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Correspondence to: Julie A. Lovshin, Room 212B, S Wing, 2075 Bayview Avenue, Sunnybrook Health Sciences Centre, Toronto, Ontario, M4N 3M5. Tel: +416-480-6100 Ext. 2264
In addition to diet and lifestyle, metformin remains the first line of treatment for type 2 diabetes as recommended by major international diabetes associations, including Diabetes Canada.
Ophthalmologists however, should be aware of the increasing use of three newer classes of antidiabetes therapies approved over the past decade for treating type 2 diabetes including; glucagon-like peptide-1 receptor agonists (GLP-1RA), dipeptidyl peptidase 4 inhibitors (DPP-4i), and sodium glucose co-transporter-2 inhibitors (SGLT2i). In addition to blood glucose lowering, the benefits of using GLP-1RA and SGLT2i in patients with type 2 diabetes also include important “non-glycemic” effects of these drugs. In particular, body weight loss, and more recently, the recognition that some GLP-1RA (liraglutide
[Invokana®, Janssen]) reduce the risk for cardiovascular and nephropathy events in patients with type 2 diabetes and clinical cardiovascular disease. As such, ophthalmologists are likely to increasingly encounter these drug classes in their clinical practice in patients with type 2 diabetes.
GLP-1RA are administered once daily or once weekly subcutaneously, with newer non-injectable investigational agents in late stage clinical development (e.g. ITCA-650 [continuous subcutaneous delivery of exenatide via a subdermally implanted mini-osmotic pump for 6-12 months], Intarcia Therapeutics, Inc.).
In subjects with type 2 diabetes, GLP-1RA potently lower blood glucose (HbA1c -1.0% to -1.5%), systolic blood pressure (-2 to -6 mmHg in hypertensive subjects), and blood cholesterol,
and following chronic use, lower body weight (~-3 to -5 Kg). GLP-1RA are recombinant human or non-mammalian GLP-1 peptides (which have low oral bioavailability) that directly stimulate GLP-1 receptors (Fig. 1) on pancreatic β-cells to stimulate insulin secretion, and inhibit glucagon release and gastric emptying, which lowers blood glucose concentrations.
Unlike sulphonylureas and insulin, the glucose-lowering effects of GLP-1RA are glucose-dependent, and therefore GLP-1RA have a low risk for hypoglycemia. GLP-1RA and DPP-4i (discussed below) are both incretin-based antidiabetes agents, however, they are distinct drug classes and should not be used together.
(Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcomes) for liraglutide [9,340 patients, HbA1c 8.7%, median 3.8 year treatment period]; SUSTAIN-6
for (Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes) semaglutide [3,297 patients, HbA1c 8.7%, 104 treatment period]), liraglutide (RRR 13%) and semaglutide (RRR 26%) reduced the risk for major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) compared to placebo (in addition to standard of care), and also significantly reduced the risk for nephropathy events. These findings have lead to diabetes
and cardiology associations recommending the use of liraglutide or empagliflozin (an SGLT-2i), as a preferred second-line therapy for patients with type 2 diabetes with clinical cardiovascular disease after metformin.
a non-significant increase in retinopathy events (defined as the need for retinal photocoagulation or treatment with intravitreal agents, vitreous hemorrhage, or the onset of diabetes-related blindness) were observed with liraglutide (HR 1.15, 95% Cl [0.87-1.52], p=0.33) compared to placebo. In LEADER,
a statistically significant increase in retinopathy events (HR 1.76; 95% CI 1.11-2.78; p=0.02) was observed with semaglutide compared to placebo. The absolute number of retinopathy events overall was low in SUSTAIN-6
baseline retinopathy screening and grading was completed and retinopathy endpoints were predefined, prospectively collected and adjudicated.
It must be emphasized that the results (including retinopathy endpoints) of these two studies (LEADER and SUSTAIN-6) cannot be directly compared due to differences in drug efficacy, heterogeneity in research design, patient populations, and median follow-up times. For example, in SUSTAIN-6,
significantly greater between group-differences in glycemic control (HbA1c -1.0%), body weight (-4.3 Kg) and blood pressure (SBP -2.6 mmHg) were observed with semaglutide compared placebo, than was observed for liraglutide vs. placebo in LEADER . These glycemic and metabolic factors alone may have modified the risk for DR progression. Post-hoc sub-group analyses recently presented at the American Diabetes Association
revealed that the majority of DR events occurring in SUSTAIN-6 occurred in older patients, in those with the greatest HbA1c reduction (HbA1c -2% to -3%), in those with insulin use at baseline, and in those with a history of proliferative DR. Importantly, retinopathy events did not occur in those without a history of proliferative DR at baseline, however standardization of retinopathy grading at baseline was non-uniform in SUSTAIN-6. Accordingly, it is presently unclear whether the risk for DR progression observed in SUSTAIN-6 occurred secondary to robust glycemic lowering effects associated with semaglutide (potentially initiating retinal ischemia) or were potentially related to direct vascular effects associated with GLP-1R signaling in the retina (the GLP-1R is expressed in the retina
), or due to as yet unidentified causative factors. Readers may recall that in the intensive glycemic lowering arm of the landmark DCCT (Diabetes Control and Complications) trial in type 1 diabetes, patients in the intensively treated group demonstrated an initial early worsening in DR (13.1%) compared to the conventionally treated group (7.6%) at 6/12 months, reversed and actually improved over time at 2-3 years.
The effect of intensive diabetes treatment on the progression of diabetic retinopathy in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial.
Archives of ophthalmology (Chicago, Ill : 1960). 113. 1995: 36-51
Importantly, these findings highlight the need for more mechanistic studies to be completed in this area in order to better understand these clinical observations and furthermore to substantiate DR safety for semaglutide and other closely related GLP-1RA. Ideally to further delineate potential relationship(s) between GLP-1RA (semaglutide, liraglutide) and early worsening in DR, prospective dedicated studies using standardized DR screening and grading at baseline, with active comparators for blood-glucose lowering are needed. Additionally, longer-term follow-up may help us better understand whether these early changes in DR progression associated with GLP-1RA administration might reverse and potentially improve over time, as was observed in the DCCT
The effect of intensive diabetes treatment on the progression of diabetic retinopathy in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial.
Archives of ophthalmology (Chicago, Ill : 1960). 113. 1995: 36-51
for patients with type 1 diabetes. Interestingly, in the long-term blood glucose intensification study in type 2 diabetes patients, the UKPDS (United Kingdom Prospective Diabetes Study) study, no initial worsening in DR was observed in the intensive glycemic control group, only a trend towards improvement in DR over time was observed.
Unlike GLP-1RA, DPP-4i are once daily, oral antidiabetic drugs, that are comparatively less potent on blood glucose lowering (HbA1c -0.5-0.7%) and do not modify body weight.
DPP-4i exert glucoregulatory effects by preventing the inactivation of the incretin hormones, GLP-1 and glucose insulinotropic peptide (GIP), which are endogenous gut-hormones that are secreted in response to food intake (Fig. 1). In the pancreas, GLP-1 promotes insulin secretion and supresses the release of the counter-regulatory hormone, glucagon,
in a glucose-dependent manner. Accordingly, like GLP-1RA, DPP-4i are associated with a low risk for hypoglycemia (even while fasting), and have a good benefit to risk profile. DPP-4 is a soluble enzyme, which presumably circulates through the retinal microvasculature, and is expressed in several vascular beds including expression in endothelial cells.
(Trial to Evaluate Cardiovascular Outcomes with Sitagliptin) is the largest cardiovascular safety study with a DPP-4 inhibitor published to date, enrolling 14,671 patients with type 2 diabetes with cardiovascular disease to either sitagliptin (a DPP-4i), or placebo, for a median follow-up of 3.8 years. From an ophthalmology perspective, in TECOS
no major safety signal for diabetic retinopathy (DR) was reported. Baseline screening and grading for DR however, was not preformed, and in total, of 226 diabetic eye disease events that were reported, those randomized to sitagliptin experienced 3.1% (n=226) events, whereas 2.5% (n=180) were reported for placebo.
SGLT2i are a class of oral, once daily antidiabetic drugs that lower blood glucose (HbA1c -0.7% to -1.0%) by inhibiting sodium glucose co-transporter 2 (a principal regulator of renal glucose reabsorption which is upregulated in type 2 diabetes) channels located in the renal proximal tubules thereby promoting glycosuria (Fig. 1). Accordingly, the effect(s) of SGLT2i on blood glucose lowering are also independent of insulin, and SGLT2i are associated with a low risk for hypoglycemia. Over time, net caloric loss of urinary glucose leads to body weight loss. Like GLP-1RA, SGLT2i (empagliflozin,
) exert important cardiac and renoprotective effects that reduce cardiovascular death and promote albuminuria-lowering in patients with type 2 diabetes and cardiovascular disease. This has led to recognition by the US Federal Food and Drug Administration that empagliflozin is a cardioprotective agent, and similar acknowledgements may soon emerge for canagliflozin as was recently done for liraglutide. These pharmacodynamic effects likely originate in the kidney secondary to SGLT2i-mediated effects on renal sodium hemostasis and natriuresis.
As such, SGLT2i lower blood pressure and reduce plasma volume, effects which may lead to volume depletion in the ill, elderly, dehydrated, or those taking diuretics. Accordingly, volume status should be assessed preoperatively for patients taking SGLT2i. Unlike GLP-1A and DPP-4i, Diabetes Canada has recognized SGLT2i as part of “sick day management”, and it is prudent to hold these medications during times of stress (including preoperatively prior to surgery) or during illness.
Overall, SGLT2i, are associated with good tolerability and safety profiles to date. In humans, expression of SGLT2 channels is predominantly restricted to the kidney and therefore no direct effects of SGLT2i are expected in the retina, notwithstanding the possibility of indirect SGLT2i-mediated hemodynamic effects on the retinal microvasculature. To date, there have been no significant safety signals for DR observed with SGLT2i in the two major cardiovascular safety studies reported with SGLT2i, EMPA-REG OUTCOME
(Canagliflozin Cardiovascular Assessment Study) trial, recognizing that these studies did not prospectively adjudicate retinopathy events.
In summary, the introduction of newer agents for the treatment of type 2 diabetes broadens therapeutic opportunities, and allows for personalized diabetes clinical care. Moreover, as GLP-1RA and SGLT2i have important non-glycemic effects including cardiac and nephroprotection, ophthalmologists will be increasingly encountering these drug classes in their type 2 diabetes patients and should become familiar with their clinical risk and benefit profiles. The observations in LEADER and SUSTAIN-6 for increased retinopathy events highlights the current unmet need for further clinical investigation into better understanding how glycemic lowering and/or GLP-1R signaling may transiently worsen DR. This may open up new avenues of research for the identification of novel glucose-dependent vascular targets and pathways which regulate the progression of retinopathy.
Disclosures
K.D.M has no disclosures to report. J.A.L. receives honoraria and/or consulting fees an/or grant support from Novo Nordisk, AstraZeneca, Merck Sharpe and Dohme, and Eli Lilly and Co.
Acknowledgements: No funding was received for this manuscript.
The effect of intensive diabetes treatment on the progression of diabetic retinopathy in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial.
Archives of ophthalmology (Chicago, Ill : 1960). 113. 1995: 36-51
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