Volume 3 - Issue 10
Consultant Geriatrics, Kauvery Hospital, Salem, India
Dapagliflozin has emerged as a possible cardio-renal game changer. The article summarizes the cardioprotective and renal beneficial effects of dapagliflozin. It is focused mainly on the side effects of the class of SGLT2 Inhibitors.
What to keep in mind before prescribing for the elderly? Look before you leap!
As a geriatric physician, I am more concerned about the side effects of a drug than its effects while prescribing an antidiabetic drug. The practice of polypharmacy on the elderly is fraught with unpredictable consequences due to multiple comorbidities and altered pharmacokinetics and pharmacodynamics in older patients.
The increased susceptibility to hypoglycemia among older people is of another major concern because of the associated increased risk of falls and bone fractures.
Decision making while prescribing a drug in elderly is based on assessment of:
The possible side effects of the SGL2 Inhibitors are:
Courtesy - The world wide web
I also assess the risk reward ratio, while making my decision and choosing a drug
Courtesy - The world wide web
A large real-world retrospective cohort study by Dave et.al.  showed an approximately three-fold increased risk of genital infections during SGLT2i therapy compared to dipeptidyl peptidase-4 (DPP-4) inhibitors and GLP-1 receptor agonists.
Furthermore, a meta-analysis by Liu et al.  showed that all SGLT2i have a significantly higher risk of urinary tract and genital infections; however, in the case of Dapagliflozin, the relationship is dose-dependent
For this reason, diabetic patients taking SGLT2i must be educated in maintaining a high standard of personal hygiene and adequate hydration to prevent infections.
SGLT2i therapy alone is associated with low risk of hypoglycemia
The incidence rates of SGLT2i-induced hypoglycemia are similar to current antidiabetic drugs such as Metformin, the Glitazones, and DDP-4 inhibitors, and they are substantially lower when compared to insulin or Sulphonylureas.
The prescribing information recommends that caution be exercised when Dapagliflozin is used in combination with insulin secretagogues (e.g. sulfonylureas) and insulin as combined use can result in hypoglycemia
Urinary glucose excretion with Dapagliflozin results in osmotic diuresis and increases in urinary volume in subjects with type 2 diabetes mellitus.
Urinary volume increases in subjects with type 2 diabetes mellitus treated with dapagliflozin 10 mg were sustained at 12 weeks and amounted to approximately 375 ml/day.
The increase in urinary volume was associated with a small and transient increase in urinary sodium excretion that was not associated with changes in serum sodium concentrations.
This phenomenon occurs due to the depletion of glucose and thus sodium, commonly leading to symptoms such as decreased blood pressure, orthostatic hypotension, and dizziness
However, a meta-analysis by Liakos et al.  compared the depletion of body volume in patients taking empagliflozin or a placebo and concluded that there was no significant difference.
Similarly, a study by Baker et al.  did not show a significant volume depletion or impact on orthostatic hypotension in patients receiving SGLT2i (p > 0.05)
Patients who have limited renal function [estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2], older patients and those taking loop diuretics are advised to use Dapagliflozin cautiously in order to avoid symptomatic hypotension
In general, patients initiating Dapagliflozin should have close follow up of both their blood glucose as well as their BP values.
Patients should be routinely assessed for volume status and signs and symptoms of hypotension to avoid any unnecessary hypotension.
A documented side effect of SGLT2i therapy is euglycemic diabetic ketoacidosis
Glucose loss via SGLT2i-induced urination leads to decrease in insulin levels.
Glucagon levels subsequently increase, leading to SGLT2i-related hyperglucagonemia and ketone production.
Finally, SGLT2i increases plasma ketone levels because of overproduction.
Interestingly, the increased production of ketone bodies has the potential to enhance cardiac metabolic efficiency.
Studies on human and animal models have proven the role of β-hydroxybutyrate in reversing ventricular remodeling, resulting in improvement of cardiac output and diastolic function.
However, a meta-analysis by Monami et. al.  analyzed 72 RCTs of T2DM patients in which only nine reported at least one incidence of diabetic ketoacidosis.
Therefore, the risk of diabetic ketoacidosis due to the SGLT2i class (MH-OR [95% CI]. 1.14 [0.45â€“2.88], p = 0.78) is negligible
As demonstrated in the CANVAS and CANVAS-Renal (CANVAS-R), Canagliflozin was affiliated with a two-fold higher risk of amputations of the toes and metatarsals when compared with placebo (6.3 vs. 3.4/1000 patient-years) .
The CANVAS program patients had a mean age of 63 years, and each participant reported a cardiovascular condition or peripheral vascular disease at baseline, suggesting that these two factors may impact the final result.
It was further investigated in a cohort study by Fralick et al.  of three US national databases of patients administered Canagliflozin GLP-1 agonists. The study concluded that the risk of amputations whilst taking Canagliflozin was greater in comparison to GLP agonists.
Patients with a history of amputation or peripheral vascular disease naturally have the highest absolute risk of amputation.
On the other hand, the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) and the Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events (DECLARE-TIMI 58) did not confirm the association between SGLT2i and the higher risk of lower limb amputations
The CANVAS arm of the CANVAS program highlighted an increased risk of nonvertebral fractures during treatment with Canagliflozin compared with placebo (HR 1.55), in contrast to the CANVAS-R trial (HR 0.86)
While CANVAS-R showed an increase in renal impairment, this group had a lower risk of fractures than those in the CANVAS study
Furthermore, the Evaluation of Canagliflozin's Effects on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE) trial reported null result for fractures; therefore, the observation in the CANVAS was most likely incidental.
Small increases in serum Parathormone (PTH) levels were observed with increases being larger in subjects with higher baseline PTH concentrations.
Bone mineral density measurements in patients with normal or mildly impaired renal function did not indicate bone loss over a treatment period of one year.
While a causal relationship between Dapagliflozin and bladder cancer is unlikely as a precautionary measure, Dapagliflozin is not recommended for use in patients concomitantly treated with pioglitazone.
Available epidemiological data for Pioglitazone suggest a small increased risk of bladder cancer in diabetic patients treated with Pioglitazone.
Because elevations in these laboratory parameters can have negative consequences, patients should be monitored for these values when initiating or titrating doses of dapagliflozin.
The paradigm of diabetes treatment has shifted from a glucose -focused approach to the pursuit of therapeutic regimen that will yield a reduction in morbidity and mortality . This is particularly true in the elderly whose life expectancy is shorter and for whom event rates are higher.
Treatment goals for diabetes mellitus in the elderly should be individualized.
Healthy patients with good functional status, few comorbidities, and intact cognitive function -goals may be similar to those of younger adults.
For patients with intermediate remaining life expectancy, targets should be less stringent.
Dapagliflozin enabled more patients to attain a clinically significant HbA1c reduction, whether striving for a standard or less stringent target.