of treatment [2]. Consequently, when metformin fails to attain glycemic control, combination therapy is required.

Given their complementary mechanisms of action, a fixed-dose metformin + DPP‑4 inhibitor combination offers good glycemic control. without the hypoglycemia and weight gain commonly associated with insulins and sulfonylureas [3,4,5]. An added advantage includes improvement in kidney function [3].


The fixed-dose metformin + DPP‑4 inhibitor combination is useful in a broad range of type 2 diabetes patient profiles, but particularly in people who are on a high dose of metformin.

The fixed-dose combination is well tolerated with safety profiles comparable to the individual agents, with certain caveats for its use in pregnant/breastfeeding patients, and in patients with severe renal impairment (chronic kidney disease stage 5 [metformin contraindicated due to increased risk of lactic acidosis]) [6,7].

It may be helpful to remember the advantages of this combination using the six “E” mnemonic shown in Table 1 below

Table 1. Advantages of DPP‑4 inhibitor + metformin fixed-dose combination


  • Effective reduction of HbA1c
  • No/minimal glycemic variability

Ease of use

  • Minimal dose required
  • Flexibility in timing of administration

Error free

  • Safety
  • Tolerability

Extra-glycemic effect

  • Renal (reduction in progression of albuminuria)
  • Cardiac (safety as seen with both the agents individually)

Elementary investigations

  • Minimum investigations required at screening
  • Minimum investigations needed for monitoring


  • Can be prescribed once or twice daily
  • Can be prescribed with all insulins/oral anti-diabetic agents except oral semaglutide

The advantages of the fixed-dose combination translate into robust indications, as listed in Table 2.

Table 2. Indications of DPP‑4 inhibitor + metformin fixed-dose combination

Glycemia based:

  • As initiation therapy at HbA1c >7.5% (58 mmol/mol)
  • As intensification therapy if metformin proves inadequate

Complication based:

  • In people with diabetes at high risk of hypoglycemia/with hypoglycemia unawareness
  • In people with diabetes with/at high risk of renal impairment


  • In people with diabetes who may not be able/willing to undergo regular follow up
  • In people with diabetes who may struggle with the complex self-care required with other regimens

My personal experience

The advantages of the DPP‑4 inhibitor + metformin fixed-dose combination include a robust HbA1c reduction, good tolerability profile, flexible dosing, and greater convenience for the patient.

These characteristics may translate into improved medication taking, better glycemic control, and greater cost-effectiveness.

The combination also reflects some of the advantages of DPP‑4 inhibitor monotherapy, such as usefulness in patients with renal impairment. However, it is critical to remember that metformin is contraindicated in people with chronic kidney disease stage 5. Therefore, the DPP‑4 inhibitor + metformin fixed-dose combination cannot be used in this subset of people.

One the greatest benefits of the DPP‑4 inhibitor + metformin fixed-dose combination is the simplicity of its use. This is a very useful and versatile combination, which adds great value to our clinical practice. The combination of safety and efficacy, coupled with flexibility and versatility, encourages its extensive use in adults with type 2 diabetes.

Availability of this fixed-dose combination allows for timely initiation and intensification of oral anti-diabetic therapy, facilitates achievement of glycemic targets, and prevents occurrence of unwanted complications.


  1. Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2018; 61: 2461–2498.
  2. Ceriello A. The emerging challenge in diabetes: the “metabolic memory”. Vascul Pharmacol 2012; 57: 133–138.
  3. Koliaki C, Doupis J. Linagliptin/Metformin fixed-dose combination treatment: a dual attack to type 2 diabetes pathophysiology. Adv Ther 2012; 29: 993–1004.
  4. Gallwitz B. Sitagliptin with metformin: profile of a combination for the treatment of type 2 diabetes. Drugs Today (Barc) 2007 43: 681–689.
  5. Halimi S, Schweizer A, Minic B, Foley J, Dejager S. Combination treatment in the management of type 2 diabetes: focus on vildagliptin and metformin as a single tablet. Vasc Health Risk Manag 2008; 4:481–492.
  6. Lipska KJ. Metformin use in patients with historical contraindications. Ann Int Med 2017; 166: 225–226.
  7. DeFronzo R, Fleming GA, Chen K, Bicsak TA. Metformin-associated lactic acidosis: Current perspectives on causes and risk. Metabolism 2016; 65: 20–29.

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