Ask The Experts

Intensifying Type 2 Diabetes Treatment with the Right Drug Combination

Review of factors to consider when adding therapy to metformin to reduce cardiorenal risks and to lessen disease complications in patients with progressing T2D, informed by ADA-EASD Consensus Report.

Strategies for informed selection of add-on therapy in the treatment of type 2 diabetes are becoming ever more attentive to the high burden of cardiovascular disease (CVD) and renal complications.  

After metformin, two key classes of glucose-lowering agents, glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose co-transporter-2 (SGLT-2) inhibitors offer beneficial cardiovascular disease and/or renoprotective effects in addition to their metabolic effects.

With these choices, what factors ought to be considered to inform clinical decision-making in patients with complicated type 2 diabetes?

Good data supports adding the appropriate agent to reduce risks of heart disease and kidney failure in diabetes.
Early Interventions for Newly Diagnosed Diabetes

Initial therapeutic strategies recognize that early and effective glycemic control improves the long-term prognosis.1

  • Lifestyle factors, most notably diet and exercise, should always provide the foundation of any diabetes management plan with weight control usually a key objective. Early diagnosis followed by rigorous lifestyle measures often may achieve disease remission.2
  • Metformin is typically preferred as the first pharmacological glucose-lowering agent to be introduced for patients diagnosed with type 2 diabetes. This is based on six decades of experience supporting its antihyperglycemic efficacy without weight gain, negligible risk of hypoglycemia, a mode of action that counters insulin resistance, and reduced long-term CV risk, all at low cost.The main limitations of metformin therapy concern adequate renal function and gastrointestinal tolerability in some patients. 
  • Separate, targeted interventions are recommended to address hypertension, dyslipidemia, and other diabetes-associated morbidities.

Given the potential to reverse early-onset T2D, the goal of identifying patients at-risk or recently diagnosed affords clinicians the chance of preventing or forestalling the cardiorenal complications that may come with long-term disease.  

Intensification of Drug Therapy for Targeted Treatment

As type 2 diabetes is a progressive disease, additional therapies are likely to be required over time, using agents with different modes of action to address common factors involved in the pathogenesis of diabetes-related complications.

  • The recently up-dated ADA-EASD consensus report promotes an individualized approach to the selection of second-line, glucose-lowering therapy as add-on to metformin,4 which suggests that this be guided firstly by presence of cardiovascular and/or renal diseases or their risk factors, and then by the status of the patient’s hyperglycemia, adiposity, risk of hypoglycemia, and personal resources.
  • The main agents for consideration in prompting supplemental glucose-lowering effects are the GLP-1RAs and SGLT-2 inhibitors. Each class provides a different mode of action, additive antihyperglycemic efficacy with little hypoglycemic risk, support weight loss and lowering of blood pressure, and there is mounting evidence of protective benefits against CV and renal disease.5-7  

Insights from the Cardiovascular Outcomes Trials

Each GLP-1RA and SGLT-2 inhibitor has been studied in a Cardiovascular Outcomes Trial (CVOT). Most patients involved in these studies were receiving antihypertensive therapies, lipid-lowering agents, and metformin, which were continued during the studies.

  • It is important to note that the various CVOTs have been conducted in populations of patients with varying characteristics, for example, with different proportions and types of prior cardiovascular disease and risk factors.
    Although head-to-head studies have been conducted comparing the metabolic effects of GLP-1RAs and SGLT-2 inhibitors,the CV and renal responses of agents from these two antidiabetes treatment classes have not been compared directly. While it is difficult to compare individual agents within and between these classes, it is possible to draw useful generalizations from the aggregated findings to date [see Table 1].
  • Beyond the CV effects, renal parameters also were assessed in most of the CVOTs with GLP-1RAs and SGLT-2 inhibitors, and there have been a few additional studies in patients with impaired renal function. 

Considerations in drug advantages and disadvantages in treating for cardiorenal disease in patients with diabetes.

Preemptive Therapy for Major Adverse Cardiovascular Events

In the CVOTs, GLP-1RAs and SGLT-2 inhibitors demonstrated a reduction in the 3-point composite of major adverse CV events (3-pt MACE) attributable to atherosclerotic CV disease (ASCVD), namely CV death, non-fatal myocardial infarction (MI), and non-fatal stroke.

  • Reductions in 3-point MACE may be slightly stronger for the once weekly GLP-1RAs than for SGLT-2 inhibitors, driven by reductions in stroke.4,7
  • Subanalyses of the 3-point MACE among different groups of patients within the CVOTs have not consistently identified or excluded any particular beneficiaries. 

It is unclear whether patients without prior CV disease but with CV risk factors share the same degree of (primary) prevention of MACE as patients who entered the trials with prior CV disease (secondary prevention). However, both the GLP-1RAs and SGLT-2 inhibitors are recommended for primary prevention in the up-dated ADA-EASD consensus report.4

Special Attention to Patients with Risk of Heart Failure

  • SGLT-2 inhibitors have consistently and strongly reduced hospitalization for heart failure in large trials whereas an effect of GLP-1RAs to reduce hospitalization for heart failure was inconsistent and modest in the trials.
  • SGLT-2 inhibitors have reduced hospitalization for heart failure in patients with and without either prior heart failure or prior ASCVD or indeed with or without type 2 diabetes. 
  • Where ejection fraction has been measured, SGLT-2 inhibitors reduce worsening of heart failure in patients with reduced ejection fraction, but an effect on preserved ejection fraction is unclear.

Accommodating for Çompromised Renal Function

  • Composite measures of renal function, which have included changes in long-term estimated glomerular filtration rate (eGFR), serum creatinine, deterioration into end stage kidney disease, renal death and onset and/or progression of albuminuria have consistently improved with use of SGLT-2 inhibitors. 
  • These renal effects of SGLT-2 inhibitors are more evident in patients at early stages of renal impairment and appear to be independent of the presence or absence of prior CV disease.  
  • SGLT-2 inhibitors typically cause an initial and temporary reduction in eGFR, but thereafter slow the rate at which eGFR deteriorates.  GLP-1RAs have not consistently slowed the deterioration of eGFR but limited data suggest they may be helpful in this respect in patients with impaired renal function.
  • SGLT-2 inhibitors and GLP-1RAs have reduced the onset and progression of albuminuria:  evidence is perhaps slightly stronger for SGLT-2 inhibitors.

Adding Agents for Optimal Diabetes Outcomes

The recommendations in the updated ADA-EASD consensus report reaffirm that after lifestyle and metformin, choosing additional glucose-lowering therapy should take full accounting of any existing cardiovascular and renal complications. The guidelines indicate that in patients who have diabetes without these complications, clinicians should assess for individual level of CVD and renal risk.

In doing so, these patients with type 2 diabetes who have not yet progressed may benefit from additional drug therapy—either GLP-1RA or SGLT-2 inhibitor—as follows:

  • Add-on use of a GLP-1RA is preferred in patients with existing or at high risk of ASCVD (especially in those over 50 years with evidence of arterial disease or left ventricular hypertrophy), including individuals with renal impairment (eg, eGFR < 60 ml/min/1.73m2 and/or albuminuria as indicated by a urine albumin-creatinine ratio > 30 mg/g).
  • Add-on use of an SGLT-2 inhibitor is preferred in patients with heart failure (especially if reduced ejection fraction) and/or deteriorating renal function (eg, eGFR range 60-30 ml/min/1.73m2 and/or albuminuria as indicated by a urine albumin-creatinine ratio >30 mg/g). Note: eGFR has usually been estimated by the MDRD equation.  Urinary albumin-creatinine ratio of 30 mg/g is approximately 3.4 mg/mmol.

Other considerations that may influence the selection of second-line therapy in patients with T2D:

  • Choosing between a GLP-1RA or an SGLT-2 inhibitor can be independent of the extent of the hyperglycemia.
  • Weight-reducing properties of GLP-1RAs and SGLT-2 inhibitors have favored use of these agents in individuals with overweight and obesity. However, their use in patients who fall in the lower end of the healthy weight range deserves caution. 
  • Combined use of a GLP-1RA and an SGLT-2 inhibitor may provide additivity of the glucose-lowering and weight-reducing effects but effects of combined use on cardiorenal parameters have not been established. 
  • Labelling restrictions or local guidelines may impinge on the suggestions offered in the ADA-EASD consensus report.1 For example, although SGLT-2 inhibitors have been shown to counter renal impairment, the product labels for these agents may limit their initiation in moderate renal impairment due to lesser glucose-lowering efficacy in these patients. Conversely, GLP-1RAs are mostly approved for use in moderate renal impairment and some are approved in severe renal impairment down to an eGFR of 15 ml/min/1.73m2.   
  • If initiating a GLP-1RA, consider the history of or susceptibility to pancreatitis and while titrating dose, keep in mind the risk of nausea developing as an adverse effect (usually temporary).
  • When initiating an SGLT-2 inhibitor, take into account significant peripheral vascular disease or previous amputation to avoid the potential for jeopardy to the lower limbs. Patients should be advised to maintain adequate daily hydration, and to recognize and address (eg, with anti-fungal cream) possible genital mycotic infection.
  • Although outside the parameters of this article, use caution in insulin-treated patients to avoid over-lowering the insulin dose.  

It is appreciated that tolerability, cost and other resource limitations may obviate the choice of a GLP-1RA and an SGLT-2 inhibitor as add-on to metformin in which case the ADA-EASD consensus report suggests preferred alternative glucose-lowering therapies in these circumstances, notably various dipeptidyl peptidase-4 inhibitors, sulphonylureas, and pioglitazone.

Continue Reading:
Cardio-Protective Benefit of Metformin Falls Short for People with Diabetes
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